Antiplatelet drugs: which targets for which treatments?

Gachet, Christian

doi:10.1111/jth.12947

Cited by 51 publications

(55 citation statements)

References 80 publications

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“…Although these new agents are effective antiplatelet drugs that have overcome some of the limitations of clopidogrel, their improved efficacy is achieved at a cost of an increase in bleeding, particularly when combined with aspirin [2,3]. Thus the research to identify novel efficacious antiplatelet targets with less bleeding risk is still warranted [3]. The P2Y 1 receptor has been proposed as one of those promising targets [3,4].…”

Section: Introductionmentioning

confidence: 97%

“…Recently, new oral antiplatelet drugs, including two next generation of the more potent P2Y 12 antagonists (prasugrel and ticagrelor) and one thrombin receptor antagonist (vorapaxar) have been developed [2]. Although these new agents are effective antiplatelet drugs that have overcome some of the limitations of clopidogrel, their improved efficacy is achieved at a cost of an increase in bleeding, particularly when combined with aspirin [2,3]. Thus the research to identify novel efficacious antiplatelet targets with less bleeding risk is still warranted [3].…”

Section: Introductionmentioning

confidence: 98%

“…Thus the research to identify novel efficacious antiplatelet targets with less bleeding risk is still warranted [3]. The P2Y 1 receptor has been proposed as one of those promising targets [3,4].…”

Section: Introductionmentioning

confidence: 99%

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The P2Y1 receptor antagonist MRS2500 prevents carotid artery thrombosis in cynomolgus monkeys

Wong

Watson

Crain

2015

J Thromb Thrombolysis

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Adenosine diphosphate directly induces platelet aggregation via the G-protein coupled P2Y1 and P2Y12 receptors. P2Y12, but not P2Y1, receptor antagonists are available in the clinic. The relevance of the P2Y1 receptor as an antiplatelet target has been studied in rodents, but not in higher species. We therefore examined effects of the pharmacological blockade of the P2Y1 receptor with its selective antagonist MRS2500 in monkey models of electrolytic-mediated arterial thrombosis (ECAT) and kidney bleeding time (KBT). Abciximab, a GPIIb-IIIa antagonist, and cangrelor, a P2Y12 antagonist, were utilized to validate these monkey models. Compounds were given IV at 15-60 min before thrombosis initiation in anesthetized monkeys. Scanning electron microscopy showed the luminal surface of thrombotic artery covered with platelet aggregates and fibrin network. Administration of abciximab at 0.25 and 0.7 mg/kg IV significantly reduced thrombus weight by 71 ± 1 and 100 ± 0 %, and increased KBT by 10.0 ± 0.1- and 10.1 ± 0-fold, respectively (n = 3/dose). Likewise, cangrelor at 0.6 and 2 mg/kg/h IV significantly reduced thrombus weight significantly by 72 ± 9 % and 100 ± 0 % and increased KBT by 2.1 ± 0.1- and 9.8 ± 0.2-fold, respectively (n = 3/dose). MRS2500 [mg/kg + mg/kg/h IV] at 0.09 + 0.14 and 0.45 + 0.68 significantly reduced thrombus weight by 57 ± 1 % and 88 ± 1 % and increased KBT by 2.1 ± 0.3- and 4.9 ± 0.6-fold, respectively (n = 4/dose). In summary, MRS2500 prevented occlusive arterial thrombosis at a dose that moderately prolonged KBT, indicating a role of P2Y1 receptors in arterial thrombosis and hemostasis in monkeys. Thus P2Y1 receptor antagonism provides a suitable target for drug discovery.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

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The P2Y1 receptor antagonist MRS2500 prevents carotid artery thrombosis in cynomolgus monkeys

Wong

Watson

Crain

2015

J Thromb Thrombolysis

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“…15,16 Similarly, patients with severe P2Y 12 deficiency can experience serious hemorrhage. 13 A recent report of the crystal structure of P2Y 12 has revealed how this receptor behaves when it binds agonists and antagonists and should provide valuable insights for the development of improved P2Y 12 antagonists.…”

Section: Hechler and Gachetmentioning

confidence: 99%

Purinergic Receptors in Thrombosis and Inflammation

Hechler

Gachet

2015

ATVB

142

101

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Abstract-Under various pathological conditions, including thrombosis and inflammation, extracellular nucleotide levels may increase because of both active release and passive leakage from damaged or dying cells. Once in the extracellular compartment, nucleotides interact with plasma membrane receptors belonging to the P2 purinergic family, which are expressed by virtually all circulating blood cells and in most blood vessels. In this review, we focus on the specific role of the 3 platelet P2 receptors P2Y 1 , P2Y 12 , and P2X 1 in hemostasis and arterial thrombosis. Beyond platelets, these 3 receptors, along with the P2Y 2 , P2Y 6 , and P2X 7 receptors, constitute the main P2 receptors mediating the proinflammatory effects of nucleotides, which play important roles in various functions of circulating blood cells and cells of the vessel wall. Each of these P2 receptor subtypes specifically contributes to chronic or acute vascular inflammation and related diseases, such as atherosclerosis, restenosis, endotoxemia, and sepsis. The potential for therapeutic targeting of these P2 receptor subtypes is also discussed.

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“…The contemporary knowledge in this field has been observed in many clinical trials (32). There are several worthwhile available reviews regarding these trials, evaluating ADP antagonists (e.g., P2Y 12 inhibitors), thromboxane antagonists and PAR-1/4 inhibitors (32)(33)(34). Figure 3 highlights the therapeutic stages of development of some drugs that target platelet adhesion molecules and the recent advances in drug development.…”

Section: Platelet Receptors As Therapeutic Targetsmentioning

confidence: 99%

Platelets: an outlook from biology through evidence-based achievements in critical care

Costa-Filho

Bozza

2017

Ann. Transl. Med.

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Since the original observations by Bizzozero and Osler, we have seen tremendous advances in the understanding of platelets far beyond haemostasis and the restoration of injured endothelium. In this minireview on platelets, we will briefly outline their historical description and the importance of their evolution, focusing on a 450 million years old living fossil of Limulus polyphemus, a marine chelicerate arthropod, which helped researchers explain the basis for the immunity role of platelets and make correlations with platelet ultrastructure and function. In addition, the impact of the Limulus Amoebocyte Lysate (LAL) test for modern medicine is highlighted. The role of platelets in cardiovascular diseases, their relevance in arterial and venous thrombosis, and the utilization of antithrombotic drugs as therapeutic agents are also reported.Furthermore, platelet receptors are crucial in aggravating or mitigating other diseases, such as cancer and infections, which can recruit cells and have numerous interactions in a process recently coined "NETosis formation", which is also briefly depicted.

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Antiplatelet drugs: which targets for which treatments?

Cited by 51 publications

References 80 publications

The P2Y1 receptor antagonist MRS2500 prevents carotid artery thrombosis in cynomolgus monkeys

The P2Y1 receptor antagonist MRS2500 prevents carotid artery thrombosis in cynomolgus monkeys

Purinergic Receptors in Thrombosis and Inflammation

Platelets: an outlook from biology through evidence-based achievements in critical care

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