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THE Pharmaceutical Journal of Kenya Vol. 23 No. 4/2018 ISSN 2411-6386

FEATURE ARTICLE: Amphotericin B toxicities among HIV infected adults with Cryptococcal Meningitis in Kiambu District Hospital

OFFICIAL JOURNAL OF THE PHARMACEUTICAL SOCIETY OF KENYA EDITOR IN CHIEF CONTENTS Prof. Jennifer A. Orwa, PhD, MSc, B.Pharm, FPSK, OGW Editorial: Substandard and Counterfeit Drugs; A 112 EDITORS Threat to Health Dr. Apollo Maima, PhD, M.Pharm, B.Pharm, MPSK Dr. Eveline Wesangula, M.Pharm, B.Pharm, MPSK Amphotericin B toxicities among HIV Dr. Nelly G. Kimani, B.Pharm, MPSK Dr. Lucy Tirop, PhD, B.Pharm, MPSK infected adults with Cryptococcal 113 Dr. Tabitha Ndungu, B.Pharm, Msc Psych, MPSK, MFIP Meningitis in Kiambu District Hospital Dr. Sara Agak, BPharm, MPSK Dr. Michael Mungoma, BPharm, MSc Toxicology, MPSK Impact of devolution on the trends Dr. Betty Mbatia, PhD, MSc. of Paediatric Malaria Admissions and 117 Dr. Mwangi Mugo, PhD, BPharm, MPSK Mortality in Homa-Bay County, Kenya- Dr. Francis Wafula, PhD, MPH, BPharm, MPSK An Interrupted Time Series Analysis

ASSISTANT EDITOR Evaluating Corchorus Olitorius Plant Dr. Nadia Butt, B.Pharm, H.BSc., MPSK Mucilage in the formulation of Oro- 122 Dispersible Paediatric Sildenafil PSK NATIONAL EXECUTIVE COUNCIL (NEC) MEMBERS tablets Dr. Louis Machogu President Dr. Qabale Golicha Deputy President Presence of Potentially Harmful Dr. Juliet Konje National Treasurer Dr. Daniella Munene CEO Alcohol Excipients in Paediatric 126 Dr. Paul Mwaniki Ex-officio Medicine Dispensed in Nairobi Dr. Sultan Matendechero Member Dr. Laban Chweya Member The Occurrence of Glucose 6 Dr. Michael Mungoma Member Phosphate Dehydrogenase Deficiency 133 Dr. Nelly Kimani Member amongst Blood Donors at the Dr. Timothy Panga Member Regional Blood Transfusion Centre- Dr. Aneez Raemtulla Member Mombasa, Kenya

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111 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 EDITORIAL SUBSTANDARD AND COUNTERFEIT DRUGS; A THREAT TO HEALTH Judy Asin & Nadia Butt

Globally the ever-present issues of substandard medicines and pharmaceutically equivalent to the originator or remain a challenge. World Health Organization (WHO) original drug. The large numbers of generic products locally defines substandard medicines as genuine medicines may hamper pharmacovigilance efforts allowing the provided by the manufacturer which do not meet quality infiltration of substandard and counterfeit medicines. specifications set for them by national standards. Circulation of substandard drugs is encouraged by the fact Substandard medicines include products with poor that drugs manufactured for export are often not regulated physical characteristics (for example friable tablets), to the same standard as those manufactured for domestic inadequate quantity of the active ingredients, poor use. In developing countries there is an abundance of dissolution or bioavailability profiles and those that are small-scale suppliers who may supply the substandard or poorly packaged and/or labeled. Counterfeit medicines on counterfeit medicines. the other hand can be described as medicines that are Substandard medicines may pose various risks to the deliberately and fraudulently mislabeled with respect to population. Product contamination can lead to toxicity and identity or source. They may contain the wrong active fatalities as highlighted by various cases in literature. In ingredient or no active ingredient and are of lesser value October 2004, a doctor working for Medicines Sans Frontier than the genuine product. Substandard medicines are in Darfur reported that a local donation of ringer’s lactate often produced by licensed manufacturers but counterfeits was contaminated with fungal growth. The death of 86 can be produced in backyards, small industries or even at children in Haiti in 1996 after ingestion of paracetamol that home. contained the anti-freeze diethylene glycol, which led to The Kenyan market is flooded with various generic acute kidney failure in those who ingested it, is another medicines and it is not always indicative that the products grave example. Recently in Kenya, some batches of still meet expected quality once they have been granted gentamycin injection were recalled as they were reported marketing authorization. Certain loopholes, particularly to cause adverse reaction of severe headaches. On the illegal importation of medicines via the country’s porous worldwide front, all valsartan medications formulated using borders, allow substandard and counterfeit medicines to drug from a Chinese manufacturer were recently recalled enter the drug supply chain. These defective medicines due to contamination of the active pharmaceutical may be subject to illegal hawking and sale or may indeed ingredient with a carcinogenic impurity. The presence of find their way into the authorized supply chain. At their suboptimal amounts of active pharmaceutical ingredient very best, these medicines are ineffective to the patient and compromises the treatment causing progression of the at their very worst, they tend to cause harm to the patient, disease, antimicrobial resistance, increased morbidity and promote development of drug resistance and increase mortality rates. A study done in Nigeria in 2001 found out morbidity and mortality rates. that almost half of randomly samples antibiotics and antiparasitics did not comply with the pharmacopoeia Pharmacy and Poison’s Board (PPB) is the national limits, containing less amounts of the active pharmaceutical medicines regulatory authority in Kenya and together with ingredient, thus posing and a threat of development of the analytical arm of National Quality Control Laboratory antimirobial resistance and hence prolonged illness. The (NQCL) and Drug Analysis and Research Unit (DARU) social and economic effects of substandard medicines ensure that pharmaceutical products are actively regulated cannot be ignored. The patient using these ineffective and comply with set specifications for safety and medicines may lose confidence in health care professionals effectiveness. However, these bodies face major challenges including their physician and pharmacist and potentially in the bid to protect the public from substandard and modern medicine as a whole. These patients also suffer counterfeit drugs. DARU reported that between 2001 and from economic losses occasioned by unsuccessful therapy 2005, 10.7-55.4% of antibiotic medicines failed to meet and worsening illness. The spread of substandard quality specifications. This finding was probably linked to medicines also has political ramifications, undermining the the emergence of resistance against commonly used governments’ investments in health delivery systems and antibiotics during this period. In the year 2000, DARU its credibility with respect to providing quality health care. reported identification of Panadol® junior tablets that contained the wrong ingredient (aspirin instead of Constant surveillance of marketed medicines through paracetamol) and faulty packaging. infrastructure development and capacity building in the country would strengthen quality assurance. For instance, Concerns about high healthcare costs have resulted in imported drugs should routinely be tested on arrival so as tremendous utilization of generic products. According to to ensure that commercially available drugs in the market the United States Food and Drug administration (USFDA), conform with the pharmacopoeial standards. generics should only be marketed if they are bioequivalent

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 112 Amphotericin B toxicities among HIV infected adults with Cryptococcal Meningitis in Kiambu District Hospital A.W. Karita 1 , D.G. Nyamu 1 , P.N. Karimi 1* , S.C. Gitau 2 1University of Nairobi, College of Health Sciences, Department of Pharmaceutics & Pharmacy Practice, P.O Box 19676-00202, Nairobi, Kenya. Emails- P.N. Karimi- [email protected], [email protected], A.W [email protected].

2Kenyatta University, Department of Pharmacy and complementary/Alternative medicine, P.O Box 43844-00100, Nairobi, Kenya, email—[email protected]

*Corresponding author (p=0.026). Monitoring of toxicity was only prevalent (70%) Abstract at the initiation of therapy but declined to less than 20% in Background: HIV infection is a worldwide epidemic with the course of treatment. the highest prevalence in sub-Saharan Africa. This has Conclusion and recommendation: Prevalence of increased the prevalence of cryptococcal meningitis which toxicity of amphotericin B in Kiambu District Hospital was is a common AIDS-related opportunistic infection with a high and related to the dose given. Therefore, care should high rate of morbidity and mortality. Amphotericin B is the be taken when dosing the drug. In addition, frequent standard treatment for cryptococcal meningitis but its use patient monitoring, adequate hydration, and is limited by toxicities resulting from a number of factors premedication are key to preventing the toxicity and such as cumulative dosage and concomitant drugs. should be encouraged. Published local studies on patterns of toxicities are scanty. Keywords: Amphotericin B, Cryptococcal meningitis, HIV/ Objectives: The main objective of the study was to AIDS, Toxicity assess toxicities associated with Amphotericin B in the management of cryptococcal meningitis among HIV infected patients aged 18 years and over in Kiambu District Introduction Hospital. Invasive cryptococcal infection is the second most common HIV/AIDS-related complication after tuberculosis and Methodology: A cross- section design was used that results in up to 20% of deaths [1]. Amphotericin B is the involved review of patients’ records at Kiambu District standard treatment for cryptococcal meningitis, but its use Hospital medical records department between January is limited by toxicity [2, 3, 4]. These toxicities include 2010 to December 2014. One hundred and six files of HIV nausea, vomiting, fever, chills, headache, rigors, infected adults with cryptococcal meningitis and treated hypertension or hypotension, cardiac arrhythmias, and skin with amphotericin B were used. Data on amphotericin B rashes [5]. toxicities, risk factors, and preventive strategies were extracted from the files using a predesigned semi-struc- Prolonged administration of the drug leads to tured data collection form. This data was entered into nephrotoxicity which manifests as renal insufficiency, Microsoft Access version 2013 to create a database and hypokalaemia, hypomagnesaemia, renal tubular acidosis then exported to IBM Statistical Package for Social Sciences and nephrocalcinosis [6, 7]. Nephrotoxicity can be Version 22.0 for analysis. Bivariate analysis using chi-square reversible or irreversible particularly in patients given large test and logistic regression were used to determine cumulative doses above 5 grams. Studies have shown that statistical significance at 0.05. P values that were equal or reversible normocytic normochromic anaemia develops in less the 0.05 were considered significant most patients due to the direct suppressive effect on erythropoietin production [8]. Prevalence of infusion-related toxicities was high Results: The risk factors for toxicity include cumulative dosage and at 87.7%, with fever being the most common (58.1%). The concomitant drugs and the consequences include overall prevalence of nephrotoxicity was at 27.4% but increased morbidity, mortality, length of hospital stay and principally characterized by hypokalemia (41.4%) and cost of seeking treatment [9]. elevated creatinine at 58.6%. Dosing of the drug was not weight based and higher amphotericin B doses were Several strategies, including, using newer amphotericin B important risk factors for toxicity (p=0.045). Prevention of with lipid conjugate, premedication, and monitoring of toxicities associated with amphotericin B involved electrolytes, have proved to be effective in preventing monitoring of serum levels of potassium (p=0.028) and toxicities. Despite this, the Kenyan public hospitals still use creatinine (p=0.019) as well as patients hydration status the conventional amphotericin B deoxycholate which is

113 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 more toxic than the newer formulations. In addition, HIV/ AIDS patients are prone to high pill burden which may Results result in drug interactions with amphotericin B. Published The baseline characteristics of the study population are local studies on assessment of toxicities remain scanty and summarised in Table 1. The mean age of the study therefore, the study sought to quantify the magnitude of participants was 37.4 (SD±8.9) years. Most (54, 50.9%) of the the problem in Kiambu District Hospital (KDH). patients were females and 55 (51.9%) were married. Thirty- three (56.5%) were unemployed and 11 (10.4%) had Methods attained the secondary level of education. About half (53, 50%) of the population was aged between 18 -35years. Before commencing the study, approval was sought and granted by Kenyatta National Hospital – University of Table 1. Social demographic characteristics

Nairobi Ethics and Research Committee (Ref KNH-ERC/A/62) Characteristic Category Frequency (n) Percent (%) and Kiambu District Hospital. This was done to ensure that Gender Male 49 46.2 the research was conducted according to the principles of Female 54 50.9 ethics which are pertinent to a sound scientific study. Not indicated 3 2.8 A cross section design was used and the target population Age (years) 18- 35 53 50 36- 65 47 44.3 was the files of adult HIV positive patients, with Above 65 1 0.9 cryptococcal meningitis who were treated with Not indicated 5 4.7 Amphotericin B while admitted in the hospital. The sample Marital status Single 22 20.8 size was determined using Fischer’s formula (10) and Married 55 51.9 findings from a similar study [11]. A list of all cryptococcal Separated 3 2.8 Divorced 3 2.8 meningitis cases starting from January 2010 to December Widowed 2 1.9 2014 was generated from the medical records department. Not indicated 21 19.8 These file numbers were presented to the medical records Employment Formal employment 11 10.4 for retrieval. The files were assessed for eligibility criteria Self -employed 16 15.1 Unemployed 35 33 and those that satisfied the requirements were included. Not indicated 44 41.5 These were records of patients who were at least eighteen Religion Christian 70 66 years old with a confirmed diagnosis of HIV/AIDS and Not indicated 36 34 cryptococcal meningitis. In addition, they were treated with Education level Informal 5 4.7 Amphotericin B. A total of 106 files were selected. Data was Primary 10 9.4 collected using a semi-structured form where sociodemo- Secondary 11 10.4 graphic characteristics, risk factors, and preventive Tertiary 2 1.9 Not indicated 78 73.6 strategies were picked. The forms did not have patient identifiers but a unique code. Data were stored in a Amphotericin B toxicity was associated with concomitant lockable cabinet and thereafter entered into a password drugs used. Antibiotics were most prevalent (84.9%) protected Microsoft Access 2013 database. To ensure followed by antiretrovirals (42.5%) and analgesics (33%) accuracy, once entry was completed, the Principal (Figure 1). Among the antibiotics, cotrimoxazole was the Investigator compared the entered data with the hard copy most common followed by benzylpenicillin and chloram- forms. Safety of the electronic data was ensured using a phenicol. password that was changed regularly and administration rights were restricted. The system was protected by keeping updated antivirus and software. It was also backed up every day on a hard disk. All aspects of quality assurance were adhered to. A pilot study was conducted to determine the reliability of the data collection tool and any error noted was corrected. Appropriate documentation was maintained at all times. External validity was optimized using adequate sample size. To ensure confidentiality, patient files were kept under lock and key and the review of the records was done within the hospital. Patients’ names were not entered in the data collection form but instead, codes were used. The extracted data were safely stored and analyzed using descriptive and Figure 1. Concomitant drugs used by the patients inferential statistics. The relationship between variables was determined at 0.05 level of significance using chi-square The most common comorbidity among the cases was and logistic regression. tuberculosis (TB) with a prevalence of 56.8%, followed by pneumonia (20.5%), candidiasis (11.4%) and gastroenteritis (11.4%) (Figure 2). The other diseases were anaemia and herpes zoster, among others.

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 114 Table 3: A bivariate analysis of factors associated with nephrotoxicity

Factor Status No Nephro- Nephrotoxicity P value toxicity Gender Male 36 ( 73.5) 13 (26.5) 0.082 Female 47 (87) 7 (13) Salt loading No 15 (78.9) 4(21.1 0.881 Yes 70 (80.5) 17(19.5) Potassium No 58(82.9) 12(17.1) 0.336 chloride use Yes 27(75) 9 (25) Fluid input and No 65 (87.8) 9 (12.2) 0.003* output Yes 20 (62.5) 12 (37.5) Figure 2. Types of comorbidities among the patients monitoring The study found both infusion-related and renal toxicities Creatinine No 63 (86.3) 10 (13.7) 0.019* monitoring Yes 22 (66.7) 11 (33.3) (Figure 3). The most common infusion-related toxicities were fever at 58.5% followed by a headache (49.1 %), Potassium No 65 (85.5) 11 (14.5) 0.028* monitoring Yes 20 (66.7) 10 (33.3) nausea and hypotension (25.5%). Blood urea No 62 (86.1) 10 (13.9 0.026* nitrogen Yes 23 (67.6) 11 (32.4) monitoring * Statistically significant relationship A number of preventive strategies were employed to reduce amphotericin B toxicities. The most common pretreatments were salt loading (82.1%) followed by analgesics (45.3%), potassium chloride (34%), steroids (3%) and antihistamines (1%). Additionally, monitoring of haemoglobin, creatinine, potassium, and Blood Urea Nitrogen (BUN) was done in over 70% of cases before administration of the drug. Nonetheless, the parameters Figure 3. Types of infusion-related toxicities were rarely monitored during the course of the treatment. Haemoglobin was monitored twice in twenty (18.9%) Most of the patients’ experienced more than one infusion- patients and thrice among four (3.8%). Creatinine was related toxicities (Table 2). Only 13 (12.3%) patients did not monitored once in 70.0% of the cases and twice in thirteen experience infusion-related toxicities. Thirty-two (30.2%) (12.3%) of them during the 14-day treatment. The experienced two infusion-related toxicities. Overall infu- frequency of patients monitoring decreased over time in sion-related toxicities were experienced by 87.7% of the the course of treatment. Fluid input and output monitoring patients. The prevalence of nephrotoxicity was 27.4%, with were done in 30.2% of the cases. The majority (62.9%) of most common manifestations being elevated serum the cases recovered and the rest died. Most (33%) of the creatinine and hypokalemia, at 58.6% and 41.4%, amphotericin B toxicities required treatment, while 22% respectively. resolved spontaneously. Death due to toxicity was reported Table 2. The frequency of infusion-related toxicities in 13% while only 1% were discontinued and substituted with fluconazole. Number of infusion n % related toxicities A bivariate analysis between age and outcome of therapy 0 13 12.3 found no significant association (p = 0.379). The only 1 30 28.3 predictor for infusion-related toxicity was the total daily 2 32 30.2 dosage of amphotericin B of 50mg (p = 0.045). Age (p = 3 24 22.6 4 5 4.7 0.422) and weight (p = 0.256) were not statistically 5 1 0.9 significantly associated with toxicity. A logistic regression 6 1 0.9 analysis found that fluids monitoring and potassium levels The factors that had a significant association with the were independent factors associated with the development development of nephrotoxicity were fluid, potassium, of nephrotoxicity. Patients whose fluids were monitored creatinine and blood urea nitrogen monitoring. Conversely, were 4 times more likely to be free from nephrotoxicity {OR gender, salt, and potassium chloride loading did not have = 4.4 [95% CI; 1.6 - 12.5], p = 0.005} and those whose any statistically significant association with the potassium levels were monitored were 3 times more likely development of nephrotoxicity (Table 3). to be free from nephrotoxicity {OR = 3.0 [95% CI; 1.1 - 8.7], p = 0.037}.

