ABSTRACT
Salvianolic acids for injection (SAI) is developed from traditional Chinese medicine and approved for the treatment of cardiovascular and cerebrovascular diseases. Clopidogrel is an inhibitor of platelet aggregation, which is often prescribed for patients in combination with SAI. This present study aimed to assess the effects of SAI on the pharmacogenomics, pharmacokinetics, and pharmacodynamics of clopidogrel, thereby ensuring the safety and efficacy of coadministration. In vitro cytochrome P450 isoenzyme assays were performed in human liver microsomes using LC-MS/MS method to assess the metabolites of CYPs substrates. The effects of SAI on the pharmacokinetic and pharmacodynamic behaviors of clopidogrel were investigated in rats. The main pharmacokinetic parameters were analyzed using LC-MS/MS. Prothrombin time, activated partial thromboplastin time, bleeding time, and inhibition of platelet aggregation were measured to evaluate the effects of pharmacodynamics. Our study revealed that the clinical dose of SAI has no significant inhibitory effect on clopidogrel-related liver microsome metabolic CYP450 isoenzymes. Moreover, SAI did not affect the pharmacokinetics of clopidogrel when rats were administered both single and multiple doses. In pharmacodynamic study, SAI has no effect on platelet aggregation rate, prothrombin time, and activated partial thromboplastin time of clopidogrel but could significantly prevent the risk of bleeding caused by clopidogrel.
Subject(s)
Isoenzymes , Platelet Aggregation Inhibitors , Alkenes , Animals , Chromatography, Liquid , Clopidogrel/pharmacology , Cytochrome P-450 Enzyme System , Humans , Platelet Aggregation Inhibitors/pharmacokinetics , Polyphenols , Rats , Tandem Mass SpectrometryABSTRACT
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.
Subject(s)
Aspirin/pharmacokinetics , Coronary Disease/drug therapy , Drugs, Chinese Herbal/pharmacokinetics , Plant Extracts/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Aged , Aspirin/adverse effects , Beijing , Biotransformation , Catechol O-Methyltransferase/blood , Coronary Disease/blood , Coronary Disease/diagnosis , Drug Interactions , Drugs, Chinese Herbal/adverse effects , Female , Gastrointestinal Absorption , Humans , Male , Metabolic Clearance Rate , Middle Aged , Mitogen-Activated Protein Kinase 8/blood , P-Selectin/blood , Plant Extracts/adverse effects , Platelet Aggregation Inhibitors/adverse effects , Receptors, Purinergic P2Y12/bloodABSTRACT
This study aimed at exploring the potential mechanism of decreased in vivo exposure of the antiplatelet agent, ticagrelor and its active metabolite, AR-C124910XX, mediated by tea polyphenols, which was first revealed by our previous study, as well as predicting the in vivo drug-drug interaction (DDI) potential utilizing an in vitro to in vivo extrapolation (IVIVE) approach. The bidirectional transport and uptake kinetics of ticagrelor were determined using Caco-2 cells. Inhibition potency of major components of tea polyphenols, epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were obtained from Caco-2 cells, human intestinal and hepatic microsomes (HIMs and HLMs) in vitro. A mean efflux ratio of 2.28 ± 0.38 and active uptake behavior of ticagrelor were observed in Caco-2 cell studies. Further investigation showed that the IC50 values of EGCG and EGC on the uptake of ticagrelor were 42.0 ± 5.1 µM (95% CI 31.9-54.8 µM) and 161 ± 13 µM (95% CI 136-191 µM), respectively. EGCG and EGC also displayed moderate to weak reversible inhibition on the formation of AR-C124910XX and the inactive metabolite, AR-C133913XX in HIMs and HLMs, while no clinically significant time-dependent inhibition was observed for either compound. IVIVE indicated a significant inhibition effect of EGCG on the uptake process of ticagrelor, while no potential DDI risk was found based on microsomal data. A 45% decrease in ticagrelor in vivo exposure was mechanistically predicted by incorporating intestinal and hepatic metabolism as well as intestinal absorption. This dual inhibition of tea polyphenols on ticagrelor revealed the underlying potential of transporter-enzyme interplay, in which the altered uptake process was more critical.
