A STUDY ON PHARMACODYNAMIC DRUG INTERACTION OF ESOMEPRAZOLE AND ANTIDIABETIC DRUGSS.
Protocol of Dissertation Submitted
By
Mr. PRASHANT DNYANDEO PHADATARE.
To
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
Under the guidance of
Mr. CHANDRASHEKHAR V.M.
Assist. Professor
(2008-2009)
Department of Pharmacology,
HANAGALSHRIKUMARESHWARCOLLEGE OF PHARMACY,
BAGALKOT- 587101, KARNATAKA
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES
BANGALORE,KARNATAKA
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
DISSERATATION
1. /Name of the Candidate and Address
/ PRASHANT DNYANDEO PHADATARE.DEPARTMENT OF PHARMACOLOGY,
H.S.K.COLLEGE OF PHARMACY,
B.V.V.S. CAMPUS,
BAGALKOT-587101. KARNATAKA.
2. /
Name of the Institution
/ H.S.K.COLLEGE OF PHARMACY,B.V.V.S.CAMPUS,
BAGALKOT-587101. KARNATAKA.
3. / Course of Study and Subject / MASTER OF PHARMACY IN
PHARMACOLOGY
4. / Date of admission to Course / 17-O7-2008
5. /
Title of the topic:
“A STUDY ON PHARMACODYNAMIC DRUG INTERACTION OF ESOMEPRAZOLE AND ANTIDIABETIC DRUGS”
6. /Brief resume of the intended work
6.1 Need for the study: Drug interaction can be defined as the modification of the effect of one drug by the prior or concomitant administration of another drug. The more drugs a patient takes the greater the likelihood that an adverse reaction will occur. One hospital study found that the rate was 7% in those taking 6 to 10 drugs, but 40% in those taking 16 to 20 drugs which represents a disproportionate increase1.According to one report , the drug interaction may be fourth to sixth leading cause of death in united sates2. Recent studies have demonstrated that may patient receive multiple drug therapy with recognize potential. When patient has subjected various therapeutics regimen increases, the greater is the risk of occurrence of drug interaction3.This may lead to enhanced or diminished effect and may be useful or harmful. The responsible position lies between these two extremes because a very substantial number of interacting drugs can be given together safely, if the appropriate precautions are taken, whereas there are relatively few pairs of drugs that should always be avoided. These drug interaction may be due to the influence of one drug on the pharmacokinetic parameter of the co-administered drug or pharmacodynamic properties of the other, Pharmacodynamic interaction are those where the effect of one drug are change by the presence of another drug at site of action. In some cases the interaction is due to direct effects at the receptor, but more often it receptor medicated with interference with biochemical or physiological mechanism4.These drug interaction may result in sever Adverse Drug Reaction, exaggerated pharmacological responses, toxic effects or decreased efficacy of drug.Diabetes mellitus is a group of syndromes characterized by hyperglycemic, altered metabolism of lipids, carbohydrates, proteins and an increasedrise of complications from vascular disease.Diabetes is the most common endocrine disorder and by the year 2010.It is estimated that more than 200 million people world wide have diabetes and 300 million will subsequently have the disease by 20255.
As thediseaseprogresses, tissue orvasculardamage ensures leading to severe diabetic complication such as retinopathy, neuropathy, cardiovascular complications and ulceration6,7.Thus diabetes covers a wide range of heterogeneous diseases. Oral hypoglycemic agents are useful in the treatment of type 2 diabetes mellitus, thus there is every possibility of multi drug interaction amongst concomitantly used drugs and may lead to severe complications. Diabetes requires the treatment for long time and gastric ulcers required specific medication. In such cases, it is vary much needed to establish the interaction between the drugs used for these two disorders e.g. - diabetes and gastric ulcer, when treatment for both diseases are given simultaneously. Esomeprazole is one of the extensively used antiulcer drug and for the diabetes, sulfonylurea (Glimepiride) and thiazolidinediones (pioglitazone) are the oral hypoglycemic agents more commonly employed. Since, proton pump inhibitor, esomprazole is know to metabolism through cytochrome P-450 and also causes enzyme induction 8. Glimepiride and pioglitazone are also under go metabolism through cytochrome P-450, there is possibility of occurrence of pharmacokinetic type of drug interactions with concomitantly administration with esomeprazole. Constant homeostasis of blood sugar level is important in diabetic patients. Theses enzyme induction with concomitant administration of other drugs may alter the plasma level of glucose, leads to decreased potency of diabetic drugs. Hence, with this above information, to find out possibility of potential interaction of glimepiride and pioglitazole with esomprazole is very much needed. Therefore, the prevent study may be useful to clinician in administration and information about drug interaction.
