Effect Of Clopidogrel Research Articles

Effect of Clopidogrel and Ticagrelor in the Treatment of Acute Myocardial Infarction

Effect of Clopidogrel and Ticagrelor in the Treatment of Acute Myocardial Infarction

Effects of Clopidogrel, Prasugrel and Ticagrelor on Microvascular Function and Platelet Reactivity in Patients With Acute Coronary Syndrome Undergoing Coronary Artery Stenting. A Randomized, Blinded, Parallel Group Trial.

Aims: In this pre-specified analysis of the “endothelium, stent and antiplatelet therapy” study, we investigate the impact of antiplatelet therapies on microvascular function in patients undergoing stenting for an acute coronary syndrome.Methods and Results: Fifty-six patients [age: 63(55–67) years, males, 10 diabetics, 27 non-ST-elevation myocardial infarction] were randomized to receive clopidogrel, ticagrelor or prasugrel in form of oral loading 2 h before stenting followed by oral therapy. Investigators were blinded to the allocation. Laser-Doppler microvascular function and ADP-induced platelet aggregation capacity were measured at baseline, 2 h after oral antiplatelet loading, and 1 day, 1 week and 1 month after stenting during chronic therapy with the same antiplatelet agent. Platelet aggregation decreased in all groups 2 h after oral loading, with a significantly larger effect in the prasugrel group (P = 0.009). Similarly, prasugrel and ticagrelor loading was followed by an increase in microvascular reactive hyperemia (P = 0.007 and P = 0.042 compared to clopidogrel). This effect disappeared one day after coronary intervention, with a significant decrease in the prasugrel group (P = 0.026). Similarly, analysis of microvascular conductance showed a larger increase in the prasugrel group 2 h after loading (P = 0.022 among groups), and a decrease in all groups after stenting.Conclusions: Oral loading with prasugrel (and less consistently ticagrelor) is associated with improved microvascular function and stronger platelet inhibition in acute coronary syndrome patients. The microvascular effect was however lost 1 day after stenting and during subsequent follow-up. Further studies are necessary to clarify the the long-term effects and potential benefits of P2Y12 inhibitors on microvascular damage.ClINICALTRIALS.gov N°: NCT01700322EUDRACT-N°: 2011-005305-73.

DNA Damage in AML-12 Hepatocytes and 3T3-L1 Adipocytes Treated with Clopidogrel.

Clopidogrel has been commonly prescribed as a selective P2Y12 receptor antagonist to reduce heart attack and stroke risk. Nearly 10% of absorbed clopidogrel is metabolized to active forms by cytochrome P450 (CYP) enzymes in the liver and 90% to inactive clopidogrel carboxylate by esterases. Since different forms of clopidogrel have cytotoxic potential, our aim was to determine the effect of 7.5, 40, and 75μM clopidogrel over DNA damage in adipocytes and hepatocytes. In the present study, DNA damage was investigated by Comet analysis using 3T3-L1 adipocytes and Alpha Mouse 12 (AML-12) hepatocytes. DNA fragmentation was found to be increased as a response to 7.5 μM, 40 μM, and 75 μM clopidogrel treatment compared to non-treated control groups in AML-12 hepatocytes (p<0.01, p<0.001, p<0.01 respectively) and 3T3-L1 adipocytes (p<0.001, p<0.001 and p<0.001respectively). DNA damage levels as a response to clopidogrel treatment were found to be higher in 3T3-L1 adipocytes than AML-12 hepatocytes. Also, DNA damage levels in adipocytes and hepatocytes were found to increase dose-dependently for 7.5 and 40 μM clopidogrel, whereas decreased as a response to 75 μM. According to our results, clopidogrel results in more DNA damage in adipocytes than in hepatocytes. The molecular mechanism of clopidogrel genotoxicity needs to be further investigated especially in adipose tissue.