Subject(s)
Models, Theoretical , Polyphenols/pharmacology , Tea/chemistry , Ticagrelor/antagonists & inhibitors , Adenosine/analogs & derivatives , Adenosine/metabolism , Biological Transport/drug effects , Caco-2 Cells , Catechin/analogs & derivatives , Catechin/pharmacology , Cell Line, Tumor , Drug Interactions , Humans , Intestinal Absorption/drug effects , Kinetics , Microsomes, Liver/metabolism , Platelet Aggregation Inhibitors/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Ticagrelor/metabolism , Ticagrelor/pharmacokineticsABSTRACT
Thrombosis initiated by abnormal platelet aggregation is a pivotal pathological event that precedes most cases of cardiovascular diseases (CVD). Recently, growing evidence indicates that platelet could be a potential target for CVD prevention. However, as the conventional antithrombotic management strategy, applications of current antiplatelet agents are somewhat limited by their various side effects, such as bleeding risk and drug resistance. Hence, efforts have been made to search for agents as complementary therapies. Ginsenoside, the principal active component extracted from Panax ginseng, has gained much attention for its regulations on multiple crucial events of platelet aggregation. From structural characteristics to clinical applications, this review anatomized the intrinsic structure-function relationship of antiplatelet potency of ginsenosides, and the involved signal pathways were specifically summarized. Additionally, the emphasis was placed on clinical studies that investigate the antithrombotic efficacy of ginsenosides in the treatment of CVD. Further, a broad overview of approaches for improving the bioavailability of ginsenosides was concluded. Limitations and prospects of current studies were also discussed. This study may provide some new insights into the systematic understanding of ginsenosides in CVD treatment and lay a foundation for future research.
Subject(s)
Blood Platelets/drug effects , Cardiovascular Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Ginsenosides/therapeutic use , Muscle, Smooth, Vascular/drug effects , Neointima , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation/drug effects , Vascular Remodeling/drug effects , Animals , Biological Availability , Blood Platelets/metabolism , Cardiovascular Agents/adverse effects , Cardiovascular Agents/pharmacokinetics , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , Ginsenosides/adverse effects , Ginsenosides/pharmacokinetics , Humans , Molecular Structure , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/pharmacokinetics , Signal Transduction , Structure-Activity RelationshipABSTRACT
Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.
Subject(s)
Caprylates/pharmacokinetics , Drug Delivery Systems/methods , Emulsifying Agents/pharmacokinetics , Glycerides/pharmacokinetics , Nanoparticles/metabolism , Palm Oil/pharmacokinetics , Pentoxifylline/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Caprylates/administration & dosage , Drug Liberation , Emulsifying Agents/administration & dosage , Glycerides/administration & dosage , Male , Nanoparticles/administration & dosage , Palm Oil/administration & dosage , Particle Size , Pentoxifylline/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacokinetics , Rats , Rats, WistarABSTRACT
Green tea is widely consumed as a beverage and/or dietary supplement worldwide, resulting in the difficulty to avoid the comedication with ticagrelor for acute coronary syndrome (ACS) patients receiving antiplatelet therapy. This study was designed to investigate the effect of the most abundant content in green tea, tea polyphenols on the oral and intravenous pharmacokinetics of ticagrelor in rats and its in vitro metabolism. Rats were orally treated with either saline or tea polyphenol extracts (TPEs) dissolved in saline once daily for 6 consecutive days. On day 6, after the last dose of saline or TPE, ticagrelor was given to the rats orally or intravenously. Plasma samples were collected for pharmacokinetic analysis. Human liver and intestinal microsomes were then used to investigate the inhibition by TPE, as well as its major constituents on the metabolism of ticagrelor to its two metabolites, AR-C124910XX and AR-C133913XX. Apparent kinetic constants and inhibition potency (IC50 ) for each metabolic pathway of each compound were estimated. Oral study indicated that exposure of ticagrelor and AR-C124910XX was significantly decreased after TPE administration, while no significant differences were observed in pharmacokinetic parameters after intravenous administration of ticagrelor. TPE effectively inhibited the metabolism of ticagrelor in vitro, with epigallocatechin-3-gallate as the major constituent responsible for the observed inhibitory effects in human liver microsomes and intestinal microsomes (IC50 = 4.23 ± 0.18 µM). Caution should be taken for ACS patients receiving ticagrelor therapy with daily drinking of green tea. PRACTICAL APPLICATION: Potential interactions between tea polyphenols and ticagrelor were revealed for the first time. Results can provide suggestions for clinicians to optimize the dosing of ticagrelor while they are in the face of ACS patients receiving ticagrelor therapy, who also take green tea or its related products in their daily life.
