INTRODUCTION Clinical trials of Compound danshen dripping pills (CDDP) indicated distinct improvement in patients with chronic stable angina. Daily fluctuation of therapeutic effect agreed with a peak-valley PK profile during a 4-week CDDP regimen, but stabilized after 8-week treatment. OBJECTIVES This article aims to explore the underlying mechanism for the time-dependent drug efficacy of the up-down fluctuation or stabilization in clinic trials. METHODS A rat model of myocardial ischemia was established via isoproterenol induction. Metabolomics was employed to analyze the energy-related substances both in circulatory system and myocardium in the myocardial ischemia model. RESULTS CDDP treatment ameliorated myocardial ischemia, reversed the reprogramming of the metabolism induced by ISO and normalized the level of most myocardial substrates and the genes/enzymes associated with those metabolic changes. After 1- or 2-week treatment, CDDP regulated plasma and myocardial metabolome in an analogous, time-dependent way, and modulated metabolic patterns of ischemic rats that perfectly matched with the fluctuated or stabilized effects observed in clinical trials with 4 or 8-week treatment, respectively. CONCLUSION Metabolic modulation by CDDP contributes to the fluctuated or stabilized therapeutic outcome, and is a potential therapeutic approach for myocardial ischemia diseases.

中文翻译：

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复方丹参滴丸使心肌缺血大鼠的重新编程代谢正常化，以解释其在临床试验中的时间依赖性功效：一项代谢组学研究。

简介复方丹参滴丸（CDDP）的临床试验表明，慢性稳定型心绞痛患者的病情明显改善。在4周的CDDP疗程中，治疗效果的每日波动与峰谷PK曲线吻合，但在8周的治疗后稳定。目的本文旨在探讨临床试验中上下波动或稳定的时间依赖性药物疗效的潜在机制。方法采用异丙肾上腺素诱导建立大鼠心肌缺血模型。代谢组学被用于分析心肌缺血模型中循环系统和心肌中与能量有关的物质。结果CDDP治疗可改善心肌缺血，逆转了ISO诱导的代谢的重新编程，并使大多数心肌底物的水平以及与那些代谢变化相关的基因/酶正常化。经过1或2周的治疗后，CDDP以类似的时间依赖性方式调节血浆和心肌的代谢组，并调节缺血大鼠的代谢模式，使其与4或8周临床试验中观察到的波动或稳定作用完全匹配治疗分别。结论CDDP的代谢调节可导致治疗结果的波动或稳定，是心肌缺血疾病的一种潜在治疗方法。和缺血大鼠的调节代谢模式，分别与4或8周治疗的临床试验中观察到的波动或稳定效应完全匹配。结论CDDP的代谢调节可导致治疗结果的波动或稳定，是心肌缺血疾病的一种潜在治疗方法。和缺血大鼠的调节代谢模式，分别与4或8周治疗的临床试验中观察到的波动或稳定效应完全匹配。结论CDDP的代谢调节可导致治疗结果的波动或稳定，是心肌缺血疾病的一种潜在治疗方法。