115 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 Discussion were routinely done with over 70% of the patients having been monitored. According to the guidelines, haemoglobin The study population was distributed almost equally should be monitored twice in the course of the treatment between both genders. The mean age was 37.4years (SD for every patient and potassium and serum creatinine 8.9). Most participants were married and unemployed. A should be monitored four times during the course of similar study carried out at KNH showed similar results [11]. treatment (16). In this study, haemoglobin was monitored The most common concomitant drugs used were twice in only 3.8% of the patients, while potassium and antibiotics with cotrimoxazole being the most prevalent serum creatinine were monitored twice. This contrasted the because it is used in both prophylaxis and treatment of guidelines despite being important predictors of opportunistic infections among the HIV infected patients nephrotoxicity according to our results. such as Pneumocystis jiroveci pneumonia, toxoplasmosis, and many bacterial infections. Tuberculosis was the most The study revealed a high mortality of 37%, which closely prevalent comorbidity as found elsewhere probably relates to similar findings [22]. However, Centre for Disease because it is common opportunistic infections in HIV Control reports a higher mortality of 50-70% (19). The high infected patients [11]. The use of cotrimoxazole was mortality could be due to a combination of factors such as followed by a combination of benzyl penicillin and chlor- Cryptococcal Meningitis (CM), drug toxicity or other amphenicol since before diagnosis the patients were being comorbidities. treated empirically for bacterial meningitis. In conclusion, the prevalence of toxicity in Kiambu District Our results indicated that the infusion-related toxicity Hospital was high. Since amphotericin B dosage is an prevalence was high at 87.7% and fever was the most important predictor of toxicity it is recommended that common followed by a headache. This compares favorably caution should be taken when dosing. In addition, patient to previous studies that displayed toxicities prevalence of monitoring, hydration, and premedication are key in 71 % with the most common being fever, chills, nausea, and preventing the toxicity and should be encouraged. headache (12, 13, 14). Our study findings showed the prevalence of nephrotoxicity at 27.4% unlike in a previous Conflict of Interest study carried out at KNH by Ochieng et al., which showed The authors declare no conflict of interest. its prevalence at 70.1% [23]. The difference in the results was probably because of erratic monitoring of adverse Acknowledgment effects. There was no statistically significant relationship between patients’ age and toxicities as revealed elsewhere The authors acknowledge the staff of Kiambu District (15). Hospital for allowing the researchers access the patients’ hospital records. Our results revealed that amphotericin B dosage was an important predictor of its toxicity as also observed by References Fischer et al. [16]. The recommended dose of Amphotericin B is 0.7mg/kg/day [17,18]. From our finding all patients 1. Mayer JDM, Vorlìcek J. Must we really fear toxicity of were given 50mg/day regardless of their weight. The mean conventional amphotericin B in oncological patients? weight of the participants was 55kg suggesting that some Support Care Cancer Off. J Multinatl Assoc Support participants were receiving an overdose leading to toxicity. Care Cancer. 1999; 7(1): 51–5. [19, 20]. 2. Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. Pretreatment was an important aspect in the prevention of Amphotericin B: time for a new “gold standard.” Clin toxicity and salt loading with normal saline has been Infect Dis. 2003; 37 (3):415–25. demonstrated to decrease nephrotoxicity [21]. In our study, 3. Gibbs WJ, Drew RH, Perfect JR. Liposomal amphotericin this was a common practice and patients were given at B: clinical experience and perspectives. Expert Rev Anti least one liter of normal saline before Amphotericin B Infect Ther. 2005; 3(2):167–81. infusion. Nevertheless, there was no statistically significant reduction in nephrotoxicity. 4. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ. et al. Clinical practice guidelines Although analgesics were commonly administered for the management of Cryptococcal disease: followed by potassium chloride as premedication, this did Infectious diseases society of America. Clin Infect Dis. not seem to be important in preventing nephrotoxicity as 2010; 50(3):291–322. demonstrated in a similar study [12]. However, the clinicians followed the guidelines, which recommend that a patient 5. Maharom P, Thamlikitkul V. Implementation of clinical should be prehydrated with one liter of normal saline practice policy on the continuous intravenous containing one ampoule of potassium chloride [22] which administration of amphotericin B deoxycholate. J Med was a common practice with 82.1% patients receiving the Assoc Thail Chotmaihet Thangphaet. 2006; 89 (5): drugs. The intention was to prevent dehydration, which is a S118–24. risk factor for toxicity [16]. 6. Patterson RM, Ackerman GL. Renal tubular acidosis due Baseline haemoglobin, potassium and serum creatinine to amphotericin B nephrotoxicity.Arch Intern Med.

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 116 1971; 127(2):241–4. Pollard, RB, Kolokathis A, et al. Amphotericin B lipid complex compared with amphotericin B in the 7. Bagnis CI, Deray G. Amphotericin B nephrotoxicity. treatment of Cryptococcal meningitis in patients with Saudi J Kidney Dis Transplant. 2002; 13(4):481–91. AIDS. Clin Infect Dis. 1996; 22(2):308–14. 8. Hoeprich PD. Clinical use of amphotericin B and 16. Fisher MA, Talbot GH, Maislin G, McKeon BP, Tynan KP, derivatives: lore, mystique, and fact. Infect Dis Soc Am. Strom BL. Risk factors for Amphotericin B-associated 1992; 14 (1):S114–9. nephrotoxicity. Am J Med. 1989; 87(5):547–52. 9. Bates DW, Su L, Yu DT, Chertow GM, Seger DL, Gomes 17. Laniado-Laborín R, Cabrales-Vargas MN. Amphotericin DRJ, et al. Mortality and Costs of Acute Renal Failure B: side effects and toxicity. Rev Iberoam Micol. 2009; Associated with Amphotericin B Therapy. Clin Infect 26(4):223–7. Dis. 2001; 32(5):686–93. 18. Bicanic T, Wood R, Meintjes G, Rebe K, Brouwer A, Loyse 10. Cochran, W.G. Sampling techniques. NewYork. John A, et al. High-dose amphotericin B with flucytosine for Wiley & Sons, Inc; 2007. the treatment of Cryptococcal meningitis in 11. Okeyo AO. Clinicians knowledge, prescribing patterns, HIV-infected patients: a randomized trial. Clin Infect toxicity, and efficacy of amphotericin B in HIV positive Dis. 2008 Jul 1; 47(1):123–30. patients at Kenyatta national hospital [Internet] 19. Veerareddy PR, Vobalaboina V. Lipid-based [Thesis]. University of Nairobi; 2010 [cited 2015 Jan 16]. formulations of amphotericin B. Drugs Today Barc Available from: http://erepository.uonbi.ac.ke:8080/ Spain 1998. 2004; 40(2):133–45. xmlui/handle/11295/24811. 20. Costa S, Nucci M. Can we decrease amphotericin 12. Bicanic T, Wood R, Meintjes G, Rebe K, Brouwer A, Loyse nephrotoxicity? Curr Opin Crit Care. 2001; 7 (6):379–83. A. et al. High-dose amphotericin B with flucytosine for the treatment of Cryptococcal meningitis in 21. Stein RS, Albridge K, Lenox RK, Ray W, Flexner JM. HIV-infected patients: a randomized trial. Clin Infect Nephrotoxicity in leukemic patients receiving empirical Dis. 2008; 47(1):123–30. amphotericin B and aminoglycosides. South Med J. 1988; 81(9):1095–9. 13. Maharom P, Thamlikitkul V. Implementation of clinical practice policy on the continuous intravenous 22. Mdodo R, Brown K, Omonge E, Jaoko W, Baddley J, et al. administration of amphotericin B deoxycholate. J Med The prevalence, clinical features, risk factors and Assoc Thail Chotmaihet Thangphaet. 2006; 89(5): outcome associated with Cryptococcal meningitis in S118–24. HIV positive patients in Kenya. East Afr Med J. 2010; 87(12): 481–487. 14. Mayer J, Doubek M, Vorlìcek J. Must we really fear toxicity of conventional amphotericin B in oncological 23. Ochieng PO, McLigeyo SO, Amayo EO, Kayima JK, patients? Support Care Cancer. J Multinatl Assoc Omonge EO. Nephrotoxicity of Amphotericin B in the Support Care Cancer. 1999; 7(1):51–5. treatment of Cryptococcal meningitis in acquired immunodeficiency syndrome patients. East Afr Med J. 15. Sharkey PK, Graybill JR, Johnson ES, Hausrath SG, 2009; 86(9):435–41. Impact of devolution on the trends of Paediatric Malaria Admissions and Mortality in Homa-Bay County, Kenya- An Interrupted Time Series Analysis Kodhiambo M.O. 1* , Amugune B.K. 2 and Oyugi J.O.3 1Department of Pharmacy and Complementary/Alternative Medicine, Kenyatta University, P.O. Box 43844-00100, Nairobi, Kenya., Cell Phone-+254724468162, Email: [email protected]

2Department of Pharmaceutical Chemistry, University of Nairobi, Kenya

3Department of Medical Microbiology, University of Nairobi, Kenya.

*Corresponding Author Abstract mainly in the endemic areas, like Homa-Bay in Kenya, which are also the resource constrained regions. It is therefore Background: Malaria is a leading cause of paediatric important for the County to prioritize preventing paediatric admissions, morbidity and mortality. Its burden is borne malaria. Paediatric malaria admission and mortality have

117 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 recently increased in the lake region unlike the rest of decision space, resource constrains and uncertainty among Kenya. It is also not clear whether after devolution was other challenges in rolling out devolution of health care implemented in the year 2013, the trend has changed. The services [2]. The typical bottle necks for progress of objective of the study was to investigate the impact of devolution often involve lack of clear policies, poor devolution on paediatric malaria admission and mortality transition processes and human resource malpractices [4, 5, trends in public health facilities in Homa Bay County. 6]. On the other hand, the main aim of devolving health care was to improve access. Studies from Cote D’Ivoire [7, 8] A retrospective quasi-experimental study Methodology: and Kenya have shown that devolution may lead to equity was performed. The study population comprised all public and edging towards universal health coverage [9, 10]. This health facilities in Homa-Bay County. We purposively is because it removes barriers to care [11] and improves sampled 164 public health facilities from which six-year ownership and public participation in health care decisions data on paediatric admissions and mortality was collected. [12, 13, 14]. For devolution of health to succeed, it is Sub-County level data was obtained on excel from the important to understand the needs of stakeholders such as electronic health records at the County headquarters. Hard the user communities, political leaders and health care copy data from the health facilities were also inspected at providers [15, 16, 17]. the 8 sub-Counties. Data was analyzed by the Interrupted Time Series (ITS) method. Devolution, which was taken as Africa has in the recent past recorded varying trends in the intervention, occurred around the 36th month of the paediatric malaria admissions from country to country and follow-up period in the year 2016. between health facilities [18]. Even though overall paediatric malaria admission rate has been on the decrease Results: From January 2013, deaths increased gradually in Kenya, that in the Kenyan lake region are on an upward until around the 33rd month when it rose abruptly to nearly trend [19]. In Malawi, the trend is similarly of an increase in 800 then declined to below 200 in the 34th month around admissions despite interventions aimed at reducing the time of devolution. This was followed by a period of transmission such increased insecticide treated nets (ITN) stability. Admissions had a similar trend. coverage [18]. Around the same time when Artemisinin Conclusions and recommendations: Paediatric combination therapy (ACT) antimalarial drugs had been malaria admission and mortality rates in Homa Bay made to be first line, Uganda also recorded a significant increased around the time of devolution. More studies are increase in paediatric malaria admission rates [19]. Mortality necessary to assess progress towards universal access to rates due to paediatric malaria were also on an increasing care post devolution. trend despite a decrease in the number of microscopically confirmed cases. These trends seemed to correlate with the Keywords: Devolution, paediatric malaria, admissions, trends in ITN use, ACT stock levels and rainfall intensity [20]. mortality, Homa-Bay. Similar trends were recorded in Ethiopia [21], Malawi [20], Rwanda [20] and Ghana [22]. In the year 2016, even though Introduction malaria cases, admissions and deaths declined significantly, Malaria is a protozoal disease prevalent mostly in the all cause admissions, all cause deaths and non-malaria tropics and sub-tropics. Children of ages 5 years and below cases and admissions increased significantly, showing the are the most vulnerable to malaria. The socio-economic need to combat childhood illnesses in an integrated burden of Malaria is greatest in the endemic areas of Kenya manner [22]. There is a deficiency of studies interrogating such as the Lake Victoria region. Devolution of health care health policy correlates and implications of these trends. It was introduced in Kenya in the year 2013 to attempt to is also not clear whether in Kenya, with devolution, the increase access to health care. This new system of trend has improved, worsened or remained the same. The government which was aimed at taking services closer to purpose of this study was, therefore, to investigate the the people was put in place after the general elections of impact of devolution on paediatric malaria admission and March 2013. Health care is among the functions of mortality trends in public health facilities in Homa Bay government that was devolved. The national government County. formulate health policy whereas the county governments are responsible for health service provision. The need to Methods assess the impact of devolution especially in the We performed a retrospective quasi-experimental study marginalized and far flung counties like Homa Bay County from January 2010 until December 2016 in Homa Bay is immense. Since the advent of devolution, health care County. The study involved analysis of county paediatric providers have consistently resisted it. Initially, the malaria admission and mortality records. This information resistance was seen in practising professionals, but was obtained by reviewing the county and sub-County empirical research has documented similar sentiments health records. The study population consisted of all public from students as well [1]. Most of them look forward to health facilities in Homa-Bay County. Homa-Bay County working in the private sector upon graduating. The public currently has 164 public health facilities with one County health managers in the county governments complain of Teaching and Referral Hospital, four County hospitals, seven poor work environment, transition challenges, restricted Sub-County Hospitals, 38 Health Centers, 88 Dispensaries, 7

