INFLUENCE OF SILDENAFIL CITRATE ON HYPOGLYCEMIC …



a study on drug - drug interaction between sildenafil citrate and oral anti-diabetic drugs

M. PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH

SCIENCES, KARNATAKA, BENGALURU

BY

AJAY PRATAP SINGH

B. Pharm.

UNDER THE GUIDANCE OF

Dr. S.V. RAJENDRA

M. Pharm., Ph.D.

P. G. DEPARTMENT OF PHARMACOLOGY

S. C. S. COLLEGE OF PHARMACY,

HARAPANAHALLI-583131

2010-11

Annexure – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

|01 |Name and Address of the Candidate |AJAY PRATAP SINGH |

| | |S/o. YOGENDRA SINGH |

| | |RAM GULAM TOLA W.N0.1, H.N0.486, |

| | |DEORIA (U.P.). (INDIA) |

| | |PIN: 274001. |

|02 |Name of the Institution |S.C.S. college of pharmacy |

| | |HARAPANAHALLI-583 131, |

| | |DAVANGERE DIST, |

| | |KARNATAKA (INDIA). |

|03 |Course of the Study |M. Pharm., |

| |Branch |Pharmacology |

|04 |Date of Admission to course |27-05-2010 |

|05 |Title of the Topic |a study on drug - drug interaction between sildenafil citrate and |

| | |oral anti-diabetic drugs |

|06 |Brief resume of the intended work | |

| |6.1. Need for the Study |Enclosure – I |

| |6.2. Review of the Literature |Enclosure – II |

| |6.3. Objective of the Study |Enclosure – III |

|07 |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 |Enclosure – VI |

| |Investigations on animals? | |

| |If yes give details | |

| |7.4. Has ethical clearance been |Yes, Registration No: 157 / 1999/ CPCSEA |

| |obtained form your institution |(Copies enclosed) |

| |in case of 7.3. | |

|08 |List of References (About 4 – 6) |Enclosure – VII |

|09 | | |

| | | |

| |Signature of the Candidate | |

| | |(AJAY PRATAP SINGH) |

|10 |Remarks of the Guide | |

| | |Enclosure – VIII |

|11 |Name and Designation of | |

| |(in Block Letters) | |

| | | |

| |11.1. Guide |Dr. S. V. RAJENDRA |

| | |M. Pharm, Ph.D. |

| | |Professor |

| | |P.G Department of Pharmacology |

| | |S.C.S. COLLEGE of Pharmacy, |

| | |Harapanahalli-583131, (Karnataka ) |

| | | |

| |11.2.Signature | |

| | | |

| | | |

| | | |

| | | |

| |11.3.Co-Guide (if any) | |

| | | |

| | |__ |

| | | |

| | | |

| |11.4.Signature | |

| | | |

| | | |

| | | |

| |11.5. Head of the Department | |

| | | |

| | |Prof. A. Veerana Gaud |

| | |M.Pharm. |

| | |Head of the dept. of pharmacology |

| | |S.C.S. COLLEGE OF PHARMACY |

| | |HARAPANAHALLI-583 131 |

| | |DAVANGERE. (DIST.) |

| | |KARNATAKA |

| |11.6. Signature | |

| | | |

| | | |

|12 |Remarks of the Principal |The intended work is related to drug-drug interaction. This study |

