INFLAMMATION AND DRUG IDIOSYNCRASY

炎症和药物特异性

• 批准号: 6798348
• 负责人: Robert Andrew Roth
• 金额: $ 23.17万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798348
• 关键词: androgen inhibitor; antineoplastics; chlorpromazine; cysteine endopeptidases; drug administration rate /duration; drug adverse effect; drug interactions; endotoxins; enzyme activity; free radical oxygen; hepatotoxin; inflammation; laboratory mouse; laboratory rat; lipopolysaccharides; neutrophil; prostaglandin endoperoxide synthase; ranitidine; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): "Drug idiosyncrasy" refers to a toxic response to a drug that occurs in a small fraction of people and bears no obvious relationship to dosing regimen. Numerous drugs developed for various therapeutic purposes have produced in people idiosyncratic responses that have resulted in serious injury to liver and other organs. These reactions typically do not become apparent in preclinical animal studies, and little is understood about underlying mechanisms. Animal models with the potential to enable prediction/early identification of idiosyncratic responses could prevent human suffering and lead to understanding of mechanisms. In preliminary studies, we have found in rats that modest inflammation produced by a small, nontoxic dose of endotoxin (LPS) can render an otherwise nonhepatotoxic drug hepatotoxic. For example, in rats given a nontoxic dose of chlorpromazine, co treatment with a small dose of LPS resulted in liver injury and elevated plasma creatine kinase activity, two responses that occur idiosyncratically in people during therapy with this and related drugs. Similarly, a nontoxic dose of LPS; can render ranitidine hepatotoxic in rats and mice. These preliminary results suggest a novel mechanism for drug idiosyncrasy and raise the possibility of creating useful animal models for such responses in humans. The hypothesis to be tested is that idiosyncratic drug reactions that occur in humans can be reproduced in animals by drug administration during a concurrent episode of mild inflammation. Several drugs that have caused idiosyncratic liver injury in humans (chlorpromazine, ranitidine, flutamide) and two that have not (promethazine, famotidine) will be used. Rats will be co exposed to a drug and to a dose of LPS that causes "modest inflammatory response" to determine if the co treatment reproduces the idiosyncratic drug responses that people experience. Dose-response and temporal relationships will be defined. Inflammatory factors (e.g. neutrophils, tumor necrosis factor-alpha, cyclooxygenase 2) likely to be critical to the toxic response will be evaluated. In addition, a cell-based, in vitro system will be developed and used to explore intracellular signaling mechanisms that enable drugs to interact with inflammatory factors to result in synergistic hepatocyte killing. Results from these studies will be an important step toward creating predictive animal models of human drugs idiosyncrasy and exploring underlying mechanisms.

描述（由申请人提供）：“药物特质”是指对少数人的药物的有毒反应，并且与给药方案没有明显的关系。 为各种治疗目的而开发的许多药物已经在人物特质反应中产生，这导致对肝脏和其他器官造成严重伤害。 这些反应通常在临床前动物研究中并不明显，几乎没有理解有关潜在机制。 有潜力可以预测/早期鉴定特质反应的动物模型可以防止人类的痛苦并导致对机制的理解。 在初步研究中，我们在大鼠中发现，由小剂量的无毒内毒素（LPS）产生的适度炎症会导致原本非脑毒性药物肝毒性。 例如，在服用氯丙嗪无毒的大鼠中，用少量LPS的CO治疗导致肝损伤和血浆肌酸激酶活性升高，这两种反应在治疗这种及相关药物时在人治疗中发生了特殊性。 同样，LPS无毒剂量；可以在大鼠和小鼠中引起ranitidine肝毒性。 这些初步结果表明了一种新颖的药物特质机制，并提高了为人类中这种反应创建有用的动物模型的可能性。 要检验的假设是，在轻度炎症的并发发作中，药物可以在动物中复制人类发生的特质药物反应。 将使用几种引起人类（氯丙嗪，兰替丁，氟丁胺）的特质肝损伤的药物，将使用两种（异丙嗪，Famotidine）。 大鼠将与药物接触和一定剂量的LP，以引起“适度的炎症反应”，以确定CO治疗是否再现了人们经历的特质药物反应。 将定义剂量反应和时间关系。 炎症因子（例如中性粒细胞，肿瘤坏死因子-Alpha，环氧合酶2）可能对有毒反应至关重要。 此外，将开发基于细胞的基于细胞的体外系统，并用于探索细胞内信号传导机制，使药物能够与炎症因子相互作用，从而导致协同的肝细胞杀伤。 这些研究的结果将是建立人类药物的预测动物模型并探索潜在机制的重要一步。