A novel, orally effective hypoglycemic agent, SaRI 59–801, in laboratory animals

Abstract

SaRl 59-801 (59-801) (c-, is a novel, orally effective hypoglycemic compound which appears to act largely, if not entirely, by stimulation of insulin release. The compound is structurally unrelated to sulfonylurea derivatives.The 2-hr hypoglycemic EDz5 in fasting mice was 110 mglkg; the plasma insulin levels were increased, with an ED50 of 47 mglkg.Significant hypoglycemic activity was observed 2 hr after oral administration of 59-801 to fasting rats (ED25 = 86 mglkg), while plasma insulin was elevated by 62% at 100 mglkg. 59-801caused an insignificant decrease in plasma lactic acid levels. The hyperglycemic response 30 min after an oral starch load was inhibited by 1-hr pretreatment with 59-801 (ED5, = 37 mglkg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats.ln monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mglkg and an ED25 of 33 mglkg for a period of 6 hr after oral administration. In genetically diabetic (db+ldb+) mice, 59-801 was more potent in producing hypoglycemia (ED25 = 47 mglkg) than their lean littermates (ED25 = 131 mglkg). In alloxan-diabetic rats or streptozotocin-diabetic mice, this agent was inactive at 200 mglkg, but at 400 mglkg, it caused reduction of blood glucose levels of 29-39 and 21%, respectively, possibly the result of stimulation of residual P-cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59-801.

Hypoglycaemic activity ofLeucas lavandulaefolia Rees. in streptozotocin-induced diabetic rats

“…The third group received glybenclamide at a dose of 1 mg/kg) orally (Jimenez et al, 1995) as a suspension in aqueous Tween 80. The control animals received the control vehicle only (Ho et al, 1985).…”

Hypoglycaemic activity of Nelumbo nucifera gaertn. (Fam. Nymphaeaceae) rhizome (methanolic extract) in streptozotocin‐induced diabetic rats

“…Animals were divided into four groups (containing six animals in each group). Methanol extract (300 mg/kg and 600 mg/kg) was administered orally as a suspension Accepted (revised) 2 May 1994 (Ho et al, 1985). Blood sugar levels were determined at 2 , 4 , 8 and 1 2 h by the ortho-toluidine method (Hultman, 1959).…”

Stimulation of Insulin Secretion from Isolated Rat Islets by SaRI 59–801

“…1 Plasma lactic acid in rats was not elevated by 59-801, and the hypoglycemic effect of the compound was retained after 28 days of administration. 1 59-801 also decreased the hyperglycemic response of rats to an oral starch load.…”

“…1 59-801 produced only small decreases in blood glucose at high doses (400 mg/kg) in alloxan-diabetic rats or streptozocin-diabetic mice, but markedly decreased plasma glucose in genetically diabetic db/db mice. 1 The decrease in blood glucose was correlated with an increase in blood insulin in rats and mice, 1 which raised the question of whether insulin secretion could be stimulated by direct action of the compound in vitro. This report describes the stimulation of insulin release from isolated rat islets by 59-801 and its independence from islet glucose metabolism.…”