INFLAMMATION AND DRUG IDIOSYNCRASY

描述(申请人提供)：“药物特性”是指对一种药物的毒性反应，这种反应发生在一小部分人身上，与给药方案没有明显的关系。许多为不同治疗目的开发的药物在人们身上产生了特殊的反应，导致了肝脏和其他器官的严重损伤。这些反应在临床前动物研究中通常不会变得明显，对潜在的机制也知之甚少。动物模型有可能预测/早期识别特殊反应，可以防止人类痛苦，并导致对机制的理解。在初步研究中，我们在大鼠身上发现，由小剂量、无毒性的内毒素(LPS)引起的适度炎症可以使原本无肝毒性的药物产生肝毒性。例如，在给予无毒剂量氯丙嗪的大鼠中，与小剂量脂多糖联合治疗会导致肝脏损伤和血浆肌酸激酶活性升高，这两种反应是在使用这种药物和相关药物治疗期间人们特有的两种反应。同样，无毒剂量的内毒素可使雷尼替丁对大鼠和小鼠产生肝毒性。这些初步结果表明了药物特性的一种新机制，并提高了为人类的这种反应创建有用的动物模型的可能性。需要检验的假设是，在轻度炎症同时发作期间，通过给药，在人类身上发生的特殊药物反应可以在动物身上重现。将使用几种对人类造成特殊肝损伤的药物(氯丙嗪、雷尼替丁、氟他胺)和两种没有引起这种损伤的药物(异丙嗪、法莫替丁)。大鼠将同时接触一种药物和一定剂量的脂多糖，以确定联合治疗是否复制了人类经历的特殊药物反应。将定义剂量-反应和时间关系。将对可能对毒性反应起关键作用的炎症因子(如中性粒细胞、肿瘤坏死因子-α、环氧合酶2)进行评估。此外，一个基于细胞的体外系统将被开发并用于探索细胞内信号机制，使药物与炎症因子相互作用，从而导致协同肝细胞杀伤。这些研究的结果将是朝着建立人类药物特性的预测性动物模型和探索潜在机制的重要一步。

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.