Abstract 9580: Impact of Clopidogrel Metabolizer Status on Incidence of Gastrointestinal Bleed

Introduction: Clopidogrel is used for secondary prevention of coronary artery disease, stroke, and peripheral vascular disease. Increased doses has been associated with increased odds of gastrointestinal (GI) complications (gastritis, gastric ulcer and bleeding). Effectiveness of clopidogrel is dependent on its conversion to active metabolite by liver enzyme CY2C19. Hypothesis: Clopidogrel metabolizer status impacts the incidence of GI bleed. Methods: Patients aged &gt;18 years, on clopidogrel and known CYP2C19 status were included in the study. Based on functional copies of CYP2C19 they were divided into two groups slow (poor or intermediate) and adequate metabolizers (normal, rapid, ultra-rapid) and were retrospectively analyzed for documented diagnosis of GI bleed after initiation of clopidogrel. Results: A total of 3778 patients were included in the study who were on clopidogrel and had known CYP2C19 status. Of these patients, 74.2% were adequate and 25.8% were slow metabolizers. Overall, there were 332 patients (8.8%) with a documented diagnosis of GI bleed following initiation of clopidogrel. There was no significant difference observed in incidence of GI bleed among slow and adequate metabolizers (8% vs 9.1%, p=0.313). Conclusions: Our study demonstrates that the clopidogrel metabolizer status does not appear to have any significant impact on incidence of GI bleeding, which further strengthens the fact that GI bleed is a multi-factorial pathology.

Abstract 12895: Superior Effectiveness and Safety of Ticagrelor in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A Nationwide Registry-Based Study

Introduction: Dual antiplatelet therapy with aspirin and a P2Y 12 inhibitor is recommended following PCI for ACS. The optimal choice of P2Y 12 inhibitor remains debated. We compared effectiveness and safety of clopidogrel, ticagrelor, and prasugrel in a large, nationwide cohort of patients with ACS undergoing PCI. Methods: Registry-based study of first-time ACS patients who underwent PCI ≤7 days of admission and redeemed a prescription of a P2Y 12 inhibitor ≤30 days of the index event. The primary outcome was major adverse cardiovascular events (MACE): a composite of cardiovascular death, recurrent myocardial infarction, stroke, or repeat revascularization at 12 months. The safety outcome was bleeding requiring hospitalization at 12 months. Multivariable logistic regression with average treatment effect modeling was used to calculate standardized absolute and relative risks for outcomes across age, sex, comorbidity, bleeding, and concomitant anticoagulant therapy distributions. Results: We included 26,997 patients; 6,585 were discharged on clopidogrel, 18,425 on ticagrelor, and 1,987 on prasugrel. Corresponding median ages were 70, 64, and 59 years (p&lt;0.001). Patients in the clopidogrel group were more likely to have had a prior bleeding episode (p&lt;0.001). Adjusted relative risks of MACE were 0.80 for ticagrelor vs clopidogrel (p&lt;0.001), 0.85 for prasugrel vs clopidogrel (p&lt;0.001), and 1.05 for prasugrel vs ticagrelor (p=0.22). Adjusted relative risks of bleeding were 0.82 for ticagrelor vs clopidogrel (p=0.001), 1.07 for prasugrel vs clopidogrel (p=0.56), and 1.30 for prasugrel vs ticagrelor (p=0.03). While statistically significant, the absolute differences in risk of bleeding among groups were modest (Figure). Conclusion: Ticagrelor and prasugrel were associated with lower risk of MACE than clopidogrel but did not significantly differ from each other. Ticagrelor was associated with a lower risk of bleeding than both clopidogrel and prasugrel.

