ANALYSIS OF THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN SITAGLIPTIN, MIFEPRISTONE AND TEMSIROLIMUS.
M. PHARM DISSERTATION PROTOCOL SUBMITTED TO THE RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BENGALURU.
By ROOHI JAMAL B. Pharm.
UNDER THE GUIDANCE OF Dr. D.K. SURESH M Pharm., Ph.D
DEPARTMENT OF PHARMACOLOGY LUQMAN COLLEGE OF PHARMACY, GULBARGA 2012-13
1 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA BANGALORE
ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. Name of the Candidate ROOHI JAMAL (In block letters) and Address D/O MWO MA JAMAL HOUSE NO.- 6/3 , SECTOR 13, GANDHINAGAR GUJARAT-382013 2. Name of the Institution LUQMAN COLLEGE OF PHARMACY, GULBARGA – 585 102.
3. Course of Study and Subject M.PHARM. (PHARMACOLOGY)
4. Date of Admission to Course 05/06/2012
5. Title of the Topic ANALYSIS OF THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN SITAGLIPTIN, MIFEPRISTONE AND TEMSIROLIMUS.
2 Brief Resume of the intended work 6.
6.1 Need for study:
A drug interaction is a situation in which a substance (usually another drug) affects the activity of a "drug when both are administered together. This action can be synergistic (when the drug’s effect is increased) or antagonism (when the drug’s effect is decreased) or a new effect can be produced that neither produces on its own.1
Diabetes is the name given to a disease in which high blood glucose concentrations occur. Type 2 diabetes is a common condition, affecting 2% of the population and 8% of people in their sixties. People with diabetes usually present with thirst, weight loss and tiredness. In people with Type 2 diabetes that is usually diagnosed in middle age, symptoms can often be controlled by diet or tablet therapy. It is therefore frequently called "mild diabetes". However, glucose levels usually remain high and these can lead to "diabetic complications". Type 1 diabetes is the form of diabetes that usually comes on in childhood or in early adulthood and requires life-long insulin treatment. Type 2 diabetes accounts for approximately 90% of diabetes, Type 1 diabetes approximately 8%, with 2% from other causes.2
The UK Prospective Diabetes Study (UKPDS), sadly, confirmed that patients with Type 2 diabetes have a high incidence of heart attacks and strokes, and have a greater likelihood of early death than the general population. After 10 years of diabetes, the people with diabetes in the study had a 2-fold greater mortality than the general population. The study has also shown that after 10 years one third have a complication that requires clinical attention, including heart attacks, strokes, laser treatment of the eyes, treatment for renal failure or amputations. Patients also develop cataracts requiring surgery.2 There are three main types of diabetes mellitus, such as Type 1, Type 2 and Gestational diabetes.3
The alarming diabetes statistics include the fact that there is one person in the world dying of diabetes every ten seconds4. Diabetes affected 246 million people worldwide, and that number is expected to rise to 380 million by the year 20255.In India, diabetes is worsening day by day. As it is truly called as the “Hub of diabetic world”. According to International Diabetic Federation report, by 2030 over 8.4 percent of the Indian adult population will suffer from diabetes.6
Various drugs have been extensively used for the treatment of Type 2 diabetes since last long many
3 years. The most commonly using antidiabetic drugs are sulfonylurea, thiazolidinediones, alpha glucosidase inhibitors, meglitinide, dipeptidyl peptidase 4 inhibitors (DPP-4) like Sitagliptin etc.7
Sitagliptin belongs to a new class of antidiabetic drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors. Locally, sitagliptin has been licensed as a single agent, under the brand name Januvia® since April 2007, and as a combination product with metformin under the brand name Janumet® since April 2008.8,9
Endogenous Cushing’s syndrome is a rare and life-threatening endocrine disorder that results from long-term exposure to excess levels of the hormone cortisol. This excess is caused by tumors that usually occur in the pituitary or adrenal glands that over-produce, or prompt the over-production of, cortisol.10
Although cortisol at normal levels is essential to health, in excess it causes a variety of problems, including hyperglycemia, upper body obesity, a rounded face, stretch marks on the skin, an accumulation of fat on the back, thin and easily bruised skin, muscle weakness, bone weakness, persistent infections, high blood pressure, fatigue, irritability, anxiety, psychosis and depression.10 If left untreated, Cushing’s syndrome has a five-year mortality rate of 50 percent. An orphan disease, Cushing’s syndrome occurs in about 20,000 people in the United States, mostly women between the ages of 20 and 50.10 Mifepristone is a recently developed 19-norsteroid with potent competitive antiprogestational and significant antiglucocorticoid as well as antiandrogenic activity.11
