Drug-drug interactions between salvianolate injection and aspirin based on their metabolic enzymes.

BACKGROUND: It is unclear whether the combination of traditional Chinese medicine and Western medicine leads to interactions in pharmacokinetics (PKs) and pharmacodynamics (PDs). In this study, the influence of salvianolate and aspirin on metabolic enzymes, and the relationship between the blood concentration and pharmacodynamic indexes, were determined. METHOD: In this, randomized, parallel-grouped, single-center clinical trial, 18 patients with coronary heart disease were randomly allocated into three groups: aspirin (AP) group, salvianolate (SV) group, and combination (A + S) group. All treatment courses lasted for 10 days, and blood samples were acquired before and after administration at different timepoints. The expression of catechol-O-methyltransferase (COMT), CD62p, procaspase-activating compound 1 (PAC-1), P2Y12, phosphodiesterase, and mitogen-activated protein kinase 8 (MAPK8) were compared with variance analysis The blood concentrations were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Sixteen subjects completed the study. No significant difference in COMT was found among groups, although there was a decrease in the SV group. The PK results indicated that the absorption time of salicylic acid was shortened and the AUC0-∞ decreased and the elimination time of salvianolic acid B was prolonged and the AUC0-∞ decreased. The PD results declined after administration. A significant difference was found in MAPK8, CD62p, and P2Y12 expression. Compared with the SV group, a significant difference in P2Y12 in the A + S group was found. CONCLUSION: A pharmacokinetic drug-drug interaction was found in the aspirin and salvianolate combination. Pharmacodynamically, there was no difference between the A + S and AP groups. However, P2Y12 expression in the combination group was superior to that in the SV group. TRIAL REGISTRATION NUMBERS: The trial was registered on October 9, 2017, ClinicalTrials.gov, NCT03306550. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0007D8H&selectaction=Edit&uid=U0003QY8&ts=2&cx=oiuc9g.

Differential proteomic analysis of platelets suggested target-related proteins in rabbit platelets treated with Rhizoma Corydalis.

CONTEXT: Corydalis yanhusuo W.T. Wang (Papaveraceae) (Rhizoma Corydalis) showed inhibitory effects on rabbit platelet aggregation induced by ADP, thrombin (THR) or arachidonic acid (AA). OBJECTIVE: This study separates and identifies the possible target-related platelet proteins and suggests possible signal cascades of RC antiplatelet aggregation. MATERIALS AND METHODS: Based on comparative proteomics, the differentially expressed platelet proteins treated before and after with 50 mg/mL RC 90% ethanol extract (for 15 min at 37 °C) were analyzed and identified by two dimensional gel electrophoresis (2-DE) and MALDI-TOF-MS/MS. To further verify the possible signalling pathways of RC antiplatelet aggregation function, the concentration of calcium (Ca2+) was measured by Fura-2/AM fluorescence (Ex 340/380 nm, Em 500 nm) (RC final concentrations of 0.0156-0.1563 mg/mL), the levels of P-selectin and cyclic guanosine monophosphate (cGMP) were quantified by ELISA (OD. 450 nm) (RC final concentrations of 0.0156-1.5625 mg/mL), and the 5-hydroxytryptamine (5-HT) level was measured using ortho-phthalaldehyde (OPT) fluorescence (Ex 340 nm, Em 470 nm) (RC final concentrations of 0.3125-1.5625 mg/mL). RESULTS: The expression of 52 proteins were altered in rabbit platelets after the treatment and the MALDI-TOF-MS analysis indicated that those proteins include 12 cytoskeleton proteins, 7 cell signalling proteins, 3 molecular chaperone proteins, 6 proteins related to platelet function, 16 enzymes and 7 other related proteins. Furthermore, RC extract could decrease the levels of 5-HT [inhibition rate of 96.80% (p < 0.05, vs. THR-activated group) treated with 0.7813 mg/mL of RC], Ca2+ [172.73 ± 5.07 to 113.56 ± 5.46 nM (p < 0.001, vs. THR-activated group) treated with 0.0313 mg/mL of RC] and P-selectin [13.48 ± 0.96 ng/3 × 108 to 11.64 ± 0.17 ng/3 × 108 (p < 0.05, vs. THR-activated group) treated with 0.0156 mg/mL of RC], and increase in cGMP level [38.93 ± 0.57 to 50.26 ± 4.05 ng/3 × 108 (p < 0.05, vs. THR-activated group) treated with 1.5165 mg/mL of RC] in ADP (10 µmol/L), THR (0.25 u/mL) or AA-(0.205 mmol/L) activated rabbit platelets. DISCUSSION AND CONCLUSION: The present study indicated that P2Y12 receptor might be one of the direct target proteins of RC in platelets. The signal cascades network of RC after binding with P2Y12 receptor is mediating Gαi proteins to activate downstream signalling pathways (AC and/or PI3K signalling pathways) for the inhibition of platelet aggregation.