Abstract 14311: Gene Guided Antiplatelet Therapy for Acute Coronary Syndrome: An Updated Meta-Analysis

Introduction: Clopidogrel has been the mainstay oral antiplatelet regimen to treat Acute Coronary syndrome (ACS) post percutaneous coronary intervention (PCI) with stents. However, there is marked inter-individual variability due to genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 in the antiplatelet effects of clopidogrel and a reduced response to this drug may be a risk factor for ischemic complications. There has been varied evidence in gene-guided antiplatelet therapy post PCI. An updated meta-analysis was conducted to study the effect of gene-guided antiplatelet therapy in ACS. Methods: A systematic literature review was performed in Embase, PubMed and SCOPUS for all the related articles until May 2021 yielding 180 publications. Nine studies fulfilled inclusion criteria including 8 randomized clinical trials and 1 observational study. The Mantel- Haenszel random-effects model was used to calculate odds ratio (OR) and 95% confidence intervals (CI). Outcomes analyzed were the composite major adverse cardiovascular events (MACE), stent thrombosis, myocardial infarction (MI), bleeding and cardiovascular (CV) death. Results: Gene guided antiplatelet therapy was performed in 7106 patients and conventional therapy in 3970 patients. The MACE events was significantly lower in gene-guided therapy arm (OR = 0.67, 95% CI [0.51 -0.87], P=0.003) driven by lower stent thrombosis (OR=0.47, 95% CI [0.25 -0.88], P=0.02) and lower MI in the gene guided therapy (OR=0.61, 95% CI [0.41 -0.92], P=0.02). The bleeding rates trended to be lower in the gene guided therapy as well (OR = 0.75, 95% CI [0.54-1.02], P=0.07). There is no significance difference in CV death. (OR=0.57, 95% CI [0.21-1.55]) Conclusions: Genotype guided antiplatelet therapy in ACS has lower adverse cardiovascular outcomes driven by lower stent thrombosis and MI with lower bleeding trends as well.

NOD2-mediated P2Y12 upregulation increases platelet activation and thrombosis in sepsis

BackgroundPlatelets from septic patients exhibit increased reactivity. However, the underlying mechanism of sepsis-induced platelet hyperactivity is still not completely understood. ObjectiveP2Y12 is a central receptor for platelet activation. In this study, we investigated the role of platelet P2Y12 in platelet hyperactivity during sepsis. MethodsWe measured platelet P2Y12 expression and aggregation in response to ADP in septic patients and cecal ligation and puncture (CLP)-treated mice. We also detected the downstream signaling of P2Y12 in resting platelets from patients and mice with sepsis. The role of nucleotide-binding oligomerization domain 2 (NOD2)/RIP2/NF-κB/P65 pathway in sepsis-induced platelet P2Y12 high expression was also investigated. Finally, we compared the antiplatelet and antithrombotic effects of clopidogrel, prasugrel, and ticagrelor in experimental sepsis in mice and rats. ResultsCompared to healthy subjects, platelets from septic patients exhibit P2Y12 hyperactivity and higher P2Y12 expression. pAkt is enhanced and pVASP is impaired in resting platelets from the patients, indicating the constitutive activation of platelet P2Y12 receptor. Mouse sepsis model recapitulates the findings in septic patients. NOD2 deficiency attenuates sepsis-induced platelet P2Y12 high expression, hyperactivity, and thrombosis. Prasugrel and ticagrelor are potent P2Y12 inverse agonists, and exhibit superior antiplatelet and antithrombotic efficacy over clopidogrel in mice and rats with sepsis. ConclusionsNOD2 activation upregulates platelet P2Y12 expression, which is constitutively activated and contributes to platelet hyperactivity in septic status. Compared to clopidogrel, prasugrel and ticagrelor are potent P2Y12 inverse agonists with superior antiplatelet and antithrombotic efficacy in experimental sepsis.

TCT-6 Impact of Diabetes Mellitus on the Effectiveness of Aspirin Versus Clopidogrel as a Chronic Maintenance Antiplatelet Monotherapy After Percutaneous Coronary Intervention: Results From the HOST-EXAM Trial

TCT-6 Impact of Diabetes Mellitus on the Effectiveness of Aspirin Versus Clopidogrel as a Chronic Maintenance Antiplatelet Monotherapy After Percutaneous Coronary Intervention: Results From the HOST-EXAM Trial

Is platelet responsiveness to clopidogrel attenuated in overweight or obese patients and why? A reverse translational study in mice

