Abstract
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.
Highlights
Clinical trials of Compound danshen dripping pills (CDDP) indicated distinct improvement in patients with chronic stable angina
Myocardial ischemia occurs when there is insufficient coronary flow, which impairs the delivery of myocardial substrates and oxygen and is a metabolic incidence that is usually accomplished by changes in the metabolism and decreases in the energy supply of cardiomyocytes and the body
The myocardial ischemia model rats were induced by ISO (15 mg/kg), and the CDDP treatment group was given with CDDP (167 mg/kg) after an initial induction of ISO for 3 days, Method S2
Summary
Clinical trials of Compound danshen dripping pills (CDDP) indicated distinct improvement in patients with chronic stable angina. Fluctuation of therapeutic effect agreed with a peak-valley PK profile during a 4-week CDDP regimen, but stabilized after 8-week treatment. 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. Metabolic properties of myocardial ischemia have received global attention, and metabolic modulation has been expected as a promising therapeutic approach for ischemic heart diseases (Lopaschuk et al 2010; Stanley et al 2005), few agent has been widely applied, except for trimetazidine (Kantor et al 2000). The PK-PD and therapeutic outcomes at 4 and 8 weeks of CDDP treatment were not consistent (Guo et al 2016)
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