Subject(s)
Microsomes, Liver/drug effects , Platelet Aggregation Inhibitors/pharmacokinetics , Polyphenols/pharmacokinetics , Tea/chemistry , Ticagrelor/pharmacokinetics , Adenosine/analogs & derivatives , Administration, Intravenous , Administration, Oral , Animals , Catechin/analogs & derivatives , Male , Microsomes, Liver/metabolism , Platelet Aggregation Inhibitors/administration & dosage , Polyphenols/administration & dosage , Polyphenols/chemistry , Rats , Ticagrelor/administration & dosage , Ticagrelor/metabolismABSTRACT
Background The high prevalence of thrombotic abnormalities has become a major concern in the health sector. This is triggered by uncontrolled platelet aggregation, which causes complications and death. The problem becomes more complicated because of the undesirable side effects of the drugs currently in use, some of which have reportedly become resistant. This study aims to evaluate the potency of o-hydroxycinnamic acid derivatives (OCA1a-22a) and their pharmacokinetic properties and toxicity for them to be developed as new antiplatelet candidates. Methods In silico analysis of pharmacokinetics was carried out using pKCSM. Molecular docking of the compounds OCA 1a-22a was performed using the Molegro Virtual Docker. In silico evaluation of the potency of biological activity was done by measuring the bonding energy of each tested compound to the target receptor i.e. COX-1 and P2Y12, as the Moldock score (MDS). Results pKCSM analyses showed that more than 90% of OCA 1a-22a are absorbed through the intestine and distributed in plasma. Most tested compounds are not hepatotoxic, and none is mutagenic. An evaluation of the COX-1 receptor showed that OCA 2a-22a have lower binding energy compared to aspirin, which is the COX-1 inhibitor used today. So, it can be predicted that OCA 2-22a have stronger activity. Interactions with P2Y12 show lower MDS than aspirin, but slightly higher than ibuprofen, which is the standard ligand. Conclusions ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile prediction shows that OCA 1a-22a have the potential to be developed as oral preparations. OCA 1a-22a have strong potential to interact with COX-1 and P2Y12 receptors, so they are prospective anti-platelet candidates.
Subject(s)
Coumaric Acids/pharmacology , Coumaric Acids/pharmacokinetics , Cyclooxygenase 1/drug effects , Protein Binding/drug effects , Receptors, Purinergic P2Y12/drug effects , Computer Simulation , Drug Evaluation, Preclinical/methods , Humans , Molecular Docking Simulation , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacologyABSTRACT
BACKGROUND: The benefit of aspirin in preventing preeclampsia is well established; however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing, and preparation of aspirin. OBJECTIVE: We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid, in pregnant women and nonpregnant women, and to examine the effect of dose (100 mg vs 150 mg), preparation (enteric coated vs non-enteric-coated), and chronotherapy of aspirin (morning vs evening) between the 2 groups. MATERIALS AND METHODS: Twelve high-risk pregnant women and 3 nonpregnant women were enrolled in this study. Pregnant women were in 1 of 4 groups (100 mg enteric coated, 100 mg non-enteric-coated, 150 mg non-enteric-coated morning dosing, and 150 mg non-enteric-coated evening dosing), whereas nonpregnant women undertook each of the 4 dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (before ingestion) and at 1, 2, 4, 6, 12, and 24 hours after ingestion of aspirin. Plasma obtained was analyzed for salicylic acid levels by means of liquid chromatography-mass spectrometry. Pharmacokinetic values of area under the curve from time point 0 to 24 hours point of maximum concentration, time of maximum concentration, volume of distribution, clearance, and elimination half-life were analyzed for statistical significance with SPSS v25 software. RESULTS: Pregnant women had a 40% ± 4% reduction in area under the curve from time point 0 to 24 hours (P < .01) and 29% ± 3% reduction in point of maximum concentration (P < .01) with a 44% ± 8% increase in clearance (P < .01) in comparison to that in nonpregnant women when 100 mg aspirin was administered. The reduction in the area under the curve from time point 0 to 24 hours, however, was minimized with the use of 150 mg aspirin in pregnant women, with which the area under the curve from time point 0 to 24 hours was closer to that achieved with the use of 100 mg aspirin in nonpregnant women. There was a 4-hour delay (P < .01) in the time of maximum concentration, a 47% ± 3% reduction in point of maximum concentration (P < .01) and a 48% ± 1% increase in volume of distribution (P < .01) with the use of 100 mg enteric-coated aspirin compared to non-enteric-coated aspirin, with no difference in the overall area under the curve. There was no difference in the pharmacokinetics of aspirin between morning and evening dosing. CONCLUSION: There is a reduction in the total drug metabolite concentration of aspirin in pregnancy, and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy, with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric-coated and non-enteric-coated aspirin and between morning and evening dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.
