Extemporaneously compounded buccal pilocarpine preparations, acceptability and pilot testing for the treatment of xerostomia (dry mouth) in Australia
Rose Motawade Lawendy Estafanos
Bachelor of Pharmacy (Honours)
Master of Pharmacy
A thesis submitted for the degree of Doctor of Philosophy at
The University of Queensland in 2019
School of Pharmacy
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Abstract
Xerostomia, the subjective feeling of dry mouth, is characterised by hypofunctioning salivary glands in which either the quantity or quality of saliva is reduced. It is a common symptom for a variety of diseases such as rheumatic and dysmetabolic diseases, and is the primary symptom associated with Sjögren’s syndrome. Xerostomia is also caused by treatments such as radiotherapy to the head and neck region and is a side effect of a range of medications.
People with xerostomia usually experience dryness of mouth, lips and throat. They are more susceptible to dental caries, oral mucositis and enhanced tooth decay. They have problems with moistening, chewing and swallowing foods and taste alterations associated with reduction in salivary flow can affect their ability to taste food. These consequences can lead to decreased food consumption, which can cause malnutrition and further suppression of their immune defence mechanisms with increased risk of morbidity and reduced quality of life.
Some approaches to managing xerostomia include sipping fluids such as water more frequently to moisten the oral mucosa, chewing sugar free gum to stimulate more saliva secretion, and using saliva replacement gels or drops. However, these strategies often do not provide sufficient relief due to the short-term effect they produce. Thus, a strong rationale exists for the development and evaluation of a medication to help treat dry mouth symptoms.
Pilocarpine oral tablets (Salagen) are available in at least 24 countries including the USA, Canada and the UK, and a wide range of countries across Europe, South America and Asia, for the treatment of radiation-induced xerostomia and xerostomia as a result of Sjögren’s syndrome. Pilocarpine is a non-selective muscarinic agonist that stimulates the muscarinic cholinergic receptors on the surface of exocrine glands, including salivary glands and sweat glands, resulting in increased salivation and sweating. An oral dose of 5 mg pilocarpine in the form of tablets or capsules to be taken three times daily produces the most effective therapeutic response in terms of subjective relief of dry mouth according to many clinical studies.
An oral dosage form of pilocarpine is not commercially available in Australia. Pilocarpine is only commercially available as 1% and 2% eye drops, which are registered on the Australian Register of Therapeutic Goods (ARTG) for the treatment of glaucoma. When these eye drops were given by mouth for the treatment of dry mouth as part of a previous clinical trial, which was done in an inpatient palliative population within a hospital setting, they tasted unpleasant to most of the patients and were not acceptable as a dosage form for dry mouth treatment for that reason. This thesis investigates the potential to use pilocarpine dosage forms that can be compounded in pharmacies for delivering 5 mg pilocarpine in the treatment of dry mouth. ii
Two buccally delivered formulations of pilocarpine were selected for study. Buccal delivery was selected, rather than using tablets or capsules that are designed to be swallowed whole and absorbed via the gastrointestinal tract, to optimise pilocarpine delivery to the salivary glands. Troches and orally dissolving tablets (ODTs) containing 5 mg of pilocarpine were compounded and subjected to quality and stability assessments. The ODTs passed the British Pharmacopeia (BP) tests for uniformity of weight and uniformity of drug content. In vitro dispersion time, in vitro disintegration time, in vivo disintegration time, wetting time and water absorption ratio tests all indicated that the compounded ODTs disintegrated instantaneously. The ODTs had an average hardness of 1.28 kg/cm2, as they were compounded by manual moulding rather than conventional tableting machines in which the high pressure applied results in a more compact product. Nonetheless, the ODTs passed the friability test, with no more than 1% loss of weight in the test conditions. The troches passed the BP tests for uniformity of weight and uniformity of drug content, and troches had an average hardness value of 2 kg/cm2 across the three tested batches. Pilocarpine content was assessed during storage of ODTs and troches in their final packaging for up to 18 months, and indicated that storage of ODTs and troches in their final packs for up to one year under shelf life conditions is associated with maintenance of more than 90% of the original pilocarpine content.
A pilot study was conducted to establish parameters for the experimental design of an acceptability study. A group of 20 healthy volunteers (age range between 24-39 years, 10 males and 10 females) sucked a whole non-medicated troche until it was completely dissolved and the time was recorded. Participants also sucked flavoured non-medicated troches (lemon, chocolate, mint, raspberry and unflavoured) until they got a sense of flavour, and then spat out the troche; troche weight remaining and time of sucking were recorded. The average time taken to suck a whole troche until completion was 2.29 minutes (SD = 0.73). Participants got a sense of flavour within 10 seconds of sucking troches. The estimated average total quantity of pilocarpine that would be absorbed after sucking five different-flavoured troches, each for 10 seconds, if the troches were medicated, was 1.9 and 1.8 mg when calculated by troche weight change and sucking time respectively.
An acceptability study was performed to determine which dosage form and flavour should be selected for use in a clinical trial of a compounded buccal pilocarpine product. Participants were healthy volunteers (n=34) and people with dry mouth (n=14). Seven of the dry mouth participants were previous head and neck cancer patients who were treated with either chemotherapy/radiotherapy and/or surgery, three patients were diagnosed with Sjögren’s syndrome, two patients had medication- induced dry mouth and the other two patients did not identify the cause of their xerostomia. The study was done in two steps. Firstly, participants tasted five medicated troches (lemon, chocolate, mint, raspberry and unflavoured) for 10 seconds and selected their favourite flavour. Secondly, each
iii participant tried a non-medicated troche and ODT, both flavoured with the selected favourite flavour, and considered which dosage form they preferred. Participants with dry mouth symptoms completed a 15-question xerostomia questionnaire and rated the change in their flavour preferences before and after experiencing xerostomia. Raspberry was the preferred flavour among the dry mouth participants and lemon among the healthy volunteers. Regarding the dosage form preference, ODTs were the preferred dosage form by 70% of the healthy volunteers and all of the dry mouth participants. The majority of participants with dry mouth reported experiencing changes in their preferences towards two or more of the four flavours tasted as a result of xerostomia.
Based upon the results of the acceptability study, the 5 mg pilocarpine raspberry flavoured ODTs were investigated for their efficacy in the treatment of dry mouth of different aetiologies using a series of double-blinded placebo controlled N-of-1 clinical trials in a cohort of 8 participants with dry mouth symptoms. The age of the participants ranged from 37-85 years (median 62.5 years), five participants were males and three were females. An N-of-1 trial is a double-blind, randomised, controlled multi- crossover trial consisting of 3 cycles (18 days of treatment). Each cycle contained two periods: 3- days treatment, 3- days placebo. The first day of each period was considered to be the washout and data collected was not included in analysis. The order of treatment and placebo was randomly allocated for each cycle with the ODTs being taken three times a day before meals. Participants completed questionnaires after each dose and collected saliva samples 1 hour after each morning and evening dose. Eight participants with dry mouth completed the trial. Of these, five (63%) responded to treatment, but for three participants the pilocarpine ODTs did not improve their xerostomia compared to placebo. A detailed report of the results was written and sent to each participant and their Medical Practitioner.
In summary, this study has found that ODTs would be an appropriate dosage form for the delivery of pilocarpine in the treatment of xerostomia, but that it may be a useful tool in the treatment of xerostomia for only some patients. Raspberry flavour can be used in compounding the 5 mg pilocarpine ODTs to help disguise the bitter taste of pilocarpine. With the N-of-1 methodology that we adopted in this study, obtaining individualized results for each participant can be easily achieved, with useful detailed information for the participants in terms of their individual response to 5 mg pilocarpine ODTs in comparison to placebo. Future research requires a larger N-of-1 trial, with an estimated 36 participants to complete the 18-day trial to provide a population-estimate of the efficacy of 5 mg pilocarpine ODTs.
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Declaration by author
This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly authored works that I have included in my thesis.
I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award.
I acknowledge that an electronic copy of my thesis must be lodged with the university Library and, subject to the policy and procedures of the University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School.
I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis.
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Publications included in this thesis
No publications included
Submitted publications included in this thesis
No manuscripts submitted for publication
Other publications during candidature
Conference abstracts Estafanos, RM, Lau, ETL, Mitchell, G, Senior, H, Steadman, KJ. Compounding buccal delivery dosage forms: consideration of the dose accuracy of troches and ODTs. Australasian Pharmaceutical Science Association Annual Conference; 2016 Dec 2-5; Sydney, Australia.
Estafanos, RM, Lau, ETL, Mitchell, G, Senior, H, Steadman, KJ. Troches or orally dissolving tablets for delivery of pilocarpine in treatment of xerostomia (dry mouth). APSA-ASCEPT Joint Scientific Meeting by the Australasian Pharmaceutical Science Association Annual Conference; 2017 Dec 5-8; Brisbane, Australia.
Contributions by others to the thesis
Chapter 5 describes a clinical trial. The members of the clinical trial team were: • Principal Investigator: Assoc Prof Kathryn Steadman (School of Pharmacy, UQ) • Trial Coordinator: Mrs Rose Estafanos (PhD Candidate, School of Pharmacy, UQ) • Study Clinician: Prof Geoff Mitchell (Faculty of Medicine, UQ) • Co-Investigator: Dr Hugh Senior (College of Health, Massey University) • Co-Investigator: Dr Esther Lau (Faculty of Health, School of Clinical Sciences, QUT) • Co-Investigator: Dr Jane Nikles (Senior Research Fellow, UQ Centre for Clinical Research) • Study Statistician: Assoc Prof James McGree (Science and Engineering Faculty, QUT) The team helped to prepare the protocol; the Study Statistician provided the randomization of the clinical trial for the N-of-1 design; the Principal Investigator prepared the trial packs according to the randomisation schedule, maintained the Randomisation Log and oversaw trial progress; the Study Clinician consulted on eligibility of participants and adverse event classification during the trial.
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Statement of parts of the thesis submitted to qualify for the award of another degree
No works submitted towards another degree have been included in this thesis
Research Involving Human or Animal Subjects
Ethics approval was obtained for three studies involving human subjects:
• The UQ School of Pharmacy Ethics Committee on behalf of the UQ Medical Research Ethics Committee approved the pilot study in Chapter 3 (approval number 2015/12) • The University of Queensland Human Research Ethics Committee A approved the acceptability study in Chapter 4 (approval number 2016001436) • The University of Queensland Human Research Ethics Committee A approved the N-of-1 clinical trial in Chapter 5 (approval number 2017001422)
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Acknowledgments
I would like to thank my supervisors Associate Professor Kathryn Steadman, Professor Geoffrey Mitchell, Dr Hugh Senior and Dr Esther Lau for guiding me and supervising me through my PhD journey. I could not have done this without your endless support, encouragement and the endless amount of patience each of you have shown to me. I would like to thank Associate Professor Kathryn Steadman in particular for helping me during this journey for her continuous support for me especially during my hard times. I would also like to acknowledge the Australian Commonwealth and the Queensland Government for their financial support in the form of the APA scholarship. Many thanks to the School of Pharmacy co-ordinators and to all the staff and my fellow PhD students at the School of Pharmacy for accompanying me for the last 4 years during my candidature. In particular, I would like to thank Juliana, Nahid, Preeti and Sitah – thank you for your friendship and for being there through all the ups and downs during the time we have spent together as we embarked on this PhD together – the experience would have been very different without you all! I would also like to thank Dr Kate Kollar for being such a nice and helpful person since she started working as scientific infrastructure and safety coordinator in the school of Pharmacy, UQ Finally, to my family I can’t even begin to thank each and every one of you enough for your unconditional love, encouragement and support, and for all that you have given me. My love and deep thanks for my mother, although she is living in Egypt, far away from Australia but she accompanied me through my PhD journey. Thank you for all the times you have picked up me when I needed it most – I could not have achieved this without you mum.
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Financial support
This research was supported by an Australian Government Research Training Program Scholarship.
Keywords
Pilocarpine, dry mouth, xerostomia, radiation induced-xerostomia, head and neck cancer, Sjogren’s syndrome, buccal delivery, orally dissolving tablets, troches.
Australian and New Zealand Standard Research Classifications (ANZSRC)
ANZSRC code: 111504, Pharmaceutical Sciences, 90%
ANZSRC code: 111204, Cancer Therapy (excl. Chemotherapy and Radiation Therapy), 10%
Fields of Research (FoR) Classification
FoR code: 1115, Pharmaceutical Sciences, 100%
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Table of Contents Chapter 1. Literature review ...... 1 1.1. Introduction to xerostomia ...... 1
1.2. Aetiology of xerostomia...... 3
1.2.1. Xerostomia due to medications and diseases ...... 3
1.2.2. Chemotherapy-induced xerostomia ...... 4
1.2.3. Radiotherapy-induced xerostomia ...... 4
1.3. Consequences of xerostomia ...... 8
1.4. Current management and treatment of xerostomia ...... 10
1.4.1. Patient information ...... 11
1.4.2. Management of the underlying disease ...... 11
1.4.3. Preventive measures to reduce sequelae of oral complications ...... 11
1.4.4. Pharmacological treament ...... 12
1.5. Review of pilocarpine for dry mouth ...... 17
1.5.1. Pilocarpine pharmacokinetics ...... 17
1.5.2. Pilocarpine delivery, dose and efficacy ...... 18
1.5.3. Systemic oral delivery ...... 19
1.5.4. Local oral delivery ...... 23
1.5.5. Alternative oral formulations of pilocarpine for systemic delivery ...... 27
1.6. Evidence to support the efficacy of pilocarpine oral use for the treatment of xerostomia of different aetiologies...... 27
1.6.1. The three trials that were included in the Cochrane review ...... 28
1.6.2. Examples of trials that were excluded from the Cochrane review ...... 31
1.7. Taste dysfunctions occurring in cancer patients ...... 33
1.7.1. Background ...... 33
1.7.2. Prevalence of taste alterations ...... 33
1.7.3. Causes of altered taste in cancer patients ...... 34
1.7.4. Radiotherapy-induced taste impairment ...... 35
1.7.5. Implications of taste alterations ...... 37 x
1.7.6. Flavours ...... 38
1.7.7. Bitter-masking tastes and others ...... 42
1.7.8. Bitter–inhibiting compounds...... 45
1.7.9. Taste of other components being added in the oral formulation ...... 48
1.8. Research plan ...... 50
1.8.1. Research rationale ...... 50
1.8.2. Aims and objectives ...... 52
Chapter 2. Compounding and quality/stability testing of potential products for buccal delivery of pilocarpine ...... 53 2.1. Introduction ...... 53
2.1.1. Lozenges ...... 54
2.1.2. Orally dissolving tablets...... 57
2.2. Materials and methods ...... 59
2.2.1. Chemicals ...... 59
2.2.2. Instrumentation ...... 59
2.2.3. Experimental design ...... 60
2.2.4. Formulation of 5 mg pilocarpine troches ...... 60
2.2.5. Formulation of 5 mg pilocarpine ODTs ...... 61
2.2.6. Quality control assessment of the compounded pilocarpine products ...... 62
2.2.7. Stability testing of the compounded products ...... 65
2.2.8. Measurement of pilocarpine and its degradation products ...... 66
2.3. Results ...... 68
2.3.1. Standard calibration curve and method validation ...... 68
2.3.2. Elution of pilocarpine degradation products and their detection by HPLC ...... 71
2.3.3. Quality control assessment of the compounded pilocarpine troches ...... 71
2.3.5. Stability testing of the compounded pilocarpine troches ...... 78
2.3.6 Stability testing of the compounded 5 mg pilocarpine ODTs ...... 81
2.4. Discussion ...... 83
2.5. Conclusion ...... 85
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Chapter 3. Establishment of experimental parameters for an acceptability trial ...... 86 3.1. Introduction ...... 86
3.2. Materials and methods ...... 87
3.3. Results ...... 88
3.4. Conclusion ...... 91
Chapter 4. Acceptability testing of dosage forms for buccal delivery of pilocarpine ...... 92 4.1. Introduction ...... 92
4.2. Experimental design ...... 92
4.3. Results ...... 94
4.3.1. Flavour preferences ...... 95
4.3.2. Dosage form preferences ...... 97
4.4. Discussion ...... 97
4.5. Conclusion ...... 98
Chapter 5. A series of N-of-1 clinical trials to assess the efficacy of 5 mg pilocarpine ODTs in the treatment of dry mouth ...... 99 5.1. Introduction ...... 99
5.1.1. Background ...... 99
5.1.2. Aims ...... 101
5.2. Methods ...... 101
5.2.1. Trial design ...... 101
5.2.2. Selection and Enrolment of Participants ...... 103
5.2.3. Intervention ...... 104
5.2.4. Outcomes ...... 105
5.2.5. Schedule of assessments ...... 108
5.2.6. End-points ...... 109
5.2.7. Sample size ...... 109
5.2.8. Randomisation ...... 111
5.2.9. Blinding ...... 111
5.2.10. Statistical methods ...... 111
5.2.11. Ethical approval ...... 112
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5.3. Results ...... 112
5.3.1. Participant flow ...... 112
5.3.2. Recruitment ...... 113
5.3.3. Baseline data ...... 113
5.3.4. Outcomes and estimations ...... 116
5.4. Discussion ...... 136
5.5. Limitations ...... 138
5.6. Conclusion ...... 140
Chapter 6. General discussion and future direction ...... 141 6.1. General discussion ...... 141
6.2. Future research ...... 147
References 149 Appendices 170
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List of Figures
Figure 1-1 The three major pairs of salivary glands (Parotid, Sublingual and Submandibular glands) within the oral cavity. Source: Encyclopaedia Britannica, Inc...... 2 Figure 1-2 Schematic of the anatomical systems mediating perception of flavours (Lawless, 1996) ...... 39 Figure 2-1 Degradation pathways of pilocarpine (Van de Merbel, Tinke et al., 1998) ...... 66 Figure 2-2 Standard calibration curve of pilocarpine in phosphate buffer at pH=5.0...... 69 Figure 2-3 HPLC Chromatogram separation of pilocarpine in the presence of its degradation products and an internal standard (nicotinamide); (A) Nicotinamide (4.971 min), (B) Isopilocarpine (6.017 min), (C) Pilocarpine (7.397 min), (D) Pilocarpic acid (8.147 min) and (E) Isopilocarpic acid (8.608 min) in phosphate buffer at pH=5.0 at 25°C...... 71 Figure 2-4 Relationship between troche weight and pilocarpine content for three batches, B1, B2 and B3...... 73 Figure 2-5 Relationship between ODT weight and pilocarpine content for three batches, B1, B2 and B3...... 76 Figure 2-6 Percentage drug content (average of 3 troches for each of 3 batches) remaining across twelve months storage at 36°C and 39% RH of the three batches of troches...... 78 Figure 2-7 Percentage drug content (average of 3 troches for each of 3 batches) remaining across 18 months storage at 20°C and 57% RH for the three batches of medicated troches...... 80 Figure 2-8 Percentage drug content (average of 3 ODTs for each of 3 batches) remaining across 12 months storage at 36°C and 39% RH for the three batches of medicated ODTs...... 82 Figure 2-9 Percentage drug content (average of 3 ODTs for each of 3 batches) remaining across 18 months storage at 20°C and 57% RH for the three batches of medicated ODTs...... 82 Figure 5-1 Flow diagram of the N-of-1 design scheme used in this study with an example randomisation schedule shown...... 102 Figure 5-2 Flow diagram for number of patients screened, enrolled, completed the trial to the end and number of N- of-1 trials analysed...... 113 Figure 5-3 Clinical improvement in subjective oral dryness (OD in the SRoS) for placebo vs. pilocarpine for participant 5. More negative numbers indicate greater clinical improvement relative to day 1 pre-dose...... 119 Figure 5-4 Clinical improvement in saliva production for placebo vs. pilocarpine for participant 5. Higher numbers indicate greater saliva production relative to day 1 pre-dose...... 119 Figure 5-5 Clinical improvement in subjective oral dryness (OD in the SRoS) for placebo vs. pilocarpine for participant 6. More negative numbers indicate greater clinical improvement relative to day 1 pre-dose...... 122 Figure 5-6 Clinical improvement in subjective oral dryness (OD in the SRoS) for placebo vs. pilocarpine for participant 7. More negative numbers indicate greater clinical improvement relative to day 1 pre-dose...... 125 Figure 5-7 Clinical improvement in subjective oral dryness (OD in the SRoS) for placebo vs. pilocarpine for participant 2. More negative numbers indicate greater clinical improvement relative to day 1 pre-dose...... 131 Figure 5-8 Clinical improvement in saliva production for placebo vs. pilocarpine for participant 2. Higher numbers indicate greater saliva production relative to day 1 pre-dose...... 131 Figure 5-9 Clinical improvement in subjective oral dryness (OD in the SRoS) for placebo vs. pilocarpine for participant 8. More negative numbers indicate greater clinical improvement relative to day 1 pre-dose...... 136
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List of Tables
Table 1-1 Classification of dry mouth related symptoms (Cho et al., 2010) ...... 8 Table 2-1 Troche formula (based on a formula provided by Medisca) for the preparation of 30 troches, each containing 5 mg pilocarpine, with 10% excess included to account for wastage...... 60 Table 2-2 Orally dissolving tablet (ODT) formula (based on a formula provided by Medisca) for the preparation of 60 ODTs, each weighing 75 mg and containing 5 mg pilocarpine, with 10% excess included to account for wastage...... 61 Table 2-3 Regression statistics, limit of detection (LoD) and limit of quantification (LoQ) for different pilocarpine concentrations ...... 69 Table 2-4 Peak area ratio (pilocarpine : internal standard) and pilocarpine retention time for five different concentrations of pilocarpine that were analysed on three different days and using two different batches of the same column within the same HPLC system. Relative standard deviation (RSD) as a percent is shown for assessment of inter-day and inter-column precision...... 70 Table 2-5 Results of uniformity of weight test made for three batches of medicated troches B1, B2 and B3...... 72 Table 2-6 Results of uniformity of drug content test made for three batches of medicated troches B1, B2 and B3. ..73 Table 2-7 Results of hardness, diameter and thickness tests made for five troches from each of three batches...... 74 Table 2-8 Results of uniformity of weight test made for three batches of medicated ODTs B1, B2 and B3...... 75 Table 2-9 Results of uniformity of drug content test made for three batches of medicated ODTs B1, B2 and B3 when ODT weight is selected to be between 70 – 80 mg...... 76 Table 2-10 Results of hardness (resistance to crushing), diameter and thickness tests made for three batches of medicated ODTs B1, B2 and B3...... 77 Table 2-11 Results of friability test made for three batches of medicated ODTs using 10 tablets rotated for 4 minutes at 25 rotations per minute...... 77 Table 2-12 Results of in vitro dispersion, in vitro disintegration, in vivo disintegration, wetting time and water absorption ratio made for three batches of medicated ODTs B1, B2 and B3...... 78 Table 2-13 Results of accelerated ageing stability testing (average of 3 troches for each of 3 batches) of diameter, thickness, weight change and % drug content loss made on medicated troches after storage at 36°C and 39% RH...... 79 Table 2-14 Results of shelf life stability testing (average of 3 troches for each of 3 batches) of diameter, thickness, weight change and % drug content loss made on three batches of medicated troches after storage at 20°C and 57% RH...... 80 Table 2-15 Results of accelerated ageing stability testing (average of 3 ODTs for each of 3 batches) of diameter, thickness, weight change and % drug content loss made for medicated ODTs after storage at 36°C and 39% RH...... 81 Table 2-16 Results of stability testing (average of 3 ODTs for each of 3 batches) for diameter, thickness, weight change and % drug content loss made for medicated ODTs after 3, 6, 9, 12 and 18 months storage at 20°C and 57% RH...... 83 Table 3-1 Flavours and the tastes that they are supposed to mask (Shrewsbury, 2015; Wiener et al., 2012) ...... 86
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Table 3-2 Flavour preferences selected by the particpants after sucking each of five different flavoured non- medicated troches (L:Lemon, M:Mint, C:Chocolate, R:Raspberry and U:Unflavoured)...... 88 Table 3-3 Sucking times taken by each participant to sense the flavour of the five different flavoured troches and to suck one troche to completion...... 89 Table 3-4 Estimated amount of pilocarpine received by each participant based on weight change...... 90 Table 3-5 Estimated amount of pilocarpine received by each participant based on sucking time...... 91 Table 4-1 Demographic results of the healthy participants and participants with xerostomia in the acceptability taste testing study...... 94 Table 4-2 Flavour preferences among healthy volunteers and dry mouth participants, showing the number and % of people who chose each flavoured medicated troche as their favourite...... 95 Table 4-3 Preferences (preferred, accepted, avoided) before and after experiencing xerostomia reported by dry mouth participants for flavours – chocolate (C), raspberry (R), lemon (L) and mint (M)...... 96 Table 4-4 Numbers of dry mouth participants who preferred/accepted/avoided the four given flavours before and after experiencing xerostomia ...... 97 Table 4-5 Participants’ preferences for ODT or troche as a dosage form if they had to take it regularly ...... 97 Table 5-1 Treatment ODT formula for the preparation of 60 ODTs, each weighing 75 mg and containing 5 mg pilocarpine, with 10% excess included to account for wastage during compounding...... 105 Table 5-2 Placebo ODT formula for the preparation of 60 ODTs, each weighing 75 mg, with 10% excess included to account for wastage during compounding...... 105 Table 5-3 Schedule of assessments ...... 108 Table 5-4 Demographic and clinical characteristics of the 8 participants, with the scores for the baseline assessments and day 1 pre-dose assessments...... 114 Table 5-5 Data collected by participant 5 across the three cycles of treatment ...... 117 Table 5-6 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 5 across the three cycles of treatment...... 118 Table 5-7 Data collected by participant 6 across the three cycles of treatment ...... 120 Table 5-8 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 6 across the three cycles of treatment...... 121 Table 5-9 Data collected by participant number 7 across the three cycles of treatment...... 123 Table 5-10 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 7 across the three cycles of treatment...... 124 Table 5-11 Data collected by participant number 1 across the three cycles of treatment ...... 126 Table 5-12 Data collected by participant number 4 across the three cycles of treatment ...... 128 Table 5-13 Data collected by participant number 2 across the three cycles of treatment ...... 129 Table 5-14 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 2 across the three cycles of treatment...... 130 Table 5-15 Data collected by participant number 3 across the three cycles of treatment ...... 132 Table 5-16 Data collected by participant number 8 across the three cycles of treatment ...... 134
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Table 5-17 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 8 across the three cycles of treatment...... 135
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List of Abbreviations
ARTG Australian Register of Therapeutic Goods CDs Cyclodextrins cGVHD chronic Graft Versus Host Disease CMC Carboxymethylcellulose 3D-CRT 3-Dimensional Conformal Radiotherapy FDA Food and Drug Administration FT-IR Fourier Transform Infra-Red spectroscopy GI Gastrointestinal HBOT Hyperbaric Oxygen Therapy HNC Head and Neck Cancer HPLC High Performance Liquid Chromatography HPMC Hydroxypropylmethylcellulose IgA Immunoglobulin A IMRT Intensity Modulated Radiotherapy LoD Limit of Detection LoQ Limit of Quantification MI Medication Induced MSG Mono Sodium Glutamate NCI National Cancer Institute NIH National Institutes of Health ODTs Orally Dissolving Tablets PACE Pharmacy Australia Centre of Excellence (School of Pharmacy, UQ) PBA Pharmacy Board of Australia PEG Polyethylene Glycol QoL Quality of Life RBP Riboflavin-binding Protein RH Relative Humidity RSD Relative Standard Deviation SJP Seikaly Jha Procedure Ss Sjogren’s syndrome Tas Taste Alterations TRCs Taste Receptor Cells TRI Transitional Research Institute
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CHAPTER 1
Chapter 1. Literature review
1.1. Introduction to xerostomia
Eating and tasting a favourite food may be a simple pleasure, but it is actually a complex sensory experience. The tastant reacts with the receptor cells on the taste buds to initiate taste sensation that together with other sensations (olfactory, chemesthetic and somatosensory) are delivered to the brain which eventually lead to saliva production (Dietsch, Pelletier et al., 2018). Saliva plays important roles within the oral cavity as it moistens the oral mucosa and the lips and maintains oral health. It aids in moistening food, enables chewing and swallowing, cleanses the mouth from any food residues and facilitates speech. Saliva also enhances the ability to taste food thus playing a vital role in balanced oral and nutritional intake. Antiviral, antibacterial and antifungal components of saliva prevent oral infections by balancing oral flora and the minerals present in the saliva are delivered to the tooth surface, thereby helping to prevent dental caries and tooth decay (Furness, Worthington et al., 2011; Humphrey et al., 2001; Salles, Chagnon et al., 2011).
The flow of saliva is controlled by a reflex action resulting from tasting and chewing of food (Chaudhari & Roper, 2010). In most adults, resting or unstimulated flow of saliva reaches about 0.5 mL/min to a total of around 1.5 L per day in normal conditions (Humphrey & Williamson, 2001). This results from the low level stimulation of the autonomic nervous system by the higher centres of the brain (Orbitofrontal cortex and amygdala) working through the salivary centres within solitary tract nuclei in the brain stem to act on the salivary glands (Carpenter, 2013). These stimulations from the higher centres are reduced during sleeping leading to decreased salivary flow to approximately 0.1 mL/min (Garrett, 1987). Conversely, saliva is secreted in its largest volume before, during and after meals and reaches a maximum level in the middle of the day and then secretion decreases considerably after that (Llena-Puy, 2006).
Some people lack the pleasure of eating and can suffer malnourishment due to a condition known as xerostomia. Xerostomia is the subjective feeling of dry mouth (Fox, Atkinson et al., 1991). It is a common symptom for a variety of diseases such as rheumatic and dysmetabolic diseases (Busato, Ignacio et al., 2009; Moore, Guggenheimer et al., 2001), treatments such as radiotherapy and chemotherapy (Brand, Bots et al., 2009; Cassolato & Turnbull, 2003; Waltimo, Christen et al., 2005), or can arise as a result of the chronic use of certain drugs (Gupta, Epstein et al., 2006; Villa & Abati, 2011). The prevalence of xerostomia in the population is estimated to be about 20%, raising to 50% in elderly people (Hopcraft & Tan, 2010; Villa et al., 2011).
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Dry mouth is usually due to the hypofunction of the salivary glands, in which either the quantity or quality of saliva secreted is reduced (Porter, Scully et al., 2004). Salivary output is considered to be reduced when the resting unstimulated saliva flow rate is less than 0.1 mL/min or that of stimulated saliva is lower than 0.5-0.7 mL/min (Kaluzny, Wierzbicka et al., 2014; Sreebny, 2000).
The major salivary glands are the parotid, submandibular and sublingual glands (Fig. 1-1) which together produce 90% of total saliva. The minor salivary glands are distributed in the oral mucosa and account for the remaining 10% of saliva (Jensen, Pedersen et al., 2010). Unstimulated salivary flow refers to the mixed oral salivary fluids that are secreted from the major and minor salivary glands (Sreebny, Banoczy et al., 1992). Stimulated salivary flow refers to the amount of saliva collected after stimulation of parotid and submandibular salivary glands by the application of 2% citric acid to the dorsal lateral surface of the tongue for 5 seconds at 30-second intervals (Fox, Van der Ven et al., 1985).
Figure 1-1 The three major pairs of salivary glands (Parotid, Sublingual and Submandibular glands) within the oral cavity. Source: Encyclopaedia Britannica, Inc.
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Saliva is produced by acinar cells, of which there are two types: serous and mucous cells. Damage or loss of the salivary acinar cells leads to the most severe and irreversible forms of reduced salivary flow rate (Taylor & Miller, 1999). The parotid gland has serous acinar cells and opens onto the buccal mucosa near the upper molar teeth; it secretes a thin, watery and amylase-rich saliva. The sublingual gland has mucous acinar cells produce a viscous mucin-rich saliva. The submandibular gland consists of serous and mucous acinar cells and produces a viscous mucin-rich saliva. The main duct of the submandibular gland and several small ducts of the sublingual gland open onto the sublingual mucosa of the floor of the mouth (Fig. 1-1). The minor salivary glands, which are in the labial, buccal, lingual and palatal mucosa, are mixed glands largely composed of mucous acinar cells; however, the palatal glands are mucous, whereas the lingual glands are serous (Mese, 2007). Under resting (unstimulated) conditions the submandibular glands produce about two-thirds of the saliva which is mainly a viscous mucin-rich fluid, while the sublingual glands contribute 1-2% of the saliva secretion (Schneyer, 1956). Upon stimulation, the serous parotid glands produce a watery and protein-rich fluid that accounts for about 50% of the total salivary output (Dawes & Ong, 1973) but it contributes a smaller amount to resting salivary flow (Carpenter, 2013). The minor salivary glands account for only 10% of the total salivary volume, however, they play an important role in lubricating the oral mucosa (Dawes & Wood, 1973).
1.2. Aetiology of xerostomia
1.2.1. Xerostomia due to medications and diseases
Over 400 medications and treatments are known to cause xerostomia. Among these are antidepressants, opiates, antihypertensives, bronchodilators, proton pump inhibitors, antipsychotics, antihistamines, diuretics, antineoplastic agents and radiation therapy (Lewis & Han, 1997; Porter et al., 2004; Thelin, Brennan et al., 2008).
Many diseases can also lead to xerostomia. Sjogren’s syndrome (Ss) is an autoimmune disease that causes damage to the cells producing saliva (Bultzingslowen, Sollecito et al., 2007). Poorly controlled diabetes (Glore, Spiteri-Staines et al., 2009), chronic graft versus host disease (Singhal, Powles et al., 1997) and haemodialysis in renal impairment with reduced fluid intake can cause dehydration and eventually cause xerostomia (Sung, Kuo et al., 2005). Dry mouth can also result from infection with hepatitis C virus (Carrozzo, 2008) and acquired immunodeficiency syndrome (Feller, White et al., 2007).
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1.2.2. Chemotherapy-induced xerostomia
Xerostomia is a common side effect of chemotherapeutic agents, which have the potential to reduce the amount of secreted saliva as well as inducing changes in the consistency or composition of the saliva (Sreebny & Schwartz, 1997). It has been claimed that this reduction in the amount of saliva secreted may be partly due to the anticholinergic antiemetics that are prescribed mainly in the early regimen of chemotherapy, and after therapy the salivary glands and their flow rates return to normal functioning (Wahlin, 1991). The prevalence of xerostomia during chemotherapy treatment has been reported to be 50% according to the systematic review of Jensen and co-workers (Jensen et al., 2010), and 59% according to a more recent cross-sectional study (Wilberg, Hjermstad et al., 2014).
There are four groups of antineoplastic agents: alkylating agents, antimetabolites, antimitotics and cytostatic antibiotics (Distelhorst, 2002). Glucocorticoids can also be used as chemotherapeutic agents. The mechanism of action of chemotherapeutics generally depends upon the inhibition of the processes taking place in the cells, especially nucleic acid metabolism, thus causing an inactivation of cell mitosis (Jensen, Pedersen et al., 2003). There is no clear conclusion about the effect of chemotherapeutic agents on salivary gland functions due to many reasons: small sample sizes of conducted studies, absence of any standard methods, short study periods, variation in underlying cancer diagnosis and type of medications used. Furthermore, oral sequelae can arise either due to adverse effects of chemotherapeutics or due to progression of the underlying malignant tumour itself (Jensen et al., 2003).
1.2.3. Radiotherapy-induced xerostomia
Radiation therapy which, together with surgery, is the main treatment of patients with head and neck cancer (Adams, 1989). Radiotherapy for treatment of primary tumours in the head and neck region usually includes all or most of the major and minor salivary glands in the radiation field due to tumour location and the path of lymphatic spread being located close to the salivary glands (Stephens, Ang et al., 1986). During radiation therapy, high energy electromagnetic rays or particles are delivered to destroy the tumour cells. These ionizing rays prevent DNA synthesis, which either leads to cellular death or prevents cell division of those that remain alive (Kakoei, Haghdoost et al., 2012). If the salivary glands are included in the radiation field, untreatable irreversible damage can be caused (Dirix, Nuyts et al., 2008). Patients who are treated with radiation therapy for their malignancy are six times more likely to develop salivary dysfunction and xerostomia than the general population (Liu, Xia et al., 2011).
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It has been reported that 93% of the head and neck cancer patients had xerostomia during radiation therapy (Dirix et al., 2008; Liu, Zeng et al., 2004; Pow, Kwong et al., 2006). Whereas 74-85% of patients experienced residual xerostomia lasting one month to two years after discontinuation of their radiation treatment (Jensen et al., 2003; Pow, McMillan et al., 2003). The highest prevalence and severity of hyposalivation following radiation therapy in the head and neck region has been reported for irradiated nasopharyngeal carcinoma, followed by radiotherapy for oropharyngeal carcinoma, and lowest with laryngeal/epilaryngeal tumour treatment (Bjordal, Ahlner-Elmqvist et al., 2001; Boscolo- Rizzo, Maronato et al., 2008; Huguenin, Taussky et al., 1999; List, Mumby et al., 1997; Morris, Schmidt-Ullrich et al., 2002; Mowry, LoTempio et al., 2006).
In a systematic review by Jensen et al. (2010) on the prevalence of xerostomia during irradiation of head and neck cancer, patients most commonly (43.6%-46.0%) experienced xerostomia rated as grade 2 (on a severity scale from 1 to 4) during treatment and one to six months post treatment (Jensen et al., 2010). Severity of xerostomia changes with time after irradiation, with grade1 xerostomia being the most prevalent (39.2%-41.7%) from 6 to 12 years post treatment. Between 4% to 16% of patients suffer grade 3 xerostomia at some stage (during radiotherapy and up to two years post treatment), and less than 3% of the patients experienced grade 4 xerostomia from 6 to 24 months or more after the completion of radiotherapy (Hsiung, Ting et al., 2006; Oates, Clark et al., 2007; Perlmutter, Johnson et al., 2002; Pow et al., 2006; Wijers, Levendag et al., 2002).
Patients receiving radiotherapy either with or without chemotherapy were more likely to develop xerostomia than those who did not receive these treatments (5.6% and 3.8%, respectively vs. 0.5%) at a median follow up of more than two years. Patients treated with both radiotherapy and chemotherapy were nine times more likely to develop xerostomia than the general population while those treated with radiation therapy alone were over six times more likely to develop xerostomia and salivary hypofunction than the general population (Liu et al., 2011).
1.2.3.1 Effect of radiation therapy on cells of the salivary glands
The serous cells of the salivary glands are very sensitive to the ionizing effects of radiation therapy, whereas mucous cells are more resistant. The parotid glands, which consists mainly of serous cells is the most sensitive to radiation among the three major salivary glands; parotid, submandibular and sublingual glands (Cooper, Fu et al., 1995; Kim, Kim et al., 1991). In humans histopathological changes occuring within 12 weeks after initiation of fractionated radiotherapy doses of 50-70 Gy lead predominantly to loss of serous acini (Cooper et al., 1995).
Many studies have tried to investigate the relationship between radiation dose and volume of the salivary glands irradiated and subsequent saliva secretion in patients with head and neck cancer. 5
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Xerostomia is directly related to the cumulative dose of radiation therapy and to the volume of the salivary gland tissues that is included in the radiation treatment field (Yeh & Huang, 2007). Franzen et al. (1992) prospectively evaluated changes in parotid gland function following radiotherapy for head and neck cancer region in 25 patients where the patients recieved < 46 Gy, 47-52 Gy and ≥ 65 Gy. The group irradiated with 45-52 Gy had a mean salivary secretion rate compared to pre-therapy of 21% and 25% at 6 and 12 months after radiotherapy. Radiation doses ≥ 65 Gy usually causes irreversible damage to the parotid glands. This study stressed that there was no relation between the amount of saliva produced after radiotherapy and the subjective sensation of xerostomia discomfort (Franzen, Funegard et al., 1992). Eisbruch et al. assessed 88 head and neck cancer patients irradiated with chemotherapy-based 3D radiation therapy and found that salivary glands irradiated with a dose below the threshold of 26 Gy returned mostly to their pretreatment salivary secretion levels, whereas glands irradiated to a mean dose higher than the threshold level showed little or non significant stimulated salivary production after treatment (Eisbruch, Ten Haken et al., 1999). Further, mean doses of more than 30 Gy to the parotid glands caused the stimulated saliva secretion rates not to return to original levels for two years (Li, Taylor et al., 2007).
Severe salivary dysfunction is usually caused by a radiation dose of 52 Gy and no significant recovery was noticed over time (permanent dysfunction) after a dose of 60 Gy to the salivary gland tissue (Epstein, Chin et al., 1998; Moller, Perrier et al., 2004; Someya, Sakata et al., 2003). Irradiation of parotid glands with doses exceeding 60 Gy leads to permanent damage with subsequent hypofunction and no recovery of gland function over time (Cheng, Downs et al., 1981; Franzen et al., 1992).
Some studies have reported that if the radiation doses delivered to the parotid glands is less than 52 Gy then partial recovery of the gland function can be achieved (Franzen et al., 1992; Funegard, Franzen et al., 1994), while other studies have documented permanent hypofunction of the gland after similar radiation doses (Liu, Fleming et al., 1990; Mira, Wescott et al., 1981). Oral cancers usually involve high radiation doses which can reach 70 Gy leading to a profound effect on saliva secretion (Davies, Shorthose et al., 2007; Porter et al., 2004).
The result of a therapeutic radiation dose ranging between 50-70 Gy to head and neck cancer patients, is chronic xerostomia in which the most pronounced hyposalivation is observed from the beginning of radiotherapy to up to three months after discontinuation. During radiotherapy, the first ten days are considered the worst as a massive decrease in salivation occurs by as much as 50%-60% (Davies et al., 2007; Franzen et al., 1992).
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1.2.3.2 Effect of radiation therapy on the quality of saliva
The quality of saliva also changes with radiation therapy with a reduction in the bicarbonate concentration, pH and amylase activity. There are increases in the lactoferrin, protein, and sodium chloride levels, and the viscosity and osmolality of saliva. It also causes an altered calcium concentration and changes in two out of eleven human mucins, namely Mucin 5b (MUC5b) and Mucin C7 (MUC7). MUC5b and MUC7 are two of the major mucins secreted by the salivary glands; MUC5b is a sticky and high molecular weight glycosylated protein, while MUC7 contains high water content and has a low molecular weight. MUC5b protects the oral mucosa from harm by forming multimers and a viscous coat to surround the oral mucosa. It also plays a role in hydrating, lubricating and moistening the oral cavity. Thus, any alteration in MUC5b contributes to the perception of xerostomia and also explains the potential correlation between xerostomia and the feeling of oral burning (Randall, Stevens et al., 2013).
1.2.3.3 Effect of different types of radiation therapy on xerostomia
There are different types of radiation therapy used for treatment of head and neck cancer. These include conventional radiotherapy, 3-dimensional conformal radiotherapy (3D-CRT), and intensity modulated radiotherapy (IMRT). The prevalence of xerostomia was greatest with IMRT in which 100% of the patients complained of dry mouth, followed by conventional radiotherapy (80%) and 3D-CRT in which less than 50% of patients reported having xerostomia one to three months post radiation. At two years post-treatment, less than 70% of the patients irradiated with IMRT reported xerostomia, whereas patients irradiated with 3D-CRT reported an increase in the incidence of xerostomia to approximately 70%, and approximately 90% of patients treated with conventional radiotherapy reported having xerostomia (Anand, Jain et al., 2006; Epstein, Emerton et al., 1999a; Harrison, Zelefsky et al., 1997; Huang, Wilkie et al., 2000; Louis, Paulino et al., 2007; Maes, Weltens et al., 2002; Olver, Hughes et al., 1996).
Commonly used for the treatment of thyroid cancer is radioactive iodine treatment. Radioactive iodine accumulates within salivary gland tissue causing salivary hypofunction and xerostomia (Alexander, Bader et al., 1998; Mendoza, Shaffer et al., 2004; Solans, Bosch et al., 2001). A low prevalence of xerostomia (5%) was recorded within a few days after low dose radioactive iodine treatment (Lin, Shen et al., 1996), but this was higher (18%) following high dose radioactive iodine (Khan, Waxman et al., 1994).
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1.3. Consequences of xerostomia
Xerostomia includes dryness of mouth, lips and throat. (Ohrn, Sjoden et al., 2001; Ohrn, Wahlin et al., 2001). Xerostomia-related subjective symptoms can be strongly associated with aetiology. A study comparing 154 patients according to the aetiology of dry mouth (Sjogren’s syndrome, post radiation therapy in the head and neck region, antipsychotic medications, systemic diseases or medications affecting salivary flow, and unknown aetiology) used a coded series of questions to assess their symptoms (Table 1-1). Patients with xerostomia secondary to radiotherapy had the most reduced values of salivary flow rates and the most severe associated symptoms, while patients with unknown aetiology of xerostomia had the least. However, patients with systemic diseases and those who were taking medications that resulted in xerostomia reported having a burning sensation in the mouth and altered taste sensation, and this was mostly prevalent among patients treated with antipsychotic medications (Cho, Ko et al., 2010).
Table 1-1 Classification of dry mouth related symptoms (Cho et al., 2010)
Code Description Dry-day PM Dryness at night or on awaking Dry-day Dryness at other times of the day Dry-eat Dryness during eating Dry-swal Difficulty in swallowing Am-sal Amount of saliva in everyday life Eff-life Effect of xerostomia on daily life activities
Patients treated with chemotherapeutic agents have shown an increased susceptibility to opportunistic oral infections such as Streptococcus mutans and Lactobacilli due to an increased bacterial load that occurs concomitantly with reduced pH of unstimulated whole saliva (Bergmann, 1991; Pajari, Poikonen et al., 1989), reduced saliva production and sialochemical changes in immunoglobulin A (IgA) levels (Main, Calman et al., 1984). Chemotherapeutic agents that suppress immunity can lead to progressive exacerbations of pre-existing periodontal diseases (Peterson, Minah et al., 1987; Reynolds, Minah et al., 1989). Reduced salivary flow rates and changes in saliva composition in cancer patients treated with antineoplastic agents can cause a higher incidence of oral candidiasis (Leung, Dassanayake et al., 2000; Main et al., 1984; Redding, Zellars et al., 1999; Spiechowicz, Rusiniak-Kubik et al., 1994; Umazume, Ueta et al., 1995; Wahlin, 1991).
Oral mucositis is a common and severe side effect, and in many cases, it is a complication of both cancer chemotherapy and radiotherapy for head and neck cancer (Dreizen, Brown et al., 1976; McCarthy, Awde et al., 1998). Patients with oral mucositis usually develop diffuse ulcerative lesions
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CHAPTER 1 of the movable mucosa of the mouth and oropharynx, with consequent pain of such severity that they require opioid-level analgesics (Elting, Keefe et al., 2008). Mucositis mainly arises as a result of direct effect of treatment on the oral mucosa (Sonis, 1998). However, the salivary disturbances and suppression of the immune defence mechanisms occurring during chemotherapy also contributes indirectly to mucositis. Thus, direct effects of chemotherapy and radiotherapy together with xerostomia and a reduced neutrophil count at baseline were the main reasons for mucositis (McCarthy et al., 1998).
Xerostomia can also lead to many other problems in the oral cavity including poor denture fit, oral discomfort, sore throat, vocal dysfunction (Roh, Kim et al., 2005). It can lead to dysphagia, a difficulty swallowing foods and/or liquids (De Graeff, De Leeuw et al., 1999), resulting in poor nutritional status of the patient and weight loss due to significant loss of appetite (Bruce, 2004; Pinna, Campus et al., 2015). Patients who suffer from salivary gland hypofunction may complain of sleep disorders, chronic burning sensation in the mouth, intolerance to spicy food and halitosis (bad breath) (Hay & Morton, 2006; Kaluzny et al., 2014).
Formation of dental caries is a major complaint among patients treated with radiation therapy for head and neck cancer due to reduced salivary secretion, dietary changes and changes in oral microflora (Brown, Dreizen et al., 1976; Frank, Herdly et al., 1965). Radiotherapy has been suggested to cause direct damage to the dental tissues leading to physical and chemical changes in the enamel (Aoba, Takahashi et al., 1981; Jervoe, 1970; Joyston-Bechal, 1985) and reduced enamel acid solubility (Jansma, Buskes et al., 1988). However, these findings have generated a debate in the dental literature, as several studies have shown no difference between irradiated and non-irradiated enamel (Kielbassa, Kielbassa et al., 2000; Shannon, Wescott et al., 1978; Walker, 1975).
A major adverse effect related to xerostomia secondary to radiotherapy is dysgeusia or taste alteration where the sense of taste may change quickly during radiotherapy when all or part of the mouth is irradiated. Patients either lose their sense of taste completely or everything tastes the same (a persistant metallic or salty taste in the mouth). Taste alterations are due to direct irradiation of taste buds and hyposalivation where changes in ionic composition of saliva is correlated to the taste sensation (Spielman, 1998).
A 2008 study evaluated the impact of xerostomia on quality of life in 75 survivors of head and neck cancer at six months post radiotherapy and without evidence of disease (Dirix et al., 2008). The patients were given a xerostomia questionnaire that was composed of three parts; xersotomia score, quality of life survey, and visual analogue scale. The study revealed that most of the patients experienced dry mouth (93%), 65% had moderate to severe xerostomia of G2 to G3, 63% of patients
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CHAPTER 1 had lost their taste and 65% had distorted taste perception, and a third reported oral pain. Xerostomia significantly contributed to emotional distress among the patients in which 64% felt worry, 64% had tension and 44% were depressed. Furthermore, patients experienced social problems with 60% having difficulty with talking to others, 54% with eating with others, and 65% felt restricted in terms of the amount and type of food they eat. These complaints were a result of radiotherapy-induced xerostomia and not from the disease as all the subjects were survivors of cancer diseases and not current patients (Dirix et al., 2008). Other early studies reported seriously diminshed quality of life for head and neck cancer survivors with xerostomia playing a crucial role (Bjordal, Kaasa et al., 1994; Epstein, Robertson et al., 2001; Harrison et al., 1997).
1.4. Current management and treatment of xerostomia
The National Institutes of Health (NIH) in the United States developed the consensus statement on the oral sequalae of cancer therapies (National Institutes of Health, 1989) that is still referred to in recent literature (Kaluzny et al., 2014). This provided strategies for the management and coping with xerostomia and salivary gland hypofunction induced by radiation therapy. The conference determined that all cancer patients should undergo a pretreatment oral examination. A volumetric assessment of the unstimulated and stimulated whole saliva was also recommended, but not approved as an indispensable diagnostic standard. Other recommendations were the development of accurate and reproducible criteria for assessing and classifying oral complications of cancer chemotherapy, radioprotective and chemoprotective agents and the development of more effective sialogogues and saliva substitutes (Kaluzny et al., 2014).
The initial step in the management of xerostomia and salivary hypofunction is to determine the underlying cause to inform appropriate treatment (Epstein, Emerton et al., 1999b; Gupta et al., 2006). However, in many situations the treatment of the underlying cause is impossible, or after treatment the symptoms are still present (Alpoz, Cankaya et al., 2014).
The planning of therapy strategies to help manage xerostomia should be tailored for every patient. A multicomponent model of care for xerostomia and salivary gland hypofunction should contain patient education, management of the underlying disease, preventive measures, and pharmacological treatment (Plemons, Al-Hashimi et al., 2014). Other approaches such as complementary therapies (particularly acupuncture), chewing gum, or more radical techniques such as submandibular salivary gland transfer may be considered.
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1.4.1. Patient information
Patients should receive complete information about xerostomia and salivary gland hypofunction regarding causes, potential sequalae (candidiasis, mucositis and other oral infections), preventive measures and how to alleviate these symptoms. Patients receiving radiation therapy for head and neck cancer should be advised that stringent oral hygiene is to be initiated with the start of radiation therapy to reduce the severity of consequences of xerostomia. Patients could also modify their food intake by including softer foods or eliminating spicy foods (Hutchinson, Suntharalingam et al., 2014).
1.4.2. Management of the underlying disease
This should be done in association with the health professional responsible for the patient especially if the disease or its treatment are known to cause xerostomia and reduced salivary secretion (Navazesh & Kumar, 2009; Scully, 2003). Dentists should be aware of the different products used to alleviate xerostomia that are available in the market in order to select the proper medication with the effective dose for the patient after consultation with the physician (Plemons et al., 2014). Clinicians should also be aware that it is preferable for most of the head and neck cancer patients to receive IMRT (a computer- controlled treatment delivery system) that delivers the radiation rays to the patient’s tumour yet significantly minimizes the amount of radiation that is delivered to the surrounding salivary glands thus preserving these glands and maintain adequate salivary flow and enhancing quality of life (Chambers, Garden et al., 2004).
1.4.3. Preventive measures to reduce sequelae of oral complications
Preventive oral care techniques are essential to obtain optimal care for patients with salivary hypofunction, who need more frequent dental supervision (Jenson, Budenz et al., 2007). This can be done concurrently with the management of secondary infections such as candidiasis and mucositis. This may include maintaining adequate hydration for patients with dry mouth as sipping water frequently, sucking on ice or using humidifier during sleep (Scully, 2003) which can produce a temporary relief of xerostomia. Tobacco use should be minimized or discontinued as it is known to cause dryness of the mouth (Thomson, Lawrence et al., 2006).
Dental caries can be reduced effectively through the use of fluoride-containing preparations either as over the counter dentifrices or prescription strength toothpastes, gels or varnishes (Jenson et al., 2007; Shiboski, Hodgson et al., 2007). Good oral hygiene is important, i.e. using topical fluoride toothpaste twice daily, regular use of floss and use of alcohol free mouth rinse.
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Uncomplicated candidiasis (without oesophageal involvement) can be controlled by using topical therapy of antifungal agents, nystatin or clotrimazole (available in suspensions, creams, powders, lozenges and ointements in those patients who suffer from xerostomia and reduced salivary secretion rates (Worthington, Clarkson et al., 2010). Systemic antifungal agents such as fluconazole and itraconazole are also available for the treament of candidiasis. Topical and systemic treaments should be prescribed for one to two weeks (Plemons et al., 2014).
1.4.4. Pharmacological treament
1.4.4.1 Saliva stimulants (sialogogues)
Saliva stimulants produce effective relief of xerostomia provided there is some residual salivary function after radiotherapy (Bjornstrom, Axell et al., 1990). These include sialogogues such as pilocarpine and cevimeline. Both pilocarpine tablets and cevimeline capsules are approved by the USA Food and Drug Administration (FDA) as sialoguges for the treatment of dry mouth that is caused by radiation or Ss (Plemons et al., 2014).
In Australia, pilocarpine is a Schedule 4 drug (Prescription Only Medicine), and pilocarpine eyedrops 1% and 2% are registered on the Australian Register of Therapeutic Goods (ARTG) for the treatment of non-congestive glaucoma, but an oral formulation of pilocarpine is currently unavailable. Pilocarpine is a naturally occuring alkaloid extracted from the leaves of Pilocarpus species (mainly P. microphyllus) that acts as a non-specific muscarinic cholinergic receptor agonist. As a parasympathomimetic agent, pilocarpine directly stimulates the cholinergic receptors on the surface of exocrine glands, including salivary glands and sweat glands, resulting in salivation, lacrimation, diaphoresis and increased pancreatic secretions (Jorkjend, Bergenholtz et al., 2008) .
