Clopidogrel, A Novel Antiplatelet and Antithrombotic Agent

Herbert, Jean‐Marc; Frehel, Daniel; Vallee, E.; Kieffer, G.; Gouy, D.; Berger, Yves; Necciari, J.; Defreyn, G.; Maffrand, Jean‐Pierre

doi:10.1111/j.1527-3466.1993.tb00275.x

Cited by 213 publications

(121 citation statements)

References 36 publications

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“…10,11,17,33,34 The present study underscores the selectivity of clopidogrel for abolishing ADP-mediated platelet activation and its lack of significant inhibitory effects on TRAP-induced platelet activation ( Table 1). The inhibition of collagen-induced platelet aggregation by clopidogrel is explained by the contribution made by ADP secretion from platelets activated by collagen ( Table 1).…”

Section: Discussionmentioning

confidence: 93%

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Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates

et al. 1998

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Background-A recent study showed that clopidogrel reduces thrombo-occlusive complications in patients with symptomatic atherosclerosis more effectively than aspirin. Methods and Results-The effects of clopidogrel and aspirin have been compared, singly and in combination, for measurements of 111 In-labeled platelets and 125 I-labeled fibrin deposition in baboon models of arterial thrombosis and related to platelet aggregation and expression of activation epitopes induced by ADP, collagen, and thrombin receptor agonist peptide (TRAP) and to template bleeding times (BTs). Low-dose oral clopidogrel (0.2 mg ⅐ kgIn-platelet and 125 I-fibrin deposition for segments of prosthetic vascular graft, deployed endovascular metallic stents, and endarterectomized aorta (PϽ0.009 in all cases); (2) elimination of ADP-induced platelet aggregation (PϽ0.001); (3) modest inhibition of collagen-induced platelet aggregation (PϽ0.01); (4) no reduction in TRAP-induced platelet aggregation; and (5) minimal prolongation of BTs (Pϭ0.03). High-dose oral clopidogrel (Ն2 mg/kg) produced the same effects within 3 hours. The effects of clopidogrel dissipated over 5 to 6 days. Aspirin 10 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 alone did not decrease 111 In-platelet and 125 I-fibrin deposition on segments of vascular graft but detectably decreased 111 In-platelet and 125 I-fibrin accumulation on stents (PϽ0.01), minimally inhibited ADP-and collagen-induced platelet aggregation (PϽ0.05 in both cases), and minimally prolonged BTs (Pϭ0.004). 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 (PϽ0.001 in all cases compared with clopidogrel alone). Conclusions-Clopidogrel produces irreversible, dose-dependent, intermediate reduction in thrombosis that is substantially enhanced by the addition of aspirin. The effects of combining aspirin and clopidogrel need to be evaluated in patients at risk of vascular thrombosis. (Circulation. 1998;98:2461-2469.)

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Section: Discussionmentioning

confidence: 93%

“…17,18 Like ticlopidine, clopidogrel is devoid of direct antiplatelet effects and must undergo hepatic metabolic modification to exhibit selective inhibition of ADP-induced platelet aggregation. 22 Clopidogrel acts by irreversibly inactivating platelet ADP receptor-initiated signaling in a dose-dependent manner.…”

mentioning

confidence: 99%

Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates

et al. 1998

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“…Notably, we also demonstrated a reversing effect of a orally administered clopidogrel (Emmons and Taylor, 2007), a well known antithrombotic compound targeting P2Y 12 R in platelets with safety profiles from an extensive clinical program (Savi and Herbert, 2005), on existing tactile allodynia. It has been reported that the antagonistic effect of clopidogrel on P2Y 12 R is dependent on its active metabolite through hepatic metabolism, and 10 mg/kg oral clopidogrel induced ϳ90% inhibition of ex vivo platelet aggregation, and a transfer of the clopidogrel or its metabolite across the blood-brain barrier was also observed (Herbert et al, 1993). Because we observed a significant effect of clopidogrel with 10 mg/kg oral administration and a higher dose (25 mg/kg) achieved a rather longer-lasting relieving effect on existing tactile allodynia, transfer of active metabolite of clopidogrel from plasma to the spinal cord parenchyma might be limited.…”

Section: Discussionmentioning

confidence: 98%

P2Y₁₂Receptors in Spinal Microglia Are Required for Neuropathic Pain after Peripheral Nerve Injury

