A Study on Drug-Drug Interaction Between Voriconazole and Oral Antidiabetic Agents
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A STUDY ON DRUG-DRUG INTERACTION BETWEEN VORICONAZOLE AND ORAL ANTIDIABETIC AGENTS
M.Pharm Dissertation Protocol Submitted to the RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
By B.HEMANTH KUMAR B. Pharm.
Under the Guidance Of Mr. BHEEMACHARI Assistant Professor, Department of Pharmacology, N.E.T Pharmacy College, Raichur.
DEPARTMENT OF PHARMACOLOGY N.E.T. PHARMACY COLLEGE, RAICHUR – 584103 2008-2009 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION B.Hemanth kumar H.no4-4-100/88A, Name of the candidate Balaji nilayam, 1. And Address: Yerigeralayout, Raichur, Karnataka.
N.E.T.Pharmacy College, 2. Name of the Institution: Raichur- 584103
3. Course of study and Subject: Master of Pharmacy in Pharmacology
4. Date of admission to the Course: 3rd may 2008
5. Title of the topic: A STUDY ON DRUG-DRUG INTERACTION BETWEEN VORICONAZOLE AND ORAL ANTIDIABETIC AGENTS 6 Brief resume of the intended work: 6.1: Need for the study: ENCLOSURE -I 6.2:Review of the literature: ENCLOSURE -II 6.3:Main objective of the study: ENCLOSURE –III 7 Material and methods: 7.1: Source of the data: ENCLOSURE -IV 7.2: Methods of the collection of the data: ENCLOSURE - V 7.3: Does the study require any investigations or interventions to be conducted on patients other human or animals ? If so, please describe briefly. YES (rats and rabbits) 7.4: Has ethical clearance been obtained from your institute in case of 7.3 ? YES: IAEC NO. : 576/2002/bc/IAEC/CPCSEA 8 List of References: ENCLOSURE-VI
9. Signature of the candidate: (B.HEMANTH KUMAR) 10. Remarks of the guide: The work proposed in this synopsis can be carried out in our institute . 11. Name and designation of 11.1 Guide: Mr. BHEEMACHARI Assistant Professor, Department of Pharmacology, N.E.T Pharmacy College, Raichur.
11.2 Signature
11.3 Co-guide (if any): ------
11.4 Signature ------
11.5 Head of the department: MR.BHEEMACHARI Assistant Professor & HOD Department of Pharmacology, N.E.T. Pharmacy College, Raichur.
11.6 Signature
12. 12.1 Remarks of the Chairman Dr. H. DODDAYYA and Principal PRINCIPAL, N.E.T PHARMACY COLLEGE, RAICHUR-584103.
12.2 Signature ENCLOSURE –I
6. BRIEF RESUME OF THE INTENDED WORK: 6.1: Need for the study: To treat the co-existing diseases in diabetic subjects polypharmacy is mandatory. However there are plenty of reports about the occurrence of drug-drug interactions when multiple drugs are used in a single patient. Further the incidence of these interactions in certain cases is even to the extent of death. According to the reports the drug interaction is fourth to sixth leading cause of death in hospitalized patients in
U.S.1
This alarming statistics emphasizes the importance of evaluation of multidrug prescriptions for such avoidable cause of hazard. Considering all the above, an attempt has been proposed to study the interaction between voriconazole an antifungal agent with glibenclamide (sulfonylurea) and pioglitazone (thiazolidinedione) an oral antidiabetic drugs.
Diabetes Mellitus (Type-II) is a metabolic disorder characterized by deranged carbohydrate, protein and lipid metabolism.2 As per the World Health Organization
(WHO) survey there were 171million diabetics in the year 2000 and this number is estimated to increase to 366 million by the year 2030. However as far as India is concerned, these statistics are highly disappointing and are in the year 2000 there were
31.7 million diabetics and the number of diabetics by the year 2030 has been estimated to be 79.4 millions.3 Disappointingly India has been occupied the first position in the world diabetic ranking since 2000, hence, called as diabetic capital of the world.
Diabetics suffer from a number of co-morbidities such as diabetic retinopathy, nephropathy, ketoacidosis, diabetic foot ulcers etc.4 At the same time diabetics being immunocompromised are highly susceptible to a number of common yet serious infections including fungal complications.5 Under such conditions inevitably poly pharmacy has to be followed using effective antifungal agents along with routine oral antidiabetic agent. When two or more drugs are used concomitantly, there is every possibility of drug-drug interaction among the coadministered drugs leading to alteration of the pharmacokinetics or the pharmacodynamic pattern of one or both of the administered drugs.
Voriconazole is an triazole new generation antifungal agent used widely for the treatment of a number of fungal infections in the clinical practice. However, most of the azole antifungal agents have been reported to interact with a number of concomitantly used drugs like imipramine and desipramine6, terfenadine7, triazolam8, efavirenz9 etc.
Nevertheless the interaction between voriconazole and oral antidiabetic agents like glibenclamide and pioglitazone has not yet been properly studied and reported. Hence, in the present protocol an effort has been proposed to study and establish the possible interaction between afore mentioned drugs.
ENCLOSURE –II 6.2: Review of Literature Literature survey revealed that, the incidence of diabetes mellitus particularly
Type II is increasing disappointingly.3 Further the diabetics suffer from varieties of
infectious diseases including mycoses. The documented reports quote that the
frequency of fungal infections. 11, 12, 13 like mucormycosis. 14,15 candidiasis.16,17 etc, are
quite common among diabetic subjects.
The candidate voriconazole has reported to interact with a number of co-
administered drugs and alters their pharmacokinetic pattern. 9,10 However, there are no reports about the possible interaction between voriconazole and oral antidiabetic agents,
glibenclamide and pioglitazone.