Overweight or obese patients exhibit poorer platelet responses to clopidogrel. However, the mechanisms behind this phenotype remain to be elucidated. Here, we sought to discover whether and why obesity could affect the metabolic activation of and/or platelet response to clopidogrel in obese patients and high-fat diet-induced obese mice. A post hoc stratified analysis of an observational clinical study was performed to investigate changes in residual platelet reactivity with increasing body weight in patients taking clopidogrel. Furthermore, high-fat diet-induced obese mice were used to reveal alterations in systemic exposure of clopidogrel thiol active metabolite H4, ADP-induced platelet activation and aggregation, the expression of genes involved in the metabolic activation of clopidogrel, count of circulating reticulated and mature platelets, and proliferation profiles of megakaryocytes in bone marrow. The relevant genes and potential signalling pathways were predicted and enriched according to the GEO datasets available from obese patients. Obese patients exhibited significantly attenuated antiplatelet effects of clopidogrel. In diet-induced obese mice, systemic exposure of clopidogrel active metabolite H4 was reduced but that of its hydrolytic metabolite was increased due to down-regulation of certain P450s but up-regulation of carboxylesterase-1 in the liver. Moreover, enhanced proliferation of megakaryocytes and elevated platelet count also contributed. Obesity attenuated metabolic activation of clopidogrel and increased counts of circulating reticulated and mature platelets, leading to impaired platelet responsiveness to the drug in mice, suggesting that clopidogrel dosage may need to be adjusted adequately in overweight or obese patients.

Drug repositioning of Clopidogrel or Triamterene to inhibit influenza virus replication in vitro.

Influenza viruses cause respiratory tract infections and substantial health concerns. Infection may result in mild to severe respiratory disease associated with morbidity and some mortality. Several anti-influenza drugs are available, but these agents target viral components and are susceptible to drug resistance. There is a need for new antiviral drug strategies that include repurposing of clinically approved drugs. Drugs that target cellular machinery necessary for influenza virus replication can provide a means for inhibiting influenza virus replication. We used RNA interference screening to identify key host cell genes required for influenza replication, and then FDA-approved drugs that could be repurposed for targeting host genes. We examined the effects of Clopidogrel and Triamterene to inhibit A/WSN/33 (EC50 5.84 uM and 31.48 uM, respectively), A/CA/04/09 (EC50 6.432 uM and 3.32 uM, respectively), and B/Yamagata/16/1988 (EC50 0.28 uM and 0.11 uM, respectively) replication. Clopidogrel and Triamterene provide a druggable approach to influenza treatment across multiple strains and subtypes.

Comparative study of specific activity of rectal suppositories with clopidogrel

One of the most effective platelet antiaggregants is clopidogrel, inhibiting platelet activation by selectively binding adenosine diphosphate (ADP) with specific receptors. However, in a number of clinical situations it is necessary to have a pronounced antithrombotic effect in the shortest possible time which gives rise to interest in the transmucose use of the drug, in particular, rectal route. The theoretical preconditions for the development of a rectal administration of clopidogrel are based on the data that the anti-aggregation effect of a substance is carried out by its main metabolite formed after “first hepatic passage”, while clopidogrel itself in this aspect is inactive. On the base of complex physico-chemical, pharmaceutical, biopharmaceutical, rheological and microbiological investigations, the rational composition of clopidogrel rectal dosage form – suppository on a hydrophilic base to prevent atherothrombotic events in patients with myocardial infarction, acute coronary syndrome, ischemic stroke, peripheral arterial occlusion, is proposed by the employees of the Department of Technology of Medications of the Zaporizhzhia State Medical University. The aim of the work is to investigate the specific activity of rectal suppositories with clopidogrel. Materials and methods. Experimental suppositories with clopidogrel 0,075 g for rectal administration were used as the objects in pre-line studies. The ability of clopidogrel to reduce the inhibitory effect of ADP on adenylate cyclase activity and decrease the number of binding sites for 2-methylthio-ADP (analogue of ADP) without altering the receptor topography is used as a base of the method of comparative study of its specific activity in the rectal dosage form (suppository) and in comparison with the reference medication Plavix (SANOFI WINTHROP INDUSTRIE, France) in the tablet form. Studies were performed on white non-linear rats of different sexes with different mass 150–210 g, aged 3.5–5.0 months. Results. Statistically significant differences in the inhibition of induced platelet aggregation were registered after 6 hours of rectal administration of clopidogrel and gastric administration of the reference medication, indicating the effectiveness of the rectal applicative transmucosal route for this active pharmaceutical ingredient (API). On the 5th day of administration, inhibition of induced platelet aggregation significantly increased, and that is supported by literature on the cumulative effect of clopidogrel in daily life. When comparing the digital material of the table, it is obvious that the rectal administration of clopidogrel is more effective in comparison with oral route which is probably due to the rapid delivery of API to the liver and the formation of an active metabolite of clopidogrel inhibiting the induction and spontaneous aggregation of platelets in human’s and animal’s blood. Obtained data provide with sound arguments for development of rectal suppositories with clopidogrel because in clinical care faster achievement of an anti-aggregation effect in patients with acute coronary syndrome is the primary task of clinical pharmacology and pharmacy. Conclusions. Using the biochemical model of pathology, it was established that the applicative semisolid medication of clopidogrel in the form of rectal suppository exhibited inductive anti-aggregation activity and its administration didn’t reveal any side effects and undesirable events. Rectal suppositories with clopidogrel have been shown to exhibit faster reliable anti-aggregation effect in comparison with intragastric administration.

