“PHARMACODYNAMIC AND PHARMACOKINETIC DRUG INTERACTIONS OF CANDESARTAN AND GLIBENCLAMIDE IN RATS AND RABBITS”

M.Pharm Dissertation Protocol

Submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore

by

S.NAGESH PATIL B.PHARM

Under the Guidance of

SUNIL KUMAR

M.Pharm., (Ph.D)

department of Pharmacology

k.r.e.Society’s Karnataka college of pharmacy

bidar 585403

2011-2012

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the Candidate and
Address (in block letters) / S.NAGESH PATIL
H.NO.1-7,AZAD GUNJ
ZAHEERABAD
2. / Name of the Institution / Karnataka College Of Pharmacy
3. / Course of the study
Branch / M. Pharm.,
Pharmacology
4. / Date of Admission to Course / 23-12-2011
5. / Title of the Research topic / “PHARMACODYANAMIC AND PHARMACOKINETIC DRUG INTERACITONS OF CANDESARTAN AND GLIBENCLAMIDE IN RATS AND RABBITS”
6. / Brief Resume Of Intended Work

6.1 Need for the study

/ Enclosure-I

6.2 Review of Literature

/ Enclosure-II
6.3 Objective of the study / Enclosure-III
7. / Materials and Methods
7.1 Source of data / Enclosure-IV
7.2 Methods of collection of data / Enclosure-V
7.3 Does the study require any
Investigation on animals?
If yes give details / Enclosure-VI
7.4 Has the ethical clearance been
obtained from your institution in
case of 7.3 / Yes, Registration number: 726
CPCSEA
8. / List of References / Enclosure-VII

ENCLOSURE –I

BRIEF RESUME OF INTENDED WORK

Need for the study

The practice of polypharmacy either for treating a single disorder or for the management of several disorders leads to the risk of drug-drug interactions. Literature survey indicates innumerable adverse effects, toxicities and antagonism of the pharmacological effect including fatalities due to drug interactions1.

Diabetes mellitus is a metabolic disorder resulting from deficiency of insulin leading to complications involving many organs. Diabetes and its complications pose a major threat to future public health resources throughout the world2,3,4. Regional studies from various urban areas of India have shown a several fold increase in the prevalence of type – II diabetes5,6.

Diabetes is of two types, type-I (IDDM) suffered by approximately 5% population, and type-II (NIDDM) suffered by approximately 95% of population, among diabetics. Insulin is the drug of choice in type-I and sulphonylureas are the drugs of choice in type –II diabetes. Among sulphonylureas, glibenclamide is the drug of choice because of its low dose and long duration of action7.

Diabetes is a chronic disease wherein lifelong treatment with drugs is required. Diabetes patients may also concurrently suffer with other diseases like depression, epilepsy, hypertension, cancer etc. In such situations the diabetic patient may also use other drugs along with antidiabetics.

Hypertension is one of the common cardiovascular disorders of modern times. According to WHO, hypertension is the state of the body in which systolic BP is 140mmHg or more and diastolic BP is 90mmHg or more8. The persons suffering from both diabetes and hypertension are likely to receive combination of both drugs, leading to drug- drug interactions. Hence to assess the interaction and suggest safe combination it is planned to study the same in lower animals.

Polypharmacy and multiple drug therapy assume importance in present day clinical practice. The clinical observations are very vital in noting the interactions of drugs, but to study the mechanisms of such interactions, clinical studies cannot be carried out using human models.

In the present study, it is proposed to study the pharmacological interactions between glibenclamide and candesartan in animal models.

ENCLOSURE – II

Review of Literature:

Literature survey indicates following works were reported that are related to the present project.

  1. Islam SI et al. have reported possible interaction between cyclosporine and glibenclamide in posttransplant diabetic patients9.
  2. Sharma VV et al. have reported interaction of anti-inflammatory agents (aspirin, phenylbutazone, indomethacin, ibuprofen) with glibenclamide in rabbits10.
  3. Losasso C et al. have reported pharmacologic interactions between quinolones (nalidixic acid, ofloxacin, pefloxacin, sparfloxacin) and oral hypoglycemic agents11.
  4. Kritz H et al. have reported interaction of sulfinpyrazone (Anturan) and glibenclamide (Euglucon) in type II diabetic patients12.
  5. Callaghan JT et al. have reported Olanzapine: interaction study with imipramine13.
  6. Okiyama M et al. have reported drug interactions between imipramine and benzodiazepines in rats14.
  7. Kulkarni SK et al. have reported action and interaction of imipraminebenztropine and L-dopa on stereotyped behaviour15.
  8. Werry JS et al. have reported interaction of imipramine and methylphenidate in hyperactive children16.
  9. S. Prashant et al. have reported interaction of carbamazepine and glibenclamide in rats.17
  10. S. Satyanarayan et al have reported the interaction of pravastatin and gliclazide in animal models.18
  11. Kaiser D.G. reported glibenclamide metabolism in man and laboratory animals19.
  12. Ferner R. reported the relationship between the pharmacokinetics and Pharmacodynamic effects of oral hypoglycemic drugs20.
  13. Trinder P. reported the determination of blood glucose using an oxidase-peroxidase system with a no carcinogenic chemogen21.
  14. Heikkila RE: reported thetheprevention of alloxan-induced diabetes in mice by dimethyl sulfoxide22.
  15. K. EswarKumar,reported the determinationofgliclazide23.