A randomized trial assessing the impact of three different glycoprotein IIb/IIIa antagonists on glycoprotein IIb/IIIa platelet receptor inhibition and clinical endpoints in patients with acute coronary syndromes.

AIMS: To compare three glycoprotein IIb/IIIa receptor antagonists (GPIs) in terms of platelet inhibition and major adverse cardiac events (MACEs), and assess the rate of bleeding and MACEs between GPIs and coadministered P2Y12 agents. METHODS: Eighty-three acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) with planned GPI use were randomized to receive high-dose bolus tirofiban, double-bolus eptifibatide, or abciximab followed by a 12-hour infusion. Glycoprotein IIb/IIIa platelet receptor inhibition was measured at baseline and at 10 minutes, 1 hour, and 24 hours postbolus dose. Major adverse cardiac events and bleeding complications at 30 days were documented. The incidence of MACEs and bleeding in patients receiving ticagrelor or prasugrel were compared to those given clopidogrel. RESULTS: There were no statistically significant differences in platelet inhibition between GPIs at 10 minutes (P=.085) and 1 hour (P=.337). At 24 hours, abciximab achieved statistically significantly higher median [interquartile range] platelet inhibition (75 [65-88]%) compared to tirofiban (28 [3-56]%; P<.0001) and eptifibatide (44 [31-63]%; P=.007). There were no differences in bleeding or MACEs depending on GPI or P2Y12 inhibitor administered. CONCLUSIONS: Glycoprotein receptor inhibitors achieve similar levels of platelet inhibition at 10 minutes and 1 hour; however, abciximab maintains this benefit 24 hours after bolus dose. We did not witness an increased rate of bleeding in patients given new potent P2Y12 inhibitors and a GPI in the modern era.

High-dose atorvastatin on the pharmacodynamic effects of double-dose clopidogrel in patients undergoing percutaneous coronary interventions: The ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study.

OBJECTIVES: The goal of this study was to investigate the impact of high-dose atorvastatin on the pharmacodynamic (PD) effects of double-dose clopidogrel in statin-naive patients with stable coronary artery disease (CAD) and high-on-treatment platelet reactivity (HTPR) while on standard-dose clopidogrel before percutaneous coronary intervention (PCI). BACKGROUND: Patients with HTPR are at increased risk of adverse cardiovascular events after PCI. High-dose statins improve prognosis in high-risk patients by lipid- and nonlipid-related mechanisms, including antithrombotic effects. METHODS: The ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study was a randomized PD study of high-dose (80 mg) atorvastatin in addition to double-dose (150 mg) clopidogrel (atorvastatin group, n = 38) versus double-dose clopidogrel alone (control group, n = 38) in patients with HTPR. HTPR was defined as P2Y(12) reaction units (PRU) ≥235 by the VerifyNow P2Y12 assay. Platelet reactivity was evaluated immediately before PCI and at 10 and 30 days. RESULTS: Patients randomized to atorvastatin had lower PRU values (188 ± 48 vs. 223 ± 53 PRU, p < 0.01; primary endpoint) and HTPR rates (16% vs. 42%, p < 0.01) at 30 days than patients in the control group. Statin treatment (odds ratio [OR]: 3.8, p = 0.011), baseline PRU <298 (OR: 10.7, p = 0.0001), noncarrier status of CYP2C19*2 loss-of-function allele (OR: 2.9, p = 0.043), and age (OR: 0.94, p = 0.032) were variables significantly associated with optimal PD response (PRU <235) at 30 days. No correlations were found between PRU and lipid fractions. CONCLUSIONS: High-dose atorvastatin significantly improved the PD effects of double-dose clopidogrel in our stable CAD patients with HTPR undergoing PCI (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity [ACHIDO]; NCT01335048).