Subject(s)
Aspirin/pharmacokinetics , Drug Chronotherapy , Platelet Aggregation Inhibitors/pharmacokinetics , Pregnancy/physiology , Adult , Area Under Curve , Aspirin/administration & dosage , Aspirin/therapeutic use , Case-Control Studies , Dose-Response Relationship, Drug , Female , Humans , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/therapeutic use , Pre-Eclampsia/prevention & control , Tablets, Enteric-CoatedABSTRACT
Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active-controlled, non-inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A-PR) over a reference product in high-risk ET patients, either anagrelide-naïve or -experienced. In a 6 to 12-week titration period the individual dose for the consecutive 4-week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 109 /l (95% confidence interval (CI) 707-936 × 109 /l) and 797 × 109 /l (95% CI 708-883 × 109 /l) for A-PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 109 /l for A-PR (95% CI 254-311) and 305 × 109 /l (95% CI 276-337) for the reference product (P < 0·0001, for non-inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged-release formulation was equally effective and well tolerated compared to the reference product. A-PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate-release anagrelide formulations.
Subject(s)
Platelet Aggregation Inhibitors/administration & dosage , Quinazolines/administration & dosage , Thrombocythemia, Essential/drug therapy , Delayed-Action Preparations , Dose-Response Relationship, Drug , Double-Blind Method , Drug Compounding , Female , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Count , Quality of Life , Quinazolines/adverse effects , Quinazolines/pharmacokinetics , Treatment OutcomeABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Dual antiplatelet therapy (DAPT) with aspirin (ASA) and clopidogrel (CLP) has been consistently shown clinical effectiveness in patients with coronary artery disease. According to the literature, four traditional Chinese medicine (TCM) herbs effective for prevention cardiovascular diseases, namely Radix Salvia Miltiorrhiza (Red sage root, Danshen), Radix Pueraria Lobata (Kudzu root, Gegen), Radix Angelica Sinensis (Angelica root, Danggui), and Rhizoma Ligusticum chuanxiong (Szehuan lovage rhizome, Chuanxiong), are of high potential to be co-administered during DAPT. Since all these herbs are blood vitalizing medicines and can promote blood circulation and eliminate blood stasis, it was hypothesized that they may potentially alter the clinical outcomes of DAPT with clopidogrel and aspirin. AIM OF STUDY: The current study is proposed aiming to preliminarily evaluate the impact of these four commonly used Chinese medicinal herbs on the pharmacokinetics and pharmacodynamics of the combination therapy with clopidogrel and aspirin and its relevant outcomes and mechanisms. MATERIALS AND METHODS: In order to mimic the standard dosing regimen for DAPT in human, various Sprague-Dawley rats treatment groups were received a bolus oral dose of DAPT on day 1 followed by DAPT for consecutive 13 days in absence and presence of orally co-administered four TCM herbs (Danshen, Gegen, Danggui and Chuanxiong) at their low and high doses. On day 14, serial blood samples were collected after dosing to obtain the plasma concentrations of ASA, CLP and their corresponding metabolites by LC/MS/MS. At the end of last blood sampling point of each rat, about 4.5â¯ml of whole blood were collected to estimate the prothrombin time from each treatment groups. After all the blood sampling, the rats were sacrificed followed by collecting their livers for evaluations of enzyme activities and expressions in the related liver microsome preparations and stomach tissues for evaluations of their potential ulcer index. In addition, gene expression and protein levels of related biomarkers (COX-1, COX-2, P2Y12) in rat livers were measured by RT-PCR and Western blot, respectively, and compared among different treatment groups. RESULTS: Co-administration of Gegen and Danggui significantly altered the pharmacokinetics of ASA and CLP in DAPT with increased systemic exposure of ASA and CLP respectively. Although minimal impact on aspirin esterase activity for all co-administered herbs, significant inhibition on rCyp2c11 and carboxylesterase activities were observed for DAPT with Danshen, Gegen and Danggui co-treatment. In addition, significantly longer PT were found in all DAPT treatment groups. However, a trend of decrease in PT of DAPT in presence of Gegen, Danggui and Chuanxiong was noticed. Nevertheless, all the treatments did not cause detectable changes in COX and P2Y12 mRNA and protein expressions. CONCLUSION: Among the four studied TCMs, it was demonstrated that co-administration of Gegen and Danggui could lead to altered pharmacokinetics of DAPT with significant inhibition on rCyp2c11 and carboxylesterase activities. Although Gegen, Danggui and Chuanxiong might potentially offset the anticoagulant activity of DAPT, the overall pharmacodynamics outcome was not considered to be harmful due to lack of risk in bleeding, which warrant further verification for its clinical impact.