On February 17, 2012, the U.S. Food and Drug Administration (FDA) approved KorlymTM (mifepristone) 300 mg tablets as a once-daily oral medicine to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing’s syndrome who have Type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery and it is widely practicing.10
Cancer is not just one disease, but a large group of almost 100 diseases. Its two main characteristics are uncontrolled growth of the cells in the human body and the ability of these cells to migrate from the original site and spread to distant sites. If the spread is not controlled, cancer can result in death.12 Renal cell carcinoma, a form of kidney cancer that involves cancerous changes in the cells of the renal tubule, is the most common type of kidney cancer in adults.13
4 Kidney cancer (excluding other and unspecified urinary organs, ICD-10 C64-C66) is the fourteenth most common cancer worldwide, with an estimated 273,500 new cases diagnosed in 2008 (2% of the total). Kidney cancer incidence rates are lowest in Western Africa and highest in Northern America, with around a 25-fold variation in male World AS incidence rates and around a 15-fold variation in female rates between the regions of the world.14,15 Around 208,500 new cases of kidney cancer are diagnosed in the world each year, accounting for just under 2% of all cancers.16 Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma. (RCC)17 Temsirolimus is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.18,19Temsirolimus is a novel mTOR inhibitor.20 Medroxyprogestrone, bevacuzimab, capecitabine, erlotinib, everolimus, axitinib drugs used in renal cell carcinoma.21 The available data indicates that temsirolimus has clinically relevant and statistically significant advantages over treatment with IFN in terms of progression free and overall survival, increasing median overall survival from 7.3 to 10.9 months (HR 0.73; 95% CI 0.58 to 0.92).21 Type 2 diabetes is independently associated with an increased risk of renal cell cancer in women. In addition, co morbidity of obesity, hypertension, and Type 2 diabetes substantially elevates the risk of renal cell cancer.22, 23 several underlying mechanisms might explain the link between diabetes and renal cell cancer. The first mechanism is hyperinsulinemia in Type 2 diabetes. Insulin acts as a growth factor for tumor cell proliferation and stimulates IGF-1 production, which also plays a role in carcinogenesis.24,25,26 Growth factors might be important contributors for renal cell cancer development given its peculiar biologic characteristics (i.e., spontaneous regression of metastatic lesions after primary tumor excision) 27,28,Second, hyperglycemia may affect carcinogenesis, since increased glucose metabolism is one of the central characteristics of malignant tissues.29,30Third, renal hypertrophy, which develops in the earlier course of diabetes, might have implications in carcinogenesis, although pathogenic significance of this mechanical change is unclear .31Finally, inflammatory cytokines, reactive oxygen, and lipid per oxidation are other possible mechanisms.
Patients who are suffering from diabetes with renal cell carcinoma are prescribed with antidiabetic drug like sitagliptin and anticancer drug like temsirolimus; Likewise patients suffering from cushing syndrome with renal cell carcinoma are prescribed with mifepristone and temsirolimus.
5 This multi drug therapy may lead to serious drug interactions as all the drugs mentioned above are metabolized by CYP450 enzymes.
Patients who take two or more medications simultaneously can be at risk for a drug interaction (DI), an event in which one medication increases or decreases the effectiveness of another. In some circumstances drug interactions can cause serious illness or even death. Unfortunately, most of what we presently know about drug interactions is based on reports of single unusual cases or studies conducted in healthy volunteers. The harm that befalls patients in the ‘real world’ setting is difficult to study and, as a result, is largely unknown.32
6.2 Review of Literature: It is evident from literature survey that several underlying mechanisms might explain the link between diabetes and renal cell carcinoma.
