Mechanism of Drug-drug Interaction Between Salvianolate Injection and Aspirin

Research on Mechanism of Drug-drug Interaction Between Salvianolate Injection and Aspirin Based on the Metabolic Enzyme and PK-PD Model

The combination of anti-platelet medicine treatment and Chinese traditional medicine (TCM) promoting blood circulation to removing blood stasis is widely used in treatment for cardiovascular disease. However, the material foundation, effective mechanism and drug-drug interaction is still not clear. In order to solve the puzzle of rational use of Joint application by TCM and Western Medicine(WM),investigators conduct a research on mechanism of drug-drug interaction between salvianolate injection and aspirin based on metabolic enzyme and PK-PD model. This clinical trial contain three groups, aspirin group, salvianolate injection group and combination (salvianolate injection+aspirin) group. Investigators collect blood samples at special time points during post-administration.Investigators have already find out the Salvianolate's pharmacokinetic characteristics in vivo and establish the biological sample-testing analysis method in previous research. Depending on these results, this clinical trial aim to explore the pharmacodynamics-pharmacokinetics(PK-PD) characteristics of combination with Salvianolate and aspirin through biomarkers, blood concentration. Finally clarify the TCM and WM material basis and mutual mechanism of drug interaction and guide reasonable clinical prescription.

Study Overview

• Status: Unknown
• Conditions: Angina, Stable
• Intervention / Treatment: Drug: Aspirin Tablet; Drug: salvianolate injection

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rui Li, MD,Phd; Phone Number: 0086+01062835651; Email: crystal005@163.com
• Study Contact Backup: Name: wantong Zhang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Meet the diagnostic criteria of coronary heart disease.
2. Meet the diagnostic criteria of stable angina pectoris.
3. Meet the diagnostic criteria of syndrome of blood stasis.
4. Angina in grade I-II according to Canadian cardiovascular society (CCS).
5. It could be enrolled if the subject taking aspirin or salvianolate injection with one month regularly。
6. The subjects were informed and voluntarily signed informed consent.

Exclusion Criteria:

1. Severe heart disease (acute myocardial infarction of acute myocardial infarction in 6 months), severe cardiopulmonary dysfunction (eg: cardiac function II)
2. Poorly controlled hypertension(systolic pressure >160mmHg or diastolic pressure >100mmHg).
3. Diabetics.
4. Severe primary diseases such as liver and renal hematopoietic system damage. Such as:liver function（ALT≥2×ULN、AST≥2×ULN）,kidney function（Cr>1.0×ULN) or nervous and mental disorder.
5. Pregnant, breast-feeding and menstrual women, or women planning pregnancy within 3 months.
6. Subjects who participated in clinical trials in recent 3 months.
7. Subjects who took surgery treatment or had hemorrhagic tendency in recent 4 weeks.
8. Subjects who had drug allergy history or with allergic constitution.
9. Subjects who has mental or physical disorders.
10. Subjects who had bad compliance or is not suitable for this clinical trial by investigator's judgement