A dose of 5 mg of pilocarpine taken three times daily for a period of eight to twelve weeks has caused a significant improvement in more than 40% of the patients who suffered from xerostomia (LeVeque, Montgomery et al., 1993; Rieke, Hafermann et al., 1995). The major side effects of pilocarpine are sweating, lacrimation, urinary frequency, headache and rhinitis (Gornitsky, Shenouda et al., 2004; LeVeque et al., 1993). Pilocarpine should be taken under medical supervision in those patients with chronic obstructive pulmonary disease and cardiovascular diseases. Consensus statements and expert recommendations support the use of an oral dose of 15-20 mg/day (Hamlar, Schuller et al., 1996; Papas, Sherrer et al., 2004; Rieke et al., 1995; Zimmerman, Mark et al., 1997).
Cevimeline is a newer muscarinic agonist that has been found safe and effective in treating xerostomia associated with Ss and it caused significant increase in the amount of resting saliva when administered in a dose of 30-45 mg three times daily for 52 weeks (Chambers et al., 2004). Cevimeline has similar
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CHAPTER 1 side effect profile to pilocarpine, primarily causing sweating, nausea and rhinitis. It may also cause headache, sinusitis and diarrhoea (Bultzingslowen et al., 2007). Cevimeline has not yet been assessed by the TGA and so is not contained in the Poisons Standard, but would be expected to be a Schedule 4 medicine.
Pilocarpine is the medication selected for further study in this thesis, and is reviewed in more detail in Section 1.5.
1.4.4.2 Saliva substitutes (salivary replacement)
Artificial saliva is made to be a neutral pH and contain electrolytes to resemble normal saliva (Visvanathan & Nix, 2010). The American Society of Clinical Oncology recommends the use of oral mucosa lubricants and/or saliva substitutes for the short term management of xerostomia secondary to radiotherapy (Kaluzny et al., 2014). The principal aim of their use is to ensure lubrication of oral mucosa and to protect the tooth tissues from decay (Hahnel, Behr et al., 2009). As these products produce a short duration of relief, the patient may prefer to drink water frequently instead of using these preparations (Kaluzny et al., 2014).
A wide range of substances can be used in the production of various saliva substitutes including carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), xanthan gum and polyacrylic acid and those used in the production of mucin-based saliva substitutes. They are present in different consistencies such as gels, sprays and mouth washes. For example, products available in Australia such as the Biotene, Colgate and Aquae ranges are based methylcellulose. CMC-based artificial saliva can produce moderate improvements in the feeling of dry mouth, especially in those for whom residual secretion is severely compromised (Oh, Lee et al., 2008).
Most research involving artificial saliva has been conducted overseas, and often using products that are not commercially available in Australia. For example, in a review conducted by Hahnel et al. (2009), mucin-based saliva substitutes such as Saliva Orthana were concluded to be beneficial for patients suffering from xerostomia secondary to radiation therapy. The review also revealed that for moderate to severe xerostomia the use of gel-like saliva replacements may be useful at night while a less viscous preparation is recommended during day time (Hahnel et al., 2009). Bioxtra is a synthetic saliva substitute gel made of polyglycerylmethacrylate, lactoperoxidase, and glucose oxidase Regelink, Vissink et al. (1998). Bioxtra showed potential benefit for patients suffering from severe xerostomia as a statistically significant reduction of the dryness-related complaints was observed in 28 patients who were suffering from moderate to severe xerostomia according to that study (Regelink et al., 1998).
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1.4.4.3 Sugar free chewing gum
The process of chewing and mastication of food induces saliva secretion by stimulating taste receptors (Risheim & Arneberg, 1993) and it does not usually cause any undesirable side effects. A study with 19 xerostomic patients (secondary to Sjögren’s syndrome or the use of medications) showed that the use of sorbitol sweetened chewing gum was associated with a statistically significant (p <0.005) increase in stimulated whole mouth and parotid salivary flow rate compared to unstimulated flow rates (Markovic, Abelson et al., 1988).
Comparison of different types of products have sometimes shown that chewing gum is more effective or preferred over lozenges or sprays. For example a crossover trial in 18 rheumatic patients with dry mouth symptoms and low salivary flow rates was conducted for two weeks with subjects randomly assigned to either chewing gum or lozenge use with a washout period of at least two weeks between treatments. Both products were sweetened with xylitol. The lozenge appeared to be superior to chewing gum in terms of mean resting and stimulated saliva flow rates but did not attain statistical significance (Risheim et al., 1993). Similarly, a prospective, randomized, open, crossover study was conducted to compare five day treatment with mucin-based saliva replacement (Saliva Orthana) spray and low-tack, sugar-free chewing gum in a group of 43 xerostomic patients with advanced cancer. The chewing gum scored better than the artificial saliva on every measure of efficacy but none of these results reached statistical significance. However both treatments were effective in the management of xerostomia, and 69% preferred the use of chewing gum over the artificial saliva (Davies, 2000).
1.4.4.4. XyliMelts
XyliMelts are a mucoadhesive disc that sticks to the teeth or gums and produces a relief of dry mouth and other related oral problems. Each disc is made to slowly release 550 mg of xylitol, a naturally occurring sugar alcohol that is known to increase saliva production (Austin, 2017) causing relief of dry mouth. XyliMelts effect is reported to last for hours, producing an optimal oral comfort by moisturising and coating the oral cavity by a soothing lubricant layer. It can be used during the day and while sleeping at night to enhance more saliva flow and as such help the users to have a non- interrupted sleep (Burgess & Lee, 2012).
In surveying 1168 dentists about the efficacy of different non-prescription remedies for dry mouth, they recommended the use of XyliMelts and rated it as the most effective product in relieving dry mouth than any other products for dry mouth (Hoeg & Burgess, 2017). In a study in 15 participants with dry mouth there was significant improvement in the perceived wetness and morning discomfort with a threefold increase in the perceived oral wetness scores after the use of the discs while sleeping 14
CHAPTER 1
(Burgess et al., 2012). More recently a randomised crossover clinical trial evaluated XyliMelts on oral health, enamel remineralization and saliva production. Five participants with xerostomia wore retainers carrying 5 demineralized enamel chips for 1 week each. Participants used the XyliMelts plus oral hygiene self-care or oral hygiene self-care only, with a 1-week washout period between both arms. The results showed that the XyliMelts disc use was accompanied with less plaque (p<0.05). Also, the saliva collected for 5 minutes was almost doubled 10 and 40 minutes after oral test disc insertion (Ho, Firmalino et al., 2017). Unfortunately, research into XyliMelts appears to have been funded by the manufacturer and published in journals produced by publishers of questionable quality, leading to questions over the independence of the results. Inclusion of XyliMelts in some good quality independent trials is needed.
1.4.4.5. Acupuncture
The use of acupuncture for the treatment of radiation-induced xerostomia is widespread (Kaluzny et al., 2014). There have been some studies investigating the effect of acupuncture on salivary flow rates and subjective symptoms of dry mouth, in which classical acupuncture was compared with placebo acupuncture (e.g. needles inserted a short distance from the standard recognised location) or compared to usual oral hygiene. Ten randomised controlled trials were included in a recent systematic review (Assy & Brand, 2018), which each included between 12 and 145 participants. Unfortunately, the review concluded that the quality of the studies limited their value of their findings, so although many of the trials reported positive effects their high risk of bias means that the results are inconclusive. Better-designed trials are required to properly test whether acupuncture is effective for symptom management or treatment of xerostomia.
1.4.4.6. Hyperbaric Oxygen Therapy
Hyperbaric Oxygen Therapy (HBOT) involves the inhalation of 100% oxygen intermittently in a total body chamber at a pressure of 2.5 atmospheres (Teguh, Levendag et al., 2009). This process enables oxygen to be quickly absorbed and dissolved in the bloodstream. HBOT is currently used for the treatment of a wide range of diseases including radiation induced xerostomia where it was found to stimulate growth of new capillaries and new healthy tissue in previously irradiated salivary tissues (Hadley, Song et al., 2013).
A systematic literature review was conducted over a period of 10 years (from 1990-2009) to evaluate the efficacy of HBOT in the management of radiation-induced side effects, including xerostomia, in the head and neck region. The review included experimental and clinical studies, although there was a scarcity of experimental studies and controlled clinical trials (Spiegelberg, Djasim et al., 2010). However, the overall conclusion of that systematic review was that most of the studies postulated a 15
CHAPTER 1 beneficial effect of HBOT on previously irradiated tissues, but further research is required to reveal the mechanism of action of HBOT and to ensure its clinical effects.
A more recent systematic review aimed to evaluate studies that tested the efficacy of HBOT on the treatment of radiation-induced xerostomia and xerostomia-related quality of life (Fox, Xiao et al., 2015). Of 293 studies, 7 studies met the inclusion criteria. The review concluded that HBOT may have utility for treating radiation-induced xerostomia that is not cured by other therapies. Additionally, HBOT can cause long-term improvement in subjective assessments of dry mouth, however the lack of randomised controlled trials limited the strength of these conclusions.
1.4.4.7. Submandibular salivary gland transfer
Also known as Seikaly-Jha procedure (SJP), submandibular salivary gland transfer involves the patient undergoing a surgical operation to transfer a single submandibular gland to the submental space on the side opposite to the primary tumour site just before radiotherapy. After the surgery, the preserved gland is shielded from the prescribed standard radiation to the site of the tumour nor to the neck nodes. A non-randomised phase II clinical trial showed that 83% of the patients who had preservation of one submandibular gland through SJP had no complaints of xerostomia. Also the patients did not report any surgical complications following the transfer procedure (Seikaly, Jha et al., 2004).
A prospective phase III multicenter randomised trial compared oral pilocarpine four times daily versus submandibular salivary gland transfer during and for three months after radiotherapy. The results of the trial showed that transfer was more beneficial than pilocarpine use in terms of saliva secretion rate and alleviation of xerostomia among the patients recruited in this study (Jha, Seikaly et al., 2009). Although patients who underwent transfer maintained better quality and consistency of saliva, according to the University of Washington Quality of Life scores, compared to patients who were treated with pilocarpine, there was no significant difference noted between the two groups for other xerostomia related quality of life measures such as speech, taste and swallowing (Jha et al., 2009).
1.4.4.8. Stem cell replacement therapy
The main cause of xerostomia secondary to radiation therapy for head and neck cancer is a lack of functional saliva-producing acinar cells, resulting from radiation-induced stem cell sterilisation. Stimulation of acinar cell division after radiotherapy only improves saliva secretion if the dose of radiation to the salivary tissues remains under a certain level or when part of the tissue is spared from being irradiated. Therefore, stem cell replacement therapy may be a good option to treat radiation- induced hyposalivation. This is not currently a therapeutic option, but recent research has made 16
CHAPTER 1 progress in understanding salivary gland cell turnover and identification of stem and progenitor cell populations, therefore stem cell therapy is a promising future development for the management of xerostomia (Pringle, Van Os et al., 2013).
1.5. Review of pilocarpine for dry mouth
1.5.1. Pilocarpine pharmacokinetics
In healthy males, 20% of the administered oral pilocarpine dose is excreted unchanged in the urine, and the rest is metabolised to pilocarpic acid and other metabolites (Aromdee, Ferguson et al., 1999). An interesting study was done by St. Peter et al. (2000) comparing the pharmacokinetics of orally administered pilocarpine in subjects with varying degrees of renal function. The participants who were classified into three groups (based upon the range of the creatinine clearance) received single oral pilocarpine doses (range from 2.5-20 mg). Plasma samples were collected at different various times for 24 hours following dose administration. Cmax (maximum pilocarpine plasma concentration), tmax (time to maximum plasma concentration), CL/F (apparent oral clearance calculated as dose/AUC) and AUC (area under the pilocarpine plasma concentration time curve) were normalised to a 5 mg exposure in those subjects who received doses other than 5 mg. The pharmacokinetic data for the three groups (healthy volunteers, elderly and subjects with impaired renal function) were calculated and given as follows: Cmax (ng/mL): 20.5±6.4, 27.3±9.8 and 30.9±12.2, tmax (h): 1.21±0.39, 1.03±0.19 and 0.61±0.03, AUC (ng/mL): 69.6±27.1, 79.3±30.1 and 69.2±31.9 and CL/F (L/h): 82.6±33.6, 71.3±25.3 and 93.8±55.6 respectively. There was some difference in Cmax, but when all of the parameters are taken into account oral pilocarpine clearance was not impaired in subjects with renal dysfunction (St Peter, Lambrecht et al., 2000).
In 2003, the effect of ethnic differences on salivary flow rates and pharmacokinetics was investigated using healthy Japanese and Caucasian volunteers, where they were randomly assigned to receive either 3 or 5 mg pilocarpine oral dose on day 1 and then they receive the opposite dose on day 3 of the study (given 48 hours as a washout period between doses). Blood samples were collected from each subject pre-dose and at various times for 24 hours post-dose. This study showed that the salivary flow rates were significantly higher (p<0.05) than the baseline at the earliest time point measured and remained elevated for 2 hours after administration, concluding that the duration of action of both doses was longer than 2 hours and there was no difference in salivary flow rates between the two groups following the administration of both doses. The pharmacokinetic data for the 5mg dose in the two groups; Japanese vs Caucasian were calculated and given as follows: Cmax (µg/mL): (24±17.3 17
CHAPTER 1 and 18.2±4.1), tmax (h):(0.8 and 1.0), AUC (ng/mL): (54.1±24.7 and 47.6±15.6), t½ (elimination half- life in h): (1.6±0.3 and 1.4±0.2) and CL/F (L/h): (117±75 and 115±34) respectively with no significant differences between the two groups in any measured pharmacokinetic data suggesting that there were no ethnic differences between the two populations upon the pharmacokinetics of the drug (Wasnich, Gallagher et al., 2003).
Based upon the previously mentioned information that were concluded in these studies, the time that it takes to reach maximum plasma concentration following oral administration of 5 mg pilocarpine is about 1.2 h, while its elimination half-life is 0.76 h (Nikles et al., 2015) with prompt effect on salivary production that lasts for 2 hours after dose administration.
1.5.2. Pilocarpine delivery, dose and efficacy
A narrative review was conducted to identify relevant articles on the use of oral pilocarpine for the treatment of dry mouth of different aetiologies including radiation-induced xerostomia, medication- induced xerostomia and Sjogren’s syndrome (Ss). The search was done to be able to get a clear idea of delivery methods of pilocarpine and the dose that the researchers around the world investigated to deliver pilocarpine in their study researches and the effficay of these methods and the drawbacks of each research study. Also, part of the aims of this review was studying the ways of assessing xerostomia and the salivary output in the reviewed studies and clinical trials.
The search was conducted over three years from June 2014 to June 2017 including all the relevant trials and studies that were published until 2017 through the databases, PubMed, CINAHL, Google Scholar and the Cochrane Central Register of Controlled Trials. The literature search was carried out using the search terms: dry mouth, xerostomia, pilocarpine, parasympathomimetic drugs, cancer patients, different aetiologies and post irradiated head and neck cancer patients. The search was limited to adult human population and English language. Studies were categorized in terms of their pilocarpine preparation and method of administration involved, and the details of the studies are presented in the Appendices as follows: Appendix A: Systemic oral pilocarpine preparations with placebo comparisons. This table includes the trials that investigated systemic pilocarpine preparations in the form of tablets vs placebo preparations. Appendix B: Systemic oral pilocarpine preparations with non-placebo comparisons. This table includes the trials that investigated systemic pilocarpine preparations in the form of tablets without placebo comparisons.
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Appendix C: Systemic oral pilocarpine preparations as capsules including placebo and non- placebo comparisons. This table includes the trials that investigated systemic pilocarpine preparations in the form of capsules only. Appendix D: Local preparations of pilocarpine including placebo, non-placebo and other drugs comparisons. This table includes the trials that investigated the efficacy of local pilocarpine preparations such as mouthwashes, lozenges, pastilles and hydrogel buccal inserts. Appendix E: Alternative oral formulations of pilocarpine for systemic delivery including placebo, non-placebo and other drugs comparisons. This table includes the trials that investigated local pilocarpine formulations that were intended to be taken systemically by swallowing rather than locally, such as ophthalmic solutions, jellies, mouthwashes and mouth sprays. Appendix F: Systemic pilocarpine preparations for the treatment of Sjogren’s syndrome (Ss). This table includes the trials that investigated different pilocarpine preparations that were administered systemically specifically for the treatment of Ss.
1.5.3. Systemic oral delivery
Pilocarpine tablets are available in some countries, such as the USA, Canada, Japan, The Netherlands, Thailand, England and France, and have been used extensively in research for investigating their potential efficacy in treating xerostomia. Most of the research done was targeted upon investigating the efficacy of pilocarpine in alleviating the dry mouth in post-irradiated head and neck cancer patients.
1.5.3.1. Systemic pilocarpine preparations - placebo comparisons Eleven studies (Appendix A) that compared pilocarpine tablets against placebo tablets (Agha- Hosseini, Mirzaii-Dizgah et al., 2007; Burlage, Roesink et al., 2008; Chitapanarux, Kamnerdsupaphon et al., 2008; Gornitsky et al., 2004; Johnson, Ferretti et al., 1993; Konno, Nishio et al., 2007; LeVeque et al., 1993; Papas et al., 2004; Rieke et al., 1995; Scarantino, LeVeque et al., 2006; Warde, O'Sullivan et al., 2002). In most of these studies, the dose used was 5 mg of pilocarpine to be taken three times daily. The targeted group of patients were previously or concurrently irradiated head and neck cancer patients who suffered from xerostomia as a result of radiation therapy or due to sequalae of their cancer disease itself. A small number of studies reported on xerostomic patients with Sjögren’s syndrome. One study reported the efficacy of pilocarpine in the alleviation of xerostomia suffered by patients with chronic Graft Versus Host Disease (cGVHD) (Agha-Hosseini et al., 2007).
The efficacy of pilocarpine use concomitantly with radiotherapy as a preventative measure against adverse effects is equivocal. Pilocarpine was not effective in alleviating the xerostomia from radiation 19
CHAPTER 1 therapy in patients with head and neck cancer even though large doses (up to 25 mg/day) were used in certain studies (Gornitsky et al., 2004; Scarantino et al., 2006; Warde et al., 2002). In contrast, Zimmerman et al (1997) found that when pilocarpine was given as 5 mg tablet or capsule four times daily to patients with head and neck malignancy together with radiation therapy, most patients had less subjective xersotomia and this effect was sustained for a further three months (Zimmerman et al., 1997); also, Valdez et al. (1993) found that the pilocarpine treated group demonstrated a lower frequency of xerostomia and a smaller decrease in the saliva secretion rate among the pilocarpine treated group compared to placebo controls (Valdez, Wolff et al., 1993).
In randomised, double blind, placebo controlled clinical trials where pilocarpine was prescribed after the completion of radiation therapy, the results were more consistently in favour of pilocarpine (Burlage et al., 2008; Johnson et al., 1993; LeVeque et al., 1993; Rieke et al., 1995). Whole saliva production was increased and most of the patients exhibited improved mouth moistness which resulted in decreased sensation of xerostomia.
Regarding the optimum therpaeutic dose of pilocarpine, it is important to note that the 5 mg dose was found to be the optimum dose concentration as investigated in all the previous studies as it produced the best clinical effects in terms of effectiveness compared to side effects. Furthermore, 2.5 mg three times daily was not beneficial (LeVeque et al., 1993), while 10 mg taken three times daily produced the best results for xerostomia treatment (Johnson et al., 1993; LeVeque et al., 1993; Rieke et al., 1995) but the occurrence of side effects was also increased and in some cases it was not well tolerated by the patients leading them to either withdraw from the study or reduce the dose.
In terms of side effects, sweating was the most common complaint in these studies followed by increased lacrimation, urine frequency, palpitation, headache, rhinitis and stomach cramps due to systemic absorption of pilocarpine. These are the most common adverse effects of pilocarpine as stated in the product leaflet supplied by Pfizer (Pfizer Canada, 2014)
1.5.3.2. Systemic pilocarpine preparations - non placebo comparisons There were twenty studies (Appendix B) that compared pilocarpine without a placebo comparison; (Abbasi, Farhadi et al., 2013; Aframian, Helcer et al., 2006; Aframian, Helcer et al., 2007; Almeida & Kowalski, 2010; Dave, 2008; Deutsch, 1998; Gorsky, Epstein et al., 2004; Horiot, Lipinski et al., 2000; Jacobs & Van der Pas, 1996; Lim, Choi et al., 2013; Masters, 2005; Mateos, Setoain et al., 2001; Mosqueda-Taylor, Luna-Ortiz et al., 2004; Nagler & Nagler, 1999; Nakamura, Sasano et al., 2009; Niedermeier, Matthaeus et al., 1998; Nyarady, Nemeth et al., 2006; Silberstein, 2008; Wasnich, Gallagher et al., 2003; Zimmerman et al., 1997).
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Two studies classified patients into two groups in which one group took pilocarpine in the specified dose regimen while the other group was not prescribed any therapy during the length of the study (Silberstein, 2008; Zimmerman et al., 1997). In another study, patients were grouped into those receiving a radiation dose ˃50 Gy and those receiving dose ˂50 Gy and all the patients received pilocarpine (Horiot et al., 2000).
Brimhall et al. (2013) used cevimeline capsules of 30 mg three times daily as the comparison with pilocarpine 5 mg three times daily in a randomised crossover double blind trial (Brimhall, Jhaveri et al., 2013). While pilocarpine is a cholinergic agonist with predominant muscarinic action and consequently stimulates systemic exocrine gland secretions leading to increased sweating, cevimeline has a high affinity for specific muscarinic receptors (M3) located on the epithelium of the lachrymal and salivary glands, and as such would be expected to produce fewer side effects (Fox, Konttinen et al., 2001). Fifteen patients with moderate to severe xerostomia resulting from a variety of causes received each treatment separated by one week washout period (t1/2 of 5 mg pilocarpine =0.76 hours). Both medications increased the stimulated and unstimulated saliva secretion and decreased the symptoms associated with xerostomia. Furthermore, there was a slightly higher increment in saliva production following pilocarpine use. However, both medications caused sweating. Thus according to this study, pilocarpine and cevimeline were found to be equally efficient in the management of xerostomia due to different aetiologies (Brimhall et al., 2013).
Abbasi et al. (2013) has conducted their study to compare the efficay of pilocarpine and bromohexine in improving radiotherapy-induced xerostomia and the related oral sequalae. Bromhexine is a mucolytic that is available in many over the counter cough preparations that reduces the viscosity of mucous secretions. Bromohexine was taken as 8 mg tablets four times daily for two weeks as the comparison with pilocarpine 5 mg tablets taken four times daily for two weeks in a single-blind, randomised crossover study. Twenty five previously irradiated head and neck cancer patients with xerostomia received the treatments separated by a one week washout period, then crossing-over to the comparator group (Abbasi et al., 2013). Saliva secretion rates before and after treatment with bromohexine was not statistically different (P=0.35), whereas it was statistically significant among pilocarpine users (P=0.0001). Furthermore, 28% and 100% of bromohexine and pilocarpine users respectively, showed improvement of xerostomia after two weeks. Thus it can be concluded that pilocarpine is more effective in improving xerostomia compared to bromohexine (Abbasi et al., 2013).
The results of these previously mentioned non-placebo controlled studies showed that there was an increase in the amount of saliva secreted following the use of pilocarpine 5 mg three times daily in
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CHAPTER 1 most of the patients, which resulted in a marked improvement of xerostomia (Abbasi et al., 2013; Aframian et al., 2006; Almeida et al., 2010; Horiot et al., 2000; Jacobs et al., 1996; Mosqueda-Taylor et al., 2004; Nakamura et al., 2009; Niedermeier et al., 1998; Nyarady et al., 2006; Silberstein, 2008; Wasnich et al., 2003).
Healthy volunteers have been used to investigate the effect of pilocarpine upon the secretion of saliva and hence its effect upon moistening of the mouth under normal conditions (Gotrick, Akerman et al., 2004; Lockhart, Fox et al., 1996; Wasnich et al., 2003). A Japansese study found no difference between Japanese and Caucasian healthy male volunteers in salivary response to 3 mg or 5 mg pilocarpine (Wasnich et al., 2003). A study on eight healthy hospitalized subjects found that a 15 mg controlled release pilocarpine formulation taken every 12 hours for three doses resulted in saliva secretion that lasted for ten hours but was not associated with side effects such as sweating or gastric discomfort (Lockhart et al., 1996), leading to the authors postulating that a controlled release pilocarpine formulation may be therapeutically more effective than the current pilocarpine preparations (Lockhart et al., 1996). Pilocarpine caused saliva production in tramadol-induced xerostomia, but some subjects did not complain of having dry mouth despite tramadol reducing their saliva secretion rates by more than 50%, while others reported a sensation of xerostomia yet their saliva secretion rate was not remarkedly decreased (Gotrick et al., 2004).
Most studies in the literature investigated the effectiveness of oral pilocarpine in the treatment of xerostomia secondary to radiation therapy in the head and neck region, but some focussed on xerostomia arising from other aetiologies. Among those studies are Nagler and Nagler (1999), Masters (2005) and Dave (2008) which investigated the effect of oral pilocarpine in alleviation of xerostomia secondary to cGVHD, psychoactive medications use and severe refractory dry mouth in association with administration of BoNTB (used for treatment of spasticity as a result of stroke) respectively. In these studies, pilocarpine was used in variable doses ranging from 5-30 mg per day and showed positive effects in alleviating the dry mouth experienced with the patients in these studies (Dave, 2008; Masters, 2005; Nagler et al., 1999).
In 2007, Aframain et al. conducted an interesting short term study (8-12 hours), where a mixed cohort of 45 xerostomic patients, were classified into three groups according to the aetiology of xerostomia (radiotherapy, Sjogren’s syndrome and sialosis/drug-induced xerostomia), were given an individual 5mg pilocarpine tablet to compare the effect of this single tablet on the salivary flow rate of the three different groups of the patients. The most significant effect of pilocarpine was seen in the sialosis/drug-induced group followed by the Sjogren’s syndrome group. The effect of pilocarpine significantly increased the saliva secretion rate 1-2 hours post-dose administration in the radiotherapy
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CHAPTER 1 group. However this effect did not last longer than three hours post-dose administration and returned to baseline (Aframian et al., 2007).
1.5.3.3. Systemic pilocarpine preparations - capsules In some countries, where pilocarpine tablets were not available, researchers had used compounded capsule formulations (Brimhall et al., 2013; Fox et al., 1991; Fox, Van der Ven et al., 1986; Gotrick et al., 2004; Haddad & Karimi, 2002; Lajtman, Krajina et al., 2000; Leek & Albertsson, 2002; Valdez et al., 1993) to conduct their trials. These were 8 trials (Appendix C).
The outcome of these studies in terms of their effect on saliva production and xerostomia was similar to that of tablet preparations with the same expected side effects due to systemic absorption.
1.5.4. Local oral delivery
Nine studies and trials were found (Appendix D) that involved the use of pilocarpine formulations such as pastilles, lozenges, jelly preparations, mouthwashes, eye drops, and buccal insert that were designed to be held in the mouth to optimise buccal absorption. A chewing gum formulation, containing 4.5 mg pilocarpine has been described in a patent (Singh & Singh, 2003) but does not appear to have been used in any published trials so is not considered further in this review.
1.5.4.1. Pastille, lozenge and jelly preparations Two studies used pastille/lozenge products aimed at local delivery (Hamlar et al., 1996;
Taweechaisupapong, Pesee et al., 2006). These formulations were to be sucked and dissolved in the mouth thus inducing mechanical stimulation within the oral cavity to produce salivation as well as releasing pilocarpine.
Hamler et al. (1996) compared four concentrations of pilocarpine in their butterscotch flavoured pastille (2.5, 5, 7.5, 10 mg), each taken three times a day for five days separated by two days of no pastille, by 34 post-irradiation head and neck cancer patients with xerostomia in a cross-over, prospective, randomized, double blind, placebo-controlled study. Saliva production at baseline, immediate postdose, and 30 minutes postdose showed gradual dose-dependent increases in saliva production, but these were not statistically significantly greater than placebo. However, 74% of the patients reported a subjective relief of symptoms of dry mouth, though some still maintained their use of a saliva replacement. The occurence of side effects were dose dependant but did not influence participant dropout. Only 24% of the 5 mg patients experienced sweating. However, when the dose increased to 7.5 mg and 10 mg, 50% and 66% of the patients reported sweating. The 5 mg pastilles caused 15% and 6% of patients to report tearing and flushing respectively, and 35% and 33% with the 10 mg pastilles. That is, when the dose was doubled it seemed that the percentage of adverse
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CHAPTER 1 effects incidence was more than doubled. In conclusion the pastille was well tolerated without producing harsh side effects and although it did not yield a significant increase in saliva production or reduction in saliva replacement use over placebo, the authors concluded that further research is warranted.
Taweechaisupapong et al. (2006) used one dose of each of four preparations (5 mg Salagen tablet, placebo lozenge, 3 mg pilocarpine lozenge, 5 mg pilocarpine lozenge). No flavouring was mentioned in the article. A single dose was taken, each separated by ten days from the next, in a double-blinded, placebo controlled, cross-over trial using 33 post-irradiation head and neck cancer patients. Each patient received four envelopes containing Salagen, 3 mg or 5 mg pilocarpine or placebo lozenge after being coded and were asked to participate in a stimulation study every ten days for 31 days. There was a statistically significant increase in saliva production and sensation of oral dryness for the three treatments (5 mg salagen tablet, 3 mg pilocarpine lozenge, 5 mg pilocarpine lozenge) compared to placebo control (P˂0.05). There were no dropouts from this crossover design, but patients only took each treatment once every ten days so no assessment of adverse effects resulting from repeated dosing could be made. Although not statistically better than the other treatments, the 5 mg lozenge produced the best clinical results regarding whole saliva production and subjective (Taweechaisupapong et al., 2006).
Sangthawan et al. (2001) administered pilocarpine as a 5 mg jelly preparation three times daily. However, unlike the lozenge and pastille described above there was no specific instruction to retain the jelly in the mouth, so it is presume here that this product was not designed for local delivery. A range of side effects were reported, which may be related to systemic absorption of the drug (Sangthawan, Watthanaarpornchai et al., 2001).
1.5.4.2. Mouthwashes Five publications have described the use of pilocarpine in the form of mouthwash to be spat out after being swilled around the mouth (Bernardi, Perin et al., 2002; Kim, Ahn et al., 2014; Mikhail, 1980; Rupel, Khoury et al., 2014; Tanigawa, Yamashita et al., 2015). Most were simple solutions prepared by dissolving pilocarpine in 0.9% saline or water or alcohol, or by diluting pilocarpine eye drops. Two studies used 0.9% saline as the placebo control in a randomized, double blind, placebo- controlled manner (Bernardi et al., 2002; Kim et al., 2014), one used tap water as the comparator (Tanigawa et al., 2015), one used commercially available alcohol-based mouthwash after adding pilocarpine to it (Mikhail, 1980) and one compared the effect of pilocarpine in healthy people with patients suffering Sjogren-related xerostomia (Rupel et al., 2014).
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Mikhail 1980, conducted his study using a commercially available mouthwash (Lavoris) and medicated it with pilocarpine (1%) for the treatment of 40 patients suffering from drug-induced xerostomia. Initially, Lavoris mouthwash was made of water alcohol solution thus pilocarpine was freely soluble in it and also it contained saccharin (sweetening agent) and other flavours that helped to mask the bitter taste of pilocarpine. The results showed that gargling with this mouthwash for 30 seconds or longer, was efficient in providing relief from xerostomia for about six to eight hours per application without producing systemic adverse effects (Mikhail, 1980).
Bernardi et al. (2002) conducted the study over 75 minutes in 40 healthy volunteers. Volunteers used 10 ml of 0.5%, 1% or 2% solution (i.e. doses of 50, 100 and 200 mg) rinsed in the mouth for one minute on one occasion. The 100 and 200 mg pilocarpine mouthwash doses significantly increased saliva production (P< 0.001) and this effect was dose dependant (Bernardi et al., 2002). As this was conducted with healthy volunteers, additional study with xerostomic patients is needed.
Kim et al. (2014) used a low dose of 10 ml of 0.1% solution (10 mg), rinsing for one minute three times a day for four weeks in a study with 40 xerostomia patients. A significant increase was measured for labial and palatal minor salivary secretion, and unstimulated whole saliva secretion at 60 minutes after mouthwashing. However subjective symptoms of dry mouth were significantly decreased in those using the 0.1% solution and those using the control, with no significant difference between them. Thus the authors concluded that 0.1% pilocarpine mouthwash increased minor salivary and unstimulated whole salivary secretions, but was not superior when compared with 0.9% saline at relieving subjective oral dryness. No adverse effects were reported.
Patients with xerostomia were also recruited for another recent study (Tanigawa et al., 2015), but this used an even lower concentration, 10 mg/100ml = 0.01% pilocarpine mouthwash, retaining in the mouth for two minutes and then spitting it out, and using as many times as needed but up to a total volume of 150 ml/day (15 mg/day). This study used 40 patients and assessed one month after starting either pilocarpine or water mouthwash. Even though the dose was low, overall improvement was observed in 47% of the pilocarpine treated group vs 14% of the control group and pilocarpine mouthwash has caused a significant increase in stimulated salivary flow rate. No adverse effects were reported.
A conference abstract provides limited information about a study into the relationship between salivary flow and blood concentration of pilocarpine (Rupel et al., 2014). The 2% mouthwash was used by healthy volunteers and patientsn with Ss, rinsing with 2.5 ml of the pilocarpine mouthwash for five minutes. Healthy volunteers took a single dose, while patients with Ss used the mouthwash three times daily for four weeks. There was a significant increase in salivary flow in both groups after
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CHAPTER 1 using the pilocarpine mouthwash and this was significantly correlated with pilocarpine blood concentration; sweating and nausea were also proportional to blood concentration.
1.5.4.3. Eye drops Two members of the supervisory team together with other researchers conducted a randomized, double-blinded, cross over N-of-1 trial to investigate the efficacy of pilocarpine eye drops for treating dry mouth in a cohort of 20 patients with advanced cancer (Nikles, Mitchell et al., 2015). Seven palliative care units in a number of different hospitals across Queensland and New South Wales, Australia participated in this trial. As previously mentioned, pilocarpine is only available in Australia as eye drops so the researchers used it as their investigated preparation with matching placebo eye drops, both with citrus flavour added. The patients were instructed to take three drops three times daily with meals (approximately 6 mg per dose) to increase salivation that can help in swallowing the food easily and to spit the residue and not to swallow it (Nikles et al., 2015). However, the taste of the eye drops was not acceptable to some of the participants as it was very bitter and the citrus flavour used was not fully effective in masking this bitterness and this was a considerable limitation of this trial. Moreover, the authors stated that because the taste criterion was not recognised in their protocol, they believed that some participants withdrew from the study due to the taste issue but this was not included in their collected data. The study design was an N-of-1 where each patient underwent three cycles, each cycle was divided into two periods, each period lasted for 3 days, a total of 18 days. Only four patients completed the trial, two of them (50%) showed a response to the pilocarpine eye drops according to the xerostomia NRS (0-10 xerostomia numerical rating scale with 0 = no complaint and 10 = the worst possible xerostomia) while the other two patients did not. The authors postulated at the end of the trial that pilocarpine eye drops used in this trial was not suitable for buccal use and that more work is warranted for buccal delivery formulation and dose of pilocarpine.
1.5.4.4. Buccal insert A hydrogel polymer buccal insert containing 5 mg of pilocarpine, which releases the drug in a controlled pattern over three hours, was tested in eight patients with Sjögren’s syndrome. The buccal inserts were placed into the buccal salcus three times daily and removed after three hours; they absorb water in the mouth, becoming swollen and then releasing pilocarpine in a controlled manner into the oral cavity. The insert can be removed from its place and put in a new place or returned back to its former position to continue to release the drug within the mouth. The length of study was 14 days and patients used the inserts from day eight to day 14 (they used the buccal inserts for seven days). Patients were assessed daily for measurement of saliva flow rates during the length of the study. The insert increased saliva flow and improved oral discomfort, but some side effects were reported due to the pilocarpine and the insert itself. The authors reported that more than 85% of the prescribed dose of 26
CHAPTER 1 pilocarpine had been delivered, based on analysis of drug remaining in the inserts after use (Gibson, Halliday et al., 2007)
1.5.5. Alternative oral formulations of pilocarpine for systemic delivery
This term applies to the trials were researchers used local oral preparations such as mouthwashes and mouth sprays that were formulated to be used locally but rather they instruct the participants to swallow the local preparations for eliciting a systemic effect instead of spitting out the mouth. These were 11 studies and clinical trials (Appendix E). These included mouthwashes, mouth sprays, oral solutions, eye drops.
1.5.5.1. Mouthwash and mouth spray Davies & Singer (1994) formulated pilocarpine as a mouthwash in a concentration of 5 mg to be taken three times daily (Davies & Singer, 1994). Patients were advised to swallow any remaining fluid, thus systemic absorption of pilocarpine occurred with this mouthwash. This may be the reason of the occurrence of adverse effects among the patients. Frydrych et al. (2002) tested pilocarpine mouth spray 90 ml, containing 15 ml 4% pilocarpine eye drops in 75 ml oralube with use being based on individual symptomatic regimen for xerostomia (Frydrych, Davies et al., 2002). However, there were no instructions to hold the spray in the mouth, so the spray was assumed to be swallowed after spraying into the mouth, and the outcome may be associated with systemic absorption rather than local effect which could explain the adverse effects noted during the study.
1.5.5.2. Oral solutions and eye drops Compounded oral solutions such as ophthalmic solutions and eye drops were used systemically rather than locally (the patients were instructed to swallow the investigated preparations instead of spitting out the mouth) in a number of trials (Alajbeg, Hladki et al., 2005; Joensuu, Bostrom et al., 1993; Jorkjend et al., 2008; Mercadante, Calderone et al., 2000; Pimentel, Filho et al., 2014; Rhodus & Schuh, 1991; Schuller, Stevens et al., 1989; Singhal et al., 1997; Sung et al., 2005). As expected, the outcome of these studies in terms of their effect on saliva production and xerostomia was similar to that of tablet preparations with the same expected side effects due to systemic absorption.
1.6. Evidence to support the efficacy of pilocarpine oral use for the treatment of xerostomia of different aetiologies
Over the past few years three systematic reviews were conducted to investigate the efficacy of pilocarpine and other saliva stimulants in the treatment of radiation induced xerostomia. Two of them 27
CHAPTER 1 were in favour of the use of pilocarpine for that purpose (Cheng, Xu et al., 2016; Mercadante, Al Hamad et al., 2017) while the third one did not support that conclusion (Davies & Thompson, 2015). Cheng et al., supported the clinical efficacy of pilocarpine for the symptomatic treatment of radiation- induced xerostomia and Mercadante et al., concluded that pilocarpine should be the first line treatment for radiation induced xerostomia in head and neck cancer survivors.
In 2015, Davies and Thompson updated their Cochrane systematic review which was investigating the use of para-sympathomimetic drugs for the treatment of salivary gland dysfunction due to radiotherapy (Davies et al., 2015). The results of the update were not different from the results they got from the original review (Davies et al., 2007). Their overall conclusion was that there is limited evidence to support the use of pilocarpine hydrochloride in the treatment of radiation-induced xerostomia. This was based on the included studies showing that approximately half of the participants will get benefit of pilocarpine use for treating their dry mouth but side effects can be troublesome. The criteria for selecting the trials to be included in their review were narrow:
• Types of trials: Randomized controlled trials. • Types of participants: Participants with radiation- induced salivary gland dysfunction only. • Types of interventions: Parasympathomimetic drugs given by any route, formulation or dose. • Types of outcome measures: Primary outcome (xerostomia), Secondary outcomes (salivary output, adverse effects and others).
Only three trials met their criteria and were included in the review. These studies were: Davies et al. 1994, Johnson et al. 1993, and LeVeque et al. 1993. In the next section these three trials will be discussed and following this a summary of the many other trials that they excluded will be presented.
1.6.1. The three trials that were included in the Cochrane review a) Davies et al. 1994
The trial published by Davies and Singer in 1994, in which 20 post-irradiated head and neck cancer patients were allocated in a single study centre to receive three-month treatment with mucin-based artificial saliva and then 5 mg pilocarpine mouthwash (to be swallowed rather than spitting of the mouth) for three months in a cross-over pattern. There is a major limitation in this trial which is the small number of the participants; 20 participants (Davies et al., 2015). Pilocarpine mouthwash did not produce significant improvement in xerostomia and dysphagia. However it produced a significant improvement in dysgeusia (p=0.04) and more than 50% of the participants preferred the pilocarpine mouthwash than the mucin-based artificial saliva (Davies et al., 1994).
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CHAPTER 1 b) Johnson et al. 1993
The trial published by Johnson et al., 1993 which was a big trial as it was conducted in 39 treatment sites with 209 patients who suffered from a clinically significant radiation-induced xerostomia were randomly assigned to receive either placebo, 5mg pilocarpine or 10 mg pilocarpine tablets three times daily for 12 weeks. Assessments included were subjective feeling of dry mouth with visual analogue scales to record the responses to six questions about dry mouth condition and objective measurement of the salivary function. The results of the trial showed that pilocarpine in the two tested doses was more effective than placebo; oral dryness improved in 44% of the patients that received the 5 mg pilocarpine tablet as compared with 25% of the patients that received placebo (p=0.027). 54% of the group that received the 5 mg dose had an overall improvement (mouth comfort and overall improvement of xerostomia) as compared with 25% of the placebo group (p= 0.003). 31% of the 5 mg group had improved oral comfort of the mouth and the tongue as compared with 10% of the placebo group (p=0.002). Speaking ability improved in 33% of the 5 mg group as compared with 18% of the placebo group (p=0.037). There were similar improvements in the group that received the 10 mg pilocarpine tablets. A higher proportion of patients in the two pilocarpine groups had a significant improvement in the sensation of intraoral dryness (p=0.037). Oral pilocarpine in the two tested doses resulted in relief of dry mouth symptoms in all the six area assessed (improvement in sensation of oral dryness, improvement in overall condition of xerostomia, improvement in speaking without requiring liquids, improved comfort of the mouth and tongue and lessened need for oral comfort agents such as artificial saliva and others).
The only limitation of this trial is that although saliva production was improved in the group that received pilocarpine, but this effect was not continued and was variable throughout the whole trial length. Moreover, this increase in the amount of saliva produced did not correlate with the clinical response resulted from pilocarpine treatment. However, even small increases in saliva production could be sufficient to produce a significant clinical improvement. This could be explained widely in terms of the ability of pilocarpine to stimulate the minor salivary glands which is known to produce less than 10% of the total volume of saliva but contribute more than 70% of the total mucin content, a saliva constituent, which is responsible for oral lubrication and preventing the dryness of the soft tissues. So any increase in saliva production, no matter how little it is, may be beneficial for those patients who suffer from dry mouth especially if it is linked with increase in the amount of the favourable saliva constituents (Johnson et al., 1993).
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At the end of this trial the authors claimed that the 5 mg dose of pilocarpine three times daily had the best clinical outcome in terms of subjective measurement of dry mouth and objective saliva production when both side effects and efficacy are to be considered together (Johnson et al., 1993). c) LeVeque et al. 1993
A similar trial to that done by Johnson is the trial published in the same year 1993 by LeVeque et al., where they ran a big trial similar to that of Johnson applying the same protocol. The length of the trial was 12 weeks where 162 head and neck cancer patients with clinically significant xerostomia were allocated randomly to receive either placebo tablets or pilocarpine tablets. Pilocarpine tablets were given as follows: 2.5 mg tablets where given in the first 4 weeks, followed by 5 mg tablets on the following 4 weeks and 10 mg tablets were given in the last 4 weeks of the trial. The dose of pilocarpine was allowed to be titrated for every participant determined by two factors: efficacy and side effects. Assessment of xerostomia was done through a 100 mm VAS to record the response for each of six questions with the objective assessment of the salivary output compared to baseline. The primary measure of efficacy was based upon the proportion of responders who had at least a 25-mm increase from baseline on the VAS assessment of dryness and by an increase in the amount of saliva collected compared to baseline. A clinically significant improvement was defined as an increase greater than 25 mm on the VAS scale. After analysis of the results the 2.5 mg dose was shown to be a sub- therapeutic dose with no potential to produce any clinical improvement of xerostomia condition. However, the 5 mg and 10 mg doses were shown to produce an overall global improvement of the dry mouth symptoms following 8 or 12 weeks of study. When compared with placebo pilocarpine produced a significant improvement in overall global assessments of xerostomia (p=0.035); the proportion of responding patients was statistically significant between treatment groups. Patients who received pilocarpine had used the oral comfort agents such as artificial saliva, hard candy and water less frequently and this was statistically significant (p=0.020). Post dose improvements in whole and parotid salivary flow were statistically significant in pilocarpine treatment groups as compared with placebo. However, this highly significant improvements in salivary output in the responding patients did not yield large volumetric changes.
The results were comparable to that of Johnson et al. trial where the small increases in the salivary output was not correlated with the major clinical benefits seen in this study. This might be attributed to the immediate dryness-to-moisture phenomenon or to the delayed effects of the increased saliva production and its constituents such as water, mucins, proteins and electrolytes with the important function of mucins to lubricate the oral cavity and to protect the oral tissues against chemicals, infections and mechanical trauma.
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Again the authors concluded that pilocarpine 5 mg three times daily was the favourable regimen for most of the patients with clinically significant or closely approaching clinically significant benefits for many end points other the global improvement of the xerostomia sensation (LeVeque et al., 1993).
Based on the results of Johnson et al. and LeVeque et al. trials that were included in the Cochrane review, pilocarpine not only clinically improved the xerostomia sensation but also produced a clinical improvement of the associated symptoms of low salivary output.
1.6.2. Examples of trials that were excluded from the Cochrane review
Some excluded trials showed the clinical efficacy of pilocarpine in treatment of dry mouth. The trials that were excluded in this review and showed clinical efficacy of pilocarpine included:
• Those which adopted the N-of-1 methodology such as that done by Nikles et al., 2015 where they concluded at the end of this trial that 50% of the patients that completed the whole trial (the three cycles) responded to the pilocarpine eye drops 4% (6 mg tds) according to the xerostomia NRS (numerical rating scale) and PGIC (patient global impression of change). Another reason for excluding this trial is that the participants were patients with advanced cancer who suffered from dry mouth (Nikles et al., 2015). • Those with mixed dry mouth aetiology. This includes the trial made in 1991 by Fox et al. in this trial the participants were a mixed cohort of patients with dry mouth of different causes such as SS, radiation induced salivary hypofunction and idiopathic salivary gland dysfunction. The results of this trial were in favour of pilocarpine use where 87% of the participants reported subjective improvement of their dry mouth sensation and that pilocarpine significantly increased the salivary output in 68% of the participants. The reason for the exclusion of that trial from the Cochrane review was that the authors did not give individualized results per every group of patients rather they aggregated the end results for all the patients together and no separate data could be obtained for the participants with radiation-induced salivary gland dysfunction (Fox et al., 1991). The same for Aframain et al, 2007 study (Aframian et al., 2007). • A pilot study conducted by Schuller et al., 1989 for the treatment of radiation side effects with 2% pilocarpine ophthalmic solution to be taken orally. The dose of the pilocarpine solution was 1 mg per drop and patients were instructed to take 3 drops three times a day in a randomized placebo-controlled trial. The authors postulated that the results of this pilot study support the claim that residual salivary glands can be stimulated by oral pilocarpine and no complete report of the results was obtained. Another limitation of this study is that a sub-therapeutic dose of pilocarpine was investigated in this trial instead of the standard therapeutic dose which is 5 mg tds (Schuller et al., 1989). 31
CHAPTER 1
• The cross-over, double blind, placebo controlled, randomized trial conducted in 1987 at the University of California, where the researchers used a concentration of 2.5 mg pilocarpine tablets to be taken as a dose of 2 to 3 tablets three to four times daily in 12 post-irradiated patients. The authors did not show full details on how they measured the primary outcome which is the subjective feeling of dry mouth which was considered as inadequate data on the primary outcome in the Cochrane review. However, the results of this trial were very promising as 75% of the patients showed symptomatic improvement when they received pilocarpine and the parotid saliva flow was significantly increased in all the patients after 90 days treatment with pilocarpine. The authors mentioned that they treated over 200 patients in a non-controlled clinical setting with pilocarpine solution (2.5-7.5 mg to be taken two to four times daily) (Greenspan & Daniels, 1987). • Trials where the targeted population were those who suffer from dry mouth as a complaint of their SS. Pilocarpine proved to produce clinical improvement in dry mouth sensation in those patients as shown in the following trials (Jorkjend et al., 2008; Papas et al., 2004; Rhodus et al., 1991; Tomiita, Takei et al., 2010; Vivino, Al-Hashimi et al., 1999; Wu, Hsieh et al., 2006).
In 2016, a systematic review and meta-analysis was funded from the National Natural Science Foundation of China to assess the efficacy and safety of pilocarpine for radiation-induced xerostomia in patients with head and neck cancer (Cheng et al., 2016). The following databases were used in this search: MEDLINE, Embase, Cochrane library and Science Citation Index Expanded. The authors used the Cochrane Collaboration’s tool (Review Manager 5.1 software) for assessing the risk of bias to improve the quality of the search. They ended with 6 articles included in this systemic review, including a total of 752 patients. This review included two out of the three used in the Cochrane review (Johnson et al., 1993; LeVeque et al., 1993) and four other studies (Haddad et al., 2002; Nyarady et al., 2006; Scarantino et al., 2006; Warde et al., 2002). They excluded Davies and Singer (Davies et al., 1994) due to the small sample size in this pilot study. The results of three of the six studies were in favour of pilocarpine use as it caused 12 point increase in the VAS score (mean difference, 12.00; 95% confidence interval [CI], 1.93-22.08; P = .02) compared with placebo. This improvement was statistically significant in terms of clinical benefit of pilocarpine for the treatment of radiation induced xerostomia in patients with head and neck (Cheng et al., 2016).
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CHAPTER 1
1.7. Taste dysfunctions occurring in cancer patients
1.7.1. Background
Products designed for local oral delivery, such as mouthwashes, lozenges, pastilles and hydrogel buccal insert are designed to be retained in the mouth for a while. As the taste of pilocarpine is known to be bitter and not acceptable, there was a need to flavour such preparations to obtain an enhanced patient compliance. Only Hamler et al. (1996) and Nikles et al. (2015) indicated that they included flavouring their prepared pilocarpine products with butterscotch and citrus flavours respectively. The butterscotch flavour was enjoyed by the patients using lozenges (Hamlar et al., 1996) but the eye drops taken by mouth were unacceptable even with lemon flavouring (Nikles et al., 2015)
Taste disorders are commonly significant in patients suffering from malignancy and their prevalence in the oncology population usually exceeds that in the normal population and can have a great effect on the quality of life (Comeau, Epstein et al., 2001; Seiden, 1997). Taste changes are a common side effect that accompanies chemotherapy in 30-75% of patients treated with antineoplastic agents (Bernhardson, Tishelman et al., 2009; Hovan, Williams et al., 2010). Over 40% of hospitalized patients suffer from malnutrition either from cancer disease itself or from chemotherapeutic agents as the ingested food does not taste the same as before, or it becomes less acceptable in taste, which makes the patients in most instances discontinue eating even if they are not full (Comeau et al., 2001). Taste alterations can lead to the development of food aversions and hence a subsequent reduction in food intake (Grant & Kravits, 2000). Malnutrition results in reduced response to therapy, poor prognosis, increased morbidity of therapeutic side effects and decreased quality of life (Comeau et al., 2001). Therefore, it is important to consider the perception of flavourings added to products that are designed to be used by these populations.
1.7.2. Prevalence of taste alterations
Taste alterations is a common complication that is usually developed after chemotherapy treatment and is reported as the most distressing side effect. Taste alterations occur in the range of 46%-77% of the patients (Bernhardson, Tishelman et al., 2008; Zabernigg, Gamper et al., 2010). Taste alterations usually start at the beginning of the chemotherapy and may last for weeks or even months after discontinuation of therapy (Henkin, 1994; Jensen, Mouridsen et al., 2008b).
A study by Jensen et al. (2008) examined the relationship between adjuvant chemotherapy and taste disturbances in breast cancer patients during treatment and one-year post treatment. During chemotherapy, 84% of the patients experienced taste disturbances, 22% developed oral mucosal
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CHAPTER 1 lesions as erythema, 16% developed ulceration and 11% were diagnosed with oral candidiasis. The tendency for dental bacterial plaque and gingival inflammation has increased during chemotherapy and the oral microflora became more acidic. However, these adverse effects were transient as salivary secretion rate returned to baseline values within one year post treatment (Jensen, Mouridsen et al., 2008a).
1.7.3. Causes of altered taste in cancer patients
Taste affects our eating patterns because when we ingest agreeable food the pleasure centre in the brain become stimulated, (Breslin & Spector, 2008) which leads to increased dopamine secretion (Volkow, Wang et al., 2011).
Taste changes are real and/or perceived alterations in taste sensation and are usually caused by cancer and/or its treatment. Taste alterations sometimes develop even before the start of the therapy (DeWys & Walters, 1975) and this may be explained by the hypothesis that the malignancy itself is responsible for that (Johnson, 2001). Taste changes arising from cancer are due to the influence of amino-acid substances secreted by tumour cells which in turn lead to changes in taste of meat, fish, oils and other substances as reported by the patients (Grant et al., 2000). Such alterations lead to further disease progression due to decreased calorie intake which lead to weight loss, protein and vitamin depletion and deterioration in the overall patient’s nutritional condition (Ravasco, 2005). Taste changes have been associated with the patient’s ‘body burden of tumour’. They scored the tumour involvement by organ system on a 0-3 scale and the sum of the scores was called the tumour extent score. A group of 50 patients with a spectrum of malignant tumours of different stages was studied. Results showed that all patients with tumour extent score 1 or 2 (with limited disease) had normal recognition thresholds for both sweet and bitter tastes, 14% of the patients who had tumour extent score 3 or 4 (with slightly more advanced disease) had an abnormality of recognition of either sweet or bitter tastes, while 75% of the patients with tumour extent score 5 or more (with extremely advanced disease) had an abnormality of recognition for sweet or bitter or both tastes (DeWys et al., 1975).
Taste alteration is a significant complaint among patients receiving chemotherapy. Lockhart and Clark found that taste alteration (37%) was the most frequent complaint among cancer patients receiving chemotherapy followed by mucositis (30%) and ulceration (22%) (Lockhart & Clark, 1990). Chemotherapeutic agents are designed to target the cancer cells which are known to be rapidly dividing; unfortunately, the human body contains other rapidly dividing cells like the mucosal cells lining the gut which are damaged by these medications leading to mucositis. Also the gustatory and olfactory receptors proliferate rapidly in 10 and 30 days respectively thus they may be too sensitive
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CHAPTER 1 to the cytotoxic effects of chemotherapies causing patients to suffer from taste and smell changes (Wickham, Rehwaldt et al., 1999).
