A STUDY ON DRUG-DRUG INTERACTION BETWEEN MODAFINIL AND ORAL ANTIDIABETIC AGENTS
M.Pharm Dissertation Protocol
Submitted to the
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
By
SIDHPURA VISHAL R
B. Pharm
Under the Guidance Of
Mr. BHEEMACHARI
Assistant Professor,
Department of Pharmacology,
N.E.TPharmacyCollege, Raichur.
DEPARTMENT OF PHARMACOLOGY
N.E.T.PHARMACYCOLLEGE,
RAICHUR – 584103
2008-2009
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
DISSERTATION
1. / Name of the candidateAnd Address:
/ SIDHPURA VISHAL R,963/1 Sector 4-d,
Gandhinagar-382006, Gujarat.
2. / Name of the Institution: / N.E.T.PharmacyCollege,
Raichur- 584103
3. / Course of study and Subject: / Master of Pharmacy in Pharmacology
4. / Date of admission to the Course: / 31st May 2008
5. / Title of the topic:
A STUDY ON DRUG-DRUG INTERACTION BETWEEN MODAFINIL 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: / (SIDHPURA VISHAL R)
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:
11.2Signature
11.3 Co-guide (if any):
11.4 Signature
11.5 Head of the department:
11.6Signature / Mr. BHEEMACHARI
Assistant Professor,
Department of Pharmacology,
N.E.TPharmacyCollege, Raichur.
---
---
MR.BHEEMACHARI
Assistant Professor & HOD
Department of Pharmacology,
N.E.T.PharmacyCollege, Raichur.
12. / 12.1 Remarks of the Chairman
and Principal
12.2 Signature / DR. H. DODDAYYA
PRINCIPAL,
N.E.TPHARMACYCOLLEGE,
RAICHUR-584103.
ENCLOSURE –I
6. BRIEF RESUME OF THE INTENDED WORK:
6.1: Need for the study:
Drugs beingreactive chemical species interact with the chemicals of both the biophase system as well as with other co-administered drugs. Indeed interaction with the chemicals of biophase system is highly desirableto get anticipated pharmacological response. However, their interaction with other co-administered drugs may be beneficial or harmful. Unfortunately in clinical practice several deaths have been reported due to harmful drug-drug interactions.1 Hence, in this regard it is very important to evaluate and understand the influence of any newly introduced drug in to the market on routinely used therapeutic agents, particularly those used for the management of Diabetes mellitus type II and hypertension. Since, even the minor alteration in their plasma concentration leads to lot of therapeutic complications.
Thedrug-drug interaction interferes with pharmacokinetics or pharmacodynamics of one or more drugs that are used concomitantly. In such cases it is needed to alter the dose and frequency of administration of one or all drugs that are to be administered simultaneously. Hence, it is essential to investigate for the possible drug-drug interaction between concomitantly used drugs.
Diabetes Mellitus is a metabolic disorder characterized by hyperglycemia, altered carbohydrate, protein and lipid metabolism.2-3According to World Health Organization (WHO) survey, in the world there were 171 million diabetics in the year 2000 and this figure is estimated to increase to 366 million by the year 2030. However as far as India is concerned, in the year 2000 there were 31.7 million diabetics and by the year 2030 it has been estimated to be 79.4 million.4 India has been occupying the first position in the world diabetic ranking since 2000, hence is also called as diabetic capital of the world.
Considering the seriousness of all the above, an attempt has been proposed to study and understand the possibility of drug-drug interaction between recently introduced central nervous system (CNS) stimulant drug Modafinil and oral antidiabetic agents glibenclamide (second generation sulfonylurea) and pioglitazone (thiazolidinedione).
ENCLOSURE –IIl
6.2: Review of Literature
Modafinil is new generation CNS stimulant. It is useful in the treatment of narcolepsy. Narcolepsy is a neurological sleep disorder characterized by overwhelming excessive day-time sleep (EDS), despite of adequate night time sleep.5Narcolepsy requires continuous medication throughout the life. According to one report narcoleptic patients suffer frequently from obesity and type II diabetes mellitus, substantiating our study objective.6 Additionally modafinil has also been reported to be useful in the treatment of cerebral ischemia and Parkinson’s disease.7 Further it is also reported that, type II diabetes mellitus may occur more frequently in people with narcolepsy.8 Hence study objective is to understand the possibility of drug-drug interaction between Modafinil and oral antidiabetic agents would be well justified.