| | |will be useful for clinicians while prescribing the |

| | |thiazoliedinediones. The work is feasible & can be carried out in |

| | |the dept. of Pharmacology, S.C.S college of pharmacy, Harapanahalli.|

| | | |

| | | |

| | | |

| | | |

| |12.1. Signature |Principal |

ENCLOSURE-I

06. Brief resume of Intended Work

6.1 Need for the study.

There are several incidences that a patient may be suffering from more than one disease at a time and require simultaneous treatment for both the diseases. In such situations, multiple drugs have been prescribed by physicians to treat more than one disease. If more than one drug has been administered, there is every possibility of occurrence of drug interactions1. It is known that the incidence of ADR to drugs rise from 4.2% when five or fewer drugs are used to 45% when twenty or more drugs are used2. This may either enhance or diminish the effect of simultaneously administered drugs which results in useful or harmful effects on the patient. The useful drug interaction is illustrated by synergistic combination of drugs such as antibiotics or antihypertensives2. Harmful drug interactions are unfortunately more numerous2. During drug interactions, one drug may influence the efficacy of other drugs either pharmacokinetically or pharmacodynamically. Infact, pharmacokinetic drug interactions are more common than pharmacodynamic interactions. Pharmacokinetic interactions may be elicited at the time of absorption, distribution of drugs, metabolism and elimination. During metabolic interactions, one drug may influence the effect of another drug either by cytochrome P450 enzyme induction or inhibition. Inhibition of CYP enzymes increases the pharmacological activity while induction reduces the efficacy of co-administered drugs. Therefore it is essential to assess the statistical possibility of occurrence of drug-drug interactions so as to enhance the efficacy, safety and to reduce toxicity.

Erectile dysfunction (ED) is defined as the consistence or recurrent inability of a man to attain and/or maintain penile erection sufficient for sexual activity3. Erectile dysfunction is a highly prevalent health problem4. Erectile dysfunction (ED) is a common complication of diabetes and an important cause of decreased quality of life in men with diabetes. The prevalence of ED is observed in many people throughout the world5. The prevalence of diabetes mellitus is also increasing with non-insulin-dependent (type 2) accounting for 90–95% of the diagnosed diabetic patients6. Erectile dysfunction frequently represents a neurovascular complication of diabetic mellitus, and it has been calculated that almost 50% of diabetic men will have erectile dysfunction within 6 years after diagnosis7. ED in diabetic men has been associated with diabetic neuropathy, peripheral vascular disease, poor glycemic control, use of specific types of medications and increased age8.

There are many instances that a patient may be suffering with diabetes mellitus associated with erectile dysfunction. Then the patient has to be treated simultaneously with antidiabetic drugs and sildenafil citrate. In the current study, it is planned to observe the influence of sildenafil citrate [a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5)] 9, more commonly prescribed drug in erectile dysfunction on the commonly used antidiabetic drugs like pioglitazone and rosiglitazone (thiazoliedinedione class). Since, sildenafil citrate is known to inhibit multiple cytochrome P-450 enzyme system; there is a possibility of occurrence of pharmacokinetic type of drug interactions with concomitantly used antidiabetic drugs like pioglitazone and rosiglitazone. The study drugs (thiazoliedinedione like pioglitazone and rosiglitazone) are metabolized by cytochrome P-450 enzyme system, while sildenafil citrate is an inhibitor of cytochrome P-450 enzymes. When such combinations are being employed, there may be occurrence of drug interactions between them. Further, maintenance of blood glucose levels is very much required in diabetic patients. The interaction could result in severe hypoglycemia or there may be reduction in the effectiveness of the one or either of the administered drugs. Since there are no reports of drug interactions between the study drugs, it is planned to undertake the influence of sildenafil citrate on the hypoglycemic activity of some selected thiazoliedinedione like pioglitazone and rosiglitazone in various experimental models. Further the outcome may be useful to the physician to adjust the dose and frequency of administration of thiazoliedinediones when concurrently administered with sildenafil citrate. Hence the study is needed and the work is justifiable.

ENCLOSURE-II

6.2 Review of literature:

Sildenafil citrate is a popular drug in the treatment of erectile dysfunction and is a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5)9. It is approved for the treatment of erectile dysfunction10, pulmonary arterial hypertension (PAH)11, useful for the prevention and treatment of high-altitude pulmonary edema associated with altitude sickness (such as that suffered by mountain climbers)12, 13. Sildenafil is also a weak inhibitor of CYP enzymes such as CYP 3A4, 2C9, 2C19, 1A2, 2D6 and 2E114. ED in diabetic patients is principally related to organic causes such as vasculogenic and neurogenic abnormalities15.