Evaluation of laboratory effectiveness of clopidogrel after elective endovascular procedures in patients with the history of the new coronavirus infection (COVID-19)

Aim. To evaluate the impact of antiplatelet agent clopidogrel on the aggregation platelet activity in patients with the history of the new coronavirus infection (COVID-19).&#x0D; Materials and methods. The impact of clopidogrel on platelet aggregation was studied in 47 patients with coronary heart disease after coronary artery stenting. The patients were assigned to 2 groups: group 1 comprised the patients who were not affected by COVID-19 (n=31), while group 2 comprised the patients who had COVID-19 (n=26) 3 months 1 year (mean, 51.3 months) before being included in the study.&#x0D; Results. The use of clopidogrel contributed to platelet aggregation decrease to the target levels in both groups. Platelet aggregation, assessed by Born technique, was 22.9 and 22.7% in groups 1 and 2, respectively. Platelet aggregation, assessed by the technique of optical transmission agregometry (system VerifyNow, P2Y12), was 152.3 and 147.2 PRU in groups 1 and 2, respectively. The data obtained in each group were not significantly different and attested to high laboratory effectiveness of clopidogrel. Besides, we did not find reliable differences in the levels of inflammation marker: C-reactive protein, fibrinogen, leucocytes, as well as of D-dimer, in the studied groups.&#x0D; Conclusion. In 3 months 1 year after COVID-19, the laboratory effectiveness of Clopidogrel used in standard dosage of 75 mg/day is compliant with target indices and does not differ from the effectiveness in patients with no history of COVID-19. At this stage of our study, the obtained results do not imply the necessity of changing the protocol of double antiplatelet therapy after coronary artery stenting in stable patients with coronary artery disease, who suffered COVID-19 three months 1 year before being included in the study, and show the necessity of further investigations.

Prasugrel or clopidogrel in patients with acute coronary syndromes at high thrombotic risk: results from the PROMETHEUS study

