A Bayesian Dose-Finding Design Adapting to Efficacy and Tolerability Response

We propose a new adaptive Bayesian design, explicitly modeling the trade-off between efficacy and tolerability in dose-finding studies. This design incorporates a continuous efficacy variable and a dichotomous tolerability variable. This adaptive design was developed in the context of a drug under development for treatment of major depression, but is easily extended to any setting with a continuous efficacy and a dichotomous tolerability or safety variable. The goal is to identify a target dose that was most efficacious while still being safe. Via simulations under various scenarios we show that our design performs extremely efficiently. Our design incorporates stopping rules, adaptive allocation, and dose-response estimation (for both efficacy and tolerability), among other features. We present various metrics from our simulation study, and conclude that this is an extremely efficient way of characterizing the risk–benefit profile of a drug during clinical development.     

基于“回阳救逆”功效附子对小鼠心电图影响的“效—毒”关联评价

目的:基于"回阳救逆"功效研究附子对小鼠心电图的影响,探讨附子药效和毒性的关联性。方法:灌胃给予小鼠不同剂量的附子各组分后,观察小鼠的心电图变化,检测血清中AST、LDH、cTn-I的含量以及心体比值变化。结果:附子各组分引起心电图QRS间期延长和S-T段抬高,血清AST、LDH、cTn-I的含量依剂量呈现不同程度的升高,以醇提组分的升高幅度显著,从药效剂量的9 g开始呈现出一定毒副作用。结论:附子药效剂量会引起小鼠心电图室早的改变和心肌损伤,缺血的血清心肌酶含量升高,必须重视附子药效剂量下毒副作用的监测工作,研究在"回阳救逆"功效下的药效作用发挥和毒性作用表达的关联性,使药效作用发挥达到最优话,毒副作用产生降到最低值,使附子的临床应用更具安全性和有效性。     

基于“效-毒”相关的Q-marker合理辨识与科学控制

有效性、安全性和可控性是药品的三大基本属性且相互联系与依托。中药“效-毒”二重性不仅是中药药性的有机组成部分,属于中药的根本属性;而且因其“多成分、多效应、多靶点、配伍应用、长期用药”等中医药特点,导致中药的可控性极端复杂,单一或多个化学成分检测无论是从质量专属性、活性与功效关联度还是毒性与安全性控制等方面都难以保证中药的质量,再加上基原、产地、采收、贮藏、提取等中药固有因素和炮制与配伍应用等中医习惯用法等方面的影响,致使中药质量控制也因此成为制约中医药现代化、国际化和中医药产业发展的关键因素和技术瓶颈。根据刘昌孝院士提出的中药质量标志物（Q-marker）的概念,本研究选择有毒中药吴茱萸为模式药物,开展基于“效-毒”关联评价的Q-marker合理辨识与科学控制研究,为临床合理、安全用药提供质量控制保证。