Compound danshen dripping pills normalize a reprogrammed metabolism of myocardial ischemia rats to interpret its time-dependent efficacy in clinic trials: a metabolomic study

IntroductionClinical 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.ObjectivesThis article aims to explore the underlying mechanism for the time-dependent drug efficacy of the up-down fluctuation or stabilization in clinic trials.MethodsA 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.ResultsCDDP 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.ConclusionMetabolic modulation by CDDP contributes to the fluctuated or stabilized therapeutic outcome, and is a potential therapeutic approach for myocardial ischemia diseases.