6.2 Review of literature :
Proton pump inhibitor or H2-receptor antagonists are widely used for effective treatment of gastric and duodenal ulcers. Most of these agents is well known to inhibit the hepatic cytochrome P450 (CY450, isoenzymes are called CYP1A2, CYP2C9, CYP2C19) metabolism of a number of concurrently administered drugs9, 10.These agents are most commonly used as a anti-secretary agents during hyper- secretion of gastric acid. Enzyme induction takes several weeks to develop fully, but enzyme inhibition
Can occur within 2 to 3 days resulting in the rapid development of toxicity. Both co-administered drug under go metabolism with same group enzymes (CY450) then competitive inhibition of hepatic cytochrome 450 involved in alteration of absorption, metabolism and excretion via altering the gastric pH, poor absorption and increased or reduced levels in plasma of drugs due to inhibition of cytochrome 450 enzymes11,12. The proton pump inhibitors like omeprazole and lansoprazole are inhibitors of CYP2C19.Hence it is likely proton pump inhibitors may influence the pharmacokinetic and pharmacodynamic parameters of sulfonylurea. Esomeprazole is an S-isomer of omeprazole. Esomeprazole suppresses gastric acid secretion by specific inhibition of the H+/K+- ATPase in the gastric parietal cell. The isoenzymes CYP3A4 is responsible for metabolism of sulfonyureas13, CYP2C8, CYP2C9 and CYP3A4 for metabolism of thiazolidinediones 14, 15. On these bases, we can assume that possible drug interaction esomeprazole with anti-diabetic drugs. Therefore, the present study is designed to assess the extent of potential interaction esomeprazole with Glimepiride and pioglitazole induced hypoglycemic activity. The present study may be useful to clinician in readjusting the dose and frequency of administration of antidiabetic agents, when they are needed to be used with esomeprazole.
6.3 Objective of the study:
Research reports indications that various drug interactions with proton pump inhibitors like esomeprazole interfere with cytochrome P-450 enzyme system and there by they alter the pharmacokinetics of various drugs administered concumintaly. In view this above information, the possibility interaction between esomeprazole and orally acting hypoglycemic agents like glimepiride and pioglitazone was planned for the study.
The objectives of present studies as follows:
1.To study the potential effect of repeated administration of esomeprazole on the hypoglycemic activity of glimepiride and pioglitazone in experimental animals.
2.To study the influence of repeated administration of esomprazole on the antidiabetic activity of glimepiride and pioglitazone in the experimentally induced diabetic animals.
7. /- To possible management of drug interaction with, adjustment dose and frequency of administration of hypoglycemic agents like glimepiride and pioglitazone, when they are used along with esomeprazole, a proton pump inhibitors for the treatment of gastric ulcers in diabetic patients.
7.1 Source of data:
This study is planned for pharmacodynamic data generation by utilizing pre-clinical laboratory
based research by using certain pharmacological tools. Estimation of blood glucose levels at pre-determined intervals after the administration of hypoglycemic agents to healthy animals (rats and rabbits) with or without pre treatment of esomeprazole is important criteria for generating required data. The additional required data also obtained from available literatures.
7.2 Materials:
Animals : Healthy Wister albino rats of either sex (150-200g)
Healthy Albino rabbits of either sex (1.5-2.0 kg.)
Instruments:Research centrifuge, Auto analyzer, UV-Spectrophotometer.