Subject(s)
Aspirin/administration & dosage , Clopidogrel/administration & dosage , Drugs, Chinese Herbal/pharmacology , Herb-Drug Interactions , Platelet Aggregation Inhibitors/administration & dosage , Animals , Aspirin/pharmacokinetics , Aspirin/pharmacology , Biomarkers/metabolism , Blotting, Western , Chromatography, Liquid , Clopidogrel/pharmacokinetics , Clopidogrel/pharmacology , Drug Therapy, Combination , Drugs, Chinese Herbal/chemistry , Gene Expression Regulation/drug effects , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Tandem Mass SpectrometryABSTRACT
Simultaneous competition for cytochrome P450 (CYP) 2C19 and CYP3A4 might diminish clopidogrel's antiplatelet effect by impacting its metabolic activation. This pharmacoepidemiologic study investigated whether proton pump inhibitors (PPIs) and CYP3A4-metabolized statins individually and jointly increase thrombotic events by attenuating clopidogrel's effectiveness. From Korean nationwide claims data (2007-2015), we selected 59,233 patients who initiated clopidogrel and statins after coronary stenting and compared thrombotic risks by PPI or CYP3A4-metabolized statin use or both. PPIs were associated with increased thrombotic risks (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45), unlike CYP3A4-metabolized statins (HR 1.03, 95% CI 0.98-1.07). PPIs with high CYP2C19-inhibitory potential were more relevant than those with low potential (HR 1.28, 95% CI 1.02-1.61). Joint effects of PPIs and CYP3A4-metabolized statins were nonsignificant (relative excess risk due to interaction -0.14, 95% CI -0.34 to 0.07). Concurrent PPIs were associated with increased thrombotic risks in patients receiving clopidogrel and statins; CYP3A4-metabolized statins did not exacerbate PPI-associated risks.
Subject(s)
Clopidogrel/pharmacokinetics , Cytochrome P-450 CYP2C19/drug effects , Cytochrome P-450 CYP3A/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Platelet Aggregation Inhibitors/pharmacokinetics , Proton Pump Inhibitors/pharmacology , Age Factors , Aged , Comorbidity , Drug Interactions , Female , Humans , Male , Middle Aged , National Health Programs , Republic of Korea , Sex FactorsABSTRACT
BACKGROUND: Acetylsalicylic acid, clopidogrel and cilostazol are well-established agents inhibiting the normal function of platelets with known advantages and limitations. The development of novel antiplatelet agents aims to provide equal or superior outcomes for patients and simultaneously minimize side effects. OBJECTIVE: The aim of this manuscript is to review the latest data on the use of novel antiplatelet agents in vascular patients. METHOD: Based on our 2016 review, a further search in the English medical literature has yielded a number of publications on cangrelor, prasugrel, ticagrelor, vorapaxar and a number of other - still experimental - agents (Ir- 6, UBO-QIC, W1, revacept and YM-254890). RESULTS: Recently published data have not altered the use and indications of cangrelor, prasugrel and vorapaxar; all of them now approved by both FDA and EMA. The EUCLID trial has recently provided valuable data on the clinical use of ticagrelor, although results regarding vascular patients and administration of ticagrelor are still under scrutiny. Vorapaxar remains the only novel antiplatelet that is approved for PAD. Randomized control trials that focus on vascular patients are necessary to establish the safety and efficacy of these novel agents. Despite their positive initial results, most novel experimental antiplatelets are still in early development, thus in preclinical or early clinical phases of their trials. Research on three novel antiplatelets is currently discontinued (atopaxar, darexaban and elinogrel). CONCLUSION: Vorapaxar remains the only novel antiplatelet that is approved for PAD. Other novel antiplatelets demonstrate positive results, but further studies focused on vascular patients are necessary. Novel experimental antiplatelets are still in the early phases of the clinical and preclinical studies.