Abstract Background Potent P2Y12 inhibitors are recommended on top of aspirin in patients presenting with acute coronary syndrome (ACS). However, guideline recommendations suggest that the optimal antithrombotic strategy should be tailored based on patients thrombotic and hemorrhagic risk profile. Purpose It is poorly investigated if the benefits derived from potent P2Y12 inhibition in patients with ACS depend on the individual thrombotic risk profile. Our aim was to evaluate if the benefits associated with prasugrel vs. clopidogrel in patients with ACS undergoing percutaneous coronary intervention (PCI) are similar in case of different thrombotic risk profiles. Methods PROMETHEUS was a multicenter observational study comparing prasugrel vs. clopidogrel in ACS patients undergoing PCI. According to the 2020 ESC guidelines for non-ST elevation-ACS, patients are defined at high thrombotic risk if presenting with a clinical (diabetes mellitus requiring medication, history of recurrent myocardial infarction [MI], multivessel coronary artery disease [CAD], polyvascular [coronary and peripheral] disease, premature (&amp;lt;45 years) CAD, and chronic kidney disease [estimated glomerular filtration rate &amp;lt;60 ml/min/1.73m2]) and procedural (≥3 stents implanted, ≥3 lesions treated, total stent length &amp;gt;60 mm, complex revascularization [left main PCI, bifurcation or chronic total occlusion]) risk features. The primary endpoint was major adverse cardiac events (MACE), a composite of death, MI, stroke or unplanned revascularization. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated using propensity-stratified analysis to assess the effect of prasugrel vs. clopidogrel and with multivariable Cox regression to evaluate the impact of thrombotic risk. Results Among 16065 patients, 4293 were defined at high thrombotic risk and 11772 at low-to-moderate thrombotic risk. Patients treated with prasugrel had less comorbidities and risk factors than those treated with clopidogrel, both in the high and low-to-moderate thrombotic risk strata. Patients at high thrombotic risk had higher rates of both ischemic and bleeding events at 90 days and at 1 year. Patients treated with prasugrel had a lower adjusted risk of MACE at 1 year (HR 0.86, 95% CI 0.77–0.96), with no significant interaction between effect estimates and thrombotic risk. However, after stratifying the study population by the number of risk factors, there was a significant interaction for a greater reduction in MACE with prasugrel in patients with ≤1 thrombotic risk factor. Conversely, there were no differences in major bleeding among patients treated with prasugrel and clopidogrel. Conclusions Patients with ACS at high thrombotic risk who undergo PCI are at increased risk of adverse events. Prasugrel, although mainly reserved to patients with lower burden of comorbidities, reduced the risk of ischemic events both in patients at high and low-to-moderate thrombotic risk as compared with clopidogrel. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo and Eli Lilly and Company Clinical outcomes at 1 year.Impact of number of risk factors

Gene polymorphisms of insulin secretion signaling pathway associated with clopidogrel resistance in Han Chinese population.

BackgroundDue to the loss of responsiveness to insulin, diabetes mellitus (DM) patients develop increased platelet reactivity and reduced response to antiplatelet agents. Nevertheless, the relationship between the single‐nucleotide polymorphisms (SNP) of the signal pathway gene of insulin secretion and the effect of clopidogrel is elusive.MethodsBlood samples were collected from patients administered with dual‐antiplatelet therapy (clopidogrel, 75 mg, once daily and aspirin, 100 mg, once daily) after 5 days and completed test within 4 h. The VerifyNow P2Y12 assay was used to measure the platelet functions, and the results were expressed as a P2Y12 reaction unit (PRU). Notably, the selected SNPs were analyzed to demonstrate the functionality of genetic variants.ResultsAnalysis of the study population showed that old age, lower plasma albumin (ALB) level, higher creatinine (CREA) level, higher uric acid (UA) level, lower platelet (PLT) count, and lower plateletcrit (PCT) potentially increased the risk of clopidogrel resistance. In a single‐nucleotide polymorphism rs6056209 of the PCLB1 gene, the AG genotype was a risk factor for clopidogrel resistance (p < 0.05, OR = 1.574). Similarly, the CC and AG genotype in GNAS rs7121 and CCKAR rs1800857 were protective factors (p < 0.05, OR = 0.094; p <0.05, OR = 0.491). TT was a protective factor in rs10814274 of the CREB3 gene (p < 0.05, OR = 0.444). In the RAPGEF4 gene polymorphism rs17746510, TG was the protective genotype, and the TT genotype was a risk factor for clopidogrel resistance. GCG rs5645 was confirmed; there was a relationship between genotypes containing A or G and clopidogrel resistance.ConclusionSingle‐nucleotide polymorphisms of insulin secretion signaling pathway genes trigger clopidogrel resistance.