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 118 Voluntary Counselling and Testing (VCT) Centers and 73 dummy variable taking the values 0 in the pre-intervention privately owned health institutions. For the purposes of this segment and 1 in the post-intervention segment. Time after study, a total of 164 public health facilities were included. intervention is 0 in the pre-intervention segment and The study adopted purposive sampling since all the health counts the quarters in the post-intervention segment at facilities which presented admission and mortality data to time. the sub-County and County aggregation centers were included in the study. Health facilities that started Results operating after 2012 were excluded from the study since Descriptive data. A total of 275,936 admissions and 10,239 they lacked adequate pre-devolution data. Data from the deaths were included in our analysis. These deaths 164 public health facilities were analyzed. Ethical approval therefore represented 37.1% of all paediatric malaria was obtained from the KNH/U.o.N-Ethics and Review admissions in the County during the period of study. The Committee (Ref-P389/05/2016). Confidentiality was deaths before 2013 were treated as death before ensured by using password protection when mailing data. devolution while deaths after 2013 were treated as deaths Hard copy data was kept under lock and key accessible to after devolution. The same applied for admissions. The the investigator only. Data was obtained from the descriptive summary statistics are shown in table 1 and electronic records at the Homa-Bay County teaching and graphically presented in figures 1 and 2 below. referral hospital after authorization by the County secretary for health and the head of County Health Management Table 1. Data on Admissions and Death Rate (%). Information Systems. The data was obtained in an excel sheet which was sent to the e-mail of the investigator Year Admissions Deaths Proportion Time of deaths Mean Total Ad- Mean Total under password protection. Data was then inspected for by admis- missions Deaths completeness and those facilities that lacked adequate sions pre-devolution data were excluded from the study. The 2010 90 1,084 8 90 8.3 Before data so obtained was an aggregate of facility level monthly 2011 2,903 34,835 140 1,683 4.8 Before 2012 3,283 39,397 204 2,442 6.2 Before admission and mortality. For purposes of triangulation, hard copy data from the health facilities were also 2013 2,847 34,167 157 1,883 5.5 After 2014 2,056 24,668 183 2,190 8.9 After inspected at the 8 sub-Counties. Data was analyzed by the 2015 2,608 31,300 163 1,951 6.2 After Interrupted Time Series (ITS) analytic model. This involved plotting monthly paediatric malaria admissions and Table 1 is an aggregated summary of yearly admissions and mortality against time from January 2010 to December deaths for three years before and three years after 2016, with devolution, being the intervention, occurring devolution. The single horizontal line above the year 2013 around the 36th month. The plot was then visually indicates the time when devolution of health services to inspected to see if devolution had an impact on the the county governments was implemented, thus being the indicators. Interrupted time series analysis is a special type intervention in this natural experiment. The average of time series analysis where treatment/intervention occurs proportion of deaths by admissions before devolution was at a specific point and the series is broken up by the 6.4 % compared to 6.9% after devolution. This represented introduction of the intervention. If the treatment has a a slight increase in deaths per admission after devolution. causal impact, the post- intervention series will have a Inferential data. The data on paediatric malaria admissions different level or slope. This design was used to and deaths were plotted against time in months. Trends of quantitatively scrutinize trends of paediatric malaria admissions and deaths were as captured in figure 1. The admissions and deaths three years prior to and three years graph was generated by a logistic regression modelling after the roll out of devolution of health care services in technique coupled with an interrupted time series analytic Kenya. model. The Model; The time series analysis was done based on the Figure 1 (Next Page) shows trends of paediatric malaria logistic regression model represented by the following deaths and admissions per month. From month zero, equation. January 2013, deaths increased gradually until around the 33rd month when it rose abruptly to nearly 800 and declined Ŷt = β0 + β1 x timet + β2 x interventiont + β3 x time after back to below 200 in the 34th month. This was then followed interventiont + et by a stable trend of deaths being around 180 per month. Where; Yt is the outcome time indicates the number of Admission data started from near zero at month zero, quarters from the start of the series, β0 estimates the base increased sharply to almost 1000 in month five then fell level of the outcome at the beginning of the series, β1 equally sharply to zero in month 10. From month 12, estimates the base trend, i.e. the change in outcome per admissions rose drastically to above 4000, stabilized around quarter in the pre-intervention segment, β2 estimates the 3800 up to month 40 then gradually declined to month 60 change in level in the post-intervention segment, β3 after which a gradual increase started. estimates the change in trend in the post-intervention segment and et estimates the error. Intervention is a

119 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 0 experienced in Tanzania where health services were 400 devolved earlier [23]. As was reported from a study in Nepal,

00 other issues that may act as bottlenecks to achievement of benefits of devolution early enough may include poor 3000 ns coordination among different sectors, improper handover ss io hs 06 at mi process, poor selection management committees and 40 De Ad

2000 incoherent capacity building [24]. It is however prudent to note that determinants of disease incidence are often a

00 complex combination of several interacting factors that may

1000 not be effectively studied retrospectively [17]. Moreover, managing specialized health services in a devolved health system is usually challenging [10]. At that time, as it is largely 02 0 still to date, there was poor harmonization of terms of

02 04 06 0 02 04 06 0 service, incentives and amenities available to health workers in remote areas like Homa Bay County [3]. This could have Time Time affected the morale of health care providers hence poor Figure 1: Normal Plot of malaria related deaths and service delivery. The process of devolution is work in admission trends before and after devolution. progress and by 2013, it was in its infancy stages. It has been noted that devolution plans are not often implemented as Discussion intended [8]. It is therefore likely that there were deviations The admissions increased from 2010 and stabilized around in implementation of health care devolution in Kenya, thus 2013. This abrupt rise was around the 36th month when leading to unintended outcomes like has been observed in devolution of health care was implemented. This was this study. followed by a gradual decline in which again stabilized around 2014. The increase in the admissions may be Conclusion and Recommendations attributed to anticipation of better services given that These findings provide evidence that devolution of devolution of other services had begun by 2011. The healthcare still has erratic and fluctuating outcomes with people’s perceptions may have improved in the backdrop of specific reference to paediatric malaria admissions and impending devolution of health services. The message that deaths in Kenya. In general, devolution seemed to have was given to citizens during the campaigns for the new increased paediatric admission and mortality rates in Homa constitution was that with devolution, they would Bay over the period of the study. More studies need to be participate more in making decisions about their health thus mounted in different Counties or as a national survey to take improving access and quality of health they would receive. stock of the benefits or otherwise of devolution of health In the year 2001, residents of Saskatchewan reported a care to the citizens. This would help unmask whether there similar experience. Most of them felt that devolution had are significant intercounty variations or not. Periodic audits resulted in greater local control and better quality of health of the progress towards universal access to health care needs care decisions [13]. Having been promulgated in the year to be conducted in many Counties in Kenya to visualize the 2010 August 27th, the new constitution seems to have given real impact of devolution on our health care service delivery. the citizens of Homa Bay County a new hope of better health A study focusing on facility level analysis of paediatric services in their public health facilities. On the other hand, malaria indicator data would be useful to unearth any trends deaths seemed to have declined between 2010 and 2011, unique to each facility as well as trends across facility levels. stabilized until 2013 after which there was a sharp increase. The possible explanation for this observation is that given References the increase of admissions around the year 2013 when devolution was implemented, the number of deaths would 1. Nyongesa H, Munguti C, Odok C, Mokua W. Perceptions be expected to similarly increase merely due to increase in of medical students towards healthcare devolution: an the number of sick children admitted to the hospitals. online cross-sectional study. Pan Afr Med J. 2015 Apr Alternatively, there is a possibility that admissions and 14; 20:355. doi: 10.11604/pamj.2015.20.355.4714. deaths increased due to better health records management e-Collection 2015. after devolution. If the increasing trend of deaths reflected a 2. Nyikuri M, Tsofa B, Barasa E, Okoth P, Molyneux S. Crises genuine pattern, then this may be attributed to many factors and Resilience at the Frontline-Public Health Facility including the fact that most health facilities were not Managers under Devolution in a Sub-County on the properly prepared for the intricate realities of devolving Kenyan Coast. PLoS One. 2015 Dec 22;10(12): health care and hence were struggling with management of health service delivery in the new context of devolution e0144768. doi: 10.1371/journal.pone.0144768. [2,5]. Autonomy of the County health care resource Collection 2015. management was also not yet adequate. For example, a lot 3. Njuguna J, Mwangi P, Kamau N. Incentives among of money was being used to upgrade the infrastructure of health workers in a remote Kenyan district: implications small facilities to higher level hospitals. Such challenges were for proposed county health system. J Health Care Poor

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 120 Underserved. 2014 Feb;25(1):204-14. doi: 10.1353/ local health boards in a decentralized setting: cases hpu.2014.0029. from the Philippines. Health Policy Plan. 2001 Dec;16 Suppl 2:61-9. 4. Flood CM, Sinclair D. Devolution--a solution for Ontario: could the lone wolf lead the pack? Healthc Pap. 16. Bossert TJ, Mitchell AD. Health sector decentralization 2004;5(1):63-8; discussion 96-9. and local decision-making: Decision space, institutional capacities and accountability in Pakistan. Soc Sci Med. 5. Tsofa B., Molyneux S., Gilson L. and Goodman C. How 2011 Jan;72(1):39-48. doi: 10.1016/j. does decentralization affect health sector planning and socscimed.2010.10.019. Epub 2010 Nov 11. financial management? A case study of early effects of devolution in Kilifi County, Kenya. International journal 17. Lomas J, Woods J, Veenstra G. Devolving authority for for equity in Health 2017 health care in Canada’s provinces: 1. An introduction to the issues. CMAJ. 1997 Feb 1;156(3):371-7. 6. Mubyazi G, Kamugisha M, Mushi A, Blas E. Implications of decentralization for the control of tropical diseases 18. Okiro EA, Kazembe LN, Kabaria CW, Ligomeka J, Noor in Tanzania: a case study of four districts. Int J Health AM, Ali D, Snow RW. Childhood malaria admission rates Plann Manage. 2004 Oct-Dec;19 Suppl 1: S167-85. to four hospitals in Malawi between 2000 and 2010. PLoS One. 2013 Apr 26; 8(4): e62214. 7. Soura BD, Coulibaly SS. Analysis of the healthcare service decentralization process in Côte d’Ivoire. Med 19. Okiro EA, Alegana VA, Noor AM, Mutheu JJ, Juma E, Sante Trop. 2014 Apr-Jun;24(2):151-6. doi: 10.1684/ Snow RW. Malaria paediatric hospitalization between mst.2013.0255. 1999 and 2008 across Kenya. BMC Med. 2009 Dec 9; 7:75. doi: 10.1186/1741-7015-7-75. 8. Ansari U, Cockcroft A, Omer K, Ansari NM, Khan A, Chaudhry UU, Andersson N. Devolution and public 20. Karema C, Aregawi MW, Rukundo A, Kabayiza A, perceptions and experience of health services in Mulindahabi M, Fall IS, Gausi K, Williams RO, Lynch M, Pakistan: linked cross sectional surveys in 2002 and Cibulskis R, Fidele N, Nyemazi JP, Ngamije D, Umulisa I, 2004. BMC Health Serv Res. 2011 Dec 21;11 Suppl 2: S4. Newman R, Binagwaho A. Trends in malaria cases, doi: 10.1186/1472-6963-11-S2-S4. hospital admissions and deaths following scale-up of anti-malarial interventions, 2000-2010, Rwanda. Malar 9. Okech TC, Lelegwe SL. Analysis of Universal Health J. 2012 Jul 23; 11:236. Coverage and Equity on Health Care in Kenya. Glob J Health Sci. 2015 Dec 18;8(7):218-27. doi: 10.5539/gjhs. 21. Aregawi M, Lynch M, Bekele W, Kebede H, Jima D, v8n7p218. Taffese HS, Yenehun MA, Lilay A, Williams R, Thomson M, Nafo-Traore F, Admasu K, Gebreyesus TA, Coosemans 10. Doyle Y, Johnstone P. Health benefits from devolution M. Time series analysis of trends in malaria cases and in England: international lessons. Postgrad Med J. 2016 deaths at hospitals and the effect of antimalarial May;92(1087):282-5. doi: 10.1136/postgradmedj-2015- interventions, 2001-2011, Ethiopia. PLoS One. 2014 Nov 133894. Epub 2016 Feb 23. 18;9(11): e106359. doi: 10.1371/journal.pone.0106359. 11. Borders S, Blakely C, Ponder L, Raphael D. Devolution’s e-Collection 2014. policy impact on non-emergency medical 22. Aregawi M, Malm KL, Wahjib M, Kofi O, Allotey NK, Yaw transportation in State Children’s Health Insurance PN, Abba-Baffoe W, Segbaya S, Owusu-Antwi F, Kharchi Programs. Soc Work Public Health. 2011;26(2):137-57. AT, Williams RO, Saalfeld M, Workneh N, Shargie EB, doi: 10.1080/19371911003776704. Noor AM, Bart-Plange C. Effect of anti-malarial 12. Fox DM. Health inequality and governance in Scotland interventions on trends of malaria cases, hospital since 2007. Public Health. 2013 Jun;127(6):503-13. doi: admissions and deaths, 2005-2015, Ghana. Malar J. 10.1016/j.puhe.2013.04.019. Epub 2013 May 30. 2017 Apr 26;16(1):177. doi: 10.1186/s12936-017-1828- 6. 13. Lewis SJ, Kouri D, Estabrooks CA, Dickinson H, Dutchak JJ, Williams JI, Mustard C, Hurley J. Devolution to 23. Kilewo EG, Frumence G. Factors that hinder community democratic health authorities in Saskatchewan: an participation in developing and implementing interim report. CMAJ. 2001 Feb 6;164(3):343-7. comprehensive council health plans in Manyoni District, Tanzania. Glob Health Action. 2015 Jun 14. Jiménez-Rubio D, García-Gómez P. Decentralization of 1;8:26461. doi: 10.3402/gha. v8.26461. e-Collection health care systems and health outcomes: Evidence 2015. from a natural experiment. Soc Sci Med. 2017 Sep; 188:69-81. doi: 10.1016/j.socscimed.2017.06.041. Epub 24. Gurung G. Nepal health sector decentralization in 2017 Jul 1. limbo: what are the bottlenecks? Nepal Med Coll J. 2011 Jun;13(2):137-9. 15. Ramiro LS, Castillo FA, Tan-Torres T, Torres CE, Tayag JG, Talampas RG, Hawken L. Community participation in

121 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 Evaluating Corchorus Olitorius Plant Mucilage in the formulation of Oro-Dispersible Paediatric Sildenafil tablets Njoroge A. N. 1* , Tirop L. J. 2

1 Gilgil Sub-county Hospital, Nakuru County. Email:[email protected]

2 Department of Pharmaceutics and Pharmacy Practice, School of Pharmacy, University of Nairobi

*Corresponding author: Abstract vasodilator used in the management of pulmonary arterial hypertension in both adults and children [1]. Sildenafil Sildenafil Citrate (SC), used in management of pulmonary formulations available locally include regular and oro-dis- arterial hypertension, is available in adult tablet dosage persible tablets, in strengths of 25 mgs, 50 mgs and 100 forms, from which paediatric doses are prepared extempo- mgs, for the treatment of erectile dysfunction in adult raneously. Sildenafil citrate oro-dispersible tablets in patients. However there is no dose specific formulation for paediatric strengths, made from Corchorus olitorius (jute) paediatric patients necessitating extemporaneous plant mucilage as the natural superdisintegrant, provides modification, viz crushing of the adult tablets and mixing for a dose specific, more stable, cheap and convenient the resultant powder with diluents to form liquid dosage dosage form in this population. forms, which is tedious and error prone. The dosing recommendation for SC in management of acute Typically synthetic superdisintegrants, namely pulmonary hypertension in children below 1 year is a croscarmellose sodium, crospovidone and sodium starch starting dose of 0.25-0.5 mg/kg orally every 4 to 8 hours, glycolate, are used in the formulation of oro-dispersible and 2.5 mgs three times a day for those aged above 1 year, tablets. This work aimed to formulate paediatric oro-dis- with a body weight less than 20 kg [2]. An oro-dispersible persible tablets of Sildenafil citrate, using mucilage of jute tablet (ODT) is a highly convenient dosage form that takes plant (Corchorus olitorius) as a novel natural superdisinte- into consideration swallowing difficulties especially among grant. The mucilage was successfully extracted with 96% paediatrics [3]. ethanol and characterized, demonstrating favorable ODTs disintegrate in the mouth within seconds, thus easily parameters for use as a tablet superdisintegrant. Twelve swallowed in the absence of water, and very little or no batches of Sildenafil oro-dispersible tablets were residue is left upon being orally administered. ODTs provide formulated by direct compression, at three levels of the rapid drug delivery with a rapid onset of action and novel superdisintegrant as well as the common synthetic increased bioavailability. There is potential pre-gastric superdisintegrants, and evaluated. absorption which eliminates pre-systemic metabolism of The Corchorus olitorius mucilage batches showed the drug [4]. Additionally, ODTs provide rapid drug delivery characteristic mean in-vitro dispersion times of 20.67, 19.33 with a very fast onset of action and increased bioavailability and 18.67s for the 5 mgs, 7.5 mgs and 10 mgs (4%, 6%, 8% [5,6]. Several conventional techniques for preparation of ODTs exist, which include: direct compression with use of w/w) tablet concentrations, respectively. The in-vitro superdisintegrants, lyophilisation, mass-extrusion dispersion time of tablets containing Corchorus olitorius spray-drying, nanonization, compaction, moulding and mucilage compared closely with that of tablets containing sublimation. Some patented technologies employing these croscarmellose sodium and sodium starch glycolate. The techniques for formulation of various drugs include: Zydis®, in-vitro dispersion time was observed to decrease with Orasolv®, Durasolv®, and Flashtab® [3]. increasing concentrations of the mucilage powder. The tablets complied with all compedial tests for quality with Superdisintegrants, which are added in optimal the exception of the friability test. Corchorus olitorius concentrations to achieve rapid disintegration, exert their mucilage may be used safely at higher concentrations to activity based on such mechanisms as swelling, porosity achieve lower in-vitro dispersion times. Further studies to and capillary action (wicking). Superdisintegrants are establish the optimum superdisintegrant concentration broadly classified as synthetic and natural. The common synthetic superdisintegrants are croscarmellose sodium, should be considered. crospovidone and sodium starch glycolate [6]. Direct Key words: Oro-dispersible tablet, Sildenafil citrate, compression with addition of superdisintegrants is an Superdisintegrant, Corchorus olitorius mucilage. economical technique, as it employs conventional manufacturing equipment [7]. Natural superdisintegrants Introduction are cheaper, biocompatible and biodegradable hence eco-friendly, easily available, non-toxic and have no Sildenafil citrate (SC), a phosphodiesterase 5 inhibitor, is a side-effects [8]. Natural superdisintegrants have, in some

