MULTIFACTORIAL COMPARISON--AMINOGLYCOSIDE NEPHROTOXICITY

多因素比较--氨基糖苷肾毒性

基本信息

批准号：
3301319
负责人：
GIRARD HOTTENDORF
金额：
$ 13.85万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-01-01 至 1994-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3301319
关键词：
aminoacid inhibitor aminoglycoside antibiotics binding proteins brush border membrane cyclic aminoacid drug adverse effect drug metabolism drug receptors electron microscopy electrophysiology histochemistry /cytochemistry human tissue kidney function radionuclides renal toxin renal tubule scintillation counter tissue /cell culture

项目摘要

Aminoglycoside antibiotics remain important life-saving drugs despite their intrinsic nephrotoxicity. Extensive studies in rats indicate differences in the nephrotoxic potential of individual aminoglycosides, but these differences are difficult to assess in seriously ill patients. Data obtained in rats on pathogenic mechanisms and toxicity inhibitors also suffer from this lack of confirmation of rats as valid human surrogates. A similar lack of validation also applies to various human and animal-derived renal tissue culture systems. The integration of two recent developments may help evaluate the human relevance of in vivo rat data as well as data obtained in several in vitro systems. Utilizing brush border membranes (BBM) isolated from the primary nephrotoxic site, proximal tubule cells (PTC), two polyamino acids were identified which block the binding of aminoglycosides to BBM of rats. Subsequent in vivo studies with these polymers revealed the complete elimination of the nephrotoxicity of co-administered aminoglycosides in rats. The second development was the serial propagation of human PTC in tissue culture for the first time. Since both capabilities are now located at this institution, we propose to investigate the binding kinetics and characteristics of aminoglycosides to BBM obtained from fresh human and rat kidneys and from PTC cultures of both species. In addition, the ability of the polyamino acids to block aminoglycoside binding to BBM and to eliminate the toxicity to tissue cultures will be examined. Results of these integrated studies will further define the appropriateness of in vivo studies in rats and the usefulness of in vitro studies in tissue cultures as well as appraise the potential human utility of the nephrotoxicity inhibitors.

氨基糖苷抗生素仍然是重要的挽救生命的药物固有的肾毒性。对大鼠的广泛研究表明差异在个体氨基糖苷的肾毒性潜力中，但这些严重患者很难评估差异。数据在大鼠的致病机理和毒性抑制剂上也获得由于缺乏对大鼠作为有效的人类替代的证实而遭受的困扰。一个类似的验证也适用于各种人类和动物肾组织培养系统。最近的两个发展的整合可能有助于评估人类体内大鼠数据以及在几个体外获得的数据的相关性系统。利用从初级分离的刷子边框膜（BBM）肾毒性部位，近端小管细胞（PTC），两个聚氨基酸为确定哪个阻断了氨基糖苷与大鼠BBM的结合。随后使用这些聚合物进行体内研究表明了完整的消除共同辅助氨基糖苷的肾毒性老鼠。第二个发展是人类PTC在第一次组织培养。由于两个功能现在都位于在该机构，我们建议调查具有约束力的动力学和从新鲜的人和大鼠获得的BBM的氨基糖苷的特征肾脏和两种物种的PTC培养物。另外，聚氨基酸以阻断与BBM结合的氨基糖苷并消除将检查对组织培养物的毒性。这些结果综合研究将进一步定义体内的适当性对大鼠的研究和组织培养的体外研究的有用性以及评估肾毒性的潜在人类效用抑制剂。