It is known that medicines usually stimulate the taste system through saliva, blood and crevicular fluid. During systemic stimulation, drugs diffuse from the blood to the taste buds and cells eliciting taste sensations (Berteretche, Dalix et al., 2004). Hence these drugs can be tasted or smelled as they enter the oral or nasal cavity. Chemotherapeutic drugs that have been reported to cause taste changes include: cisplatin, cyclophosphamide, carboplatin, doxorubicin, 5-flurouracil, levamisole, methotrexate and paclitaxel (Wickham et al., 1999). Cisplatin and doxorubicin have been reported to cause the most severe taste changes (Wickham et al., 1999). Some patients reported that they suffer the presence of bitter taste during the administration of antineoplastic drugs (Comeau et al., 2001).
1.7.4. Radiotherapy-induced taste impairment
Around the world, head and neck cancer (HNC) is ranked the sixth most prevalent type of cancer affecting people. Every year more than 500,000 patients are being reported having HNC worldwide (Larizadeh, Damghani et al., 2014; Parkin, Bray et al., 2005). The American Cancer Society postulates that more than 50,000 Americans are diagnosed with HNC every year (Siegel, Naishadham et al., 2012). Fortunately, the incidence rates have remained constant and moreover the mortality rates from oral/pharyngeal cancers have remarkably decreased in the last 30 years (McLaughlin, 2014; Siegel et al., 2012).
Patients who experience malignant tumours in the head and neck area are usually treated with radiation therapy. However, the vast majority of those patients report altered taste during and after treatment. Taste alteration occurs a few weeks after the commencement of therapy and all such patients experience loss of taste acuity at a dose of 60 Gy (Ruo Redda & Allis, 2006). Taste dysfunction is one of the most common complaints among patients undergoing radiotherapy for HNC. About 75% of patients treated with radiation for HNC report their development of taste disorders and 93% of these patients complain of long-term (for years following radiotherapy) xerostomia (Mossman, Shatzman et al., 1982).
One of the major aspects of taste alteration among patients receiving radiotherapy for HNC is the change in their threshold perception for the four common taste modalities (sweet, sour, salty and bitter). Many studies that investigated such changes have reported ambiguous results. Some of these studies reported reduced threshold for sweet solutions while the threshold for bitter solutions increased (DeWys, 1974; Gallagher & Tweedle, 1983), but others postulated that the greatest impairments are seen in the bitter and salty solutions while the sweet modality showed the least
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CHAPTER 1 impairment (Bonanni & Perazzi, 1965; Mossman, 1982; Mossman & Henkin, 1978). In contrast, a study done by Schwartz et al. revealed near normal thresholds for the four basic taste modalities in patients receiving radiotherapy for HNC (Schwartz, Weiffenbach et al., 1993).
Yamashita et al. conducted a clinical investigation into impairment of the four basic tastes associated with irradiated tongue volume in patients with HNC. They concluded that when the anterior part of the tongue was not exposed to irradiation the taste alteration would not be noticeable, but when it was irradiated, even a low radiation dose delivered such as 20 Gy caused a temporal taste loss. Besides, the taste changes that accompanied the radiation therapy appeared to be temporary (Yamashita, Nakagawa et al., 2006).
A prospective study investigated the frequency and the dose level at which the taste disturbances occur during radiotherapy of the tongue and to which extent these deficiencies persist in three groups of patients. The first group received radiotherapy for the posterior two thirds of the tongue, the second received whole tongue radiation therapy, and the third group was with non-small lung cancer receiving definitive radiation therapy. The results showed that the gustatory function of the third group was not affected, while the first and second groups suffered from gustatory disturbances after a total dose of 20 Gy with a maximum between 40-60 Gy. However, these disturbances disappeared within eight weeks after radiotherapy in patients with partial tongue irradiation and almost completely in patients with entire tongue irradiation. Thus the study postulates that if the volume of the tongue being irradiated is reduced by means of intensity modulated radiotherapy this may result in a reduction of these undesirable side effects (Kamprad, Ranft et al., 2008).
A fifth taste modality has been recognized and referred to by the Japanese Word Umami is now known. A few studies have determined the changes that occur in the ability to detect umami among patients who are irradiated for HNC (Shi, Masuda et al., 2004; Yamashita, Nakagawa et al., 2009). Shi et al. found that the ability to detect the umami taste was impaired and such impairment proceeded after irradiation dose at 30 Gy, while Yamashita et al. found that the thresholds of umami taste increased significantly after three weeks from the start of radiation therapy and recovered and returned to their normal state at eight weeks.
In conclusion many studies have revealed the presence of taste alteration among HNC patients (Loewen, Boliek et al., 2010; Mirza, Machtay et al., 2008) and this may be due to several factors: surgical intervention for the treatment of HNC may cause damage or complete removal of taste receptor cells which are present on the tongue, pharynx and upper part of the oesophagus, The epithelium of the oral cavity may be disrupted by radiation therapy and chemotherapy for cancer thus leading to interrupted contact between tastants and taste buds. Besides, tumour cells secrete
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CHAPTER 1 inflammatory cytokines which may disrupt the transmission of taste impulse at any level of taste sensation transmission (McLaughlin, 2013).
1.7.5. Implications of taste alterations
Several studies have reported that taste alterations can eventually lead to deteriorated quality of life as measured with the functional Assessment of Cancer Therapy and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (Kano & Kanda, 2013; Wickham et al., 1999; Zabernigg et al., 2010).
The hedonic responses in the brain can elicit their influence upon eating behaviours. This is reflected in that when people feel pleasure when they eat, they usually tend to eat more and feel full later but those who find food is not tasting good will eat less. This eventually cause changes in food selection which may affect both nutritional status and quality of life (Volkow et al., 2011).
Taste alterations that the patients usually develop after radio/chemo therapy for HNC can have a profound psychological effects on the patients. The usual taste of the common foods that they used to experience is now changed. This happens at this stressful time as after diagnosis of cancer or during its treatment. This new relationship to food can compromise the patient’s morale and possibly leading to depression which in turn can influence the response to therapy and hence decrease the chances of survival leading to increased risk of morbidity (Comeau et al., 2001).
Oral complications resulting from cancer and cancer therapies cause acute and late toxicities. Acute oral complications include mucositis, dysphagia, salivary changes (volume and consistency) and neurosensory changes (taste alteration and taste changes). Late complications may also include neurosensory changes such as saliva, taste, and functional changes, oral and dental infections, increased tendency of dental disease and necrosis of the jaw leading to reduced energy and nutrient intake. Patients may also suffer from social withdrawal and depression due to speech difficulties as a result of hyposalivation. All these complications negatively impact patients’ quality of life (Epstein, Thariat et al., 2012).
Cancer and chemotherapeutics usually cause malnutrition in a significant number of patients. This eventually leads to low caloric intake and a noticeable reduce in total body weight. About 45% of hospitalized adult patients lose 10% of their body weight and 82% of patients who receive antineoplastic agents develop food aversion (Berteretche et al., 2004; Holmes, 1993). Bernstein in 1978, has postulated that cancer patients lose their appetite partly as they develop conditioned avoidance towards food and beverages after being treated by chemotherapy medications (Bernstein, 1978). Honea et al. investigated that “when chemotherapy stimulates chemoreceptor trigger zones, it
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CHAPTER 1 causes nausea and vomiting” (Honea, Brant et al., 2007). This in turn is accompanied by loss of appetite, taste disturbances and whole malaise. The patients eventually suffer from secondary anorexia (Shragge, Wismer et al., 2006).
Radiotherapy for HNC is known to cause many oral complications, either during or after the therapy, which affects patient overall quality of life (Gotay & Moore, 1992). Patients who receive high intensity radiation as a therapy for HNC complain from measurable weight loss. This results from reduced food and nutrient intake as they lose their desire for food due to nausea caused by the therapy itself or due to taste and smell changes that usually develop during and after therapy. Also these patients suffer from mucositis that could be painful to the extent that limit their food consumption. Weight loss may occur due to reduced absorption of nutrients as a result of toxic effects of therapy on the lining of the gut or due to altered patterns of absorption of nutrients resulting from graft-versus- host disease (GVHD) or due to increased energy requirement due to fever and anabolic demands (Comeau et al., 2001). Patients who suffer from alteration in their taste usually lose more weight than those who do not report changes in their taste (Bolze, Fosmire et al., 1982).
1.7.6. Flavours
The term ‘flavour’ refers to a complex combination of taste, smell, texture, appearance and temperature. It is usually used to describe the taste of any particular food or drink and the chemical sensation perceived by a person when something is put in the mouth (Sohi, Sultana et al., 2004). As previously mentioned, there are five basic different distinguishable taste sensations known: sweet, salty, sour and bitter, and umami (Tomita & Ikeda, 2002).
1.7.6.1 Flavours that elicit the five basic taste modalities Flavour perception is a process in which the nose and the mouth work together in a relatively speed mechanism with little cognitive effort. Flavour is mediated through two sensations, oral chemoreception “taste” and nasal chemoreception “smell” (Figure 1-2).
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Figure 1-2 Schematic of the anatomical systems mediating perception of flavours (Lawless, 1996)
There are three different but interrelated factors; taste, flavour and food hedonics, that contribute to the overall eating and drinking experience. There is a need for a better understanding of each of these three factors to figure out the changes that may occur in any of these factors and eventually lead to taste changes that are experienced by cancer patients. (Bartoshuk, 1990).
• Taste refers to the feeling perceived when certain chemicals stimulate the taste receptors which are present in the tongue, soft palate and oropharyngeal region within the oral cavity. The taste perception is recognized by five taste modalities: sweet, salty, sour, bitter and umami (savoury) (Breslin et al., 2008). • The perception of flavour is somewhat complicated, and it is worth mentioning that taste is one of many other components of flavour. In addition to the senses of taste and smell, flavour is affected by other physical factors such as temperature and texture as well as by other perceptual and cognitive factors (Delwiche, 2004; Prescott, 1999). • Food hedonics refers to the psychological determination of the extent of pleasure or displeasure that is provided by eating and drinking and it is an independent component of the eating and drinking processes (Kahneman, Diener et al., 1999).
There are distinct differences between these three factors. However, healthcare providers and patients still use the terms “taste” and “flavour” interchangeably or use the word “taste” to express their hedonic attitude to food (Boltong, Keast et al., 2011).
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Most food flavours are present as complex mixtures that partially mask one another. The sweet taste of sucrose is reduced when bitter quinine is present and vice versa (holding concentration constant) (Bartoshuk, 1975). However, there are some exceptions to the suppression rule. Small concentrations of NaCl increase the sweetness of sucrose may be due to an intrinsic sweet taste of NaCl (Bartoshuk, Murphy et al., 1978). Mixtures of monosodium glutamate and 5’ ribonucleotides, have highly enhanced potent umami flavours compared to their individually tasted components (Lawless, 1996).
• Sweet taste is produced by the addition of sugars such as sucrose, which is mainly extracted from sugar cane and sugar beet. Sugar is usually added to pharmaceutical products to increase its palatability (Spillane, 2006). Polyols can also impart a sweet taste, and most polyols, e.g. erythritol, sorbitol, xylitol and mannitol, are naturally occurring in plants. Lactitol, isomalt and hydrogenated starch hydrolyzate (HSH) are synthetic substances that are not found in nature; their sweetness is close to that of sucrose but without cariogenicity which is caused by sugars. There are 11 low-calorie sweeteners approved for use around the world: acesulfame-K, alitame, aspartame, aspartame-acesulfame salt, cyclamate, neohesperidin dihydrochalcone (NHDC), neotame, saccharin, stevioside, sucralose and thaumatin. Other sugars, produced by starch hydrolysis, are used as sweeteners, including: fructose, galactose, glucose, isomaltulose, lactose, lactulose, leucrose, maltose, sorbose, tagatose, and trehalose. Fructose and sucrose have the highest sweet taste (Spillane, 2006). • Salty taste can be brought by the addition of different types of salts such as NaCl (Breslin & Beauchamp, 1995). • Sour taste can be brought by the addition of different types of acids such as acetic acid, HCL, citric acid, lactic acid, malic acid and tartaric acid (Breslin et al., 1995).
• Bitter taste can be brought by the addition of quinine HCL, quinine SO4 and caffeine (Breslin et
al., 1995). In the present study we do not need to add bitterness because the taste of pilocarpine itself is bitter and we need to mask its bitter taste in order to increase its palatability. • Umami taste which is also known as a savoury taste is present in a wide variety of foods such as soy sauce, parmesan and other pungent cheeses, seaweed, anchovies, smoked fish, tomatoes and tomato sauce, bacon and other smoked meat, Meat and fowl stock, mushrooms and wine. It is produced in food by the addition of some Asian condiments such as Disodium Inosinate (IMP), Disodium Gyanylate (GMP), L-glutamate, Disodium Adenylate (AMP), and Mono Sodium Glutamate (MSG) (Taylor & Hort, 2007). It is important to mention that recently umami flavour was found to be the most potent taste modality that stimulates saliva production followed by sour taste (Sasano, Satoh-Kuriwada et al., 2010).
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1.7.6.2. Flavours that are disliked/preferred by post radiation HNC patients or patients receiving chemotherapy. Cancer patients usually have decreased palatability and develop food aversions for certain kinds of food such as meat, coffee and chocolate (DeWys, 1970; DeWys, 1974). As result of this, patients don’t get enough food to meet their nutritional requirements (Morrison, 1973). This bad nutrition as a result of inadequate food intake is reflected in decreased tolerance to chemotherapy or reduction in the beneficial effects of chemotherapy received by cancer patients (Copeland, Daly et al., 1977).
Comparisons between cancer patients and healthy volunteers have been done regarding the threshold of the four basic taste modalities (Carson & Gormican, 1977; DeWys et al., 1975). The recognition thresholds for the cancer patients’ vs the healthy control group was found to be:
• Increased for salt taste modality (Carson et al., 1977). • Decreased for sour taste modality according to (Williams & Cohen, 1978), but increased according to (Henkin, 1977). • Increased for sweet taste modality (DeWys et al., 1975; Gorshein, 1977; Henkin, 1977). • Decreased for bitter taste modality according to (DeWys et al., 1975; Gorshein, 1977), but increased according to (Henkin, 1977).
A more recent study with a group of 30 HNC patients during radiotherapy included umami as well as the four basic taste modalities. It showed that the thresholds for sweet, salty, sour and bitter tastes were slightly increased during treatment but no statistical difference was found between the threshold before radiotherapy and that at radiation doses of 15, 30, 45 and 60 Gy in any taste quality. However, the threshold for umami taste was significantly impaired at a dose of 30 Gy and remained so for the following increased doses (45 and 60 Gy) (Shi et al., 2004).
In 2014, an important study was done to investigate taste dysfunction and eating behaviours in survivors of head and neck cancer treatment. The study group comprised of 88 survivors who were treated for advanced cancer in the head and neck area by different combined remedies (surgery, radiation, surgery and radiation, radiation and chemotherapy, or the three of them together). For most of the participants, more than two years had elapsed since the last treatment. The results of this study included that less than 7% of the subjects ate more sweet foods whereas, 13.7% of them preferred to eat fewer sweet foods. Regarding salty foods, about 20% of the subjects ate fewer salty foods. However, 11.4% of the participants reported using more table salt to flavour their food. No subject reported eating more sour foods, instead 16% of them ate fewer sour foods. Ten percent of the subjects reported drinking less coffee or tea (bitter beverages) or used to sweeten these beverages since completing treatment (McLaughlin, 2014). 41
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Overall, according to the above given information no clear statement can be made on the perceived bitter taste intensity among HNC patients, as some studies showed that the threshold for bitter taste among those who were not receiving any treatment at the time of the study was decreased (DeWys et al., 1975; Gorshein, 1977) while others (Henkin, 1977) showed that the threshold of bitter taste increased. If only cancer patients receiving radiotherapy for head and neck are considered, the study by Shi et al. (2004) found the threshold for bitter taste increased. This means that they need a higher concentration for recognition of the perceived bitter taste, thus they may notice the bitterness of pilocarpine less than healthy subjects. As far as we know there is no literature to inform this study about preferences for pharmaceutical flavourings among people with dry mouth. So for our present study we are not able to make any assumptions based on the literature regarding whether people will or will not complain of the bitter taste of pilocarpine.
1.7.6.3. Modifying the taste of pilocarpine and bitter eliciting active ingredients Bitter taste is perceived when bitter compounds interact with receptors within the foliate circumvallate papillae of the tongue. (Hoon, Adler et al., 1999). Within these two papillae there are hundreds of taste buds that contain taste receptor cells (TRCs), which for bitter taste includes the transmembrane G-protein coupled receptor family, TAS2Rs (Chandrashekar, Mueller et al., 2000).
The food industry proposes several methods to mask or suppress the bitter taste elicited by functional products. These methods include the use of either sweet, salty or umami tasting compounds as well as odorants or textures to mask the perceived bitter taste. Additionally, bitter inhibiting compounds are used in the food and pharmaceutical industries (Gaudette & Pickering, 2013).
1.7.7. Bitter-masking tastes and others
Sweet taste In 1990, Calvino et al. found that the addition of sucrose suppressed the bitter taste of caffeine and upon increasing the concentrations of added sucrose, corresponding decreases in perceived bitterness intensity was noticed (Calvino, Garcia-Medina et al., 1990). Conversely, upon increasing the caffeine concentrations the sweetness produced by sucrose addition is suppressed (Calvino et al., 1990). Although, bitterness and sweetness have the property of mutual suppression the relationship depends upon concentration, as low concentrations of sweet tasting compounds will not essentially suppress the low concentration of bitter eliciting compounds (Keast, 2003; Keast & Breslin, 2003).
Non-caloric sweeteners are intensely sweet, as aspartame and sucralose are 200 and 500-750 times sweeter than sucrose, respectively (Wiet & Beyts, 1992). Some sweeteners can be used to suppress the bitter taste of pharmaceuticals such as aspartame and sucralose (Suzuki, Onishi et al., 2004), as
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CHAPTER 1 in suppressing the bitterness of quinine (Nakamura, Tanigake et al., 2002), but high concentrations of these sweeteners can produce a bitter aftertaste (Ott, Edwards et al., 1991). Thus, care should be taken upon using such sweeteners in creating new products.
Sweet eliciting compounds are extensively used for their known ability to suppress perceived bitterness. However, many traditional sweeteners such as sucrose may become less preferred in food industry because of their high caloric value and their role in tooth decay. Also, non-caloric sweeteners may be considered as unnatural or synthetic sweeteners by the consumers. Therefore, naturally derived plant sweeteners or any other natural sweeteners with minimal side effects can replace the other sweeteners (Ley, 2008).
Salty taste Studies have shown that salts can be able to suppress the perceived bitterness of some compounds (Breslin et al., 1995; Keast & Breslin, 2002). While both sodium and lithium ions can suppress bitterness (Breslin et al., 1995; Keast et al., 2002), sodium was found to be the best cation in suppressing a number of bitter oral pharmaceutical products (Keast et al., 2002). In a binary mixture of sucrose and urea (a complex sweet-bitter mixture) the addition of sodium acetate salt increases the perceived sweetness while decreasing the bitterness of the mixture (Breslin et al., 1995). It is known that bitterness suppresses sweetness but sodium acetate addition in the previously mentioned mixture was thought to release this suppression allowing the sweet taste to be perceived (Breslin et al., 1995).
The mechanism of action of sodium in its salts may be to do with modulating ion channels and pumps, stabilising the cell membrane, blocking TAS2Rs or interacting with secondary messenger systems within TRCs (Keast et al., 2002).
Although sodium salts were proven to be effective in reducing the bitterness of many compounds, practically the use of such salts become less preferred in food industry as there is a strong push to decrease the salt content of food due to its negative effects on health (Sacks, Svetkey et al., 2001).
Umami taste Is also known as a “savoury” taste equality and it is produced by glutamate-containing anion salts, the most important of them is monosodium glutamate (MSG) (Loliger, 2000) and also adenosine monophosphate sodium and disodium salts (NaAMP, Na2AMP) (Keast et al., 2002; Keast, Canty et al., 2004). Umami tastants were found to elicit bitter inhibiting capacity on various bitterants. At concentrations above the threshold, MSG was found to inhibit the bitter taste of quinine sulfate although at threshold concentrations of MSG no inhibition of the bitter taste of quinine was noticed (Kemp & Beauchamp, 1994). NaAMP was shown to decrease the bitterness of a number of oral pharmaceuticals such as ranitidine, acetaminophen, pseudoephedrine, quinine and urea (Keast et al., 43
CHAPTER 1
2002). One hundred mM of NaAMP reduced the bitter taste intensity by 65% across all oral pharmaceutical products (Keast et al., 2002). Similar results were also achieved by the addition of MSG. However, other anion salts such as chlorine, gluconate and salicylate are not good in inhibiting bitter taste of pharmaceuticals compared to MSG and NaAMP (Gaudette et al., 2013).
The mechanism of action of MSG may be due to oral peripheral rather than a central cognitive effect
(Keast et al., 2003). The mechanism by which NaAMP/ Na2AMP impart their bitter inhibiting capacity is unknown but it is believed to be similar to that of MSG as they have the same transduction pathway (Keast et al., 2002). Additionally, bitter masking activity due to the presence of sodium would be significant and thus it is possible that AMP has only a minimal participation in this bitter masking function.
There is conflicting information regarding the safety of MSG on human health. Nakanishi et al., suggested that the use of MSG may lead to negative health effects (Nakanishi, Tsuneyama et al., 2008), while the use of glutamate salts in food has been reported to be safe for the general human population (Beyreuther, Biesalski et al., 2007). Overall, high doses of MSG might cause adverse symptoms in some people who have a particular sensitivity, but in moderate amounts it is unlikely to cause any problems.
Texture There is some evidence that increasing the viscosity of aqueous solutions may impart textural cues that are capable of reducing the bitterness intensity. The bitterness of caffeine was decreased by about 60% when stimuli are presented in a gelatine matrix compared with water only (Calviño, García- Medina et al., 1993). In this study also, there was a trend of decreased bitter perception intensity in a carboxymethyl cellulose (CMC) matrix compared with water. A number of hydrocolloids have been tested for their bitter inhibiting activity such as hydroxypropyl cellulose, low-viscosity CMC (CMC- L), medium viscosity CMC (CMC-M), sodium alginate and xanthan gum (Pangborn, Trabue et al., 1973). Of these, CMC-L, sodium alginate and xanthan gum are the most effective in reducing the bitterness of caffeine (0.46-3.7Χ10-3 M) (Pangborn et al., 1973). In a similar study the use of these three mentioned hydrocolloids at an increasing intensity to bitter beverages leads to noticeable reduction in caffeine bitterness especially for CMC-L (about 54% bitterness reduction) (Pangborn, Gibbs et al., 1978).
The inhibition of bitterness depends both on the concentration of the hydrocolloid used and the type of bitterant present. This is explained in a study in which CMC-M was found to decrease the bitterness of caffeine and coffee when a series of increasing intensities of CMC-M were used (Pangborn et al.,
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1978). Interestingly, CMC-M does not change the taste intensity of caffeine (Pangborn et al., 1973) or the bitterness of grape seed tannin (Smith, June et al., 1996).
The use of texture modifying compounds to decrease the perceived bitterness may be of particular importance in the formation of functional beverages. Naturally occurring gums of plant origin have an added function of providing a source of a dietary fibre beside their main function in reducing bitterness thus increasing the nutritional value of the product to which they are added. However, the use of such compounds requires the optimization of the gum type as well as the concentration of the ingredient being used as for example CMC-M does not reduce the bitterness produced by grape-seed polyphenolics (Smith et al., 1996).
Odorants When an odorant is added to a solution the intensity of the taste is either enhanced or suppressed (Delwiche, 2004). Enhancement of odour-induced taste is more likely to occur when the odour and the taste are cognitively related to each other. For instance, when strawberry odour is added to a sucrose solution, intensity of sweetness is received to be higher than that produced by sucrose solution alone. A mixture of strawberry odour with NaCl solution does not increase perceived salt taste (Frank & Byram, 1988).
Many studies have shown the effect of odorants on the perception of sweet, salty, sour and umami tastes. However, only a few studies only explored the association with bitter taste. The odours of coffee and chocolate were found to increase the bitterness of caffeine in fat-free milk by 17% and 32% respectively (Keast, 2008) and cocoa flavour significantly increased the perceived bitterness of cocoa beverages when compared to cocoa beverages without cocoa flavouring (Labbe, Damevin et al., 2006). These findings are not surprising as bitterness is cognitively associated with these odours and flavours. However, in the latter study the addition of vanilla flavour, which is associated with sweetness, was found to increase the perception of sweet taste but did not affect the bitter taste intensity. Moreover, the addition of vanilla flavour to bitter milk beverages increased perceived bitterness, suggesting that previous food preferences and/or neophobia (extreme or irrational fear or dislike of anything new or unfamiliar) should be taken into consideration when adopting strategies for modifying bitterness by the use of odorants and flavours (Gaudette et al., 2013).
1.7.8. Bitter–inhibiting compounds
In addition to the previously mentioned traditional techniques used nowadays to modify bitter taste, bitter inhibiting compounds or “bitter blockers” are now used as they act to decrease the perceived bitterness by complexation with the bitterant or encapsulation of it. They interact with bitter binding
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CHAPTER 1 sites on TRCs or may interfere with taste transduction mechanisms from mouth to brain (Gaudette et al., 2013; Walsh, Cram et al., 2014). There is a number of bitter blockers that are currently in use in food and pharmaceutical industries.
BitterDB, is a free, easily searchable database that includes information about more than 550 bitter compounds as previously documented in the literature and their associated human bitter taste receptors. At least 25 bitter taste receptors are identified nowadays and they exhibit great diversity in their genetic properties and this explains the different sensation to bitter tastes within the population (Walsh et al., 2014). The information about each bitter compound in BitterDB includes its molecular properties, references for the bitterness category (e.g. a ‘bitter-sweet’ or ‘slightly bitter’), whether the compound is a natural product or a synthetic one and the effective concentration for receptor activation (Wiener, Shudler et al., 2012).
A. Cyclodextrins
Cyclodextrins (CDs) are cyclic oligosaccharides (Gaudette et al., 2013) with a hydrophobic cavity and hydrophilic exterior shell (Szejtli & Szente, 2005). The bitter chemical interacts with the inside of the CD forming an inclusion complex (Szejtli, 1990). As a result, the bitter eliciting compounds are complexed within the CD molecule, rendering them unable to bind to TRCs leading to reduction in the perceived bitterness.
β–CD is the most commonly used CD because they have lower production cost and increased efficiency in bitterness reduction compared to the other types (Szejtli, 1990). Also they have ‘generally recognized as safe’ status with the US FDA, so they are especially attractive as bitter blockers for use in food industry (Szente & Szejtli, 2004). β–CDs have been successfully used to reduce bitterness in a wide variety of food products such as citrus juice (Konno, Misaki et al., 1982). Also they were used to remove limonin and naringin from aqueous solutions where addition of 0.5% β–CD to these aqueous solutions yielded a total reduction in bitterness intensity by about 50% (Konno et al., 1982). At higher concentrations, β–CD can impart sweetness to the product to which they are added (Gaudette et al., 2013). ß-CD is not very water soluble, hence it is the water-soluble derivatives such as hydroxypropyl ß-cyclodextrin that are much more water soluble and are preferred for use in aqueous pharmaceutical solutions (Saokham, Muankaew. et al., 2018).
B. Riboflavin-binding protein
Riboflavin-binding protein (RBP), present in chicken eggs, transfers and stores riboflavin (vitamin
B2) thus providing essential nutrients for the growth of the chick embryo (Croguennec, Guérin- Dubiard et al., 2007). RBP is a potent bitter blocker and is used to decrease the bitterness intensity in
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CHAPTER 1 a number of compounds such as naringin, denatonium, caffeine, theobromine, glycl-L-phenylalanine and quinine hydrochloride (Maehashi, Matano et al., 2008).
RBP exerts its action by more than one mechanism, as it decreases the bitterness of quinine hydrochloride through hydrophobic interaction, while it suppresses other bitterants via competition for sites on bitter taste receptors (Maehashi et al., 2008). Also it selectively inhibits the sweetness of some proteins while it has no effect on the sweetness of other sweeteners (Maehashi, Matano et al., 2007). It suitable for use in functional foods, where the sweetness of commonly used sweeteners would remain while suppressing perceived bitterness (Keast, 2003; Keast et al., 2003).
C. Neodiosmin
Neodiosmin is a glycosylated flavone found in citrus fruit (Del Rio, Benavente et al., 1992). It is derived from the bitter flavonone neohesperidin. At low concentrations of neodiosmin it has no taste or odour (Guadagni, Maier et al., 1976). A maximum concentration of neodiosmin up to 40 ppm was found to be tasteless (Guadagni et al., 1976) and at lower concentrations it efficiently reduces the bitterness of various bitterants thus it can be an attractive addition in food formulations (Gaudette et al., 2013).
D. Zinc salts
Zinc salts such as zinc lactate and zinc sulphate have a low molecular weight and are able to significantly reduce the bitterness of many compounds including caffeine, quinine hydrochloride, tetralone and denatonium benzoate (Keast & Breslin, 2005). Twenty five mM of zinc sulphate can suppress the bitterness of a wide range of quinine hydrochloride concentrations (0.04-0.4 mM) by 70% (Keast, 2003). Zinc sulphate may alter the integrity of TAS2R receptors, hindering them from functioning normally through interaction with specific amino acids (serine and threonine) on the extracellular portion of these bitter taste receptors (Keast, 2003).
Zinc sulphate salt also has the ability to decrease the sweetness intensity of a variety of sweeteners (> 70% reduction in taste) commonly used in the food industry as sucrose, glucose and fructose (Keast, 2003; Keast et al., 2005). This dual ability of suppressing both bitter and sweet tastes may not be required in the food industry if sweet taste would like to be imparted (Keast, 2003; Keast et al., 2003). Thus, it can be useful in formulations with savoury taste. The use of zinc sulphate as a bitter suppressant could be useful for populations with zinc deficiency and may add an additional therapeutic value to the use of zinc sulphate in functional foods (Salgueiro, Zubillaga et al., 2002).
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E. Magnesium sulphate
Magnesium sulphate was found to decrease the bitterness of quinine hydrochloride by about 52% without altering the perception of the other basic taste qualities (Keast, 2003) thus it may preferred as a bitter suppressant more than zinc sulphate. Magnesium sulphate should be used in a concentration less than 0.025 M to decrease the bitterness of functional ingredients otherwise in concentrations more than 0.025 M magnesium sulphate can elicit other taste qualities such as sour and salty (Delwiche, Buletic et al., 2001)
F. Fatty acids
It has been suggested that fatty acids may affect bitter taste perception by acting as a mouth coat or as a physical barrier between the bitter tastants and TRCs thereby decreasing the overall perceived taste intensity (Lynch, Liu et al., 1993). On the other hand, lipids may increase the concentration of non-polar compounds in the water phase leading to increased intensity of the perceived taste (Yamamoto & Nakabayashi, 1999).
G. Lecithin and lecithin-like compounds
Formulations with a large excess of lecithin or lecithin-like compounds are assumed to have the potential of controlling bitter taste in pharmaceutical industry. Homogenated suspensions of phosphatidic acid and β- lacto globulin from soybeans and milk, respectively, completely suppress the bitter taste of quinine, L-leucine, iso-leucine, caffeine and papavarine HCl without affecting sour, sweet or salty taste qualities (Sohi et al., 2004).
H. Proteins, gelatins and prolamines (zein)
Different forms of proteins have been used widely for masking of unpleasant tastes. Prolamine constitutes the main protein ingredients of cereal grains and flour. Most important prolamines are zein, gliadin and hordein. Different types of antibiotics, vitamins, dietary fibres, analgesics, enzymes and hormones have been effectively taste masked using prolamine coatings. The masking of taste is effective over a long period of time and does not affect the immediate bioavailability of the active substance (Sohi et al., 2004). In mint flavoured oral pharmaceutical gums, the use of prolamine/ cellulose ingredient of high pH can reduce the perceived bitter taste of flavour (Patel, Broderick et al., 1901).
1.7.9. Taste of other components being added in the oral formulation
Many researchers have used the commercially available eye drops formulations of pilocarpine to conduct their studies. In these studies, the patients were instructed to use such eye drops as mouth
48
CHAPTER 1 washes in which the patient is to gargle his mouth with a specified volume of this eye drops for 1-2 minutes. After gargling, the patient either spit the residue out (Kim et al., 2014) or swallow it (Joensuu et al., 1993; Mercadante et al., 2000; Singhal et al., 1997).
These commercially available eye drops also contain other ingredients such as buffers and preservatives that may impart additional bitterness to the whole product and as such when used as eye drops, the concern of bitter taste will not matter. However, in such cases when these ophthalmic preparations are intended to be taken orally, one should consider its taste before being used in any study to assure good patient compliance as a function of enhanced palatability of the prepared formula.
Benzalkonium chloride is an antimicrobial agent with bactericidal activity that is used as a preservative in many formulations including alcohol-free mouthwashes (Thompson, 1991). It will impart a bitter taste to the whole formulation thus a sweetener may be added to mask this bitterness.
Other mouthwashes may contain Poloxamer 407 as a gelling agent to increase the consistency of the formulated mouthwashes (Mikhail, 1980). As poloxamer concentration increases, gelation occurs at lower temperature and the viscosities of the resultant products increases at any given temperature. Poloxamers are principally available in the registered trademark of Pluronic F127® (Dumortier, Grossiord et al., 2006). Poloxamers have been tested as vehicles for topical applications and appear to be useful as controlled delivery systems. Besides, Poloxamer 407 have a nonspecific bio adhesive capacity that prevents the adherence of bacteria and thus it exhibits an antibacterial action (Veyries, Couarraze et al., 1999).
In some oral preparations such as mouthwashes, parabens are added as they act as antimicrobial preservatives (Frederiksen, Jorgensen et al., 2011). Parabens in general have many benefits; they are considered safe with low toxicity, have no taste or odour and are relatively low cost to use (Soni, Carabin et al., 2005). The most commonly used parabens are methylparaben (MeP), ethylparaben (EtP), n-propylparaben (n-PrP), iso-propylparaben (i-PrP), n-butylparaben (n-BuP), iso-butylparaben (i-BuP) and benzylparaben (BzP), and to increase the activity against microbial contamination in the product, different parabens may be used in combination (Andersen, 2008).
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1.8. Research plan
1.8.1. Research rationale
The need to develop more effective sialogogues and saliva subsitutes has long been recognised (National Institutes of Health, 1989). Xerostomia is underrecognised and causes major reduction in quality of life for those who suffer from it. Treatment options are limited. This is particularly the case in Australia, where there is no commercial pilocarpine product available on the market. Pilocarpine is a well known sialogogue that has been used clinically for this purpose in many countries for many years. A 5 mg tablet is available in at least 24 countries for the treatment of dry mouth, including the USA, Canada, the UK, and a wide range of countries across Europe, South America and Asia. In Australia, the only way to access pilocarpine is by having it compounded by a pharmacy in response to a prescription from a medical practitioner. Therefore, this study focuses on the use of dosage forms that can be easily compounded in pharmacies.
Many trials have been conducted to investigate the efficacy of oral pilocarpine for treatment of xerostomia, most of which showed that systemic delivery of pilocarpine is associated with side effects. This was usually the primary cause for participants to drop out of the studies. The concept of delivering pilocarpine locally to oral mucosa as a means to reduce side effects has been around for over 35 years, as a patent was filed in the USA relating to pilocarpine mouthwash for relief of dry mouth (Mikhail, 1980). A small number of trials have been conducted to investigate the effect of pilocarpine in the alleviation of xerostomia using formulations aimed at mucosal absorption in the mouth rather than systemic absorption from the gastrointestinal tract (GIT). The formulations of pilocarpine were pastilles, lozenges, buccal inserts, mouthwashes and eye drops to be taken by mouth (Bernardi et al., 2002; Gibson et al., 2007; Hamlar et al., 1996; Kim et al., 2014; Nikles, Mitchell et al., 2013; Rupel et al., 2014; Tanigawa et al., 2015; Taweechaisupapong et al., 2006).
Mouthwashes designed to be gargled and then spat out of the mouth were quite variable in terms of effective dose reported with all of the following resulting in a significant increase in salivary flow: gargling with 10 ml of 0.1% (10 mg) for 1 minute (Kim et al., 2014), rinsing with 2.5 ml of 2% (50 mg) for 5 minutes (Rupel et al., 2014) and rinsing with 1% or 2% (100 mg or 200 mg) mouthwash for 1 minute (Bernardi et al., 2002). Even holding 0.01% pilocarpine in the mouth for 2 minutes as often as needed to a maximum of 150 ml (15 mg) per day caused a statistically significant increase in saliva production (0.83±0.12 mL/min one month after treatment versus 0.71 ± 0.14 mL/min before treatment (Tanigawa et al., 2015). A critical drawback with the use of the mouthwashes is that most of the dose is spat out after gargling in the mouth, so a suitable dose for a mouthwash is unclear.
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In some studies mouthwashes or eye drops were gargled in the mouth and then swallowed, so the dose consumed was known which in most cases was 5 mg to be taken three times daily. The dose used was effective both in terms of objective and subjective dry mouth improvement. The majority of the mouthwash formulations used in the trials were simply drug dissolved in water or diluted eyedrops (Joensuu et al., 1993; Jorkjend et al., 2008; Nikles et al., 2015; Sung et al., 2005), which are bitter in taste, and would need to have appropriate preservative concentration and flavouring to be useful in a clinical setting. Buccal inserts are not appropriate for compounding in local community pharmacies and are not suitable for all people, especially those who wore dentures and those with no or little saliva production (Gibson et al., 2007). For these reasons, eye drops to be administered orally, mouthwashes and buccal inserts were excluded as potential buccal products for testing pilocarpine efficay.
Lozenges can be compounded in many community pharmacies in Australia. Both publications that tested a lozenge or pastille indicated that the 5 mg pilocarpine formulation is optimal in terms of effect on xerostomia and limiting side effects (Hamlar et al., 1996; Taweechaisupapong et al., 2006). Thus the dose of pilocarpine that should be incorporated in a lozenge appears likely to be 5 mg. Orally dissolving tablets (ODTs), also referred to as rapidly dissolving tablets (RDTs) are a relatively new oromucosal dosage form and while it hasn’t been previously researched with pilocarpine, it has received interest for delivery of a variety of medications (Bhanja, Hardel et al., 2012; Comoglu, Inal et al., 2015; Kasgavade & Swapnil, 2016). Some community pharmacies in Australia have the facilities to prepare ODTs. Therefore, lozenges and ODTs were selected for investigation in this thesis.
In terms of the flavours that were used in the previously investigated buccal pilocarpine formulations, only two studies mentioned the use of flavours in order to disguise the bitterness of pilocarpine (Hamlar et al., 1996; Nikles et al., 2015). Patients enjoyed the butterscotch flavoured lozenges in the first study whlist the citrus flavour was not effective in masking the bitter taste of pilocarpine eye drops used in the second study. Thus effective masking of the bitter taste of pilocarpine in the buccally delivered preparations that will be compounded is strongly required, followed by a clinical trial to evaluate the effectiveness of these flavoured preparations in the treatment of xerostomia, their effect on saliva production, subjective feelings of symptoms (including dry mouth) and quality of life measures.
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1.8.2. Aims and objectives
The aim of this thesis is to formulate an extemporaneously compounded preparation for the buccal delivery of pilocarpine and test the efficacy to treat dry mouth arising from different aetiologies.
Objectives a) Prepare potential pilocarpine formulations for buccal delivery to the salivary glands rather than for direct swallowing and systemic delivery, and establish stability of pilocarpine in these formulated products. The chosen formulations should be easily extemporaneously prepared in hospital or community compounding pharmacies (Chapter 2). b) Test the acceptability of the potential formulations in terms of dosage form and flavouring according to people with and without xerostomia (Chapter 3 and 4). The results of these chapters will determine the preferred formulation and flavour to take forward into clinical trials. c) Investigate the efficacy of the dosage form selected in Chapter 4, flavoured with the flavour selected by people with xerostomia and containing 5 mg pilocarpine, in the treatment of dry mouth (Chapter 5).
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CHAPTER 2
Chapter 2. Compounding and quality/stability testing of potential products for buccal delivery of pilocarpine
2.1. Introduction
This chapter describes the preparation of potential products for buccal delivery of pilocarpine, flavouring these formulations to disguise the bitter taste of pilocarpine, and testing the fomulated products for quality and stability. As the product must be suitable for compounding within a hospital or community compounding pharmacy, the range of dosage forms available for this purpose is restricted. Possible available dosage forms include capsules, tablets, lozenges (also known as troches) and lollipops (Falconer & Steadman, 2017). Tablets and capsules designed to be swallowed whole were excluded in order to focus on products that could deliver pilocarpine buccally. Pilocarpine has been previously formulated in the form of a buccal insert (Gibson et al., 2007), mouthwashes (Kim et al., 2014; Tanigawa et al., 2015), eye drops administered orally (Nikles et al., 2013), pastilles (Hamlar et al., 1996), lozenges (Taweechaisupapong et al., 2006) and chewing gum (Singh & Singh, 2003). The buccal inserts are not suitable for extemporaneous compounding in community compounding pharmacies. Also they are not suitable for those wearing dental dentures and those producing no or little saliva. The therapeutic dose of pilocarpine given via mouthwashes is unclear and difficult to determine, with a large proportion of it being wasted, and the eye drops when taken by mouth were not agreeable in taste. Chewing gum is not widely compounded in Australia, and the slow release of drug during extended chewing may not be appropriate for three-times daily dosing of pilocarpine. There is published evidence supporting the usefulness of pilocarpine pastilles and lozenges (Hamlar et al., 1996; Taweechaisupapong et al., 2006) for subjective relief of xerostomia and increasing saliva production. Based upon these results, lozenges were selected to be one of our investigated pilocarpine buccal formulations.
Lozenges are topically flavoured medicated dosage forms intended to be sucked and held in the mouth (Pattanayak & Das, 2012). Lozenges are also defined as solid dosage forms of various shapes, usually can contain one or more active drugs in a flavoured sweetened base as it will be slowly sucked and dissolved in the mouth and exert its effect first locally in the oral cavity then systemically via absorption into the blood circulation (Allen, 1999; Majekodunmi, 2015). Lozenges, are also known as troches or pastilles. Pastilles are also known as confections as they generally have a soft texture and contain a high percentage of sugar, or a combination of sugar and gelatin and are either prepared by compression or moulding (Allen, 1999). Due to their local effects, they can be used for the treatment of local irritation or infection of mouth or pharynx or for soothing and purging the throat
53 CHAPTER 2 and in some conditions used as cough sedative (Majekodunmi, 2015). Lozenges can also be used for systemic effects, being either absorbed buccally or after being swallowed into the gastro-intestinal tract (Firriolo, 1994).
In addition to lozenges, orally dissolving tablets (ODTs) were chosen as the second buccally delivered formualtion of pilocarpine in this chapter as they can easily be compounded and flavoured to mask the taste of the active drug. Additionally, they are the dosage form of choice particularly for people who have difficulty swallowing (Arora & Sethi, 2013) and hence will be suitable for our target population as dry mouth can lead to difficulty swallowing. Some community pharmacies in Australia have the facilities to prepare ODTs.
ODTs, also known as mouth dissolving/disintegrating tablets (MDTs) or rapidly dissolving tablets (RDTs) are a type of tablet that dissolve or disintegrate in the saliva within few seconds without the need of water (Kamalapurkar, Chitali et al., 2015). As the ODTs disintegrate when placed in the mouth, they instantly release the active ingredient which dissolves rapidly in the saliva. The buccal cavity offers an opportunity for direct systemic delivery of drugs formulated as ODTs. A portion of the active ingredients are absorbed through mucous membranes in the mouth and pregastric region of the gastrrointestinal tract, while the rest enters the stomach. Pregastric absorption is expected to avoid metabolism by the stomach acids and enzymes, so ODTs may increase the bioavailability of drugs in comparsion to conventional tablets (Hirani, Rathod et al., 2009). A number of different active ingredients have been formulated as ODTs. These include losartan potassium (Bhanja et al., 2012), amlodipine besylate (Sukhavasi & Kishore, 2012), ketoprofen (Comoglu et al., 2015), ciprofloxacin (Kasgavade et al., 2016), benzocaine (Köllmer, Popescu et al., 2013) and oxcarbazepine (Kamalapurkar et al., 2015). The concentration of active ingredient contained in the ODTs in these studies ranged from 5% to 50% depending upon ODT weight and the standard therapeutic dose of each drug used.
The literature identifies many studies, clinical trials and reviews that all stated that the effective standard dose of pilocarpine is 5 mg to be taken three times daily (Cheng et al., 2016). Based upon this information, the pilocarpine dose that was tested in this thesis is 5 mg. Two buccal pharmaceutical preparations were selected to be formulated and tested: lozenges and ODTs.
2.1.1. Lozenges
Lozenges are used for the treatment of minor sore throat pain and irritation of the oral cavity and have been used widely for the delivery of topical anesthetics and antibacterials (Allen, 1999). Additionally, wide range of medications are incorporated into lozenges including analgesics, anesthetics,
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There are many advantages to the use of lozenges:
• They can be used for some patients who have difficulty swallowing conventional oral dosage forms (Pundir et al., 2014). • They are economical and can be safe for use by geriatric and paediatric populations (Majekodunmi, 2015). • They can easily be taken by the patient without the need for water (Majekodunmi, 2015). • They are easy to manufacture and store (Pundir et al., 2014). • They can achieve higher bioavailability as any portion of the drug that is absorbed through the oral mucosa avoids first pass metabolism (Pundir et al., 2014).
However, some disadvantages to lozenges have been also noted in the literature:
• They are not suitable for use by patients who are unconscious, suffer from chronic vomiting or those who are not co-operative such as children and infants. • They are not suitable for use in case of gastrointestinal disorders such as diarrhoea, constipation, ulceration and gastric hyperacidity, or malabsorption syndrome where absorption through small intestine is not stable. • They are not suitable for medicines that can be destroyed or inactivated in the gastrointestinal tract. • Uneven distribution of the drug within saliva targeted for local effects and possible draining of the drug down into the stomach as the saliva goes down (Majekodunmi, 2015; Pundir et al., 2014).
Lozenges can be classified into various types based on composition and texture (Majekodunmi, 2015; Pundir et al., 2014).
a) Chewy or caramel based medicated lozenges (Pundir et al., 2014)
This type of lozenge involves the incorporation of the active drug into a caramel base, which is designed for chewing instead of dissolving in the mouth (Pundir et al., 2014). Most formulations are based upon the formula of glycerinated gelatin suppository, which is made mainly of glycerin, gelatin and water, and requires heating to melt the base prior to incorporation of the added ingredients. These lozenges usually contain fruit flavours that impart a slightly acidic taste to mask the strong taste of glycerin. They are made of a candy base (a mixture of sugar and corn syrup), whipping agent (to incorporate air in toffee-based confections to obtain the texture of soft chew), humectants (to improve 55
CHAPTER 2 chewing and mouth feel properties), lubricants (to avoid sticking of the candy to teeth upon chewing), flavour and active drug (35-40%).
b) Compressed tablet lozenges
This type is particularly suitable for heat sensitive drugs as they can be formulated into lozenges by compression (Peters, 1989). The granulation process is similar to that used for the preparation of compressed conventional tablets. However, the lozenge tablets differ in organoleptic characteristics, non-disintegrating properties and slower dissolution profile. This type of lozenge is usually made of a sugar vehicle such as dextrose or sucrose but can be made with a sugar-free vehicle such as mannitol, sorbitol, and polyethylene glycol (PEG) 6000 and 8000 (Majekodunmi, 2015). They also contain binders to hold the particles together (such as acacia, corn syrup, gelatin, polyvinyl-pyrrolidone, tragacanth and methyl cellulose), lubricants to enhance the flow of the final product (such as magnesium stearate, calcium stearate, stearic acid and PEG), and colours and flavours (Majekodunmi, 2015).
c) Hard candy lozenges
These are made of mixtures of sugar and other carbohydrates in a non-crystalline state and are also termed as solid syrups of sugars (Majekodunmi, 2015). The moisture content in them ranges from 0.5-1.5% and their weight usually ranges from 1.5-4.5 g. Ideally, they should undergo a uniform slow dissolution over 5-10 min without disintegration. Their manufacture usually involves the use of very high temperature and accordingly heat-sensitive ingredients are not good candidates for these lozenges. Hard candy lozenges are constituted of a base (corn syrup available on Baume basis), sweeteners (such as sucrose, dextrose, maltose and lactose), acidulents (such as citric, tartaric, fumaric and malic acids) are usually added to the base to strengthen the flavour of the final product, colours and flavours. Medicines can be incorporated in hard lozenges in a concentration up to 2-4% (Allen, 1999).
d) Soft lozenges or troches
These are meant either for chewing or sucking for slow drug release in the mouth, and are mixtures of sugar and other carbohydrates in a non-crystalline or a glassy state (Pundir et al., 2014). They can be prepared using either PEG 1000 or 1450, chocolate or sugar-acacia base while some soft candy formulations can also contain a mixture of both acacia and silica gel. Acacia is used to provide the appropriate texture and smoothness while silica gel is used as a suspending agent to prevent the settling of the mixture at the bottom of the mould during cooling. As the process involves heating the mixture up to 50°C, the temperature stability of components should be considered. Soft lozenges are usually prepared by pouring a melted mass into moulds. Examples of this type include: medicated 56
CHAPTER 2 lozenge for the treatment of dry mouth (Shah & Goodreau, 1997), ketoconazole lozenges for treatment of oral thrush in paediatric patients (Nagoba, Rao et al., 2011) and paracetamol lozenges for pediatric use (Pattanayak et al., 2012).
A common problem among patients with xerostomia resulting from reduced salivary production is the high incidence of dental caries. In radiation-induced xerostomia, the loss of the salivary function usually results in increased caries-forming bacteria in the oral cavity (Chambers, Artopoulou et al., 2007). The recommended measures for limiting this includes strict oral hygiene and limitation of cariogenic foods and sweeteners (Vissink, Burlage et al., 2003). Some researchers have incorporated non-cariogenic sweetening agents in the formulation of their tested lozenges such as non-cariogenic lozenge for the treatment of dry mouth (Grodberg, 1992) and sucrose-free lozenges of curcumin (Turmeric) (Achhra & Lalla, 2017).
Soft troches are a dosage form that can be readily compounded in pharmacies in Australia, and can be formulated to use non-cariogenic sweeteners, so this dosage form will be used in the present study.
2.1.2. Orally dissolving tablets
Orally dissolving tablets (ODTs) are a solid dosage form similar to conventional tablets but contains a superdisintegrant, a substance that aids in rapid disintegration of the tablets in the mouth without the need of water within a minute before swallowing (Arora et al., 2013). ODTs can be formulated with bitter-inhibiting agents that mask the bitter taste of the active ingredient (Siddiqui, Garg et al., 2010), which is favourable for pilocarpine use.
A number of advantages of ODTs are given in the literature. ODTs:
• Are suitable for use by patients who have difficulty swallowing (dysphagia) and those who refuse to swallow medicines whole such as: ▪ paediatrics, geriatrics and psychic patients (Wilson, Washington et al., 1987), ▪ patients suffering from strokes, renal failure and those who are bedridden (Fix, 1998), ▪ patients who are fear of risk of choking with the conventional tablets due to physical obstruction (Indurwade, Rajyaguru et al., 2002), ▪ patients with depression and are not able to swallow the conventional tablets and those with persistent nausea, patients who would like to change the regular oral dosage form used due to bitterness especially children under 10 years of age (Wilson et al., 1987), ▪ patients with schizophrenia who may hide the conventional tablet form under their tongue to skip doses and alter the daily treatment schedule (Siddiqui et al., 2010).
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• Achieve better bioavailability through rapid pregastric absorption of the drug in the mouth, pharynx and oesophagus before reaching the stomach as the saliva goes down and hence faster onset of action (Nand, Vashist et al., 2010). • Are a solid dosage form, with the benefits in terms of stability that the solid phase brings, that quickly converts to a liquid dosage form in the mouth (Nand et al., 2010). • Do not need water for swallowing as it instantly disintegrates in the mouth owing to the presence of the disintegrating agent, which eases ingress of water in its structure forming a porous matrix and facilitate swallowing. • Feels pleasant in the mouth due to the presence of taste masking agents as a component in its formulation with other flavours that mask the taste of bitter drugs. • Disintegrates into very small particles thus leaving minimal or no residue after administration. • Is cost effective as manufacture involves conventional production methods and equipment.
There are also some disadvantages noted in the literature that should be considered. ODTs:
• Are hygroscopic in nature (Arora et al., 2013) and must be kept in dry place (Nagar, Singh et al., 2011). • Require careful handling due to lack of mechanical strength and high friability (Chang, Xiaodi et al., 2000). • Are suitable only for incorporation of small amount of the drug per each dose (Arora et al., 2013) and so formulation of drugs with large doses (e.g. rifampicin 600 mg and ethambutol 1000 mg) in the form of ODTs is difficult (Siddiqui et al., 2010) . • Require special packing for proper stability of the final product (Nagar et al., 2011). • If not well formulated, the tablets may leave an unpleasant taste and/or grittiness in the mouth (Chang et al., 2000).
For this study, the direct compression method was used for the production of pilocarpine ODTs because it included the use of standard equipment that is available for compounding ODTs in hospitals and local community compounding pharmacies. This method is the simplest as the ingredients together with the active drug are mixed and then compressed directly in moulds and has been used for the formulation of many drugs, such as epinephrine bitartrate, ibuprofen, indomethacin, naproxen, diclofenac, ondansetron, fexofenadine, olanzapine, donepezil and chlorpromazine hydrochloride (Arora et al., 2013; Siddiqui et al., 2010). Other methods for ODT production include a cotton candy process (involves the formation of a polysaccharide matrix by simultaneous action of flash melting and spinning, then milling of the candy floss matrix and mixing with active ingredients and excipients after re-crystallization and subsequently compressing to ODT), and nanonization 58
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(involves size reduction of drug to nanosize by grinding the drug using a proprietary wet-milling technique, stabilizing of the nanocrystals of the drug against agglomeration by surface adsorption on selected stabilizers, which are then incorporated into ODTs). Several technologies for ODT production have been designed and patented by many pharmaceutical industries such as Zydis, Orasolv, Durasolv, Flashdose, Flashtab, Wow tab, Oraquick and Ziplet (Nagar et al., 2011; Siddiqui et al., 2010).