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 122 cases, been shown to exhibit faster drug dissolution and muslin cloth. The mucilage was then flocculated by improved bioavailability of the active pharmaceutical pre-extraction with 96% ethanol for duration of 24 hours at ingredient [9]. Indeed, various studies have demonstrated room temperature, recovered by washing with 3 volumes the superiority or equivalent superdisintegrant activity of of acetone, followed by drying in an oven at 45oC. The natural superdisintegrants to synthetic ones. For instance, dried mucilage was then grinded using a mortar and pestle in their study on Trigonella foenum-graceum (Fenugreek and passed through sieve number 70. The powder was seed) Kumar R. et al. demonstrated that mucilage of weighed and stored in a desiccator until use [14]. fenugreek seeds showed better disintegration than Physicochemical characterization of the mucilage synthetic superdisintegrants in ODTs of metformin [10]. powder: The extracted mucilage was evaluated for the Shirsand S.B. et al. showed that disintegration results organoleptic properties of taste, odor, color and texture. obtained from Plantago ovata mucilage in formulation of Iodine test was used for identification, by adding 1ml of 0.2 prochlorperazine maleate, were comparable and slightly N iodine solution to 100 mg of dried mucilage powder. better than those of crospovidone [11]. The swelling index was determined by placing one gram of Corchorus olitorius is a common indigenous leafy vegetable the Corchorus olitorius mucilage powder in a 25 ml in Western Kenya popularly known as ‘mrenda’. It is grown measuring cylinder, 25 ml of distilled water was then all year round, has excellent disease and pest resistance and poured into the measuring cylinder and shaken thoroughly gives stable yields even under difficult climatic conditions. every 10 minutes for 1 hour. The mixture was left to stand It can be harvested 3-4 weeks after planting and is a good for 24 hours and volume occupied by the mucilage powder source of proteins, vitamin A,C,E, and mineral nutrients like noted. The swelling index (SI) was then calculated. To calcium and iron [12]. determine the loss on drying, one gram of Corchorus Corchorus olitorius was investigated as a potential source of olitorius mucilage powder was accurately weighed and a cheap, non-toxic and easily available natural superdisinte- dried in a hot air oven at 105°C with the weight being grant, owing to its mucilaginous nature, given that most checked at intervals of 10min. When there was no further natural superdisintegrants are sourced from plant change in the weight of powder, the loss on drying was mucilages and gums [13], for the formulation of oro-dis- calculated. The pH of a 1% w/v aqueous solution of the persible sildenafil tablets. Corchorus olitorius mucilage powder was determined using a digital pH meter. 1% w/v of the mucilage in water was prepared and its viscosity determined using a Cole- Methods Parmer® rotational viscometer, spindle L2 and torque 50.8%. The solubility was determined by shaking the The Corchorus olitorius plant material was collected by powdered mucilage in different solvents viz warm water, proxy, from Kakamega rainforest area in Western Kenya. The cold water, acetone, ethyl alcohol and chloroform. Mucilage plant material was uprooted by the roots, packed in a clean size and shape was determined by optical microscopy, sack which was sealed and transported by road. using a Nikon®, Japan, phase contrast microscope. Finally, the flow properties of the mucilage, were assessed by determination of tapped and bulk densities, to calculate Hausner’s ratio and Compressibility index. Pre-formulation studies on powder blends: The powder blends of sildenafil citrate and excipients were prepared by obtaining the required amounts of pure drug and excipients for every formulation, which were ground to fineness and mixed. The blends were evaluated for flow properties as described for mucilage powder above. Drug excipient compatibility studies of the drug excipient blends in 1:1 ratio, was carried out using FTIR spectroscopy over the range of 4000 to 600cm-1. Samples were subjected to FTIR immediately after mixing and the resultant scans used to establish any predictable incompatibilities. Figure 1. Image of the leaves of Corchorus olitorius Formulation and evaluation of sildenafil citrate ODTs: All other materials, which were of pharmaceutical grade, Twelve tablet batches comprising of three different were obtained from the School of Pharmacy, University of concentrations (4%, 6%, 8% w/w) of a superdisintegrant, Nairobi and from collaborators. Corchorus olitorius mucilage, croscarmellose, crospovidone Extraction of mucilage: The leaves of Corchorus olitorius or sodium starch glycolate, were prepared (Table 1). Other were washed with water to remove any foreign material, tablet excipients used included mannitol (filler), microcrys- dried at 50o C and milled using a cutter mill. 400 g of plant talline cellulose (binder), colloidal silicon dioxide (glidant), material was soaked in 2 litres of distilled water for 6 hours magnesium stearate (lubricant), sodium saccharin at 60oC with continuous stirring using a magnetic stirrer, (sweetener) and strawberry flavor. All ingredients were until the mucilage was completely released into the water. ground individually using a pestle and mortar then passed Thereafter, the plant material was filtered using a modified through sieve number 60 separately to ensure ideal particle

123 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 size was achieved. The required quantities of the various indicating fair flow properties. Hausner’s ratio and com- ingredients were weighed and mixed uniformly in a mortar pressibility index of 1.28 and 21.9%, respectively, predict for 10 minutes, with the exception of magnesium stearate, passable flow character according to USP 29. which was added last and mixed with the rest of the blend Preliminary formulation studies on powder blends for a further 3 minutes. The powder blends were then compressed into 125 mg tablets with each batch The FTIR scans of the freshly mixed powder blends revealed comprising of one hundred tablets. The amount of no predictable drug excipient incompatibilities. FTIR sildenafil citrate in each tablet was 2.5mgs. studies of powder blends after storage under different conditions were not performed due to time constraints. Table 1. Master formula for the preparation of sildenafil citrate oro-dispersible tablets (quantities in mgs) The powder blends exhibited fair and passable flow

Batch Sildenafil Mannitol Corchorus Cros- Cros- Sodium Micro Colloidal Magnesium Sodium Strawberry Total citrate olitorius carmellose povi done starch crystalline silicon stearate saccharin flavor Weight mucilage gylcolate cellulose dioxide SC01 2.5 73.5 5.0 - - - 37.5 1.5 1.5 2.5 1.0 125 SC02 2.5 71.0 7.5 - - - 37.5 1.5 1.5 2.5 1.0 125 SC03 2.5 68.5.5 10 - - - 37.5 1.5 1.5 2.5 1.0 125 SC04SC0 2.5 73.5 - 5.0 - - 37.5 1.5 1.5 2.5 1.0 125 SC05 2.5 71.0 - 7.5 - - 37.5 1.5 1.5 2.5 1.0 125 SC06SC0 2.5 68.5.5 - 10 - - 37.5 1.5 1.5 2.5 1.0 125 SC07 2.5 73.5 - - 5.0 - 37.5 1.5 1.5 2.5 1.0 125 SC08SC0 2.5 71.0 - - 7.5 - 37.5 1.5 1.5 2.5 1.0 125 SC09SC0 2.5 .68.55 - - 10 - 37.5 1.5 1.5 2.5 1.0 125 SC10 2.5 73.5 - - - 5.0 37.5 1.5 1.5 2.5 1.0 125 SC11 2.5 71.0 - - - 7.5 37.5 1.5 1.5 2.5 1.0 125 SC12 2.5 68.5.5 - - - 10 37.5 1.5 1.5 2.5 1.0 125

The tablets were then evaluated for weight variation, properties, with Hausner’s ratio in the range of 1.25-1.33 hardness, thickness, friability, assay and content uniformity and Compressibility index range of 20.8% to 25%, thus as per USP guidelines. They were also assessed for wetting acceptable for tablet manufacture. time, water absorption ratio and in-vitro dispersion time as described by Naazia and Neeharika [15]. Evaluation of tablets The results for evaluation of tablets are presented in Table Results and Discussion 2. Weight variation: All the tablet batches passed the weight Physicochemical characterisation of mucilage powder uniformity test; whereby not more than two tablets The mucilage yield was 7% w/w, which was quite intra-batch varied from the average tablet weight by ±7.5 % significant, given the anticipated small quantity needed as deviation. a tablet superdisintegrant. The organoleptic characteristics Assay: All tablet batches except SC01 and SC07 were within of the mucilage are an ash brown powder with a the compendial limits of 90%-110% for low dose mucilaginous (mucourish) taste, fine texture and formulations. The slightly low API content in these two characteristic smell. No color change was observed in the tablet batches out of the twelve batches may have resulted iodine test, indicating the absence of starch. Mucilage is a from non-homogenous mixing of the API with the other non-starch heterogeneous branched polysaccharide. A excipients. value of 85.7% was obtained as the swelling index. Mucilage contains several hydroxyl groups that impart the Content uniformity: All tablet batches conformed to high swelling index. Weight loss of 0.71% w/w was compendia specifications, where the relative standard recorded in loss on drying, a value within the acceptable deviation (RSD) should be less than 6% and no value is range for tablet formulation. The pH of 1% solution was outside 85-115%. 6.605, which is unlikely to be irritating to mucous Hardness, thickness and friability: The hardness values membranes. The mucilage forms a dilute suspension with a obtained were variable and seemingly dependent on the low viscosity (35.1 centipoises) predicting minimal impact compression pressure which was varied manually, on drug release. The mucilage was soluble in warm water, in-process, to attain a hardness of 10-35N ideal for ODTs. slightly soluble in cold water, acetone and ethyl alcohol and The friability (limit <1%) attained could not guarantee insoluble in non-polar chloroform. This solubility pattern robust tablets, a common challenge with ODTs. ODTs are indicates that the mucilage is quite polar. The particle size usually fragile due to their low mechanical strengths and range obtained by light microscopy was 1-4 μm. The the hygroscopic nature of the superdisintegrants. particles were sub-spherical or irregular in shape, light Furthermore the tablet thickness of 1.2mm, contributed to brown in color and singly distributed with a puffy the friable nature of the tablets. appearance. An angle of repose of 36.4° was obtained,

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 124 Wetting time and water absorption ratio: These incorporated at 5 mgs, 7.5 mgs and 1 gms (4%, 6%, 8% measurements were carried out in pH 6.8 phosphate buffer w/w) concentrations to make a total of twelve tablet at a temperature of 37±0.5o to simulate the conditions of batches. saliva. Tablets comprising crospovidone superdisintegrant Post-compression tests demonstrated that tablets had a displayed shortest wetting times and lowest water good distribution of the API and low in-vitro dispersion absorption ratios. times of <30 s. The in-vitro dispersion time of tablets In-vitro dispersion time: The in-vitro dispersion time, containing Corchorus olitorius mucilage compared closely carried out in pH 6.8 phosphate buffer at a temperature of with that of tablets containing croscarmellose sodium and 37±0.5o to simulate the conditions of saliva, was used as a sodium starch glycolate. The in-vitro dispersion time was modified disintegration test due to the very short observed to decrease with increasing concentrations of the disintegration times involved. The end point for complete mucilage powder. The tablets complied with all compendial disintegration is the state whereby any residue that remains tests for quality with the exception of the friability test. is a soft mass, having no palpable firm core. Corchorus olitorius mucilage has the advantage of being All batches met the FDA specification for ODTs, of non-toxic, a nutritional supplement and eco-friendly. disintegration time < 30 seconds. A direct relationship Higher concentrations can be safely used to achieve lower between the wetting time and water absorption ratio to in-vitro dispersion times. Further work should be carried the in-vitro dispersion time was observed across the out to establish the optimum concentration of Corchorus batches. Dispersion time decreased with an increase in the olitorius mucilage powder, for its superdisintegrant activity. concentration of mucilage. Disintegration is achieved by Subsequently, stability studies on the optimized tablets swelling from the edges, very rapid initially, but rather slow should be performed. at the end due to formation of gel coat that slows water movement to the remaining tablet core. The dispersion time of the SC tablets containing Corchorus olitorius References mucilage compared closely with that of tablets comprising 1. http://pulmonaryhypertensionrn.com/ Types of sodium starch glycolate and crosscarmellose sodium. Pulmonary Hypertension. 2015. Table 2. Evaluation of the sildenafil citrate oro-dispersible 2. Teresa B. Guidelines on the use of sildenafil (Revatio) in tablets Batch Weight (mgs) Hardness (N) Thickness Friability Wetting time Water Dispersion Assay (% ) Content (mm) (% ) (s) absorption time (s) uniformity ratio (% ±RSD)

SC01 132±4.62 23.80±3.25 1.3±0.06 4.47 5.67±0.58 4.91±1.79 20.67±1.15 82.4±8.79 100±0.10

SC02 129±4.20 15.33±9.61 1.3±0.06 6.30 5.60±1.15 7.61±2.60 19.33±1.15 92.9±5.92 100±0.05

SC03 129±4.68 9.67±2.34 1.2±0.00 10.89 5.33±0.58 5.42±1.42 18.67±1.15 92.0±5.11 100±0.11

SC04 132±6.06 32.00±2.28 1.3±0.06 1.79 5.33±0.58 2.17±0.89 19.33±1.15 92.9±2.60 100±0.10

SC05 136±8.03 30.30±7.53 1.2±0.00 2.16 13.67±0.58 4.84±1.59 25.67±0.58 101.1±6.52 100±0.05

SC06 134±5.49 24.40±4.92 1.2±0.06 8.29 13.00±2.00 2.78±0.29 24.33±0.58 90.9±1.21 100±0.08

SC07 133±3.79 30.20±7.00 1.2±0.00 1.52 2.00±0.00 2.86±2.29 4.33±0.58 85.8±3.35 100±0.05

SC08 133±4.27 30.00±7.35 1.2±0.00 1.71 2.00±0.00 1.80±0.95 6.33±2.08 94.1±2.86 100±0.12

SC09 129±3.07 31.00±7.98 1.2±0.00 1.40 2.00±0.00 1.01±0.27 4.00±0.00 98.3±12.44 100±0.03

SC10 133±6.23 13.00±6.16 1.3±0.06 7.60 15.67±2.52 3.22±0.48 20.00±1.00 93.3±2.50 100±0.05 SC11 130±5.46 15.6±5.18 1.1±0.06 4.96 15.00±3.00 4.39±2.42 17.00±1.00 106±2.59 100±0.05

SC12 135±8.37 16.4±6.23 1.3±0.06 2.95 15.30±2.00 1.42±0.23 17.67±1.15 101±3.15 100±0.07

Conclusion and Recommendation acute pulmonary hypertension for paediatric cardiac patients. Leeds Med. Management and Pharmacy Mucilage powder of Corchorus olitorius leaves was Services 2013. successfully extracted and characterised. The mucilage was deemed suitable for tablet manufacture as a superdisinte- 3. Nagar P., Singh K., Chauhan I., Verma M., Yasir M., Khan grant, owing to its high swelling index of 85.7%. Powder A., Sharma R., Gupta N. Orally disintegrating tablets : flow characterization on all tablet powder blends predicted formulation, preparation techniques and evaluation. passable flow character. Direct compression, using Journal of Applied Pharmaceutical Science 2011; mannitol as the filler, was used to formulate the sildenafil 1(04):3545. citrate tablets. Each of the four superdisintegrants, 4. Deshmukh B., Narkhede K., Chaudhari P. Formulation Corchorus olitorius mucilage powder, croscarmellose, and In Vitro evaluation of fast dissolving tablet crospovidone and sodium starch glycolate was

125 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 containing sildenafil citrate nanocrystals. International Fenugreek Seed Mucilage. International Journal of Journal of Pharma Research and Review 2014; PharmTech Research 2009; 1(4):982–96. 3(06):10–18. 11. Shirsand S.B., Suresh S., Para M.S., Swamy P.V., Kumar 5. Parkash V., Maan S., Yadav S.K., Jogpal V. Fast D.N. Plantago ovata Mucilage in the Design of Fast disintegrating tablets : Opportunity in drug delivery Disintegrating Tablets. Indian Journal of system. Journal of Advanced Pharmaceutical Pharmaceutical Sciences 2009; 71(1):41-45. Technology and Research 2016; 2(4):223–35. 12. Choudhary S.B.,Sharma H.K.Karmakar P.G., Kumar A.A, 6. Kumar N.P., Nayyar P., Kumar S.P. Superdisintegrants- Saha A.R, Hazra P., et al. Nutritional profile of cultivated current approach. Journal of Drug Delivery and and wild jute (Corchorus) species. Australian Journal of Therapeutics 2014; 4(3):37–44. Crop Sciences 2013;7(13):1973-82. 7. Velmurugan S., Vinushitha S. Oral Disintegrating 13. Waruttaya K., Werner P., Helmut V., Ampai P., Darunee H. Tablets : An Overview. International Journal of Characterization of the mucilages extracted from Chemical and Pharmaceutical Sciences 2010; 1(2):1–12. Hibiscus rosa-sinensis linn and Hibiscus mutabilis linn and their skin moisturizing effect. International Journal 8. Sharma V., Arora V., Ray C. Use of natural superdisinte- of Pharmacy and Pharmaceutical Sciences 2014; 6(11) grant in mouth dissolving tablet- an emerging trend. :453-7. International Bulletin of Drug Research 2012; 1(2):46–54. 14. Nazni P., Vigneshwar P. Study on extraction and organoleptic evaluation of okra and hybiscus mucilage 9. Pahwa R., Sharma S., Rana A.S., Garg A., Singh I., Pahwa incorporated in homemade foods. International R. Emergence of natural superdisintegrants in the Journal of Food and Nutritional Sciences 2014; 3(1) development of orally disintegrating tablets. Indo :99-103 American Journal of Pharmaceutical Sciences 2016; 3(8):777–87. 15. Naazia Z., Neeharika P. Formulation and Evaluation of Sildenafil Citrate Fast Dissolving Tablets. International 10. Kumar R., Patil S., Patil M.B., Patil S.R., Paschapur M.S. Journal of Research in Ayurveda and Pharmacy 2014; Isolation and Evaluation of Disintegrant Properties of 5(3):352–8. Presence of Potentially Harmful Alcohol Excipients in Paediatric Medicine Dispensed in Nairobi 1 Maureen W Chege , Sylvia A Opanga2*

Muranga County Hospital, Kenya. 1 School of Pharmacy, University of Nairobi, Kenya. [email protected] [email protected] 2 *Corresponding Author Abstract Results: Out of 290 products sampled, 87 (30%) were found to have alcohol excipients. Ethanol was the most Background: Alcohol, as an excipient in pharmaceutical common type of excipient (46.0%), followed by propylene preparations, serves as a preservative and solvent. It is glycol (27.6%). Syrups had the highest number of products commonly found in oral and topical formulations, elixirs with alcohol (58.6%). Antihistamines recorded the highest and spirits. Although it has been widely used in paediatric number of products with alcohol (39.1%). Most of the formulations, its safety in children has not been well products with alcohol were over the counter drugs (79.3%). characterized though toxicity has been reported. Of the drugs that contained alcohol, 53% (n=46) were not recommended for use by patients less than 6 years of age. Objective: The aim of the study was to document the The daily dose of alcohol in the drug with the highest presence and content of alcohol excipients in paediatric alcohol content was equivalent to 28.8 ml of beer. drug products dispensed in pharmacies in Nairobi. Conclusion: Over the counter drugs had more products Methods: A cross sectional study was conducted at containing alcohol than the prescription only drugs. seven randomly selected pharmacies in Nairobi. The Ethanol and propylene glycol were the most commonly investigators selected all paediatric products and perused used excipients. The propylene glycol content was not their packages, labels and package inserts for information stated in all its products. The highest amount of alcohol per on presence of alcohol, content, type of alcohol excipients daily dose of drugs was equivalent to 28.8 ml of beer. and recommendations for use. The data was entered into Nearly half of the products were not recommended for Microsoft Excel 2010 worksheet, and descriptively analysed. children less than 6 years old.