7.3 Methods:
The Animal were divided into different treatment groups
Pharmacodynamicstudy in Normal/ Diabetic Rats.
A group of six rats were administered with glimepiride and pioglitazone, orally. The same group was administered with of esomeprazole and combination of esomeprazole with glimepiride and pioglitazone One-week washout period was maintained between treatments. The same treatment was repeated in a group of six alloxan-induced diabetic rats. Blood samples were withdrawn by retro orbital puncture16, 20 at 0, 1, 2,3,4,6,8,10, and 12 hours and were analyzed for blood glucose by GOD/POD method17,20 using commercial glucose kits (Span diagnostics).
Pharmacodynamic study in Rabbits.A group of five rabbits were administered with of glimepiride and pioglitazone, orally. The same group was administered withesomprazole, orally after a further washout period the same group was administered with combination ofglimepiride and pioglitazone with esomeprazole .After interaction study the same group was continued with the daily treatment of interacting drug (esomeprazole) for the next eight days with regular feeding. Later after 18-hour fasting, they were again given the combined treatment on the ninth day. Blood samples were withdrawn from the marginal ear vein of each rabbit at 0,1,2,3,4,6,8,12,18, and 24hours.They were analyzed for glucose by GOD/POD 18,20
Induction of Diabetes:
Diabetes was induced in rats by the administered of alloxan monohydrate in two doses, that is,50mg/kg and 100mg/kg body weight intraperitoneally for two consecutive days19,20
Statistical analysis:
All the data were expressed in mean ± SEM. The significance of differences in mean between control and treated animals for different parameters determined by one way using ANOVA followed by Dunnett’s comparison test. Significance for difference between groups was evaluated for student’s t-test to come to final conclusion .
7.4 Dose the study requires any investigation or intervention to be conducted on patients or other humans or animals? If so, please describe briefly.
Yes, the above study requires investigation on experimental animals like Wister albino rats and albino rabbits for this research work.
7.5Has ethical clearance been obtained from your institution for performing various tests on animals?
Yes, the study is cleared from Institutional Animal Ethics Committee. The copy is enclosed with this protocol.
8. / References
1. Smith J.W., Seidl L.G., Cluff.L.E. Studies on the epidemiology of adverse drug reactions.
V. Clinical factors influencing susceptibility. Ann Intern Med.1969; 65:629.
2. Ramesh Goyal., Parloop Bhatt., Mahesh Burnade. Element of Clinical Pharmacy 2003-2004:
133-148.
3. Fusun yaris., Ersin yasir., Mine Kadioglu. Normal pregnancy outcome following inadvertent
exposure to Rosiglitazone, Glibenclamide, and Atorvastatin in a diabetic and hypertensive
woman. Reproductive Toxicology 2004; 18(4): 619-621.
4. Roger W., Clive E. Clinical Pharmacy and Therapeutic 3rd ed, Elsevier Science Limited, 2003.
- Stephen., Davis N., Daryl K.Granner. Insulin, oral hypoglycemic agents, and the pharmacology
McGraw-Hill,NewYork,1996:1493
6. Saely C.H., Aczel S., Marte T. Cardiovascular complication in type 2 diabetes mellitus depend
on the coronary angiographic state rather than on the diabetes state. Diabetologia, 2004;
47:145-146.
7. Wallce C., Reiber G.E., LeMaster J. Incidence of falls, risk factors for falls, and fall-related
fractures in individuals with diabetes and a poor foot ulcer. Diabetes Care 2002; 25:1983-86.
8. Robinson M., Horn J. Clinical pharmacology of proton pump inhibitors: what the practicing
physician need to know. Drugs 2003; 63(24):2739-54.
9. Bayes M., Rbasseda X., Prous J.R. Gateways to clinical trials. Meth Find Exp clin Pharmacol
2002; 24 (1): 33-55.
10. Naritomi Y., Treashita S., Kagayama A. Identification and relative contribution of human
cytochrome P450 isoforms involve in the metabolism of glibenclamide and lansoprazole
evaluation of an approach based on the in vitro substrate disappearance rate. Xenobiotica
2004; 34(5):415-427.