2.2. Materials and methods
2.2.1. Chemicals
• Powders: Powders were purchased from Medisca (Sydney, Australia). This included pilocarpine hydrochloride USP, troche base, Medi RDT base, stevia (stevioside), bitterness reducing agent (NF01) (Natural), raspberry powder flavour, lemon powder flavour, chocolate powder flavour, mint powder flavour. Nicotinamide was used as the internal standard for RP- HPLC analysis and was from Sigma-Aldrich (St. Louis, MO) and sodium hydroxide from Chem-Supply (South Australia, Australia). • Liquids: Methanol of HPLC grade, ethanol of HPLC grade, and phosphoric acid (85%-90%) were from Merck (Darmstadt, Germany), triethylamine (TEA; pro-analysis) and formic acid 99% were from Ajax Finechem (Sydney, Australia) and ammonium hydroxide (28%-30%) was from Sigma-Aldrich (St. Louis, MO). Raspberry liquid flavour from Medisca. The water was from a Milli-Q system (Millipore, Billerica, MA). • Materials: Medi-RDT KIT which includes: Medi-RDT Mold (96 × 750mg Cavities), Medi- RDT Blister Pack (20 Cavities w/Cold Seal & Sleeve, 160 Doses), 1 Hot Hand® Protector, Sieve & Receiver Pan (50 Mesh) and Powder Scraper. Medi-RDT KIT was purchased from Medisca.
2.2.2. Instrumentation
• Conthern Thermotec 2000 Oven (Thermo Fischer Scientific, QLD). • Tablet Hardness Tester, TBH 125 (Erweka; Germany). • TAR (friability/abrasion tester) (Erweka; Germany). • Solid phase BCX Extraction Columns CLEAN-UP ®, CUBCX15Z from United Chemical Technologies, Inc. (Bristol, PA). • Disintegration tester ZTX20 (Erweka; Germany). • IKA RCT Basic hot plate magnetic stirrer (Merck, Australia).
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• pH meter from METTLER TOLEDO (Victoria, Australia). • Digital weight balance scale (Analytical balances AES-C / AEJ-CM) from Lab Friend (Australia). • An Agilent Technologies 1260 series HPLC system (Agilent Technologies, Boeblingen, Germany) with a quaternary pump, degasser, an auto sampler, a thermostat column compartment, and a diode array detector.
2.2.3. Experimental design
Two raspberry flavoured buccal formulations of pilocarpine were prepared, lozenges and ODTs. One batch of lozenges (30 lozenges) and one batch of ODTs (60 ODTs) were subjected to quality assessments. The quality assessments were conducted over a period of 2 weeks after preparation, during which the troches were stored in plastic troche packs and the ODTs were stored in cold-seal blister packs at normal room temperature and relative humidity.
Stability was assessed using two storage environments: 20ºC/57% RH and 36ºC/39% RH. Three replicate batches of each dosage form were prepared separately to ensure true replication. The troches were stored in troche packs that were closed and placed inside card dispensing sleeves. ODTs were packaged into cold-seal blister packs that were placed inside card dispensing boxes. ODTs and troches were assessed during storage for up to 18 months for pilocarpine concentration, variation in weight, diameter and thickness.
2.2.4. Formulation of 5 mg pilocarpine troches
A theoretical formula for the preparation of 5 mg pilocarpine troches was provided by pharmacists at Medisca, a supplier of pharmacy compounding products (Table 2-1). The troche base is a proprietary product made of a mixture of gelatin, PEG 1450, PEG 400, saccharin sodium and stevia powder (stevioside). Saccharin sodium and stevia are the non-cariogenic sweeteners. Raspberry liquid was incorporated as the flavour. As with the majority of Medisca formulas, it was stated that this theoretical formula has never been tested in their labs.
Table 2-1 Troche formula (based on a formula provided by Medisca) for the preparation of 30 troches, each containing 5 mg pilocarpine, with 10% excess included to account for wastage.
Ingredients Quantity Medisca troche base 31.3 g Flavour (liquid) 0.419 mL Pilocarpine HCL 0.165 g
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The formulation was prepared by following these steps:
a) The troche base was melted at 50°C-55°C while stirring using a hotplate (the base should not be melted in a microwave oven). b) Using a mortar and pestle, the pilocarpine hydrochloride was triturated to a fine powder. c) The powder from the previous step was then sifted into the melted base (while still at 50- 55°C) and stirred until evenly dispersed for about 5-10 minutes. d) The flavour was then added and mixed well. e) The whole mixture was poured into the 30-cavity plastic troche moulds. f) Allowed to congeal at room temperature (a heat gun may be used to polish the troche tops).
2.2.5. Formulation of 5 mg pilocarpine ODTs
A theoretical formula for ODTs containing 5 mg of pilocarpine with a total weight of 75 mg per ODT was suggested by pharmacists at Medisca (Table 2-2). Medi-RDT Base is a sucrose-free, finely granulated powder that is compatible with a wide range of active ingredients. Bitterness Reducing Agent is a beige odourless powder, which is incorporated in the formula to mask the bitter taste of pilocarpine. An additional 10% of the required quantities of the listed ingredients was added to account for losses during preparation.
Table 2-2 Orally dissolving tablet (ODT) formula (based on a formula provided by Medisca) for the preparation of 60 ODTs, each weighing 75 mg and containing 5 mg pilocarpine, with 10% excess included to account for wastage.
Ingredient Name Quantity Unit Pilocarpine Hydrochloride 0.327 g Flavour (Powder) 0.218 g Bitterness Reducing Agent (NF01) Natural (Powder) 0.218 g Stevia Powder (Stevioside) 0.218 g Medi-RDT Base 3.924 g
The formulation was prepared by following these steps:
a) The Medi-RDT base was passed through a 40-mesh sieve and the required quantity was weighed. b) Powders were mixed for a total maximum time of 5 minutes in two stages: i. By geometric addition with a pestle and mortar, the following ingredients were combined and triturated together to form a homogenous powder blend: pilocarpine hydrochloride, flavour powder, bitterness reducing agent and stevia powder. 61
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ii. The sieved Medi-RDT base was mixed into the homogeneous powder blend in the mortar by geometric addition (without trituration). c) The 60 tablet mould cavities were filled by tapping the mixed powders into the cavities and pressed into place using the upper part of the mould. This step was then repeated nine times, to ensure a total of 10 presses, so that the cavities were completely filled. d) The tablet mould was placed into a preheated oven for 10-15 minutes. The oven was set to 108.7°C in order to achieve a measured temperature of 110°C. e) The tablet mould was carefully removed from the heated oven, and the tablets were immediately removed by flipping over the mould onto a piece of wax paper and gently tapping the mould with a small mallet. f) Tablets were allowed to cool for 30 minutes before being packed into cold-seal blister packs, with one ODT per blister.
2.2.6. Quality control assessment of the compounded pilocarpine products
The British Pharmacopeia defines lozenges (troches) and pastilles as oromucosal preparations. Oromucosal preparations are solid, semi-solid or liquid preparations, containing one or more active substances intended for administration to the oral cavity and/or the throat to obtain a local or systemic effect. Orally dissolving tablets (ODTs) are considered as buccal tablets under the definition of the BP for the oromucosal preparations. Buccal tablets are solid, single-dose preparations to be applied to the buccal cavity to obtain a systemic effect. They are prepared by compression of mixtures of powders or granulations into tablets with a shape suited for the intended use (British Pharmacopoeia Commission, 2018b). According to the BP there are certain tests that can be done to check the quality control of the ODTs: uniformity of weight, uniformity of drug content, resistance to crushing, friability, in vitro dispersion time, in vitro disintegration test, in vivo disintegration test and wetting time and water absorption ratio test. Some of these tests are not applicable to troches due to the different nature of the dosage form.
2.2.6.1. Uniformity of weight The BP uniformity of weight test was followed (British Pharmacopoeia Commission, 2018b). For both lozenges and ODTs, 20 units were randomly selected, individually weighed and the mean was determined. The test was replicated for 3 batches. As the mass of each lozenge was more than 250 mg, the % deviation allowed was 5%. As the mass of each ODT was less than 80 mg, the % deviation allowed was 10%. The BP states that not more than 2 of the individual masses deviate from the average mass by more than the percentage deviation and none deviates by more than twice that percentage. 62
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2.2.6.2. Uniformity of drug content This test was performed for 10 ODTs and troches from 3 batches. The BP specifies that the preparation complies with the test if the average content of 10 dosage units is between 90% and 110% of the content stated on the label and if the individual content of each dosage unit is between 75% and 125% of the average content (British Pharmacopoeia Commission, 2018b).
A. Extraction of pilocarpine from compounded ODTs
One ODT was dissolved in 10 mL phosphate buffer at pH=5.0 containing 0.1 mg/mL nicotinamide as an internal standard. The resulting solution was then filtered through a 0.45 μm PTFE membrane filter (Thermo Fischer Scientific, QLD) and pilocarpine concentration was measured by HPLC-UV analysis.
B. Extraction of pilocarpine from compounded troches
Pilocarpine was extracted from the compounded lozenges in a sequence of steps that started by preparing the sample, dissolving one lozenge in 20 mL of 70% ethanol and adjusting the pH to 4.0 with 1% formic acid and mixing. A CUBC X15Z SPE ion exchange column (GE Healthcare Life Sciences) was conditioned by adding 2x4 mL methanol, adding 4 mL deionized water and final addition of 4 mL 1% formic acid without letting the column dry. The sample was then applied by loading directly on to the column at a rate of 1-2 mL/min. The column was washed by adding 2x4 mL 1% formic acid, 2x4 mL 70% ethanol at pH=4.0 and then drying the column for 5 minutes using nitrogen gas. Elution of pilocarpine was achieved by adding 4x4 mL methanol containing 2% ammonium hydroxide and then drying the resultant eluted pilocarpine using nitrogen gas. The dried sample was mixed with 10 mL phosphate buffer at pH=5.0 containing 0.1 mg/mL nicotinamide which was used as an internal standard. The resulting solution was filtered through 0.45 μm PTFE membrane filter and pilocarpine concentration was measured by HPLC-UV analysis.
2.2.6.3. Diameter and thickness Five troches and 10 ODTs were measured for diameter and thickness using a Vernier calliper, and the mean and standard deviation were calculated (Nagoba et al., 2011). The test was replicated for 3 batches.
2.2.6.4. Resistance to crushing Ten ODTs were selected at random for determination of their hardness using an Erweka hardness tester, and the mean and standard deviation were calculated (Comoglu et al., 2015). The test was replicated for 3 batches. Although it is not stated in the BP for testing of troches, this test was also done for the troches in order to compare between both formulations. The test was replicated for 3 batches. 63
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2.2.6.5. Friability Friability of ten ODTs were measured using a FAB-2S friability tester, with the drum rotating at 25 rpm for 4 min. Friability was calculated according to the following equation:
% Friability = (Initial weight-Final weight)/Initial weight x 100
The BP specifies that a maximum loss of total weight not greater than 1% is considered acceptable for most products provided that no single tablet is cracked, cleaved or broken after tumbling (British Pharmacopoeia Commission, 2018a). The test was replicated for 3 batches.
2.2.6.6. In vitro dispersion time This test was performed by placing one ODT in 10 mL of simulated salivary fluid (phosphate buffer solution at pH=6.8) at 37 ± 0.5°C. Time required for complete dispersion of tablet was then recorded (Kamalapurkar et al., 2015). Six ODTs from each of the 3 batches were assessed.
2.2.6.7. In vitro disintegration test This test was performed for the ODTs using disintegration test apparatus. One ODT was placed in each of the 6 replicate tubes of the basket. The basket was immersed in water bath at 37 ± 2°C. The time required for complete disintegration of each ODT in each tube was recorded using a stop watch (Sukhavasi et al., 2012). Orodispersable tablets are expected to disintegrate within 3 min in water (British Pharmacopoeia Commission, 2018c). The in vitro disintegration test was used in lieu of dissolution test due to the rapid dissolution of the tablets (typically less than one minute) (Siewert, Dressman et al., 2003). The test was replicated for 3 batches.
2.2.6.8. In vivo disintegration test The ODTs were tested for disintegration time in vivo. One healthy volunteer (the PhD student) tested 3 ODTs from each of the 3 replicate batches. One whole ODT was placed in the mouth between the gum and the cheek after rinsing the mouth with 3 ml of water prior to administration, and the time taken for complete disintegration was recorded (Siddiqui et al., 2010). The ODT was then spat out to minimise absorption of the pilocarpine and the mouth was rinsed with water. Ethical approval was granted by the UQ School of Pharmacy Ethics Committee on behalf of the UQ Medical Research Ethics Committee (approval number 2015/12).
2.2.6.9. Wetting time and water absorption ratio This test was performed for the ODTs, where 3 ODTs from each of 3 batches were tested. A piece of paper folded twice was kept in a Petri dish containing 6 mL of purified water. For wetting time, a tablet having a small amount of Rosaline dye powder on the upper surface was placed on the tissue paper and the time required to develop a red colour was recorded. For water absorption ratio, the
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R= [(Wb-Wa)/Wb] x 100 where Wb and Wa are the weights of the tablet before and after water absorption respectively (Sukhavasi et al., 2012).
2.2.7. Stability testing of the compounded products
2.2.7.1. Accelerated ageing Three batches of 30 troches and three batches of 60 ODTs were stored for 12 months in a controlled temperature room at 36°C. The plastic troche packs containing the troches were closed and placed into card dispensing sleeves. The ODTs were packaged into cold-seal blister packs and placed into card dispensing boxes. These were placed on a shelf in the room. Temperature and humidity inside the room were measured during the storage period and the averages were 36°C and 39% RH. Three troches and ODTs from each batch were randomly withdrawn after 1, 2, 3, 6, 9 and 12 months for testing variation in weight, diameter and thickness as well as calculation of the % loss in drug concentration during storage by HPLC-UV analysis of the drug content.
2.2.7.2. Shelf life Three batches of 30 troches and three batches of 60 ODTs were stored for 18 months in a temperature- controlled incubator set at 20°C. The plastic troche packs containing the troches were closed and placed into card dispensing sleeves. The ODTs were packaged into cold-seal blister packs and placed into card dispensing boxes. These were placed on a shelf in the room. Temperature and humidity inside the incubator were measured during the storage period and the averages were 20°C and 57% RH. Three troches and ODTs from each batch were withdrawn after 1, 2, 3, 6, 9, 12 and 18 months for testing variation in weight, diameter and thickness as well as calculation of the % loss in drug concentration during storage by HPLC analysis of the drug content.
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2.2.8. Measurement of pilocarpine and its degradation products The stability of pilocarpine in aqueous solutions has been the subject of many investigations (Bundgaard & Hansen, 1982; Neville, Hasan et al., 1976; Nunes & Brochmann-Hanssen, 1974) and the two main degradation pathways are known (Figure 2-1):
A. Epimerization at the α-carbon of the lactone ring yielding isopilocarpine. B. Hydrolysis of the γ-lactone moiety producing pilocarpic acid from pilocarpine or isopilocarpic acid from isopilocarpine.
Figure 2-1 Degradation pathways of pilocarpine (Van de Merbel, Tinke et al., 1998)
The epimer isopilocarpine and the hydrolysis products isopilocarpic acid and pilocarpic acid have no pharmacological activity (Gomez-Gomar, Gonzalez-Aubert et al., 1989). The competition between these degradation products depends both on temperature and pH (Neville et al., 1976; Nunes et al., 1974). The hydrolysis of the γ-lactone ring is catalysed by the presence of hydrogen and hydroxide ions (Chung, Chin et al., 1970; Neville et al., 1976). Epimerisation of pilocarpine to isopilocarpine is irreversible at any pH and the pilocarpic acid and isopilocarpic acid have no ability to epimerize (Neville et al., 1976; Nunes et al., 1974).
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2.2.8.1. Method and chromatographic conditions In this study the HPLC method was based on Fan et al. (1996) and El Deeb et al. (2006); these studies resulted in complete separation of pilocarpine and the degradation products in less than 20 minutes. An Agilent Technologies 1260 series RV-HPLC system and diode array detector (Agilent Technologies, Boeblingen, Germany) with Agilent Lab Advisor software (Agilent Technologies) was used for data acquisition and handling. Chromatography was performed on a reversed-phase Zorbax
Extend C18 column (Agilent Technologies) of 250 x 2.1 mm i.d. and 5 μm particle size. The mobile phase consisted of HPLC grade methanol (solvent A) and phosphate buffer at pH=3.0 (solvent B). The phosphate buffer solution was prepared by mixing 13.5 mL of phosphoric acid, 3 mL of triethylamine and Millipore water to a total volume of 1 litre, and the pH was adjusted to 3.0 by the addition of 50% sodium hydroxide solution (Fan, Wall et al., 1996). Gradient elution was 7 to 10% solvent A from 0 to 8 min, at 1 mL/min. The column temperature was set at 25ºC ± 0.5 and the injection volume was 20 μL. Detection and quantification were performed at 214 nm.
2.2.8.2. Preparation of pilocarpine degradation products The degradation products of pilocarpine were prepared according to Fan et al. (Fan et al., 1996). Iso- pilocarpine was prepared by mixing 0.5 mL of 0.5 mg/mL pilocarpine aqueous solution with 2 mL 1M sodium hydroxide solution. The pH of the mixture was then adjusted to 2.5 using concentrated hydrochloric acid solution and 50% sodium hydroxide solution. Pilocarpic acid and iso-pilocarpic acid were prepared by mixing 2 mL of 0.5 mg/mL pilocarpine aqueous solution with 40 μL 50% sodium hydroxide solution. This mixture was heated to 70°C for one hour. To identify the retention time for each of the degradation products, they were used individually and as a mixture spiked immediately prior to HPLC analysis with 0.5 mg/mL pilocarpine in phosphate buffer at pH=5.0 containing 0.1 mg/mL nicotinamide.
2.2.8.3. Standard calibration curve of pilocarpine in phosphate buffer at pH5 A stock solution of pilocarpine was prepared by dissolving 10 mg pilocarpine in 20 mL phosphate buffer solution to generate a solution with a concentration 0.5 mg/mL. Phosphate buffer at pH=5.0 containing nicotinamide at 0.1 mg/mL as the internal standard was prepared by mixing 13.5 mL phosphoric acid solution with 3 mL triethylamine and made up to 1 L with water. The pH was then adjusted to 5 using 50% sodium hydroxide solution. The internal standard (100 mg) was added to the prepared buffer solution to produce a concentration of 0.1 mg/mL.
Five concentrations of pilocarpine were used to construct the calibration curves. The stock solution of 0.5 mg/mL pilocarpine in phosphate buffer at pH=5.0 containing 0.1 mg/mL nicotinamide was diluted, using phosphate buffer containing 0.1 mg/mL nicotinamide, to produce 0.1, 0.2, 0.3 and 0.4
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2.2.8.4. Method validation Validation of the HPLC method was done by assessing linearity, sensitivity, repeatability and intermediate precision (Shabir, 2003). Linear regression through the five pilocarpine concentrations was used for assessing the linearity of the method. System sensitivity was tested using the residual standard deviation of the regression line (SD) and slope (S) of the regression through five pilocarpine concentrations by calculation of limit of detection (LoD = 3.3SD/S) and limit of quantification (LoQ = 10SD/S) (Shabir, 2003). Intermediate precision was tested by comparing results performed on three different days and using a second column of the same type on the same HPLC system. The relative standard deviation (RSD) of the replicate injections was calculated (Shabir, 2003). All calculations and data manipulation were performed using Excel 2016.
2.3. Results
2.3.1. Standard calibration curve and method validation
The regression statistics were calculated from the calibration curve (Fig. 2-2) constructed for the different concentrations of pilocarpine (Table 2-3) and showed satisfactory linearity with the correlation coefficient (r) of 0.997. The method was sensitive for the detection of less than 0.05 mg/mL of pilocarpine and capable of quantifying as low as 0.1 mg/mL of pilocarpine (Table 2-3).
The inter-day and inter-column RSD for peak area ratio of different pilocarpine concentrations to internal standard were less than 5% (Table 2-4) but greater than 2%, so RSD was good but not as tight as it should be for a stability indicating assay. Comparison of the retention time between days and between columns showed particularly good repeatability, with RSD less than 1%.
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Table 2-3 Regression statistics, limit of detection (LoD) and limit of quantification (LoQ) for different pilocarpine concentrations
Parameter Pilocarpine Conc. Range, mg/mL 0.1 – 0.5 Slope Y=0.372X+0.0155 R2 0.994 LoD, mg/mL 0.034 LoQ, mg/mL 0.104 R2= correlation coefficient; LoD: lower limit of detection; LoQ: lower limit of quantification
2.5
2.0
1.5
1.0
0.5
0.0 Ratio of pilocarpine:IS area peak pilocarpine:IS Ratio of 0 1 2 3 4 5 6 Ratio of pilocarpine:IS concentration
Figure 2-2 Standard calibration curve of pilocarpine in phosphate buffer at pH=5.0.
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Table 2-4 Peak area ratio (pilocarpine : internal standard) and pilocarpine retention time for five different concentrations of pilocarpine that were analysed on three different days and using two different batches of the same column within the same HPLC system. Relative standard deviation (RSD) as a percent is shown for assessment of inter-day and inter-column precision.
Pilocarpine concentration (mg/mL) 0.1 0.2 0.3 0.4 0.5 Peak area ratio Column 1 Day 1 0.387 0.774 1.162 1.542 1.946 Day 2 0.390 0.775 1.160 1.524 1.894 Day 3 0.385 0.722 1.083 1.440 1.781 average 0.387 0.757 1.135 1.502 1.874 inter-day RSD (%) 0.6 3.3 3.3 3.0 3.7 Column 2 Day 1 0.403 0.805 1.208 1.604 1.966 Day 2 0.415 0.824 1.237 1.634 2.04 Day 3 0.425 0.836 1.246 1.660 2.072 average 0.414 0.822 1.230 1.633 2.026 inter-day RSD (%) 2.2 1.6 1.3 1.4 2.2 Inter-column RSD (%) 3.4 4.1 4.0 4.2 3.9 Pilocarpine retention time (min) Column 1 Day 1 7.65 7.63 7.61 7.61 7.60 Day 2 7.59 7.63 7.70 7.68 7.65 Day 3 7.72 7.72 7.70 7.69 7.68 average 7.65 7.66 7.67 7.66 7.64 inter-day RSD (%) 0.7 0.6 0.6 0.5 0.5 Column 2 Day 1 7.66 7.62 7.67 7.64 7.63 Day 2 7.72 7.60 7.69 7.69 7.65 Day 3 7.62 7.65 7.57 7.70 7.59 average 7.67 7.62 7.64 7.67 7.62 inter-day RSD (%) 0.5 0.3 0.7 0.3 0.3 Inter-column RSD (%) 0.1 0.2 0.2 0.1 0.1
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2.3.2. Elution of pilocarpine degradation products and their detection by HPLC
Pilocarpine and the three degradation products isopilocarpine, isopilocarpic acid and pilocarpic acid were fully retained and eluted within 9 minutes with a flow rate of 1 mL/min and pH=5.0 (Fig. 2-3). Previously it took between 13-25 minutes to elute and separate pilocarpine in the presence of its degradation products using both normal and reversed phase chromatography (El Deeb, Schepers et al., 2006; Gomez-Gomar et al., 1989; Kennedy & McNamara, 1981; Noordam, Waliszewski et al., 1978; Sternitzke, Fan et al., 1992).
Figure 2-3 HPLC Chromatogram separation of pilocarpine in the presence of its degradation products and an internal standard (nicotinamide); (A) Nicotinamide (4.971 min), (B) Isopilocarpine (6.017 min), (C) Pilocarpine (7.397 min), (D) Pilocarpic acid (8.147 min) and (E) Isopilocarpic acid (8.608 min) in phosphate buffer at pH=5.0 at 25°C.
2.3.3. Quality control assessment of the compounded pilocarpine troches
A. Uniformity of weight
The troches weighed around 990 mg each. Overall, the three tested batches of troches passed the test, which requires that not more than 2 of the individual masses deviate from the average mass by more than the percentage deviation and none deviates by more than twice that percentage. Within the three batches, four troches deviated by more than 5% from the mean batch weight (British Pharmacopoeia Commission, 2018b); two troches from B1, one troche from B2 and one troche from B3 (Table 2-5). These troches deviated by more than 5% but less than 10% of the mean batch weight.
B. Uniformity of drug content
The three batches of troches had an average drug content that was within the range 90-110% of the stated dose. Although four troches in B1, two troches in B2 and two troches in B3 (
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Table 2-6) did not contain between 90-110%, they did contain within 75-125% of average pilocarpine content, so the batches passed the BP uniformity of drug content test (British Pharmacopoeia Commission, 2018b).
For the purpose of this thesis, production of a consistent pilocarpine dose of 5 mg was important, so further investigation was made to determine whether it would be possible to control for drug content by selecting certain troche weights. There was a positive relationship between troche weight and pilocarpine content (Fig. 2-4), but only 48% of the variation in the data was described by a single regression line through all three batches. Consequently, it was difficult to determine a definitive troche weight range that would consistently select only troches containing 4.5-5.5 mg and exclude only troches outside this range.
Table 2-5 Results of uniformity of weight test made for three batches of medicated troches B1, B2 and B3. Batch Number B1 B2 B3 0.939 1.025 0.945 0.993 1.030 0.955 1.047 0.954 0.992 0.986 1.030 0.965 0.958 0.996 1.003
1.010 1.050 1.002 0.963 0.956 1.001 0.949 1.020 1.016 0.940 0.990 1.002 0.973 0.963 0.998 0.974 0.950 0.963 0.944 0.980 1.001 Troche Weight (g) Weight Troche 1.023 0.970 1.042 1.029 1.000 0.929 1.005 1.001 0.997 1.018 1.020 1.012 0.943 0.960 0.990 1.041 0.970 1.020 1.019 0.990 1.030 1.005 1.030 1.021 Mean (g) 0.988 0.994 0.994 SD (g) 0.035 0.030 0.028 Deviation allowed (±5%) (g) ±0.049 ±0.050 ±0.050 Fails 2 1 1
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Table 2-6 Results of uniformity of drug content test made for three batches of medicated troches B1, B2 and B3.
B1 B2 B3 Troche Drug Drug Troche Drug Drug Troche Drug Drug Weight Content Content Weight Content Content Weight Content Content (mg) (mg) (%) (mg) (mg) (%) (mg) (mg) (%) 1060 5.62 112.4 1047 5.48 109.6 1021 5.07 101.4 1030 5.33 106.6 1017 4.77 95.4 1044 5.14 102.8
1060 5.49 109.8 1050 5.48 109.6 1052 4.90 98 891 4.33 86.6 992 4.22 84.4 1055 5.09 101.8 1011 5.15 103.0 1015 4.71 94.2 1013 4.57 91.4 999 5.33 106.6 1024 4.65 93 1018 4.73 94.6 1028 5.21 104.2 999 4.39 87.8 972 4.50 90 1054 5.56 111.2 1026 4.89 97.8 993 4.42 88.4 871 4.27 85.4 1031 4.89 97.8 1010 4.48 89.6 1024 5.3 106.0 1015 4.71 94.2 1018 4.73 94.6 Mean 1003 5.16 103.2 1022 4.82 96.38 1020 4.81 95.3 SD 64 0.45 9.0 16.68 0.37 7.70 23.38 0.37 5.2 Fails 0 0 0
6.0 y = 0.0069x - 2.0401 5.5 R² = 0.4793 5.0
(mg) 4.5
4.0 B1
3.5 B2
Troche pilocarpine content B3 3.0 800 850 900 950 1000 1050 1100 Troche weight (mg)
Figure 2-4 Relationship between troche weight and pilocarpine content for three batches, B1, B2 and B3.
C. Hardness, diameter and thickness
Troches, which were prepared in square-shaped moulds, had edges that were 12.7 mm in length, were 5.6 mm thick, and had hardness of 2 kg/cm2 (Table 2-7).
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Table 2-7 Results of hardness, diameter and thickness tests made for five troches from each of three batches.
Hardness Thickness Diameter (kg/cm2) (mm) (mm) 1.4 5.36 12.52 Batch 1 1.0 5.96 12.97 1.4 5.85 12.77 1.5 5.76 12.97 4.7 5.41 12.65 Mean 2.0 5.67 12.77 SD 1.5 0.24 0.18 1.4 5.8 12.89 1.0 5.54 12.63 Batch 2 3.4 5.36 12.65 1.9 5.83 12.50 1.0 5.32 12.80 Mean 1.7 5.60 12.70 SD 1.0 0.21 0.14 3.1 5.44 12.73 2.4 5.39 12.56 Batch 3 1.3 5.59 12.56 3.3 5.69 12.59 1.2 5.75 12.55 Mean 2.3 5.57 12.60 SD 1.0 0.14 0.07
2.3.4. Quality control assessment of compounded pilocarpine ODTs
A. Uniformity of weight
The ODTs were prepared in a mould containing 60 small circles designed to prepare ODTs weighing approximately 75 mg, and in this case mean ODT weight was 73 mg (Table 2-8). Overall, the three tested batches of ODTs passed the test, which states that not more than two of the individual masses deviate from the average mass by more than the percentage deviation and none deviates by more than twice that percentage. The weight of all ODTs was in the range of 10% deviation from the average weight of every batch (Table 2-8), which is the acceptable range according to the BP for this tablet weight (British Pharmacopoeia Commission, 2018b). Only one ODT in B2 failed the specification of the test, being 87.4% of the batch mean weight, and it should be noted that this ODT would have passed if it was prepared as part of B1 or B3 which had slightly smaller mean batch weights. However, the whole batch passed the test according to the criteria of the BP.
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Table 2-8 Results of uniformity of weight test made for three batches of medicated ODTs B1, B2 and B3.
Batch Number B1 B2 B3 72.0 77.0 69.0 73.0 76.6 68.0 70.0 72.0 70.0 70.0 79.5 76.8 71.6 73.0 72.5 73.0 72.4 80.0 72.0 71.4 71.0 70.0 75.5 70.0 71.0 72.7 71.2 75.0 71.4 73.5 70.5 67.2 70.0 67.0 72.8 77.4
ODTWeight (mg) 69.5 77.5 73.5 67.5 72.7 77.8 71.5 75.2 70.0 70.0 64.6 77.2 70.0 76.5 77.5 72.0 80.5 71.0 76.0 73.5 72.0 75.0 76.0 73.0 Mean (mg) 71.3 73.9 73.1 SD (mg) 2.26 3.71 3.42 Deviation allowed (±10%) (mg) ±7.13 ±7.39 ±7.31 Fails 0 1 0
B. Uniformity of drug content
During the development of the method for ODT production, a strong relationship between ODT weight and pilocarpine content was found. A single regression line (Fig. 2-5) described 92% of variation in the data across three batches. Based on this relationship, selecting ODTs weighing between 70 – 80 mg consistently provided 4.5 – 5.5 mg pilocarpine, which is important for the clinical trial (Chapter 5). With the ODT selection constraint imposed, the three batches of ODTs had an average drug content and individual ODT contents within the range 90-110% of the stated dose (Fig. 2-5). In fact, individual ODTs are required to be in the range 75-125% of average pilocarpine content to pass the BP uniformity of drug content test (British Pharmacopoeia Commission, 2018b), so the batches would pass the test even if no selection according to ODT weight was imposed.
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6.0
5.5 y = 0.0472x + 1.4081 R² = 0.9216 5.0
4.5
4.0 B1 3.5 B2 B3 ODT pilocarpine (mg) content pilocarpine ODT 3.0 50 60 70 80 90 ODT weight (mg) Figure 2-5 Relationship between ODT weight and pilocarpine content for three batches, B1, B2 and B3.
Table 2-9 Results of uniformity of drug content test made for three batches of medicated ODTs B1, B2 and B3 when ODT weight is selected to be between 70 – 80 mg.
B1 B2 B3 ODT Drug Drug ODT Drug Drug ODT Drug Drug Weight Content Content Weight Content Content Weight Content Content (mg) (mg) (%) (mg) (mg) (%) (mg) (mg) (%) 74.5 4.92 98.4 74.0 4.87 97.4 77.3 5.11 102.2 74.0 4.89 97.8 76.3 4.97 99.4 74.8 4.82 96.4
75.0 4.94 98.8 76.3 4.95 99.0 74.6 4.86 97.2 74.5 4.91 98.2 79.3 5.08 101.6 76.0 5.04 100.8 73.0 4.93 98.6 75.2 4.76 95.2 79.3 5.14 102.8 76.5 5.19 103.8 74.2 5.06 101.2 74.8 4.95 99.0 72.7 4.75 95.0 72.8 4.78 95.6 76.0 5.00 100.0 72.5 4.79 95.8 76.5 5.09 101.8 71.3 4.79 95.8 73.0 4.87 97.4 74.0 4.95 99.0 73.1 4.77 95.4 71.3 4.96 99.2 76.0 5.04 100.8 76.0 5.00 100.0 Mean 73.70 4.92 98.3 75.46 4.96 99.1 75.32 4.95 98.96 SD 1.42 0.11 2.23 1.75 0.11 2.26 2.08 0.13 2.51 Fails 0 0 0
C. Hardness, diameter and thickness
The circular ODTs had an average diameter of 5.45 mm and thickness of 3.38 mm (Table 2-10). The low standard deviation values indicate the uniformity of diameter and thickness within each of the three batches. The mean value for hardness was 1.28 kg/cm2.
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Table 2-10 Results of hardness (resistance to crushing), diameter and thickness tests made for three batches of medicated ODTs B1, B2 and B3.
Hardness (kg/cm2) Thickness (mm) Diameter (mm)
B1 B2 B3 B1 B2 B3 B1 B2 B3 1.03 1.23 1.17 3.37 3.43 3.32 5.48 5.36 5.52 1.44 1.03 1.44 3.35 3.40 3.22 5.31 5.45 5.44 1.37 1.03 1.17 3.37 3.40 3.29 5.48 5.45 5.47 1.44 1.37 1.78 3.41 3.37 3.3 5.46 5.39 5.57 1.23 1.03 1.30 3.43 3.37 3.35 5.36 5.48 5.56 1.03 1.44 1.44 3.4 3.35 3.35 5.45 5.31 5.31 1.03 1.37 1.37 3.4 3.37 3.37 5.45 5.48 5.48 1.37 1.44 1.44 3.37 3.41 3.41 5.39 5.46 5.46 1.23 1.10 1.10 3.31 3.36 3.36 5.36 5.43 5.43 1.10 1.23 1.23 3.36 3.31 3.31 5.43 5.36 5.36 Mean Mean Mean 1.23 1.23 1.37 3.38 3.38 3.30 5.42 5.42 5.51 SD SD SD 0.16 0.17 0.19 0.03 0.03 0.05 0.06 0.06 0.06
D. Friability test
According to the BP, a maximum loss of mass (obtained from a single test or from the mean of three tests) not greater than 1% is considered acceptable for most products. All the ODT batches tested passed the friability test with an average percentage loss of ≤ 1% loss of weight (Table 2-11). There were no cracked, cleaved or broken ODTs after tumbling in the drum of the friability tester.
Table 2-11 Results of friability test made for three batches of medicated ODTs using 10 tablets rotated for 4 minutes at 25 rotations per minute.
Initial Weight Final Weight Batch Number % Friability (mg) (mg)
B1 680 675 0.74 B2 702 695 1.00 B3 695 689 0.86 Mean 692.3 686.3 0.87 SD 11.24 10.26 0.13
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E. In vitro dispersion, in vitro disintegration, in vivo disintegration, wetting time and water absorption ratio
Wetting time and water absorption ratio are two important factors that determine the ability of the ODTs to swell in the presence of small amount of water (Bhanja et al., 2012). The wetting time was only 50-55 sec and the water absorption ratio was around 45%. The results of the in vitro dispersion time, in vitro disintegration time and in vivo disintegration time all indicate that the compounded ODTs disintegrate instantaneously (Table 2-12).
Table 2-12 Results of in vitro dispersion, in vitro disintegration, in vivo disintegration, wetting time and water absorption ratio made for three batches of medicated ODTs B1, B2 and B3.
Formulation Properties B1 B2 B3 In vitro Dispersion Time (Sec) 20 30 26 In vitro Disintegration Time (Sec) 50 45 55 In vivo Disintegration Time (Sec) 15 17 16 Wetting Time (Sec) 53 50 55 Water Absorption Ratio (%) 45.24 45 44.82
2.3.5. Stability testing of the compounded pilocarpine troches
A. Accelerated ageing After 12 months storage at 36°C and 39% RH there was no measurable change in the average diameter and thickness of the tested troches of each batch (Table 2-13). There was an initial decrease in troche weight, followed by a second decrease between 6 and 9 months, however, this represented a maximum change of only 3% of the original troche weight. The drug content showed an initial loss of 10-15% of the amount measured at the start of the test, followed by a slower decline, such that an average of 81% was remaining after storage for 12 months at 36°C and 39% RH (Figure 2-6). Accordingly, % drug content loss under these accelerated storage conditions was less than 20% of the labelled amount after 12 months.
105 y = -1.0753x + 92.151 100 R² = 0.5948 95 90 85 80 remaining remaining (%) 75 Pilocarpinecontent 0 2 4 6 8 10 12 Storage time (months) Figure 2-6 Percentage drug content (average of 3 troches for each of 3 batches) remaining across twelve months storage at 36°C and 39% RH of the three batches of troches.
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Table 2-13 Results of accelerated ageing stability testing (average of 3 troches for each of 3 batches) of diameter, thickness, weight change and % drug content loss made on medicated troches after storage at 36°C and 39% RH.
Time Batch Number Properties (months) A1 A2 A3 Mean Diameter (mm) 12.55 12.91 12.62 1 Mean Thickness (mm) 5.71 5.76 5.87 Mean Weight Change (mg) -12.33 -11.53 -10.73 Mean % Drug Content Loss (mg) 18.38 10.16 11.20 Mean Diameter (mm) 12.46 12.50 12.51 2 Mean Thickness (mm) 5.72 5.52 5.56 Mean Weight Change (mg) -10.30 -10.70 -6.43 Mean % Drug Content Loss (mg) 15.22 12.72 7.41 Mean Diameter (mm) 12.54 12.70 12.53 3 Mean Thickness (mm) 5.46 5.73 5.48 Mean Weight Change (mg) -7.13 -6.60 -6.77 Mean % Drug Content Loss (mg) 16.51 7.18 16.76 Mean Diameter (mm) 12.48 12.38 12.50 6 Mean Thickness (mm) 5.52 5.51 5.60 Mean Weight Change (mg) -10.67 -9.00 -18.33 Mean % Drug Content Loss (mg) 16.05 14.76 15.97 Mean Diameter (mm) 12.48 12.38 12.48 9 Mean Thickness (mm) 5.52 5.51 5.55 Mean Weight Change (mg) -24.33 -22.33 -26.33 Mean % Drug Content Loss (mg) 19.49 18.28 14.20 Mean Diameter (mm) 12.46 12.36 12.40 12 Mean Thickness (mm) 5.50 5.53 5.43 Mean Weight Change (mg) -25.60 -23.70 -28.90 Mean % Drug Loss (mg) 21 20.2 15.8
B. Shelf life After 18 months of storage at 20°C there was no measurable change in the average diameter and thickness of the tested troches of each batch (Table 2-14). Troche weight indicated a small decrease of up to 2.3% during the treatment period. Drug content showed an initial drop to 90-95% of the original, which then remained similar for the 18-month study. The average % drug content measured after storage for 18 months at 20°C and 57% RH was 90.3% (Fig. 2-7). Accordingly, drug content loss under these storage conditions was around 10% of the labelled amount.
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Table 2-14 Results of shelf life stability testing (average of 3 troches for each of 3 batches) of diameter, thickness, weight change and % drug content loss made on three batches of medicated troches after storage at 20°C and 57% RH.
Time Batch Number Properties (months) S1 S2 S3 Mean Diameter (mm) 12.48 12.54 12.49 3 Mean Thickness (mm) 5.69 5.73 5.60 Mean Weight Change (mg) -0.33 -5.27 -0.67 Mean % Drug Content Loss (mg) 7.14 10.93 7.81 Mean Diameter (mm) 12.57 12.55 12.54 6 Mean Thickness (mm) 5.79 5.62 5.64 Mean Weight Change (mg) -4.13 -2.33 -3.70 Mean % Drug Content Loss (mg) 8.96 14.89 7.50 Mean Diameter (mm) 12.57 12.55 12.54 9 Mean Thickness (mm) 5.79 5.62 5.64 Mean Weight Change (mg) -13.33 -17.00 -23.00 Mean % Drug Content Loss (mg) 4.40 12.26 11.61 Mean Diameter (mm) 12.57 12.55 12.54 12 Mean Thickness (mm) 5.79 5.62 5.64 Mean Weight Change (mg) -18.33 -18.67 -10.00 Mean % Drug Content Loss (mg) 9.77 6.45 5.22 Mean Diameter (mm) 12.57 12.55 12.54 18 Mean Thickness (mm) 5.73 5.65 5.60 Mean Weight Change (mg) -17.00 -13.50 -12.60 Mean % Drug Content Loss (mg) 8.96 12.26 7.85
105 y = -0.4594x + 96.653 R² = 0.3365 100 95 90
85 remaining Percentage 80
0 2 4 6 8 10 12 14 16 18 Pilocarpine content Storage time (Months)
Figure 2-7 Percentage drug content (average of 3 troches for each of 3 batches) remaining across 18 months storage at 20°C and 57% RH for the three batches of medicated troches.
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2.3.6 Stability testing of the compounded 5 mg pilocarpine ODTs
A. Accelerated ageing
After 12 months of storage at 36°C and 39% RH there was no measurable change in the average diameter and thickness of the tested ODTs of each batch (Table 2-15). ODT average weight generally increased slightly in comparison to the starting average ODT weight under these storage conditions. The changes were small, representing an increase in weight of less than 3%. Drug content dropped initially within the first month to around 95% of expected, followed by a slow decline to 90.6% after storage for 12 months (Fig. 2-8). Accordingly, the drug content loss under these storage conditions for the three batches of ODTs was less than 10% of the labelled amount after 12 months of storage.
Table 2-15 Results of accelerated ageing stability testing (average of 3 ODTs for each of 3 batches) of diameter, thickness, weight change and % drug content loss made for medicated ODTs after storage at 36°C and 39% RH.
Time Batch Number Properties (months) A1 A2 A3 Mean Diameter (mm) 5.88 6.06 6.05 1 Mean Thickness (mm) 3.43 3.34 3.35 Mean Weight Change (mg) +0.56 +0.12 +0.96 Mean % Drug Content Loss (mg) 5.97 4.35 3.31 Mean Diameter (mm) 6.07 6.07 6.12 2 Mean Thickness (mm) 3.32 3.31 3.34 Mean Weight Change (mg) +0.32 +0.08 +0.28 Mean % Drug Content Loss (mg) 6.27 4.68 4.14 Mean Diameter (mm) 6.14 6.10 5.99 3 Mean Thickness (mm) 3.36 3.33 3.38 Mean Weight Change (mg) +0.46 +1.44 +0.50 Mean % Drug Content Loss (mg) 5.35 4.28 2.03 Mean Diameter (mm) 6.02 6.04 6.04 6 Mean Thickness (mm) 3.41 3.28 3.29 Mean Weight Change (mg) +0.27 +0.37 +0.83 Mean % Drug Content Loss (mg) 5.45 3.70 5.05 Mean Diameter (mm) 6.02 6.04 6.04 9 Mean Thickness (mm) 3.41 3.28 3.29 Mean Weight Change (mg) +0.03 +0.33 -0.57 Mean % Drug Content Loss (mg) 8.43 6.32 3.92 Mean Diameter (mm) 6.02 6.04 6.04 12 Mean Thickness (mm) 3.41 3.28 3.29 Mean Weight Change (mg) -0.07 +0.40 +2.07 Mean % Drug Loss (mg) 11.78 9.12 7.41
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105 y = -0.6293x + 98.459 R² = 0.6367 100
95 remaining
90 % % Pilocarpinecontent 85 0 2 4 6 8 10 12 Storage time (Months)
Figure 2-8 Percentage drug content (average of 3 ODTs for each of 3 batches) remaining across 12 months storage at 36°C and 39% RH for the three batches of medicated ODTs.
B. Shelf life
After 18 months storage at 20°C there was no measurable change in the average diameter and thickness of the tested ODTs from each batch (Table 2-16). The weight of ODTs increased slightly, with a maximum increase of only 2% of starting average ODT weight. Average % drug content loss was uniform and consistent along the whole storage time. The average % drug content remaining in the three batches of ODTs across the 18 months storage at 20°C and 57% RH was 86.6% (Fig. 2.9). Accordingly, the % drug content loss under the normal storage conditions over 18 months was less than 14% of the labelled amount.
y = -0.8561x + 100.22 105 R² = 0.7873
100
95
90 remaining
85 % % Pilocarpinecontent 0 5 10 15 Storage time (Months)
Figure 2-9 Percentage drug content (average of 3 ODTs for each of 3 batches) remaining across 18 months storage at 20°C and 57% RH for the three batches of medicated ODTs.
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Table 2-16 Results of stability testing (average of 3 ODTs for each of 3 batches) for diameter, thickness, weight change and % drug content loss made for medicated ODTs after 3, 6, 9, 12 and 18 months storage at 20°C and 57% RH.
Time Batch Number Parameter (months) S1 S2 S3 Mean Diameter (mm) 5.44 5.73 5.70 3 Mean Thickness (mm) 3.39 3.32 3.33 Mean Weight Change (mg) +0.23 +1.03 +1.40 Mean % Drug Content Loss (mg) 7.94 7.12 4.74 Mean Diameter (mm) 5.71 5.78 5.80 6 Mean Thickness (mm) 3.25 3.23 3.29 Mean Weight Change (mg) +0.53 +1.3 +1.73 Mean % Drug Content Loss (mg) 3.08 4.64 4.75 Mean Diameter (mm) 5.83 5.79 5.65 9 Mean Thickness (mm) 3.24 3.23 3.23 Mean Weight Change (mg) -0.43 +0.70 +1.50 Mean % Drug Content Loss (mg) 9.39 8.80 8.80 Mean Diameter (mm) 5.83 5.79 5.65 12 Mean Thickness (mm) 3.24 3.23 3.23 Mean Weight Change (mg) -0.10 +0.53 +1.03 Mean % Drug Content Loss (mg) 9.23 11.96 11.61 Mean Diameter (mm) 5.83 5.79 5.75 18 Mean Thickness (mm) 3.24 3.23 3.26 Mean Weight Change (mg) -0.07 +0.27 +1.50
Mean % Drug Content Loss (mg) 15.73 12.71 11.75
2.4. Discussion
Troches and ODTs containing 5 mg pilocarpine were compounded and then subjected to quality control assessment and stability testing. Troches and ODTs passed the BP tests for uniformity of content, but this test allows drug content to be 75-125% of the intended content. It is felt that restricting content to the tighter range of 90-110% is more appropriate for this study, given that it will be used in a clinical trial. The relationship between weight and drug content was stronger for ODTs than troches, and selection of ODTs weighing 70 – 80 mg consistently selected ODTs containing 90- 110% of 5 mg pilocarpine. The strong relationship between weight and pilocarpine content for ODTs reflects consistent mixing of active pharmaceutical ingredient within the excipient powders. The less consistent relationship for troches indicates that mixing varied between batches, even though the pilocarpine was mixed manually with the melted troche base for 5-10 minutes for all batches, which we believe to be at least as much mixing as would be likely in clinical practice. The variation is also associated withs (mg) the fact that the active ingredient was only 0.5% of the total troche weight, while it is 83
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6.7% of total ODT weight. Products that are prepared in a compounding pharmacy are usually not tested for their concentration of active ingredients and hence it is not known how individual doses vary or the extent of batch to batch variation in practice (Mullarkey, 2009).
For the hardness test, the British Pharmacopeia did not set any limits for the buccal tablets to whether they pass or fail the test. Instead, the results of this test provide information about the characteristics of the ODTs. The three batches of the ODTs had an average hardness of 1.28 kg/cm2. It is known that moulded tablets are usually much less compact than compressed tablets, which facilitates their quick disintegration in the mouth (Siddiqui et al., 2010). In the context of orodispersable tablets prepared by direct compression rather than by moulding, the mean hardness values for ondansetron hydrochloride orodispersable tablets (weighing approximately 80 mg) prepared by direct compression was measured to be between 3.0-3.2 kg/cm2 using different superdisintegrants across the tested batches (Gosai, Patil et al., 2008). Although it is not stated in the BP for testing the hardness of troches, this test was also done for the troches in order to compare between both formulations. The average hardness of the three tested batches of troches was 2 kg/cm2. Regarding the friability test, the three tested batches of ODTs had friability of less than 1% and so may be expected to withstand packaging in a compounding pharmacy and transport by the patient to their home. Friability was not assessed for the troches due to the nature of this dosage form and because it is not required according to the BP.
Although the conditions used were not exactly those recommended by the ICH, they still provide some useful information. Pilocarpine content remained above 90% of the intended dose in both ODTs and troches for 11.9 months or more when stored in the usual blister or troche packaging at 20°C/57% RH or 36°C/39% RH. While this shows that storage of sealed packages for almost a year can be expected to retain pilocarpine content, extemporaneously prepared products such as ODTs and troches containing a Schedule 4 medicine should be compounded for a specific person in response to a prescription, so extended storage is not expected. Of primary importance is the fact that ODTs were moisture sensitive and hence increase in weight and may degrade at higher humidity conditions, which was a general observation for ODTs in this study. Special packaging and storage conditions are required (Bandari, Mittapalli et al., 2014), particularly considering the high humidity in Queensland, so storage of ODTs with silica gel is recommended to prevent their moisture uptake and maintain their original weight.
The HPLC-UV method developed and validated here for quantification of pilocarpine is adapted from already published methodologies for fast and efficient quantification of pilocarpine in pharmaceutical preparations. The method is simple, does not require expensive instrumentation and can be easily
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CHAPTER 2 applied for simultaneous detection of pilocarpine and its degradation products in the presence of an internal standard. The method had a short run time of 9 minutes, for separation and detection of the three degradation products of pilocarpine, on a C-18 column with a mobile phase consisting of methanol (gradient 7 to 10%) and phosphate buffer at pH=5.0 containing 0.1 mg/mL nicotinamide as the internal standard and detection at a single UV wavelength of 214 nm. In previous studies it took less than 20 minutes for complete separation of pilocarpine and its degradation products using YMC Pack ODS-AM column (Fan et al., 1996), 16 minutes on a cyano column (Gomez-Gomar et al., 1989) and 12 minutes on C-18 column (O'Donnell, Sandman et al., 1980). Results from validation of the method proved satisfactory with respect to sensitivity, linearity, accuracy and intermediate precision that make it suitable for routine quantification of pilocarpine in compounded products.
2.5. Conclusion
The compounded troches and ODTs proved to be suitable for compounding in local pharmacies for the treatment of dry mouth. The mould used for compounding the ODTs, and the blister packs required for packaging, can be purchased from pharmaceutical compounding suppliers in Australia. The method adopted for compounding of troches was simple and required only the purchase of troche packs, which function as both the mould and the product packaging. Although the storage conditions were not those recommended by the ICH. However, some useful information was obtained under the adopted storage conditions in this study. The amount of pilocarpine that remained in both the troches and ODTs was more than 90% for almost one year when stored under shelf life storage conditions (36℃ typical Aussie temperature). The strong relationship between ODT weight and pilocarpine content allows selection of a specific range of ODT weights to ensure pilocarpine contents in the range 90-110% of required dose.
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Chapter 3. Establishment of experimental parameters for an acceptability trial
3.1. Introduction
The preparation, quality and stability testing of two dosage forms for buccal delivery of pilocarpine were described in Chapter 2. The next step is to determine which of these dosage forms, and what flavour, should be prioritised for future testing regarding safety and efficacy for use in xerostomia. This chapter describes a pilot study that was conducted to define the experimental design for the subsequent acceptability study described in Chapter 4.
The acceptability study compares the ability of flavourings to mask the bitterness of pilocarpine. There are different techniques available for masking the bitter taste of pharmaceuticals to improve palatability of the formulated oral dosage forms (Kleinert, Baker et al., 1993). One of these techniques is the masking of taste with ingredients such as flavours, sweeteners and amino acids (Sohi et al., 2004). Based on empirical testing in the literature, the flavours listed in Table 3-1 are considered to work well to mask specific tastes as indicated. Based on the information in Table 3-1, chocolate, mint and raspberry were selected for the present study because these flavours were recommended for masking bitter tastes, together with lemon (citrus) flavour because it is known that the use of citric acid is associated with enhanced salivary stimulation (Villa, Connell et al., 2015).
Table 3-1 Flavours and the tastes that they are supposed to mask (Shrewsbury, 2015; Wiener et al., 2012)
Taste to Flavour mask Cinnamon, Raspberry, Orange, Maple, Salty Butterscotch, Liquorice
Sweet Fruit, Berry, Vanilla Cocoa, Chocolate, Mint, Cherry, Walnut, Bitter Liquorice, Raspberry, Tutti fruitti Sour/Acid Fruit, Citrus, Cherry
The acceptability study requires multiple troches containing 5 mg pilocarpine to be tasted in order to determine which flavour is preferred. Therefore, this study was designed to determine the quantity of pilocarpine that would likely be swallowed during this process by measuring the time needed to make a decision on flavour perception.
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3.2. Materials and methods
The study was was conducted with healthy volunteers. The primary aim was to determine the time taken for a whole troche to be sucked until it is completely dissolved in the mouth and the time taken to get a sense of flavour when sucking five different flavoured non-medicated troches. This was required to enable estimation of the quantity of pilocarpine that may be absorbed during the acceptability trial (Chapter 4). The secondary aim was to determine which flavour troche was preferred by the participants.
This study used troches that contained flavours but not pilocarpine. Consequently, any person aged 18 years or older was able to participate. Volunteers were recruited via email invitations to staff and postgraduate students at the School of Pharmacy and the Transitional Research Institute (TRI) at the University of Queensland. Volunteers who showed interest in participating in the study were provided with the participant information sheet and asked to provide informed consent form before participation. Ethical approval was granted by the UQ School of Pharmacy Ethics Committee on behalf of the UQ Medical Research Ethics Committee (approval number 2015/12). The study was conducted at the School of Pharmacy, University of Queensland.
The following steps were undertaken: a. Participants sucked one un-flavoured non-medicated troche, compounded as previously mentioned in Chapter 2 (average weight 994 mg), until it had completely dissolved in the mouth using a timer to measure the time from start to finish. The saliva produced was swallowed whenever required. b. Participants sucked each of five different flavoured non-medicated troches for as long as necessary to get a sense of the flavour of the troche and then spat it out, with a thorough rinse with water between each. The troches were numbered, and the flavour was not revealed. Sucking time was recorded by stopwatch. The weight of the troche before and after sucking was measured (after air-drying) to estimate the proportion of troche that was swallowed by the participant during the flavour tasting. Participants rated their flavour preferences as they tasted the troches by selecting either ‘Hate/Yuk’, Don’t like’, ‘Ok’, ‘Like’ or ‘Like a lot’.
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3.3. Results
The study population was 20 healthy adult volunteers of which half were female in the age range 24- 39 years (mean age = 31 years). All of the participants were postgraduate students and staff of the School of Pharmacy, UQ.