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 126 Key words: Paediatric medicine; Alcohol; Ethanol; Excipient; and death in neonates who received injectable flush or Propylene glycol lavage saline solutions containing benzyl alcohol. Neonates, especially if ill, may not be able to adequately Introduction metabolize benzyl alcohol [8]. High concentrations can lead to breathing difficulties, vasodilation, low blood pressure, Pharmaceutical excipients are substances that are included seizures, and paralysis. in a pharmaceutical dosage form not for their direct therapeutic action, but to aid the manufacturing process, to Propylene glycol is commonly used in topical, oral and protect, support or enhance stability, or for bioavailability injectable formulations as a drug stabiliser. Neonates are or patient acceptability [1]. Ideally, an excipient is pharma- vulnerable to its toxicity because they have a longer half- cologically inactive, non-toxic, and does not interact with life (16.9 hours) compared to adults (5 hours). Adverse the active ingredients or other excipients. However, in effects of its use include serum hyperosmolality, seizures at practice few excipients meet these criteria. Toxicity may high doses of over 3g/day from intravenous solutions, relate to compounds used as excipients in the final dosage central nervous system toxicity, cardiac arrhythmias, form or to residues of compounds (such as solvents) used hemolysis and agitation [9]. The conversion of propylene during the manufacturing process. [2] glycol to lactic acid causes lactic acidosis. Other adverse effects include acute kidney injury, respiratory and central The excipients to be used in formulations for the paediatric nervous system depression. Rapid infusion of propylene population should be selected with special care, taking into glycol containing medications causes respiratory consideration the differences in the paediatric age group depression, arrhythmias, hypotension and seizures [9]. and maturity of organ systems [3]. Despite this, many paediatric preparations that were licensed prior to the new Although most studies attribute adverse drug reactions to European Union paediatric regulation contain excipients the active pharmaceutical ingredients, very few studies that are no longer recommended for use in children. have studied the effects of excipients, particularly alcohol. Besides this, the available safety data for excipients are A study in the UK neonatal intensive care unit often extrapolated from adult data, which makes it difficult demonstrated that neonates were exposed to an to characterise the safety and toxicity profiles specific to equivalent of 0.07 to 15.2 adult UK alcohol intakes per paediatrics [3]. week, through excipients in medication [10]. There have been no studies in Kenyan patients and in pharmacies to The paediatric population is particularly vulnerable to demonstrate the content of potentially harmful alcohol adverse reactions owing to organ immaturity and excipients in paediatric medicines, which could contribute differences in pharmacokinetic and pharmacodynamic to adverse drug reactions reported in children. This study profiles compared with adults [4].The toxicity of excipients sought to shed light on the types and amount of alcohol in may differ across the paediatric subsets. Children, especially drugs dispensed to children in Nairobi. the younger age groups, may require age-appropriate formulations, which sometimes have to be compounded within hospitals, without guidelines on excipient content. Methods Use of certain excipients which contain alcohol may be A cross sectional study of selected community pharmacies harmful and may lead to effects such as neurological in Nairobi was conducted between March and September dysfunction [5]. Use of combinations of drugs with alcohol 2015. Community pharmacies around Kenyatta National excipients in children, especially over the counter drugs, Hospital, which is the largest referral hospital in Kenya further increases the chances of toxicity [6]. serving patients from all parts of the country, were selected. Patients who do not get prescribed drugs at the KNH Different types of alcohol are used as excipients in different paediatric pharmacy buy drugs at the pharmacies. From the drug formulations. These include: ethanol, benzyl alcohol list of selected 21 community pharmacies, every third and propylene glycol. Ethanol is widely used as a co-solvent pharmacy was selected, to form a sample of seven to aid solubility. In the USA, maximum permitted quantities pharmacies. in over the counter (OTC) products: <0.5% for children under 6-years, <5% for children 6-12-years, <10% for The investigator sampled all paediatric drugs at all the children over 12-years.The effects of ethanol on the selected pharmacies and perused the drug packages, labels paediatric population have only been elucidated in the and package inserts for information on alcohol content. cases of acute and chronic poisoning. These effects include: Data on the name of the drug (brand and generic), type of hypoglycaemia, acidosis, loss of consciousness, drugs and their pharmacologic classification, type of hypothermia and tachycardia. Long term effects on hepatic alcohol, and alcohol content (percentage), was collected and neurological function have been documented. There is and entered into a pretested data collection form. Data was paucity of information on the physiological effects of entered into a Microsoft Office Excel 2010 worksheet and ethanol in paediatrics apart from poisoning [7]. descriptive data analysis done. The results were presented in form of charts and tables. Benzyl alcohol is used as a common preservative in many injectable drugs. Together with its derivative benzoic acid, benzyl alcohol has been associated in the past with toxicity

127 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 Results 1. Selected Pharmacies and Number of Paediatric drugs Sampled per Pharmacy The study was carried out in seven community pharmacies around Kenyatta National Hospital whereby a total 290 drugs were sampled and out of the 290 drugs, 87 drugs were found to have alcohol. The pharmacies were coded with serial numbers for confidentiality. Pharmacy number 005 recorded the highest number of products with alcohol excipients (Table 1). Table 1. Number of drugs sampled at each pharmacy

Community Total num- No of drugs Cumulative pharmacies ber of drugs with alcohol % from each sampled (n) sample 001 58 12 (13.8%) 20.7 Figure 2. Pharmaceutical dosage forms with alcohol 002 55 13 (14.9%) 23.6 excipients 003 50 14 (16.1%) 28.0 4. Pharmacological Class of Drugs and alcohol content 004 45 13(14.9%) 28.9 Antihistamines were the class of drugs with the highest 005 40 16 (18.4%) 40.0 number of products containing alcohol (39.1%), followed 006 30 13 (14.9%) 43.3 by cough suppressants (16.1%). The anti-epileptics had the 007 12 6 (6.9%) 50.0 lowest number of products with alcohol as an excipient (Figure 3). Total 290 87(100.0%)

2. Over the Counter Versus Prescription only Medication containing alcohol excipients Most of the medication with alcohol comprised the OTC medication (79.3%) as opposed to 20.7% which were prescription only medication (Figure 1)

n

Figure 3. Pharmacologic class of drugs with alcohol excipients 5. Types of alcohol excipients Ethanol was the most common type of alcohol excipient Figure 1. Over the Counter and Prescription only found in the drugs (46.0%, n=40), followed by propylene medication with alcohol content glycol (27.6%). Some product labels and inserts did not specify the type of alcohol contained in the drug but simply 3. Pharmaceutical dosage forms and alcohol content stated it as “alcohol” (25.3%, n=22). Benzyl alcohol was the With regard to pharmaceutical dosage forms, syrups had least used excipient at 1.1% (Table 2). the highest number of products with alcohol (58.6%) Table 2. Types of alcohol excipients followed by solutions at 25.3% (Figure 2). Alcohol excipient Frequency (n, %) Cumulative % from sample Ethanol 40 (46.0%) 13.8

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 128 Propylene glycol 24 (27.6%) 8.3 Paralief Paracetamol 3(13.0%) - Alcohol* 22 (25.3%) 7.6 Benzyl alcohol Benzyl alcohol 1 (1.1%) 0.3 Pharmaton Vitamin D, Vitamin B5 1 (100.0%) - Total 87 (100.0%) . Kiddi *Products did not specify the type of alcohol excipient but 7. Alcohol consumption per daily dose of drug simply referred to them as ‘alcohol’ For the drugs whose alcohol content was indicated, we 6. Product brand versus alcohol content calculated the equivalent daily dose of alcohol intake through excipients by children, using the daily dosing Out of the 87 products that contained alcohol, only 49 regimen for each drug. Ercefuryl had the highest alcohol (56.3%) had the alcohol content specified. Of these, 55.1% content per dose per day, followed by Plactinic. The (n=27) contained ethanol, while 44.9% (n=22) contained European Medicines Agency recommends that the amount unspecified alcohol. The content of ethanol varied by of alcohol excipient should be stated in terms of its product, and ranged from 0.1% to 9.6% while that of equivalent amount of beer or wine, using 5% alcohol unspecified alcohol ranged from 3.6% to 5.0%. The alcohol content for beer and 12% for wine. Using this, we calculated content was not indicated for all products containing the equivalent amount of alcohol in the medicines in terms propylene glycol (Table 3). of volume of beer consumed per day (Table 4). Table 3: Product alcohol content by brand Drug Active ingredi- Maxi- % Daily Equiva- Product brand Active Pharmaceu- Frequency Alcohol con- ent mum alcohol alco- lent name tical Ingredient (n, %) tent (% w/v) daily content hol amount dose (w/v) dose of beer/ Ethanol (mg) day (ml) Bronchicum Herbal (Thymus 6 (15.0%) 4.9 Bronchicum Herbal (Thymus 15ml 4.9 735 14.7 elixir vulgaris, Primula elixir vulgaris, Primula veris) veris) Rhinathiol Carbocisteine 7 (17.5%) 1.34 Rhinathiol Carbocisteine 15ml 1.34 201 4.02 250mg/5ml 250mg/5ml Ranferon-12 Folic acid, ferrous 7(17.5%) 3.61 Ranferon-12 Folic acid, ferrous 10ml 3.61 361 7.22 elixir ammonium citrate, elixir ammonium ferrous fumarate, citrate, ferrous cyanocobalamin, fumarate, ascorbic acid, zinc cyanocobalamin, sulfate ascorbic acid, Tres orix forte 7(17.5%) - zinc sulfate Atarax Hydroxyzine 25ml 0.1 25 0.5 Flagyl Metronidazole 6(15.0%) - 10mg/5ml 200mg/5ml Ercefuryl Nifuroxazide 15ml 9.6 1440 28.8 Atarax Hydroxyzine 3(7.5%) 0.1 218mg/5ml 10mg/5ml Benylin Dextrometho- 10ml 5 500 10.0 Ercefuryl Nifuroxazide 4 (10.0%) 9.6 paediatric rphan HBr 218mg/5ml Piriton Chlorphenira- 15ml 3.6 540 10.8 Alcohol syrup mine maleate Benylin Dextromethorphan 7 (31.8%) 5 Piriton Chlorphenira- 15ml 3.6 540 10.8 paediatric HBr expectorant mine maleate, Piriton syrup Chlorpheniramine 7(31.8%) 3.6 ammonium maleate chloride, sodium citrate Piriton Chlorpheniramine 7(31.8%) 3.6 expectorant maleate, ammonium Plactinic Cyproheptadine 15ml 5 750 15.0 chloride, sodium hydrochloride citrate 8. Recommendations for paediatric use by age Plactinic Cyproheptadine 1(4.5%) 5 hydrochloride Different drugs had different recommendations for children Propylene less than 6 years and those more than six years old as Glycol shown in Figures 5 and 6. Only 3 drugs containing ethanol Claritin Loratadine 6 (26.1%) - as an excipient were recommended for use in patients Aerius Desloratadine 6(26.1%) - below 6 years of age. A total count of 24 and 22 drugs 0.5mg/ml which contained ethanol and alcohol respectively were not Zyrtec Cetrizine HCl 6(26.1%) - recommended for patients below 6 years of age. All products containing propylene glycol did not have labels Tegretol Carbamazepine 2 (8.7%) - for recommended use in children less than or more than six

129 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 years old. There were variations in recommendation of use unspecified alcohol. by product in children older than six years old.

24 24

22

13

3 1

Figure 7: Recommendation for patients below 6 years

Figure 5: Number of drugs recommended for children below 6 years

Figure 8: Recommendation for patients above 6 years Discussion In our study, over the counter (OTC) products were found to have more products containing alcohol (79.3%) compared to prescription only drugs (21.7%). This can be explained by the fact that there is tighter regulation for Figure 6: Number of Drugs Recommended for Patients prescription only medication compared to over the counter above 6 years medication. Antihistamines comprised the highest number A total count of 8 and 23 drugs containing alcohol and of products with alcohol as an excipient in our study, and ethanol respectively were recommended for patients above most of them are OTCs. Additionally, most OTCs include 6 years of age. A total count of 4 and 14 drugs containing vitamin preparations, herbal and homeopathic ethanol and alcohol respectively were not recommended preparations, which require a significant amount of alcohol for patients above 6 years of age. There were no recommen- in their formulation [3]. dations for both groups for drugs containing propylene Syrups had the highest percentage of alcohol as an glycol and benzyl alcohol. excipient (68.6%) compared to solutions, followed by 9. Recommendation of use of drugs across suspensions. During formulation of drugs, several factors pharmaceutical dosage forms are considered when selecting the appropriate excipient. Recommendations for use of products varied across the The pH at which the drug is most stable should be close different pharmaceutical dosage forms as illustrated in enough to the solubility of the drug required to deliver the Figures 7 and 8. For drugs containing ethanol, syrups were drug in approximately 5ml. Oral solutions and syrups are the most commonly recommended for use in children therefore developed in this case. Suspensions are below six years of age. There was no recommendation for formulated when the pH of the drug is not close enough to drugs containing the unspecified alcohol and propylene the solubility. This explains the fact that syrups and glycol. For those above six years, syrups were the most solutions, as opposed to suspensions had the highest recommended for use for products with ethanol and number of products with alcohol [11].

