Disease relevance of clopidogrel

• Late thrombosis occurred in irradiated patients only after the discontinuation of oral antiplatelet therapy (with ticlopidine or clopidogrel) and only in patients who had received new stents at the time of radiation treatment [1].
• Thrombotic thrombocytopenic purpura associated with clopidogrel [2].
• The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel [3].
• Although 10 of the 11 patients had a response to plasma exchange, 2 required 20 or more exchanges before clinical improvement occurred, and 2 had relapses while not receiving clopidogrel [2].
• Clopidogrel and membranous nephropathy [4].

Psychiatry related information on clopidogrel

• For the large number of patients undergoing percutaneous coronary intervention in the CURE trial, there was a substantial risk reduction with clopidogrel pretreatment followed by long-term therapy (p < 0.002) [5].
• This finding may be due to the more rapid onset of an antiplatelet effect seen with the loading dose of clopidogrel, which was used in most of these studies, or to better patient compliance with clopidogrel therapy [6].
• We suggest that individual differences in clopidogrel metabolization could cause relevant variations in clopidogrel responsiveness despite the use of a 300 mg clopidogrel loading dose [7].
• The aim of this study was to describe the effect of the addition of clopidogrel to aspirin using ex vivo measures of platelet activation in patients with life-style limiting intermittent claudication [8].
• PlA2 carriers had a higher degree of GPIIb/IIIa activation (P = 0.05) and P-selectin expression (P = 0.02) during the overall study time course and a lower antiplatelet effect to a 300 mg clopidogrel loading-dose up to 24 h following intervention (P < 0.05) [9].

High impact information on clopidogrel

• The estimated incidence of ticlopidine-associated thrombotic thrombocytopenic purpura is 1 per 1600 to 5000 patients treated, whereas no clopidogrel-associated cases were observed among 20,000 closely monitored patients treated in phase 3 clinical trials and cohort studies [2].
• The molecular identity of the Gi-linked receptor is still elusive, even though it is the target of efficacious antithrombotic agents, such as ticlopidine and clopidogrel and AR-C66096 (ref. 9). Here we describe the cloning of this receptor, designated P2Y12, and provide evidence that a patient with a bleeding disorder has a defect in this gene [10].
• There is evidence that in a crossover trial of 21 patients with PAD and IC, aspirin alone, or clopidogrel alone, significantly increased bleeding times, but cilostazol alone did not [11].
• P2Y12 has been shown to be the target of the thienopyridine drugs, ticlopidine and clopidogrel [12].
• Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death, myocardial infarction, or any revascularisation (p=0.03), and of cardiovascular death or myocardial infarction (p=0.047) [13].

Chemical compound and disease context of clopidogrel

• We reviewed the results of the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) and Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trials, with special emphasis on comparing the outcomes in high-risk patients with those of the total populations in the trials [14].
• OBJECTIVES: The present study hypothesis was that eptifibatide offered further antiplatelet efficacy above clopidogrel in non-ST-elevation myocardial infarction (NSTEMI) patients before an expeditive coronary intervention [15].
• The thienopyridines, ticlopidine hydrochloride and clopidogrel, appear to be at least as effective as aspirin in the management of unstable angina [16].
• Forty-three patients with non-valvular atrial fibrillation who were receiving long-term warfarin and had a stable international normalized ratio (INR) between 2 and 3 were randomly assigned to clopidogrel 75 mg daily or placebo for 8 days (Days 1-8) [17].
• Antithrombotic effects of ximelagatran plus acetylsalicylic acid (ASA) and clopidogrel plus ASA in a human ex vivo arterial thrombosis model [18].

Biological context of clopidogrel

• Within 3 hours of aspirin administration, the antithrombotic effects of acute high-dose or chronic low-dose clopidogrel were substantially enhanced, and BTs were modestly prolonged without inhibiting platelet aggregation induced by TRAP (P<0.001 in all cases compared with clopidogrel alone) [19].
• P2Y12, a G protein-coupled receptor that plays a central role in platelet activation has been recently identified as the receptor targeted by the antithrombotic drug, clopidogrel [20].
• Clopidogrel did not prevent neuronal apoptosis, glial reactivity, capillary cell apoptosis, or acellular capillaries in the retina of diabetic rats [21].
• Furthermore, clopidogrel increased bleeding risk in early cardiac surgery [22].
• Therefore, inhibition of the platelet P2Y(AC) ADP receptor and its intracellular signaling, including decreased VASP phosphorylation, is suggested as a molecular mechanism of clopidogrel action [23].