Regarding the best selected flavour, mint had the highest preferences for non-medicated troches among this population as 35% preferred mint flavour, 30% preferred raspberry, 20% preferred chocolate, 15% preferred lemon, and none preferred the un-flavoured troches (Table 3-2).
Table 3-2 Flavour preferences selected by the particpants after sucking each of five different flavoured non-medicated troches (L:Lemon, M:Mint, C:Chocolate, R:Raspberry and U:Unflavoured).
Flavour Hate/Yuk Don’t OK Like Like a Best like lot flavour selected Lemon 2 2 4 11 1 3 Chocolate 0 3 6 9 2 4 Raspberry 0 4 4 9 3 6 Mint 0 1 4 9 7 7 Unflavoured 0 7 12 1 0 0
The mean time taken to suck a whole non-medicated troche until completion was 2.29 minutes (range: 1.42 - 3.48 minutes) (Table 3-3). The mean total sucking time taken to get a sense of the flavour of the five tasted troches was 45.3 seconds (range: 26.8-73.2 seconds). Mean sucking times to get a sense of flavour for each type of troche individually were 6.7 seconds for raspberry, 7.7 seconds for chocolate, 8.6 seconds for mint, 10.2 seconds for lemon, and 12.1 seconds for non-flavoured (Table 3-3). In terms of flavour preferences nominated by the participants, 35% preferred mint flavour, 30% preferred raspberry, 20% preferred chocolate, 15% preferred lemon, and none preferred the un- flavoured troches.
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Table 3-3 Sucking times taken by each participant to sense the flavour of the five different flavoured troches and to suck one troche to completion.
Sucking time (seconds) to sense the flavour Time (minutes) Participant Un- to suck one number Lemon Mint Chocolate Raspberry Total flavoured troche to completion 1 9.96 6.04 4.31 7.29 18.58 46.18 3.42 2 5.88 5.08 8.49 7.06 12.89 39.40 2.34 3 7.59 33.32 12.09 5.93 14.24 73.17 2.55 4 10.26 5.72 4.16 3.63 5.54 29.31 1.56 5 8.00 13.33 11.95 10.52 11.97 55.77 1.51 6 12.00 8.79 8.49 5.24 15.22 49.74 1.51 7 7.00 7.08 9.83 10.47 9.83 44.21 2.21 8 7.00 4.65 4.44 5.48 5.23 26.80 1.54 9 7.97 4.98 4.47 6.10 8.08 31.60 3.06 10 9.49 4.78 6.11 5.31 8.76 34.45 1.56 11 11.40 15.09 11.00 10.69 9.98 58.16 3.48 12 9.22 6.79 7.20 7.10 18.98 49.29 2.14 13 6.43 5.55 6.64 6.19 8.27 33.08 1.42 14 8.31 8.26 6.70 5.71 15.40 44.38 3.28 15 12.71 2.94 4.49 3.07 10.88 34.09 3.09 16 16.43 5.90 6.31 6.00 12.72 47.36 3.15 17 7.98 8.85 9.49 7.57 22.21 56.10 2.14 18 24.58 4.90 4.85 4.99 15.00 54.32 2.27 19 11.13 10.63 10.00 8.09 11.52 51.37 1.48 20 9.59 9.21 13.73 7.99 7.56 48.08 2.10 Max 24.58 33.32 13.73 10.69 22.21 73.17 3.48 Min 5.88 2.94 4.16 3.07 5.23 26.80 1.42 Mean 10.15 8.59 7.74 6.72 12.14 45.34 2.29 SD 4.22 6.56 2.98 2.10 4.53 11.59 0.73
The estimated amount of pilocarpine that would have been received by each participant if the troches had contained 5 mg pilocarpine was calculated by two methods, based on change in troche weight (Table 3-4) and based on sucking time (Table 3-5). These methods produced an average total quantity of pilocarpine that would have been absorbed of 1.9 and 1.8 mg respectively.
The average sucking time that was required by every participant to sense the flavour of the five tasted troches was 45.34 seconds (Table 3-3). The amount of pilocarpine received by each participant if the troches were medicated that corresponds to the average sucking time would have been 1.9 mg based on the weight change calculations (Table 3-4) and 1.7 mg based on sucking time calculations (Table 3-5). Assuming that the average sucking time is 50 seconds (so that each troche of the five flavoured troches can be sucked only for 10 seconds using a timer) this will correspond to 2.1 mg and 1.9 mg
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CHAPTER 3 of pilocarpine that would be absorbed based on weight change and sucking time calculations respectively.
Table 3-4 Estimated amount of pilocarpine received by each participant based on weight change. The proportion of each sucked troche that was received by each participant was calculated by subtracting the weight of the troche after sucking from the original troche weight. The weight change values were used to calculate the estimated amount of pilocarpine that would have been received by each participant if the troches had been medicated with 5 mg pilocarpine as follows: Estimated amount of pilocarpine received = weight change x 5 mg/ original troche weight
Estimated quantity (mg) of pilocarpine received during tasting based on troche weight change Participant number lemon Mint Chocolate Raspberry Un-flavoured Total
1 0.380 0.308 0.234 0.284 0.575 1.781 2 0.255 0.167 0.275 0.195 0.578 1.471 3 0.121 1.141 0.487 0.179 0.423 2.351 4 0.423 0.319 0.270 0.208 0.265 1.485 5 0.547 0.544 0.595 0.387 0.467 2.541 6 0.448 0.306 0.263 0.190 0.465 1.673 7 0.302 0.328 0.507 0.514 0.368 2.019 8 0.346 0.242 0.207 0.143 0.192 1.132 9 1.151 0.196 0.152 0.125 0.263 1.888 10 0.330 0.168 0.260 0.191 0.299 1.249 11 0.227 0.279 0.421 0.327 0.231 1.485 12 1.486 0.339 0.373 0.359 0.958 3.515 13 0.282 0.259 0.381 0.293 0.475 1.690 14 0.404 0.294 0.401 0.169 0.703 1.970 15 0.502 0.107 0.112 0.060 0.397 1.179 16 0.583 0.162 0.206 0.241 0.538 1.731 17 0.321 0.248 0.427 0.274 0.868 2.138 18 1.316 0.305 0.176 0.203 0.759 2.759 19 0.460 0.463 0.454 0.375 0.362 2.113 20 0.333 0.435 0.558 0.404 0.348 2.078 Max 1.486 1.141 0.595 0.514 0.958 3.515 Min 0.121 0.107 0.112 0.060 0.192 1.132 Mean 0.511 0.331 0.338 0.256 0.477 1.912 SD 0.368 0.218 0.141 0.112 0.212 0.576
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Table 3-5 Estimated amount of pilocarpine received by each participant based on sucking time. The time spent on sucking each troche to get a sense of flavour (taste sucking time) and the time taken to suck each troche to completion (completion sucking time) were used to calculate the estimated amount of pilocarpine that would have been received by each participant if the troches had been medicated with 5 mg pilocarpine as follows: Estimated amount of pilocarpine received = taste sucking time x 5 mg/ completion sucking time
Estimated quantity (mg) of pilocarpine received during tasting based on sucking time Participant Un- number lemon Mint Chocolate Raspberry Total flavoured 1 0.24 0.15 0.11 0.18 0.45 1.13 2 0.21 0.18 0.30 0.25 0.46 1.40 3 0.25 1.09 0.40 0.19 0.47 2.39 4 0.55 0.31 0.22 0.19 0.30 1.57 5 0.44 0.74 0.66 0.58 0.66 3.08 6 0.66 0.49 0.47 0.29 0.84 2.75 7 0.26 0.27 0.37 0.39 0.37 1.67 8 0.38 0.25 0.24 0.30 0.28 1.45 9 0.22 0.14 0.12 0.17 0.22 0.86 10 0.51 0.26 0.33 0.28 0.47 1.84 11 0.27 0.36 0.26 0.26 0.24 1.39 12 0.36 0.26 0.28 0.28 0.74 1.92 13 0.38 0.33 0.39 0.36 0.49 1.94 14 0.21 0.21 0.17 0.15 0.39 1.13 15 0.34 0.08 0.12 0.08 0.29 0.92 16 0.43 0.16 0.17 0.16 0.34 1.25 17 0.31 0.34 0.37 0.29 0.86 2.18 18 0.90 0.18 0.18 0.18 0.55 1.99 19 0.63 0.60 0.56 0.46 0.65 2.89 20 0.38 0.37 0.54 0.32 0.30 1.91 Max 0.90 1.09 0.66 0.58 0.86 3.08 Min 0.21 0.08 0.11 0.08 0.22 0.86 Mean 0.40 0.34 0.31 0.27 0.47 1.78 SD 0.18 0.24 0.16 0.12 0.19 0.64
3.4. Conclusion
After sucking five different flavoured non-medicated troches until sensing that flavour, the estimated amount of pilocarpine that would be received by each participant for medicated troches is about 2 mg when calculated by either weight change calculations or sucking time calculations. As the widely recognised therapeutic dose of pilocarpine is 5 mg, this total dose is considered sub-therapeutic. The average time to suck a troche to completion was 3 minutes and 18 seconds. Mint and raspberry had the highest number of preferences with 35% and 30% of the participants preferring them, respectively.
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Chapter 4. Acceptability testing of dosage forms for buccal delivery of pilocarpine
4.1. Introduction
This study describes an acceptability study to determine the most acceptable formulation (troches or orally dissolving tablets) and flavour (lemon, chocolate, raspberry, mint or un-flavoured) according to people with and without xerostomia. The design of the study was based on the results described in Chapter 3, in which it was found that 10 seconds should be enough time to sense the flavour of a troche. Furthermore, sucking 5 troches containing 5 mg pilocarpine, each for less than 10 seconds, would be expected to result in a participant a sub-therapeutic dose of pilocarpine (approximately 2 mg).
The primary aim of this acceptability study was to determine the preferred dosage form of pilocarpine (troches or the ODTs) as well as the preferred flavour to disguise the bitter taste of pilocarpine. By conducting the study in both healthy individuals and those with xerostomia, it was hoped to reveal whether there were any differences regarding the dosage form and flavour preferences selected according to each participating group. Additionally, this study presented the opportunity to ask participants suffering with xerostomia about the impact of xerostomia upon their flavour preferences i.e. the flavour preferences before and after experiencing xerostomia.
4.2. Experimental design
The study population consisted of adults who do and do not suffer from xerostomia, and adults with xerostomia caused by any aetiology and living in the community. Inclusion criteria for healthy volunteers were (1) aged 18 years or older, (2) provided informed consent. Inclusion criteria for dry mouth participants were (1) currently experiencing xerostomia, both diagnosed and self-reported, (2) aged 18 years or older, (3) provided informed consent.
Participants were excluded if they met any of the following criteria:
a. Ocular problems contraindicating the use of parasympathetic agents (e.g. irido-cyclitis, increased intra-ocular pressure) b. Other comorbidity where there is a risk of worsening co-existing medical problems during the study period
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c. A change to active treatment is contemplated e.g. severe or uncontrolled asthma or pulmonary disease, uncontrolled hypo-or hypertension, hyperthyroidism, uncontrolled seizures or cardiac arrythmias, (especially bradycardias) and Parkinson's disease d. An active oral infection i.e. candidiasis, herpetic infections, mucositis or mouth ulcers e. Known hypersensitivity to pilocarpine, chemically related drugs, or non-steroidal anti- inflammatory drugs f. Suspected or confirmed pregnancy (self-report) g. A poor understanding of written or spoken English that would preclude completion of all study requirements Healthy volunteers were recruited via email invitations to staff and postgraduate students at the School of Pharmacy and the Transitional Research Institute (TRI) at the University of Queensland. Patients living with xerostomia were recruited through advertisement of the project in the 'Volunteers' section of the UQ Update e-newsletter, and via email and social media invitations disseminated by Brisbane-based head and neck cancer support groups, and through Cancer Council Queensland.
Prior to undertaking the study, volunteers were provided with a participant information sheet and provided informed consent. The acceptability study was approved by the University of Queensland Human Research Ethics Committee A (approval number 2016001436) and was conducted at the School of Pharmacy, University of Queensland.
At baseline, participants were asked to undertake the following tasks: 1. Complete the contact details form and a questionnaire regarding their demographics (age, gender, country of birth and ethnicity) and medical history including medical conditions and all current medications. 2. Participants with xerostomia completed a questionnaire about the aetiology of their dry mouth and completed the xerostomia questionnaire. This xerostomia questionnaire contained 15 questions and gives a measure of the severity of radiation-induced xerostomia as it affects patient quality of life such as the effect of xerostomia on: physical functioning, pain and discomfort issues, personal/psychological functioning and social functioning (Pellegrino, Groff et al., 2015). The xerostomia questionnaire was developed and validated at the University of Michigan. 3. Complete the product tasting: Participants were asked to: a. Rinse the mouth thoroughly with water then place a troche containing 5 mg pilocarpine on the tongue and hold it there for 10 seconds and then spit it out of the mouth and back into the labelled container. Complete a 4-point scale (strongly dislike, dislike, like, strongly like) to provide an opinion of the acceptability of the flavours tasted. Rinse the mouth thoroughly with water. Repeat for each of four other troches containing different flavours. The order that 93
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troches were tasted was randomised for each participant; the troches were numbered, and the flavour was not revealed to the investigator or the participant. b. Select the favourite troche from the five tasted. c. Hold a non-medicated troche in the mouth until it completely dissolved. After rinsing the mouth with water, hold a non-medicated ODT in the mouth until it is completely dissolved, and consider the acceptability of the dosage form. These both contained the flavour selected by each participant as the favourite in part b. 4. After completing the product tasting part, participants were asked to complete the flavour preferences questionnaire. Participants with xerostomia completed an extra question to rate their flavour preferences (avoid/accept/prefer) towards mint, lemon, chocolate and raspberry flavours before and after experiencing xerostomia.
4.3. Results
A total of 48 participants were recruited, 34 healthy volunteers and 14 people with dry mouth. A greater proportion of females than males participated, and the majority of them were of Caucasian/European ethnicity (Table 4-1).
Table 4-1 Demographic results of the healthy participants and participants with xerostomia in the acceptability taste testing study.
Healthy volunteers Dry mouth participants
n 34 14
Females % 62.5 82
Age range 19-69 23-74 (SD= 12, Mean=35.5) (SD= 17.6, Mean=51.5)
Ethnicity 32% Caucasian/European, 60% Caucasian/European, 26% Asian, 15% Maori, 18% Caucasian, 15% Asian, 18% Indian, 15% Australian/Aboriginal, 3% African, 15% Japanese/European 3% Iranian
The cause of the dry mouth was head and neck cancer (HNC; squamous cell carcinoma to the tongue, tonsils and others) for seven participants, Sjogren’s syndrome (Ss) for three, medication-induced for two (amitriptyline used for migraine treatment; lithium carbonate used as mood stabiliser) and two with non-identified aetiology of dry mouth. All the head and neck cancer patients received either chemotherapy and/or radiotherapy and/or surgery for the treatment of their malignant tumours within 94
CHAPTER 4 six months to one year prior to participation in this study. All the dry mouth participants were drinking or sipping water more frequently as a current treatment for their dry mouth. Some of them tried other interventions such as gargling the mouth with Biotene products (mouthwash, spray, and gel), brushing their teeth with Biotene toothpaste or any other fluoride rich toothpaste, chewing sugar free gums and mints, or using XyliMelts oral adhering tablets. Other interventions for dry mouth relief included receiving acupuncture treatment and massaging the parotid gland daily.
4.3.1. Flavour preferences
Lemon was the preferred troche flavour among healthy volunteers followed by raspberry, whereas raspberry was the flavour preferred among dry mouth participants followed by chocolate and lemon (Table 4-2).
Table 4-2 Flavour preferences among healthy volunteers and dry mouth participants, showing the number and % of people who chose each flavoured medicated troche as their favourite.
Flavours Healthy volunteers, n=34 Dry mouth participants, n=14
Lemon 12 (34%) 3 (21%)
Raspberry 7 (21%) 5 (36%)
Mint 5 (15%) 1 (7%) Chocolate 5 (15%) 3 (21%) Un-flavoured 5 (15%) 2 (14%)
For dry mouth participants, their perception of any change in flavour preferences towards lemon, raspberry, mint and chocolate flavours before and after experiencing dry mouth was investigated (Table 4-3). The majority of participants with dry mouth reported experiencing changes in their preferences towards two or more of the four flavours (Table 4-4). These were 57% of the participants with dry mouth secondary to previously treated HNC, all of the participants with dry mouth resulting from Ss, and half of the participants with medication-induced xerostomia or non-identified cause of their dry mouth.
Flavour preferences among participants with dry mouth were also analysed according to participants’ gender and age. The majority of men preferred raspberry flavour (60%), while 20% preferred chocolate and 20% preferred lemon flavour. No men preferred either mint or the un-flavoured troches. Among women, there was no particular flavour that was preferred by most of them, with equal numbers preferred lemon, raspberry, chocolate and the un-flavoured troches (22% for each flavour) and 11% preferred the mint-flavoured troches. 95
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According to the age range, most of the young aged-participants (age range from 23-45 years) preferred the un-flavoured troches (40%) and had equal preferences to raspberry, lemon and mint flavours (20% each). For the participants with age range from 52-74 years, raspberry was the most flavour preferred (44.5%), followed by chocolate (33.5%) while lemon was the least preferred flavour (22%) and none preferred either the mint or the unflavoured troches.
Table 4-3 Preferences (preferred, accepted, avoided) before and after experiencing xerostomia reported by dry mouth participants for flavours – chocolate (C), raspberry (R), lemon (L) and mint (M).
Before Xerostomia After Xerostomia
b
a
flavour
Age C R L M C R L M
Gender
Aetiology
% % Change
articipant no.
P Preferred Preferred
1 57 M HNC C Preferred Preferred Accepted Accepted Preferred Preferred Avoided Accepted 25 2 71 M HNC L Preferred Accepted Accepted Accepted Avoided Accepted Accepted Accepted 25 3 57 F HNC R Preferred Preferred Preferred Preferred Preferred Preferred Accepted Accepted 50 4 74 F Ss C Preferred Accepted Accepted Preferred Avoided Preferred Preferred Preferred 75 5 23 F MI R Accepted Accepted Preferred Accepted Accepted Accepted Preferred Avoided 25 6 23 F MI L Accepted Avoided Avoided Accepted Preferred Accepted Accepted Accepted 75 7 45 F HNC U Preferred Preferred Preferred Preferred Avoided Accepted Avoided Avoided 100 8 40 F Ss U Accepted Accepted Preferred Avoided Preferred Accepted Preferred Accepted 50 9 71 F Ss C Preferred Preferred Avoided Preferred Accepted Accepted Avoided Preferred 50 10 27 F NI M Preferred Preferred Accepted Preferred Preferred Preferred Accepted Preferred 0 11 53 F NI L Preferred Accepted Accepted Accepted Accepted Avoided Accepted Accepted 50 12 60 M HNC R Preferred Preferred Preferred Preferred Accepted Accepted Accepted Accepted 100 13 66 M HNC R Preferred Preferred Accepted Accepted Accepted Preferred Accepted Accepted 25 14 52 M HNC R Preferred Preferred Preferred Preferred Avoided Avoided Preferred Preferred 50 a HNC: head and neck cancer; Ss, Sjogren’s syndrome; MI, medication-induced; NI, non-identified cause were the four listed causes of dry mouth. b 25% change refers to only one flavour preference change after experiencing xerostomia, 50% change refers to 2 flavour preferences changed after experiencing xerostomia, 75 % change refers to 3 flavour preferences changed after experiencing xerostomia and 100% change refers to all 4 flavour preferences changed after experiencing xerostomia.
The numbers of participants that said that they either preferred/accepted or avoided the 4 tested flavours before and after experiencing xerostomia (Table 4-3) were not the same as their actual flavour preferences (Table 4-2). For example, participant #4 selected chocolate troche as his preferred flavour in the actual taste testing, while he rated chocolate as an avoided flavour after experiencing xerostomia. Similarly, participant #14 preferred raspberry flavour troches in the taste testing, while he rated raspberry as an avoided flavour after experiencing xerostomia.
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Table 4-4 Numbers of dry mouth participants who preferred/accepted/avoided the four given flavours before and after experiencing xerostomia
Flavour Preferred Accepted Avoided Before Xerostomia 8 5 1 Raspberry After Xerostomia 5 7 2 Before Xerostomia 11 3 0 Chocolate After Xerostomia 5 5 4 Before Xerostomia 6 6 2 Lemon After Xerostomia 4 7 3 Before Xerostomia 7 6 1 Mint After Xerostomia 4 8 2
4.3.2. Dosage form preferences
All of the participants with xerostomia and the majority (70%) of the healthy volunteers preferred the ODT rather than the troche (Table 4-5). The reasons given by the participants for that preference were faster dissolution, easier consumption and smaller size of ODT (75 mg) compared to troche (994 mg). Small size of ODT is particularly important for people with hemiglossectomy, where part or all of the tongue is surgically removed due to malignancy and the remaining part of the tongue cannot deal with large sized troches. Other reasons included social acceptability and enjoyment of ODT more than the troche.
Table 4-5 Participants’ preferences for ODT or troche as a dosage form if they had to take it regularly
Healthy volunteers, n=34 Dry mouth participants, n=14 ODT 24 (70%) 14 (100%) Troche 10 (30%) 0 (0%)
4.4. Discussion
Dry mouth can lead to taste alterations where patients either lose their sense of taste completely or everything tastes the same (a persistant metallic or salty taste in the mouth). Reduced salivary output also casues changes in ionic composition of saliva which is correlated to the impaired taste sensations (Spielman, 1998). Additionally, many studies concluded that the disintegration rate is various in patients with dry mouth, so people with dry mouth should be advised to rinse their mouth with 3 ml of water before administration of oral pilocarpine dosage forms (Rolan, Lim et al., 2013).
The present study revealed that all the dry mouth participants with previously treated HNC experienced flavour preference changes due to the treatment received, which is comparable to the 97
CHAPTER 4 results obtained by Epstein et al. (1999) where 75% of the HNC patients who had completed their radiation therapy more than six months earlier reported taste changes (Epstein et al., 1999a). Taste alterations are reported in most HNC patients who have been treated with either chemotherapy or radiotherapy (Spielman, 1998). For those who receive radiotherapy for the treatment of their cancer, 70-100% of them usually suffer from altered taste (Epstein & Barasch, 2010). Sometimes taste alterations are due to the malignancy itself and not due to the treatment received (Ruo Redda et al., 2006). Taste impairment caused by radiotherapy is either directly due to direct damage to the taste receptors and taste buds or indirectly through reduced delivery of molecules to the receptor sites and hence reduced exposure of receptors to salivary-delivered growth factors caused by hypo-salivation (Spielman, 1998).
All three people with Ss reported experiencing changes in their taste preferences before and after suffering from xerostomia. This supports the study of Henkin et al. (1972) as 29 people with Ss had a significant decrease in their taste acuity (Henkin, Talal et al., 1972).
Numerous drugs also can negatively influence taste perception either by decreasing the function of the taste buds or by producing unreal taste and in some cases these effects are long lasting and don’t disappear by drug cessation (Doty, Shah et al., 2008). The two medications that were consumed by the patients were amitriptyline and lithium carbonate, both are known to cause dry mouth and altered taste (Schiffman, Zervakis et al., 1999; Terao, Watanabe et al., 2011).
Interestingly, in this study we found that the troche flavour preferences didn’t necessarily match with the flavour preferences questionnaire among the dry mouth participants. This might be because the flavours used in this study are pharmaceutical flavours, which differ from the natural flavour of the relevant food. Another reason might be because the flavours were used in combination with pilocarpine and the final taste of that added flavour differs after mixing it with the drug than the natural flavour taste. Indeed, in this chapter it was determined that 34% of the healthy volunteers preferred lemon and only 15% preferring mint for 5 mg pilocarpine troches. However, when troches were non-medicated (Chapter 3) 35% preferred mint and 15% preferred lemon.
4.5. Conclusion
For the participants with xerostomia, the raspberry flavour was the preferred flavour by the most participants, and all the participants preferred the ODT more than the troche dosage form for the delivery of pilocarpine. Therefore, raspberry ODTs were selected as the dosage form for further study.
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Chapter 5. A series of N-of-1 clinical trials to assess the efficacy of 5 mg pilocarpine ODTs in the treatment of dry mouth
5.1. Introduction
The aim of this chapter was to assess the efficacy of 5 mg pilocarpine ODTs compared to placebo ODTs in the treatment of dry mouth of different aetiologies in a prospective, double-blinded, series of N-of-1 clinical cross-over trials. Raspberry flavoured ODTs were chosen as the dosage form to be tested for delivering 5 mg pilocarpine based on results of the acceptability study described in Chapter 4. The study is described according to the recommendations of the CONSORT statement for reporting N-of-trials (CENT) 2015 (Shamseer, Sampson et al., 2015). Therefore, this study set out to test pilocarpine ODTs using the same trial design and with a wider range of assessments to monitor objective and subjective measures of dry mouth and quality of life.
5.1.1. Background
Xerostomia is the subjective feeling of dry mouth, resulting from Sjögren’s syndrome, and treatments such as radiotherapy (especially to the head and neck region) and chemotherapy. It can also follow the regular use of certain medications including anticoagulants, antidepressants, steroid inhalers and others. People with xerostomia suffer from dryness of mouth, lips and throat. Additionally, they suffer from more complicated consequences of dry mouth such as dental caries, oral mucositis and enhanced tooth decay. They commonly suffer from impaired oral communication with others leading to emotional distress. They have problems with moistening, chewing and swallowing foods as well as taste alterations associated with reduction in salivary flow that can affect their ability to taste food. These consequences can lead to decreased food consumption, which can cause malnutrition and further suppression of their immune defence mechanisms with increased risk of morbidity and reduced quality of life.
Some approaches to dealing with xerostomia include sipping fluids such as water more frequently to moisten the oral mucosa, chewing sugar free gum to stimulate more saliva secretion, and using saliva replacement gels or drops. However, these strategies often do not provide sufficient relief. Thus, a strong rationale exists for a medication to help treat dry mouth symptoms.
Pilocarpine oral tablets (Salagen) are available in at least 24 countries including USA, Canada, UK and a wide range of countries across Europe, South America and Asia. In these countries, Salagen tablets are prescribed for the treatment of dry mouth secondary to radiation-induced xerostomia and
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Sjögren’s syndrome (Pfizer Canada, 2014). Pilocarpine is a parasympathomimetic agent that directly stimulates the cholinergic receptors on the surface of exocrine glands including salivary glands, resulting in increased salivation (Jorkjend et al., 2008). An oral dose of 5 mg pilocarpine in the form of tablets or capsules to be taken three times daily produces the most effective therapeutic response according to many clinical studies (Hamlar et al., 1996; Taweechaisupapong et al., 2006).
An oral dosage form of pilocarpine is not commercially available in Australia. The available preparations of pilocarpine in Australia are 1% and 2% eye drops, which are registered on the ARTG for the treatment of glaucoma. Thus, physicians currently prescribe these ophthalmic preparations ‘off-label’ to be taken by mouth for the treatment of xerostomia. Unfortunately, they taste very bitter and so compromise patient compliance, which affects their health status and overall quality of life (Nikles et al., 2013). This study investigates the potential for ODTs, which can be compounded in local community pharmacies, to be used as a dosage form to deliver 5 mg pilocarpine for the treatment of dry mouth.
N-of-1 methodology was selected for this trial because it can provide a way to evaluate the effects of a treatment for each participating individual. It is listed as Level 1 evidence in the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence (Oxford Centre for Evidence-Based Medicine, 2016). N-of-1 trials are multiple-cycle (usually 3 cycles), double blind, placebo-controlled crossover trials using standardised measures of effect. Within each cycle, the participant takes the placebo and the test treatment, with the order of the placebo and test being randomised. At the end of the trial the order is revealed, and the participant response is compared against the presence or absence of the test treatment.
Individual participants receive direct evidence about the effect of the test treatment versus the comparator on their own symptoms, allowing treatment to be tailored to the individual. A series of N-of-1 trials of a given test treatment can be combined to yield an estimate of the population effect. Using a Bayesian analysis, data from individuals who have completed at least one cycle can be included in the final analysis, thereby reducing loss of data from non-completion. By comparison, in parallel arm RCTs, withdrawal of a participant may lead to the loss of all data collected for that individual, and consequently larger numbers of participants are required for RCTs than N-of-1 trials (Nikles et al., 2015). There are some limiting factors for the success of N-of-1 trials as they work best where the half-life of a treatment is short, there is immediate onset and offset of action and the medicine does not alter the actual condition (Nikles et al., 2015). Pilocarpine is a suitable medication in this regard.
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Members of the supervisory team have previously conducted a trial to test whether pilocarpine eye drops given orally help treat dry mouth in patients with advanced cancer using N-of-1 trials (ANZCTR: 12610000840088). The trial was conducted in palliative care units of seven hospitals across Queensland and New South Wales. Eligible participants had advanced cancer and were suffering from dry mouth. Each participant was offered three cycles of pilocarpine drops 4%, each 6 mg tds (3 days) and placebo drops (3 days) in random order, to a total of 18 days. The results showed that administration of pilocarpine drops helped to improve the dry mouth fatigue in 50% of the participants. However, the tested eye drops were unacceptable in taste to most participants and caused over-salivation, leading to high rates of withdrawal from the trial. They concluded that the pilocarpine eye drops were not suitable for oral use and they stressed the need for more work to determine an appropriate formulation, dose and method of delivery of pilocarpine (Nikles et al., 2015).
5.1.2. Aims
Primary aim To assess the efficacy of 5 mg pilocarpine ODTs compared to placebo on symptomatic improvement of xerostomia using a series of N-of-1 trials.
Secondary aims • To assess the efficacy of 5 mg pilocarpine ODTs compared to placebo on the weight of saliva produced as a result of the given interventions and collected by the participant across the three cycles of the study. • To assess the efficacy of 5 mg pilocarpine ODTs compared to placebo on the given questionnaires; SXI-D, VAS and each of the three domains of the EQ-5D and OHIP scores across the three cycles of the study. • To report any experienced adverse events following the use of 5 mg pilocarpine ODTs and placebo across the three cycles of the study. • To report the need to use other saliva substitutes while taking 5 mg pilocarpine ODTs and placebo across the three cycles of the study.
5.2. Methods
5.2.1. Trial design
The study consisted of a series of N-of-1 (single patient) trials of 5 mg pilocarpine ODTs (treatment) vs matching placebo ODTs (control) as a treatment for dry mouth, taken 3 times daily.
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Participants completed 18 days of treatment, consisting of 3 cycles. Each cycle contained two periods: 3-days treatment, 3-days placebo (Fig. 5-1). The order of treatment and placebo was randomly allocated for each cycle. Treatment allocation was blinded to the participant and to the trial coordinator. Data collected on the first day of each period was not included in the analysis because it was considered to be the washout between cycles. A wash out period of 1 day was considered to be sufficient given the short half-life of pilocarpine (Gornitsky et al., 2004; Wiseman & Faulds, 1995) as used previously (Nikles et al., 2015).
Figure 5-1 Flow diagram of the N-of-1 design scheme used in this study with an example randomisation schedule shown
Participants took one dose of trial medication 60 minutes prior to breakfast, lunch and dinner, each day for the 18-day trial. They collected saliva samples in pre-labelled tubes, twice daily, 60 minutes after taking the breakfast and dinner doses. Participants completed a daily diary recording symptom scores using validated measures for dry mouth and related symptoms, the presence of any side effects and their estimate of which drug they believe they were taking at the time. At the end of the trial, the order of medications within each of the three cycles was unmasked and compared with the participant’s observations. The study protocol was written according to the checklist that was developed by SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) which is a guideline to the minimum content of a clinical trial protocol (Chan, Tetzlaff et al., 2013).
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5.2.2. Selection and Enrolment of Participants
Inclusion criteria • Males and females aged 18 years or over.
• To ensure that xerostomia was significant enough to warrant treatment with pilocarpine, participants must self-report xerostomia of any aetiology as a score of 3 or more on a numerical rating scale of oral dryness from 0 – 10 (where 0 = no dry mouth and 10 = worst possible dry mouth) (Nikles et al., 2013).
• As pilocarpine action requires some residual salivary function, participants must self-report evidence of saliva production in the mouth upon chewing a piece of gum (Hamlar et al., 1996).
• Participants were able and willing to give appropriate informed consent.
Exclusion criteria • Ocular problems contraindicating the use of parasympathetic agents (e.g. irido-cyclitis, increased intra-ocular pressure).
• Other comorbidity where there was a risk of worsening co-existing medical problems during the trial period and/or active treatment is contemplated. For example, severe or uncontrolled asthma or pulmonary disease, uncontrolled hypotension or hypertension, hyperthyroidism, uncontrolled seizures or cardiac arrhythmias, (especially bradycardias) and Parkinson's disease. If these diseases are well controlled, they do not constitute exclusion criteria.
• An active oral infection i.e. candidiasis, herpetic infections, mucositis, mouth ulcers.
• Suspected or confirmed pregnancy.
• Intervention (e.g. radiotherapy, chemotherapy, surgery) that might alter dry mouth symptoms during the 2 weeks prior to the study period or plans to undergo such therapy during the study period.
• Plans to change any medication with the potential to cause dry mouth within the trial period.
• Plans to use any other prescribed medication known to increase saliva production and relieve dry mouth during the trial period. Patients already taking pilocarpine were eligible but must have stopped taking it 1 week before trial commencement.
• A poor understanding of written or spoken English that would preclude completion of all trial requirements.
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Study Enrolment Procedures Participants with dry mouth symptoms were recruited via various patient support groups including: Cancer Council Queensland, Head and Neck Cancer support group, Cancer Connections online space, the Australia & New Zealand Head and Neck Cancer Society and the Australian Sjögren’s syndrome Association. Additionally, requests for participation were included in the UQ electronic newsletter, UQ Faculty of Health and Behavioural Sciences Facebook page and UQ School of Pharmacy Facebook page. Recruitment by social media (Facebook) included: Head and neck cancer survivors’ support network, Survivors of head and neck cancer, Angel’s national oral head and neck cancer awareness event, Head and Neck Cancer Support Australia and Sjogren’s syndrome support group, and community-based dentists. People who were interested in participating in the study were provided with a participant information sheet, followed by interview in person or by telephone, in which the purpose and requirements of the trial were fully explained. They were asked to complete a form with their contact details and those of their regular Medical Practitioner (MP), and to give the study team authorization to contact their MP (Form Z).
As a participant may not be aware that they have a condition that should exclude them from participation, we contacted their regular MP to confirm eligibility. The MP was asked to complete a form to indicate whether they have or do not have any of the conditions that would exclude them from participating (Form E). In the event that the potential participant did not have a regular MP or the MP does not respond, the study clinician undertook a medical interview with the potential participant to establish eligibility. Confirmation of eligibility was recorded in Form S.
The patient was then invited to attend the study center, the UQ School of Pharmacy building, 20 Cornwall Street, Woolloongabba, or to take part in an online video teleconference, where they again received a explanation of the trial. Fully informed patients were asked to sign written consent before registration into the trial, and then were registered with the trial (Form S) and baseline investigations undertaken (Form B). Details and any reasons for non-eligibility were recorded in the screening log (Log S) for all potentially eligible patients approached.
5.2.3. Intervention
The trial consisted of 3 cycles, each containing two periods: 3-days treatment, 3-days placebo. The order of treatment and placebo was randomly allocated for each cycle. Treatment allocation was blinded to the participant and the trial co-ordinator. Participants took one dose of trial medication 60 minutes prior to breakfast, lunch and dinner, each day for the 18-day trial.
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Pilocarpine ODTs were compounded by the trial coordinator to contain the components given in Table 5-1 using the compounding method described in Chapter 2. Placebo ODTs were prepared to match the flavour of the treatment ODTs (Table 5-2). Pilocarpine ODTs were selected in the weight range between 70-80 mg to ensure pilocarpine in the range 5 ± 0.25 mg based on the results obtained in Chapter 2. Placebo ODTs in the same weight range were selected to match the treatment ODTs.
Table 5-1 Treatment ODT formula for the preparation of 60 ODTs, each weighing 75 mg and containing 5 mg pilocarpine, with 10% excess included to account for wastage during compounding.
Ingredient Name Quantity Unit Pilocarpine Hydrochloride 0.327 g Raspberry Flavour (Powder) 0.5 g Bitterness Reducing Agent (NF01) Natural (Powder) 0.33 g Stevia Powder (Stevioside) 0.11 g Medi-RDT Base 3.68 g
Table 5-2 Placebo ODT formula for the preparation of 60 ODTs, each weighing 75 mg, with 10% excess included to account for wastage during compounding.
Ingredient Name Quantity Unit Raspberry Flavour (Powder) 0.22 g Bitterness Reducing Agent (NF01) Natural (Powder) 0.55 g Stevia Powder (Stevioside) 0.22 g Medi-RDT Base 3.96 g
5.2.4. Outcomes
5.2.4.1. Primary outcome
Symptomatic improvement in xerostomia was assessed using the oral dryness component of the Subjective Rating of Symptoms (SRoS) questionnaire. The SRoS contains three questions related to oral dryness, soreness of mouth and speaking ability that are each scored on an 11-point numerical rating scale (0-10). The oral dryness question component of the SRoS was used to assess primary outcome in this study, as done previously (Nikles et al., 2013). The SRoS numerical rating scale was set up with positive responses as the left anchor (Not dry, Comfortable and Easy) and with negative responses as the right anchor (Extremely dry, Extreme discomfort and Extremely difficult) such that a score of 0 refers to no complaint and score of 10 refers to the worst possible complaint. This tool is
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5.2.4.2. Secondary outcomes
A range of secondary outcome measures were used to allow assessment of any potential change in xerostomia or quality of life associated with the treatment.
Saliva production was measured as the amount of saliva secreted in 3 minutes compared to baseline salivary output. Participants were instructed to spit any saliva produced during a 3-minute period into a pre-labelled tube. This was performed twice daily, 60 minutes after taking the breakfast and dinner doses. Participants were asked to store tubes in a fridge until the end of the trial. After return of the tubes to the laboratory, tubes were weighed, and the weight of saliva collected was calculated as the difference between the original tube weight and its weight after saliva collection.
Summated Xerostomia Inventory - Dutch Version (SXI-D) was used to assess the severity of xerostomia, a validated summated rating scale (Thomson, Van der Putten et al., 2011). The SXI-D is a five-item questionnaire with three responses representing three scores. The responses are: Never (score 1), Occasionally (score 2) and Often (score 3). Responses to each question were summed to give a single XI score. This version is shortened from the original 11-items and although it is called ‘Dutch Version’, the language used is English (Thomson, Chalmers et al., 1999). The SXI-D has been tested in a number of diverse samples of elder people (≥60 years) from Australia, The Netherlands, Japan and New Zealand and is a valid measure for discriminative use in clinical and epidemiologic research. The 5 items in this version are more focused on the dry mouth syndrome rather than burning mouth syndrome of the 11 items in the original version. In line with the recommendation provided by the authors, as with the original XI, it was used in tandem with the standard question on xerostomia “How often does your mouth feel dry?” with four response options “Never”, “Occasionally”, “Frequently” and “Always”. The SXI-D and standard question were self-measured daily throughout the trial.
Xerostomia-related Quality of Life Scale (XeQoLS) was used to assess quality of life. The XeQoLS is a 15-item validated questionnaire (Henson, Inglehart et al., 2001) that deals with four aspects (‘domains’) that can be affected by a participant’s xerostomia: physical functioning (responses to questions 1, 6, 10, 12), pain/discomfort issues (responses to questions 2, 3, 7, 9), personal/physiological functioning (responses to questions 8, 13, 14, 15) and social functioning (responses to questions 4, 5, 11). Each XeQoLS domain score was calculated by averaging the values
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EQ-5D was used to measure overall health status. The EQ-5D is a validated questionnaire that was created by the EuroQol group (Rabin & Charro, 2001). It consists of five questions for classification of health status and a 100 mm visual analogue scale (VAS) to provide a self-rating of health. The EQ- 5D has been used as a useful tool for assessing the quality of life of patients with different diseases such as those suffering from Parkinson’s disease (Schrag, Selai et al., 2000) and is used in many countries by researchers in a number of clinical disciplines. Note that in contrast to all other measures used in this study, the VAS is scored such that a high score indicates better health. The EQ-5D was self-measured at the end of each 3-day period for the duration of the trial.
Oral Health Impact Profile (OHIP) was used to measure oral health. OHIP is a 14-item questionnaire that has been validated in a population with xerostomia (Baker, Pankhurst et al., 2006). This questionnaire is designated to measure the frequency of problems associated with the mouth, teeth, or dentures on seven dimensions: functional limitation (1, 2), pain (3, 4), psychological discomfort (5, 6), physical disability (7, 8), psychological disability (9, 10), social disability (11, 12) and handicap (13, 14). The ratings to these questions are on a five-point scale from 0 (never) to 4 (very often). Two summary measures were calculated: additive and number of impacts. The additive measure is the unweighted sum of all items (0-56) (OHIP-additive) with higher scores indicating poor oral health. The impact measure is the number of items rated as 2 or above (i.e. occasionally, often and very often) (range 0-14) (OHIP-impacts) with higher scores indicating a greater number of impacts. This questionnaire was self-measured at the end of each 3-day period.
Other secondary outcomes were
a) Adverse events (according to NCI Common Terminology for Adverse Events), selected from a list of potential adverse events associated with pilocarpine. b) Assessment of the daily use of other saliva substitutes and / or medications. Consideration of use was important because it may affect their rating of the Subjective Rating of Symptoms questionnaire. c) Participants’ opinion at the end of each day of whether they took the intervention or placebo was considered as an indication of adequate blinding.
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5.2.5. Schedule of assessments
After completing screening and registration, participants completed the full set of assessments at baseline. Then participants completed particular assessments at different stages of the trial as detailed in Table 5-3.
Table 5-3 Schedule of assessments
Evaluation Pre-trial Baseline Cycle 1 2 3 Contact Details • Patient, next of kin, MP; Consent to contact MP X Contact MP to confirm eligibility of patient to join trial X Screening and Registration: • Informed consent to join trial X • Demographics (age, sex) X • Oral dryness numerical rating scale (0-10) X • Re-confirm eligibility X Baseline CRF assessments: • Perceived cause of xerostomia X • Treatments used to ease dry mouth X • Subjective Rating of Symptoms Questionnaire (SRoS) X • Xerostomia Inventory (SXI-D) X • Xerostomia-related Quality of Life Scale (XeQoLS) X • Overall health status (EQ-5D) X • Oral Health Impact Profile (OHIP) X • Symptom (Adverse Events) Checklist X Daily diary assessments: • Day 1 pre-dose saliva collection X • Day 1 pre-dose Subjective Rating of Symptoms Questionnaire X • Morning ODT ➢ Morning saliva collection X X X ➢ Subjective Rating of Symptoms Questionnaire X X X • Afternoon ODT ➢ Subjective Rating of Symptoms Questionnaire X X X • Evening ODT ➢ Evening saliva collection X X X ➢ Subjective Rating of Symptoms Questionnaire X X X ➢ Xerostomia Inventory (SXI-D) X X X ➢ Other saliva substitutes/ medications X X X ➢ Symptom (Adverse Events) Checklist X X X At the end of each 3-day experimental period: ➢ Xerostomia-related Quality of life Scale XeQoLS X X X ➢ Overall health status (EQ-5D) X X X ➢ Oral Health Impact Profile (OHIP) X X X ➢ Which medication do you think you were taking in X X X the last 3 days? Phone diary assessment on the 3rd day of each period: ➢ Symptom (Adverse Events) Checklist X X X ➢ Treatment Compliance X X X
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5.2.6. End-points
5.2.6.1. Primary end-point
Mean change from baseline in the oral dryness component of the Subjective Rating of Symptoms questionnaire (SRoS) across the 3 cycles of the trial; an improvement of 2 or more on the 0-10 NRS compared to baseline was classified as a response (Nikles et al., 2013). Repeated results in the same direction favouring the treatment over the placebo control for primary outcomes in at least two of three cycles was taken as an indication that the result is true for the individual participant (Nikles et al., 2013).
5.2.6.2. Secondary end-points
• Mean change from baseline in weight of saliva across the 3 cycles of the trial. • Mean change from baseline in the SXI-D scores across the 3 cycles of the trial. • Mean change from baseline in the XeQoLS score across the 3 cycles of the trial. • Mean change from baseline in the scores for each of the three domains and the VAS of the EQ- 5D across the 3 cycles of the trial. • Mean change from baseline in the global score for the Oral Health Impact Profile (OHIP) across the 3 cycles of the trial. • Differences between treatment and placebo in adverse events during the 3 cycles of the trial. • Differences between treatment and placebo regarding the need to use other saliva substitutes during the 3 cycles of the trial. • Each participant’s opinion of whether they had taken the treatment or placebo over the previous three days.
5.2.7. Sample size
Sample size requirement for statistical analysis of a series of aggregated case studies was calculated by the study statistician using information derived from the previous trial conducted by members of the supervisory team (Nikles et al., 2013). It was predicted that 106 cycles would be required to detect a 2-point change in numerical rating scale for dry mouth between treatments with 80% power at the 5% level of significance, and that allowing for dropouts, these would be delivered by 42 people. However, in a cross-over, double blinded, placebo controlled trial of pilocarpine lozenges in 33 participants (with previous head and neck cancer), all 33 participants satisfactorily completed the 31 day trial to the end without any noted side effects (Taweechaisupapong et al., 2006). In the present trial design, if all participants complete all three cycles, 35 participants would suffice. 109
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The major causes of xerostomia include previously treated head and neck cancer, Sjogren’s Syndrome, elderly people and the use of a number of medicines. The number of people living in Queensland (Australia) who may suffer from dry mouth, as a result of a number of reasons, can be estimated as follows:
a- Dry mouth secondary to previously treated HNC: according to the Australian Government statistics for head and neck cancer, number of people living with head and neck cancer at the end of 2014 in Australia =16,529. The population in Australia is 25M while that of Queensland is 5M, thus 3,305 (16,529×5÷25) people suffer from HNC in Queensland. According to a study conducted by Weber et al., (2010), they found that 92% of the investigated patients who received different treatments of HNC including surgery, radiotherapy and/or chemotherapy suffer from post-treatment xerostomia. Hence in Queensland, 3,040 (92×3,305÷100) people are estimated to suffer from dry mouth secondary to HNC treatment (Weber, Dommerich et al., 2010). b- According to the Australian Sjogren’s Syndrome Association (https://www.sjogrens.org.au) , Ss affects as many as 0.5% of Australians, thus the estimated number of people with Ss in Queensland is 25,000 (0.5×5M÷100). c- According to age, the number of people aged 65 years and more living in Queensland in 2015 was 14% of the state’s population according to the Australian Bureau of Statistics, which is equal to 700,000 (14×5M÷100). In a study conducted by Thomson in 2015 (Thomson, 2015), he found that on average, 21% of the older population suffer from dry mouth. Thus, the number of elderly people living in Queensland who may suffer from dry mouth is estimated to be 147,000 (21×700,00÷100). d- A common cause for dry mouth is the use of medicines. As documented in the literature, over 500 medicines can cause dry mouth as an adverse effect and the likelihood of experiencing dry mouth varies with age and the medicines used (ranges from 7% of patients using medicines for the treatment of cardiovascular problems to 71% of patients who are treated with antidepressants) (Aliko, Wolff et al., 2015) . Accordingly, an estimate of the number of people in Queensland who may suffer from dry mouth secondary to medication use is hard to predict.
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5.2.8. Randomisation
Sequence generation and allocation concealment mechanism The Study Statistician supplied the randomisation code for pilocarpine and placebo ODTs. A random number generator determined the order of medication and placebo bags within each cycle, structured in blocks of eight participants.
The Trial Coordinator (this PhD student) compounded the pilocarpine and placebo ODTs in batches of 60, packaged them into blister packs, and cut the blister packs into strips of 3 ODT blisters (representing the supply for one day). The Trial Coordinator also prepared the trial packs containing the daily diary and 18 labelled plastic bags (1 for each of the 18 days of the trial). Each plastic bag contained two labelled saliva collection tubes.
The Principal Investigator placed one strip of 3 ODT blisters, either pilocarpine or placebo according to the randomisation code, into each of the labelled plastic bags. The identity of the ODTs as being pilocarpine or placebo was according to compounding batch number. The Principal Investigator allocated pre-packaged, numbered medication packs to participants consecutively. The batch number of the treatment and placebo ODTs contained in each pack was recorded against the relevant participant number on the Randomisation Log.
The Trial Coordinator allocated a participant number to each participant on entry into the study, explained the study and consented them into the study, and completed all documentation including the Medication Accountability log (Log MA). The Principal Investigator recorded participant name against participant number and medication batch numbers in the Randomisation Log. The Randomisation Log was stored securely in the office of the Principal Investigator.
5.2.9. Blinding
Placebo ODTs were identical in appearance, texture, weight, and colour to pilocarpine ODTs. Blister packaging and labelling was identical for both placebo and pilocarpine ODTs. All patients and the Trial Coordinator were blinded to all randomisation procedures. The order of pilocarpine and placebo was revealed by the Principal Investigator only after all data had been collected and transferred into an excel spreadsheet for data analysis.
5.2.10. Statistical methods
Data analysis followed that performed for similar N-of-1 trials. For each cycle, data from day 1 was discarded as the washout period, and data from days 2 and 3 were analysed. Each individual’s response was assessed separately. Data collected from each participant were tabulated and mean 111
CHAPTER 5 values calculated for pilocarpine and placebo for each cycle and overall mean across all three cycles. A participant was defined to be a “responder” based on subjective improvement in the oral dryness score in the SRoS. An improvement of 2 or more on the 0-10 numerical rating scale for oral dryness compared to baseline and to placebo was considered to be a positive response (Nikles et al., 2015). Repeated positive response in 2 or 3 of the cycles indicated that the participant was a responder. When a participant was considered a responder, the magnitude of clinical improvement was calculated by subtracting the value of each period from the baseline data.
The number of participants reporting any SAEs and AEs, the occurrence of specific SAEs and AEs, and discontinuation due to SAEs and AEs were tabulated. If the required number of cycles to provide statistical power were completed, the study statistician planned to apply a Bayesian hierarchical model to analyse population treatment differences (Nikles et al., 2013).
5.2.11. Ethical approval
The clinical trial was approved by the University of Queensland Human Research Ethics Committee A (2017001422). The trial was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12617001067369p).
5.3. Results
5.3.1. Participant flow
Following interest from 21 participants, who were recruited as previously mentioned under the section of study enrolment procedures,13 were excluded. Reasons for exclusion were: 3 were ineligible (1 with ocular problems that contraindicates the administration of pilocarpine, 1 with recurrent HNC, 1 had a xerostomia NRS less than 3); 2 declined to participate (were too frail and sick to cope with the trial schedule), and 8 declined for reasons that were not related to their health (communication, travel commitments, location). Finally, for 8 participants eligibility was either confirmed by the patient’s MP, or by the Study Clinician if the MP did not respond to communications (Fig. 5-2). Their reported xerostomia score at screening was between 3 and 8. They were consented and enrolled in the trial and the randomisation schedule was applied consecutively.
All 8 participants (100%) completed the full 3 cycles of treatment. Four participants completed the 18-day length of the trial consecutively without interruption. Four participants interrupted their participation due to different reasons; two took a break for a pre-planned holiday (1 after the first cycle and 1 after the second cycle), one interrupted her participation during the first period due to perceived side effects and the other took a break after the second cycle due to work commitments). 112
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Overall, 216 doses of pilocarpine were administered and the same number of placebos. All of the data from the 8 participants were analysed for the primary and secondary outcomes. No change in medications or dose that the patients were taking before enrolment in the trial was recorded for any patient during the length of the trial.
Figure 5-2 Flow diagram for number of patients screened, enrolled, completed the trial to the end and number of N-of-1 trials analysed.
5.3.2. Recruitment
Recruitment started in November 2017 and ended in May 2018. Twenty-one showed interest in participation but 8 of them were included and 13 were excluded. Reasons for exclusion from participation are mentioned in the previous section (Participant flow). Of the 13 excluded participants, 8 did not participate in the trial due to other reasons. These included: studying in other state (Victoria), pre-planned travel commitments at the time of running the trial and subscription through UQ advert after the closing date of the trial.
5.3.3. Baseline data
Five participants were males and three were females. Age of participants ranged from 37-85 years (Median 62.5 years). The SRoS at baseline ranged from a minimum score of 3 to maximum score of 9, and average of 6.5 for the oral dryness component (Table 5-4). Scores for the XeQoLS, SXI-D, OHIP and EQ-5D are shown in Table 5-4.
Salivary output during a 3-minute period was measured on day 1 of the trial, before the first dose (Table 5-4). For five participants salivary output was below 1 ml, and for the other three participants
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CHAPTER 5 it was between 1 and 3.4 ml, leading to a mean of 1.4 ml. The SRoS was also assessed on day 1 pre- dose (Table 5-4). Participants 3, 5 and 6 reported a worse dry mouth on day 1 than at baseline even though these were only 1 day apart. Participant 8 was considerably improved since measurement at baseline, which had been 12 days prior.
Table 5-4 Demographic and clinical characteristics of the 8 participants, with the scores for the baseline assessments and day 1 pre-dose assessments.