Clopidogrel-herb Interactions: A Pharmacokinetic and Pharmacodynamic Assessment in a Rat Model.

Herbs usually contain a mixture of biologically active constituents, which can interact with numerous prescribed drugs and alter their safety profiles. The current investigation was aimed to evaluate the effect of commonly used herbal products including black seed (Nigella sativa), garden cress (Lepidium sativum), and fenugreek (Trigonella foenum-graecum) on the pharmacokinetics and pharmacodynamics of clopidogrel using a Wistar rat model. A GC-MS analysis revealed the presence of several phytoconstitutents (polyphenols) in the extracts of black seed, garden cress, and fenugreek. These polyphenols have the potential to interfere with clopidogrel effect. Plasma concentrations of clopidogrel were measured at different time points in the absence and presence of the concurrent use of tested herbal products and the pharmacokinetic parameters were calculated. Bleeding time was measured in various groups as a measure of the antiplatelet effect of clopidogrel. Area under the plasma concentration-time curves (AUC0-∞) of clopidogrel were 35.53 ±0.89 μg/ml*h (p<0.05), 26.01 ±0.90 μg/ml*h (p>0.05) and 32.80 ±2.51 μg/ml*h (p<0.05) in the black seed, garden cress and fenugreek group, respectively, compared with that of the control group (27.02 ±0.42 μg/ml*h). Treatment with black seed also caused an increase in clopidogrel Cmax by 31.52% (p<0.05) and with fenugreek by 21.42% (p<0.05); Cmax, did not changed with garden cress treatment (6.48 ±0.15 μg/ml versus 6.12 ±0.21 μg/ml, p>0.05). The pharmacodynamic evaluation of the antiplatelet effect of clopidogrel in the presence of herbal products treatment showed a significant prolongation in the bleeding time from a control baseline by ~22-26%, and by added ~8-12% in reference to clopidogrel therapeutic effect (p<0.05). The concurrent use of black seed, fenugreek, or garden cress can alter the pharmacokinetics and pharmacodynamics of clopidogrel to varying degrees due to the presence of various bioactive polyphenols. This is probably due to changes in drug disposition and its antiplatelet action. Further confirmation can determine the clinical relevance of these observations and identify the exact constituents responsible for such activities.

Synergistic inhibition of platelet function by NADPH oxidase inhibitors and clopidogrel

Previous studies have shown platelets play an important role in prothrombotic complications due to several factors such as hyperglycemia, oxidative stress, and hypercholesterolemia, which affected platelets reactivity. Platelets activation involves ADP stimulation via P2Y12 receptor, whereas reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide (H2O2) produced by NADPH oxidase (Nox) act as the second messenger, which involved in platelets activation and may contribute to thrombus formation. The aim of the present study was to investigate the influence of Nox on the purinergic receptor (P2Y12 receptor) in activation of human platelets function stimulated by platelets agonist. This research explored the effects of Nox inhibitors and clopidogrel either alone or in combination, on various agonist-stimulated human platelets, including platelets aggregation and adhesion measured by modified LTA, expression of platelets activation markers, and calcium mobilization using flow cytometry, and ROS formation, NADPH oxidase activity, as well as cAMP levels by chemiluminescence assay. Taken together, findings from these experiments suggest that the combination of clopidogrel and Nox inhibitors synergistically reduced platelets aggregation, platelets adhesion, and expression of platelets activation marker during late activation, ROS formation, NADPH oxidase activity, calcium mobilization and increased cAMP levels in vitro. This combination showed that P2Y12receptor reactivity was influenced by the activation of NADPH oxidase. Thus, these data demonstrated a potential combination therapy to reduce the risk of thrombosis formation.&#x0D;

