RESUMEN
The purpose of this study was to assess the embryotoxic, fetotoxic, and teratogenic potential of METASYSTOX-R (MSR) in the rat. Furthermore, the study was designed to determine if maternally toxic doses of MSR altered fetal brain acetylcholinesterase (AChE), compromised neonatal survival, growth, and development, or affected neurobehavioral development. Inseminated female rats (45/dose group) received single daily oral doses of 0, 0.5, 1.5, or 4.5 mg/kg of MSR from Days 6 to 15. Dose groups were subdivided into three termination phases: Phase I, 5 females terminated on Day 16 of gestation; Phase II, 28 females terminated on Day 20 of gestation; Phase III, 12 females terminated on Day 21 postpartum. MSR produced a dose-related reduction in maternal plasma (30-72%), red blood cell (18-56%), and brain (21-68%) cholinesterase (ChE) activity, when measured on Day 16 of gestation. The high dose of MSR significantly (p less than or equal to 0.05) reduced food consumption, suppressed body weight gain, and produced tremors in 98% of the dams. MSR administered at maternally toxic doses as high as 4.5 mg/kg was devoid of embryotoxic, fetotoxic, and teratogenic effects. Fetal brain AChE was not substantially different from control for any dose level in Day 20 fetuses. Furthermore, neonatal survival, growth, and development were unaffected and an extensive neurobehavioral testing scheme demonstrated no alteration of sensory or reflex functions, maze learning ability, or open field activity for neonates.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Insecticidas/toxicidad , Compuestos Organotiofosforados/toxicidad , Animales , Encéfalo/enzimología , Colinesterasas/análisis , Femenino , Feto/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Embarazo , Ratas , Ratas Endogámicas , Reproducción/efectos de los fármacosRESUMEN
The toxicity of rioprostil was extensively investigated. Studies in rodents, dogs and monkeys indicate a low order of acute toxicity. Oral subchronic and chronic toxicity studies in rats and dogs produce effects that would be expected based on the pharmacological activity of the compound. In reproduction studies with rioprostil, male and female fertility is unaffected in rats at doses up to 2.0 mg/kg/day and there is no evidence of embryotoxicity, fetotoxicity, or teratogenicity in rats at doses up to 1.7 mg/kg/day. In rabbits a maternally toxic dose (1.5 mg/kg) also increases resorptions, reduces fetal weight, and increases the incidence of malformations. Evaluation of 24-month carcinogenicity studies in mice and rats at oral doses up to 2.0 and 1.5 mg/kg/day, respectively, are in progress. Mutagenicity studies are negative.
Asunto(s)
Antiulcerosos/toxicidad , Prostaglandinas E/toxicidad , Animales , Pruebas de Carcinogenicidad , Femenino , Masculino , Pruebas de Mutagenicidad , Prostaglandinas Sintéticas/toxicidad , Reproducción/efectos de los fármacos , RioprostiloRESUMEN
Pathologic examination of sternums from young growing rats revealed a number of skeletal lesions involving both cartilage and bone elements. Degeneration or aseptic necrosis of the intersternebral cartilage was a frequent finding in most rats that were examined either at 130 or 180 days of age. Thickening of the sternal cortices and trabeculae containing prominent cement lines were less frequently occurring lesions in these sternums. These changes were absent in rats of 70 days of age. The etiology of the lesions is not understood, although several factors may be incriminated.
Asunto(s)
Enfermedades Óseas/veterinaria , Ratas/crecimiento & desarrollo , Enfermedades de los Roedores/epidemiología , Animales , Enfermedades Óseas/epidemiología , Enfermedades Óseas/patología , Necrosis , Enfermedades de los Roedores/patología , Esternón/patologíaRESUMEN
Histologic, histochemical, and electron microscopic studies of generalized ceroid-lipofuscinosis in a cynomolgus monkey are presented. Histologically, a wide variety of tissue cells contained numerous bright eosinophilic intracytoplasmic granules that varied in size from 0.5 micron to 4.0 microns in diameter. Histochemically, the granules gave a weakly positive reaction with periodic acid-Schiff and for lipids. They were weakly acid fast and capable of emitting autofluorescence. Ultrastructurally, the granules were single unit membrane-bound, and contained dense osmiophilic material with frequent concentric or fingerprint-type lamellar formation. The granules were different than hemofuscin, iron, and bilirubin. Tinctorially the granules were unique--they were bright red with hematoxylin and eosin and, thus, differed from typical age-related lipofuscin pigment.
Asunto(s)
Macaca fascicularis , Macaca , Enfermedades de los Monos/patología , Lipofuscinosis Ceroideas Neuronales/veterinaria , Envejecimiento , Animales , Gránulos Citoplasmáticos/metabolismo , Gránulos Citoplasmáticos/ultraestructura , Histocitoquímica , Humanos , Lipofuscina/metabolismo , Masculino , Enfermedades de los Monos/metabolismo , Lipofuscinosis Ceroideas Neuronales/metabolismo , Lipofuscinosis Ceroideas Neuronales/patologíaRESUMEN
The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.