Participant number 1 2 3 4 5 6 7 8 Mean (SD) Age at screening (y) 58 37 72 67 72 58 57 85 63.3 (13.3) Gender M M F M M F M F Cause of xerostomia HNC MI Ss HNC HNC HNC HNC NI Baseline assessments OD 6 8 7 7 4 3 8 9 6.5 (1.9) Baseline SRoSa SM 5 1 2 1 1 1 2 8 2.6 (2.4) S 6 6 2 5 0 5 0 3 3.4 (2.3) PF 12 9 4 7 14 9 14 7 9.5 (3.4) PDI 14 10 4 6 5 6 8 7 7.5 (3.0) Baseline PPF 11 10 5 6 5 7 12 12 8.5 (2.9) XeQoLSb SF 10 7 1 2 3 7 8 1 4.9 (3.3) Overall 47 36 14 21 19 29 42 27 29.4 (10.8) Score Baseline Score 15 14 15 12 10 13 13 10 12.8 (1.9) c SXI-D SQ 4 3 4 3 2 3 4 3 3.3 (0.7) FL 7 3 0 4 4 4 4 5 3.9 (1.8) P 6 3 5 4 2 1 5 2 3.5 (1.7) PDC 7 3 2 2 1 2 4 2 2.9 (1.8) PD 5 3 1 1 4 4 8 5 3.9 (2.1) Baseline OHIPd PDA 5 3 1 1 1 2 4 3 2.5 (1.4) SD 5 0 0 1 1 1 2 2 1.5 (1.5) H 4 3 0 2 2 0 5 3 2.4 (1.7) Additives 39 18 9 15 15 14 32 22 20.5 (9.5) Impacts 13 6 2 4 4 5 10 6 6.3 (3.3) Baseline Score 22333 11122 11121 11222 21111 11121 11112 31232 N/A e EQ-5D VAS 50 70 70 70 80 80 60 40 65 (13.2) Day 1 pre-dose assessments Day 1 pre-dose 3.37 2.8 0.8 0.9 0.43 0.75 1.28 0.63 1.4 (1.0) Saliva weightf (g)
Day 1 OD 5 7 10 7 8 8 7 4 7.0 (1.7) pre-dose SM 4 1 1 6 1 0 1 2 2.0 (1.9) SRoSa S 4 5 2 6 1 1 1 9 3.6 (2.7) aSRoS (Subjective Rating of Symptoms) questionnaire consists of 3 questions (OD: Oral dryness, SM: Sore Mouth and S: Speaking) each with numerical rating scale 0-10, a high score indicates worse symptoms. bXeQoLS (Xerostomia-related Quality of Life Scale) is a 15 item summative scale containing 4 domains; PF: Physical Functioning, PDI: Pain and Discomfort Issues, PPF: Personal and Psychological Functioning, SF: Social Functioning. Overall Score is the sum of all domains with range from 0-60 and a high score indicates worse symptoms. cSXI-D (Summated Xerostomia Inventory-Dutch Version) is a 5 item summative scale with a score range 5-15, and SQ (standard question of xerostomia) range 1-4. A high score indicates deteriorated dry mouth symptoms. dOHIP (Oral Health Impact Profile) is a 14 item summative scale that contains 7 domains; FL: Functional Limitation, P: Pain, PDC: Psychological Discomfort, PD: Physical Disability, PDA: Psychological Disability, SD: Social 114
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Disability, H: Handicap. Additives: the overall score (sum of all domains) with a range 0-56 and Impacts: number of items rated as 2 or above. A higher score indicates a lower oral health-related quality of life eEQ-5D is a measure of health status. Score refers to 5 domains: 1-mobility, 2-self-care, 3-usual activities (work, study, housework, family or leisure activities), 4-pain/discomfort, 5-anxiety/depression each of which are scored as 1-no problem, 2-some problem, 3-extreme problems. The VAS is a scale from 0-100, note that a high score indicates improved health status. fSaliva weight in grams collected during a 3-minute period.
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5.3.4. Outcomes and estimations
According to the primary outcome findings (oral dryness component of the SRoS), five participants were found to be responders to 5 mg pilocarpine ODTs. These were participants 2, 5, 6, 7 and 8. In support of this finding, one of the secondary outcomes, salivary output, was greater in response to pilocarpine treatment for participants 2 and 5.
Recruitment of people in the community suffering xerostomia was slow, and with 8 participants the study was underpowered so aggregation of N-of-1 trials for overall assessment of the efficacy was not possible. However, the outcomes for each individual still provide valuable information that can inform the participant and their MP about their response to pilocarpine ODTs.
For ease of reporting, the details of each participant’s outcome are described below according to the aetiology of their dry mouth:
A. Xerostomia resulting from previously treated head and neck cancer: three responders and two non-responders B. Medication-induced xerostomia: one responder C. Xerostomia secondary to Sjogren’s syndrome: one non-responder D. Xerostomia with non-identified cause: one responder
A. Participants with dry mouth resulting from previously treated HNC
Participant 5 This participant was a responder to the trial medication for the following reasons:
• Across the 3 cycles, the mean score for oral dryness (OD in the SRoS; Table 5-5) while taking pilocarpine (1.9) was more than two points lower than baseline (4; Table 5-4). This resulted in clinical improvement compared to baseline that was more than a two-point change (-2.1; Table 5-6). The dry mouth experienced by participant 5 was worse when assessed on day 1 before the first dose than at baseline (8 vs 4; Table 5-4); improvement associated with the pilocarpine (-6.1) and placebo (-3.4) was greater if compared to the day 1 pre-dose value than baseline (Fig. 5-3).
• The mean change from baseline for oral dryness was greater for pilocarpine than placebo for all three cycles (Fig. 5-3).
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Table 5-5 Data collected by participant 5 across the three cycles of treatment
Cycle Cycle 1 Cycle 2 Cycle 3 Mean across all cycles Period 1 2 3 4 5 6 Placebo Pilocarpine Pilocarpine Placebo Pilocarpine Placebo Pilocarpine Placebo Medication 1 1 2 2 3 3 OD 3.8 1.7 1.6 3.8 2.3 2.6 1.9 3.4 SRoSa SM 1.6 2.0 2.2 2.2 1.8 2.3 2.0 2.0 S 1.0 1.0 0.2 0.0 0.0 0.0 0.4 0.3 PF 3.0 3.5 3.5 4.0 4.5 4.5 3.8 3.8 PDI 3.0 3.5 3.5 3.0 3.0 3.0 3.3 3.0
XeQoLSb PPF 4.0 4.0 4.0 4.0 4.0 3.5 4.0 3.8 SF 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Overall 10.0 11.0 11.0 11.0 11.5 11.0 11.2 10.7 Score Score 12.0 11.3 10.3 10.5 10.5 11.0 10.7 11.2 SXI-Dc SQ 3.0 2.5 2.3 2.0 2.5 2.5 2.4 2.5 FL 0.0 0.0 0.0 2.0 2.0 2.0 0.7 1.3 P 2.0 3.0 3.0 4.0 4.0 4.0 3.3 3.3 PDC 1.5 1.5 1.5 2.0 2.0 2.0 1.7 1.8 PD 3.0 3.0 3.0 2.0 2.0 2.5 2.7 2.5 OHIPd PDA 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 SD 0.0 0.0 0.0 1.0 1.0 1.0 0.3 0.7 H 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Additives 8.5 9.5 9.5 13.0 13.0 13.5 10.7 11.7 Impacts 1.0 1.0 1.0 3.0 3.0 3.0 1.7 2.3 Score 11111 11111 11111 11111 11111 11111 11111 11111 EQ-5De VAS 85 85 85 80 85 80 85 81.7 Saliva weightf (g) 0.9 1.9 1.6 0.7 1.3 0.9 1.6 0.8 aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
Some of the secondary end-points supported this conclusion:
• Across the 3 cycles, the mean quantity of saliva produced following pilocarpine use was higher than the mean salivary outcome due to placebo use (1.6 g vs 0.8 g; Table 5-5), indicating increased moisture in the mouth as a result of pilocarpine use. The improvement in saliva production was better with pilocarpine than placebo for all 3 cycles (Fig. 5-4).
• The mean OHIP Additives and Impacts values were slightly lower with pilocarpine than placebo, leading to an overall greater clinical improvement with pilocarpine. However, all scores were quite low (8.5 – 13.5 on a scale of 56; Table 5-5) and increased week by week in the trial.
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• The mean EQ-5D VAS score indicated better overall health status with pilocarpine than with placebo (85 vs 82; Table 5-5), both of which were a slight improvement over baseline (80; Table 5-4).
Participant 5 scored the EQ-5D questions as 1 throughout the trial, indicating no problem in any of the five health domains. The XeQoLs snd SXI-D scores showed very little change through the trial.
Table 5-6 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 5 across the three cycles of treatment.
Cycle Cycle 1 Cycle 2 Cycle 3 Clinical improvement Period 1 2 3 4 5 6 across all cycles Placebo Pilocarpine Pilocarpine Placebo Pilocarpine Placebo Pilocarpine Placebo Medication 1 1 2 2 3 3 OD -0.2 -2.3 -2.4 -0.2 -1.7 -1.4 -2.1 -0.4 Baseline SRoSa SM 0.6 1.0 1.2 1.2 0.8 1.3 1.0 0.8 S 1.0 1.0 0.2 0.0 0.0 0.0 0.4 0.3 PF -11.0 -10.5 -10.5 -10.0 -9.5 -9.5 -10.2 -10.2 PDI -2.0 -1.5 -1.5 -2.0 -2.0 -2.0 -1.7 -2.0 Baseline PPF -1.0 -1.0 -1.0 -1.0 -1.0 -1.5 -1.0 -1.2 XeQoLSb SF -3.0 -3.0 -3.0 -3.0 -3.0 -3.0 -3.0 -3.0 Overall -9.0 -8.0 -8.0 -8.0 -7.5 -8.0 -7.8 -8.3 Score Baseline Score 2.0 1.3 0.3 0.5 0.5 1.0 0.7 1.2 SXI-Dc SQ 1.0 0.5 0.3 0.0 0.5 0.5 0.4 0.5 FL -4.0 -4.0 -4.0 -2.0 -2.0 -2.0 -3.3 -2.7 P 0.0 1.0 1.0 2.0 2.0 2.0 1.3 1.3 PDC 0.5 0.5 0.5 1.0 1.0 1.0 0.7 0.8 PD -1.0 -1.0 -1.0 -2.0 -2.0 -1.5 -1.3 -1.5 Baseline PDA 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 OHIPd SD -1.0 -1.0 -1.0 0.0 0.0 0.0 -0.7 -0.3 H -1.0 -1.0 -1.0 -1.0 -1.0 -1.0 -1.0 -1.0 Additives -6.5 -5.5 -5.5 -2.0 -2.0 -1.5 -4.3 -3.3 Impacts -3.0 -3.0 -3.0 -1.0 -1.0 -1.0 -2.3 -1.7 Baseline Score 10000 10000 10000 10000 10000 10000 10000 10000 EQ-5De VAS 5 5 5 0 5 0 5 2 Day 1 pre-dose 0.5 1.5 1.2 0.3 0.9 0.5 1.2 0.4 Saliva weightf (g)
Day 1 OD -4.2 -6.3 -6.4 -4.2 -5.7 -5.4 -6.1 -3.4 pre-dose SM 0.6 1.0 1.2 1.2 0.8 1.3 1.0 0.8 a SRoS S 0.0 0.0 -0.8 -1.0 -1.0 -1.0 -0.6 -0.5 *Note that a negative value indicates positive clinical improvement compared to baseline values for all the questionnaires except for the EQ-5D VAS and saliva weight. aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
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The participant took two sugarless mint tablets during placebo in cycle 1 only, and no further saliva substitutes were taken for the rest of the trial. No side effects or adverse events were reported during the trial. The participant did not miss a dose during the whole 18 days of the trial.
There was a direct relationship between the subjective improvement of the oral dryness and the amount of saliva produced following the use of pilocarpine relative to placebo (Figure 5-3 and Figure 5-4). Even given this, the participant’s guesses at the end of each period of what treatment they had taken did not match the actual treatment schedule for any of the 6 periods.
0 1.6 1.4 -1 1.2 -2 1 -3 0.8 -4 0.6 -5 0.4 Saliva (g)Saliva weight 0.2
Oral dyrness score Oral dyrness -6 -7 0
Figure 5-3 Clinical improvement in subjective Figure 5-4 Clinical improvement in saliva oral dryness (OD in the SRoS) for placebo vs. production for placebo vs. pilocarpine for pilocarpine for participant 5. More negative participant 5. Higher numbers indicate greater numbers indicate greater clinical improvement saliva production relative to day 1 pre-dose. relative to day 1 pre-dose.
Participant 6 This participant was a responder to the trial medication for the following reasons:
• Across the 3 cycles, the mean score for oral dryness (OD in the SRoS; Table 5-7) while taking pilocarpine (3.5) or placebo and (4.8) were more than two points lower than the day 1 pre- dose assessment (8; Table 5-4). This resulted in clinical improvement (Table 5-8) compared to the day 1 pre-dose assessment with pilocarpine (-4.5) and placebo (-3.2). Note that the baseline assessment of oral dryness, conducted one day prior, was 3 (Table 5-4), so if compared to baseline oral dryness was slightly worse with pilocarpine (0.5) and placebo (1.8).
• Pilocarpine use was associated with improved symptoms of oral dryness compared to placebo in two out of the three cycles (Figure 5-5).
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Table 5-7 Data collected by participant 6 across the three cycles of treatment
Cycle Cycle 1 Cycle 2 Cycle 3 Mean across all cycles Period 1 2 3 4 5 6 Pilocarpine Placebo Pilocarpine Placebo Placebo Pilocarpine Medication Pilocarpine Placebo 1 1 2 2 3 3 OD 2.0 4.3 3.6 5.8 4.2 4.8 3.5 4.8 SRoSa SM 0.7 0.2 0.0 0.0 2.3 0.2 0.3 0.8 S 2.2 2.8 2.0 2.3 2.5 2.2 2.1 2.5 PF 4.0 4.0 6.0 7.0 5.0 4.0 4.7 5.3 PDI 1.0 6.0 3.0 3.0 2.0 3.0 2.3 3.7 XeQoLSb PPF 3.0 5.0 5.0 6.0 6.0 5.0 4.3 5.7 SF 1.0 3.0 1.0 2.0 1.0 1.0 1.0 2.0 Overall Score 9.0 18.0 15.0 18.0 14.0 13.0 12.3 16.7 Score 12.5 11.5 11.0 10.5 10.0 11.5 11.7 10.7 SXI-Dc SQ 3.0 3.0 2.0 3.0 3.0 2.5 2.5 3.0 FL 3.0 4.0 5.0 1.0 4.0 3.0 3.7 3.0 P 2.0 2.0 2.0 1.0 4.0 2.0 2.0 2.3 PDC 1.0 2.0 2.0 1.0 2.0 2.0 1.7 1.7 PD 0.0 0.0 1.0 0.0 0.0 0.0 0.3 0.0 OHIPd PDA 1.0 2.0 2.0 2.0 1.0 1.0 1.3 1.7 SD 0.0 2.0 0.0 0.0 0.0 0.0 0.0 0.7 H 0.0 1.0 0.0 0.0 1.5 0.0 0.0 0.8 Additives 7.0 13.0 12.0 5.0 12.5 8.0 9.0 10.2 Impacts 2.0 5.0 4.0 1.0 4.0 3.0 3.0 3.3 Score 11121 11111 11111 11111 11111 11111 11111 11111 EQ-5De VAS 70 80 80 80 80 80 77 80 Saliva weightf (g) 0.63 0.09 0.22 0.18 0.10 0.11 0.3 0.1 aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
Some of the secondary end-points supported this conclusion:
• The speaking component of the SRoS indicated a slightly better score with pilocarpine (2.1) than with placebo (2.5), and this was consistent in all 3 cycles (Table 5-7). Thoughout the trial, speaking was considerably better than that reported at baseline (5) but not that reported at day 1 pre-dose (1). Speaking is a critical problem for this participant as a large part of the tongue was surgically removed due to malignant tumour. • The XeQoLS overall score was lower for pilocarpine than placebo in all three cycles (Table 5-7). This lead to better mean clinical improvement compared to baseline for pilocarpine (- 16.7) than placebo (-12.3). • The OHIP results indicated lower scores for pilocarpine in two out of three cycles.
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In cycle 1, salivary output following administration of pilocarpine was higher than placebo use (Table 5-7). However, saliva production during cycles 2 and 3 was very low and similar between pilocarpine and placebo ODTs, and all collections were less than the day 1 pre-dose sample (0.75 ml), so overall salivary output did not indicate improvement due to pilocarpine ODTs. The SXI-D scores varied only slightly through the trial but suggested placebo was better than pilocarpine, and the XeQoLs scores and VAS were largely unchanged compared to baseline.
Table 5-8 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 6 across the three cycles of treatment.
Cycle Cycle 1 Cycle 2 Cycle 3 Clinical improvement Period 1 2 3 4 5 6 across all cycles Pilocarpine Placebo Pilocarpine Placebo Placebo Pilocarpine Medication Pilocarpine Placebo 1 1 2 2 3 3 OD -1.0 1.3 0.6 2.8 1.2 1.8 0.5 1.8 Baseline -0.3 -0.8 -1.0 -1.0 1.3 -0.8 -0.7 -0.2 SRoSa SM S -2.8 -2.2 -3.0 -2.7 -2.5 -2.8 -2.9 -2.5 PF -5.0 -5.0 -3.0 -2.0 -4.0 -5.0 -4.3 -3.7 PDI -5.0 0.0 -3.0 -3.0 -4.0 -3.0 -3.7 -2.3 Baseline PPF -4.0 -2.0 -2.0 -1.0 -1.0 -2.0 -2.7 -1.3 XeQoLSb SF -6.0 -4.0 -6.0 -5.0 -6.0 -6.0 -6.0 -5.0 Overall -20.0 -11.0 -14.0 -11.0 -15.0 -16.0 -16.7 -12.3 Score Baseline Score -0.5 -1.5 -2.0 -2.5 -3.0 -1.5 -1.3 -2.3 c SXI-D SQ 0.0 0.0 -1.0 0.0 0.0 -0.5 -0.5 0.0 FL -1.0 0.0 1.0 -3.0 0.0 -1.0 -0.3 -1.0 P 1.0 1.0 1.0 0.0 3.0 1.0 1.0 1.3 PDC -1.0 0.0 0.0 -1.0 0.0 0.0 -0.3 -0.3 PD -4.0 -4.0 -3.0 -4.0 -4.0 -4.0 -3.7 -4.0 Baseline PDA -1.0 0.0 0.0 0.0 -1.0 -1.0 -0.7 -0.3 OHIPd SD -1.0 1.0 -1.0 -1.0 -1.0 -1.0 -1.0 -0.3 H 0.0 1.0 0.0 0.0 1.5 0.0 0.0 0.8 Additives -7.0 -1.0 -2.0 -9.0 -1.5 -6.0 -5.0 -3.8 Impacts -3.0 0.0 -1.0 -4.0 -1.0 -2.0 -2.0 -1.7
Baseline Score 00000 00010 00010 00010 00010 00010 00010 00010 e EQ-5D VAS -10 0 0 0 0 0 -3.3 0.0 Day 1 pre-dose -0.1 -0.7 -0.5 -0.6 -0.6 -0.6 -0.4 -0.6 Saliva weightf (g)
Day 1 OD -6.0 -3.7 -4.4 -2.2 -3.8 -3.2 -4.5 -3.2 pre-dose SM 0.7 0.2 0.0 0.0 2.3 0.2 0.3 0.8 SRoSa S 1.2 1.8 1.0 1.3 1.5 1.2 1.1 1.5 *Note that a negative value indicates positive clinical improvement compared to baseline values for all the questionnaires except for the EQ-5D VAS and saliva weight. aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
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The participant did not take any saliva substitutes throughout the whole trial length. No side effects or adverse events were reported during the trial. The participant did not miss a single dose during the whole 18 days of the trial and the patient’s guessing of what treatment was administered at the end of each period matched the actual treatment schedule except for period 3 (pilocarpine 2) and period 6 (pilocarpine 3) where the active treatment was administered.
0 -1 -2 -3 -4 -5
Oral dryness score Oral dryness -6 -7
Figure 5-5 Clinical improvement in subjective oral dryness (OD in the SRoS) for placebo vs. pilocarpine for participant 6. More negative numbers indicate greater clinical improvement relative to day 1 pre-dose.
Participant number 7
This participant was considered to be a responder to the trial medication because the criteria for the primary end-points were met:
• Across the 3 cycles, the mean score for oral dryness (OD in the SRoS; Table 5-9) while taking pilocarpine (5.1) was more than two points lower than baseline (8; Table 5-4). In fact, clinical improvement compared to baseline was -2.9, though it was only -1.9 if compared to the day 1 pre-dose assessment (Table 5-10).
• The mean change from baseline for oral dryness was greater for pilocarpine than placebo for all three cycles (Fig. 5-6).
However, the secondary end-points did not provide any additional support for this finding:
• Mean salivary output across the 3 cycles was higher with pilocarpine than with placebo (0.9 g vs 0.6 g respectively) but both values were low, and both were lower than the day 1 pre- dose salivary output (1.3 g).
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• There was no difference between pilocarpine and placebo in terms of XeQoLS, SXI-D, OHIP and EQ-5D (Table 5-9).
The participant did not report taking any saliva substitutes throughout the trial. Rhinitis was the only adverse event reported during the trial with both active and placebo. The participant did not miss a single dose during the whole 3 cycles of treatment. He correctly guessed the medication identity in 4 out of 6 periods but was incorrect for periods 3 (placebo 2) and period 6 (placebo 3).
Table 5-9 Data collected by participant number 7 across the three cycles of treatment.
Cycle Cycle 1 Cycle 2 Cycle 3 Mean across all cycles Period 1 2 3 4 5 6 Placebo Pilocarpine Placebo Pilocarpine Pilocarpine Placebo Medication Pilocarpine Placebo 1 1 2 2 3 3 OD 6.3 5.4 5.7 5.3 4.5 5.7 5.1 5.9 SRoSa SM 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 S 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 PF 9.0 9.0 9.0 9.0 6.0 6.0 8.0 8.0 PDI 6.0 5.0 5.0 5.0 3.0 4.0 4.3 5.0
XeQoLSb PPF 9.0 9.0 9.0 9.0 5.0 6.0 7.7 8.0 SF 5.0 6.0 6.0 6.0 3.0 4.0 5.0 5.0 Overall 29.0 29.0 29.0 29.0 17.0 20.0 25.0 26.0 Score Score 14.0 14.0 14.0 14.0 10.0 10.0 12.7 12.7 SXI-Dc SQ 3.0 3.0 3.0 3.0 2.0 2.0 2.7 2.7 FL 1.0 1.0 1.0 1.0 2.0 2.0 1.3 1.3 P 3.0 3.0 3.0 4.0 2.0 2.0 3.0 2.7 PDC 2.0 2.0 2.0 2.0 1.0 1.0 1.7 1.7 PD 3.0 3.0 3.0 3.0 4.0 4.0 3.3 3.3 OHIPd PDA 0.0 0.0 0.0 0.0 1.0 1.0 0.3 0.3 SD 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 H 2.0 2.0 2.0 2.0 1.0 1.0 1.7 1.7 Additives 11.0 11.0 11.0 12.0 11.0 11.0 11.3 11.0 Impacts 4.0 4.0 4.0 4.0 3.0 3.0 3.7 3.7 Score 11111 11111 11111 11111 11111 11111 11111 11111 EQ-5De VAS 80 80 80 80 80 80 80 80 Saliva Weightf (g) 0.7 0.8 0.5 0.8 1.0 0.7 0.9 0.6 aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
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Table 5-10 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 7 across the three cycles of treatment.
Cycle Cycle 1 Cycle 2 Cycle 3 Clinical improvement Period 1 2 3 4 5 6 across all cycles Pilocarpine Placebo Pilocarpine Placebo Placebo Pilocarpine Medication Pilocarpine Placebo 1 1 2 2 3 3 OD -1.7 -2.6 -2.3 -2.7 -3.5 -2.3 -2.9 -2.1 Baseline SRoSa SM -1.0 -1.0 -1.0 -1.0 -1.0 -1.0 -1.0 -1.0 S 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 PF -5.0 -5.0 -5.0 -5.0 -8.0 -8.0 -6.0 -6.0 PDI -2.0 -3.0 -3.0 -3.0 -5.0 -4.0 -3.7 -3.0 Baseline PPF -3.0 -3.0 -3.0 -3.0 -7.0 -6.0 -4.3 -4.0 XeQoLSb SF -3.0 -2.0 -2.0 -2.0 -5.0 -4.0 -3.0 -3.0 Overall -13.0 -13.0 -13.0 -13.0 -25.0 -22.0 -17.0 -16.0 Score Baseline Score 1.0 1.0 1.0 1.0 -3.0 -3.0 -0.3 -0.3 c SXI-D SQ -1.0 -1.0 -1.0 -1.0 -2.0 -2.0 -1.3 -1.3 FL -3.0 -3.0 -3.0 -3.0 -2.0 -2.0 -2.7 -2.7 P -2.0 -2.0 -2.0 -1.0 -3.0 -3.0 -2.0 -2.3 PDC -2.0 -2.0 -2.0 -2.0 -3.0 -3.0 -2.3 -2.3 PD -5.0 -5.0 -5.0 -5.0 -4.0 -4.0 -4.7 -4.7 Baseline PDA -4.0 -4.0 -4.0 -4.0 -3.0 -3.0 -3.7 -3.7 OHIPd SD -2.0 -2.0 -2.0 -2.0 -2.0 -2.0 -2.0 -2.0 H -3.0 -3.0 -3.0 -3.0 -4.0 -4.0 -3.3 -3.3 Additives -21.0 -21.0 -21.0 -20.0 -21.0 -21.0 -20.7 -21.0 Impacts -6.0 -6.0 -6.0 -6.0 -7.0 -7.0 -6.3 -6.3
Baseline Score 00001 00001 00001 00001 00001 00001 00001 00001 e EQ-5D VAS 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Day 1 pre-dose -0.1 -0.7 -0.5 -0.6 -0.6 -0.6 -0.4 -0.6 Saliva weightf (g)
Day 1 OD -0.7 -1.6 -1.3 -1.7 -2.5 -1.3 -1.9 -1.1 pre-dose SM 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 SRoSa S 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 *Note that a negative value indicates positive clinical improvement compared to baseline values for all the questionnaires except for the EQ-5D VAS and saliva weight. aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
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0 -0.5 -1 -1.5 -2 -2.5
-3 dry mouth score mouth dry -3.5 -4
Figure 5-6 Clinical improvement in subjective oral dryness (OD in the SRoS) for placebo vs. pilocarpine for participant 7. More negative numbers indicate greater clinical improvement relative to day 1 pre-dose.
Participant number 1
The participant was a non-responder to the trial medication. Although the mean score across all 3 cycles for oral dryness (1.9; Table 5-11) was more than two points lower than baseline (6) and the day 1 pre-dose assessment (5), the improvement was not greater for pilocarpine than placebo in any of the cycles. In fact, oral dryness scores were better with placebo than with pilocarpine.
The secondary end-points (Table 5-11) supported this finding:
• Although pilocarpine ODT use was associated with an increase in saliva secretion (4.3 g) compared to day 1 pre-dose (3.4 g), pilocarpine was not superior to placebo use (4.4 g). • Placebo ODTs improved the speaking ability and soreness of mouth (SRoS) in cycle 1 and 2 more than pilocarpine ODTs (1, 0 vs 3.2, 0.8) and (1.5, 0 vs 3, 1) compared to baseline speaking (6, 4) and baseline soreness of mouth (5, 4). • Mean XeQoLS Score across the three cycles was much improved following placebo use than with pilocarpine use (23 vs 31) relative to baseline data (47). • Mean VAS Score (EQ-5D) across the three cycles was improved following placebo use than with pilocarpine use (66.7 vs 60) relative to baseline data (50).
The participant did not take any saliva substitutes throughout the trial. No side effects or adverse events were reported during the trial. The participant did not miss a single dose during the whole 18 days of the trial. The participant correctly selected whether they had taken pilocarpine or placebo at the end of each period except for the 5th period (pilocarpine 3).
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Table 5-11 Data collected by participant number 1 across the three cycles of treatment
Cycle Cycle 1 Cycle 2 Cycle 3 Mean across all cycles Period 1 2 3 4 5 6 Pilocarpine Placebo Pilocarpine Placebo Pilocarpine Placebo Pilocarpine Placebo Medication 1 1 2 2 3 3 OD 4.0 2.8 1.8 0.2 0.0 0.0 1.9 1.0 SRoSa SM 3.0 1.5 1.0 0.0 0.0 0.0 1.3 0.5 S 3.2 1.0 0.8 0.0 0.0 0.0 1.3 0.3 PF 9.0 9.0 10.0 5.0 6.0 4.0 8.3 6.0 PDI 9.0 10.0 10.0 5.0 6.0 4.0 8.3 6.3
XeQoLSb PPF 8.0 8.0 8.0 4.0 6.0 6.0 7.3 6.0 SF 8.0 7.0 8.0 4.0 5.0 3.0 7.0 4.7 Overall 34.0 34.0 36.0 18.0 23.0 17.0 31.0 23.0 Score Score 14.0 14.0 14.0 11.0 10.0 10.0 12.7 11.7 SXI-Dc SQ 3.0 3.0 2.0 2.0 2.0 2.0 2.3 2.3 FL 5.0 6.0 6.0 4.0 3.0 3.0 4.7 4.3 P 4.0 5.0 5.0 4.0 3.0 4.0 4.0 4.3 PDC 6.0 6.0 6.0 3.0 2.0 3.0 4.7 4.0 PD 4.0 5.0 5.0 4.0 3.0 4.0 4.0 4.3 OHIPd PDA 4.0 6.0 6.0 3.0 3.0 4.0 4.3 4.3 SD 2.0 3.0 4.0 2.0 2.0 3.0 2.7 2.7 H 2.0 4.0 3.0 2.0 2.0 2.0 2.3 2.7 Additives 27.0 35.0 35.0 22.0 18.0 23.0 26.7 26.7 Impacts 10.0 12.0 13.0 9.0 5.0 10.0 9.3 10.3 Score 22222 22222 12222 12122 12222 12222 N/A N/A EQ-5De VAS 50 50 60 70 70 80 60.0 66.7 Saliva weightf (g) 3.5 3.2 4.6 4.3 4.7 5.7 4.3 4.4 aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
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Participant number 4
The participant was a non-responder to the trial medication. Although the mean score across all 3 cycles for oral dryness (3.3; Table 5-12) was more than two points lower than baseline (7) and the day 1 pre-dose assessment (7), the improvement was only greater for pilocarpine than placebo in one cycle. In fact, oral dryness scores were slightly better with placebo (2.9) than with pilocarpine (3.3).
Compared to day 1 pre-dose salivary output (0.9 g), there was an increase in the amount of saliva produced as a result of both pilocarpine and placebo, with pilocarpine being slightly greater (1.8 g) than placebo (1.5 g) overall and in two out of three cycles. However, the other secondary end-points (Table 5-12) supported the conclusion that participant 4 was not responding to pilocarpine:
• With the speaking ability (SRoS), the use of pilocarpine (2.8) and placebo (2.8) produced the same improvement compared to the baseline assessment (6). • There was an improvement in the OHIP additives and OHIP Impacts values compared to baseline following both pilocarpine and placebo use, with minimal differences between them. • Across the three cycles, both treatments caused an equal improvement of the XeQoLS overall score (11.3 for each) compared to baseline (21).
The participant did not report taking any saliva substitutes throughout the trial. Mild side effects were reported during the trial while on placebo and the active treatment. These included increased urination, difficulty breathing and cold feet. The participant was compliant with the treatment schedule except for one dose, as he missed the evening dose of the fourth period (Pilocarpine 2) due to travel commitments. The participant was not able to correctly guess what treatment was received in period 1 (pilocarpine 1), period 3 (placebo 2) and period 6 (placebo 3).
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Table 5-12 Data collected by participant number 4 across the three cycles of treatment
Cycle Cycle 1 Cycle 2 Cycle 3 Mean across all cycles Period 1 2 3 4 5 6 Placebo Pilocarpine Placebo Pilocarpine Placebo Pilocarpine Pilocarpine Placebo Medication 1 1 2 2 3 3 OD 3.2 2.7 2.8 3.0 2.8 4.1 3.3 2.9 SRoSa SM 2.8 2.2 2.5 2.0 2.1 2.6 2.3 2.5 S 3.3 2.7 2.3 2.2 2.8 3.5 2.8 2.8 PF 4.0 2.0 3.0 4.0 6.0 4.0 3.3 4.3 PDI 3.0 3.0 3.0 4.0 5.0 4.0 3.7 3.7
XeQoLSb PPF 3.0 3.0 3.0 4.0 3.0 3.0 3.3 3.0 SF 0.0 0.0 0.0 1.0 1.0 2.0 1.0 0.3 Overall 10.0 8.0 9.0 13.0 15.0 13.0 11.3 11.3 Score Score 10.0 9.0 9.5 13.0 11.0 12.0 11.3 10.2 SXI-Dc SQ 2.0 2.0 2.0 2.0 2.0 2.5 2.2 2.0 FL 1.0 0.0 2.0 1.0 3.0 3.0 1.3 2.0 P 0.0 4.0 4.0 4.0 5.0 4.0 4.0 3.0 PDC 0.0 1.0 2.0 3.0 2.0 2.0 2.0 1.3 PD 0.0 0.0 2.0 0.0 2.0 0.0 0.0 1.3 OHIPd PDA 0.0 1.0 1.0 0.0 1.0 0.0 0.3 0.7 SD 1.0 1.0 3.0 1.0 1.0 2.0 1.3 1.7 H 1.0 2.0 2.0 1.0 1.0 2.0 1.7 1.3 Additives 3.0 9.0 16.0 10.0 15.0 13.0 10.7 11.3 Impacts 0.0 3.0 5.0 3.0 4.0 4.0 3.3 3.0 Score 11122 11111 11122 11122 11121 11121 11221 11221 EQ-5De VAS 75 75 75 75 78 70 73.3 76.0 Saliva weightf (g) 1.0 1.7 1.4 1.7 2.2 2.1 1.8 1.5 aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
B. Participant with medication-induced xerostomia
Participant number 2 This participant was been prescribed roaccutane for the treatment of acne at the age of 18 years old and since then he has suffered from dry mouth and dry eyes as side effects of this medication. These symptoms continued even though he ceased the medication long ago.
This participant was a responder to the trial medication for the following reasons:
• Across the 3 cycles, the mean score for oral dryness (OD in the SRoS; Table 5-13) while taking pilocarpine (4.0) was more than two points lower than both baseline (8) and the day 1 pre-dose assessment (7). This resulted in clinical improvement that was -3.0 when compared to baseline and -2.0 when compared to the day 1 pre-dose assessment (Table 5-14). 128
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• The mean change from baseline for oral dryness was greater for pilocarpine than placebo for all three cycles (Fig. 5-7).
Table 5-13 Data collected by participant number 2 across the three cycles of treatment
Cycle Cycle 1 Cycle 2 Cycle 3 Mean across all cycles Period 1 2 3 4 5 6 Placebo Pilocarpine Pilocarpine Placebo Placebo Pilocarpine Pilocarpine Placebo Medication 1 1 2 2 3 3 OD 7.3 4.1 5.8 7.0 4.2 2.0 4.0 6.2 SRoSa SM 1.0 1.0 1.0 1.0 0.7 0.0 0.7 0.9 S 6.1 4.2 4.9 5.8 3.8 2.0 3.7 5.2 PF 8.0 7.0 8.0 8.0 7.0 1.0 5.3 7.7 PDI 10.0 10.0 10.0 10.0 8.0 5.0 8.3 9.3
XeQoLSb PPF 9.0 7.0 10.0 8.0 7.0 5.0 7.3 8.0 SF 7.0 6.0 6.0 6.0 5.0 3.0 5.0 6.0 Overall 34.0 30.0 34.0 32.0 27.0 14.0 26.0 31.0 Score Score 11.0 10.0 11.5 11.0 8.5 6.0 9.2 10.2 SXI-Dc SQ 3.0 2.0 2.0 3.0 2.0 2.0 2.0 2.7 FL 2.0 2.0 3.0 2.0 3.0 1.0 2.0 2.3 P 2.0 1.0 2.0 2.0 1.0 1.0 1.3 1.7 PDC 4.0 3.0 2.0 4.0 3.0 4.0 3.0 3.7 PD 4.0 3.0 3.0 4.0 2.0 2.0 2.7 3.3 OHIPd PDA 4.0 3.0 4.0 3.0 2.0 3.0 3.3 3.0 SD 4.0 2.0 1.0 2.0 1.0 0.0 1.0 2.3 H 3.0 2.0 3.0 2.0 1.0 1.0 2.0 2.0 Additives 23.0 16.0 18.0 19.0 13.0 12.0 15.3 18.3 Impacts 11.0 5.0 5.0 7.0 2.0 4.0 4.7 6.7 Score 11122 11112 11122 11122 11122 11122 11112 11122 EQ-5De VAS 70 74 65 65 70 80 73 68.3 Saliva weightf (g) 2.2 3.8 2.7 2.3 2.0 3.4 3.3 2.2 aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
Many of the secondary end-points supported this finding:
• Across the three cycles the mean quantity of saliva produced following pilocarpine use was on average 0.5 g higher than the day 1 pre-dose saliva production (Table 5-14). Mean saliva production after placebo use was 0.6 g lower. Saliva production was greater with pilocarpine in all three cycles (Fig. 5-8).
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• The 5 domains of the XeQoLS demonstrated greater improvement after pilocarpine use than placebo, with 5-point difference from baseline for the overall score of the questionnaire with pilocarpine compared to placebo (-10.0 vs -5.0 respectively). • The clinical improvement in OHIP scores was greater with pilocarpine compared with placebo.
Table 5-14 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 2 across the three cycles of treatment.
Clinical improvement Cycle Cycle 1 Cycle 2 Cycle 3 across all cycles Period 1 2 3 4 5 6 Placebo Pilocarpine Pilocarpine Placebo Placebo Pilocarpine Medication Pilocarpine Placebo 1 1 2 2 3 3 OD -0.7 -3.9 -2.2 -1.0 -3.8 -6.0 -4.0 -1.8 Baseline SM 0.0 0.0 0.0 0.0 -0.3 -1.0 -0.3 -0.1 SRoSa S 0.1 -1.8 -1.1 -0.2 -2.2 -4.0 -2.3 0.8 PF -1.0 -2.0 -1.0 -1.0 -2.0 -8.0 -3.7 -1.3 PDI 0.0 0.0 0.0 0.0 -2.0 -5.0 -1.7 -0.7 Baseline PPF -1.0 -3.0 0.0 -2.0 -3.0 -5.0 -2.7 -2.0 XeQoLSb SF 0.0 -1.0 -1.0 -1.0 -2.0 -4.0 -2.0 -1.0 Overall -2.0 -6.0 -2.0 -4.0 -9.0 -22.0 -10.0 -5.0 Score Baseline Score -3.0 -4.0 -2.5 -3.0 -5.5 -8.0 -4.8 -3.8 c SXI-D SQ 0.0 -1.0 -1.0 0.0 -1.0 -1.0 -1.0 -0.3 FL -1.0 -1.0 0.0 -1.0 0.0 -2.0 -1.0 -0.7 P -1.0 -2.0 -1.0 -1.0 -2.0 -2.0 -1.7 -1.3 PDC 1.0 0.0 -1.0 1.0 0.0 1.0 0.0 0.7 PD 1.0 0.0 0.0 1.0 -1.0 -1.0 -0.3 0.3 Baseline OHIPd PDA 1.0 0.0 1.0 0.0 -1.0 0.0 0.3 0.0 SD 4.0 2.0 1.0 2.0 1.0 0.0 1.0 2.3 H 0.0 -1.0 0.0 -1.0 -2.0 -2.0 -1.0 -1.0 Additives 5.0 -2.0 0.0 1.0 -5.0 -6.0 -2.7 0.3 Impacts 5.0 -1.0 -1.0 1.0 -4.0 -2.0 -1.3 0.7
Baseline Score 00000 00010 00000 00000 00000 00000 00000 00000 e EQ-5D VAS 0 -10 0 0 0 0 -3.3 0.0 OD 0.3 -2.9 -1.2 0.0 -2.8 -5.0 -3.0 -0.8 Day 1 pre-dose SM 0.0 0.0 0.0 0.0 -0.3 -1.0 -0.3 -0.1 SRoSa S 1.1 -0.8 -0.1 0.8 -1.2 -3.0 -1.3 0.2 Day 1 pre-dose -0.6 1.0 -0.1 -0.5 -0.8 0.6 0.5 -0.6 saliva weightf (g) *Note that a negative value indicates positive clinical improvement compared to baseline values for all the questionnaires except for the EQ-5D VAS and saliva weight. aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period. 130
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The participant did not take any saliva substitutes throughout the length of the trial. Adverse events were low level and occurred during both placebo and pilocarpine periods.
1 1.5 0 1 -1 0.5 -2 0 -3 -0.5
-4 -1 Salliva weight(g)Salliva Oral dryness score Oral dryness -5 -1.5 -6 -2
Figure 5-7 Clinical improvement in subjective oral Figure 5-8 Clinical improvement in saliva dryness (OD in the SRoS) for placebo vs. production for placebo vs. pilocarpine for pilocarpine for participant 2. More negative participant 2. Higher numbers indicate greater numbers indicate greater clinical improvement saliva production relative to day 1 pre-dose. relative to day 1 pre-dose.
C. Participant with Sjogren’s syndrome-induced xerostomia
Participant number 3 The participant was a non-responder to the trial medication. Although the mean score across all 3 cycles for oral dryness (8.5; Table 5-15) was lower than the day 1 pre-dose assessment (10), the difference was less than two points and oral dryness was worse than baseline (7). Furthermore, pilocarpine was better than placebo in only one cycle.
Secondary end-points (Table 5-15) confirmed this outcome for participant 3:
• For all three cycles, saliva production was very low and unaffected by pilocarpine.
• Scores for XeQoLS, SXI-D, OHIP and EQ-5D were either no different between placebo and pilocarpine or indicated slightly worse scores with the active drug.
The participant continued to use Xylimelts tablets throughout the three cycles of the clinical trial except in period 4 (pilocarpine 2). No side effects or adverse events were reported during the trial. The participant was strictly compliant with the treatment schedule and did not miss a single dose during the whole treatment period. The participant’s guessing of what treatment was received at the 131
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Table 5-15 Data collected by participant number 3 across the three cycles of treatment
Cycle Cycle 1 Cycle 2 Cycle 3 Mean across all cycles Period 1 2 3 4 5 6 Pilocarpine Placebo Placebo Pilocarpine Pilocarpine Placebo Pilocarpine Placebo Medication 1 1 2 2 3 3 OD 8.0 8.7 8.8 8.8 8.8 8.2 8.5 8.6 SRoSa SM 0.5 0.0 0.0 0.0 0.0 0.0 0.2 0.0 S 5.0 5.0 7.0 4.7 4.7 5.0 4.8 5.7 PF 8.0 7.0 8.0 8.0 7.0 1.0 7.7 5.3 PDI 10.0 10.0 10.0 10.0 8.0 5.0 9.3 8.3 XeQoLSb PPF 9.0 7.0 10.0 8.0 7.0 5.0 8.0 7.3 SF 7.0 6.0 6.0 6.0 5.0 3.0 6.0 5.0 Overall 34.0 30.0 34.0 32.0 27.0 14.0 31.0 26.0 Score Score 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 SXI-Dc SQ 4.0 3.5 4.0 4.0 4.0 4.0 4.0 3.8 FL 0.0 0.0 0.0 0.0 0.0 1.0 0.0 0.3 P 1.0 2.0 2.0 0.0 1.0 0.0 0.7 1.3 PDC 1.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 PD 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.3 OHIPd PDA 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 SD 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 H 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Additives 2.0 3.0 2.0 0.0 1.0 1.0 1.0 2.0 Impacts 0.0 1.0 1.0 0.0 0.0 0.0 0.0 0.7 Score 11111 11121 11121 11121 11121 11121 N/A N/A EQ-5De VAS 76 76 76 74 74 74 74.7 75.3 Saliva Weightf (gm) 0.3 0.3 0.3 0.4 0.3 0.3 0.3 0.3 aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
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D. Participant with non-identified cause of xerostomia
Participant number 8 This participant was not sure what was causing her xerostomia. Her current medications were methotrexate and hydroxychloroquine for the treatment of rheumatoid arthritis, which are not known to cause dry mouth, and ceasing the medications for one month did not lead to improvement in dry mouth.
This participant was considered to be a responder to the trial medication because the criteria for the primary end-points were met:
• Across the 3 cycles, the mean score for oral dryness (OD in the SRoS; Table 5-16) while taking pilocarpine (2.2) was more than two points lower than baseline (9; Table 5-4). In fact, clinical improvement compared to baseline was -6.8. However, the day 1 pre-dose dry mouth score was 4, considerably better than the baseline score, so clinical improvement with pilocarpine was -1.8 if compared to the day 1 pre-dose assessment (Table 5-17).
• The mean change from baseline for oral dryness was greater for pilocarpine than placebo for two of the three cycles (Fig. 5-9).
One secondary end-point supported the view that this participant was responding to pilocarpine. Two out of three cycles showed reduced ED-5D VAS scores with pilocarpine over placebo, and the pilocarpine score (but not placebo) was less then baseline.
However, other secondary end-points did not provide any additional support for this finding:
• Although there was a small increase in salivary output with pilocarpine compared to day 1 pre-dose (Table 5-17), saliva production was greater than placebo in only one cycle, and the mean across the three cycles was greater for placebo than with pilocarpine (1 g vs 0.9 g respectively).
• XeQoLS and OHIP both indicated worse scores with pilocarpine or placebo than at baseline.
This participant reported symptoms at baseline that continued throughout the trial: increased sweating, rhinitis, increased urge for urination, headache, increased tear production and difficulty breathing (due to controlled asthma). The participant suffered from an unbearable headache during period 1 (pilocarpine 1) and as such the evening doses of day 2 and day 3 were missed and the participant took a break between period 1 and period 2. The headache subsided, she decided to continue with the trial, and the headache did not return.
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The participant was unable to guess which treatment was received, and was only correct for period 1 (pilocarpine 1) where the active treatment was administered. She was not sure which treatment she received for the rest of the trial. The participant continued to use saliva substitutes throughout the trial.
Table 5-16 Data collected by participant number 8 across the three cycles of treatment
Cycle Cycle 1 Cycle 2 Cycle 3 Mean across all cycles Period 1 2 3 4 5 6 Pilocarpine Placebo Placebo Pilocarpine Placebo Pilocarpine Pilocarpine Placebo Medication 1 1 2 2 3 3 OD 4.8 3.2 2.5 0.8 1.3 1.0 2.2 2.3 SRoSa SM 1.3 2.0 1.2 0.2 0.8 0.0 0.5 1.3 S 0.8 0.7 0.8 0.3 0.0 0.3 0.5 0.5 PF 10.0 12.0 9.0 7.0 8.0 7.0 8.0 9.7 PDI 12.0 9.0 11.0 8.0 11.0 13.0 11.0 10.3
XeQoLSb PPF 13.0 13.0 13.0 13.0 12.0 12.0 12.7 12.7 SF 3.0 5.0 1.0 2.0 4.0 1.0 2.0 3.3 Overall 38.0 39.0 34.0 30.0 35.0 33.0 33.7 36.0 Score Score N/A 10.0 10.0 10.0 11.0 10.0 10.0 10.3 SXI-Dc SQ N/A 3.0 3.0 3.5 3.0 3.5 3.5 3.0 FL 4.0 3.0 5.0 6.0 5.0 4.0 4.7 4.3 P 2.0 3.0 3.0 5.0 5.0 4.0 3.7 3.7 PDC 5.0 1.0 3.0 2.0 4.0 5.0 4.0 2.7 PD 6.0 6.0 4.0 5.0 5.0 6.0 5.7 5.0 OHIPd PDA 2.0 1.0 4.0 3.0 5.0 4.0 3.0 3.3 SD 3.0 2.0 5.0 2.0 2.0 2.0 2.3 3.0 H 8.0 4.0 4.0 2.0 3.0 3.0 4.3 3.7 Additives 30.0 20.0 28.0 25.0 29.0 28.0 27.7 25.7 Impacts 10.0 7.0 8.0 10.0 10.0 9.0 9.7 8.3 Score 31322 31212 31322 31122 31222 31111 N/A N/A EQ-5De VAS 30 50 30 30 50 30 30.0 43.3 Saliva weightf (g) 0.4 0.7 1.0 1.4 1.2 0.8 0.9 1.0 aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
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Table 5-17 Magnitude of clinical improvement compared to baseline and day 1 pre-dose assessments for participant 8 across the three cycles of treatment.
Clinical improvement Cycle Cycle 1 Cycle 2 Cycle 3 across all cycles Period 1 2 3 4 5 6 Placebo Pilocarpine Pilocarpine Placebo Placebo Pilocarpine Medication Pilocarpine Placebo 1 1 2 2 3 3 OD -4.2 -5.8 -6.5 -8.2 -7.7 -8.0 -6.8 -6.7 Baseline SM -6.7 -6.0 -6.8 -7.8 -7.2 -8.0 -7.5 -6.7 SRoSa S -2.2 -2.3 -2.2 -2.7 -3.0 -2.7 -2.5 -2.5 PF 3.0 5.0 2.0 0.0 1.0 0.0 1.0 2.7 PDI 5.0 2.0 4.0 1.0 4.0 6.0 4.0 3.3 Baseline PPF 1.0 1.0 1.0 1.0 0.0 0.0 0.7 0.7 XeQoLSb SF 2.0 4.0 0.0 1.0 3.0 0.0 1.0 2.3 Overall 11.0 12.0 7.0 3.0 8.0 6.0 6.7 9.0 Score Baseline Score N/A 0.0 0.0 0.0 1.0 0.0 0.0 0.3 c SXI-D SQ N/A 0.0 0.0 0.5 0.0 0.5 0.3 0.0 FL -1.0 -2.0 0.0 1.0 0.0 -1.0 -0.3 -0.7 P 0.0 1.0 1.0 3.0 3.0 2.0 1.7 1.7 PDC 3.0 -1.0 1.0 0.0 2.0 3.0 2.0 0.7 PD 1.0 1.0 -1.0 0.0 0.0 1.0 0.7 0.0 Baseline OHIPd PDA -1.0 -2.0 1.0 0.0 2.0 1.0 0.0 0.3 SD 1.0 0.0 3.0 0.0 0.0 0.0 0.3 1.0 H 5.0 1.0 1.0 -1.0 0.0 0.0 1.3 0.7 Additives 8.0 -2.0 6.0 3.0 7.0 6.0 5.7 3.7 Impacts 4.0 1.0 2.0 4.0 4.0 3.0 3.7 2.3
Baseline Score 00110 00020 00110 00110 00010 00121 00120 00110 e EQ-5D VAS -10.0 10.0 -10.0 -10.0 10.0 -10.0 -10.0 3.3 OD 0.8 -0.8 -1.5 -3.2 -2.7 -3.0 -1.8 -1.7 Day 1 pre-dose SM -0.7 0.0 -0.8 -1.8 -1.2 -2.0 -1.5 -0.7 SRoSa S -8.2 -8.3 -8.2 -8.7 -9.0 -8.7 -8.5 -8.5 Day 1 pre-dose -0.2 0.1 0.4 0.8 0.6 0.2 0.2 0.3 saliva weightf (g) *Note that a negative value indicates positive clinical improvement compared to baseline values for all the questionnaires except for the EQ-5D VAS and saliva weight. aSRoS Subjective Rating of Symptoms questionnaire, bXeQoLS Xerostomia-related Quality of Life Scale, cSXI-D Summated Xerostomia Inventory-Dutch Version, dOHIP Oral Health Impact Profile, eEQ-5D is a measure of health status with VAS scale from 0-100, fSaliva weight in grams collected during a 3-minute period.
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1 0.5 0 -0.5 -1 -1.5 -2 -2.5
dry mouth score mouth dry -3 -3.5 -4
Figure 5-9 Clinical improvement in subjective oral dryness (OD in the SRoS) for placebo vs. pilocarpine for participant 8. More negative numbers indicate greater clinical improvement relative to day 1 pre-dose.
5.4. Discussion
Recruitment of community-dwelling participants with dry mouth was our biggest challenge during this study, the fact that being based in the community and not having links to patients via specialists or GPs meant that it was difficult to make contact. Additionally, some of the recruitment strategies that we adopted to find our targeted population did not work well including advertising through Facebook and other social media pages. A visit to the support group of patients with previous head and neck cancer who also suffer from dry mouth, which takes place once monthly at Cancer Council Queensland, was a good source of participants. In fact, 6 participants with dry mouth secondary to radiotherapy and/or chemotherapy for head and neck cancer were recruited from the support group. However, most of the participants (15) were from enquiries through the advertisement that was posted about the study through UQ E-newsletter.
One of the main advantages of the N-of-1 methodology is that the results are individualised for each participant. In our pilot study, we were able to obtain useful detailed information for the participants who completed their trials in terms of their individual response to 5 mg pilocarpine ODTs in comparison to placebo. Of those who completed their trials to completion, 5 of the 8 participants (63%) showed a positive response towards our investigated product, and we were able to inform them of this outcome. Had we used a standard randomised clinical trial design it would not have been possible to determine this information for these participants.
The results of this pilot study came in line with a previous feasibility study in a hospital setting completed by some members of the supervisory team. They investigated the efficacy of pilocarpine
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CHAPTER 5 eye drops when administered by mouth at a dose of 6 mg three times a day in a cohort of 20 patients with advanced cancer who were suffering from dry mouth. The results showed that 50% of the participants who completed the trial to the end (completed the 3 cycles of the trial) showed positive clinical response to pilocarpine ophthalmic drops, although there were some concerns among the participants regarding the bitter taste of these drops (Nikles et al., 2015). That study was confined to patients of palliative care units who had advanced cancer (in any body organ), whereas participants with dry mouth due to various aetiologies were included in the present study.
Davies et al. (1998) conducted a cross-over study to compare the efficacy of Saliva OrthanaTM (artificial saliva) and SalagenTM tablets (pilocarpine) in relieving xerostomia among patients with advanced cancer. Pilocarpine was found to be more effective than the artificial saliva in terms of mean change in visual analogue scale scores for xerostomia (P = 0.003) at a dose of 5 mg tds. However, 50% of the patients preferred the artificial saliva than pilocarpine, as the former was a spray rather than tablet dosage form (Davies, Daniels et al., 1998). In our present study, most of the participants did not express any dislike for the ODTs in terms of the method of administration or to the taste, except for one participant who complained of the little perceived bitterness of both the medicated and non-medicated ODTs, and all of the participants completed the 18 days of the trial to the end. All of the participants expressed their satisfaction with the ease of taking their doses especially without the need for water to swallow the ODTs (as would be required with conventional tablets).
Three participants out of the eight were non-responders, participants 1, 3 and 4. The reasons for not responding to pilocarpine are numerous and individualised for each participant. One of the non- responders, participant 3, had dry mouth caused by Ss. For treatment of dry mouth caused by Ss, the dose should be 5 mg four times a day, as documented in the consumer information sheet for Salagen® (Pfizer Canada, 2014). The three times daily dosing used in this study is the recognised dose for treating dry mouth resulting from treatment for head and neck cancer. Therefore, it is possible that the participant with Ss may experience some benefit with a higher dose.
The other two non-responders had xerostomia due to treatment for HNC. In our study 60% of participants with radiation-induced xerostomia were identified as responders to 5 mg pilocarpine ODTs in terms of subjective improvement of xerostomia. This is similar to a study using pilocarpine pastilles, in which 74% of participants with radiation-induced xerostomia reduced their use of saliva replacements when using the pastilles (Hamlar et al., 1996). It is well documented in the literature that the cumulative effect of cancer treatments can cause damage to the salivary glands, which in turn might cause lower saliva secretion and perceived dry mouth sensation that can last up to two years after cessation of these therapies (Jensen et al., 2003; Pow et al., 2003). Although the secretion of
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CHAPTER 5 saliva by the minor salivary glands is small compared to the major salivary glands (about 10% of the total salivary output), minor glands produce 70% of total mucin in saliva. Mucins are known to provide excellent lubrication to the oral tissue via the rheological properties of the large mucin molecules in solution and thus minor salivary glands can play a major role in moistening of oral tissues and helps in treatment of dry mouth through wetting the mouth (Tabak, Levine et al., 1982). These minor salivary glands can be stimulated by pilocarpine and so any increase in saliva production, no matter how small it is, if it is accompanied by an increase in mucin may cause subjective benefit to people with xerostomia (Nieuw Amerongen, Aarsman et al., 1984). Therefore, it is possible that the minor glands were impacted by HNC treatments in the two non-responders.