Subject(s)
Drug Discovery , Drugs, Investigational/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Vascular Diseases/drug therapy , Clinical Trials as Topic , Drug Evaluation, Preclinical , Drugs, Investigational/pharmacokinetics , Drugs, Investigational/therapeutic use , Humans , Molecular Structure , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/therapeutic useABSTRACT
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.
Subject(s)
Aspirin/pharmacokinetics , Carboxylic Ester Hydrolases/blood , Catechol O-Methyltransferase/blood , Coronary Disease/drug therapy , Herb-Drug Interactions , Models, Biological , Plant Extracts/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Administration, Oral , Adult , Aged , Aspirin/administration & dosage , Aspirin/adverse effects , Aspirin/blood , China , Coronary Disease/blood , Coronary Disease/diagnosis , Drug Monitoring , Drug Therapy, Combination , Female , Humans , Injections, Intravenous , Male , Middle Aged , Plant Extracts/administration & dosage , Plant Extracts/adverse effects , Plant Extracts/blood , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/blood , Prospective Studies , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
CONTEXT: Andrographolide and warfarin are often used together in clinics in China. However, the herb-drug interaction between andrographolide and warfarin is still unknown. OBJECTIVE: This study investigates the herb-drug interaction between andrographolide and warfarin in vivo and in vitro. MATERIALS AND METHODS: A sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in male Sprague-Dawley rats plasma, and then the pharmacokinetics of orally administered warfarin (0.5 mg/kg) with or without andrographolide (30 mg/kg/day for 7 days) pretreatment was investigated. In addition, Sprague-Dawley rat liver microsomes incubation systems were used to support the in vivo pharmacokinetic data and investigate its potential mechanism. RESULTS: The method validation results showed that a sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in rat plasma samples. The pharmacokinetic results indicated that co-administration of andrographolide could increase the systemic exposure of warfarin significantly, including area under the curve (118.92 ± 18.08 vs. 60.58 ± 9.46 µg × h/mL), maximum plasma concentration (3.32 ± 0.41 vs. 2.35 ± 0.25 µg/mL) and t1/2 (22.73 ± 3.28 vs. 14.27 ± 2.67 h). Additionally, the metabolic stability of warfarin increased from 23.5 ± 4.7 to 38.7 ± 6.1 min with the pretreatment of andrographolide, and the difference was significant (p < 0.05). DISCUSSION AND CONCLUSION: In conclusion, andrographolide could increase the systemic exposure of warfarin in rats when andrographolide and warfarin were co-administered, and possibly by slowing down the metabolism of warfarin in rat liver by inhibiting the activity of CYP3A4 or CYP2C9.
Subject(s)
Anticoagulants/pharmacokinetics , Diterpenes/pharmacokinetics , Herb-Drug Interactions/physiology , Platelet Aggregation Inhibitors/pharmacokinetics , Warfarin/pharmacokinetics , Animals , Chromatography, Liquid/methods , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Tandem Mass Spectrometry/methodsABSTRACT
The use of warfarin, the most commonly prescribed oral anticoagulant, is being questioned by clinicians worldwide due to warfarin several limitations (a limited therapeutic window and significant variability in dose-response among individuals, in addition to a potential for drug-drug interactions). Therefore, the need for non-vitamin K antagonist oral anticoagulants (NOACs) with a rapid onset of antithrombotic effects and a predictable pharmacokinetic (PK) and pharmacodynamic (PD) profile led to the approval of five new drugs: the direct factor Xa (F-Xa) inhibitors rivaroxaban, apixaban, edoxaban and betrixaban (newly approved by FDA) and the direct thrombin (factor-IIa) inhibitor dabigatran etexilate. The advantages of NOACs over warfarin are a fixed-dosage, the absence of the need for drug monitoring for changes in anti-coagulation and fewer clinically significant PK and PD drug-drug interactions. NOACs exposure will likely be increased by the administration of strong P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4-inhibitors and may increase the risk of bleeds. On the contrary, P-gp inducers could significantly decrease the NOACs plasma concentration with an associated reduction in their anticoagulant effects. This manuscript gives an overview of NOACs PK profiles and their drug-drug interactions potential. This is meant to be of help to physicians in choosing the best therapeutic approach for their patients.