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: aspirin arm; only take aspirin (100mg,qd) orally for 10 days treatment course	Drug: Aspirin Tablet; Anti-platelet medicine treatment and Chinese traditional medicine (TCM) promoting blood circulation to removing blood stasis is widely used in treatment for cardiovascular disease.
Active Comparator: salvianolate injection arm; only inject salvianolate(200mg+5%Glucose Injection 250ml，iv) for 10 days treatment course	Drug: salvianolate injection; The main ingredient of salvianolate injection is salvianolic acid B(SAB) which is extracted from the root of red salvia. Red salvia is used in traditional Chinese Medicine. It could promote blood circulation to removing blood stasis,which is clinically effective in treatment for cardiovascular disease.
Experimental: aspirin and salvianolate injection arm; take aspirin (100mg,qd) orally and inject salvianolate(200mg+5%Glucose Injection 250ml，iv) for 10 days treatment course	Drug: Aspirin Tablet; Anti-platelet medicine treatment and Chinese traditional medicine (TCM) promoting blood circulation to removing blood stasis is widely used in treatment for cardiovascular disease.; Drug: salvianolate injection; The main ingredient of salvianolate injection is salvianolic acid B(SAB) which is extracted from the root of red salvia. Red salvia is used in traditional Chinese Medicine. It could promote blood circulation to removing blood stasis,which is clinically effective in treatment for cardiovascular disease.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of P-selection expression(platelet activation-dependent granule membrane) at different time points.	Use flow cytometric method to detect the P-selection expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelet interaction adhesion during drug concentration-time curves.	Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h
Change of PAC-1 expression (platelet-associated complement) on the activated platelets at different time points.	Use flow cytometric method to detect the PAC-1 expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelet aggregation during drug concentration-time curves.	Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h
Change of P2Y12 acceptor expression on platelets at different time points. (P2Y12 acceptor is a receptor for ADP(adenosine diphosphate) and ATP (adenosine triphosphate )coupled to G-proteins that inhibit the adenylyl cyclase second messenger system)	Use flow cytometric method to detect the P2Y12 acceptor expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelets aggregation activated by ADP or ATP during drug concentration-time curves.	Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h
Change of PDE enzymes（phosphodiesterase）expression on platelet at different time points.	Use ELISA method to detect the PDE enzymes expression at different time points. Analyse the influence of Asprin/Salvianolate on platelets activated by PDE enzymes during drug concentration-time curves.	Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Aspirin esterase activity at different blood concentration of Asprin/Salvianolate	Conduct biological analysis by LC-MS/MS(liquid chromatography tandem mass spectrometry) to detect Aspirin and salicylic aspirin and salicylic acid:CSA/C(ASA+SA).The activity of combination arm and of the asprin arm is compared by t test.	Getting blood sample before taking aspirin in day 8 and day 9.In the day 10, getting blood sample before taking aspirin and after taking aspirin in 5min、15min、30min、45min、1h、2h、4h、8h、12h、24h
Change of Catechol-o-methyltransferase (COMT) activity at different blood concentration of Asprin/Salvianolate	COMT activity is the main metabolic enzymes of SAB.Use kit to detect COMT activity .	Getting blood sample before injection in day 8 and day 9.In the day 10, getting blood sample before injection and after injection in 5min、15min、30min、45min、1h、2h、4h、8h、12h、24h

Collaborators and Investigators

• Sponsor: Xiyuan Hospital of China Academy of Chinese Medical Sciences

Publications and helpful links

General Publications

• Cao W, Yang Q, Zhang W, Xu Y, Wang S, Wu Y, Zhao Y, Guo Z, Li R, Gao R. Drug-drug interactions between salvianolate injection and aspirin based on their metabolic enzymes. Biomed Pharmacother. 2021 Mar;135:111203. doi: 10.1016/j.biopha.2020.111203. Epub 2021 Jan 3.
• Zhang W, Zhu B, Cao W, Li R, Wang S, Gao R. 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. Trials. 2018 Sep 14;19(1):491. doi: 10.1186/s13063-018-2861-7.

Study record dates

Study Major Dates

• Study Start (Anticipated): October 10, 2017
• Primary Completion (Anticipated): April 10, 2018
• Study Completion (Anticipated): October 10, 2018

Study Registration Dates

• First Submitted: September 4, 2017
• First Submitted That Met QC Criteria: October 9, 2017
• First Posted (Actual): October 11, 2017

Study Record Updates

• Last Update Posted (Actual): October 11, 2017
• Last Update Submitted That Met QC Criteria: October 9, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: drug-drug interaction; metabolic enzymes; Asprin; salvianolate injection; PK-PD model
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Pain; Neurologic Manifestations; Chest Pain; Angina Pectoris; Angina, Stable; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: zz0908022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No