Antidiabetic drugs like rosiglitazone is a substrate for the CYP2C8 and to a lesser extent CYP2C9 pathways, and pioglitazone is a substrate for CYP2C8 (39%) and CYP3A4 (17%), as well as several other CYP450 pathways17, 18. Rosiglitazone and pioglitazone metabolism in vivo may be affected by inhibitors or inducers of CYP2C9 and CYP3A4, but no significant drug-drug interactions have been reported with sildenafil citrate which weakly inhibits the cytochrome P-450 isoenzyme CYP 3A4 and CYP 2C9 which is involved in the metabolism of pioglitazone17,18,25 and rosiglitazone17,18. There are reports that sildenafil citrate can interact with drugs such as atazanavir, indinavir, saquinavir, and ritonavir etc16. Sildenafil also interacts with azole antifungals, erythromycin, cimetidine (causes symptomatic hypotension) 22, grapefruit juice, rifampicin23, adrenergic blockers like doxazocin24. But there are no reports of drug interactions between sildenafil citrate and oral antidiabetic agents such as pioglitazone and rosiglitazone. Further sildenafil citrate is a weak inhibitor of many CYP enzymes which are involved in the metabolism of thiazoliedinediones under study14, 17, 18, 25. Therefore the present study is planned to investigate the influence of sildenafil citrate on the hypoglycemic effect of some selected thiazoliedinedione like pioglitazone and rosiglitazone in normal as well as diabetic animals.

.

ENCLOSURE – III

6.3 Objectives of the study:

Since there are several reports that sildenafil citrate interfere with cytochrome P-450 enzyme system and there by alter the pharmacokinetics of various drugs that are metabolized by this enzyme system when they are used concomitantly. Even sildenafil citrate is likely to alter the pharmacokinetic properties of orally administered anti-diabetic agents like pioglitazone and rosiglitazone. Hence, the present study is planned with the following objectives.

01. To study the influence of repeated administration of sildenafil citrate per se on the blood glucose levels in experimental animals.(rats and rabbits)

02. To study the influence of single and multiple doses of sildenafil citrate on the hypoglycemic activity of pioglitazone and rosiglitazone in experimental animals. (rats and rabbits)

03. To study the influence of single and multiple doses of sildenafil citrate on the anti-diabetic activity of pioglitazone and rosiglitazone in the experimentally induced diabetes in rats (alloxan induced diabetic rats).

04. It is also planned to investigate the effects of sildenafil citrate on the insulin levels in experimental animals

05. To suggest the alteration in the dose and frequency of administration of hypoglycemic agents like pioglitazone and rosiglitazone when they are used along with sildenafil citrate.

ENCLOSURE – IV

7. Material & methods

7.1 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 and diabetic rats in the experiments. Estimation of blood glucose levels at a regular interval after the administration of hypoglycemic agents to normal/diabetic animals with or without pre treatment of sildenafil citrate is important criteria for generating required data. This study is also intended to generate data by using certain pharmacological tools. In addition it is also planned to take some data from the available literature.

ENCLOSURE – V

7.2 Method of collection of data:

The whole study is divided into three phases to generate data. Following are the four phases.

Phase-I: It is planned to study the influence of sildenafil citrate per se on the blood glucose levels in rats, rabbits and alloxan induced diabetic rats. It is also planned to investigate the effect of single and multiple doses of sildenafil citrate on the hypoglycemic activity of anti-diabetic drugs (pioglitazone and rosiglitazone) in normal albino rats.

Phase II: In this phase, the experiments of previous phase will be repeated in the normal albino rabbits (It is mandatory to establish drug interactions in two dissimilar species). Further, there are reports that the carnivorous animals (rats) and herbivorous animals (rabbits) responds differentially to insulin variations, i.e. rats are more sensitive to insulin lack than rabbits19. In the present study, there is a possibility of occurrence of insulin variations during interaction. Therefore in the II phase of study, rabbits have been selected.

Phase III: In this phase, it is planned to estimate the insulin concentrations in experimental animals before and after pretreatment with sildenafil citrate.

Phase IV: In this phase, diabetic rats (alloxan induced diabetic rats) will be used to study the possible drug-drug interaction of sildenafil citrate and oral anti-diabetic drugs (pioglitazone and rosiglitazone) when they are used concomitantly in the patho-physiological conditions.