Subject(s)
Anticoagulants/pharmacokinetics , Administration, Oral , Animals , Drug Interactions , Humans , Phytotherapy , Platelet Aggregation Inhibitors/pharmacokinetics , Vitamin K/antagonists & inhibitors , Warfarin/pharmacokineticsABSTRACT
Cardiovascular diseases (CVDs) are becoming major contributors to the burden of disease due to genetic and environmental factors. Despite current standard oral care, cardiovascular risk remains relatively high. A triple antiplatelet therapy with a cyclooxygenase-1 (COX-1) inhibitor, a P2Y12 receptor antagonist, and a protease-activated receptor-1 (PAR-1) antagonist has been established in the secondary prevention of atherothrombosis in patients with acute myocardial infraction and in those with peripheral artery disease. However, due to the combinatorial use of three different drugs, patients receiving this triple therapy are exposed to enhanced risk of bleeding. Conforming to polypharmacology principles, the discovery of a single compound that can simultaneously block the three platelet activation pathways (PAR-1, P2Y12, and COX-1) is of importance. Natural products have served as an inexhaustible source of bioactive compounds presenting a diverse pharmaceutical profile, including anti-inflammatory, antioxidant, anticancer, and antithrombotic activity. Indeed, principal component analysis indicated that natural products have the potential to inhibit the three aforementioned pathways, though existed reports refer to single inhibition mechanism on specific receptor(s) implicated in platelet activation. We thus set out to explore possibilities that take advantage of this potential of natural products and shape the basis to produce novel compounds that could simultaneously target PAR-1, P2Y12, and COX-1 platelet activation pathways. Polyunsaturated fatty acids (PUFAs) have multiple effects leading to improvements in blood pressure and cardiac function and arterial compliance. A promising approach to achieve the desirable goal is the bioconjugation of natural products with PUFAs. Herein, we describe the principles that should be followed to develop molecular hybrids bearing triple antiplatelet activity profile.
Subject(s)
Blood Platelets , Cyclooxygenase 1 , Cyclooxygenase Inhibitors , Fatty Acids, Unsaturated , Plasma/chemistry , Platelet Aggregation Inhibitors , Receptor, PAR-1/antagonists & inhibitors , Receptors, Purinergic P2Y12 , Blood Platelets/chemistry , Blood Platelets/metabolism , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacokinetics , Cyclooxygenase Inhibitors/pharmacology , Drug Evaluation, Preclinical/methods , Drug Stability , Fatty Acids, Unsaturated/chemistry , Fatty Acids, Unsaturated/pharmacokinetics , Fatty Acids, Unsaturated/pharmacology , Humans , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Purinergic P2Y Receptor Antagonists/chemistry , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacology , Receptor, PAR-1/metabolismABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The Dengzhan Shengmai capsule (DZSM) is known in China for its remarkable curative effect as a treatment of cardiovascular diseases, such as coronary heart disease and ischemic stroke. DZSM is a Chinese herbal compound preparation that consists of four ingredients, including Erigeron breviscapus (Vaniot) Hand.-Mazz., Panax ginseng C.A. Mey, Ophiopogon japonicas (Thunb.) Ker-Gawl. and Schisandra chinensis (Turcz.) Baill., and was indexed in the Chinese Pharmacopoeia 2010. DZSM and clopidogrel are often co-prescribed in the clinic to prevent the recurrence of stroke or other cardiovascular and cerebrovascular diseases. However, the effect of DZSM on the pharmacokinetics of clopidogrel remains unclear. AIM OF THE STUDY: The purpose of the study is to explore the pharmacokinetics and potential interaction between DZSM and clopidogrel and the underlying mechanism. MATERIALS AND METHODS: Rats were used to investigate the effect of DZSM on the pharmacokinetics of clopidogrel and its active metabolite in vivo. The plasma concentrations were simultaneously determined using LC-MS/MS. The effects of DZSM on the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel were investigated using MDCKII-MDR1 cells and rat liver microsomes, respectively. RESULTS: After pretreatment with DZSM, the Cmax and AUC0-∞ of clopidogrel increased from 0.4±0.1 to 1.7±0.6ng/mL and 0.9±0.4 to 2.0±0.2ng/mLh, respectively. The Cmax and AUC0-∞ of the derivatized active metabolite of clopidogrel decreased from 8.2±1.2 to 2.8±0.5ng/mL and 18.2±5.6 to 6.4±3.7ngh/mL, respectively. In MDCKII-MDR1 cells, the P-gp-mediated efflux transport of clopidogrel was significantly inhibited by the DZSM extract. In rat liver microsomes, DZSM inhibited clopidogrel metabolism with an IC50 of 0.02mg/mL. CONCLUSIONS: DZSM significantly affects the pharmacokinetics of clopidogrel and its active metabolite by inhibiting the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel. Thus, caution is needed when DZSM is co-administered with clopidogrel in the clinic because the interaction of these drugs may result in altered plasma concentrations of clopidogrel and its active metabolite.