6 Patients who are suffering from diabetes with renal cell carcinoma are prescribed with antidiabetic drug like sitagliptin and anticancer drug like temsirolimus; Likewise patients suffering from cushing syndrome with renal cell carcinoma are prescribed with mifepristone and temsirolimus. This multi drug therapy may lead to serious drug interactions as all the drugs mentioned above are metabolized by CYP450 enzymes.
From literature survey it is apparent that, multi drug therapy may lead to serious drug interactions.
1) Ketoconazole may inhibit the metabolism and increase the serum concentration of mifepristone.33,34 2) Erythromycin may inhibit the metabolism and increase the serum concentration of mifepristone.33,34 3) Rifampin may increase the metabolism of Mifepristone and decrease its serum concentration.33, 34 4) Strong CYP3A4 inhibitors nefazodone, clarithromycin, itraconazle, indinavir, grape fruit juice may increase blood concentrations of sirolimus, the active metabolite of temsirolimus.35 5) Strong CYP3A4/5 inducers carbamazepine, rifampin, phenobarbital, may decrease blood concentrations of sirolimus, the active metabolite of temsirolimus.35 6) Sitagliptin may increase the serum concentration of digoxin. Increased digoxin blood levels may result when it is co administered with sitagliptin. There were slight elevations in the AUC and Cmax of digoxin when the combination was used in a study.36, 37 7) Bioavailability of sitagliptin was increased by 54% when co-administered with gemfibrozil, this interaction may not have any clinical significance as sitagliptin has a wide therapeutic index.38
If a patient is taking two drugs and one of them increases the effect of the other it is possible that an overdose may occur. The interaction of the two drugs may also increase the risk that side effects will occur. On the other hand, if the action of a drug is reduced it may cease to have any therapeutic use because of under dosage. Notwithstanding the above, on occasion these interactions may be sought in order to obtain an improved therapeutic effect.39
6.3 Objective of the study:
Whenever two or more drugs are being taken, there is a chance that there will be an interaction among the drugs. The interaction may increase or decrease the effectiveness of the drugs or the side
7 effects of the drugs. The likelihood of drug interactions increases as the number of drugs being taken increases. Therefore, people who take several drugs are at the greatest risk for interactions. Drug interactions contribute to the cost of healthcare because of the costs of medical care that are required to treat problems caused by changes in effectiveness or side effects. Interactions also can lead to psychological suffering that can be avoided.40 If the diabetic patient is suffering from renal cell carcinoma, in such condition anticancer drug temsirolimus are prescribed along with routine antidiabetic drugs, Likewise if patient is suffering from cushing syndrome along with renal cell carcinoma, mifepristone is given with temsirolimus. This multi drug therapy may lead to drug - drug interaction.
From literature survey, it is clear that drug interaction studies of sitagliptin, mifepristone and temsirolimus has not been reported, therefore the study of this interaction may prove to be useful clinically, and hence aim of the study is to establish the possible interaction between the above mentioned drugs.
8 7 Materials and Methods
7.1. Source of Data:
Whole work is planned to generate data from laboratory based experimental animal models as described in various national and international journals and books available with our college and other reputed institutions at India through e-publishing and HELINET of RGUHS, Bangalore.
7.2 Method of collection of Data: The blood samples for rats will be collected from retro orbital plexus/tail vein41, for rabbits from marginal ear vein42. Standard procedures are adopted for estimating blood sugar levels, as mentioned in the journals and books. The study is planned and designed in following phases.
Phase-1: In this phase rats of one group (n=6) will be treated with Themsirolimus (1.35-1.8 mg/kg B.W. P.O.) 43, 44, 45 for seven consecutive days and its influence on the blood glucose levels will be studied. Phase-2: In this phase, two groups are used (n=6). The rats of one group will be administered with sitagliptin (10 mg/kg B.W. P.O.) 46 and the other group will be administered with mifepristone (10-25 mg/kg B.W. P.O.) 47 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 by GOD/POD method using semi auto analyzer (BCA201) 41. This phase provides the per se influence of sitagliptin and mifepristone on blood sugar level.