11. Gerson LB., Triadailpoulos G. Proton pump inhibitors and their drug interactions: an
evidence based approach. Eur J Gastroenterol Hepatol 2001:13 (5): 611-16.
12. Robinson M., Horn J. Clinical pharmacology of proton pump inhibitors: what the practicing
physician need to know. Drugs 2003; 63(24):2739-54.
13. Naritomi Y., Terashita S., Kagayama A. Identification and relative contribution of human
cytochrome P450 isoforms involve in the metabolism of glibenclamide and lansoprazole
evaluation of an approach based on the in vitro substrate disappearance rate. Xenobiotica
2004; 34(5):415-427.
14. Mikko Niemi M.D., Janne T., Perrti J. Effect of trimethoprim and rifampin on the
pharmacokinetics of the cytochrome P4502C8 substrate rosiglitazone. Clinical Pharmacol
and Therapeutics 2004; 76:239-249.
15. Park J.Y., Kim K.A., Kang M.H., Kim S.L., Shin J.G. Effect of rifampin on the
pharmacokinetic of rosiglitazone in healthy subject. Clinical Pharmacol Thera 2004;
75(3):157-162.
16. Riley V. Adaptation of orbital bleeding technic to rapid serial blood studies. Proceedings of
the society for Experimental Biology and Medicine 1960; 104:751-754.
17. Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-
carcinogenic chromogen. J.Clin.Pathol 1969; 22(2):158-161.
18. Heikkla R.E The prevention of alloxan-induced diabetes in mice by dimethyl sulfoxide.
European J. Pharmacol 1977; 44(2):191-193.
19. Eswar Kumar K., Ramesh A., Yadav R.S., Satyanarayana S. Determination of gliclazide in
rabbit serum by RP-HPLC. Acta Ciencia Indica. Chem 2007; 33(3): 273-278.
- Satyanarayana S., Chandrasekhar M.S., Palakshi Gouda O., Eswar Kumar K. Drug-Drug
Exchange 2008; 1-6.
9. / SIGNATURE OF CANDIDATE / (PRASHANT DNYANDEO PHADATARE)
10. / REMARKS OF THE GUIDE / Drug-Drug interaction especially pharmacokinetic interaction like enzyme induction & inhibition alter the plasma conc of drug, when administered concumintaly .In this view, glucose estimation is main criteria in our studies in diabetic animal with or without esomeprazole (enzyme inhibitor) with antidiabetic drugs. This suggesting that clinician to adjust the dose & frequency of administration this combination of drugs.
11. / NAME AND DESIGNATION OF
THE GUIDE / Mr. CHANDRASHEKHAR V.M.
Assist. Professor
12. / SIGNATURE
13. / CO-GUIDE
14. / SIGNATURE
15. / HEAD OF THE DEPARTMENT / Dr. I.S.MUCHANDI
H.O.D. , Department of Pharmacology
H.S.K.College of Pharmacy,
B.V.V.S. Campus, Bagalkot-587101.
16. / SIGNATURE
17. / REMARKS OF THE PRINCIPAL / The above mentioned information is correct and I recommended the same for approval.
18. / NAME OF THE PRINCIPAL / Dr. I.S.MUCHANDI
H.O.D. , Department of Pharmacology
H.S.K.College of Pharmacy,
B.V.V.S. Campus, Bagalkot-587101.
19. / SIGNATURE
OFFICE OF THE INSTITUTIONAL ANIMAL ETHICS COMMITTEE (IAEC)
HANAGALSHRIKUMARESHWARCOLLEGE OF PHARMACY,
BAGALKOT-587101, KARNATAKA
REG NO.821/01/a/CPCSEA, Dated: 6th AUG 2004 UNDER THE RULES 5(a) OF THE
“BREEDING OF AND EXPERIMENTS ON ANIMALS (Control and Supervision)
RULES 1998”
Ref: HSKCP/IAEC, Clear / 2008-09/1-8
CERTIFICATE
This is to certify that Mr. PRASHANT DNYANDEO PHADATARE a student of first M.Pharmacy is permitted to carry out experiments on animals for the dissertation / thesis work entitled as “A STUDY ON PHARMACODYNAMIC DRUG INTERACTION OF ESOMEPRAZOLE AND ANTIDIABETIC DRUGS” as per details mentioned and after observing the usual formalities laid down by IAEC as per provision made by CPCSEA.