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 130 Even though the package inserts of drugs like Atarax 0.25g/dl, and all over the counter liquid products, including (hydroxyzine), Piriton (Chlorpheniramine), Ercefuryl topical products, should not contain more than 5% ethanol. (nifuroxazide), Benylin (dextromethorphan), Flagyl In our study, some products had higher than the (Metronidazole) and Rhinathiol (Carbocisteine) indicated recommended 5% alcohol level content. This can be that alcohol should not be taken with these drugs, they still explained by the fact that there are no regulations from the contained alcohol excipients. Alcohol can potentiate Pharmacy and Poisons Board on labelling for the alcohol drowsiness caused by the antihistamines such as content and recommended blood alcohol level for hydroxyzine, chlorpheniramine as well as cough medicines paediatric products in Kenya. like dextromethorphan. Hydroxyzine is one of the drugs The European medicines Agency recommends that used to treat alcoholism, and has been shown to interact package inserts of drugs containing ethanol should state its with alcohol. Metronidazole, when taken together with equivalent volume in terms of beer and wine, with 5% alcohol, causes disulfiram like reactions, which present with ethanol used for beer and 12% for wine. In our study, the vomiting, tachycardia, flushing, visual disturbances, daily consumption of alcohol for the drug with the highest hypotension, syncope and circulatory collapse [1]. amount of alcohol was equivalent to 28.8 ml of beer. This Ethanol and propylene glycol were the most commonly was not indicated on the packaging as there are no Kenyan used excipients in our study. This agrees with studies that guidelines for that. show that it is the most commonly used excipient after There were several limitations to our study. First, a lot of the water [7]. Even though ethanol use in medicines has been paediatric medications selected, especially the generics did discouraged due to interaction with other drugs, diseases, not indicate the presence of excipients in their packaging. effects on performance and driving, pregnancy and Only branded drugs did. Of the drugs that indicated the breastfeeding, it continues to be widely used as an presence of alcohol, only few of them indicated the alcohol excipient [3]. content. We were not able to verify the content of alcohol In children, metabolism of alcohol varies with age due to in the drugs through laboratory testing due to time and immature systems. The effects of ethanol in children have financial constraints. been reported in acute intoxication and they include: hypothermia, hypoglycaemia, coma, seizures, hypotonia, Conclusion hyporeflexia, gastritis, acute hepatitis and pancreatitis, Over the counter drugs had more products containing hypokalemia and lactic acidosis. A study demonstrated alcohol than the prescription only drugs. Ethanol and these effects in paediatric intensive care patients [10]. The propylene glycol were the most commonly used alcohol use of ethanol in medicines has been restricted in Europe, excipients. The propylene glycol content was not stated in but there has been no such restriction in Kenya and other all products containing it. The highest amount of alcohol developing countries [3]. per daily dose of drugs was equivalent to 28.8 ml of beer. Propylene glycol is a potentially toxic excipient. It can cause Most of the products were not recommended for children life threatening effects like seizures, lactic acidosis, hypers- less than 6 years old. osmolality, acute kidney injury and respiratory and central nervous system depression [9]. In our study, its content was Conflict of Interest not specified in the drug packaging and inserts. Omission of information and inaccuracy in labelling of drugs may We declare that we have no conflict of interest. expose children to these adverse reactions, especially if the content of excipient is high [6-8]. References For the drugs whose alcohol content was specified, the 1. Anderson CW, Ng KJ, Anderson B and Cordero L (1984). alcohol content ranged from 0.1% to 9.6%. The World Benzyl alcohol poisoning in a premature newborn Health Organisation (WHO) proposes that the amount of infant. Am. J. Obstet. Gynecol. 148:344-346. ethanol in OTC preparations should be less than 0.5% for 2. Augsburger LL and Zellhofer MJ (2006). Tablet children less than 6 years old, less than 5% for children 6-12 formulation .In: Swarbrick J, Boylan JC, editors. years old and less than 10% for children over 12 years. In Encyclopedia of Pharmaceutuical Technology .3rd ed. our study, most of the products with the stated alcohol New York: Marcel Dekker; 2006. content were not recommended for use in children less than six years of age. 3. Bekeris L, Baker C, Fenton J, Kimball D and Bermes E (1979). Propylene glycol as a cause of an elevated The French Medicines Agency recommends that if ethanol serum osmolality. Am. J. Clin. Pathol. 72:633-636. is included in medicines for children, the amount of ethanol contained should not produce a blood alcohol 4. Bitunjac K., and Saraga M (2009). Alcohol intoxication in concentration of more than 0.125g/l. The total volume of paediatric age: Ten-year retrospective study. Croat. alcohol in the medication should be such that it should not Med. J. 50 (2): 151-156. exceed 3g/kg in case the entire bottle is consumed by a 5. Brent J (2009). Fomepizole for ethylene glycol and child. The FDA recommends that in case alcohol is included methanol poisoning. N. Engl. J. Med. 360(21):2216-23. as an excipient, the blood alcohol levels should not exceed

131 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 6. Chikwava K., Lower DR., Frangiskakis SH., Sepulveda J.I., 21. LeBel M, Ferron L, Masson M, Pichettee J, and Carrier C Virji MA., and Rao KN (2004). Acute ethanol (1988) Benzyl alcohol metabolism and elimination in intoxification in a 7-month-old infant. Pediatr. Dev. neonates. Dev Pharmacol Ther, 11;347-356. Pathol. 7(4):400-402. 22. Lim TY, Poole RL, and Pageler NM (2014). Propylene 7. Cronin CM, Brown DR, and Ahdab-Barmada M (1991) glycol toxicity in children. J.Paediatr. Pharmacol.Ther, Risks factors associated with kernicterus in the 19(4):277-282. newborn infant: importance of benzyl alcohol 23. Lobert S (2000). Ethanol, isopropanol,methanol, and exposure. Am. J. Perinatol. 8:80-85 ethylene glycol poisoning. Crit. care. nurse. 20 (6): 41-7. 8. Demey HE, Daelemans RA, and Verpooten GA (1988). 24. MacDonald MG,Getson PR,Miller MK .Propylene Propylene glycol induced side effects during glycol:increased incidence of seizures in low bith intravenous nitroglycerin therapy. Intensive Care Med. weight infants. Paediatrics 79 14:221-226 25. Marek E, Kraft WK (2014), Ethanol pharmacokinetics in 9. Detoxification and substance abuse treatment; neonates and infants. Curr. Ther. Res. Clin. Exp. Ethanol, http://www.ncbi.nlm.nih.gov/books/ 76:90-97. NBK64115/pdf/TOC.pdf. Accessed 20.2.15 26. Martindale (2011). The complete drug reference. 37th 10. European Medicines Agency (2015). Committee for ed. London: Pharmaceutical Press. http://www.medici- Human Medicinal products. Excipients in the label and nescomplete.com/mc/martindale/current/551-f.htm?q package leaflet of medicinal products for human use =ethanol&t=search&ss=text&p=19. Accessed (CPMP/463/00). www.ema.europa.eu. Accessed 17.02.2016. 12.3.2015. 27. McCormick T.,Levine M.,Knox O. and Claudius I. (2013). 11. FDA, department of health and human services (2015). Ethanol ingestion in two infants under 2 months old: A Over the counter drug products intended for oral previously unreported cause of ALTE. Paediatr. 131(2): ingestion that contain alcohol. http://www.fda.gov/ e604-e607 downloads/Drugs/Development ApprovalProcess/OTC. Accessed 18.3.2015. 28. Murty RB (2004) .The biochemistry of alcohol toxicity. Resonance. 9(10): 41-47. 12. Fong HF and Muller AA (2014) .An unexpected clinical course in a 29-day-old infant with ethanol exposure. 29. Reiter PD (2002). Neonatal pharmacology and pharma- Pediatr. Emerg. Care. 30 (2): 111-113 cokinetics .Neo. Rev. 3 (11). 13. Food and Drug Administration (1989) Parenteral drug 30. San Diego State University, Center for Alcohol and Drug products containing benzyl or other antimicrobial Studies and Services, www.centreforaod.sdsu.edu. preservatives: withdrawal of notice of intent. Fed Red. Accessed 14.4.2015. 54;49772. 31. Sisson JH (2007). Alcohol and airway function in health 14. Ghosh T.K ,Jasti B.R. CRC Press and Boca Raton (2005). and disease. Alcohol. 41(5): 293-307. Theory and practice of contemporary pharmaceutics. 32. Star K, Edwards IR (2014). Pharmacovigilance for 15. Glasgow AM, Boeckx RL, Miller MK, and MacDonald MG children’s sake. Drug. Saf. 37: 91-98. (1983). Hyperosmolality in small infants due to 33. Tayman C, Rayyan M and Allegaert K (2011). Neonatal propylene glycol. Paediatrics .72(3):353-355 pharmacology: Extensive inter-individual variability 16. Grant JA, Bilodeau PA, Guernsey BG and Gardner despite limited size. J. Paediatr. Pharmacol. Ther. 16 (3). FH(1982). Unsuspected benzyl alcohol hypersensitivity 34. Turner MA, Duncan JC, Shah U and Metsvant T (2014). reaction. Drug. Intell. Clin. Pharm . 20:689-691. Risk assessment of neonatal excipient exposure: 17. Huggon I,James I, and Macrae D (1990).Hyperosmolal- lessons from food safety and others. Adv. Drug. Del. ity related to propylene glycol in an infant treated with Rev. 73:89-101. enoximone infusion .BMJ .301:19-20. 35. Whittaker A., Currie A. E., Turner MA., Field D.J., Mulla H., 18. International Excipients Certification Project. London and Pandya H.C (2009). Toxic additives in medication (2013). Pharmaceutical Quality Group. www. for preterm infants. Arch. Dis. Child. Fetal Neonatal Ed. ipec-europe.org. Accessed 17/02/2017. 94 (4): F236-F240. 19. Isaac R., Khan I., and Langley C (2013). Ethanol intake 36. WHO (2010). Pharmaceutical excipients overview, of paediatric intensive care patients. Arch. Dis. Child. 98 including considerations for paediatric dosing, Beijing. (6) 11-11. http://apps.who.int/prequal/trainingresources/pqpres/ workshop. Accessed 17.4.2015. 20. Kaye JL (2011).Review of paediatric gastrointestinal physiology data relevant to oral drug delivery. Int. J. 37. Yorgin PD, Theodorou AA, Al-Uzri A. Propylene glycol Clin. Pharm, 33 (1). induced proximal renal tubular cell injury. Am. J. Kid. Dis.

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 132 The Occurrence of Glucose 6 Phosphate Dehydrogenase Deficiency amongst Blood Donors at the Regional Blood Transfusion Centre-Mombasa, Kenya 1,3* 2 Wigina, R. N , Kaggia S. N , Kahato M. N 3 , Mzee S. S1

1Technical University of Mombasa, Faculty of Applied and Health Sciences, Department of Medical Sciences, PO Box 90420, – 80100 Mombasa. Email: [email protected], [email protected]

2Jomo Kenyatta University of Agriculture and Technology, College of Health Sciences, Department of Human Pathology, PO Box 62000 – 00200 Nairobi. Email: [email protected]

3Jomo Kenyatta University of Agriculture and Technology, College of Health Sciences, Department of Medical Laboratory Sciences, PO Box 62000 – 00200 Nairobi. Email: [email protected]

*Corresponding authors

neonates. It would also aid in establishing risk in the use of Abstract drugs associated with triggering clinical manifestations. Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is Key Words: Transfusion, Glucose-6-Phosphate an X-linked hereditary genetic defect that is estimated to dehydrogenase, deficiency, blood donors. affect 400 million people worldwide. This deficiency is associated with hemolytic disorders that may manifest depending on the molecular variant present, exposure to Introduction hemolytic triggers such as consumption of foods including Red blood cells are an important part of the body’s fava beans and exposure to drugs including dapsone and metabolic processes. With a lifespan of 120 days, the primaquine. This disorder has been found to be more non-nucleated red cells perform their metabolic functions prevalent in malaria endemic zones of Asia, Africa and and are also able to perform their specialized core function South America. This study determined the occurrence of of oxygen transport and delivery to the body tissues [1]. G6PD deficiency among the donors at the Regional Blood The transfer of oxygen across cell membranes and its Transfusion Centre-Mombasa, and whether any correlation utilization are dependent on the cytochrome P24 group of existed between the occurrence of G6PD deficiency and molecules, the Embden Meyerhof glycolysis pathway and either ABO blood type or haemoglobin concentration. the hexose monophosphate shunt. The free oxygen radicals Methaemoglobin reduction test was used to check for the that are produced during these processes are harmful to presence of G6PDd among the blood donors, anti A and cells and tissues [2]. To mitigate the effects of these free anti B sera were used to determine the blood types. radicals, various enzymes and metabolic intermediates are Haemoglobin concentration was estimated using involved in these glycolytic pathways. These include the 2-3 haematology analyzer. Multivariate analysis was done to diphosphoglycerate, pyruvate kinase and glucose 6 establish the point prevalence of G6PDd in the donor phosphate dehydrogenase (G6PD) enzymes [3]. Glucose- population, the relationship between G6PD and ABO blood 6-phosphate dehydrogenase plays an important role in all types and the correlation between G6PDd and cells particularly the red blood cells (RBC) [4]. It protects the haemoglobin concentration. Out of the 676 donors 9.6% cells from potential damage by reactive oxygen species were deficient of G6PD activity while 13.17% had red cells (ROS) [5]. G6PD reduces nicotinamide adenosine exhibiting partial activity. The point prevalence for all forms dinucleotide phosphate (NADP) to nicotinamide adenoside of G6PDd was found to be 22.79%. Blood group AB donors dinucleotide phosphate hydrogenase (NADPH). The NADPH were least likely to exhibit G6PD deficiency compared to then reduces oxidised glutathione (GSSG) to reduced the rest of the ABO blood types. The association between glutathione (GSH). The reduced glutathione is then able to G6PDd and haemoglobin concentration was inconclusive. bind to the ROS and protect the cells from oxidative stress The current findings indicate that G6PD deficiency exists [6]. The lack of mitochondria in the RBCs make the action among healthy donors without manifestation of clinical of G6PD vital in the protection against oxidants [5]. A symptoms. G6PDd screening as part of donor blood testing Glucose 6 Phosphate Dehydrogenase deficiency (G6PDd) regime would therefore allow for the discriminate use of would therefore be potentially hazardous to Red Blood G6PDd blood in transfusion dependent patients and Cells (RBCs) in particular due to their role in oxygen

133 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 transport. The G6PDd was first reported by the Greek was then added to stimulate the pentose phosphate philosopher Pythagoras who noticed that the consumption pathway. Control tubes comprising of one milliliter of blood of fava beans resulted in an ailment to some of his subjects, without reagents and another containing sodium nitrite which he named favism [4]. without methylene blue were also mixed. All the tubes were then incubated at 370C for 90 minutes, 0.1mL of the The G6PD gene has been shown to have several mutant mixtures were then obtained and subjected to lysis using alleles that have decreased enzyme activity thus expressing 10mL of distilled water. the G6PD deficient phenotype [7]. The deficiency of G6PD enzyme is an X-linked recessive in-born error of metabolism The presence of various degrees of lysis was representative [2]. This condition predisposes individuals especially males of the G6PD activity of the sample. Normal blood takes the to acute red blood cell haemolysis and neonatal jaundice. color of the normal reference tube (clear red), G6PD The condition occurs in the presence of exogenous factors deficient blood takes the color of the deficient reference such as consumption of fava beans, oxidative stress due to tube (brown). Intermediate reactions will show the infections, anaemia and certain drugs among them presence of heterozygote G6PD conditions. ABO blood dapsone, methylthioninium chloride (methylene blue), type was assayed using microtiter plates and reagents nitrofurantoin, phenazopyridine, primaquine, rasburicase ACCUCARE™ (Lab-care diagnostics, India) blood type using and tolonium chloride (toluidine blue) [8]. G6PDd is the the anti “A” and anti “B” sera these were used to correlate most common genetically determined red blood cell with the findings of the G6PDd to check for association. enzyme deficiency in the world [1]. Currently about 160 Haemoglobin concentration was estimated using the different variants of G6PDd have been isolated and it is Medonic TM haematology analyzer. Consent was inferred estimated that 400 million people are affected worldwide after the donors signed the donor health assessment [1]. The disease presentation in most individuals is largely questionnaire. All information obtained was treated with asymptomatic in the absence of exogenous triggers [9]. In confidentiality in conformity to the Kenya National Blood severe variants however, G6PD deficiency may result in Transfusion Service (KNBTS) guidelines on donor records. non-spherocytic haemolytic anaemia even without Prior permission to use the samples was obtained from the oxidative stress [10]. The manifestations of severe director of KNBTS. The study was approved by the Pwani haemolysis due to G6PDd start early and has been University Ethical Review Board (PU-ERB). implicated as a common cause of severe neonatal jaundice [11]. Enzyme deficiencies have been implicated in Results hemolytic symptoms after transfusion and are viewed as potentially fatal to patients transfused with such blood Overall G6PD deficiency [12,13]. The reaction of nitrites with haemoglobin may be A total of 676 samples were assayed for G6PDd. Donor exploited to screen donors for G6PD. Sodium nitrite samples showing complete deficiency in G6PD activity converts the haemoglobin to haemiglobin via an were 9.6% of the total donors assayed. Intermediate autocatalytic reaction that involves the formation of reactions were observed in 13.2% samples. The total methaemoglobin and nitrate as the stable end product number of donors having G6PDd was 154 (22.8%) of the [14]. The current study aimed to determine the occurrence donor population. The proportion of normal and abnormal of G6PD deficiency amongst blood donors at the Regional blood samples based on G6PD enzyme activity was 77.2% Blood Transfusion Centre – Mombasa and the correlation and 22.8%, respectively (fig. 1). between occurrence of deficiency and ABO blood type or haemoglobin concentration.