Phase-3: In this phase, the same animals of phase-2 study will be utilized. However, the animals of phase-2 will be allowed for a period of one week to completely washout the previously administered drugs from their body. Thereafter, both the groups of animals will be administered with temsirolimus (1.35-1.8 mg/kg B.W. P.O.) 43, 44, 45 for a period of one week. On 8th day one hour after temsirolimus, one group will receive sitagliptin (10 mg/kg B.W. P.O.) 46 and the other mifepristone (10-25 mg/kg B.W. P.O.) 47Thereafter the blood samples are collected and analyzed for glucose concentration by GOD/POD method using semi auto analyzer (BCA201) as mentioned in phase-2.
9 This phase is expected to produce data regarding occurrence of interaction (if any) among administered combination.
Phase-4: In this phase, the entire protocol of phase-2 and phase-3 will be repeated using streptozotocin induced diabetic rats.
Phase-5: In this phase, albino rabbits of either sex, weighing between 1.5-1.8 kg will be divided into several groups. The entire protocol ranging from phase-1 to phase-3 will be repeated to understand the influence of temsirolimus on anti diabetic effect of sitagliptin and mifepristone. . Induction of Diabetes:
Rats fasted for 18 hours, will be subjected to single intraperitonial injection of streptozotocin (STZ) at the dose of 50mg/kg body weight/rat. Rats that exhibit blood glucose Conc. more than 250mg/dl after 48hrs of STZ injection will be considered as diabetic and selected for the proposed study.48The blood glucose concentration before and after respective treatment at above specified time intervals will be determined by GOD/POD method.
INCLUSION CRITERIA Normal and healthy animals of either sex weighing between 150-180 gms for rats and 1.5-1.8kg for rabbits will be included in the study.
EXCLUSION CRITERIA The albino rats and rabbits which do not fall the above mentioned weights are excluded from study.
STATISTICAL ANALYSIS All values will be expressed as mean SEM from 6 animals in any group. Results will be subjected to statistical analysis using one-way ANOVA and allowed by post hoc test (Dunnet ‘T’ test). p<0.05 will be considered as statistically significant.
10 7.3 Does the study require any investigation or intervention to be conducted on patients or other humans? If so please mention briefly.
Yes, the above study requires investigation on animals like albino rats and rabbits.
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
Yes, the study is cleared from institutional animal ethics committee (IAEC copy enclosed).
11 8 List of References:
1. MA Cos, J. Flórez. Interacciones de fármacos y sus implicancias clínicas. In: Farmacología Humana. Chap. 10 (J. Flórez y col. Eds): Masson SA, Barcelona; 1997. P. 165–176.Available from: URL:http://en.wikipedia.org/wiki/Drug_interaction
2. Turner R et al. Why UK Prospective Diabetes Study was needed and why its results are important. Diabetes Today.1999; 2: 22-24. Available from: URL: http://www.dtu.ox.ac.uk/ukpds_trial/protocol.php .
3. National Diabetes Information Clearinghouse. Bethesda, Maryland: National Institute of Diabetes and Digestive and Kidney Diseases; National diabetes statistics, 2011. February 2011; NIH Publication No. 11-3892; Available from: Accessed on February 24, 2011. URL:http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm.
4. Diabetes statistics; India is the Diabetic capital of the world. Available from: URL: http://health.savvy-cafe.com/diabetes-statistics-india-is-the-diabetic- capital-of-the- world-2008-02-25/
5. Diabetes activities around the world. Available from: URL:http://www.bd.com/press/newsroom/diabetes.asp
6. India sitting on diabetes bomb. Available from: URL:http://igovernment.in/site/India-sitting-on-diabetes-bomb-report-says/
7. Tripathi KD. Essentials of medical pharmacology. 6th Edition. New Delhi; Jaypee brothers’ medical publishers 2008; 254p.
