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At least 919 records · Page 51Linked to original sources
PubMed1984

Disposition in rats and dogs of ciglitazone, a new antidiabetic agent.

Oral 14C-ciglitazone was well absorbed by rats to give a maximum plasma level at two hours and an apparent half-life of 4.9 h. In dogs, the plasma level of the compound, after oral administration, reached a plateau at one hour, persisted till ten hours and then declined with a half-life of 23.5 h. In rats, plasma levels of metabolites were higher than those of unchanged ciglitazone, whereas the reverse was noted in dogs. Plasma metabolites were the monohydroxycyclohexyl derivatives (mono-ol) and monoketocyclohexyl derivatives (mono-oxo), together with other components consisting largely of dihydroxycyclohexyl derivatives (di-ol) and unknown polar metabolites. Metabolites found in rats were pharmacologically active trans-4'-ol, 3'-ol, 4'-oxo, cis-4'-ol, 3'-oxo and 2'-ol in the decreasing order listed, and those in dogs were 3'- and/or 4'-ols. Ciglitazone was highly bound to plasma protein of both animals. After oral administration of 14C-ciglitazone to rats, 14C was widely distributed in tissues, with the highest concn. in the gastrointestinal tract, followed by liver, adipose, plasma, adrenal gland, kidney, pancreas, spinal cord, heart and lung, and the lowest in the brain. The concn. of 14C in erythrocytes of rats and dogs was very low, as was the level of 14C in rat fetuses. Elimination of 14C-ciglitazone was complete within 96 h in rats and 144 h in dogs. In both animals, the dosed 14C was excreted largely in faeces as metabolites, with the remainder appearing in urine. Biliary excretion and reabsorption of 14C were obvious in rats. In both rats and dogs, the major metabolites found in faeces were 3'- and/or 4'-ols and other components derived from bile, and those in urine were other components. On repeated oral administration of 14C-ciglitazone to rats for seven days, no accumulation of 14C occurred in plasma and tissues, and 97.5% of the dose was eliminated from the body within 96 h after the last administration.

Administration, Oral↗
PubMed1980

Effects of gliclazide--a new antidiabetic agent--on blood platelet function in vitro and in vivo.

UNLABELLED: The effect of gliclazide on platelet activity was investigated and compared to that of tolbutamide and glipizide. IN VITRO STUDIES: adenosine diphosphate induced human platelet aggregation was inhibited by gliclazide in high concentrations (0.5--2.0 mg/ml). In the same concentration range tolbutamide exhibited a slightly less pronounced inhibitory effect. Collagininduced human platelet aggregation was inhibited by gliclazide, glipizide and tolbutamide in a concentration range of 0.5--2.0 mg/ml. Gliclazide had a similar effect on rabbit platelets. In vivo studies: Both acute and seven days administration of gliclazide to rabbits resulted in prolonged primary and total hemostatic plug formation time both in arterioles and venules. Similar results were obtained with tolbutamide and glipizide. Experiments with laser-induced platelet plug formation in the rabbit ear chamber demonstrated that 100 mg gliclazide/kg body weight and 25 mg gliclazide/kg body weight during 7 days significantly reduced the number of platelet emboli formed during 10 minutes after laser injury.

Adenosine Diphosphate↗
PubMed1992

Antiobesity and antidiabetic actions of a new potent disaccharidase inhibitor in genetically obese-diabetic mice, KKA(y).

AO-128 is a potent and structurally novel inhibitor of the intestinal disaccharidases, such as maltase and sucrase. Genetically obese-diabetic mice, KKA(y), were used to examine the acute or long-term effectiveness of this compound. AO-128 decreased a postprandial rise in blood glucose after sucrose solution loading dose-dependently; the ED50 to reduce a delta increment of blood glucose by 50% was 0.22 mg/kg. The intestinal sucrase and maltase activities were suppressed to 7 and 48% of the control levels, respectively, at a dose of 0.21 mg/kg. Four-week-old female KKA(y) mice were kept on a laboratory diet containing 10 or 50 ppm of AO-128 for 12 weeks. The high dose of AO-128 reduced food intake and body weight gain throughout the experimental period. On the other hand, the low dose reduced body weight gain for the first 4 weeks without any effect on food intake. Development of the hyperglycemia and hyperinsulinemia characteristic of KKA(y) mice was moderately prevented by the low dose, and completely by the high dose. Hypertriglyceridemia tended to be suppressed by the AO-128 treatment. The high dose decreased the hemoglobin A1 level and parametrial adipose tissue weight. Hepatomegaly and fatty liver were ameliorated by AO-128 dose-dependently. Nephropathy was ameliorated by the high dose. These findings indicate that AO-128 may be useful for treating human obesity and diabetes.

Animals↗
PubMed2002

PPARgamma activation and adipocyte differentiation induced by AS-6, a prenyl-phenol antidiabetic antibiotic.

The prenyl-phenol antibiotics ascochlorin-related compounds, are known to reduce serum cholesterol and triglyceride, suppress hypertension, and ameliorate types-I and II diabetes. However, little is known about the molecular mechanism for these physiological effects. Here we report that the ascochlorin derivative, 4-O-carboxymethyl ascochlorin (AS-6) acts as a potent activator of the nuclear hormone receptor, PPARgamma, although it does not activate the related receptors, PPARalpha, PPARdelta or RARalpha. AS-6 interacts directly with the PPARgamma molecule in vitro, and induces differentiation of the mouse preadipocyte cell line 3T3-L1. Our results suggest that AS-6 is a partial agonist for PPARgamma with a novel chemical structure.

Adipocytes↗