Anatomical context of clopidogrel

• Clopidogrel abolished cyclic flow variations in the coronary and femoral arteries of all five baboons (frequency of cyclic flow variations, 0/h versus 14/h at baseline, P < .001) [24].
• In addition, we showed the predominant association of P2Y12 oligomers to cell membrane lipid rafts and the partitioning of P2Y12 out of rafts in response to clopidogrel and Act-Met [20].
• Ex vivo inhibition of the P2Y12 ADP receptor by clopidogrel administration diminished the rapid exposure of tissue factor (TF), the major initiator of coagulation, in conjugates of platelets with leukocytes established by the contact of whole blood with fibrillar collagen [25].
• Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment [26].
• The clopidogrel group had higher 24-h mean chest tube output (1,224 ml vs. 840 ml, p = 0.001), and more transfusions of red blood cells (2.51 U vs. 1.74 U, p = 0.036), platelets (0.86 U vs. 0.24 U, p = 0.001) and fresh frozen plasma (0.68 U vs. 0.24 U, p = 0.015) [27].

Associations of clopidogrel with other chemical compounds

• Adding dipyridamole to aspirin, substituting clopidogrel for aspirin, and carotid endarterectomy are all expensive interventions to prevent stroke, but if ways could be found to focus them on those patients at especially high risk, they would become more affordable [28].
• The adenosine diphosphate receptor antagonists, ticlopidine and clopidogrel, inhibit the early steps of platelet activation, degranulation, and release of prothrombotic and inflammatory mediators, while also preventing activation of the glycoprotein IIb/IIIa receptor [5].
• METHODS; We randomized 70 patients with nonvalvular AF who were not on any antithrombotic therapy to either dose-adjusted warfarin (international normalized ratio 2 to 3) (Group I) or combination therapy with aspirin 75 mg and clopidogrel 75 mg (Group II) [29].
• Generalizing the results of clinical trials to actual practice: the example of clopidogrel therapy for the prevention of vascular events. CAPRA (CAPRIE Actual Practice Rates Analysis) Study Group. Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events [30].
• All received aspirin, subcutaneous enoxaparin (1 mg/kg), and were randomized to one of three groups: (A) tenecteplase (TNK) and usual care, (B) TNK and mandatory invasive study < or = 24 h, including rescue PCI for reperfusion failure, and (C) primary PCI with 300 mg loading dose of clopidogrel [31].
• The plasma concentration of prasugrel AM was higher than that of clopidogrel AM despite tenfold higher doses of clopidogrel, indicating more efficient in vivo production of prasugrel AM than of clopidogrel AM [32].

Gene context of clopidogrel

• P2Y12 receptor inhibitors clinically in use such as clopidogrel are postulated to decrease platelet aggregation through partial inhibition of PAR1 signaling [33].
• In the repair protocol, clopidogrel significantly limited aneurysm formation and fibrinogen deposition, as well as glomerular matrix expansion, TGF-beta 1, fibronectin, and PAI-1 expression [34].
• A chemical mechanism is discussed based on the known metabolic activation of clopidogrel and on the finding that hemoprotein integrity of recombinant CYP2B6 was not affected by irreversible inhibition [35].
• Clopidogrel interacts with human CYP3A4 with a spectral dissociation constant (K(s)), K(m), and V(max) of 12 microM, 14 +/- 1 microM and 6.7 +/- 1 nmol min(-1) nmol p450(-1), respectively [36].
• Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases [37].
• The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel [38].

Analytical, diagnostic and therapeutic context of clopidogrel

• We report the clinical and laboratory findings in 11 patients in whom thrombotic thrombocytopenic purpura developed during or soon after treatment with clopidogrel [2].
• From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo [39].
• In vitro treatment with Act-Met or in vivo oral administration to rats with clopidogrel induced the breakdown of these oligomers into dimeric and monomeric entities in P2Y12 expressing HEK293 and platelets respectively [20].
• BACKGROUND: Clinical trials suggest that prolonging clopidogrel therapy for up to one year after PCI reduces downstream cardiac events [40].
• METHODS: Blood samples obtained from 23 ACS patients before and 24 h after a loading dose of clopidogrel (300 mg) were analyzed by whole-blood flow cytometry, light transmission aggregometry in platelet-rich plasma, and plasma enzyme-linked immunoassays [41].

References