Methods This was a cross-sectional study conducted in Mombasa Kenya. Samples were collected from donors at the Regional Blood Transfusion Centre (RBTC) Mombasa and analysis done at the Technical University of Mombasa department of medical science laboratories. Ethical review was obtained from the Pwani University Ethical review board under reference number ERC/MSc/009/2017. A no objection statement was also obtained from the Director, Kenya National Blood Transfusion Service. Figure 1: Proportions of G6PD activity in the blood samples collected at the Regional Blood Transfusion Centre (RBTC) A total of 676 samples were drawn from donors recruited Mombasa, Kenya. and bled by the RBTC staff. These blood samples were assayed for G6PD activity using the Methaemoglobin reduction method. One milliliter of blood was added to a 0.1mL combined nitrite, dextrose and methylene blue reagent and the two mixed by inversion. Methylene blue

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 134 Correlation between ABO blood type and G6PDd Yemen found that among healthy male donors, 7.2% had occurrence G6PDd in the capital city of Sanaa. In Kenya, the estimated prevalence for G6PDd is in the range of 10% to 13% [15]. The current study compares favourably with the results from Nigeria by Akanni et al., who found a prevalence of 19.5% in blood donors in Osogbo, [16] and Nguetse et al., who reported that 73% of the study subjects in selected African countries had normal G6PD activity [17]. However these findings do not correspond with estimates by Howes et al which indicate that prevalence of G6PDd in Kenya is about 13% [15]. This may be due to the high prevalence rate of malaria in the coastal region. G6PDd has been shown to have a high prevalence in malaria endemic zones [15]. The association of G6PDd with health conditions is a major area of study today. Akanni et al have associated neonatal jaundice to the deficiency Figure 2. Correlation between the ABO blood types and showing 47% of the jaundiced neonates in the study were the occurrence of glucos 6 phosphate dehydrogenase G6PD deficient [16]. It has also been found that altered deficiency in the donor population G6PD activity may play a critical role in severe pulmonary The test results showed that there was a marginal hypertension [18]. This study established that G6PD correlation in the likelihood of having G6PDd between condition of a donor was associated with ABO blood types blood type AB and type A. Blood type A individuals had a (figure 2). A marginal significance was established between higher likelihood of having G6PD deficiency compared to the A and AB Donors. A person with Blood type “A” was blood type AB individuals. The Chi square test for more likely to be deficient than a person with blood type association showed that there was a correlation between “AB” at a p-value 0.03989 (coefficient of variance=1.09, ABO blood type and occurrence of G6PD deficiency Standard error=0.63. p-value=0.08). The relationship (p-value 0.003989) A marginal significance of AB in between G6PD deficiency and haemoglobin concentration reference to Blood type A was observed. Donors with Blood was difficult to establish (Table 1) even though an ANOVA type AB were more likely to be normal compared to those model revealed that there is indeed a difference between of Blood type A (coef=1.09, s.e =0.63. p-value=0.08). the G6PD condition and the Hb levels of the donor (F-value 0.0426, CI 95%). This correlation is not however reflected in G6PD in relation to Haemoglobin concentration the pair wise comparisons. Future studies to incorporate a Table 1: relationship between haemoglobin and G6PD larger sample size needs to be done to establish this condition in donors relationship. HB<12.0 HB>=12.0 Conclusion NORMAL 10.5% 89.5% Glucose 6 phosphate dehydrogenase deficiency is present INTERMEDIATE 7.9% 9 2.1% in donated blood at the regional blood transfusion center, DEFICIENT 10.8% 89.2% Mombasa. ABO type “A” individuals seem to have a marginally higher probability of having G6PD deficiency in ABNORMAL 9.1% 9 0.9% comparison to the “AB” blood type. The percentage Analysis of variance (ANOVA) showed that at least one of occurrence of G6PD is higher than has been previously the G6PD groups had a different Haemoglobin estimated. There is therefore need to determine the concentration than the others with a calculated F-value of presence of this condition in donors for documentation and 0.0426 (CI 95%) this was not however reflected in the reference, and in neonates when jaundice of unknown pairwise comparisons. origin is encountered. The effect of G6PD deficient blood to the recipients is still a grey area that should be investigated Discussion further. There was a marginal statistically significant relationship between haemoglobin concentration of The current study shows a point prevalence of 9.6% for normal and G6PD deficient donors. This study was not homozygous G6PD and 13.2% showing heterozygosity. A however able to conclusively determine the relationship point prevalence of 22.8% for all forms of G6PD was found between G6PD and haemoglobin concentration. Further amongst the donors’ assayed (figure 1). Studies worldwide studies are needed to establish the relationship. have shown that the G6PD deficiency offers either partial or full resistance to P. falciparum infection and has therefore Conflicts of Interest been found in polymorphic proportions in malaria endemic areas [15]. These studies show that the condition is The authors declare no conflict of Interest. predominant in Asia and sub-Saharan Africa [4]. A study in

135 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 Acknowledgements genotype-phenotype association. Blood Rev. Elsevier; 2007;21(5):267–83. Special thanks to The Technical University of Mombasa for providing an enabling environment space and funding 10. Beutler E. Glucose-6-phosphate dehydrogenase support for the project. deficiency: a historical perspective. Blood. Am Soc Hematology; 2008;111(1):16–24. We are grateful to The Kenya National Blood Transfusion Service director and The Regional blood transfusion center 11. Slusher TM, Zamora TG, Appiah D, Stanke JU, Strand – Mombasa staffers who enabled us to collect samples MA, Lee BW, et al. Burden of severe neonatal jaundice: a during their blood campaigns. systematic review and meta-analysis. BMJ Paediatr Open. BMJ Specialist Journals; 2017;1(1):e000105. References 12. Grace RF, Zanella A, Neufeld EJ, Morton DH, Eber S, Yaish H, et al. Erythrocyte pyruvate kinase deficiency: 1. Hoffbrand VA, Catovsky D, Tuddenham EGD, Green AR, 2015 status report. Am J Hematol. Wiley Online Library; editors. Post Graduate Haematology. 6th ed. oxford: 2015;90(9):825–30. Wiley-Blackwell Scientific; 2011. 13. Machado P, Manco L, Gomes C, Mendes C, Fernandes N, 2. Suchdev PS, Ruth LJ, Earley M, Macharia A, Williams TN. Salomé G, et al. Pyruvate kinase deficiency in The burden and consequences of inherited blood sub-Saharan Africa: identification of a highly frequent disorders among young children in western Kenya. missense mutation (G829A; Glu277Lys) and association Matern Child Nutr. 2014;10(1):135–44. with malaria. 2012; 3. Magnani M, Rossi L, Bianchi M, Serafini G, Stocchi V. 14. Keszler A, Piknova B, Schechter AN, Hogg N. The Role of hexokinase in the regulation of erythrocyte Reaction between Nitrite and Oxyhemoglobin: A hexose monophosphate pathway under oxidative Mechanistic Study. J Biol Chem [Internet]. American stress. Biochem Biophys Res Commun. Elsevier; Society for Biochemistry and Molecular Biology; 2008 1988;155(1):423–8. Apr 11;283(15):9615–22. Available from: http://www. 4. Howes RE, Battle KE, Satyagraha AW, Baird JK, Hay SI. ncbi.nlm.nih.gov/pmc/articles/PMC2442280/ G6PD Deficiency. Global Distribution, Genetic Variants 15. Howes RE, Dewi M, Hogg MM, Battle KE, Padilla CD, and Primaquine Therapy [Internet]. Advances in Baird JK, et al. G6PD deficiency prevalence and Parasitology. Elsevier; 2013. 135-201 p. Available from: estimates of affected populations in malaria endemic http://dx.doi.org/10.1016/B978-0-12-407826-0.00004-7 countries: a geostatistical model-based map. PLoS 5. Circu ML, Aw TY. Reactive oxygen species, cellular redox Med. Public Library of Science; 2012;9(11):e1001339. systems, and apoptosis. Free Radic Biol Med. Elsevier; 16. Akanni EO, Oseni A, Agbona VO, Tijani BA, Tosan E, 2010;48(6):749–62. Fakunle EE, et al. Glucose6phosphate dehydrogenase 6. Al-nood HA, Bazara FA, Al-absi R. Glucose-6-Phosphate deficiency in blood donors and jaundiced neonates in Dehydrogenase Deficiency among Male Blood Donors Osogbo, Nigeria. J Med Lab Diagnosis. 2010;1(1):14. in Sana’a City, Yemen. Oman Med J. 2012;27(1):46–9. 17. Nguetse CN, Meyer CG, Adegnika AA, Agbenyega T, 7. Sansone G, Segni G. New aspects of the biochemical Ogutu BR, Kremsner PG, et al. Glucose-6-phosphate alterations in the erythrocytes of patients with favism; dehydrogenase deficiency and reduced haemoglobin almost complete absence of glucose-6-phosphate levels in African children with severe malaria. Malar J. dehydrogenase. Boll Soc Ital Biol Sper. 1958;34(7):327– 2016;15(1). 9. 18. Chettimada S, Gupte R, Rawat D, Gebb SA, McMurtry IF, 8. Youngster I, Arcavi L, Schechmaster R, Akayzen Y, Gupte SA. Hypoxia-induced glucose-6-phosphate Popliski H, Shimonov J, et al. Medications and glucose- dehydrogenase overexpression and-activation in 6-phosphate dehydrogenase deficiency. Drug Saf. pulmonary artery smooth muscle cells: implication in Springer; 2010;33(9):713–26. pulmonary hypertension. Am J Physiol Cell Mol Physiol. 9. Mason PJ, Bautista JM, Gilsanz F. G6PD deficiency: the American Physiological Society Bethesda, MD; 2014;308(3):L287–300.

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 136 Provider perspectives on the Strengths and Weaknesses of the Devolved Health Care in a Rural County in Kenya

1* 2 Kodhiambo M.O. , Ogweno J.O.

1School of Pharmacy, Kenyatta University, P.O. Box 43844-00100, Nairobi, Kenya., Email: kodhi- [email protected]

2Pathologists Lancet Kenya Limited

*Corresponding Author

real, there are fears that the devolved governments are not Abstract capable of handling the daunting task of providing Background: Devolution of health services in Kenya was universal access to healthcare services in the country. intended to enhance access to health care services. It is not Initially, the resistance was seen in practising health care clear to what extent this has been achieved. providers, but empirical research has now documented similar sentiments even from trainee health care workers in Objective: To establish the perspectives of health care our local Universities [1]. Because of devolution, they have managers on the impact of devolution on health systems lost interest in working in the public health sector in the within Homa Bay County. country and look forward to working in the private sector upon graduating. The public health managers in the county Methodology: We performed a health facility based governments have in the recent past complained about the qualitative study, adopting a phenomenological approach. work environment, transition challenges, restricted decision The study population comprised all health care managers space, resource constrains and uncertainty among other in eight public health facilities in Homa Bay County. The challenges in rolling out devolution of health care services study used quota sampling involving different cadres of [2]. They also complained of poor work conditions like health care providers. Seven informants were interviewed inadequate housing, water supply, electricity supply, and in each sub-county leading to a total of 56 informants. Data educational facilities [3]. From a study in Pakistan, the was collected by use of structured interview guides and typical bottle necks for progress of devolution include lack analyzed by a thematic approach. of a clear devolution policy, poor coordination among Results: Progress of devolution was reported to be different sectors of the economy, improper handover experiencing several challenges. The factors that were cited processes, poor selection process of local health as bottlenecks to achieving full benefits of devolution were management committees, lack of coherence in the process poor medical supplies, poor human resource recruitment of capacity building in local organizations, and different and retention practices, remuneration uncertainties, positions on political ideologies on decentralization [4]. A corruption, nepotism and political interference. The main similar study in Kilifi County, Kenya, also found out that the positive outcome of devolution was cited as enhanced process of implementation of devolution presented community participation in health care issues. Opinion was opportunities for local level prioritization and community divided as to whether devolution of health care should stay involvement in health planning. However, these or be reversed. opportunities were not adequately harnessed due to poor preparation and lack of capacity building by the devolved Conclusions: From the foregoing, it is evident that units prior to the implementation [5]. Implementation devolution of health care is yet to be embraced fully by problems are also cited as impediment to devolution from health care managers. Further studies to enhance evidence a study in Tanzania [6]. In this study, they decried informed decision making is necessary. sub-optimal multisectoral collaboration, low community Keywords: Devolution, health care, provider perspectives, participation and inappropriate and weak information Homa-Bay County. systems as some of the specific impeding factors. On the other hand, the main gain aimed at when devolving health care services in different countries is to improve access to Introduction and public participation in health and health care decision Since the year 2013 when the health docket was devolved making at the grassroot level. It is therefore probably in Kenya, resistance to devolution of health care services by proper to postulate that as much as the health care health care providers has been a consistent theme in providers may be complaining, the citizens may be very discussions with stakeholders in the sector. Perceived or optimistic about devolution despite the challenges

137 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 experienced so far. This is evident from the findings of a respondents. study on the impact of devolution on health planning and administration in Cote D’Ivoire [7, 8]. Some studies have Data collection procedure: Data was collected by shown that devolution has shown signs of likelihood of use of structured interview guides. The interview guides equity and edging towards universal health coverage in were pre-tested in Migori County and further refined as the Kenya and other Countries [9,10]. This is not only because it study progressed. removes transportation barriers to care [11], but also Data Analysis: Data was analyzed by a thematic because it improves ownership and public participation by approach. The key themes used in the analysis were citizens in their health care decisions thus leading to better financing, infrastructure, human resources, pharmaceutical quality and socially acceptable health decisions [12,13]. supplies, community participation, overall process of There are scholars who argue that benefits of devolution implementing devolution and whether it should be would accrue mostly to regions with full fiscal and political reverted to the national government or not. power and which were rich before devolution [14]. If this is true, then Homa-Bay County, which has been one of the Ethical Considerations: Research authorisation was poorest in the country, may take long before experiencing obtained from the Kenyatta National Hospital/University of the benefits of devolution. People in such far-flung areas, Nairobi-Ethics and Research Committee (Ref- emerging from previously centralized and nearly P389/05/2016). Voluntary informed consent of the authoritarian health decision making culture, are likely to participants was also obtained before recruitment into the be ignorant of the benefits of devolution [15,16]. Targeted study. Participants were informed about the study purpose, health and civic education may therefore help them realize procedures, benefits, risks and their rights as participants. the full utility of devolution of health care services The participants were free to leave study at any time especially with respect to making use of the new decision without any consequences to them. They were however not space through community participation. For meaningful compensated or paid to participate in the study. Confiden- benefit of devolution to be realised, the interests of the user tiality was ensured by use of codes to represent participants communities, political elites and health care providers must instead of their names. Data was kept safely in a computer be taken care of [17]. The objective of the study was to under a password available to the principle investigator establish the perspectives of health care managers on the only. impact of devolution on health systems within Homa Bay County. Results The baseline socio-demographic characteristics of the Methods respondents were as summarized in the table 1 below. Study design: The study was conducted as a health Table 1. Socio-Demographic Characteristics of facility based qualitative study, adopting a phenomenologi- Respondents cal approach. The reason for using qualitative research approach in this study was to illicit in-depth views of health Characteristic Attribute Number Percentage care managers on the impact of devolving health care Gender Male services in Homa Bay County Female Age Below 30 years Study Population: The study population comprised all 31 to 50 years health care managers in public health facilities in Homa Bay Above 30 years County. The County has one referral hospital in Homa Bay Designation Medical Officer I/C 8 16.7 town and seven sub County hospitals. In each of these Pharmacist I/C 8 16.7 facilities, there is a Sub-County Medical officer of Health, Nursing Officer I/C 8 16.7 Medical Officer in Charge, Pharmacist in Charge, Nursing Lab Tech I/C 8 16.7 Matron 8 16.7 officer in charge, Health administrator, a public health Hospital Admin 8 16.7 officer in charge and the head of the medical laboratory Highest Level of Post-Graduate 13 27 department. These form the health management team and education Degree 26 54 were therefore purposively selected as the key informants Tertiary 9 19 for the study. Number of years in Below 5 7 15 service 5-20 22 46 Sampling Procedure and sample size. The study used Above 20 19 39 purposive sampling to settle on the health managers to interview as key informants. A total of 56 key informants The interviews revolved around one stem question with were interviewed from the eight sub-Counties, with each sub-questions. The stem question was, ‘In your opinion, sub-County having seven informants. Saturation of data how has devolution of health care services impacted on the was anticipated after 12 to 15 interviews [18, 19]. following issues in Homa-Bay County? Theoretical saturation of data was experienced after 25 1. Pharmaceutical supplies including procurement interviews, but we continued with the interview for procedures and policies completion purposes until we interviewed all the 48 On the pharmaceutical commodities supplies procedures