8. Health science authority. Available from: URL:http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/safety_informatio n/product_safety_alerts/safety_alerts_2010/sitagliptin-_a_new.html
9. FDA Medwatch: Sitagliptin (marketed as Januvia and Janumet). Available from: URL:"http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedical Products/"/ucm183800.htm
12 10. MENLO PARK, Calif. - March 22, 2012. Available from: URL:http://www.corcept.com/news_events/pr_1332427156
11. Tripathi K.D.Essentials of medical pharmacology.5th edition. New Delhi; Jaypee Brothers medical publisher 2003; 283.
12. Available from: URL:"http://medical-dictionary.thefreedictionary.com/Death". http://medical- dictionary.thefreedictionary.com/Cancer+%28disease%29
13. Renal Cell Carcinoma Medication | Drugs.com. Available from: URL:www.drugs.com http://www.drugs.com/condition/renal-cell-carcinoma.html
14. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Available from: URL: "http://globocan.iarc.fr/"GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10 [Internet].
15. Lyon, France: International Agency for Research on Cancer; 2010. Available from: URL:http://globocan.iarc.fr/. Accessed May 2011.
16. Lindblad, P. and Adami H.O, Kidney Cancer, in Textbook of Cancer.8
17. Available from:URL:http://www.drugbank.ca/drugs/DB06287
18. TORISEL® Kit (temsirolimus) Prescribing Information, June 2011. Available from: URL: "http://pfizermedinfo.com/"Pfizermedinfo.com
19. Hudes et al. ASCO 2006) (J. P. Dutcher, C. Szczylik, N. Tannir, P. Benedetto, P. Ruff, A. Hsu, A. Berkenblit, A. Thiele, A. Strahs, J. Feingold.
20. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007; 356:2271-2281.
21. Avialable from:URL:http://www.drugs.com/condition/renal-cell-carcinoma.html
13 22. Hee-Kyung Joh, Walter C. Willett, and Eunyoung Cho, Type 2 Diabetes and the Risk of Renal Cell Cancer in Women Diabetes Care. 2011 July; 34(7): 1552–1556. Published online 2011 June 17. doi: 10.2337/dc11-0132 .Avialable from: URL :http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120193/
23. Diabetes Care. 2011 July; 34(7): 1552–1556. Published online 2011 June 17. doi:10.2337/dc11-0132.avialable from: URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120193/
24. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579–591.
25. Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr 2007;86:s823–s835.
26. Zhou JR, Blackburn GL, Walker WA. Symposium introduction: metabolic syndrome and the onset of cancer. Am J Clin Nutr 2007;86:s817–s819.
27. Oya M. Renal cell carcinoma: biological features and rationale for molecular-targeted therapy. Keio J Med 2009;58:1–11.
28. Laboratory evidence (22. Stadler W, Vogelzang NJ. Human renal cancer carcinogenesis: a review of recent advances. Ann Oncol 1993;4:451–462.
29. Jones SC, Saunders HJ, Qi W, Pollock CA. Intermittent high glucose enhances cell growth and collagen synthesis in cultured human tubulointerstitial cells. Diabetologia 1999;42:1113–1119.
30. Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr 2007;86:s823–s835.
31. Lindblad P, Chow WH, Chan J, et al. The role of diabetes mellitus in the aetiology of renal cell cancer. Diabetologia 1999; 42:107–112.