I) Study Subjects and groups: Normal rats, normal rabbits and alloxan induced diabetic rats will be used. Six rats and rabbits will be used in each group. Groups are made for single/ multiple dose/doses study in various experimental animals.

For single dose study: Sildenafil citrate is given one hour prior to thiazoliedinediones and then the blood samples will be collected at frequent intervals on the same day.

Doses are converted to animals doses from human doses.

Human doses for sildenafil citrate are 25mg and 100 mg. Then the two lower and higher subsequent doses in animals will be 2.5mg/kg and 10 mg/kg.

For multiple dose study: Sildenafil citrate is administered for 7 consecutive days and on 8th day, one hour after sildenafil citrate, thiazoliedinediones are administered and the blood samples will be collected. However, same doses of sildenafil citrate are considered for the current investigation.

II) Inclusion criteria:

Normal rats: Albino Wistar rats of either sex, weight range 200-250 G.

Normal rabbits: Albino rabbits of either sex, weight range 1.5-2.0 kg.

Diabetic rats: Alloxan induced diabetic rats of either sex; weigh between 200-250G. The diabetic rates with more than 200 mg/dl of blood glucose levels will be selected for study.

Exclusion Criteria: Any animal which do not comply with the above criteria are excluded from the study.

III) Study sampling & design:

A. Estimation of plasma glucose- GOD-POD method20.

It is one such evolved method by Trinder in 1969. This method is simple, single, stepped, rapid & reliable and there is precision. Hence, this method is adopted in the present investigation. Trinders method (1969) utilizes two enzymes glucose oxidase (GOD) and peroxidase (POD) along with the chromogen L-amino antipyrine and phenol. This method is for in vitro quantitative determination of glucose in serum / plasma or cerebrospinal fluid. Hemoglobin or bilirubin upon 10 mg % does not affect the test.

Principle

Glucose is determined after enzymatic oxidation in the presence of oxidase. The hydrogen peroxide so formed reacts under catalysis of peroxidase with phenol and 4-amino antipyrine (4 AAP) to form red colored quinoneimine compound that is measured at 505nm and the intensity is directly proportional to glucose concentration.

Glucose + O2 + H2O GOD Gluconic acid + H2O2

H2O2 + 4AAP + Phenol POD Red quinoneimine complex + H2O

Blood is withdrawn from the experimental animals at predetermined time intervals i.e. 00, 0.5, 1. 2. 4. 8. 12 and 24 h (rat blood through retro-orbital sinus and rabbit blood through marginal ear vein).

B. Estimation of plasma insulin

The serum insulin levels were estimated by Radio-immuno assay26, 27.

Assay principle

The radio-immuno assay method is based on the competition of unlabelled insulin in the standard or samples and radio-iodinated (I-125) insulin for the limited binding sites on a specific antibody.

At the end of incubation, the antibody bound and free insulin were separated by the second antibody-polyethylene glycol (PEG) aided separation method. Insulin concentrations of samples are quantitated by measuring the radioactivity associated with the bound fraction of sample and standard.

Procedure

For the estimation of insulin in serum, a standard curve is to be prepared. For the preparation of standard curve, the reagents given in the assay kit are added, when the addition of insulin antiserum is completed, the tubes are mixed gently and incubate all the tubes at +2 to +40 C overnight. Then radiolabeled iodine i.e. I125 Insulin is added to all the tubes. Mixed gently and incubate all the tubes for 3 h at room temperature. The second antibody and PEG are added to all these tubes. Then the tubes are vortexed and they are kept at room temperature for 20 min. The tubes are centrifuged at 1500 rpm for 20 min. After centrifugation, supernatant fluid is decanted off and radioactivity is counted in the precipitate using gamma scintillation counter.

Similarly, the sample/test tube is also run as per the flow chart and the calculations were done using below mentioned formula:

Calculations

Count of standard/sample

% Binding (B/Bo) = x 100

Count of zero standard tube

Where

Bo = Zero standard binding (counts)

B = standard/sample binding (counts)

A standard graph is plotted i.e. % B/Bo against µU/ml of insulin on logit log paper. Then the results are analysed by Paired Student’s- t- test using Graph pad prism.

