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Research on the mechanism of drug-drug interaction between salvianolate injection and aspirin based on the metabolic enzyme and PK-PD model: study protocol for a PK-PD trial.

ABSTRACT: BACKGROUND:Coronary heart disease (CHD) is a common cardiovascular disease accounting for 10-20% mortality by heart disease worldwide. The gold standard treatment to manage CHD is aspirin, which may prevent myocardial infarction and sudden death; however, long-term use of aspirin may increase its side effects. Currently, more and more clinicians are exploring different approaches to use the right combination of medicine to enhance the efficacy and reduce side effects. Salvianolate can significantly inhibit the aggregation and activation of platelets in patients with CHD; however, its optimum combination with western medicine is not established or supported by clinical trial results. METHODS/DESIGN:This trial is a prospectively planned, open-labeled, parallel-grouped, single-centered clinical trial with aggregated pharmacodynamics-pharmacokinetics (PK-PD) data. All treatment courses will last for 10 days and blood sample will be acquired before administration on days 8, 9, and 10, and after administration at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h on day 10. This trial uses PK-PD modeling to provide a description of the concentration-effect relationship and an estimate of pharmacological potency of the medicine. The primary outcome will be changes in aspirin esterase and catechol-o-methyltransferase (COMT) activity at different blood concentrations to determine the PK-PD characteristics of the combination of salvianolate and aspirin, followed by analysis of the correlation between exposure level and pharmacodynamic index of the medicines. DISCUSSION:This trial will aim to evaluate the relationship between changes in the pharmacokinetics and therapeutic effect index in the combined use of salvianolate and aspirin. It also discusses the possible mechanism of medicine combination in the treatment for CHD and provides an experimental basis for a clinically rational medicine combination. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03306550 . Registered on 9 October 2017. ClinicalTrials.gov https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0007D8H&selectaction=Edit&uid=U0003QY8&ts=2&cx=oiuc9g.

SUBMITTER: Zhang W

PROVIDER: S-EPMC6137745 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Research on the mechanism of drug-drug interaction between salvianolate injection and aspirin based on the metabolic enzyme and PK-PD model: study protocol for a PK-PD trial.

Zhang Wantong W Zhu Baochen B Cao Weiyi W Li Rui R Wang Shuge S Gao Rui R

Trials 20180914 1

<h4>Background</h4>Coronary heart disease (CHD) is a common cardiovascular disease accounting for 10-20% mortality by heart disease worldwide. The gold standard treatment to manage CHD is aspirin, which may prevent myocardial infarction and sudden death; however, long-term use of aspirin may increase its side effects. Currently, more and more clinicians are exploring different approaches to use the right combination of medicine to enhance the efficacy and reduce side effects. Salvianolate can si ...[more]

PMID: 30217228

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Project description:BackgroundComplicated with the impact of aging population and urbanization, coronary heart disease (CHD) incurs more and more disease burdens in China. Salvianolate injection is a Chinese patent drug widely used for treating CHD in China. A series of studies have verified the efficacy of salvianolate injection , but the high drug cost has raised concerns. It is, therefore, important to conduct cost-consequence analysis to demonstrate whether salvianolate injection is associated with outcome improvement and cost containment. The aim of this study was to retrospectively evaluate the cost-consequence of salvianolate injection for the treatment of coronary heart disease by combining salvianolate injection with conventional treatment from a societal perspective.MethodsWe retrospectively studied hospitalized patients with CHD from August 2011 to December 2015 by using electronic medical record database. Patients who received salvianolate injection combined with conventional treatment were selected as exposed group, while those who received conventional treatment alone were selected as unexposed group. Propensity score matching (PSM) analysis was used to balance the characteristics of patients. After PSM, we evaluated hospital stay, total nitrates dosage, total medical costs, and subcategories costs. Patients with chronic ischemic heart disease were analyzed as a highly selected subcohort.ResultsFor the overall group, hospital stay was significantly decreased by 2.9 days (P < 0.05) and total nitrates dosage was significantly decreased by 172.4 mg (P < 0.05) in exposed group; cost savings of pharmacy cost, examination cost, laboratory cost, operation cost and treatment was observed as significant (at P < 0.05); and the additional expenditure of Chinese patent drug (1174.9 CNY) was less than the saving of total medical costs (2636.4 CNY). For chronic ischemic heart disease subcohort, compared with unexposed group, significant decreases were also found in hospital stay and total nitrates dosage (P < 0.05); cost savings were significant (P < 0.05) for exposed group in terms of total medical costs (4339.5 CNY) and subcategories costs (including pharmacy cost, examination cost, operation cost and treatment cost); and the additional expenditure of Chinese patent drug (1189.3 CNY) was less than the saving of total medical costs.ConclusionCompared with conventional treatment for the treatment of CHD, combination of salvianolate injection and conventional treatment was associated with a reduction in hospital stay and total nitrates dosage. The acquisition cost of Chinese patent drug (including salvianolate injection) was offset by a higher reduction in total medical costs, especially for chronic ischemic heart disease.

Project description:The mixture of Salvia miltiorrhiza and Carthamus tinctorius (Danhong injection, DHI) is widely prescribed in China for the treatment of cardiovascular and cerebrovascular diseases. In most cases, DHI is used in combination with acetylsalicylic acid (aspirin, ASA). However, the interaction between DHI and ASA remains largely undefined. The purpose of this study is to explore the interaction profile and mechanism between DHI and ASA. The frequency of drug combination of DHI and ASA was analyzed based on 5,183 clinical cases. The interaction characteristics were evaluated by analyzing the pharmacokinetics and disposition profile of salicylic acid (SA, the primary metabolite of ASA) in rats. The interaction mechanisms were explored through evaluating the hydrolysis of ASA regulated by ASA esterase, the tubular secretion of SA mediated by influx and efflux transporters, and the tubular reabsorption of SA regulated by urinary acidity-alkalinity. The inhibitory potential of DHI on organic anion transporters (OATs) was further verified in aristolochic acid I (AAI) induced nephropathy. Clinical cases analysis showed that DHI and ASA were used in combination with high frequency of 70.73%. In drug combination of DHI and ASA, the maximum plasma concentration of SA was significantly increased by 1.37 times, while the renal excretion of SA was significantly decreased by 32.54%. The mechanism study showed that DHI significantly inhibited the transport function, gene transcription and protein expression of OATs. In OATs mediated AAI nephropathy, DHI significantly reduced the renal accumulation of AAI by 55.27%, and alleviated renal damage such as glomerulus swelling, tubular blockage and lymphocyte filtration. In drug combination of DHI and ASA, DHI increased the plasma concentration of SA not through enhancing the hydrolysis of ASA, and the tubular reabsorption of SA was not significantly affected. Inhibition of tubular secretion of SA mediated by OATs might be the reason that contributes to the decrease of SA renal excretion.

Dataset Information

Research on the mechanism of drug-drug interaction between salvianolate injection and aspirin based on the metabolic enzyme and PK-PD model: study protocol for a PK-PD trial.

Publications

Research on the mechanism of drug-drug interaction between salvianolate injection and aspirin based on the metabolic enzyme and PK-PD model: study protocol for a PK-PD trial.

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