Making benznidazole a better drug for Chagas disease

项目总结/摘要 有两种非常广泛使用和有效的药物用于治疗克氏锥虫感染-苄硝唑和 硝呋替莫司虽然这两种药物在宿主中实际实现寄生虫学治愈的条件尚不确定 - 由于检测T. Cruzi，特别是在慢性感染的宿主中-这些化合物可以 治愈是没有争议的。本建议的目的是确定为什么苯并咪唑（BZ）未能实现充分 感染控制在某些情况下，并根据这些结果，朝着更好的协议， 这将带来更高的成功率。BZ是一种高效的药物，可迅速杀死绝大多数T。 cruzi在宿主中的单剂量治疗。然而，持续治愈感染需要40天的时间， 用“BZ敏感株”治疗，但不能治愈“BZ耐药”株的感染。这些数据表明，在 在T.在cruzi感染中，宿主细胞内存在寄生虫，无论出于何种原因， 药本提案中要检验的主要假设是， 治愈T.克氏锥虫与大多数菌株的耐药性以及部分菌株对苯并咪唑诱导的治愈的抗性，是由于T. cruzi来侵入药物无法进入的宿主细胞。备择假设，即T. 克氏杆菌在受感染宿主中处于休眠状态，因此对药物不敏感，也将进行研究。根据机制 BZ治疗的体内抗性，该项目还将探索将提高治疗成功率的方案， BZ敏感T. Cruzi菌株，同时还使递送的药物剂量最小化， 不良事件。更好地治疗恰加斯病的最快速途径是优化已知的， 高效的药物如BZ。该项目将实现这一目标，同时还将生成关于 生物学的T.这将有助于指导制定更好的治疗方案， 有效的药物。

Project Summary/Abstract There are two very widely used and effective drugs for the treatment of Trypanosoma cruzi infection - benznidazole and nifurtimox. Although the conditions under which these 2 drugs actually achieve parasitological cure in hosts is uncertain - due to the difficulty of detection T. cruzi, particularly in chronically infected host - the fact that these compounds can achieve cure is not debated. The purpose of this proposal is to determine why benznidazole (BZ) fails to achieve full infection control in some cases and based on these results, move toward the development of better protocols of treatment that will yield a much higher success rate. BZ is a highly effective drug, and rapidly kills the vast majority of T. cruzi in a host with a single dose of treatment. Nevertheless, consistent cure of the infection requires 40 days of treatment with "BZ-sensitive strains and fails to cure infection with "BZ-resistant" strains. These data suggest that at any one time during T. cruzi infection, there are parasites within host cells that are, for whatever reason, inaccessible to drug. The primary hypothesis to be tested in this proposal is that both the requirement of a long course of treatment for cure of T. cruzi with most strains and the resistance of some strains to BZ-induced cure, is due to the propensity of T. cruzi to invade host cells that are inaccessible to drug. The alternative hypothesis, that a subset of the population of T. cruzi in infected hosts is dormant and as a result insensitive to drug, will also be explored. Depending on the mechanism of in vivo resistance to BZ treatment, this project will also explore protocols that will improve treatment success rate for both BZ-sensitive and BZ-resistant T. cruzi strains while also minimizing dosage of drug delivered and thus the potential for adverse events. The most rapid path to better treatments for Chagas disease is to optimize the delivery of known, highly effective drugs such as BZ. This project will accomplish that goal while also generating basic information on the biology of T. cruzi infection that will help guide the development of even better treatment protocols and more highly effective drugs.