ENCLOSURE – III

Objectives of the study:

Since there are several reports that anti hypertensive drugs are metabolized with cytochrome P-450 enzyme system. Antidiabetic drugs like glibenclamide are metabolized by similar enzyme system cytochrome P-450 isoenzymes. When they are used concomitantly, there are chances of interactions between antihypertensive drugs and antidiabeticdrugs. Antihypertensive drugs are likely to alter the pharmacodynamic and pharmacokinetic properties of orally acting antidiabeitc agents. Hence, the present study is planned with the following objectives.

  1. To study the influence of candesartan on the hypoglycemic activity of antidiabetic drug (glibenclamide) in rats and rabbits.
  2. To study the safety of the drug combination of glibenclamide and candesartan.

ENCLOSURE - IV

Materials and Methods:

Source of Data

This study is planned to generate data by conducting laboratory –based research in animals. It is also planned to use rats/rabbits in the experiments. Estimation of blood glucose levels at a regular interval after the administration of hypoglycemic agents in animals.

Other data is collected from

Pharmacology reviews, journals.

Electronic data like CD-ROM and internet.

Helinet, Delnet, Pubmed.

Library of Karnataka College of Pharmacy, Bidar.

The animals will be procured from Hyderabad.

Glibenclamide pure sample will be procured from reputed manufacturers.

Candesartan pure sample will be procured from reputed manufacturers.

GOD / POD kits will be purchased from market.

Alloxan / STZ will be purchased from market.

ENCLOSURE – V

Method of Collection of Data

The whole study is divided into following three phases for collection of data.

Phase – I

Stage-I: To establish a dose-response curve of glibenclamide on blood glucose level in normal rats in our laboratory. Stage- II: To study the influence of candesartan on blood glucose levels in normal rats.

Stage III: To study the influence of candesartan on hypoglycemic activity of glibenclamide.

Phase – II

The above study will be repeated in diabetic rats that represents the condition of actual use of drug.

Phase - III

Stage-I: To establish a dose-response curve of glibenclamide on blood glucose level in normal rabbits in our laboratory.

Stage-II: To study the influence of above selected combination in rabbits.

Inclusion Criteria:

1) Normal rats: Adult albino rats of either sex, weighing 200– 250g.

2) Diabetic rats: Alloxan / STZ induced diabetic rats of either sex, with blood glucose more than 250 mg/dL.

3) Normal rabbits: Adult albino rabbits of either sex, weighing 1.8 to 2.5 Kg.

Exclusion criteria:

1) The albino rats which do not fall in the above mentioned weight are excluded from study.

2) The albino rabbits which do not fall in the above mentioned weight are excluded from study.

Study Sampling and Design

Method: ByGOD-POD method using semi autoanalyzer, blood withdrawn at predetermined timing from the animals by established standard methods.

Size: 12 groups each with 6 no’s for rats and 3 groups each with 5 no’s for rabbits.

Parameters: Blood glucose level measured at regular intervals of time. Viz 0,1,2,4,6,8…..hours.

Statistical test: Student’s t- Test.

Duration of Study: Total duration of experimentation will be 10 months.

ENCLOSURE –VI

7.3 Does the study require any investigation on animals? If so, please prescribe briefly

Yes, the above study requires investigation on animals that is albino rats and rabbits to study drug interactions between glibenclamide and candesartan.

7.4 Has the ethical clearance has been obtained from your institution in case of 7.3

Yes, the study is cleared from institutional animal ethics committee (IAEC Certificate enclosed).