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 138 and policies, most of the respondents gave reasons why Most of the informants reported that devolution had devolution has made matters worse as follows; worsened health care financing in the County. Despite most of them agreeing that donor funding has been the pillar of On professionalism being applied especially in tendering funding for most programs, they also stated that County for the medical supplies, most of the respondents faulted governments were responsible for making the funding to the County government. For example, a pharmacist in one stagnate. The words of the respondent quoted below paints of the referral hospitals had this to say. a picture of despair and desperation on matters of funding ‘Things are not being done professionally. Today, drugs are of health programs in the County after the onset of procured even without the knowledge of the pharmacist in devolution; charge. There are more stock outs. Suppliers are chosen ‘Generally, funding is poor for all departments in health. You based on cronyism. It is not structured. There are many can plan as a team, yet disbursement is not there. When it unethical practices. Because of corruption, technical staff is comes, it comes too little too late. The situation is not involved, and drugs don’t reach health facilities’- worsening. The county is not releasing money to facilities. Informant Number 1, Hospital Number 1. All the funds end at the County. Quarterly remissions are no Political interference from the county government and longer there. Since devolution started, I don’t know county assembly was cited as the main reason for the lack whether County government has scared donors. They no of professionalism in the procurement procedures. They longer pump a lot of money especially on health programs. were viewed as non-professional outsiders of the medical We rely 75 % on facility improvement fund, not county professions but who wield greater power delegated to government’- Informant Number 1, Hospital Number 2. them by the people compared to the health care providers. It also became apparent that most free maternity money is ‘Things have become worse because the challenge is that often diverted to other health care issues when the County people at the top are not professionals. Tenders are given to government does not allocate or release enough money for those are friends or relatives. Some top management health care services. For example, a respondent in one of people have never worked on the ground. They are also the sub-county hospitals said; hired politically’ Informant Number 4, Hospital Number 8. ‘Particularly, what we receive regularly is free maternity Another issue that came up prominently was lack of prompt money. The rest is erratic and hence unreliable. The county payment of the Kenya Medical Supplies Authority (KEMSA) government also slashes even the free maternity money. It thus delaying supply of medicines and other supplies. This is true that the donors are funding the trainings of health was seen to derail the restocking of medicines hence care workers on malaria case management. However, the denting the confidence of health are users on the health county government does not allocate funds for malaria. We systems of the county. survive on our collections and free maternity money’ ‘OK. What I can say, mmh...... , when we were receiving drugs Informant Number 3, Hospital Number 7. from the national government, KEMSA used to supply In the Contrary, an informant stated that financing of health antimalarials regularly. Now, we don’t get even the programs improved with devolution. They however antimalarials from KEMSA. Commodities are now difficult to acknowledged that the improvement could be attributed procure. KEMSA doesn’t supply because of late payment. mainly to the efforts of the development partners and not We understand that since last year, KEMSA has never been often the County government per se. paid. We therefore have problems with pharmaceutical and other supplies. Pharmaceutical supplies have become ‘Financing is better under devolution. Like recently we had inconsistent. Like now, the last time we got drugs was a malaria prevention campaign funded by a donor March. Again, quantities are also small. It appears KEMSA organization. So far, the funding is good. PSI supplies us people are not sure about transition of counties.’- Informant with nets consistently. We have partners supporting malaria Number 3, Hospital Number 6. programs. The county government and NGOs support malaria programs especially in pregnancy and under-fives’ On the other hand, a respondent thought that devolution Informant Number 2 Hospital Number 6. has helped to improve procurement procedures as captured in the statement below. 3. Cost of health care borne by the patient ‘Mmh....it’s OK because the counties do their orders from On whether patients now pay less or more for services after KEMSA directly. We haven’t had so many negative issues. We devolution of health care services, majority of the are not experiencing any problem with procurement. They informants felt there was no major difference before and have been supplying us well. We are supplied quarterly. after devolution. Earlier, we had push and pull system. Today, what you order ‘Generally speaking, there is no change in cost borne by the is what you are given’- Informant Number 2, Hospital patients. We still charge the same prices for services and Number 3. drugs and cost sharing is still the same. Waiver forms are 2. Health care financing including donor funding and also available. But now, the problem is that they must buy budgetary allocation almost everything else apart from laboratory diagnosis and medicines’

139 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 Respondent Number 3, Hospital Number 8. elevated thus forcing the county government to provide infrastructure to match the new status’ Informant Number Others believed that since the advent of devolution, 2, Hospital Number 5. patients pay less compared to before devolution. ‘There is a lot of improvement. Maternity is being built. The ‘Patients bear less costs. The county government is very equipment are ready waiting but am not sure whether the close to the people. They know malaria is a major problem equipment came from the county government or from the here. It is almost free. They may pay only 20 shillings for national government. The building am sure is being registration. It is like now the common citizens have a say constructed by the county government’ Informant Number on their health. Since devolution, in this facility, staffing has 1, Hospital Number 3. improved, services are of better quality and patients wait less’ Respondent Number 2, Hospital Number 4. Others also attributed improvement in infrastructure to support from partners rather than the county The role of NHIF was hailed as very important in helping government. the patients to bear less cost. ‘There are no labs and no RDTs especially in the ‘I don’t know but because nowadays we have NHIF cover dispensaries. The county government has not done a lot of for patients and most people use them, those who have improvement. All equipment here are supplied by partners them pay less but those who don’t pay much more. I don’t like UNICEF and MSF’ Informant Number 1, Hospital think devolution has helped a lot like the NHIF cover. Since Number 4. devolution, uptake of NHIF by the patients has increased and release of money by the fund has also improved. You 5. Community involvement in health matters can see even now I am working on some payments which On whether the community is now more involved in health are due’ Respondent Number 1, Hospital Number 1. decisions after devolution compared to before, the 4. Healthcare infrastructure and equipment respondents largely agreed that devolution has made it easier for the community to participate in their health Majority of the informants felt that the County government matters. This was mainly attributed to the community had done nothing or too little to improve healthcare strategy which revived the role of community health infrastructure and equipment in the county. workers(CHWs). ‘The county government is totally not helpful. We do not ‘Good. They have upgraded and employed new community have a lot of equipment we need. We have forwarded health workers and community health officers. They have requisitions to county government to buy or repair. Before also created awareness and demand for healthcare services. devolution, there was money for such repairs and Community strategy is working. Community health maintenance. Totally its poor today. For example, there is a volunteers a lot of rapid diagnostic tests but this is building where the national government was to provide sponsored mainly by the donor partners. Devolution has three quarters (¾) of the cost and the county government a led to recruitment of more community health workers on quarter (¼). It is not complete to date and there are no the ground. Community dialogue is good, but the impact is equipment’ Informant Number 4, Hospital Number 4. not yet very good because the girl child education is still Some informants stated that the situation of poor. However, in general, it is better because we have infrastructure has improved with devolution community strategy where the community health workers have direct involvement with the community. They give ‘Devolution has brought a lot of development in so far as essential drugs and gather health data from the community’ infrastructure is concerned. In our facility for example, we Informant Number 2, Hospital Number 5. have a new renal unit, theatre, ultrasound, x-ray and oxygen plant. All these I can associate with devolution as much as it Other respondents also attributed the improvement to the is the national government that provided most of them. We role of local politics through the members of county now have modern first-class machines. They are just like assembly (MCAs). This is most likely because they are now what you would find in Aga-Khan or Nairobi Hospital. This more recognized by law, better remunerated and bear a was not possible before devolution’ Informant Number 2, greater expectation of accountability to the people. Their Hospital Number 1. sentiments were generally captured by the following respondent. Maternity was cited as the greatest focus of health infrastructure development in the county since the advent ‘It is better. They think they own the county government. In of devolution. This may be because of the financial support case of anything, they know whom to complain to because from the national government since the inception of the the government is now closer to the people. There is a local National free maternity program. person who is the chairman of the hospital. They are involved. If they are not satisfied, they give him feedback. ‘Maternity wing has been constructed and this now has MCAs are also involved as they get feedback from the created demand for maternity services unlike before people’ Informant Number 4, Hospital Number 6. devolution when this facility was a health center. The good thing is that with devolution, many facilities have been One respondent, however, felt that devolution has indeed

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 140 worsened community involvement in health matters. She Lack of adequate staffing; said that; ‘Generally, how can we gauge this. Well, compared to ‘There are a lot of problems. Even ward administrators national government, the county government has not done should oversee the process of involving the community, well as was expected. We don’t have professionals. They but they don’t know their role and they have no resources bring equipment, but buildings are not complete. X-rays for that. The community is involved minimally since and computers are not repaired. Sometimes we go manual devolution started’ Informant Number 2, Hospital Number and no one addresses the Devolution is failing. Informant 7. Number 2, Hospital Number 6. 6. Recruitment and retention of health workforce Incompetent management and political interference; Majority of the informants felt that staff welfare became ‘Eih!...... for me as an individual who worked in the national worse with devolution. They had varied reasons as captured government, I would prefer the national government. The below; quality of care has gone down. Everything has become political. With the counties, they have brought health closer Corruption and nepotism; to the community. But, a lot still needs to be done. They ‘Recruitment is not being done professionally. People don’t employ enough clinicians. Nepotism is rampant, and employ who they know. Retention is not good. No accountability is little. Today, many pharmacists and pharm promotions and payment of salaries delays. For example, techs are leaving public service because of late and poor today is 15th and Doctors haven’t received their salary for payment and bad work environment. All this is due to last month. People rarely get leave. Study leave applications political interference’ Informant Number 4, Hospital are not processed. There are no structures here’ Informant Number 5. Number 1, Hospital Number 8. Inadequate funding; Late payment of monthly salaries; ‘The only thing they are doing is employment, but drugs ‘There are no enough laboratory personnel. It has not and money are not there. Here is a small place so improved. The county is not employing people. Motivation collections are not enough. In a year, they may give us is not very good. There is a lot of movement to the private money once and it may not be enough. There is a time I sector. Even today, we have not been paid last month’s was talking to a nurse and she said there are delays in salary, yet it is already mid-month’ Informant Number 2, disbursement of free delivery funds. The free delivery is Hospital Number 6. therefore not really free since they have to buy a lot of things. The county government should improve on the Employment is not based on need on the ground. process of approving finances’ Informant Number 2, ‘What I can say is, what the county is doing is not recruiting Hospital Number 4. clinical staff. People we are getting from the county are Those who thought devolution had improved the quality of support staff. For example, all in patient nurses are health care services in Homa-Bay county supported their employed by MSF. Promotion has become an issue. Maybe feelings with the following points; they fear spending’ Informant Number 2, Hospital Number 4. Community strategy improving employment of community health workers; A few respondents felt that recruitment and retention of health workforce had improved with devolution. However, ‘There is an improvement. The improvement is seen at the all of them had some aspect of dissatisfaction appended to preventive and promotive level. Those in community their approval. malaria management strategy give RDTs and if they don’t have they refer. Health care has generally improved except ‘We have received a good number of officers but not for delays’ Informant Number 1, Hospital Number 5. optimum. They have better retention strategies except for delays in salaries which makes people anxious. What I can Better staffing; say, if you compare with the number which was there ‘It has improved because new health care providers have before, there is improvement. We are receiving staff. We been employed. There are so many health care providers only don’t know the criteria for their appointment. Even who have been employed since devolution came in’ partners are recruiting for the County’ Informant Number 3, Informant Number 4, Hospital Number 3. Hospital Number 3. Proximity of health services to the people; 7. The general quality of health care services in the County ‘It is in a way better because in the past, Nairobi was far. Today, all clients have direct access to the county Most of the informants felt that devolution had a negative government in one way or another. In case of any problem, impact on the quality of health care services in the county. they intervene fast’ Informant Number 3, Hospital Number They gave the following as some of the reasons for the 2. deterioration.

141 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 8. Should health docket remain devolved or returned to propagate their own political agenda. This is because they the national government know that almost all citizens hold health care very dearly. This is a reality that needs to be internalized by county On this matter, most of the respondents strongly felt that health care managers and service providers if they are to health care should be reverted to the national government. survive in the murky waters of health care and politics [21]. One of them expressed her opinion as captured below; Funding of health programs by development partners ‘The interest of health care providers is that health care seems to have slowed down after devolution. Another should go back to the national government. I think the problem cited by most informants was that money meant political leadership should consider this. We don’t have for free maternity care was often diverted to other uses in much to do in the County government. Devolution of times of scarcity. These findings show that health policies health care was more of an error. We don’t see these current need to work in support of each other and not eat into the problems being solved soon. County governments don’t gains of one another. For example, if the proponents of free even want to employ doctors. Even if you come, they keep maternity services could have foreseen a situation where you away. I think for me one thing is seconding staff to the funds meant for free maternity services could be counties was done in a hurry and it’s inappropriate. The diverted to other medical services, they could have government should find a way of financing facilities directly advocated for better funding for all other essential health without money going to the county treasury’ Informant care services and not only the maternal health component. Number 1, Hospital Number 8. Health infrastructure development was reported to be lagging and the main reason given for this trend was that There are a few informants who felt that devolution is a health budget was often redirected to other sectors. good idea and only needs to be reinforced. The had Recruitment and retention of health workforce was also following is a typical example of their views. said to be poor. The respondents stated that the County ‘What I think is, devolution was a good idea poorly government employed so many support staff and few implemented especially on health. It is not performing as clinical service providers thus ballooning the wage bill with expected. However, going back to national government will no significant improvement in direct health service not help. I think they should just work on the weak areas delivery. The main positive impact of devolution seems to and strengthen it’ Informant Number 3, Hospital Number 1. be community involvement in health care decisions. Most informants mentioned that since the implementation of Discussion devolution, most citizens got more interested in health care governance since they gained a sense of ownership. The The feelings of health care managers concerning the County government also deliberately strengthened the impact of devolution on health systems were mixed. community strategy policy to increase public participation However, majority of the informants seemed to agree that in health policy debates. These finding contrast those of a there are so many challenges that if left unchecked, could study in Tanzania which observed that despite national reverse the little gains achieved so far by devolution. Such rhetoric on decentralization, the actual practice in the field challenges were cited as nepotism and cronyism, lack of had little community involvement [22]. This poor proper recruitment procedures, political interference in the participation was attributed to lack of awareness, poor professional work of health care providers, waste of communication and information sharing unclear definition resources, late payment of salaries and poor supply chain of roles and responsibilities, lack of management capacity management among others. Devolving healthcare was and lack of financial resources [23]. Opinion on whether intended at taking services closer to the people. They health docket should be returned to the national would then have more say on the quality and access to government was divided as some thought this was healthcare services offered to them [7]. To date, this overdue, yet others felt that devolution was actually a good objective seems not to have been adequately realized since idea poorly and hurriedly implemented and if the mistakes challenges such as inadequate medical supplies, and low of implementation are corrected, there would be no need staff morale persist even after devolution much like they for reverting health care to the National government. As it were before [3]. These challenges were attributed to has been observed in other developing countries, the corruption, nepotism, poor financial management and progress of devolution of heath care is often slow but with political interference by the members of County assembly desirable outcomes in the long run [24]. A little patience on the work of clinicians. These results concur with those of and persistence would therefore be necessary to push our a study in Kilifi County that found that management of health devolution agenda to fruition. health care services in the era of devolution was marred with lack of job clarity and preparedness, unclear accountability and responsibility structures coupled with Conclusions shortages in key resources and remuneration inconsisten- From the findings of this study, it is evident that devolution cies. [2]. Similar findings were also reported from a study in of health care is yet to be embraced fully by health care Pakistan [20]. However, healthcare, by its very nature, is managers. There seems, however, to be goodwill since most highly political. Many politicians are interested in the of the managers seemed positive that devolution can work politics of health care which they use as a platform to if the bottlenecks are addressed. Health managers need to

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Presentation of Manuscripts a) Manuscript length: Not more than12 pages b) Authors: Lead author’s name first, surname followed by 2 initials e.g. Njuguna, A. K. c) Authors’ affiliation (e.g. Institution), complete postal and email addresses. d) Abstract: Not exceeding 300 words excluding the title and the key words. No abbreviations. Abstract not required for short communications or letters to the Editor. Presentation of Abstract to be similar to the format for content below (sub-titles ii – vi). The abstract must be concise, clear and informative. e) Declaration of Conflict of Interest (if applicable) f) Key words: 3-6 key words to be listed.

145 Vol. 23, No 4/ Pharmaceutical Journal of Kenya / 2018 g) Declaration of sources of funding, technical or any other support related to the research/manuscript.

Format for Content i. Abstract ii. Introduction iii. Aims/Objective/Hypotheses iv. Methodology v. Results vi. Discussion/Conclusion and Recommendations vii. References References – Vancouver Style References are to be cited using Vancouver style. Citations must appear in order of appearance in the text with square brackets after the end of a sentence, i.e., [3]. The citation must electronically refer to the Reference Listing at the end of the manuscript. References cited only in tables or in legends to figures should be numbered in accordance with a sequence established by the first identification in the text of the particular table or illustration. Figures must be labelled at the bottom, whilst tables shall be labelled at the top. The number of references should normally be restricted to a maximum of 25 for a full paper, whereby not more than 20% should be not more than 5 years old, and no more than 10% should be more than 10 years old. References older than 10 years should ideally be classical subject material references. Papers which have been submitted and accepted, but not yet published may be included in the list of references with the name of the journal and indicated as “In press”. Use of abstracts as references should be avoided. The “unpublished observations” and “personal communications” may not be used as references but may be inserted (in parentheses) in the text.

RIGHT TO REJECT MANUSCRIPT The editors reserve the right to reject a manuscript for publication if it does not meet the requirements of the Pharmaceutical Journal of Kenya. Manuscripts should be submitted to: The Editor-in-Chief, Pharmaceutical Journal of Kenya, P.O. Box 44290 – 00100 GPO, NAIROBI, KENYA. Email: [email protected]

Vol. 23, No 4 / Pharmaceutical Journal of Kenya / 2018 146 PHARMACEUTICAL SOCIETY OF KENYA

Become A Member

In order to become a member with the Pharmaceutical Society of Kenya (PSK), you must provide your registration number. This information will be verified by the Secretariat before any member has access to their account.

Qualification Member PSK (MPSK)

A graduate pharmacist registered by the Pharmacy and Poisons Board (PPB)

Fellow PSK (FPSK)

A full member who has rendered distinguished service to the society or in the field of pharmacy or who has made outstanding original contribution to the advancement of pharmaceutical knowledge or who has attained exceptional proficiency in a subject embraced by or related to the practice of pharmacy

PSK is a closed society. Membership is by annual subscription. Paid up members’ benefits include:

• Elect representation to elective and nominated positions • Stand for elective and nominated positions • Access to Professional networks both locally and internationally • Publish on the Pharmaceutical Journal of Kenya (PJK) • Access to members empowerment programmes

Contact us Hurlingham, Jabavu Road PCEA Foundation, Block C, Rm 22, Tel:0722 817 264 P.O. Box 44290-00100 GPO Email:[email protected] Nairobi, Kenya 106 Vol. 23, No 3/ PharmaceuticalWeb: www.psk.or.ke Journal of Kenya / 2018