Two of the participants, both responders to the pilocarpine ODTs, had tried other therapies shortly before enrolling in our study. Their baseline xerostomia at screening were relatively low scores of 3 and 4. The participants said that these low scores are due to the other therapies that they had tried (acupuncture and hyperbaric oxygen therapy). They also mentioned, that without receiving these therapies they would have high baseline xerostomia scores of more than 7. In fact, they both scored were 8 for dry mouth at the day 1 pre-dose measurement conducted in the early morning.
All the participants mentioned that they have tried other products to help relieve their dry mouth before enrolling in the study but these products did not help their dry mouth a lot and they could not find any marketed product so far that can treat their xerostomia. Among the mentioned products were different Biotene products for dry mouth treatment (mouthwash, oral gel, spray and toothpaste), Xylimelts tablets and artificial saliva. All the participants used to carry water with them and have few sips of water whenever needed to help relieve their dry mouth during daytime, but this was hard to follow at night especially during sleeping.
As the therapeutic effect of 5 mg pilocarpine dose lasts 4-5 hours, this can be of particular benefit for people who usually suffer from interrupted sleeping at night as they have to wake up and drink water to relieve their dry mouth. In fact, some of the non-responders expressed interest of trying pilocarpine ODTs to see if it could help them having an uninterrupted sleep at night if they take a dose just before going to bed. This was a consideration even for those for whom it was not beneficial during daytime.
5.5. Limitations
The primary limitation found during the progression of this chapter was in terms of participant recruitment, and ultimately this led to the clinical trial ceasing early, resulting in a pilot study rather than a full clinical trial. Consequently, it was not possible to determine whether pilocarpine was more
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CHAPTER 5 clinically significant than placebo in treating dry mouth based upon population estimates. Potential reasons for recruitment difficulties included:
• The trial was restricted to Queensland due to regulatory issues with supply of compounded medicines out of state, and so people who showed interest to take part in our trial from other states across Australia could not participate. • Community-dwelling individuals who suffer from dry mouth due to any reason especially as a result of radiotherapy was our targeted population, but we couldn’t access them through patient databases which are available in hospitals as our protocol didn’t include working through hospitals (more complicated protocol is required for hospital-based trials). We were very reliant on support groups such as that of Cancer Council Queensland and posting through different groups in social media such as Facebook.
Other issues with the study:
• The protocol contained many questionnaire tools in an attempt to analyse all the xerostomia- related problems with validated tools. However, participants found time consuming to complete all these questionnaires three times every day for 18 days, and this in fact was extremely troublesome to some of them. This may have affected the quality of the data collected. • Although the questionnaire tools used in this study were validated measures, but they were also very subjective, and for many participants they were not able to precisely score their feelings of dry mouth three times a day after each dose especially with those participants whom their baseline xerostomia scores were not bad enough. • The protocol was not suitable for frail elderly people owing to the fact that they had to take the trial medications 3 times daily, complete some questionnaires 3 times daily with more questionnaires at the end of each period and collect saliva samples 2 times daily which was a burden to do every day. In fact, two people with dry mouth showed interest to participate but were unable to participate in the study due to the quantity and complexity of the trial procedures. The trial design was not suitable for those with Ss. For those people, they should be prescribed with 5 mg of pilocarpine to be taken 4 times daily (rather than 3 times daily in the protocol) in order to get a positive clinical effect as described in Salagen® patient information leaflet (Pfizer Canada, 2014).
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5.6. Conclusion
The aim of this study was to be able to decide if pilocarpine 5 mg ODTs were beneficial in treating dry mouth following an N-of-1 design that can give individualized patient results. Five participants out of eight responded. A full clinical trial is warranted to provide a high-evidence level of the efficacy of 5 mg pilocarpine ODTs in treatment of dry mouth. In order to reach the required number of patients, either a longer period of recruitment, or involvement of GPs and specialists would be needed to direct patients towards the trial (which would therefore require QLD Health ethical approval). A clinical trial is planned to take place at the Mater Hospital (Brisbane, Qld) to test the efficacy of our 5 mg pilocarpine ODTs for participants with xerostomia in the palliative care unit.
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Chapter 6. General discussion and future direction
6.1. General discussion
Pilocarpine is an effective pharmacological treatment for dry mouth secondary to radiation-induced xerostomia and Ss and is commercially available as tablet in at least 24 countries around the world. An oral dose of 5 mg pilocarpine taken three times daily produces the most effective therapeutic response in terms of subjective relief of dry mouth according to many clinical studies.
An oral dosage form of pilocarpine is not commercially available in Australia. Pilocarpine is commercially available as 1% and 2% eye drops, which are registered on the ARTG for the treatment of glaucoma. The only way to access pilocarpine for dry mouth treatment in Australia is via ‘off label’ use of the eye drops, or for it to be compounded for an individual patient by a pharmacy. Eye drops were given by mouth for the treatment of dry mouth as part of a clinical trial, but they tasted unpleasant to most of the patients and were not acceptable as a dosage form for dry mouth treatment for that reason (Nikles et al., 2015).
This thesis investigated pilocarpine dosage forms that can be compounded in pharmacies for the treatment of dry mouth. These pilocarpine dosage forms were targeted towards topical oral delivery (buccal) rather than systemic in order to encourage some absorption to occur through the buccal mucosa rather than it all being swallowed and absorbed into the systemic circulation.
The ultimate aim of this thesis was the formulation of buccal pilocarpine preparations and testing their efficacy to treat dry mouth. Thus, this section describes the stepwise progression towards this aim in terms of each of the three objectives.
OBJECTIVE 1: Prepare potential pilocarpine formulations for buccal delivery to the salivary glands rather than for direct swallowing and systemic delivery, and establish stability of pilocarpine in these formulated products. The chosen formulations should be easily extemporaneously prepared in hospital or community compounding pharmacies.
This objective was achieved in Chapter 2, where two buccal formulations were chosen for delivering of pilocarpine to be used in the treatment of dry mouth. These buccal preparations were lozenges (troches) and orally dissolving tablets. Both formulations were chosen as they can easily be compounded in local community pharmacies and they don’t require expensive instruments for their production.
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Both formulations were subjected to some quality control assessments according to the BP. The ODTs passed the BP quality control tests; uniformity of weight, uniformity of drug content, diameter and thickness, resistance to crushing (hardness) and friability. They were also subjected to other quality control assessments to determine the ability of the ODTs to swell in the presence of small amount of water and the disintegration time, in vitro dispersion time, in vitro disintegration time, in vivo disintegration time, wetting time and water absorption ratio tests. The results of these tests showed the ability of the ODTs to disintegrate within seconds in the presence of small amount of water. ODTs, though not as hard as commercially produced tablets, were not fragile as they lost less than 1% of their mass according to a friability test. For the troches, they passed all the quality control measurments that was specified by the BP for troches. These were uniformity of weight, uniformity of drug content, diameter and thickness.
Both formulations (three batches each under each storage condition) were subjected to stability testing under two different temperature and relative humidity conditions for an extended period of time; shelf life storage conditions (20°C/57% RH) for 18 months and accelerated aging storage conditions (36°C/39% RH) for 12 months. The products were stored in the packaging that a patient would receive the product in. Pilocarpine remained at 90% or more in both troches and ODTs for almost 1 year. However, even though pilocarpine content changed very little, the weight of the ODTs changed, which indicates that they were susceptible within their packaging to absorb humidity from their environment. Based on this observation, for the clinical trials in the rest of this thesis, we stored packaged ODTs with sachets containing silica gel to maintain a dry storage environment. The use of silica gel has assisted with moisture control and it should be assessed in future studies
The relationship between weight and drug content was stronger for ODTs than troches, and selection of ODTs weighing 70 – 80 mg consistently selected ODTs containing 90-110% of 5 mg pilocarpine. The strong relationship between weight and content for ODTs reflects consistent mixing of active pharmaceutical ingredient within the excipient powders. The less consistent relationship for troches between the troche weight and drug content indicated that mixing varied between batches and is also associated with the active ingredient being only 0.5% of the total troche weight, while it is 6.7% of total ODT weight. In this study no assessment of mixing time was made, and it would have been interesting to consider what period of stirring time would have produced optimal mixing. Accordingly, it was hard to predict the drug content in each troche based on its weight. Quality parameters of troches and other compounded dosage forms is not usually measured. Standard compounding methods were used in this study, probably with more time spent mixing than would be possible in a pharmacy, but even given this, it is clear that the dose of the active ingredient in each compounded troche could be quite variable. 142
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Previously, buccal preparations of pilocarpine in the form of pastilles and lozenges that were used in clinical trials did not provide information on method of production, quantification of the drug content, stability or the storage life. Products were supplied by a university pharmacy research division (Hamlar et al., 1996), a pharmaceutical company (Taweechaisupapong et al., 2006) or a hospital pharmacy (Sangthawan et al., 2001). Trials that used pilocarpine solutions as an oral liquid or mouthwash either didn’t describe a method (Schuller et al., 1989) or described a simple method used for production. These include dilution of commercial eye drops with saline (Kim et al., 2014) or with sterile water (Joensuu et al., 1993), or the dissolution of commercial pilocarpine tablets in a specified volume of tap water (Tanigawa et al., 2015). Even given a method of production, there was no data given on the quality of the tested pilocarpine products nor on stability. However, oral preparations of pilocarpine that was made from eye drops containing citrate buffer and maintained at pH5.5 were found to be chemically stable when stored at 25°C or 4°C for 60 and 90 days respectively (Fawcett, Tucker et al., 1994). In this thesis, our compounded pilocarpine products were good quality and are expected to maintain 90% of pilocarpine if stored for up to one year.
OBJECTIVE 2: Test the acceptability of the potential formulations in terms of dosage form and flavouring according to people with and without xerostomia.
There was a two-step process to achieving this objective. Firstly, a pilot study using healthy volunteers was conducted to determine the time taken for a whole troche to be sucked until it is completly dissolved in the mouth, and time taken to get a sense of flavour when sucking different flavoured troches and then spitting out of the mouth (Chapter 3). This was required to enable estimation of the quantity of pilocarpine that may be absorbed during the acceptability trial (Chapter 4). The pharmaceutical flavours lemon, mint, chocolate and raspberry were selected for comparison with unflavoured as they were recommended for masking of bitter eliciting medicines (Shrewsbury, 2015). The average time taken by 20 healthy volunteers to suck a whole non-medicated troche until completion was 2.3 minutes and 10 seconds was generally enough time to get a sense of flavour. Change in troche weight and sucking time were used to calculate the quantity of pilocarpine that would be removed from the troche during sucking for 10 seconds; an expected dose of 1.8-1.9 mg would be expected from sucking 5 troches for 10 seconds. The therapeutic dose of pilocarpine is 5 mg so this is classified as sub-therapeutic.
In the acceptability study (Chapter 4), flavour preference was assessed by asking participants to taste five troches containing 5 mg pilocarpine and differing only in flavour. Dosage form preference was assessed by asking the participants to suck one non-medicated troche and one non-medicated ODT
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CHAPTER 6 to completion. The total number of participants that were recruited in the acceptability study was 48 participants; 34 were healthy volunteers and 14 were people with xerostomia. The results of the acceptability test showed that lemon was preferred among healthy volunteers followed by raspberry, whereas raspberry was the flavour preferred among participants with dry mouth followed by chocolate and lemon.
Healthy volunteers were recruited in the acceptability study in order to compare between taste preferences and dosage form preferences among healthy volunteers and people with xerostomia. Difference in taste preferences arise from the fact that people with xerostomia usually suffer from reduced salivary output, which in turn greatly affects their taste perception as food particles when ingested need to be present in a solution form so that they can stimulate the receptor cells in the taste buds within the lingual papillae inside the oral cavity. Additionally, taste sensitivity is directly related to saliva composition as the upper surface of the receptor cells is bathed by the oral fluids (Pedersen, Bardow et al., 2002). The difference in preference between our groups of participants confirmed that it is important to test products in the target population group.
Regarding the dosage form preferences, all of the xerostomic participants preferred the ODT rather than the troche. The ability of people with dry mouth to suck and dissolve the large sized troches was limited by their reduced salivary output, their oral comfort and their oral health status, while they dealt well with the small size of the ODTs as it vanished quickly from their mouth. This was accompanied by feelings of greater social acceptability and enjoyment for these patients. For healthy volunteers, 70% of them preferred the ODTs for the reason of small size of ODTs compared to troches and hence faster dissolution in the mouth. Others preferred troches, with some commenting that troches would stimulate more saliva secretion than the ODTs and others thought that troches were slippery in their mouth and lasted longer than the ODTs.
OBJECTIVE 3: Investigate the efficacy of the dosage form selected in Chapter 4, flavoured with the flavour selected by people with xerostomia and containing 5 mg pilocarpine, in the treatment of dry mouth.
This objective was achieved in Chapter 5, which describes a prospective series of double-blinded N- of-1 clinical trials with raspberry flavoured 5 mg pilocarpine ODTs (intervention) vs matching placebo ODTs (control), taken 3 times daily. The N-of-1 methodology was adopted instead of a standard RCT design because each individual participant receives direct evidence about the effect of the treatment versus the comparator for their own symptoms. Additionally, statistical analysis of a
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CHAPTER 6 series of N-of-1 trials of a treatment can produce an estimate of the population effect that is comparable to an RCT.
Participants completed 18 days of treatment, consisting of 3 cycles. Each cycle contained two periods: 3 days treatment, 3 days placebo, the order of which was blinded. The first day of each period was considered to be the washout and data collected was not included in analysis. A wash out period of 1 day was deemed to be sufficient, given the short half-life of pilocarpine (Gornitsky et al., 2004; Wiseman et al., 1995) and as used previously (Nikles et al., 2015). Participants took one dose of trial medication 60 minutes prior to breakfast, lunch and dinner, each day for the 18-day trial. They collected saliva samples in pre-labelled tubes, twice daily 60 minutes after taking the breakfast and dinner doses. Participants completed a daily diary recording symptom scores using validated measures for dry mouth and related symptoms, the presence of any side effects and their estimate of which drug they believe they are taking at the time. At the end of the trial, the order of medications within each of the three cycles was unmasked and compared with the participant’s observations.
Eight people were eligible and consented to take part in the trial and were then enrolled in the trial consecutively and assigned to the randomisation schedule. Five participants were males and three were females. Age of participants ranged from 37- 85 years (Median 62.5 years). All 8 participants completed 3 cycles of treatment. Five participants (63%) were found to be responders to the 5 mg pilocarpine ODTs while the other 3 participants were non-responders. Three of the 5 responders had dry mouth due to HNC, one was medication-induced xerostomia, and one had no identified cause.
Conclusions on whether each participant was a responder or non-responders was based upon analysis of the primary outcome measure, the dry mouth component of the SRoS questionnaire. These 5 responders all showed a greater than two-point improvement in dry mouth score compared to baseline and/or the day 1 pre-dose assessment, and pilocarpine was better than placebo in at least two out of three cycles. However, this is a subjective measure. Only for one of the responders, participant 5, did the objective measure, saliva production, also strongly point towards a beneficial effect from pilocarpine. Saliva production was not a useful measure in the other participants – as the measurements were done by the participants at home it was not possible to ensure that they used a consistent approach to saliva collection. The other secondary end-point measures were inconsistent in whether they supported the primary end point or not. XeQoLs and OHIP were the most useful of the set, with EQ-5D and SXI-D generally providing little useful information in this study.
Participant recruitment was particularly difficult, and ultimately this led to Chapter 5 ceasing early, resulting in a pilot study rather than a full clinical trial. Consequently, it was not possible to determine whether pilocarpine was more clinically significant than placebo in treating dry mouth based upon
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CHAPTER 6 population estimates. More participants could have been recruited if we were able to enrol participants who reside outside of Queensland – this would require the ODTs to be compounded at a registered compounding pharmacy rather than in the university laboratories, and it would require the one-on- one explanation of the trial procedures to be performed by teleconference. A future approach for more efficient recruitment strategies should be via lists held by specialists. This may be a better way to advertise the existence of the trial to potential volunteers, and this would require connections with a hospital and ethical approval to be obtained through the hospital ethics committee in addition to the UQ committee.
The overall aim of this thesis was to formulate oral pilocarpine dosage forms that can be compounded extemporaneously and to test their efficacy in the treatment of dry mouth resulting from different aetiologies. The suggested oral pilocarpine dosage forms that we found to be easily compounded in community pharmacies were troches and ODTs. However, based upon the quality control assessments, troches were found to be a poor candidate to be further assessed for testing their efficacy in treating dry mouth as the drug content was much poorer for troches than for ODTs.
Formulation of the ODTs was done by a simple compounding procedure, provided that the kits used in compounding can easily be supplied from any pharmaceutical company such as Medisca. However, one of the challenges that need careful consideration upon production of ODTs is the ease of their moisture uptake and hence drug degradation, an issue that can be handled either by storing the ODTs in the refrigerator during the length of their administration or better to store them with silica gel. Also, during the formulation of ODTs, there were many factors that needed to be well controlled and standardised from the beginning to the end of formulation. These factors were: a) Ensuring that the temperature of the oven was accurately set at 110℃ (this was done by measuring the temperature of the oven by an external thermometer) for baking of the ODTs, an attribute that helped in the easy removal of the ODTs from the mould after being removed from the oven, b) Overall number of presses during the production of the ODTs were 10 presses, this helped to obtain an optimum drug concentration of around 5 ±0.5 mg in each dosage form.
While ODTs can be stored up to one year while retaining more than 90% of their labelled dose when stored at room or accelerated conditions, extemporaneously compounded preparations would usually be expected to be taken within a much shorter period than this, perhaps up to 90 days. Therefore, pilocarpine ODTs can be expected to retain the pilocarpine content for the storage that is relevant to compounded products.
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Further, this study concluded that raspberry ODTs were a reasonable dosage form for people with dry mouth, as 5 out of 8 participants responded to treatment. Likewise, participants enjoyed the butterscotch-flavoured pastilles used in the study by Hamlar et al. (1994). This is a definite improvement over the use of pilocarpine eye drops given orally, where the very bitter taste of the formulation was an issue to patients (Nikles et al. 2015). ODTs are also a better option than mouthwashes that were tested in some studies (see Chapter 1), for which doses ranging from 50 mg to 200 mg were rinsed in the mouth and then spat out, leading to the wastage of the pharmaceutical drug.
The N-of-1 methodology was useful because it allowed the determination of the outcome for each individual participant. However, the protocol used in running this study was full of many questionnaire tools and this was very burdening to the participants and did not add much to the conclusion whether they were responders or not. Some of these assessments could have been omitted from the protocol: OHIP (Oral Health Impact Profile), EQ-5D (a measure of health status with VAS scale from 0-100) and XeQoLS (Xerostomia-related Quality of Life Scale). The questionnaires that proved useful were the SRoS (Subjective Rating of Symptoms questionnaire), SXI-D (Summated Xerostomia Inventory-Dutch Version) and the collected Saliva weight assessments.
According to our findings, ODTs are considered to be the dosage form of choice for the treatment of dry mouth due to the ease of their use without swallowing a whole tablet or capsule, especially for these patients with difficulty swallowing large dosage forms, and without the need of water and the mechanical stimulation.
6.2. Future research
A full clinical trial is warranted to provide a high-level evidence of the efficacy of 5 mg pilocarpine ODTs in treatment of dry mouth. The clinical trial should:
• cover all the states of Australia. • include recruitment of participants with dry mouth through hospital databases. • be designed with a protocol that focuses on questionnaire tools that scores the xerostomia itself such as SRoS and not on the quality of life-related questionnaires such as XeQoLS, SXI-D and OHIP. • include saliva collection but ensure a method for more precise collecting of saliva by the participants is included. This requires a full detailed demonstration by the researchers at a baseline meeting with the participants to ensure accurate outcome of this measure throughout the whole clinical trial from its beginning until its end. 147
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• be flexible in terms of dosing so that it can be adjusted to be suitable for those with Ss and other aetiologies of dry mouth.
Market production of an oral dosage form containing 5 mg pilocarpine will help to provide this product to the Australian community in a fairly reasonable price that can be afforded by most of the people who suffer from dry mouth. At the time of writing, the price quoted to compound 90 pilocarpine ODTs, enough for a one-month supply if taken three times a day is around $75. This is not affordable by many patients for ongoing treatment.
ODTs are a useful dosage form that have potential to help oral delivery of medicines. As they dissolve in the mouth, they can be taken by anyone that cannot easily swallow tablets and capsules whole. Though they require some specialist equipment to prepare (a mould and an oven), and careful calculation and mixing to ensure the correct dose is contained in each ODT, they are reasonably easy to prepare. The cost of preparation of pilocarpine ODTs is no different to the cost to prepare capsules. Future research could further investigate the extent to which this dosage form is used, and barriers to uptake of this dosage form.
Compounded dosage forms rarely are assessed for quality and efficacy. The troches in this study passed the BP requirements, but this only required the range of active drug to be within the range 75- 125% of the required dose. The pilocarpine was believed to be well mixed manually into the melted troche base for 5-10 minutes, but even so the uniformity of drug content was much poorer for troches than ODTs. Efficient mixing of the drug into the melted troche base was not assessed in this thesis. So for future studies investigating troches, it is recommended that good mixing of the active drug be assessed in terms of the extent of mixing and the time length required for adequate distribution in the troche base. Measurements such as uniformity of weight, uniformity of drug content are rarely performed on compounded products, so it is not possible to compare the data obtained in this thesis with other studies. Future investigation into quality of troches, and other types of dosage forms, prepared by pharmacies is required in order to understand the accuracy and variability of compounded products dispensed in Australia.
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Appendices Appendix A. Systemic oral pilocarpine preparations - placebo comparisons.
Name of study Greenspan et al., 1987 LeVeque et al., 1993 Johnson et al., 1993 Rieke et al., 1995 Warde et al., 2002
Type of treatment Tablets Tablets Tablets Tablets Tablets product Type of compared Placebo tablets Placebo tablets (made of cellulose and Placebo tablets Placebo tablets Placebo product stearic acid) Frequency of use Three to four times daily Three times daily Three times daily Three times daily Three times daily Concentration 2.5 mg ( 2 o3 tablets per dose) 2.5, 5 and 10 mg 5 and 10 mg 2.5, 5, 10 mg 5 mg
Mouth movement Not stated Not stated No gustatory stimulation for 60 min Not stated Not stated prior to first saliva collection. Spitting/ no swallow Swallow with water Swallow whole tablet with water Swallow with water Swallow whole tablet Swallowing whole tablet Flavour Not stated Not stated Not stated Not stated Not stated
Number of patients 12 162 207 369 (207 for the fixed dose protocol and 130 recruited 162for the dose titration one) Diagnosis Post irradiated head and neck Post irradiated head and neck cancer Patients who had received at least 4000 Post irradiated head and neck cancer Postoperative RT for squamous cell cancer patients patients cGy RT for head and neck cancer for patients (˃50 Gy) with a history of head and neck cancer with at least 50% more than 4 months before entry in the clinically significant xerostomia and of both parotid glands irradiated to study with clinically important evidence of residual salivary function. doses ˃50 Gy xerostomia. Age range 16-79 59.4±10.7 56.1±12-58.7±10.4. 56.1±12-59.4±10.7 56.2±10.5 (test gp), 57.8±11.5 (control gp) Gender Not stated. 115M /47F 142 M / 65F 257 M/ 112 F 94 M/ 36 F Length of study 90 days 12 weeks 12 weeks 12 weeks Started at day 1 of RT and continued until 1 month after completion of RT and for further 6 months thereafter Dropout rate None 18.5% (132patients of 162 completed 19.8% (41 patients withdrew from 19.24% (298 of 369 completed the 9.2% (12 patients stopped their the study) treatment before completing the study) study) medication) Reason for dropout None Lack of efficacy, adverse experience, Lack of efficacy, adverse effects, Lack of efficacy Due to toxicity. protocol deviation, non-compliance, deviation from protocol, personal and other causes noncompliance, personal and other causes
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Side effects Sweating and abdominal Sweating (most frequent), rhinitis, No serious adverse effects. The primary Sweating (dose dependent), Mentioned as toxicity % occurring in cramps. Mild side effects headache, nausea and urinary adverse effect was sweating and other vasodilation, asthenia, headache, mucous membrane, pharynx and larynx frequency minor cholinergic effects urinary frequency, diarrhoea and dysphagia. Method adopted Double blind, placebo Multicentre, randomized, double blind, A prospective, randomized, double Two randomized, double blind, Double blind, randomized method. controlled, cross-over placebo controlled, dose titration study blind, placebo-controlled trial placebo controlled, multicentre clinical randomized method. trials Assessment of Not clearly stated. Depended VAS Global questionnaire relative to Questionnaire and VAS Subjective self-rating VAS and Patient completed linear analogue scale xerostomia on patient's symptoms the overall condition of xerostomia categorical questions (LASA) as well as QOF assessment All patients on pilocarpine There were statistically significant Increased saliva flow was noted in the Fixed dose protocol: the evaluation of Not studied showed significant increase in increases in whole saliva production patients treated with pilocarpine in 5 salivary flow demonstrated significant
parotid flow rate at 90 days of compared with placebo at every visit. and 10 mg doses but the effect was not sialometric improvement in whole (p= treatment. There were statistically significant post sustained, and it varied throughout the 0.043) and unstimulated parotid dose improvements in whole and treatment period with best responses (p=0.011) saliva production through parotid salivary flow in pilo treatment occurring at 12 weeks. There were week 8 with pilo use. gp versus placebo.(the best results were comparable improvements with 10 mg + dose titration protocol: whole saliva obtained at the end of the study when dose. production increased in 69% of pilo
most patients were taking pilo 10 mg patients vs 43% of placebo patients and
Saliva production Saliva thrice daily after having taken active parotid salivary flow increased in 35% drug for 12 weeks) of pilo patients vs 3% of placebo patients. Results Nine of the twelve patients Pilo dose 2.5 mg thrice daily was an 44% of the patients received 5 mg drug Fixed dose protocol: a significantly No beneficial effect of pilocarpine was showed symptomatic effective dose. After 8 or 12 weeks of demonstrated improved oral dryness as greater number of pilo patients detected on RT induced xerostomia improvement while on study when the patients took 5 and 10 compared with 25% of patients indicated overall improvement than did induced xerostomia when administered pilocarpine. mg doses thrice daily the overall global receiving placebo placebo patients (p= 0.016)(51% vs during RT improvement reached statistical 25% for the 5 mg pilo tablet). significance. There was a reduced need + dose titration protocol: 42% pilo vs
Dry mouth mouth Dry for oral comfort agents and dryness 27% placebo showed improvement of closely approached statistical xerostomia. significance (p=0.057)
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Appendix A continued. Systemic oral pilocarpine preparations - placebo comparisons.
Name of study Gornitsky et al., 2004 Scarantino et al., 2006 Agha-Hosseini, 2007 Konno, 2007 Chitapanarux et al., 2008 Type of treatment Tablets Not stated Tablets (Salagen) Tablets (Salagen) Tablets (Salagen) product Type of compared Placebo tablets Placebo Placebo tablets Placebo tablets Placebo tablets product Frequency of use Five times daily during RT and Four times daily Four times daily Three times daily Three times daily 4 times daily for 5 weeks thereafter. Concentration 5 mg 5 mg 5 mg 5 mg 5 mg Mouth movement Not stated For unstimulated collection, patients Not stated Not stated Not stated. were instructed to minimize orofacial movements
Spitting/ no swallow Swallowing whole tablet Before unstimulated collection they The tablet is assumed to be swallowed Assumed to be swallowed with water. Patients were instructed to take 1 tablet were instructed to swallow with water 3 times daily at mealtime with water.
Flavour Not stated Not stated Not stated Not stated Not stated Number of patients 58 249 28 (13 assigned for treatment and 15 175 patients 33 recruited assigned for placebo. Diagnosis Patients with head and neck Oral and oropharyngeal squamous cell Patients with cGVHD who suffer from Japanese patients with radiation induced Post irradiated head and neck cancer cancer with 2/3 of all major and carcinoma, KPS score ≥ 60 with no xerostomia with some remaining xerostomia for head and neck patients with both parotid glands in the minor salivary glands being prior head and neck radiotherapy salivary function. malignancy. Patients received radiation treated field at least 40 Gy and with a irradiated with a minimum of dose at least 40 Gy history of clinically significant 5000 cGy for 5- 7 weeks. xerostomia Age range Mean age 59.8 years 60.8 in the pilocarpine group and 59.2 Treatment gp: 20-48 years old (33.5). 62.3 ±11.1 for the pilocarpine group and 32-77 years old with mean age of 55.9 in the control group. Placebo gp:20-49 years old (31.6) 59.2 ± 11.5 for the placebo group. years Gender 50 M/ 8 F 76 %M /24%F 18M/ 10 F 137 Mm/ 35F 63.6% M /36.4%F Length of study During RT and 5 weeks after From the start of scheduled radiation 7 days 12 weeks. One-month treatment with placebo then completion of RT therapy (concurrently taken with three months treatment with pilocarpine radiotherapy) and for 6 months after the (the duration of protocol was 20 weeks) completion of radiation therapy Dropout rate 38% (22 patients discontinued 1.6% (245 out of 249 completed the None 17.7% (144 patients of 175 completed 10% lost to follow up in visit 4, 21% in the study in the first study study the study) visit 5 and 30% in the last visit phase Reason for dropout Due to severity of symptoms in Ineligibility (wrong primary cancer, no None Occurrence of adverse effects and Patients knew all the schedule of the their xerostomia, discomfort, histologic confirmation of cancer and recurrence or onset of other cancer. protocol. Also, the long-distance difficulty in speech and eating lymphoma. patients have to travel to the tertiary and loss of patients due to care centre. reactions caused by chemotherapy
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Side effects Sweating, rhinitis, tearing and Sweating, rhinitis, nausea/vomiting, One patient claimed that his migraines Sweating was the most common Sweating (30.3%), nausea (9.1%), stomach cramps increased lacrimation, skin flushing and increased in intensity adverse effect (pilo 63.6%; placebo palpitation (6%) and mild tearing (6%) motor tremors, urinary frequency and 9.2%) asthenia Method adopted Double blind, placebo- RTOG 97-07 phase III, double blind, Double blind, placebo-controlled study Phase III, multicentre, double blind, A single centre, single blind clinical controlled study placebo-controlled study placebo-controlled study trial. (six clinic visits during the study)
Assessment of Questionnaire and VAS as well RTOG scale for acute toxicities of Not studied VAS A subjective xerostomia assessment of xerostomia as QOF questionnaire xerostomia efficacy was undertaken by questionnaire. Also, objective xerostomia assessment was also performed according to LENT SOMA) The use of pilocarpine during Following the completion of radiation Saliva flow rate of the pilo gp was Not studied. Not studied RT did not significantly affect therapy, the average unstimulated higher than the placebo gp one hr post
saliva production salivary flow was statistically greater in dose. However, the difference in saliva
the pilocarpine group, whereas no flow rate between the 2 groups was not difference was noted following parotid statistically different in the third and stimulation. Also 28% of the patients four samples (1 day, 1 week post who received pilocarpine had an dose).also there was a significant increased salivary flow at the difference between the 2 groups in
completion of radiotherapy compared mean salivary sodium and total protein Saliva production Saliva with 15% in the placebo group. output changes 1 hr post dose with no significant difference in calcium and IgA outputs among the two groups.
Results The use of pilocarpine during The results of QOL scales did not Patients who had received pilocarpine Compared with placebo, the pilo group The subjective and objective RT did not significantly affect reveal any significant difference expressed their satisfaction with their demonstrated a significantly greater xerostomia grades were significantly
xerostomia or 5 weeks after between the pilocarpine and placebo treatment improvement from baseline in dryness correlated (p=0.001). Also, xerostomia completion of RT group with regard to xerostomia and of mouth at weeks 4, 8, 12 and at study was improved after one month of mucositis endpoint (p=0.002) pilocarpine treatment. Also, the mean objective xerostomia score showed
statistically significant improvement Dry mouth mouth Dry after 12 weeks of treatment and thereafter
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Appendix B: Systemic oral pilocarpine preparations- non placebo comparisons.
Name of study Lockhart et al., 1996 Jacobs & van der Pas, 1996 Zimmerman et al., 1997 Niedermeier et al., 1998 Deutsch, 1998 Nagler, 1999 Horiot et al., 2000
Type of Controlled release Tablets Not stated (oral preparation) Not stated Salagen tablets Salagen tablets Salagen (oral preparation) treatment tablet. product Type of None None A group of head and neck None None None Patients are divided into 2 compared cancer patients who didn’t groups: Unfavourable gp: product receive pilocarpine during with radiation dose˃50 Gy, their radiation regimen favourable gp with dose˂50 Gy Frequency of use Every 12 hours for three Three times daily or twice Four times daily Once daily three times daily Not stated Three times daily with a 5 doses daily mg optional increase at 5 weeks up to a daily dose of 25 mg beyond 9 weeks. Concentration 15 mg 5 mg with possible 5 mg 3 mg + additional 3mg 5 mg. 30 mg / day 5 mg adjustments from 2.5 to 10 given at the post radiation mg visits after the post stimulation measurements. (A dose of 0.1 mg/kg of body weight was not exceeded). Mouth movement Not stated Not stated Not stated Not stated Not stated Not stated. Not stated Spitting/ no Not stated Assume to swallow with Not stated Assume to swallow with Assume to swallow with Not stated Not stated swallow water water water. Flavour Not stated Not stated Not stated Not stated Not stated Not stated Not stated Number of 8 265 22 test group and 18 control 13 One patient (a black 6 156 patients recruited group male). Diagnosis Healthy hospitalized Post irradiated head and neck Head and neck cancer Post irradiated squamous A child with Xerostomia secondary to Patients with severe volunteers with no cancer patients who had patients who were being cell carcinoma of oral nasopharyngeal GVHD. Four patients radiation induced significant complaints of previously participated in a irradiated during the study cavity and oropharynx carcinoma treated with had moderate chronic xerostomia ( head and neck xerostomia. prior study of oral pilo tablets patients chemotherapy and graft versus host disease cancers or lymphomas with radiotherapy. (GVHD) and two with symptoms of xerostomia) severe GVHD. Age range At least 20 years of age 58 years old Not stated Not stated 10 years old. 18-39 with median age 25-86 years old (60 years) of 22 years. Gender Not stated 185M/ 76 F Not stated Not stated Male. 4 M/ 2 F 119 M/ 37 F
Length of study 3 days 36 months From the start of radiation 9 months Not stated. 6 months From June 1995 to February therapy and continuing for 1996 three months after completion of radiation. Xerostomia was evaluated at 17 and 16 months after
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completion of radiation for both groups.
Dropout rate None 51.3% (129 discontinued the 22.7 % of the test group and 7.6% (12 0f 13 patients None None 26% (38 patients stopped drug) none of the control (5 gave their consent to take treatment before week 12) patients of 22 were not part in this trial) analysed) Reason for None Adverse experience, lack of Four of the five patients not Not stated. None None Acute intolerance dropout efficacy, personal reasons or analysed had died prior to the (sweating, nausea, noncompliance and recurrent time of evaluation and one vomiting) or no response. cancer declined to fill out the questionnaire. Side effects No complaints of Sweating (most frequent), Only one patient couldn’t Minimal side effects Sweating on the nose. All patients experienced Sweating (21%), urinary sweating or urinary frequency, tolerate pilocarpine due to (decrease in blood pressure increased sweating 1- hrs frequency (10), nausea gastrointestinal distress. lacrimation and rhinitis headache and blurred vision. and increase in urination) after drug administration vomiting (5%), lacrimation (8%), dizziness and diarrhoea (6% each). Method adopted Open- labelled pilot Multicentre maintenance Retrospective pilot study Not stated. Pilocarpine was Open study. The first A prospective French study. open label study administered orally three three patients took the cooperative study times daily starting with drug for 6 months, while the initiation of the second 3 patients radiotherapy. took the drug for 2 months then stopped taking it for 2 weeks and then continued to take the drug until the end of the 6-month study period. Assessment of Not studied VAS questio Questionnaire and VAS as Standardized VAS Not stated. Subjective evaluation by Questionnaire as well as xerostomia well as assessment of questionnaire. questionnaire from 0 to 4 evaluation of QoL xerostomia components
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A significant (p˂0.05) Not studied Not studied Pilo produced a significant Not stated. The mean flow rates of The favourable response to increase in both parotid increase of salivary flow resting whole saliva at 2 the drug seems to occur and whole saliva output from the palatal glands weeks, 2 months and 6 primarily from the followed all three doses before and 7 months after months following pilo stimulation of ectopic beginning within 1 hour radiation while secretory use were increased by salivary glands present of dosing and lasting performance of the parotid 224-284% when outside of the irradiated over 10 hours. glands could not be compared to baseline volume. Pilocarpine can be sufficiently increased values. Also, there was a beneficial to patients through stimulation with pronounced increase in suffering from severe
pilocarpine immediately the parotid, xerostomia regardless of
after or 7 months after submandibular and radiotherapy dose and radiotherapy sublingual flow rates at volume of salivary gland the specified time being irradiated. intervals. When the drug was discontinued in some patients for 2
Saliva production Saliva weeks this resulted in a drop in the whole saliva flow rate to baseline.
When the drug was
reinstituted, a rapid profound increase was
Results seen similar to that occurred initially followed by partial decrease later.
Not studied. Oral pilocarpine at these The use of pilocarpine during The sensation of a dry During the course of Within two weeks of Salagen decreases doses effectively and safely RT and 3 months thereafter mouth could be radiotherapy, the patient drug administration the xerostomia symptoms and reduces the symptoms of was associated with significantly relived by an had minimal complaints subjective xerostomic improves QOF in about 2/3 radiation induced xerostomia. significantly less subjective increase in the palatal flow. related to xerostomia. score was altered to of the patients. Dryness of the mouth and xerostomia than that reported Seven months later the normal values (0.0).
tongue improved from a by a similar cohort of oral mucosa was still Some patients even mean baseline of 23.9 to 42 patients who didn’t receive moist, and the patient reported hyposalivation. (p˂0.01). oral pilo is pilocarpine. was asymptomatic. moderately effective in
reducing the symptoms of Dry mouth mouth Dry radiation induced xerostomia and this effect can be maintained up to 36 month m (a starting dose of 5 mg three times daily appears to be optimal)
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Appendix B continued: Systemic oral pilocarpine preparations- non placebo comparisons.
Name of study Mateos, 2001 Wasnich et al., 2003 Mosqueda-Taylor et Gorsky, 2004 Masters, 2005 Aframian et al., 2006 Nyarady et al., 2006 al., 2004 Type of treatment Not stated Tablet Tablet Salagen tablets Not stated Not specified Salagen tablets product Type of compared None None None Urecholine tablets None None None product (Bethanechol) Frequency of use Three times daily 2 doses of 2 different Three times daily Salagen tablets:3 times Divided into dosing of two Single dose Three times daily strengths were given daily can be increased to or three times a day. separately to each gp on first 4.bethanechol: one tablet 3 and third days of the study. times daily can be increased to 2 tablets three times daily. Concentration 5mg 3, 5 mg 5 mg Salagen tablets: 5 mg. 10-30 mg daily 5 mg 5 mg Bethanechol tablets: 25 mg Mouth movement Not stated Not stated. Not stated. Not stated. Not stated Not stated Not stated. Spitting/ no swallow Assume to swallow Swallow with 240 ml of Administered with Swallow with water. Assume to swallow with Not stated Assume to swallow with with water water. water. water water Flavour Not stated Not stated Not stated Not stated. Not stated Not stated Not stated Number of patients 49 14 J/ 13 C 20 42 patients Not stated 5 70 recruited Diagnosis Head and neck cancer Japanese (J) and Caucasian Mexican patients Post irradiated head and Xerostomia secondary to Patients suffering from Post irradiated head and neck patients who will (C) healthy male volunteers. affected by neck cancer patients who psychoactive medications thyroid cancer treated with cancer patients. receive radiotherapy hyposalivation suffered from xerostomia. use. radioiodine therapy and during the study secondary to suffering from long term radiotherapy of the head salivary gland impairment. and neck region. Age range 29-87 years old (mean 19-45 years old (23 years J), 35-80 years old (59.5 Mean age was 55.9 years. 20-69 years old 39-72 years old (53 years) 58.98±10.34 age 61) 20-44 years old (23 years C) years).
Gender Not stated All were men. 8 M/ 12F. 31 M/ 11F Not stated 2 M/ 3F 53 M/ 13F
Length of study One year after 4 days. 10 weeks. For 2-3-week courses Not stated 4 hours (the study 18 weeks completion of depending upon the need conducted between 8:00 radiotherapy to raise dose or discontinue and 12:00 am.) with one week washout period between the two treatments. Dropout rate 36.7% (31 patients 11.11% (3 out of 27 None. 27 patients completed the Not stated None 5.7% (4 out of 70 dropped completed the whole withdrew from the study crossover study (35.7%) out) study) after their first dose).
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Reason for dropout 10 patients died by Positive results obtained None. Personal reasons and some Not stated None Failure to appear at controls. six-month post from the drug screen tests. patients only completed treatment, five patients one arm of the study. abandoned the study after 6 months' follow up and three patients were monitored for up to 9 months after radiotherapy. Side effects Not stated Treatment related A/E Sweating (85%), and Both medications caused: Sweating and increased Patient no.1 experienced Not stated included mild urticaria with headache, diarrhoea, sweating, dizziness, urination. fatigue that resolved after both doses of pilo (J). Non blurred vision, chills cramps, urination, blurred an hour. treatment A/E included (30%). vision, rapid heart rate, sweating, headache after 3 nausea. mg dose (J). Also, headache, diarrhoea, nausea and vomiting after the 3 mg dose (C). Asymptomatic enlargement of the tonsils. Method adopted Patients were Single centre, randomized, Not stated. Open label randomized Not stated Not stated Prospective randomized classified into two single blind, 2- way crossover study. study in which the patients groups: P group crossover study. are divided into two groups. (n=26) who treated Gp D taking the drug from with pilocarpine the beginning of radiotherapy starting at the day over a period of 12 weeks. before radiotherapy Gp A: taking the same dose and continued of the drug in the second 6 throughout the first weeks following irradiation. year of follow up. NP (n=23) who received radiotherapy without pilocarpine and were used as the control group. Assessment of VAS and salivary Not studied. Questionnaire with an Patient self-evaluation. Not stated Recorded during the study. VAS questionnaire across a xerostomia gland scintigraphy. ordinal scale ranging 100 mm scale. (assessment of from 0-10. overall, daily and nocturnal xerostomia)
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There were no Salivary flow rates were Initial whole saliva test Patients reported Not stated All patients except patient The recorded saliva secretion statistical differences significantly increased over had a mean salivary subjective improved saliva no.3 responded to is always better in group D between the two baseline (p˂0.05) at the production of 0.8 cm. with both drugs. At the end pilocarpine intake with (p˂0.05). saliva flow groups regarding initial time point of 0.3 after 10 weeks of of the study analysis of the increased unstimulated and decrease was lower in the saliva production from hours post dose for both the treatment saliva results showed that stimulated whole salivary group treated with Salagen parotid and 3 and 5 mg doses for both production increased to a statistically significant flow rate (UWSFR, WSFR from the beginning of RT. submaxillary glands as ethnic groups. These values mean of 2.24 cm. there differences were seen for respectively). Significant Stimulated salivary gland
both of them were remained significantly was a salivary flow resting saliva for both elevation was found after suffers a smaller decrease in rapidly impaired after elevated compared with increase of 64.5% and medications and subjective 120 min for UWSFR saliva production capability irradiation. However, a baseline (p˂0.05) the difference between improvement in saliva was (p=0.05) and after 60 and during RT. The increased tendency to recover throughout the 2- hour post production before and similar for both drugs. 120 min for WSFR saliva flow reduced the side within the pilocarpine dose time period. The after treatment was (p=0.042). effects of RT. group was observed in salivary flow rates were statistically different the parotid and similar between both groups. (p˂0.001). Saliva production Saliva submaxillary glands at one year follow up. (pilocarpine taken during radiotherapy did not significantly
Results improve salivary gland dysfunction caused by radiotherapy). After radiotherapy Not studied. There were significant The patients' subjective Substantial relief of All patients except no.3 Overall xerostomia: The 83% of the NP and improvements in oral increase in mouth xerostomia was achieved reported improvement of recorded VAS after initiation 81% of the P groups dryness, mouth comfort, moistening was reported as in the majority of the their subjective dry mouth of RT was always experienced ability to speak and a mean increase of 25% patients. sensation. significantly better in group xerostomia ability to swallow following the use of D (p˂0.001).Daily respectively. At one (p˂0.01). pilocarpine and 33% xerostomia: The recorded year follow up no following the use of VAS after initiation of RT differences were found Bethanechol. was always significantly comparing the two better in group D
Dry mouth mouth Dry groups and this data (p˂0.05).Nocturnal surprisingly did not xerostomia: there was a correlate with the significant increase of salivary gland symptoms due to NX by the dysfunction observed six week (p˂0.05). on scintigraphy.
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Appendix B continued: Systemic oral pilocarpine preparations- non placebo comparisons.
Name of study Aframian et al., 2007 Dave, 2008 Silberstein, 2008 Nakamura et al., Almeida & Abbasi et al., 2013 2009 Kowalski, 2010 Type of treatment Tablet Not known but Not specified Not specified Not specified Tablet product assumed to be a tablet formulation Type of compared None None Patients are classified None None Bromhexine tablets product into 2 groups; one of (8mg) them is taking pilo while the other is not. Frequency of use Single dose Three times daily Every 8 hours for one Three times daily Three times daily Four times daily week. Concentration 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg Mouth movement Not stated Not stated. Not stated Not stated Not stated Not stated Spitting/ no Not stated Not stated. Not stated. Not stated Not stated Not stated swallow Flavour Not stated Not stated. Not stated Not stated Not stated Not stated Number of patients 45 One patient 60 39 5 25 recruited Diagnosis Patients with a primary Severe refractory dry Patients with papillary Post irradiated head and Patients treated for well Patients with a medical complaint of xerostomia mouth in association and follicular thyroid neck patients (parotid differentiated thyroid history of head and neck due to radiotherapy, with administration of carcinoma with glands are irradiated) carcinoma undergoing radiotherapy and Sjogren’s syndrome or BoNTB (used for concurrent therapy with or not adjuvant currently suffering from sialosis and xerosgenic treatment of spasticity 131 I therapy. radioiodine therapy. xerostomia medications with persistent as a result of stroke) painless enlargement of parotid glands for at least 3 months. Age range 52±18, 61±11, 57±15 73-year-old 47.3±17.0, 46.6±16.5 39-84 years old (61 36-65 years old (52.1 All patients were over years) years) 18 years of age Gender 9 M/ 36 F Female 12 M/ 48F 35 M/ 4F Not stated Not stated Length of study Between 8:00 hours and One week January 2006-july 2006 One week 10 weeks 12:00 hours. for at least 12 weeks. Dropout rate 2.2% (44 out of 45 None Not stated 56.4% (22 out of 39 None Not stated completed the study) patients didn’t complete the study)
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Reason for dropout Not stated. None 3 patients out of 39 None Not stated were excluded from the analysis because they stopped taking pilocarpine within 12 weeks for reasons other than adverse effects and 19 patients stopped taking pilocarpine within 12 weeks because of adverse effects. Side effects Urinary frequency (28%), Flu like symptoms 3 patients believed they Sweating (64%), nausea The most commonly Not stated. dizziness (15%) and were perspiring more (8%), rhinitis (6%) and reported side effect was sweating (11%), flushing, than normally. 1 had headache (3%) and sweating followed by headache, tremor, nausea psychologic reaction others. fatigue, headache, (11%), chest pressure, that resolved within 12 increased urinary tiredness, GI irritation, h of discontinuing pilo. frequency, tearing, rhinitis, blurred vision and No patients in either shivering, dizziness and weakness. group had new nausea. One patient gastrointestinal or presented an altered urinary symptoms. arterial blood pressure and tachycardia. Method adopted Patients were divided into Not stated. Single blind controlled Not stated Prospective, non- Single blind, three groups according to prospective study. randomized study. randomized crossover aetiology of xerostomia study. Assessment of Not studied Patient feedback Simple questions. VAS Not stated Self-administered xerostomia questionnaire (15 questions) by Dichotomous format.
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The most significant and Not studied Pilo did not reduce the Not studied. Not studied The difference between persistent elevation of occurrence of radiation saliva secretion rates salivary flow rate was sialadenitis or somatitis. before and after observed in the sialosis/ The occurrence, medications was not drug induced gp followed however, was lower significant for by SS gp. The radiotherapy than had previously Bromhexine users at group presented a been reported in the two steps of the study significant elevation of literature possibly (p=0.35); however, it salivary secretion rate after because of the was significant for 1 and 2 h but returned to concurrent stringent pilocarpine users baseline at 3 h. application of (p=0.0001)
physiologic sialagogues Salivaproduction (candy,gum,fluids),
dexamethasone and dolasterone mesylate, a serotonin receptor
Results antagonist. Not studied. Pilocarpine has No patient in this study Response rate was 40% Two patients reported 28% and 100% of alleviated the noted xerostomia up to at 12 weeks. relief of xerostomia by Bromhexine and pilo xerostomia that was at least 8 months after using pilocarpine; two users showed experienced by this therapy, with follow up patients reported a improvement of patient. on 30% of these significant improvement xerostomia after 14 patients for 5 years. of dry mouth days, respectively. Statistical analysis showed significant
Dry Dry mouth differences in improvement of xerostomia for users of both medications (p=0.0001).
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Appendix C: Systemic oral pilocarpine preparations - capsules
Name of study Fox et al., 1986 Fox et al.1991 Valdez et al. , 1993 Lajtman, 2000 Leek & Albertsson, 2002 Haddad & Karimi, 2002 Gotrick, 2004 Brimhall, 2013
Type of Capsules Capsules Capsules Capsules Capsules Capsules Capsules Capsules treatment product
Type of Placebo capsule Placebo capsules Placebo capsules Placebo capsules None Placebo capsules Placebo capsules and Cevimeline capsules compared control group 30 mg product Frequency of use Once daily at 10 am Three times daily at Four times daily. Four times daily Three times daily Three times daily Single dose Three times daily fixed times. for both drugs
Concentration 5 mg 5 mg 5 mg. 5 mg 5 mg 5 mg 5 mg 5 mg
Mouth Not stated. Not stated. Not stated Not stated Not stated Not stated Not stated Not stated movement Spitting/ no Swallowing whole Swallowing whole Not stated Assumed to be Not stated Swallow the whole capsule Swallow the whole Assumed to be swallow capsule capsule swallowed with water capsule with water swallowed with water Flavour Not stated. Not stated. Not stated. Not stated Not stated Not stated Not stated not stated Number of 6 39 10 43 40 60 65 15 patients recruited Diagnosis Oral dryness caused 21 with SS, 12 with Head, neck or Patients whose their Post irradiated head and Post irradiated head and Healthy volunteers Patients with by salivary gland radiation induced mantle radiation major salivary glands neck cancer patients with a neck cancer patients, with (opioid induced moderate - severe dysfunction (marked salivary therapy patients with would be completely (24 troublesome xerostomia of both parotid glands in the xerostomia) xerostomia due to salivary gland hypofunction, 6 with no subjective patients) or partially (19 at least 1-year duration. radiation field of minimum SS, medication disease) idiopathic salivary xerostomia before patients) included in the 40 Gy. induced, radiation gland hypofunction. radiation. radiation field for head therapy and and neck cancers. unknown aetiology.
Age range 62-76 years old 14-76 years old Not stated. Not stated Not stated 18-70 years old ( mean age 23±0.5 years Not stated (mean age was is 42 years) 55.4±13.3) Gender All were women 29 F/ 10 M 6 M/ 4F Not stated 30 M/ 10F 60% M/ 40% F 28 M/ 37 F Not stated Length of study 4 consecutive days 6 months 3 months beginning 12 months but drug 3 months The drug was given from Not known but 4 weeks treatment (pilocarpine was the day before being taken in the first 3 the start of radiation and assumed to be one with either drugs, given for 5 of the 6 radiation therapy. months of the study. continued until 3 months week or less one-week washout months and placebo Examination was after the end of period then another was randomly repeated at 3 months radiotherapy and 4 weeks period assigned for 1 and 4, 5, 6 and 12 xerostomia was evaluated treatment with the month during months. 6 months after the end of other drug months 2 to 6. radiation. 183
APPENDIX
Dropout rate None 20.5% (31 patients 10% (9 out of 10 None 5% (38 out of 40 patients 35% (39 out of 60 26%(60 out of 65 20% completed the patients completed completed the protocol). completed the study) subjects completed the protocol) the protocol) protocol)
Reason for None Three due to loss of Not stated. None Gastrointestinal tract 9 patients died and 12 Five subjects Not stated dropout medical eligibility intolerance and minimal patients did not come back withdrawn due to due to recurrence of benefit. for the evaluation of adverse effects of malignant tumours, xerostomia in the required tramadol and illness, 2 due to GIT time period. 12 excluded as the intolerance and 1 reduction in their due to minimal saliva production benefit. induced by tramadol was less than 40% Side effects Two patients Sweating (65%), Not stated. Not stated Were uncommon, were No serious side effects Sweating due to pilo Increased sweating, reported increased flushing (42%), generally mild and caused were observed. Excessive use among two of the watering from eyes, lacrimal secretion. urination (38%), no treatment interruption. lacrimation by one patient. subjects headache, nausea, increases in lacrimal stomach upset, and nasal secretions, diarrhoea and pain mild GIT distress around eyes for both (13%). drugs. Method adopted Double blind, Double blind, Double blind, A randomized, double Not stated A randomized, double Randomized double Cross over, double placebo controlled, placebo controlled, placebo-controlled blind, placebo-controlled blind, placebo-controlled blind placebo- randomized trial. cross over design. cross over design. trial. trial. (with treatment trial. controlled study in starting in the day just which patients are before radiotherapy and allocated to 3 groups continued for three after taking tramadol months) to induce xerostomia (control gp, pilo gp, placebo gp) Assessment of Patients were asked Standard series of Standardized Standardized VAS VAS questionnaire. Not specific Not fully studied xerostomia at the conclusion of questions questionnaire questionnaire. Assessment of subjective each day to assess concerning the and objective (LENT the xerostomia patient's perceptions SOMA) xerostomia. during that day. of changes in oral dryness, oral functions and comfort and side effects in the preceding month.