IV). Parameters of the study: Onset of action: The beginning of pharmacologic response. It corresponds to the time for the plasma concentration to reach minimum effective concentration after administration of drug.

Peak effect: It is the maximum pharmacologic response produced by the peak plasma concentration of drug.

Duration of action: The time period for which the plasma concentration of drug remains above the MEC level is called duration of drug action21.

Statistical test: Student’s t-test (paired t- test is used for statistical significance)

V) Duration of study: Total duration of experimentation will be around 08 months.

However, follow up is not required during our study.

Study structure and design

The general scheme of the study which is followed though out the investigation is compiled in the following table;

| | | | | |

|Study |Pretreatment medication and dose |Duration of pretreatment|Study drug and dose |Washing period |

| | | | |(weeks) |

|1 |2% w/v gum acacia (normal rats), dose | | | |

| |volume matched with the average of |7 days at 08:00 am |2% w/v gum acacia on 8th day |- |

| |volume of drug treatments in the | |at 08:00 am | |

| |subsequent studies | | | |

| | | | | |

| 2 |Sildenafil citrate 10mg/kg (normal rats)|7 days at 08:00am |Sildenafil citrate on 8th day | |

| | | |at 8 am |- |

|3 |None |On day 1 |Pioglitazone 10mg/kg & | |

| | | |rosiglitazone 720µg/kg (normal |2 |

| | | |rats) p.o. on the day at 08:00| |

| | | |am | |

|4 |Sildenafil citrate 2.5mg/kg, |Same day and 7 days at |Pioglitazone 10mg/kg & | |

| |& 10mg/kg (normal rats) |08:00 am |rosiglitazone 720µg/kg |2 |

| |(Total 8 groups containing 6 in each) | |(normal rats) on 8th day at | |

| | | |09:00 am * | |

|5 |Sildenafil citrate 10mg/kg (normal rats)|7 days at 08:00am |Sildenafil citrate on 8th day | |

| | | |at 8 am (normal rabbits) |- |

|6 |None |On day 1 |Pioglitazone 10mg/kg& | |

| | | |rosiglitazone 720µg/kg (normal |2 |

| | | |rabbits) p.o. on the day at | |

| | | |08:00 am | |

|7 |Sildenafil citrate2.5mg/kg, &10mg/kg |Same day and 7 days at |Pioglitazone 10mg/kg & | |

| |(normal rabbits) |08:00 am |rosiglitazone 720µg/kg |2 |

| |(Total 08 groups containing 5 rabbits in| |(normal rabbits) on 8th day at | |

| |each) | |09:00 am | |

|8 |Sildenafil citrate 10mg/kg (diabetic |7 days at 08:00am |Sildenafil citrate on 8th day | |

| |rats) | |at 8 am |- |

|9 |None |On day 1 |Pioglitazone 10mg/kg & | |

| | | |rosiglitazone 720µg/kg |2 |

| | | |(diabetic rats) p.o. on the | |

| | | |day at 08:00 am | |

|10 |Sildenafil citrate 2.5mg/kg & 10mg/kg |Same day and 7 days at |Pioglitazone 10mg/kg & | |

| |(diabetic rats) |08:00 am |rosiglitazone 720µg/kg |2 |

| |(Total 08 groups containing 6 diabetic | |(diabetic rats) on 8th day at | |

| |rats each of animals) | |09:00 am | |

* Many groups are considered as per the need of the study

*Insulin levels are also estimated by Radio immune assay

ENCLOSURE – VI

7.3 Does the study require any investigation or interventions to be conducted on patients or other humans or animals? If so, please describe briefly.

Yes, the above study requires investigation on animals i.e., albino rats & rabbits for drug-drug interaction study.

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 certificate enclosed).

ENCLOSURE –VII

8.1 List of references

1. Yadav AV, Yadav BV. Hand book of Clinical Pharmacy; Jun 2004.

2. Satoskar RS, Bhandarkar SD, Ainapure SS. Pharmacology and Pharmacotherapeutics; 2001.

3. Lewis RW, Fugl-Meyer KS, Bosch R et al.: Definitions, Classifications and epidemiology of Sexual Dysfunction. In: Sexual medicine. Sexual dysfunctions in men and women. Lue TF, Basson R, Rosen R, Giuliano F, Khoury S, Montorsi F (Eds), Plymbridge F, Distributors Ltd. Plymouth, UK 2004; 37-72.

4. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151:54–61.

5. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. New England Journal of Medicine. 1998;338: 1397– 1404.

6. Rendell MS, Rajfer J, Wicker PA, Smith MD, Sildenafil Diabetes Study Group. Sildenafil for treatment of erectile dysfunction in men with diabetes. JAMA 1999; 281421–6.

7. Expert Opinion, Drug Metabolism Toxicology 2007; 3(3); 451-464.

8. McCulloch DK, Young R.J, Prescott RJ, Campbell IW, Clarke BF. (1984). The natural history of impotence in diabetic men. Diabetologia; 26; 437– 440.

9. Wagner G, Montorsi F, Auerbach S, Collins M. Sildenafil citrate (VIAGRA) improves erectile function in elderly patients with erectile dysfunction: a subgroup analysis. J Gerontol A Biol Sci Med Sci. 2001; 56:M113—M119.

10. Vardi M, Nini A. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus. Cochrane Database Syst Rev (1): CD002187 [Internet]. 2007. Available from: DOI:10.1002/14651858.CD002187.PUB3

11. Pfizer. 2005 June 6. (FDA Approves Pfizer's Revatio as Treatment for Pulmonary Arterial Hypertension). [Internet]. 2005 [updated 2005 news releases. Pfizer; cited 2005 December 27]. Available from:

12. Richalet JP, Gratadour P, Robach P. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am. J. Respir. Crit. Care Med. 171 (3): 275–81. [Internet]. 2005 Available from: DOI: 10.1164/rccm.200406-804OC

13. Perimenis P. "Sildenafil for the treatment of altitude-induced hypoxaemia". Expert Opin Pharmacother 6 (5): 835–837. [Internet] 2005. Available from: DOI: 10.1517/14656566.6.5.835

14. Pfizer. 1999 March. (Viagra US Prescribing Information. Revised). [Internet]

1999. Available from: ‚s/ viagrapi.html

15. Saenz de Tejada I, Goldstein I. Diabetic penile neuropathy. Urol Clin North Am 1988; 15:17–22.

16. Karen Baxter. Stockley’s Drug Interactions Pocket Companion, Pharmaceutical Press, 2009; 371

17. Baldwin SJ, Clark SE, Chenery RJ. Characterization of the cytochrome P450

enzymes involvedin the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol. 1999; 55: 53 –56.

18. Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin Pharmacol Ther. 2004; 76:239 –249.

19. Laddprosser C. Comparative animal physiology. 3rd edition, Santhosh book enterprises. Agra, 1985 ; 864.

20. Trinder P. Annals of Clin bio chem; 1969.

21. Brahmankar DM. Sunil BJ. Biopharmaceutics and Pharmacokinetics-A Treatise. Vallabh Prakashan; 1995.

22. Dresser GK, Spence JD, Bailey DG, Pharmacokinetic-Pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000; 38(1):41-57.

23. Carson CC, Lue TF, Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int. 2005; 96: 257-280.

24. Kloner RA, Brown M, Prisant LM, Colllins M. for the sildenafil study group:effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Am J. Hypertens. 2001; 14:70-73

25. Jaakkola T, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin Pharmacol Ther. 2005; 77: 404 –414.

26. Yalow RS and Berson SA. Immunoassay of endogenous plasma insulin in man. J Clin Invest 1960; 39:1157.

27. 27. Jorgensen KR. Radioimmuno assay of insulin in plasma and urine in obese subjects and in diabetic patients. Acta endocr 1969; 60:719.

ENCLOSURE-VIII

Remarks of the guide: -

The intended work is related to drug-drug interaction. This study will be useful for clinicians while prescribing the thiazoliedinediones along with sildenafil citrate in a patient suffering with DM with ED. The work is feasible and can be carried out in the dept. of Pharmacology, S.C.S College of pharmacy, Harapanahalli.

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