Subject(s)
Cardiovascular Agents/administration & dosage , Drugs, Chinese Herbal/administration & dosage , Herb-Drug Interactions , Platelet Aggregation Inhibitors/pharmacokinetics , Ticlopidine/analogs & derivatives , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Activation, Metabolic , Administration, Oral , Animals , Area Under Curve , Cardiovascular Agents/toxicity , Chromatography, Liquid , Clopidogrel , Cytochrome P-450 Enzyme System/metabolism , Dogs , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/toxicity , Madin Darby Canine Kidney Cells , Male , Metabolic Clearance Rate , Microsomes, Liver/metabolism , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/blood , Platelet Aggregation Inhibitors/toxicity , Rats, Sprague-Dawley , Risk Assessment , Tandem Mass Spectrometry , Ticlopidine/administration & dosage , Ticlopidine/blood , Ticlopidine/pharmacokinetics , Ticlopidine/toxicity , TransfectionABSTRACT
Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P(1),P(4)-di(adenosine-5') tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents.
Subject(s)
Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Receptors, Purinergic P2Y12/metabolism , Receptors, Purinergic P2Y1/metabolism , Animals , Chemistry Techniques, Synthetic , Dinucleoside Phosphates/chemistry , Dinucleoside Phosphates/metabolism , Drug Evaluation, Preclinical/methods , Drug Stability , Humans , Platelet Aggregation Inhibitors/pharmacokinetics , Purinergic P2X Receptor Antagonists/chemistry , Purinergic P2X Receptor Antagonists/pharmacology , Purinergic P2Y Receptor Antagonists/chemistry , Purinergic P2Y Receptor Antagonists/pharmacology , Rats , Receptors, Purinergic P2X1/metabolism , Structure-Activity RelationshipABSTRACT
Patients with coronary artery disease are usually treated with dual antiplatelet therapy (DAPT) after percutaneous coronary intervention. Patients on DAPT are at risk of both ischaemic and bleeding events. Although side-lined for a long time, real-life studies have shown that both the incidence and the associated morbidity and mortality of out-of-hospital bleeding are high. This indicates that prevention of (post-interventional) bleeding is as important as prevention of ischaemia. For this purpose it is crucial to reliably identify patients with a high bleeding risk. In order to postulate an algorithm, which could help identifying these patients, we performed a systematic review to determine the value of previously proposed prognostic modalities for bleeding. We searched and appraised the following tools: platelet function tests, genetic tests, bleeding scores and questionnaires and haemostatic tests. Most studies indicated that low on-treatment platelet reactivity (LTPR), as measured by several platelet function tests, and the carriage of CYP2C19*17 allele were independent risk factors for bleeding. A bleeding score also proved to be helpful in identifying patients at risk. No studies on haemostatic tests were retrieved. Several patient characteristics were also identified as independent predictors of bleeding, such as older age, female sex and renal failure. Combining these risk factors we propose an algorithm that would hypothetically facilitate identification of those patients at highest risk, warranting prevention measures for bleeding. This could be a starting point for further research concerning the topic.
Subject(s)
Coronary Artery Disease/therapy , Hemorrhage/chemically induced , Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/adverse effects , Algorithms , Coronary Artery Disease/blood , Coronary Artery Disease/diagnosis , Critical Pathways , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP2C19/metabolism , Decision Support Techniques , Drug Resistance , Drug Therapy, Combination , Genotype , Humans , Percutaneous Coronary Intervention/adverse effects , Pharmacogenetics , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Function Tests , Predictive Value of Tests , Risk Assessment , Risk Factors , Treatment OutcomeABSTRACT
The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg(-1) for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg(-1) were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.