Tozaki‐Saitoh¹,

Tsuda²,

Miyata³

et al. 2008

J. Neurosci.

259

249

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Extracellular nucleotides have been implicated as signaling molecules used by microglia to sense adverse physiological conditions, such as neuronal damage. They act through purinoceptors, especially the G-protein-coupled P2Y receptor P2Y 12 R. Emerging evidence has indicated that activated spinal microglia responding to nerve injury are key cellular intermediaries in the resulting highly debilitating chronic pain state, namely neuropathic pain. However, the role of microglial P2Y 12 Rs in neuropathic pain remains unknown. Here, we show that the level of P2Y 12 R mRNA expression was markedly increased in the spinal cord ipsilateral to the nerve injury and that this expression was highly restricted to ionized binding calcium adapter molecule 1-positive microglia. An increase in the immunofluorescence of P2Y 12 R protein in the ipsilateral spinal cord was also observed after nerve injury, and P2Y 12 R-positive cells were double labeled with the microglial marker OX-42. Blocking spinal P2Y 12 R by the intrathecal administration of its antagonist AR-C69931MX prevented the development of tactile allodynia (pain hypersensitivity to innocuous stimuli), a hallmark of neuropathic pain syndrome. Furthermore, mice lacking P2ry 12 (P2ry 12 ؊/؊ ) displayed impaired tactile allodynia after nerve injury without any change in basal mechanical sensitivity. Moreover, a single intrathecal administration of AR-C69931MX or oral administration of clopidogrel (a P2Y 12 R blocker clinically in use) to nerve-injured rats produced a striking alleviation of existing tactile allodynia. Together, our findings indicate that activation of P2Y 12 Rs in spinal microglia may be a critical event in the pathogenesis of neuropathic pain and suggest that blocking microglial P2Y 12 R might be a viable therapeutic strategy for treating neuropathic pain.

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“…It has been suggested that clopidogrel is probably a more potent antiplatelet agent than dipyridamole as measured by overall platelet activity ex vivo, for example, the effect on cutaneous bleeding time. 19 This, combined with the equivalence in reducing ES in our study, suggests that nonplatelet effects of dipyridamole such as reducing white cell 20 and endothelial activity (reduction of von Willebrand factor 18 ) may also be important in reducing emboli. This is the first study to use ambulatory TCD to compare therapies.…”

Section: King Et Al Clopidogrel Versus Dipyridamole In Reducing Embolimentioning

confidence: 89%

Clopidogrel Versus Dipyridamole in Addition to Aspirin in Reducing Embolization Detected With Ambulatory Transcranial Doppler

King

Bath²,

Markus³

2011

Stroke

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Background and Purpose-After stroke and transient ischemic attack there is a high early risk of recurrent stroke, particularly in large artery disease. It has been suggested more intensive antiplatelet regimens are required, but trial data are lacking. Treatment efficacy can be evaluated using transcranial Doppler detection of embolic signals. Ambulatory transcranial Doppler has recently been developed; prolonged recording may reduce subject numbers required to determine therapeutic efficacy. In a randomized trial (ISRCTN68019845) with blinded end point evaluation, we determined whether treatment with dipyridamole or clopidogrel, in addition to aspirin, was more effective at reducing embolization. Methods-Consecutive patients with recent symptomatic carotid stenosis were recruited. Ambulatory transcranial Doppler and platelet aggregometry were performed at baseline and 48 hours. Patients, all on aspirin, were randomized to dipyridamole or clopidogrel. Recordings were analyzed offline masked to subject identity. Results-Sixty patients were recruited, 30 in each arm. The primary end point of change in embolic signal frequency did not differ between groups (Pϭ0.36). In patients with embolic signals at baseline, there was no difference in reduction in embolic signal frequency: dipyridamole (75.5; SD 17.7%) versus clopidogrel (77.5; SD 20.5%; Pϭ0.77). Baseline platelet aggregation was not different between regimens, but at 48 hours, adenosine 5Ј-diphosphate aggregation rate (but not collagen) was lower with clopidogrel (PϽ0.001). Conclusions-Both dipyridamole and clopidogrel reduced embolization to a similar extent. Embolic signals are strong predictors of future stroke rate in this patient group. Our results suggest these 2 treatment regimens have similar efficacy in early secondary prevention of stroke, although this now needs testing in large Phase III trials. (Stroke. 2011;42:650-655.)

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Clopidogrel, A Novel Antiplatelet and Antithrombotic Agent

Cited by 213 publications

References 36 publications

Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates

Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates

P2Y₁₂Receptors in Spinal Microglia Are Required for Neuropathic Pain after Peripheral Nerve Injury

Clopidogrel Versus Dipyridamole in Addition to Aspirin in Reducing Embolization Detected With Ambulatory Transcranial Doppler

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Clopidogrel, A Novel Antiplatelet and Antithrombotic Agent

Cited by 213 publications

References 36 publications

Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates

Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates

P2Y12Receptors in Spinal Microglia Are Required for Neuropathic Pain after Peripheral Nerve Injury

Clopidogrel Versus Dipyridamole in Addition to Aspirin in Reducing Embolization Detected With Ambulatory Transcranial Doppler

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P2Y₁₂Receptors in Spinal Microglia Are Required for Neuropathic Pain after Peripheral Nerve Injury