ENCLOSURE -III 6.3 Main objective of study:
In clinical practice there may arise several situations, where a diabetic patient whose blood glucose level has been stabilized using either glibenclamide or pioglitazone need to be treated with voriconazole either for topical or systemic fungal infections.
However, the influence of voriconazole on antidiabetic activity of above mentioned drugs has not yet been properly studied and reported. Hence, in the present study the main objective is to understand the influence of voriconazole administration for specified period on the antidiabetic potency of glibenclamide and pioglitazone.
If at all, any influence is noticed, the study also proposes to suggest modification of either dose or frequency of administration of antidiabetic agent to avoid possible hazards based on animal model studies.
ENCLOSURE – IV
7. Materials and Methods:
7.1: Source of the data: The entire project is planned is planned to generate the data from the laboratory based work using experimental animal models as described in various
National/International journals and books available with our college and other reputed institutions of India and through e-publishing and Helinet consortia of RGUHS,
Bangalore.
ENCLOSURE – V
7.2: Methods of collection of the data (including sampling procedure if any): Inclusion and exclusion criteria:
There are several methods used in practice for estimating blood glucose levels. Few of them are mentioned below,
1. Nelson somogyi method.
2. End point O-Toludine method
3. GOD/POD (Glucose oxidase and peroxidase) method
The older methods were based on reducing property of glucose. But these methods do not measure glucose because of interferences. Subsequently other chemical and enzymatic methods were evolved to overcome this problem. The GOD/POD method18 is one which is simple, single step, rapid, reliable, safe and of acceptable precision . Hence in the present study it is planned to adopt this method. It utilizes two enzymes GOD and POD.
Method of collection of blood sample: The blood samples required to estimate the glucose concentration will be collected either from tail vein (or) retro orbital puncture method in rats. In case of rabbits, blood samples will be collected from marginal ear vein.
Method of collection of plasma: The plasma will be obtained by centrifuging the blood samples containing a suitable anticoagulant at 5000 rpm, for 10 minutes decanting supernatant fluid into clean and dry test tubes. Experimental Procedure:
Pipette into tubes marked Blank Standard Test
Plasma - - 10 µL Standard - 10 µL - Glucose reagent 1000 µL 1000 µL 1000 µL
Mix well, incubate at 37oC for 10 minutes. Measure the absorbance of standard
and sample against a reagent blank within 60 minutes on an autoanalyser at 505 nm.
Rats of either sex weighing between 150-200 gm will be randomly distributed
into different groups and the study will be conducted in different phases as mentioned
below.
PHASE-I:
In this phase rats of one group (n=6) will be treated with voriconazole (3.6 mg/kg,
p.o., twice a day) for seven consecutive days and its influence on the blood glucose levels
will be studied.
PHASE-II:
In this phase, two groups are used (n=6). The rats of one group will be
administered with pioglitazone (270 µg/kg, p.o) and the other group will be administered
with glibenclamide (180 µg/kg, p.o). Thereafter the blood samples will be withdrawn at
0, 0.5, 1, 2, 4, 6, 8, 12, 18 and 24 hours intervals and will be analyzed for blood glucose
concentration determination18. This phase provides the per se influence of pioglitazone
and glibenclamide on blood sugar level. PHASE-III:
In this phase, the same animals of phase-II study will be utilized. However, the animals of phase-II will be allowed for a period of one week to completely wash out the previously administered drugs from their body. Thereafter both the groups of animals will be administered with voriconazole (3.6 mg/kg, p.o., twice a day) for a period of one week. On 8th day one hour after voriconazole administration, one group will receive pioglitazone (270 µg/kg, p.o) and the other glibenclamide (180 µg/kg, p.o). Thereafter the blood samples are collected and analyzed for glucose concentration as mentioned in phase-II.
This phase is expected to produce data regarding occurrence of interaction (if any) among the contemporaneously administered drugs
PHASE-IV:
In this phase, the entire protocol of phase-II and phase-III will be repeated using alloxan/streptozotocin induced diabetic rats.
Induction of diabetes19, 20,21:
Rats fasted for 24 hours will be subjected to single intramuscular injection of streptozotocin (STZ) at the dose of 4-mg/0.1 ml of citrate buffer/100 gm body weight/rat.
Rats that exhibit blood glucose concentration more than 250mg/dl after 24hrs of STZ injection will be considered as diabetic and selected for the proposed study. The blood glucose concentration before and after respective treatment at above specified time intervals will be determined by GOD/POD method.
Hyperglycemia can also be induced by using alloxan in this method rats are fasted for 18 hours and then a single intraperitoneal injection of freshly prepared alloxan monohydrate in normal saline (150 mg/ kg body weight) in volume 1ml/ kg body weight is given. Hyperglycemia was confirmed by elevated glucose level in plasma determined at 48 hr after injection.
PHASE-V:
In this phase, albino rabbits of either sex, weighing between 1-1.5 kg will be divided into several groups. The entire protocol ranging from phase-I to phase-III will be repeated to understand the influence of voriconazole (14 mg/kg, p.o., twice a day) on antidiabetic effect of pioglitazone (270 µg/kg, p.o) and glibenclamide (180 µg/kg, p.o).
STATISTICAL ANALYSIS
All values will be expressed as mean ± SEM from 6 animals in any group. Results will be subjected to statistical analysis using paired t test or one-way ANOVA (analysis of variance) followed by Dunnet‘t’ test. Depending on study design. p< 0.05 will be considered as statistically significant.
7.3: Does the study require any investigations or interventions to be conducted on patients other human or animals? If so, please describe briefly: Study requires investigation on albino rats and albino rabbits.
7.4: Has ethical clearance been obtained from your institute in case of 7.3: YES: IAEC NO.: 576/2002/bc/IAEC/CPCSEA
ENCLOSURE –VI
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