Animal house in charge CHAIRMAN
FormB
See rule [6 (a) and 8(a) PART A
(1) / Name and address of the Establishment: / HSKCollege Of Pharmacy, B.V.V.S Campus, Bagalkot.587101,Karnataka(2) / Date and Registration Number of the Establishment: / 821/01/a CPCSEA
(3) / Name, address and Registration NO. of the
breeder from whom acquired and the date of
acquisition: / OFFICE OF CPCSEA,
Ministry of environment and forest,
IIIrd seaward road, Valmiki nagar,
Thiruvanmiyur, Chennai-600041.
Tamil Nadu
(4) / Place where the animals are presently kept: / Animal House
HSKCollege Of Pharmacy, B.V.V.S Campus, Bagalkot.587101,Karnataka
(5) / Place where the experiment is to be performed: / PG Lab-II, Department of pharmacology, HSK College Of Pharmacy, B.V.V.S Campus, Bagalkot.587101,Karnataka
(6) / The date on which the experiment is to commence and the duration of the experiment: / 15-May-2009
The protocol form for the research proposal- PART B in the case of experiments using other than non-human primate animals for ongoing/new projects, PART C for use of non-human primates for new projects and PART D for use of non-human primate for extension of ongoing projects – should be duly filled, singed and annexed with this form.
Signature
Dated: (Name and Designation)
Place:
PART – BProtocol form for Research Proposal to be submitted to the
Committee on use of small animals / Animals other than non human
Primate in Biomedical Research for ONGOING / NEW PROJECTS
1. / Project Title : /
A STUDY ON PHARMACODYNAMIC DRUG INTERACTION OF ESOMEPRAZOLE AND ANTIDIABETIC DRUGS
2. / Investigation (s) :Designation / Mr.CHANDRASHEKHAR V.M.
Assist. Professor
3. / Department (s) : / Department of pharmacology, HSK College Of Pharmacy, BVVS Campus, Bagalkot.587101,Karnataka
4. / (a) Funding Source (s): if any
(b) Are sufficient funds available for purchase and maintenance of the animals / ------
© / Duration of present project :
(1)Number of months : / 6 month
(2)Date of start of the Project :
(Experiment) / 15thmay 2009
(3)Date of termination of the project : / 15thNovember 2009
5. / Date by which approval is needed incase the project is to be funded by outside agency (If less than six weeks from the date of admission, please justify below): / ------
6. / Summary of project briefly summarize in laymen’s term the background, the objective and the experiment approach.
(a)Background: / Enclosed
(b)Objectives / Enclosed
(c) Experimental procedure: / Enclosed
7. / (a) Name of species
Age / Sex / Weight
4-6 Weeks / Either / 200-250gm
(b) / Rationale for selection
Approximate number of animals required during the first 12 months. / 96
Justification of number (define treatment group andnumber per group) / Each group contain six
animal
Number of animals housed per weeks / 40
8. / List all invasive Non Surgical Animal Procedures and Potentially Stressful Noninvasive procedures to be used (Example IM injection, foot pad injection, venapunctures). / Invasive surgical procedure
Procedure and Approximate Frequency: / Enclosed
9.
10.
11. / Anesthetic and/or Analgesic and Dosage:
NO
Test substance injected and/or applied:
Injected Intraperitonially
Does the protocol prohibit the use of anaesthetic and analgesic for the conduct of painful procedures?
NO
With surgical procedure/Experimental procedure be performed?
NO
(a) Will the animal be sacrificed after surgery?
NO
Will hazardous agent such as radioisotopes, carcinogens, radiation exposure, microbial and parasitic agent be administered to animals?
No
INVESTIGATOR SIGNATURE
DATE: ______