...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Parasitology >Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis
【24h】

Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis

机译：药物动力学和药效学利用未受限制的靶组织暴露作为基于方位的基本原理来优化苯并恶硼酸铅在治疗2期人类非洲锥虫病中的应用

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

SUMMARY This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection models.
机译：发明内容本综述提供了用于发现新的抗寄生虫药物的进展策略，所述新的抗寄生虫药物使用体外敏感性，时间杀灭性和可逆性措施来定义动物感染模型的靶组织中所需的治疗相关暴露。通过发现SCYX-7158作为2期（CNS）人类非洲锥虫病（HAT）的潜在口服治疗，可以举例说明该策略。包括对第二阶段HAT的当前治疗方法的评论，以为实现目标组织配置的挑战以及在发现范式的早期建立药代动力学-药效学（PK-PD）措施的需求提供背景。该策略包括三个阶段。最初，对目标生物表现出有希望的体外生物活性和对哺乳动物的选择性的化合物已进行了体外代谢稳定性，屏障通透性和组织结合测定，以建立在生命功效研究期间可能达到并维持治疗浓度的化合物。其次，采用体外时间杀灭和可逆动力学，以将暴露量（基于未结合的浓度）与体外活性相关联，并确定最能预测疗效的药效学指标。最后，此信息用于设计动物感染模型中关键药代动力学-药代动力学研究的给药方案。

著录项

相似文献

  • 外文文献
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号