Glibenclamide

Byline: A. Jain, S. Mehta, N. Shrivastava

Type-2 diabetes (noninsulin-dependent diabetes mellitus or NIDDM) is a major health problem because of its high frequency, long duration and high risk of chronic complications. At present sulfonylureas (II and III) generation,[1],[2] biguanides, a-glucosidase inhibitors and thiazolidinediones are the pharmacological agents used orally in the management of this condition. However, their use causes variable incidence and range of untoward effects, lsuch as skin rashes, dilutional hyponatremia, transient leucopenia, thrombocytopenia, myocarditis, severe hypoglycemia, increased chances of cardiovascular deaths of unknown mechanism, lethal lactic acidosis (rare), weight loss or weight gain and edema. This highlights the importance for alternative drugs having insulinotropic effects with minimal and tolerable adverse effects.

In order to improve the therapeutic variety, we have synthesized sulfonyloxy derivatives of azalactone, sulfonyloxy compounds have close structural resemblance to sulfonylureas and compounds bearing sulfonyl group (sulfonylureas, sulfonamides, etc.) have shown eminence biological activities.[1],[2] However, these compounds have not been studied extensively. The synthesis and structure ellucidation[3] of these compounds were reported earlier.[3] In the present study, derivatives of these compounds having the structure given below were tested for their acute antihyperglycemic and hypoglycemic activity in alloxan-induced diabetic and normal fasted rabbits, respectively[Table 2].

The solutions of compounds were prepared in polyethylene glycol (P.E.G.400) to get a concentration of 40 mg/ml. Glibenclamide 2% suspension was prepared using gum acacia.

Albino rabbits of either sex (1-2kg) were selected as test animals. They were fed pellet food (Chakan Oil mills, Pune), green vegetables, soaked grams and water ad libitum and maintained under standard laboratory conditions (temperature 24-28oC, relative humidity 60-70%). Fasted rabbits were deprived of food for 16 hours but had free access of water. Rabbits were made diabetic by injecting alloxan monohyhrate (BDH) intravenously in the marginal vein of ear at a dose of 150 mg/kg. [4],[5],[6]After 12 days rabbits showing blood sugar levels of 200-250 mg/dl were considered as diabetic and included for the study.

The normal fasted rabbits and diabetic rabbits were divided into five groups of six each. Group-I served as control and received the vehicle (P.E.G. 400). Groups II-V received the solutions of newly synthesized compounds MTDA, MNADA, OCADA (at a dose of 100 mg/kg) and glibenclamide suspension (0.25 mg/kg) orally, respectively. Blood samples were collected from the marginal ear vein at 0, 1, 3, 5, 7, 24 and 48 hours after the administration of drugs.

Blood glucose level was estimated by autoanalyser (Make - Transasia, Erbachem-5, Bombay) using the commercial enzyme estimation kit (Monozyme India limited, Secundrabad, A.P.)

The results are expressed as mean <u> +</u> S.D. The difference between the groups was determined using the one way analysis of variance (ANOVA) followed by Dunnett's test with 5% significance level (P< 0.05).[7],[8]

The vehicle (P.E.G. 400) did not produce any significant alteration in blood glucose level. All the compounds produced significant hypoglycemic and antihyperglycemic effect and peak effects were observed at an interval of 5 hours [Table 1].

MTDA produced comparatively less hypoglycemic (17.39<u> +</u> 4.61%) and antihyperglycemic (18.87<u> +</u> 5.29%) peak effects as compared to that produced by glibenclamide (i.e. 39.95%<u> +</u> 3.43% and 38.55%<u> +</u> 4.92%, respectively). However, compounds MNADA and OCADA produced somewhat equipotent hypoglycemic and antihyperglycemic peak effects to that produced by glibenclamide. [Table 1]

The study reports for the first time the hypoglycemic and antihyperglycemic effects of sulfonyloxy derivatives of azalactone. The compound MTDA (m-toluidine derivative of azalactone) showed little fall in blood glucose levels, where as compound MNADA (m-nitroaniline derivative of azalactone) and OCADA (o-chloroaniline derivative of azalactone) produced significant hypoglycemic as well as antihyperglycemic effects in normal and alloxan-induced diabetic rabbits.

It is evident from the study that compounds MNADA and OCADA have similar antihyperglycemic and hypoglycemic effects. The data suggest that compounds MNADA and OCADA could have therapeutic usefulness in diabetes mellitus.

Studies are in progress to elucidate in detail the mechanism of action of these compounds at cellular and molecular levels and their toxic effects.

Acknowledgments

The authors would like to thank Dr. S.D. Tonpay, Professor and Head, Department of Pharmacology for his valuable suggestions, encouragement and support during study.

References

1. Melander A. Non insulin dependent diabetes mellitus treatment with sulfonyl ureas. In: Natrass M, Halle P, editors. Clinical endocrinology and metabolism. London: Billiere Tindal; 1988.

2. Inzucchi SE. Oral antihyperglycemic therapy for type-2 diabetes; scientific review. JAMA 2002;287:360-72.

3. Jain AK, Mehta SC, Shrivastava NM. Synthesis, structure ellucidation and antimicrobial activity of N-substituted a-benzamido-?-[3-methoxy-4-(p-toluene sulfonyloxy)]-cinnamamides. Asian J Chem 2004;16:357-64.

4. Rerup CC. Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev 1970;22:485-518.

5. Khosla P, Bhanwra S, Singh J, Seth S, Shrivastava RK. A study of antihyperglycemic effects of Azadirachta indica (Neem) in normal and alloxan induced diabetic rabbits. Indian J Physiol Pharmacol 2000;44:69-74.

6. Babu BV, Moorti R, Pugazhenthi S, Prabhu KM, Murthy PS. Alloxan recovered rabbits animal model for screening for hypoglycemic activity of compounds. Indian J Biochem Biophys 1988;25:714-8.

7. Seth UK, Dadkar NK, Kamat UG. Selected topics in experimental pharmacology. Mumbai: Kothari Book Depot; 1972.

8. Ciminera JL, Randolph LK. Statistics. In: Remington's pharmaceutical sciences. Osol A, editor. 16th ed. Chapter 10. Philadelphia: Philadelphia College of Pharmacy and Science; 1980

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