Coronary Heart Disease (CHD) in Elderly Patients: Which Drug to Choose, Ticagrelor and Clopidogrel? A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: A new generation P2Y12 receptor inhibitor (ticagrelor) is recommended in current therapeutic guidelines to treat patients with coronary heart disease (CHD). However, it is unknown if ticagrelor is more effective than clopidogrel in elderly patients. Therefore, a systematic review was done to assess the effectiveness and safety of ticagrelor and clopidogrel in older patients with CHD to determine the appropriate antiplatelet treatment plan. Methodology: We performed a systematic review of randomized controlled trials (RCTs) to compare the effectiveness and safety of ticagrelor vs. clopidogrel in elderly patients with CHD. We selected eligible RCTs based on specified study criteria following a systematic search of PubMed and Scopus databases from January 2007 to May 2021. Primary efficacy outcomes assessed were major adverse cardiovascular events (MACEs), myocardial infarction (MI), stent thrombosis (ST), and all-cause death. The secondary outcome assessed was major bleeding events. We used RevMan 5.3 software to conduct a random-effects meta-analysis and estimated the pooled incidence and risk ratios (RRs) with 95% confidence intervals (CIs) for ticagrelor and clopidogrel. Results: Data from 6 RCTs comprising 21,827 elderly patients were extracted according to the eligibility criteria. There was no significant difference in the MACE outcome (incidence: 9.23% vs. 10.57%; RR = 0.95, 95% CI = 0.70–1.28, p = 0.72), MI (incidence: 5.40% vs. 6.23%; RR = 0.94, 95% CI= 0.69–1.27, p = 0.67), ST (incidence: 2.33% vs. 3.17%; RR = 0.61, 95% CI= 0.32–1.17, p = 0.13), and all-cause death (4.29% vs. 5.33%; RR = 0.86, 95% CI = 0.65–1.12, p = 0.25) for ticagrelor vs. clopidogrel, respectively. In addition, ticagrelor was not associated with a significant increase in the rate of major bleeding (incidence: 9.98% vs. 9.33%: RR = 1.37, 95% CI = 0.97–1.94, p = 0.07) vs. clopidogrel. Conclusions: This study did not find evidence that ticagrelor is significantly more effective or safer than clopidogrel in elderly patients with CHD.

Clinical Effect of Clopidogrel on Prevention of Cardiovascular Adverse Events in Patients with Coronary Heart Disease

Clinical Effect of Clopidogrel on Prevention of Cardiovascular Adverse Events in Patients with Coronary Heart Disease

Effects of ticagrelor and clopidogrel on vascular endothelial function of patients with coronary heart disease

Effects of ticagrelor and clopidogrel on vascular endothelial function of patients with coronary heart disease

P2RY12-Inhibitors Reduce Cancer-Associated Thrombosis and Tumor Growth in Pancreatic Cancers.

Platelet function can be modified by cancer cells to support tumor growth, causing alterations in the delicate hemostatic equilibrium. Cancer-cell and platelet interactions are one of the main pillars of Trousseau’s syndrome: a paraneoplastic syndrome with recurring and migrating episodes of thrombophlebitis. Altogether, this leads to a four-fold risk of thrombotic events in cancer patients, which in turn, portend a poor prognosis. We previously demonstrated that anti-P2RY12 drugs inhibit cancer-associated-thrombosis and formation of tumor metastasis in pancreatic cancer models. Here, we aimed to (1) compare the effects of aspirin and clopidogrel on pancreatic cancer prevention, (2) characterize the effects of clopidogrel (platelet P2RY12 inhibitor) on cancer-associated thrombosis and cancer growth in vivo, (3) determine the effect of P2RY12 across different digestive-tract cancers in vitro, and (4) analyze the expression pattern of P2RY12 in two different cancer types affecting the digestive system. Clopidogrel treatment resulted in better survival rates with smaller primary tumors and less metastasis than aspirin treatment. Clopidogrel was also more effective than aspirin at dissolving spontaneous endogenous thrombi in our orthotopic advanced cancer mouse model. P2RY12 expression gives pancreatic adenocarcinomas proliferative advantages. In conclusion, we propose the hypothesis that clopidogrel should be further studied to target and prevent Trousseau’s syndrome; as well as diminish cancer growth and spread. However, more studies are required to determine the implicated pathways and effects of these drugs on cancer development.