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At low dose, Pilocarpine Salivary flow After radiation all Pilocarpine significantly Not studied Baseline saliva Both drugs were pilocarpine significantly decreased in all patients had reduced increased the salivary flow production rates did found to decrease increased saliva increased salivary patients within the salivary output, and this rates in this group of not differ among the the symptoms production by output in 68% of the first week of persisted throughout the patients with salivary three groups and associated with parotid/submandibul patients radiation therapy one-year study period. dysfunction (p˂0.03). tramadol lowered the xerostomia
ar and / or and persists However, pilocarpine secretion at the same sublingual glands. throughout the year use caused lower level in all groups. the quantity and of study. However, decreases in stimulated However, pilo has composition of the pilo treated gp parotid function than the caused a 4-fold saliva produced by had smaller losses in placebo use provided increase in saliva flow our drug was similar stimulated function that some of the glands rate more than that to that produced than the placebo are spared from achieved by placebo Saliva production Saliva after stimulation treated gp. irradiation. This and that occurred in with 2% citrate difference was the control gp. statistically significant between the two groups at the three months follow up examination.
Results Mean Subjective 87% reported that Pilocarpine treated None of the patients 52.5%of the participants Subjective relief of There was no Both medications xerostomia was 40.3 their oral symptoms gp reported complained of reported their oral xerostomia. All patients correlation between increased the saliva mm in the pilo gp improved after the significantly fewer xerostomia prior to symptoms improved after commented that the saliva secretion rates secretion stimulated and 57 mm in the first month of oral symptoms than radiotherapy. However, pilocarpine treatment. subjective feeling was and subjective feeling and unstimulated at placebo gp pilocarpine the placebo treated all of them had There was a significant different from that of xerostomia as some the end of four (statistically treatment. gp during treatment. xerostomia after being improvement in xerostomia obtained by sipping water subjects did not report weeks of each significant irradiated. But the (p˂0.01). any feeling of treatment and there difference p=0.02). pilocarpine treated group xerostomia although was a slightly higher also the mean reported significantly their saliva secretion increment in saliva objective xerostomia fewer oral symptoms rated was reduced by production
Dry mouth mouth Dry grade was 2.2 in the than the placebo treated more than 50% and following pilo gp and 2.6 in group during drug contrastly some of pilocarpine use but the placebo gp treatment. them experienced the there was no (statistically sensation of dry mouth statistical difference significant even though there was between pilocarpine difference p=0.01) a reasonable saliva and Cevimeline. secretion.
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Appendix D: Local preparations of pilocarpine
Name of author Mikhail, 1980 Hamlar et al., Bernardi et al., Taweechaisupapong, Gibson et al., 2007 Kim, 2014 Tanigawa, 2015 Rupel, 2014 Nikles et al., 2015 1996 2002 2006
Type of Mouthwash Pastille Mouthwash Lozenge Hydrogel buccal Mouthwash Mouthwash Mouthwash Pilocarpine eye treatment (pilocarpine is insert containing drops product incorporated into a pilo. commercially available mouthwash LAVORIS Type of None Placebo pastille 0.9% Saline Salagen tablet (5mg None 0.9% Saline Water rinse. None Placebo drops compared pilocarpine) and product placebo lozenge Frequency of According to the Each weekly 4 groups of 10 4 envelopes Three times daily Three times daily As many times as Three times daily Three drops orally use patient's package contained individuals took 10 containing the 4 needed but the total for the patients. three times daily. xerostomia 15 pastilles to be ml to be by mouth preparations, each is volume of liquids condition (varied taken three times rinsed for 1 min given to the patient must not exceed 150 from once every daily for 5 days every 10 consecutive ml (i.e. 15 mg) per other day to about followed by 2 days. day. twice daily) days off Concentration Ranged from 2.5,5,7.5 and 10 0.5%, 1% and 2% 3 or 5 mg 5 mg 10 ml of the 15 mg pilocarpine 2.5 ml of 2% 4% (40 mg/ml), 6 0.025% to 1% by mg solution (50 mg, 100 0.01% solution tablet dissolved in mouth wash mg per dose. weight of the mg, 200 mg with (10 mg) for 1 min. 150 ml of tap water (equivalent to 50 mouthwash. spitting out) Made by diluting (10 mg/100ml = mg) 2% pilo eye drops 0.01%) with 0.9% saline. Mouth Mechanical Mechanical Mechanical Mechanical Not stated Gargled. Patients Not stated. Mechanical To be taken orally movement stimulation is stimulation stimulation is stimulation for the were asked to stimulation is expected with the prohibited within 90 lozenge minimize any expected with the mouth wash use. min before the mouth movement mouth wash use. experience. when using the mouthwash Spitting/ no Gargle the The pastille Mouth rinsing with The lozenge should The insert to be Not stated Retain in the mouth Rinse in the To spit the residue swallow mouthwash in the should be 10 ml sol. and be dissolved in mouth placed in the (presume with for 2 minutes then mouth for five and not to swallow mouth for 30 dissolved in the spitting the entire without chewing buccal sulcus in the spitting excess spit out. minutes. (assumed (assume to be seconds or longer mouth without volume after 1 min. mouth for 3 hours after I min based to be spat out of gargled in the mouth and then spit from chewing and then remove on results). mouth after use) first and then the the mouth. residue was to be spat) Flavour Flavours that are Butterscotch Not stated Not stated Not stated None added (2% Not stated. Not stated Citrus flavour present in eye drops diluted LAVORIS. using 0.9% saline) Number of 40 40 40 33 8 60 40 (25 pilo group, 14 SS patients and 20 patients 15 control group) 10 healthy recruited subjects
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Diagnosis Patients with dry Post irradiated Healthy volunteers Post irradiated head Patients with a Patients with Elderly patients with Patients with Patients with mouth caused by head and neck (medical students) and neck cancer confirmed xerostomia lasting xerostomia lasting xerostomia advanced cancer and some medications cancer patients patients diagnosis of SS for 3 months or for 3 months or secondary to SS. dry mouth (defined such as (primary and longer more with as having a score of antidepressants, secondary). xerostomia score of ≥3 on an 11-point antipsychotics, and 2 or greater xerostomia antihypertensive. according to by numerical rating clinical scale) classification scale of xerostomia (grade 0=not dry, grade 1=saliva shows viscosity, grade 2=saliva shows tiny bubbles on the tongue, grade 3= dry tongue without viscosity and little or no saliva shown). Age range Not stated. 18 years or old 18-30 years old 20-60 years old 49-70 years old (60 Mean age 53.6 71.5±4.7 (pilo Not stated 46-81 (62.3±9.7 years) (51.9±11.4years) years) years for group), 75.4±3.5 exp.group and (control group). 50.2 years for control group Gender Not stated. 28 m/ 6 f 14 m/ 26 f 22 m / 11 f 2 m/ 6 f 8 m/ 45 f 7m/ 26 f Not stated 4 M/ 16 F Length of study Not stated. 5 successive 75 minutes 31 days (single dose 14 days 4 weeks Before and one 4 weeks 18 days. weeks (5 days for with 10 days between month after each of 5 each of 4 treatments) treatmen.t treatments with 2 days off in between) Dropout rate Not stated. 15% (34 were None None 12.5% (one patient 11.6% (53 out of 17.5% ( 7 out of 40 Not stated 80% (20% had determined to be withdrew from the 60 completed the patients withdrew complete data for evaluable) study) study) from the study) the three cycles of the trial). Reason for Not stated. 2 patients (5%) None None Localised oral Not stated Side effects as oral Not stated Withdrawal of dropout side effects; others ulceration because discomfort, tongue consent for (4 patients) of the presence of a discomfort, chest unknown reasons, transportation complete upper pain and due to deteriorating difficulty, denture and the unknown reasons. condition, appointment too resulting rubbing unacceptable long and cancer of the insert on the toxicity, non- recurrence. adjacent buccal compliance to mucosa. protocol and admission to hospital for symptom control.
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Side effects No adverse effects Flushing, No adverse effects Negligible Abdominal No adverse effects Irritation of the Sweating and Nausea, headache have been sweating, tearing, occurred. discomfort, are reported on mouth (13%) and nausea were and visual reported. increased flushing, sweating the questionnaire tongue (1%), mild minor side effects. disturbance. urination and oral and headache. during the chest pain (4%) in irritation Unusual taste and exp.time. the pilo group all of sore or dry throat these side effects (2 patients). Local disappeared on mucosal erythema stopping mouth at the site if insert wash use. placement (1 patient) Method adopted Not stated. Cross over, Placebo controlled, Cross over, Open, uncontrolled Controlled, double Prospective, Prospective Randomised, prospective, double blind, randomized, double pilot study. blind, randomized randomized study. controlled study in double- blind, cross randomized, randomized clinical blind, placebo clinical trial which 10 healthy over N-of-1 clinical double blind, trial controlled volunteers used trial. placebo controlled the mouthwash once and then monitored for 30 minutes and 14 SS patients used the mouth wash 3 times daily by rinsing in the mouth for 5 minutes. Assessment of Not stated. Questionnaire VAS VAS and sialometry Not studied NRS VAS (100 mm Not studied Mean scores of dry xerostomia scale) mouth in the previous 24 hr using the XI, 11-point scale xerostomia NRS, OHIP and PGIC.
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Not stated. Increased salivary Mouth washing with Statistically There is marked Significant After one month A significant Not studied. flow rate was 1 or 2% pilocarpine significant increase in improvement in the increase in labial treatment with increase in noted in the significantly saliva production for mean change in and palatal minor pilocarpine the salivary flow was patients while increased saliva the three treatments salivary flow rate salivary secretion saliva secretion rate apparent they were taking flow (p=0.006) over placebo (p˂0.05) at day 8 compared and in increased to following pilo pilocarpine albeit (dose dependant). to day 1 values unstimulated 0.83±0.12 ml/ min mouth wash use in
a small range of (increase from 0 to whole saliva (was 0.71 ± 0.14 ml/ both groups. doses was used in 1.2 ml). This new secretion. min) which was Significant this study. elevated flow rate considered to be a correlation was However, no is sustained for a statistically demonstrated significant further 4 days. The significant increase between blood increase in saliva results suggest that while in the control concentration of production over there is an increase group the increase in pilo and increased Saliva production Saliva placebo occurred. in salivary flow in saliva secretion saliva production patients at day 12 produced by water after mouthwash when compared to rinse for one month use. day 1 (p= 0.0078) was not statistically different than that produced before water rinse.
Gargling with 1% 74% reported Additional studies Significant Not studied but No long-term The VAS scores Friedman 50% of the patients mouthwash has relief of on patients with improvement with 5 instead oral effect on before treatment statistical analysis were responders been found to be symptoms. xerostomia are mg lozenge (p=0.03). comfort scores xerostomia.0.9% were 70±12.9 in the showed that (responders are
Results effective in Topical pilo needed. Non-significant were studied. (the saline solution pilo gp and 70.7±8 subjective feeling defined as those providing relief of administration has improvement with 3 data suggests that alleviates in the control gp. of xerostomia was who got a clinically xerostomia for shown similar mg lozenge (p=0.08). there is a xerostomia at One month after improved over significant response from about 6 to results to previous Improved response difference between night or on treatment the VAS time among the to pilocarpine as a ≥ about 8 hours per systemic delivery with Salagen the VAS oral awakening. No score was reduced to patients 2 -point application. methods for (p=0.01). The 5 mg comfort score data significant 47.9±13.1 following (p˂0.000). improvement in
radiation induced lozenge produced the collected at day 7 decrease in pilo use (statistically xerostomia NRS xerostomia but best clinical results. and day 12 xerostomia after significant score compared to with improved p=0.0469. the using pilocarpine difference) while for placebo). patient tolerance. results suggest that mouthwash and the control group it the values on day no significant diff. was reduced to only Dry mouth mouth Dry 12 are lower than between both 66.4±9.9 which was those collected on solutions. not considered to be day 7 which shows a statistically an improvement in significant comfort) difference. Overall improvement was observed in 47% of the pilo gp compared to 14% of the controls.
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Appendix E: Alternative oral formulations of pilocarpine for systemic delivery
Name of author Schuller et al., 1989 Rhodus, 1991 Joensuu et al., 1993 Davies & Singer, Singhal, 1997 Mercadante, 2000 1994
Type of treatment Ophthalmic solution to Liquid ophthalmic drop Oral solution prepared Mouthwash (swallow Ophthalmic preparation Eye drops (2%) product be taken orally preparation. from Oftan pilocarpine excess) (eye drops) (swallow excess) eye drops.
Type of compared Placebo Identically appearing 2 mg tablets of Spray of Mucin based None None product placebo solution of Carbacholine artificial saliva (Saliva deionized water Orthana)
Frequency of use Three drops, three Four drops three times Control: Three drops Placebo: 2-3 sprays Three times daily (1 ml Three times daily times daily daily three times daily. when required, Active: of 0.5% solution) Placebo: one tablet 5 mg three times daily (=5mg/ml) thrice daily Concentration 3 mg dose using 2% 2% equivalent to 5 mg 6 mg (3 drops of Not stated how dose of 5 mg 5 mg solution (contains 1 three times daily. 40mg/ml pilocarpine 5 mg was obtained mg/drop) mixed with 10 ml sterile water) (0.6%) Mouth movement Rinse in the mouth. Swish in the mouth Not stated Mechanical stimulation To be taken orally Not stated
Spitting/ no swallow Swallow The whole Swish and swallow Swallow Swallow any remaining Swallow All patients were treated dose fluid with pilo eye drops to be taken by mouth Flavour Ophthalmic solution Not stated Not stated Not stated Not stated Not stated Number of patients 43 18 (9 patients receiving 24 20 13 21 recruited pilocarpine and 9 age and sex matched SS control subjects receiving placebo)
Diagnosis Upper areodigestive Patients with diagnosed Post irradiated head and Post irradiated 16 head With moderate and Patients suffering from tract malignancies and primary and secondary neck cancer patients and neck cancer and 4 severe xerostomia due xerostomia secondary to who are post irradiated SS with radiation induced non-Hodgkin’s to GVHD (7) or TBI (6) opioid use for the with KPS≥60 xerostomia lymphomas total body irradiation alleviation of pain in those patients with advanced cancer Age range Not stated 37-73 years old (57.6 28-83 years old 46-82 years old (63.4 Not stated years). years)
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Gender Not stated All were females. 18 M / 6F 12 M / 8 F Not stated 11 M/ 10 F Length of study 3 months treatment 6 weeks 7 months (3 months 3 months treatment with The duration of 19 Week and 3 months after treatment with pilo, 4- Saliva Orthana spray, courses of therapy was completion of week drug-free period one-week washout 7-245 days (median 73) treatment (6 months). and another 3 months period, 3 months with carbacholine) treatment with pilocarpine mouthwash. Dropout rate 67.4% (14 out of 43 None 30.7% (16 out of 24 15% (17 of 20 7 patients out of 13 None completed the study) completed the study). completed the study) were still on pilocarpine Only 8 patients who at the last follow up. took pilocarpine and Only one patient never treated with discontinued treatment carbacholine. from the beginning. Reason for dropout Pregnancy, None Death from cancer, Side effects. Adverse effects None deterioration of health marked deterioration of (sweating with and side effects the general condition, abdominal cramps) (diarrhoea, nosebleeds, wish to discontinue bradycardia and medication because mucosal irradiation) xerostomia was not disturbing and side effects following pilo treatment. Side effects Not stated Initial slight glossalgia Headache and altered Nausea, sweating, Wheezing, increased No A/E with significant and oral burning vision, increased lacrimation and local sweating with or intensity was sensation, and slightly sweating and impotence. irritation without abdominal accompanied with pilo increased diaphoresis. cramps. use. Method adopted Two arm prospective Single- blind, placebo- Cross over, open, non- Cross over placebo Open simple non Open simple non placebo randomized double controlled study. blind, no placebo. controlled placebo study study blind placebo pilot study Assessment of xerostomia Questionnaire Subjective patient Assessed periodically by Questionnaire and VAS On arbitrary scale 0-10 0-3 scale standard sheet complaints of the patient on a linear (0-3; severe, 4-6; assessment xerostomia were scale from 0-10 moderate, 7-10; mild) recorded.
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3 of 5 pilo patients had The parotid saliva flow No significant difference Not studied 77% of the patients had Not studied an increase in mucin after pilo dosing was in the basal and a significant increase in production during and more than twice the stimulated salivary flow saliva production and after treatment and baseline. The subjects rates when 12 h improve in oral also 3 of 5 had with secondary SS measured after taking symptoms which increased salivary flow demonstrated a greater the last dose of the drugs reached its maximum
during treatment and 3 stimulatory response to and also, they didn’t after 7-186 days of 5 had a decrease in the pilo than the increase during drug (median 46). saliva flow 3 months primary SS gp. No treatment. after treatment appreciable change was stopped. found in salivary flow for either unstimulated or parotid stimulated Salivaproduction flow in the control gp. Pilo significantly
stimulated both unstimulated and parotid stimulated
Results saliva in more than 755 of the patients. 3 of 5 pilocarpine 7 of the subjects in the The median subjective 12 of 17 patients felt The ophthalmic Pilocarpine has caused a patients reported no pilo gp reported the score of xerostomia of relieved of their preparation of pilo was significant decrease in change in xerostomia increased sensation of the 8 pilo patients was symptoms (p=0.04) effective as the tablets xerostomia feeling among during treatment and 3 oral moisture and 1.3 before pilo and 4.5 with pilocarpine for alleviation of the patients starting from
reported slight lubrication while all the after 3-month use of mouthwash. Significant xerostomia and was day 1 to day 7 throughout improvement 3 months patients in the placebo pilocarpine. Also, both improvement of equally acceptable to the study (p˂0.0005 after, 1 no change and gp reported no change pilo (p=0.01) and dysgesia by the patients and the cost compared to T0) 1 felt it was worse than of any kind. carbacholine (p=0.03) mouthwash. was one tenth that of during treatment. improved mouth tablets Dry Dry mouth moistness on a subjective linear scale. (increased preference towards Carbacholine).
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Appendix E continued: Alternative oral formulations of pilocarpine for systemic delivery
Name of author Sangthawan et al. ,2001 Frydrych et al., 2002 Alajbeg, 2005 Sung, 2005 Jorkjend, 2008 Pimentel, 2014
Type of treatment product Jelly Mouth spray (assume 2% PILOKARPIN ocular 1 % pilocarpine Oral solution (pilocarpine Pilocarpine oral solution swallow) drops. ophthalmic solution dissolved in 20 ml water). (assume swallow)
Type of compared product Placebo jelly Placebo spray of 90 ml 25% D-panthenol was used 3:7 mixture of normal None Saline solution Oralube as a placebo. saline and Milli-Q water. Frequency of use Three times daily Variable: each subject was 5 mg as one dose in exp 1, Ten drops four times daily One treatment only Three times daily encouraged to continue while in exp 2 patients took using their individual 5 mg three times daily. symptomatic regimens for xerostomia Concentration 5 mg 90 ml containing 15 ml 4% 5 mg (patients were Ten drops equivalent to 5 0.7 mg per 10 kg body 5 mg eye drops +75 ml Oralube instructed to take 5 drops of mg. weight (0.7%) – dose unknown. 2% eye drops which were equivalent to 5 mg) Mouth movement Mechanical stimulation Not stated To be taken orally. To be taken orally To be taken orally To be taken orally for the jelly Spitting/ no swallow No specific instructions Not stated (assume Swallow the whole dose Assume swallow the whole Swallow Assumed to be swallowed to retain in the mouth. swallow the spray) dose. whole solution. Flavour Not stated Not stated Not stated. Not stated but patients Not stated Not stated complained of the bitter taste of the solution that lead to inconvenience. Number of patients recruited 60 23 18 60 51 patients and 10 healthy 11 volunteers as controls Diagnosis Squamous cell carcinoma Patients with radiation 12 patients with drug Patients who undergone Patients diagnosed with Recently diagnosed head and of head and neck cancer induced hyposalivation induced xerostomia and 6 haemodialysis and usually secondary SS neck cancer patients who patients (all patients were (head and neck) patients with Sjögren suffer from lowered were not undergoing treated with cobalt-60 or syndrome and all with salivary flow rate that radiotherapy and started it 6 MV photon machine objective evidence of causes subjective feeling of later on during the study. during the study) salivary gland dysfunction xerostomia. Age range 58±12.95 60-65 ±8.7 46-69 years old (61 years) Not stated. 38-85 years old (61 years) Mean age of 60 years. Gender 49M /11 F Not stated 2M / 16F Not stated. 2M /49 F 8 M/ 3F Length of study From the start of 8 weeks The first experiment was 7 months. 2 hours 5 weeks. radiotherapy and for six done in one week, the months after completion second experiment was of radiotherapy done in 5 weeks.
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Dropout rate 25% 34.70% None 35 out of 60 patients None None completed the study (41.6%) Reason for dropout Intolerance to radiation Side effects None Adverse effects and None None mucositis and personal noncompliance. reasons Side effects Nausea, vomiting, Diarrhoea, increased Not stated. Sweating (most frequent), Warm or cold feeling, No noticeable side effects dizziness, palpitation, urinary frequency, rhinitis, anorexia, dizziness, occasional sweating while were observed nor reported tearing, rhinitis, urinary blurred vision, sweating, headache, dyspepsia and one patient had difficulty during this study. frequency and sweating vomiting and dizziness. diarrhoea. breathing probably due to asthma Method adopted Randomized double blind Randomized double blind Two consecutive single Short term, single blind, Open method Prospective, double blind placebo-controlled study placebo controlled blind placebo-controlled placebo controlled, randomized clinical study. experiments. crossover for 7 weeks, and long term, single blind, placebo-controlled study for 5 months. Assessment of xerostomia VAS questionnaire (100 Questionnaire, VAS, Not stated. VAS. self-questionnaire of oral Not specified. mm) Likert scale for frequency complaints Not studied All patients taking In exp 1: significant During the short-term Pilo administration Patients who took pilocarpine with saliva increase in whole saliva, study pilocarpine increased increased the RWS to >0.1 pilocarpine simultaneously flow˃ 0 ml/min showed labial saliva and palatal the unstimulated whole ml/min in 25% of the with their radiation therapy improvement in stimulated saliva flow after pilo intake saliva output and during patients (responders) while had higher values of salivary and unstimulated saliva compared to baseline and the long term study also the rest of the patients who flow rate than those who flow while those with placebo, whereas no pilocarpine increased were non responders the treated with saline solution saliva flow rates 0 ml/min significant change in saliva unstimulated whole saliva RWS remained < 0.1 ml/ as showed by the data remained so with one production following secretion. min as the baseline value obtained at the end of the exception (no residual placebo. In exp 2: no before pilo administration study. salivary function). significant increase in
Saliva production Saliva whole or stimulated saliva
production after 5 weeks
treatment with pilocarpine compared to baseline and
Results placebo. Results of the study No significant differences Not studied. VAS scores of oral After pilo, oral complaints Concomitant treatment with showed that patients in improvements in dryness, oral comfort and were significantly fewer pilocarpine during radiation administered pilo during xerostomia between cases speaking were statistically among the responders therapy had lower incidence radiation therapy did not and controls improved following (p<0.01). Both groups of xerostomia than saline experience less pilocarpine intake, with exhibited a significant solution during radiation xerostomia than those in overall improvement in decrease of intraoral therapy. Only 40% of the placebo group thirst. After 3 months of symptoms after pilo patients in the pilocarpine
Dry mouth mouth Dry treatment significant compared to baseline group suffered from improvements in 3 of 5 (responders p<0.001 and xerostomia while 83.3% of xerostomia related items. non-responders p< 0.05) patients in the saline group had xerostomia.
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Appendix F: Systemic pilocarpine preparations for the treatment of Sjogren’s syndrome (Ss).
Name of study Rhodus & Schuh, 1991 Vivino et al., 1999 Papas et al., 2004 Wu, 2006 Jorkjend, 2008 Tomiita, 2010
Type of treatment product Liquid ophthalmic drop Tablet (Salagen) Tablet Tablet (Salagen) Oral solution (pilocarpine Pilocarpine tablets preparation. dissolved in 20 ml water Type of compared product Identically appearing placebo Placebo tablets Placebo Placebo tablets None None solution of deionized water Frequency of use Four drops three times daily Four times daily Four times daily. Four times daily One treatment only Twice daily
Concentration 2% equivalent to 5 mg three 2.5, 5 mg 5, 7.5 mg 5 mg 0.7 mg per 10 kg body weight Patients younger than 15 times daily. years old took 2.5 mg twice daily while those who were older than 15 years in age took 5 mg tablets twice daily Mouth movement Not stated. Not stated Not stated Not stated To be taken orally Not stated. Spitting/ no swallow Swish and swallow Swallow the tablet. Swallow Swallow the tablet with a Swallow Not stated. cup of water at meals Flavour Not stated. Not stated Not stated. Not stated Not stated Not stated. Number of patients 18 (9 patients receiving 373 256 44 51 patients, 10 healthy 5 recruited pilocarpine and 9 age and sex volunteers as controls matched SS control subjects receiving placebo) Diagnosis Patients with diagnosed Patients with primary or Patients with previous diagnosis Patients diagnosed with Patients diagnosed with Xerostomia in patients with primary and secondary SS secondary SS and clinically of either primary or secondary primary and secondary SS secondary SS juvenile onset Sjögren’s significant xerostomia SS in Taiwan syndrome. Age range 37-73 years old (57.6 years). 55.4±13.3 (pilo gp), 57.8±13 patients were older than 18 38-85 years old (61 years) 6-17 years old (placebo gp) years Gender All were females. 16 M/ 357 F 14 M/ 242F Not stated 2M/49 F All were females Length of study 6 weeks. 12 weeks 12 weeks 12 weeks 2 hours 4 weeks Dropout rate None. 13% (87% of the patients 10.15% (26 patients withdrew 85.7% in the placebo group; None None completed the study) from the study. 69.6% in the treatment group
Reason for dropout None. Drug related adverse Adverse effects as sweating, In the placebo group: on None None experiences and due to death increased urination and/ or patient lost follow up due to as a result of complications of diarrhoea, personal reasons, SARS outbreak period in a probable pulmonary embolus poor compliance and lack of Taiwan and 2 withdrew due and enterocolitis. efficacy. to lack of efficacy. In the pilo group:3 withdrew due to marked sweating and 2 due to SARS and 2 due to unknown reason. 195
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Side effects Initial slight glossalgia and Sweating was the most Sweating, headache, urinary In the pilo group 5 patients Warm or cold feeling, Patient 4 had experienced oral burning sensation, and common adverse effect. Also, frequency, nausea, dyspepsia exhibited perspiration, one occasional sweating while one excessive sweating, so the slightly increased diaphoresis. headache, flu syndrome, and diarrhoea. patient with palpitation. In patient had difficulty breathing pilocarpine dose was nausea, rhinitis, dizziness and the placebo group one probably due to asthma decreased to 5 mg once urinary frequency. patient exhibited palpitation daily. Method adopted Single- blind, placebo- A randomized, placebo Multicentre, placebo-controlled Double blind, randomized Open method Open uncontrolled pilot controlled study. controlled, fixed dose, study placebo-controlled trial. study. multicentre trial. Assessment of xerostomia Subjective patient complaints 100- mm VAS and 3-point 100- mm VAS and 3-point Questionnaires with 100 By patient self-questionnaire of Subjective self-evaluations of xerostomia were recorded. categorical questions categorical questions mm visual analogue scales oral complaints of xerostomia symptoms and categorical checkboxes using a face scale with a score from 0 to5. The parotid saliva flow after Salivary flow was significantly Analysis of post dose flow rates At the end of the study, Pilo administration increased At the beginning of the pilo dosing was more than increased 2- to 3- fold showed that pilo gp patients treated with pilo the RWS to >0.1 ml/min in study, saliva production was twice the baseline. The (p˂0.001) after administration demonstrated a statistically exhibited a higher response 25% of the patients decreased to less than 2 g/ 2 subjects with secondary SS of the first dose of 5 mg pilo significant increase in post dose (65.2%) in 60-minute post (responders) while the rest of min using the Saxon test in demonstrated a greater and was maintained salivary flow at 30, 45, and 60 dose saliva production than the patients who were non all patients. On the end of stimulatory response to the throughout the 12-week study. minutes compared with placebo the placebo group (28.6%) responders the RWS remained the study 1 hour after pilo than the primary SS gp. At study end point there was (p≤0.0001). this response was (p=0.02). Also, the median < 0.1 ml/ min as the baseline pilocarpine intake, saliva No appreciable change was no statistically significant maintained throughout the increase in saliva production value before pilo production was significantly found in salivary flow for difference between the 2.5 mg study. among the pilo group was administration increased (p=0.03). either unstimulated or parotid pilo and the placebo groups in significantly greater than stimulated flow in the control 60-minute post dose mean that in the placebo group
Saliva production Saliva gp. Pilo significantly salivary flow. (0.05 g/ min vs 0.02 g/ min, stimulated both unstimulated p=0.0014) at 12 weeks. and parotid stimulated saliva
in more than 755 of the
patients. Results 7 of the subjects in the pilo gp A significantly greater For pilo patients compared with Global assessment showed After pilo, oral complaints Overall abnormality of the reported the increased proportion of patients in the 5 placebo, there was a highly that a significant proportion were significantly fewer among mouth including dryness sensation of oral moisture and mg pilo gp showed significant subjective global of patients in the pilo group the responders (p<0.01). Both improved in four patients lubrication while all the improvement compared with improvement in dry mouth (69.6%) had improvement groups exhibited a significant and overall improvement of
patients in the placebo gp the placebo gp (p≤0.01) in (p≤0.0001) both at 6 weeks (5 in the dry mouth sensation decrease of intraoral symptoms dry mouth was assessed as reported no change of any global assessment of dry mg) and week 12 (7.5 mg). The compared to the placebo after pilo compared to baseline improved in all patients. kind. mouth. The 2.5 mg pilo gp pilo gp reported a significant group (23.8%) (p=0.0032) (responders p<0.001 and non- didn’t demonstrate differences improvement in overall dryness with a total improvement in responders p< 0.05) in symptomatic relief of oral (66% vs 45% at week 6; 5 mg; the oral discomfort Dry mouth mouth Dry symptoms compared with the p≤0.0009). at 12 week (7.5 mg) complains following pilo placebo gp. there was again a significant use. difference between groups favouring pilo (77%vs 41%, p≤0.0001)
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Appendix G: Documents relating to Chapter 3.
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198
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199
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Appendix H: Documents relating to Chapter 4.
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201
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202
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CONTACT DETAILS
Project title: A study to determine the most appropriate dose form and flavour for oral treatment of dry mouth with pilocarpine
Principal investigator: Mrs Rose Estafanos (PhD Student, UQ) Project coordinators: A/Prof Kathryn Steadman, Prof Geoffrey Mitchell, Dr Hugh Senior and Dr Esther Lau
PARTICIPANT TODAY’S NUMBER: DATE:
PARTICIPANT DETAILS
1 Title: First Last name: name:
2 Street Address:
Suburb: Town:
Postcode:
3 Home Phone: Mobile:
4 Date of Birth:
Please hand this form to the researcher. It will be stored in a locked cabinet and separately to the data collection sheets.
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Demographics and medical history
PARTICIPANT TODAY’S NUMBER: DATE:
1.1 Age
1.2 Gender Male Female Other
1.3 Country of birth
1.4 Ethnicity
1.5 Do you smoke tobacco (e.g. cigarettes)? Yes No 1.6 Do you currently have: • Problems with your eyes such as Yes No irido-cyclitis or glaucoma • Severe or uncontrolled asthma Yes No
• Severe or uncontrolled pulmonary Yes No disease • Uncontrolled high or low blood Yes No pressure • An over active thyroid Yes No
• Uncontrolled seizures or heart Yes No rhythm problems • Parkinson's disease Yes No • hypersensitivity to pilocarpine Yes No • An active oral infection i.e. thrush, Yes No cold sores, shingles, mouth ulcers • Suspected or confirmed pregnancy Yes No
1.7 Please give any medical conditions that you currently have
1.8 Please list any medications that you currently take
1.9 Have you been diagnosed with xerostomia (dry mouth) by a medical practitioner?
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Xerostomia questionnaire (participants with xerostomia)
PARTICIPANT NUMBER:
1.1 Have you been diagnosed with xerostomia (dry mouth) by a medical practitioner? Yes No
1.2 Is your dry mouth associated with cancer? Yes No
If Yes:
Please indicate which type of cancer?
Please indicate what treatment you received for cancer (Select all that apply)
Chemotherapy Radiotherapy Surgery Other Time since last treatment received for cancer therapy (Select one) More than one year ago Within six months to one year ago Less than six months ago
If No: What is the reason for your dry mouth? (Select all what apply) Drinking alcohol Snoring Breathing through your mouth Drinking caffeinated beverages Depression/ Stress Dehydration (e.g. from fever, vomiting, diarrhoea, sport or inadequate fluid intake) Sjogren’s syndrome Other medical conditions: please describe------Other medications: please describe ------
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1.3 What do you currently do or use to ease your dry mouth?
Please place crosses in the table below using 0-10 Likert scale as your guide for the ratings, with higher scores indicating greater dryness or discomfort due to dryness
Increasing dryness or discomfort
0 1 2 3 4 5 6 7 8 9 10 Rate your oral dryness during daytime X X X X X X X X X X X Rate your oral dryness at night X X X X X X X X X X X Rate your difficulty in talking due to dryness X X X X X X X X X X X Rate your difficulty in chewing due to dryness X X X X X X X X X X X Rate your difficulty in swallowing solid food due to dryness X X X X X X X X X X X Rate the frequency of sleeping problems due to dryness X X X X X X X X X X X Rate your mouth or throat dryness when eating X X X X X X X X X X X Rate your mouth or throat dryness when not eating X X X X X X X X X X X Rate the frequency of sipping liquids to aid swallowing food X X X X X X X X X X X Rate the frequency of sipping liquids for oral comfort when not eating X X X X X X X X X X X
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Product acceptability data sheet
PARTICIPANT NUMBER:
PART 1 considers your opinion of flavours that could be used in pilocarpine troches.
You have been given:
• Five medicated troches (A, B, C, D, E). They each contain 5 mg pilocarpine and differ only in flavour. Please:
1. Rinse mouth with water, then hold one medicated troche in your mouth for 10 seconds and then remove it from your mouth and place it back in the tray. 2. Indicate how much you like the troche in the following table Note that you don’t have to recognise the flavour but rather to rate its acceptability of taste to you. 3. Rinse your mouth or drink some water and rest if required. 4. Repeat 1 – 3 until you finish the five troches.
Strongly Troche Dislike Like Strongly like dislike
A X X X X B X X X X C X X X X D X X X X E X X X X
5. Which ONE of the five troches did you like the best?
A B C D E
X X X X X
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PART 2 compares two dosage forms: troches and orally dissolving tablets.
You have been given one troche and one orally dissolving tablet with the best flavour you selected in Part 1. These are non-medicated, i.e. they do not contain any pilocarpine.
Please consider the dosage form, not the flavour, while you undertake the next task:
1. Hold the non-medicated flavoured troche in your mouth (under your tongue or between your cheek and gum) until it is completely gone. You can move it around your mouth but it is intended to slowly dissolve in the mouth rather than to be strongly sucked.
2. Rinse mouth with water.
3. Hold the non-medicated flavoured orally dissolving tablet in your mouth (under your tongue or between your cheek and gum) until it is completely gone.
4. Considering the dosage form (not the flavour), do you prefer the troche or orally dissolving tablet? Why?
5. If you needed to use something regularly (e.g. three times a day) to treat dry mouth: a) Would you be willing to use this type of dosage form regularly to stimulate saliva production?
Yes No
Troche X X Orally dissolving tablet X X
b) Which dosage form would you PREFER to use regularly (choose one option)
Troche X Orally dissolving tablet X
6. Any other comments?
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Flavour preferences (Non-xerostomic participants)
PARTICIPANT NUMBER:
Please indicate in the table whether the following food or medicine flavourings are generally preferred, acceptable or avoided by you:
Preferred Acceptable Avoided
Chocolate flavour
Raspberry flavour
Lemon flavour
Mint flavour
Are there any other flavours that you think might be good for the medicine in this study?
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Flavour preferences (Participant with xerostomia)
PARTICIPANT NUMBER:
Please indicate in the table whether the following food or medicine flavourings are generally preferred, acceptable or avoided by you before and after experiencing xerostomia:
Flavour Before experiencing xerostomia After experiencing xerostomia
Preferred Acceptable Avoided Preferred Acceptable Avoided
Chocolate
Raspberry
Lemon
Mint
Are there any other flavours that you think might be good for the medicine in this study?
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Appendix I: Documents relating to Chapter 5.
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Participant Information Sheet
Single patient multiple cross-over trials to determine the efficacy of pilocarpine 5 mg orally dissolving tablets in relieving xerostomia
Trial Coordinator Mrs Rose Estafanos, PhD candidate, School of Pharmacy, UQ Principal Investigator A/Prof Kathryn Steadman, School of Pharmacy, UQ Study Clinician Prof Geoffrey Mitchell Co-Investigators Dr Hugh Senior, Dr Esther Lau, Dr Jane Nikles, A/Prof James McGree Study Centre UQ School of Pharmacy, 20 Cornwall St, Woolloongabba, Qld 4102
We are looking for people who suffer from dry mouth to take part in this trial. Dry mouth is when you feel the amount of saliva in your mouth is minimal or reduced; it causes you to have difficulties chewing food and you often sip fluids to help wet your mouth.
You can take part in this trial if: • You suffer from clinically significant dry mouth (xerostomia) • You are able to produce saliva (even a little amount) upon chewing a piece of gum, because pilocarpine, the medicine that will be used in this trial, only works if some salivary glands are still functioning. • You are aged 18 years or more.
WHAT IS THE TRIAL ABOUT? Dry mouth (xerostomia) is a major problem that many people experience, especially those who have received radiotherapy for the treatment of head and neck cancer. It also accompanies other diseases such as Sjögren syndrome. Saliva plays many vital roles in our daily life and people with reduced saliva production can experience a variety of health problems. Pilocarpine is a medication that stimulates the nerves supplying the salivary glands. This stimulates the production of your own saliva. The effect lasts for about three hours, and so it is usually taken three times daily. Pilocarpine is usually taken before a meal to produce more saliva in time for eating. Pilocarpine is only available as eye drops to treat glaucoma in Australia, but tablets are available for treating dry mouth in many countries around the world. This trial investigates pilocarpine orally dissolving tablets (ODTs), which are little tablets that dissolve rapidly in the mouth and can be compounded in pharmacies. This trial will provide information about whether pilocarpine ODTs are effective in treating dry mouth, and this information will help to improve management of dry mouth in Australia.
WHAT ARE THE TRIAL PROCEDURES AND ASSESSMENTS? The medicine: The length of the trial is 18 days. You will receive 18 paper envelopes labelled with a number from 1 to 18. Each envelope contains 3 ODTs in a blister pack. Nine of these envelopes contains the active treatment (pilocarpine 5 mg) in every tablet, while the other 9 will contain no active ingredient (placebo). You will be asked to take one ODT three times daily (first ODT in the morning before breakfast, second ODT in the afternoon before lunch and the third ODT in the evening before dinner). All blister packs and ingredients will appear, taste and smell similar and neither you nor the Trial 213
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Coordinator or Principal Investigator will know whether you are taking the active treatment or the placebo each day until the end of the trial. The reason for using a placebo treatment is to reduce the chance of any bias occurring in the results of the trial. If, in an emergency, we need to know whether you are taking pilocarpine or placebo at any particular time, the Study Clinician will have the details of your personal trial schedule.
The assessments:
We want to see if your level of dry mouth is any different on the days you are taking pilocarpine compared to when you are taking the placebo, so: • twice a day, just before breakfast and dinner, you will be asked to spend 3 minutes collecting your saliva in a labelled container that we give you. • three times a day, after each meal, we will ask you to complete the daily diary, which contains short questionnaires that record your level of dry mouth and any side effects that may or may not be associated with pilocarpine. • every three days the Trial Coordinator will call you to find out if you have remembered to take your medications and to hear of any symptoms or side affects you might be experiencing. Before the trial starts you will be required to have an introductory meeting with the Trial Coordinator, at a mutually agreeable time, to obtain your consent to participate, gather some background information, and take the trial pack (containing the medications, tubes for saliva collections, and daily diary) home with you. If you will not be able to attend a meeting, the Trial Coordinator will send the forms to be completed, explain the trial and ask you some questions by telephone, and you will send back the forms before the trial pack is mailed to you. At the end of the trial you will send the saliva specimens that you have collected, and the daily diary, and all 18 blister packs with any remaining ODTs, by mail to the Trial Coordinator in a pre-paid envelope that we supply.
ARE YOU ELIGIBLE TO PARTICIPATE IN THIS TRIAL? We would like your permission for our Study Clinician to contact your regular medical practitioner in order to confirm your eligibility to participate, because if you experience any of the following you will not be able to take part in this study: • Problems with your eyes which may be made worse with the medicine you will take. For example, problems of the iris (coloured part of the eye) or glaucoma. • A co-existing medical problem that is not well controlled and there is a risk of it worsening, or where a change to active treatment is contemplated. For example, severe or uncontrolled asthma or pulmonary disease, uncontrolled low or high blood pressure, overactive thyroid, uncontrolled seizures or heart rhythm problems (especially prolonged slow heart rate – a pacemaker doesn’t prevent you from participating) or Parkinson's disease • An active infection in your mouth i.e. thrush, cold sores, shingles, or mouth ulcers. • Suspected or confirmed pregnancy. • Intervention (e.g. radiotherapy, chemotherapy, surgery) that might alter dry mouth symptoms during the 2 weeks prior to the study period, or plans to undergo such therapy during the study period. • Plans to change any medication with the potential to cause dry mouth within the trial period. • Plans to use any other prescribed medication which is known to increase saliva production and relieve dry mouth during the trial period. You should also be able to understand written English language.
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IS THERE ANY RISK IN PARTICIPATING? There is a risk of side effects which may be unpleasant but are very unlikely to be dangerous. Common side effects due to pilocarpine are sweating, the need to pass urine more frequently, increased tear production, nausea, rhinitis, diarrhoea, chills, flushing, dizziness and asthenia (weakness). The medicine is short acting, and these should abate quickly should they occur. The other components in the orally dissolving tablets are commonly used in foods and pharmaceuticals. Adverse reactions to the components are very unlikely. They are sweetened with the natural sweetener stevia and do not contain any sugar. There is a small risk that answering the questions about the cause of your condition and the quality of your life may cause you to reflect on your life and situation, and may cause distress. Please tell the Principal Investigator about these feelings and stop the questionnaire if you feel unable or too upset to continue.
IS THERE ANY BENEFIT IN PARTICIPATING? After your results have been analysed, a personalised report of the outcome will be sent to you and to your medical practitioner. A detailed formula and instructions on how to prescribe pilocarpine ODTs will also be sent to your medical practitioner. Therefore, if you wish to use pilocarpine ODTs in the future you can discuss this with them. A compounding pharmacy will be able to prepare and dispense pilocarpine ODTs in response to a prescription from your doctor. There is no payment or incentive to participate. If registration occurs at the study centre, you will be reimbursed for the travel with a $30 Coles/Myer voucher. At the end of the trial, you will receive $90 Coles/Myer vouchers as a token of our appreciation for your participation.
WILL YOUR PRIVACY BE RESPECTED? This trial is confidential. All paper and electronic copies of your data will be identified only by a unique identification number and your initials. Your name and contact details will be collected on a separate form in case we need to contact you regarding the trial or if you wish to withdraw from the trial. This will be kept in a locked cabinet under the supervision of the Principal Investigator. The Principal Investigator will also have your first name and preferred telephone number in order to contact you every 3 days during the trial to discuss your progress. The only identifier that will link your contact details to data collection sheets will be your participant number. All of these paper forms will be securely stored for 15 years and then shredded. Data collection sheets will be transferred into Excel spreadsheets for analysis – these will not contain any information that can be used to identify you. Electronic data files will be password-protected and stored indefinitely, and made available for use if requested by other researchers.
NOTIFYING THE INVESTIGATOR Please tell us if you are already taking part in any other studies or if you are asked about taking part in a new study. This is to make sure that the treatment for this trial does not interfere with the treatments of other studies. The Principal Investigator will be able to discuss with you if you are able to take part in more than one study at a time. Please tell us if you need to have any elective or emergency surgery while you take part in this trial. You should inform the Trial Coordinator as soon as you know or able to.
SERIOUS ADVERSE EVENTS OR INJURY We do not expect you to suffer any serious effects or injury from the treatment or from participating in this trial. However, if you think you have an injury or illness resulting from the treatment or from
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PARTICIPATION IS VOLUNTARY
You are able to withdraw your participation at any time without penalty or prejudice, and you do not need to provide a reason. If you do choose to leave the trial, you must return all of the trial documents and the blister packs containing the treatments to the Trial Coordinator in order that the appropriate assessments can be completed and suitable care provided where required. You can withdraw during data collection, or after data collection is complete and before publication of the results. If you choose to withdraw from the trial you can decide whether the data already collected from you can be used or removed from analysis.
I WANT TO PARTICIPATE – WHAT NEXT? Please contact the Trial Coordinator, Mrs Rose Estafanos. You will be asked to provide contact details of your regular medical practitioner so our Study Clinician can make sure that you do not have a medical condition that means that you shouldn’t take pilocarpine. Once this has been checked, she will arrange a time with you to have the introductory meeting and give you the trial pack. Thank you for your time. A summary of the results from this trial will be available on request. If you are interested, please contact one of the investigators.
RESEARCH TEAM Please feel free to contact any member of the research team for further inquiries. Trial Coordinator: Mrs Rose Estafanos (PhD student, UQ) [email protected] Principal Investigator: A/Prof Kathryn Steadman (UQ) [email protected] Study Clinician: Prof Geoffrey Mitchell (UQ) [email protected] Co-Investigators: Dr Hugh Senior (Massey Uni, NZ) [email protected] Dr Esther Lau (QUT) [email protected] Dr Jane Nikles (UQ) [email protected] A/Prof James McGree (QUT) [email protected]
This trial adheres to the Guidelines of the ethical review process of The University of Queensland and the National Statement on Ethical Conduct in Human Research. Whilst you are free to discuss your participation in this trial with project staff (contactable on 07-3346 1886 or email [email protected]), if you would like to speak to an officer of the University not involved in the trial, you may contact the Ethics Coordinator on 3365 3924.
THANK YOU FOR CONSIDERING THIS TRIAL
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CONSENT FORM
Project title: Single Patient Multiple Cross-Over Trials to Determine the Efficacy of Pilocarpine 5mg Orally Dissolving Tablets in Relieving Dry Mouth in Patients Experiencing Xerostomia I agree to participate in the above University of Queensland research project. I have had the project explained to me and I have read the Information Sheet, which I will keep for my records. I understand that my participation is voluntary, that I can choose not to participate in part or all of the project, and I can withdraw at any stage of the project without being disadvantaged in any way.
I have ▪ Read and understood the information sheet; ▪ Had any questions or queries answered to my satisfaction; ▪ Been informed of the possible risks or side effects of the medication; ▪ Understood that the project is for the purpose of research and not for treatment; ▪ Been informed that the confidentiality of the information will be maintained and safeguarded; • Been assured that I am free to withdraw at any time without comment or penalty; and • Agreed to participate in the project.
I understand that • A full dose of pilocarpine can cause some adverse effects. These include sweating, the need to pass urine more frequently, increased tear production, nausea, rhinitis, diarrhoea, chills, flushing, dizziness and asthenia (weakness). • My full name and contact details will be collected on a separate form and retained in a locked cabinet within the UQ School of Pharmacy by the Principal Investigator. This information will not be shared with anyone. • Information that I write on the data collection sheets will be transcribed into excel spreadsheets, retained indefinitely, and may be shared with other researchers. This will not include any information that can be used to identify me. • No data will be published that may identify individuals participating in this research. • I will derive no personal benefit by participating in this research. • If I decide to withdraw during data collection, or after data collection is complete and before publication of the results, I can choose whether data already collected from me can be used or destroyed.
PARTICIPANT NAME
PARTICIPANT SIGNATURE
/ / 2018 DATE
Thank you for participating in this project. Principal Investigator: A/Prof Kathryn Steadman, School of Pharmacy, UQ Trial Coordinator: Mrs Rose Estafanos (PhD Student, UQ). Co- Investigators: Prof Geoffrey Mitchell, Dr Hugh Senior, Dr Esther Lau, Dr Jane Nikles, A/Prof James McGree.
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Baseline questions and all survey tools used in this trial
Yes 1. Is your dry mouth associated with cancer? (select one) If Yes, go to question 1.1
No If No, go to question 1.4
If Yes, Larynx 1.1 Please select the type of Oropharynx cancer (select all that apply) Hypopharynx
Salivary glands
Oral cavity
Head and neck Other
1.2 Please indicate the Chemotherapy treatment received for Radiotherapy cancer (select all that apply) Surgery Other
1.3 Time since last treatment Less than six months received for cancer therapy Within six months to one year (select one) More than one year ago
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1.4 If not associated with Sjögren syndrome cancer, what is the reason Other medical conditions for your dry mouth? (please describe) (select one)
Side effects of medications taken for other diseases (please describe)
Don’t know
2. Do you currently use a medicine or therapy Y es If Yes, go to question 2.1 to ease your dry mouth? (select one answer) If No, go to question 3 No
If Yes, 2.1 Please describe what you use
2.2 How many times daily do Once daily you use this? Twice daily Three times daily Other
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3. Do you currently use any other method Yes to ease your dry mouth? (select one answer) If Yes, go to question 3.1
No If No, go to question 4 If Yes, 3.1 Please describe what you use
3.2 How many times daily do Once daily you use this? Twice daily Three times daily Other
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Subjective rating of symptoms questionnaire
1. Oral dryness. Please rate your dry mouth by crossing (x) the one number that best describes your dry mouth now and then write the number inside the score box.
Score=
2. Sore mouth. Please rate the soreness of your mouth by crossing (x) the one number that best describes it now and then write the number inside the score box.
Score=
3. Speaking. Please rate your talking ability by crossing (x) the one number that best describes it now and then write the number inside the score box.
Score=
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Xerostomia Inventory Please answer each of the following questions by circling the appropriate number.
Never Occasionally Often
My mouth feels dry when eating a meal 1 2 3
My mouth feels dry 1 2 3
I have difficulty in eating dry foods 1 2 3
I have difficulties swallowing certain foods 1 2 3
My lips feel dry 1 2 3
Please answer the following question by circling the appropriate answer
Never Occasionally Frequently Always How often does your mouth feel dry? 1 2 3 4
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Xerostomia-related Quality of Life Scale
Please answer the questions by checking the box that describes best how true each statement has been for you during the past 7 days: 1. My mouth/throat dryness limits the kinds or amounts of food I eat. □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 2. My mouth/throat dryness causes discomfort. □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 3. My mouth/throat dryness causes a lot of worry or concern □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 4. My mouth/throat dryness keeps me from socializing (going out) □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 5. My mouth/throat dryness makes me uncomfortable when eating in front of people □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 6. My mouth/throat dryness makes me uncomfortable speaking in front of people □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 7. My mouth/throat dryness makes me nervous □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 8. My mouth/throat dryness makes me concerned about the looks of my teeth and mouth □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 9. My mouth/throat dryness keeps me from enjoying life □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 10. My mouth/throat dryness interferes with my daily activities □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 11. My mouth/throat dryness interferes with my intimate relationships □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 12. My mouth/throat dryness has a bad effect on tasting food □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 13. My mouth/throat dryness reduces my general happiness with life □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 14. My mouth/throat dryness affects all aspects of my life □ Not at all □ A little □ Somewhat □ Quite a bit □ Very much 15. If you were to spend the rest of your life with your mouth/throat dryness just the way it is now, how would you feel about this? □ Delighted □ Mostly □ Mixed: equally □ Mostly □ Terrible satisfied satisfied/dissatisfied dissatisfied
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EQ-5D By placing a tick in one box in each group below, please indicate which statements best describe your own health state today.
1 Mobility
a) I have no problems in walking about b) I have some problems in walking about c) I am confined to bed
2 Self-Care
a) I have no problems with self-care b) I have some problems washing or dressing myself c) I am unable to wash or dress myself
3 Usual Activities (e.g. work, study, housework, family or leisure activities)
a) I have no problems with performing my usual activities b) I have some problems with performing my usual activities c) I am unable to perform my usual activities
4 Pain/Discomfort
a) I have no pain or discomfort b) I have moderate pain or discomfort c) I have extreme pain or discomfort
5 Anxiety/Depression
a) I am not anxious or depressed b) I am moderately anxious or depressed c) I am extremely anxious or depressed
6 Your own health state today
To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0.
We would like you to indicate on this scale how good or bad your own health is today, in your opinion.
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Oral health impact profile
Please answer each of the following questions by circling the appropriate number.
During the past 7 days Never Hardly Occasio Fairly Very Ever nally Often Often
Have you had trouble pronouncing any words 0 1 2 3 4 because of problems with your teeth, mouth or dentures?
Have you felt that your sense of taste has worsened 0 1 2 3 4 because of problems with your teeth, mouth or dentures?
Have you had painful aching in your mouth? 0 1 2 3 4
Have you found it uncomfortable to eat any foods 0 1 2 3 4 because of problems with your teeth, mouth or dentures?
Have you been self-conscious because of your teeth, 0 1 2 3 4 mouth or dentures?
Have you felt tense because of problems with your 0 1 2 3 4 teeth, mouth or dentures?
Has your diet been unsatisfactory because of your 0 1 2 3 4 teeth, mouth or dentures?
Have you had to interrupt meals because of problems 0 1 2 3 4 with your teeth, mouth or dentures?
Have you found it difficult to relax because of 0 1 2 3 4 problems with your teeth, mouth or dentures?
Have you been a bit embarrassed because of 0 1 2 3 4 problems with your teeth, mouth or dentures?
Have you been a bit irritable with other people 0 1 2 3 4 because of problems with your teeth, mouth or dentures?
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During the past 7 days Never Hardly Occasio Fairly Very Ever nally Often Often
Have you had difficulty doing your usual jobs 0 1 2 3 4 because of problems with your teeth, mouth or dentures?
Have you felt that life in general was less satisfying 0 1 2 3 4 because of problems with your teeth, mouth or dentures?
Have you been totally unable to function because of 0 1 2 3 4 problems with your teeth, mouth or dentures?
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Adverse Event Assessment
Occasionally, people develop unwanted symptoms from their medications. Please tell us about any of the following symptoms that you may have experienced during the last 24 hours by ticking the appropriate boxes. Common symptoms YES NO 9.1 Sweating 9.2 Nausea 9.3 Rhinitis (stuffy nose, runny nose) 9.4 Chills 9.5 Redness of the face and neck (flushing) 9.6 Increased or frequent urge to urinate 9.7 Dizziness 9.8 Headache 9.9 Upset stomach 9.10 Increased tear production 9.11 Diarrhoea 9.12 Vomiting Uncommon serious side effects (seek immediate emergency medical help) 9.13 Weakness 9.14 Confusion, agitation or very depressed 9.15 Vision abnormalities 9.16 Chest pain, rapid heartbeat, racing pulse 9.17 Difficulty breathing 9.18 Severe pain in your stomach or abdomen 9.19 Fainting 9.20 Allergic reaction: rash, itching, swelling of face/lips/tongue, difficulty swallowing Others : 9.21 9.22
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