32. Avialable from: URL:http://www.ices.on.ca/webpage.cfm? site_id=1 & org_id=2 & morg_id=0 & gsec_id=2133 & item_id2133 & c)
33. Mifepristone (Mifeprex). Danco Laboratories, LLC. Mifepristone (Mifeprex) by Product
14 Information.,[online].,[cited2000sept]. Available from: URL:http://www.medicinenet.com/mifepristone-oral/page5.htm
34. Tripathi K.D.Essentials of medical pharmacology.5th edition.New Delhi;Jaypee brothers medical publisher 2003;284
35. Avialable from:URL: http://www.pfizerpro.com/hcp/torisel/drug-interactions
36. Facts and Comparisons 4.0: Wickersham RM. Sitagliptin phosphate: Drug Facts and Comparisons. Wolters Kluwer Health, Inc, St. Louis, MI, USA. Available from: URL: http://online.factsandcomparisons.com [Accessed on 19/09/2007]
37. Lexi-Comp Online: Anon. Digoxin / Sitagliptin: Lexi-Interact. Lexi-Comp, Inc, Hudson, Ohio, USA. Available from: URL: htp://www.crlonline.com [Accessed on 19/09/2007] )
38. K P A, Meda VS, Kucherlapati VS, Dubala A, M D, P R AV, K E, B S., Pharmacokinetic drug interaction between gemfibrozil and sitagliptin in healthy Indian male volunteers. Eur J Clin Pharmacology. 2012 May; 68(5): p 709.Avialable from: URL:http://www.ncbi.nlm.nih.gov/pubmed/22173280
39. María Soledad Fernandez Alfonso, Mariano Ruiz Gayo. Fundamentos de Farmacología Básicay Clínica. Published by Editorial Ramón Areces, 2005; page 232. ISBN 84-8004-689-
40. Avialable from: URL:http://www.medicinenet.com/drug_interactions/article.htm
41. Sunil Kumar K, Amrit Patel, Devendra shirode, S.Ramachandra setty. Influence of Metronidazole on hypoglycemic activity of thiazolidinediones in normal and alloxan induced diabetic rats. Indian J. Pharm 2009; 43(1):91-95.
42. Guleff P.S, and Beck R.R. Maternal and fetal adrenocortical function in the diabetic rabbit. Am. J. Physiol. Endocrinal. Metab., AJP, Endocrinology and Metabolism 1981; 240(3):217- 225.
43. Buckner JC, Forouzesh B, Erlichman C, Hidalgo M, Boni JP, Dukart G, Berkenblit A,
15 Rowinsky EK. Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer. .Invest New Drugs. 2010 Jun;28(3):334-42. doi: 10.1007/s10637-009- 9257-1. Epub 2009 May 5.Available from: Mayo Clinic, Rochester, MN, USA.URL:[email protected] file:///G:/19415181.htm
44. M.N.Ghosh.Fundamentals of experimental pharmacology: Toxicity studies.5.Hilton and company 109 college street kolkata73012:S.K.Ghosh and others;2011.165.
45. Paget,G.E and Barnes J.M.(1964) in Evaluation of drug activities: Pharmacometrics, eds. Lawrence,D.R. and Bacharach A.L:vol.1,Acedemic press.New York.2nd Edition
46. Cristina Mega,Edite Teixeria de Lemos,Helena Vala,Rosa Fernandes,Jorge Oliveira,Filipa Mascarenhas Melo,Fredrico Teixeira,Flavio Reis., Diabetic nephropathy amelioration by a low dose sitagliptin in an animal model of type 2 diabetes(Zucker diabetic fatty rat ). [online]., 2011 [2011 Aug 29];vol2011(2011),Article ID 162092,12 pages doi:10.1155/2011/162092.Available from: URL:file:///G:/dose of sitagliptin.xhtml
47. Australian Public Assessment Report for Mifepristone. Curr Med Res Opin. 2007 Jun;23(6):1329-39. Epub 2007 Apr 30.
48. Parthasarathy R, Ilavarasan R, Karrunakaran C.M. Antidiabetic activity of Thespesia Populnea bark and leaf extract against streptozotocin induced diabetic rats. International Journal of PharmTech Research 2009; 1(4):1069-1072.
16 9. Signature of Candidate ( ROOHI JAMAL)
The candidate is working under my direct 10. Remarks of the Guide supervision in laboratories of Luqman college of Pharmacy. Gulbarga-585102
11. Name & Designation of (in block letters)
Dr. D.K. SURESH M.Pharm, Ph.D 11.1 Guide PROFESSOR
11.2 Signature
11.3 Co-Guide ----
11.4 Signature ----
11.5 Head of Department Dr. D.K. SURESH M.Pharm, Ph.D PROFESSOR DEPT. OF PHARMACOLOGY LUQMAN COLLEGE OF PHARMACY, GULBARGA-585102
11.6 Signature
12. 12.1 Remarks of the Chairman Recommended and Forwarded & Principal
12.2 Signature
17