ENCLOSURE – VII

REFERENCES

  1. Steel KK, Gertman PM, Cresienze C, Anderson J. Iatrogenic illness on a general medical service at a university hospital. N Eng J Med. 1981; 34: 638-42.
  2. Zimmet PZ. Diabetes epidemiology as a tool to trigger diabetes research and care. Diabetologia. 1999; 42: 499-518.
  3. King H, Aubert RE, Herman WH. Global burden of diabetes 1995-2025. Prevalence, numerical estimates and protection. Diabetes care 1998; 2: 1414-31.
  4. Songer TJ, Zimmet PZ. Epidemology of type –II diabetes on international perspective, Pharmacometrics 8 (Supl.): 1995; 1-11.
  5. Ramachandran A, Jali MV , Mohan V, Snehalatha G, Viswanath M. High prevelance of diabetes in an Urban population in India. B M J. 1998; 297: 587-90.
  6. Ramaiya KL, Kodali VRR, Alberti KGMM. Epidemiology of diabetes in Asians of the Indian Sub-continent. Diabetes Metab Rev. 1990; 6: 125-46.
  7. Goodman and Gilman. The Pharmacological Basis of Therapeutics. 10th Ed. New York, McGraw Hill: 2001.
  8. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th Ed. Edinburg: Churchill Livingstone; 2003.
  9. Islam SI, Masuda QN, Bolaji OO, Shaheen FM, Sheikh IA. Possible Interaction between Cyclosporine and Glibenclamide in Posttransplant Diabetic Patients. Therapeutic Drug Monitoring. 1996; 18(5): 624-26.
  10. Sharma VV, Srivastava YK, Kulshrestha VK, Prasad DN. Interaction of anti-inflammatory agents with glibenclamide in rabbits. Indian J Pharmacol. 1981; 13(2): 207-10.
  11. Losasso C, Loffreda A, Angrisani M, Marabese I, Vacca C, Rossi F. Pharmacologic interactions between quinolones and oral hypoglycemic agents. An experimental study on rabbits. G Ital Chemioter. 1992; 39(1-3): 1-4.
  12. Kritz H, Najemnik C, Irsigler K. Interaction of sulfinpyrazone (Anturan) and glibenclamide (Euglucon) in type IIdiabetic patients. Wien Med Wochenschr. 1983; 133(9): 237-43.
  13. Callaghan JT, Cerimele BJ, Kassahum KJ, Nyhart EH, Hoyes-Beehler PJ, Kondraske GV. Olanzapine:interaction study with imipramine. J ClinPharmacol. 1997; 37: 971-78.
  14. Okiyama M, Ueno K, Ohmari S, Igarashi T, Kitagawa H. Drug interactions between imipramine and benzodiazepines in rats. J Pharm Sci. 2006; 77(1): 56-63.
  15. Kulkarni SK, Dandiya PC. Action and interaction of imipraminebenztropine and L-dopa on stereotyped behaviour. Indian J Pharmacol. 1974; 6(4): 181-85.
  16. Werry JS, Michael G, Diamond AE. Imipramine and Methylphenidate in hyperactive children. J Child PsycholPsyc. 2006; 21(1): 27-35.
  17. Prashant.S, Anil kumar. A, Madhu.B, Rama.N, VidyaSagar.J. Pharmacokinetic and Pharmacodynamic drug interactions of carbamazepine and glibenclamide in health albino wistar rats. Journal of pharmacology and pharmacotherapeutics.2011;2(1):7-10.
  18. Galani VJ, Vyas M. In vivo and In vitro drug interacations study of glimepride with atorvastatin and rosuvastatin.
  19. Kaiser D.G., Forest A.A. 1975; A review of glibenclamide metabolism in man and laboratory animals. In Micronase: Pharmacological and clinical evaluation, ed.Rifkin, H. pp. 31¬ 43. Interaction Congress series 382. Amsterdam: ExcerptaMedica.
  1. Ferner R. Av Chaplin S. The relationship between the pharmacokinetics and Pharmacodynamic effects of oral hypoglycemic drugs. Clin. Pharmacokinet. 1987; 12,379-401.
  2. Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non carcinogenic chemogen. J ClinPathol 1969; 22:158-61.
  1. Heikkila RE: The prevention of alloxan-induced diabetes in mice by dimethylsulfoxide. Eur J Pharmacol 1977; 44(2): 191-93. Indian J Pharm.Educ.Res. 2008:42(3):282
  2. K. Eswar Kumar, A. Ramesh, R. SurendraYadav and S. Satyanarayana. Determination of gliclazide

9.0

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SIGNATURE OF THE CANDIDATE

/

S.NAGESH PATIL

10.

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REMARKS OF THE GUIDE

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To find out the safe and effective drug combinations, for patients suffering with diabetes and hypertension.

11.

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NAME AND DESIGNATION

11.1 GUIDE

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Mr.SUNIL KUMAR

M.Pharm (Ph.D)

Asst.Professor

DEPT. OF PHARMACOLOGY,

KARNATAKA COLLEGE OF PHARMACY

BIDAR-585403

11.2 SIGNATURE

11.3 CO-GUIDE (IF ANY)

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11.4 SIGNATURE

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11.5 HEAD OF THE DEPARTMENT

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Mr. RAGHAVENDRA PATIL.

H.O.D;

DEPT. OF PHARMACOLOGY,

KARNATAKA COLLEGE OF PHARMACY

BIDAR-585403

11.6 SIGNATURE

12.

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12.1 REMARKS OF THE PRINCIPAL

12.2 SIGNATURE

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Dr.SIRSE KRANTI KUMAR

PRINCIPAL,

KARNATAKA COLLEGE OF PHARMACY

BIDAR-585403

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