ENCLOSURE -III
6.3 Main objective of study:
In clinical practice as there arises several situations, where a diabetic patient receiving either glibenclamide or pioglitazone need to be administered with modafinil, a CNS stimulant. However, the influence of modafinil 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 modafinil 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.
ENCLOSURE – IV
7. Materials and Methods:
7.1: Source of the data:
The entire project, is planned to generate data from laboratory based 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 consortium 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,
- Nelson somogyi method.
- End point O-Toludine method
- 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 method9 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 / TestPlasma
Standard
Glucose reagent / -
-
1000 µL / -
10 µL
1000 µL / 10 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 gms 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 modafinil (1.8 mg/kg/day, p.o) 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 glibenclamide (180µg/kg, p.o) and the other group will be administered with pioglitazone (270µg/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 determination.10This phase provides the per se influence of glibenclamide and pioglitazone 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 modafinil (1.8 mg/kg/day, p.o.)for a period of one week. On 8th day one hour after modafinil administration, one group will receive glibenclamide (180 µg/kg, p.o)and the other pioglitazone (270µg/kg, p.o). Thereafter the blood samples are collected and analyzed for glucose concentration as mentioned in phase-II.9
This phase is expected to produce data regarding occurrence of interaction (if any) among thecontemporaneous administereddrugs.
PHASE-IV:
In this phase, the entire protocol of phase-II and phase-III will be repeated using either streptozotocin or alloxan induced diabetic rats.
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 modafinil (7 mg/kg/day,p.o) on antidiabetic effect of glibenclamide (0.7mg/kg, p.o) and pioglitazone (1.05mg/kg, p.o).
Induction of diabetes:
Rats fasted for 24hourswill 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.10 The blood glucose concentration before and after respective treatment at above specified time intervals will be determined by GOD/POD method.9
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.11-12
STATISTICAL ANALYSIS
All values will be expressed as mean ± SEM from 6 animals in any group. Results will be subjected to statistical analysis using either paired `t` test or one-way ANOVA (analysis of variance) depending upon the study design, followed by Dunnet‘t’ test. `p` value of less than 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
List of References:
- Nies Alan S. Principles of Therapeutics. Goodman and Gillman’s The Pharmacological Basis of Therapeutics. 10th ed. McGraw-Hill, Medical Publishing Division.2001. p.54.
- Hardman JG, Limbird LE. Goodman and Gilman’s The pharmacological basics of therapeutics. 9th ed. New York: McGraw Hill 1996; p. 1493.
- Jolanda M A Boea, Edith J M Feskens, Doan Kromhout. Charecteristics of non-insulin dependent diabetes mellitus in elderly men effect modifications by family history. Int J Epidemiology 1996; 25(2):394-402.
- Sarah Wild, Gojka Roglic, Anders Green, Richard Sicree, Hilary King. Global prevalence of diabetes estimated for the year 2000 and projection for 2030. Diabetes care 2004; 27: 1047-53.
- on 17/10/2008
- Dahmen N, Becht J, Engel A, Thommes M, Tonn P. Prevalence of eating disorders and eating attacks in narcolepsy.Neuropsychiatr dis Treat.2008;4 (1):257-61.
- Huang Q, Zhang L, Tang H, Wang L, Wang Y. Modafinil modulates GABA-activated currents in rat hippocampal pyramidal neurons. Brain research.2008; 1208; p.74-8.
- accessed on 18/10/2008
- Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol 1969; 22:158-161.
- Chhanda Mallick, Kausik Chatterjee, Mehuli Guha Biswas, Debidas Ghosh. Antihyperglycemic effects of separate and composite extract of root of Musa Paradisiaca and leaf of Coccina Indica in streptozotocin induced diabetic male albino rat. AJTCAM 2007; 4 (3):362-371.
- Vijay S. Patel, V. Chitra, Lakshmi Prasanna, V. Krishnaraju. Hypoglycaemic effect of aqueous extract of Parathenium Hysterophourus L. in normal and alloxan indused diabetic rats. Indian J Pharmacol 2008; 40(4): 183-85
- T.Szkudelski. The mechanism of alloxan and streptozotocin action in beta cells of rat pancreas. Physiol.Res.2001;50:536-546.