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TERATOGENIC EFFECTS OF ORAL HYPOGLYCEMIC AGENTS

口服降糖药的致畸作用

基本信息

批准号：
2673690
负责人：
IDA M. WASHINGTON
金额：
$ 10.54万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 1999-12-31
项目状态：
已结题

项目摘要

Oral hypoglycemic agents (OHAs), including sulfonylureas and biguanides, are widely used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), but the teratogenic effects and mechanisms of these drugs are poorly understood. OHA teratogenicity has been suggested in humans and demonstrated in laboratory animals in vivo, but these findings are complicated by an increased risk of congenital malformations in the offspring of diabetics, in general, as well as the inability to distinguish in vivo between teratogenic effects of a compound, per se, and the influence of metabolic changes produced in the maternal system. Preliminary work in this laboratory using the in vitro method of whole- embryo culture and the neurulating mouse embryo as a model has demonstrated embryopathic effects of two widely-used sulfonylureas, tolbutamide and chlorpropamide, and the biguanide, metformin. The most important side-effect of sulfonylurea therapy is hypoglycemia, but this factor was found not to be responsible for the observed embryopathic effects. The hypothesis of this proposal is that teratogenesis produced by tolbutamide, chlorpropamide, and metformin is due to placenta transfer and direct effect of these agents on the embryo during the sensitive stage of organogenesis. Tolbutamide and chlorpropamide are proposed to act by blocking ATP-dependent K+ (KATP) channels and/or alteration of glucose uptake and metabolism. whereas metformin is proposed to act by altering glucose uptake and metabolism. The specific aims of this research will address this hypothesis by determining whether or not the sulfonylureas, tolbutamide and chlorpropamide, 1) cross the placenta during organogenesis using HPLC assays of maternal serum and embryonic fluid and tissues following maternal dosing; 2) block KATP channels during organogenesis and are counteracted by KATP channel openers by patch-clamping single embryonic cells; and 3) alter glucose uptake and metabolism within the embryo undergoing organogenesis by measuring glucose uptake, incorporation, and glycolytic metabolism following OHA exposure, and are counteracted in vitro by superoxide dismutase (SOD). Metformin will be investigated to determine whether or not this drug 1) crosses the placenta during organogenesis; and 2) alters glucose uptake and metabolism in embryos undergoing organogenesis, and is counteracted in vitro by SOD. The goal of this work is to better define teratogenic risks and mechanisms of OHAs in order to provide information critical to the therapeutic management of pregnant NIDDM patients. In addition, these experiments will provide new information regarding the potential role of KATP channels in normal and abnormal embryonic development.

口服降糖药（OHA），包括磺酰脲类和双胍类，广泛用于治疗非胰岛素依赖型糖尿病糖尿病（NIDDM），但致畸作用和机制，这些对毒品了解甚少。OHA致畸性已被认为是在人类和实验室动物体内证明，但这些发现由于先天性畸形的风险增加，一般来说，糖尿病患者的后代，以及无法在体内区分化合物本身的致畸作用，和母体系统产生的代谢变化的影响。本实验室使用体外方法进行的初步工作- 胚胎培养和神经发育小鼠胚胎作为模型，证明了两种广泛使用的磺脲类药物的胚胎病效应，甲苯磺丁脲和氯磺丙脲，以及双胍，二甲双胍。最磺酰脲类药物治疗重要副作用是低血糖，因子被发现不是负责所观察到的胚胎病方面的影响. 这一提议的假设是，甲苯磺丁脲、氯磺丙脲和二甲双胍是由于胎盘转移以及这些药剂在敏感期对胚胎的直接作用器官形成的过程甲苯磺丁脲和氯磺丙脲的作用方式如下：阻断ATP依赖性K+（KATP）通道和/或改变葡萄糖吸收和代谢。而二甲双胍被认为是通过改变葡萄糖摄取和代谢。这项研究的具体目标将通过确定磺酰脲类药物，甲苯磺丁脲和氯磺丙脲，1）在器官发生期间穿过胎盘使用母体血清和胚胎液及组织的HPLC测定在母体给药后; 2）在器官发生期间阻断KATP通道，被KATP通道开放剂通过膜片钳单胚胎细胞;和3）改变葡萄糖摄取和代谢内通过测量葡萄糖摄取进行器官形成的胚胎， OHA暴露后的糖酵解代谢，在体外被超氧化物歧化酶（SOD）所抵消。梅特涅将是研究以确定该药物1）是否穿过胎盘在器官发生过程中;和2）改变葡萄糖的摄取和代谢，胚胎经历器官形成，并在体外被SOD抵消。的这项工作的目标是更好地确定致畸风险和机制， OHA，以便提供治疗关键信息妊娠NIDDM患者的管理。此外，这些实验将提供关于KATP通道的潜在作用的新信息正常和异常的胚胎发育。