8 research outputs found
EMBRYOTOXICITY OF FUSARIUM MYCOTOXINS, ZEARALENONE AND T-2 TOXIN, IN RATS
The embryotoxicity of the estrogenic mycotoxin, zearalenone (ZEN), and a cytotoxic trichothecene mycotoxin, T-2 toxin (T-2), was investigated in a series of separate experiments. ZEN administered as a single oral dose (50 mg ZEN/kg BW) to 26 mated female rats, during the period of embryonic transport (either 1 or 3 days after mating), completely inhibited embryonic implantation in 18 rats. When examined 12 days after mating, only 2 of the remaining 8 rats had sites of embryonic implantation with morphologically viable embryos. The other 6 rats had sites of embryonic resorption characterized microscopically as deciduomas without embryonic tissue or with embryonic tissue that was retarded in development and degenerate. In an additional 25 pregnant rats similarly treated with ZEN, embryonic transport was accelerated. At least 1 embryo was recovered prematurely from the uterine horns of 18 rats. The number of embryos recovered per rat was diminished indicating that some embryos had been expelled through the vagina. Embryos were not morphologically altered. These findings confirm the estrogenic activity of ZEN in rats, as indicated by altered endometrial responsiveness to embryonic implantation and accelerated embryonic transport. T-2 administered as a single oral dose (2.5 mg/kg BW) to 10 mated female rats, during the period of embryonic organogenesis (11 days after mating), caused complete embryonic resorption in 8 surviving rats examined 5 days after treatment. Eleven of 16 surviving pregnant rats similarly treated but examined 6 to 28 hours after treatment had embryos with multifocal necrosis exemplified by extensive apoptosis of neuroepithelial cells. Two of these rats were moribund and their embryos had diffuse hydropic degeneration indicating hypoxic injury. Although T-2 is directly toxic to rapidly-proliferating cell populations, maternal toxic effects, such as decidual thrombosis, may have contributed secondarily to the embryotoxic effect. Eight surviving pregnant rats treated similarly with a lower dose of T-2 (1.5 mg/kg BW) had partial embryonic resorption, but also had clinical signs and lesions of T-2 intoxication. Fetuses of 5 pregnant rats treated similarly with a nontoxic dose of T-2 (1.0 mg/kg BW) had no morphological evidence of congenital malformation
Hyperglycemic Zucker diabetic fatty rats are resistant to the adverse effects of a potent glucokinase activator
Glucokinase, which catalyzes the initial step in glycolysis (glucose-6-phosphate formation), is a key regulator of glucose homeostasis. As a result, glucokinase activators have been in development for the treatment of type 2 diabetes. Daily administration of a Bristol-Myers Squibb glucokinase activator (BMS-GKa) to healthy euglycemic Sprague Dawley (SD) rats and beagle dogs in 1-month studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures that were comparable to those expected at therapeutic clinical exposures. A subsequent study was conducted in markedly hyperglycemic, insulin-resistant Zucker diabetic fatty (ZDF) rats. Daily oral administration of BMS-GKa to male ZDF rats for 1 month did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1-month SD rat study at exposures that exceeded those observed in SD rats. This confirmed that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GKa activation and would not occur in diabetics where baseline glucose levels would be much higher providing a compelling justification to proceed to early clinical studies in diabetic patients
The Dual Peroxisome Proliferator-Activated Receptor α/γ Activator Muraglitazar Prevents the Natural Progression of Diabetes in db/db
Utilization of the Zucker Diabetic Fatty (ZDF) Rat Model for Investigating Hypoglycemia-related Toxicities
Epidemiologic study of relationships between consumption of commercial canned food and risk of hyperthyroidism in cats
Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes
Systemic Loss of C-terminal Src Kinase Expression Elicits Spontaneous Suppurative Inflammation in Conditional Knockout Mice
Synthesis and Antiobesity Properties of 6‑(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)Âmethoxy)-3-methoxyphenyl)Âthieno[3,2‑<i>d</i>]pyrimidin-4(3<i>H</i>)‑one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor
The potent MCHR1 in vitro and in vivo
antagonist activity of a series of cyclic tertiary alcohols derived
from compound <b>2b</b> is described. Subsequent pharmacokinetic
and pharmacodynamic studies identified BMS-814580 (compound <b>10</b>) as a highly efficacious antiobesity agent with a relatively
clean in vitro and in vivo safety profile