Antiplatelet therapy: Current strategies and future trends

ArticleinFuture Cardiology 2(3):343-66 · May 2006with21 Reads
DOI: 10.2217/14796678.2.3.343 · Source: PubMed
Abstract
Pharmacological management of thrombotic complications is strongly influenced by antiplatelet treatment strategies. Recent clinical trials have clearly indicated that current antiplatelet strategies may not inhibit recurrent thrombotic events in selected patients and improvement is necessary. Recently, there has been a gradual modification in the guidelines for clopidogrel dosing. In addition, newly developed P2Y(12) receptor inhibitors and thrombin inhibitors are undergoing Phase II and III clinical trials. Moreover, research related to novel agents that interfere with other steps in coagulation and platelet adhesion, and platelet thromboxane and thrombin receptor blockers, show promise. An important future step will probably be the development of personalized therapy based on defining the individual patient's propensity for thrombosis through investigation of platelet-thrombin-fibrin interactions. Such an approach will enhance the targeting of specific therapy based on the pathophysiology of the individual patient.
    • "Activated platelets stimulate thrombus formation in response to a rupture of the atherosclerotic plaque, promoting cardiovascular diseases (CVD) [6]. Multiple pathways contribute to platelet activation, including those triggered by thrombin, arachidonic acid, adenosine diphosphate (ADP) and collagen, among others [7,8] . As a result , platelets release different inflammatory mediators such as soluble P-selectin (sP-selectin, CD62P), soluble CD40 ligand (sCD40L), interleukin (IL)-1β, transforming growth factor-β1 (TGF-β1), chemokine (C-C motif) ligand 5 (CCL5), matrix metalloproteinases, tumor necrosis factor alpha (TNF-α) and IL-6 [9][10][11][12][13]. "
    Full-text · Dataset · Apr 2016 · PLoS ONE
    • "Activated platelets stimulate thrombus formation in response to a rupture of the atherosclerotic plaque, promoting cardiovascular diseases (CVD) [6]. Multiple pathways contribute to platelet activation, including those triggered by thrombin, arachidonic acid, adenosine diphosphate (ADP) and collagen, among others [7, 8]. As a result, platelets release different inflammatory mediators such as soluble Pselectin (sP-selectin, CD62P), soluble CD40 ligand (sCD40L), interleukin (IL)-1β, transforming growth factor-β1 (TGF-β1), chemokine (C-C motif) ligand 5 (CCL5), matrix metalloproteinases, tumor necrosis factor alpha (TNF-α) and IL-6 [9][10][11][12][13]. "
    [Show abstract] [Hide abstract] ABSTRACT: In different nucleated cells, NF-κB has long been considered a prototypical proinflammatory signaling pathway with the expression of proinflammatory genes. Although platelets lack a nucleus, a number of functional transcription factors are involved in activated platelets, such as NF-κB. In platelet activation NF-κB regulation events include IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation. Multiple pathways contribute to platelet activation and NF-κB is a common pathway in this activation. Therefore, in platelet activation the modulation of NF-κB pathway could be a potential new target in the treatment of inflammation-related vascular disease therapy (antiplatelet and antithrombotic activities).
    Full-text · Article · Mar 2016
    • "Antiplatelet therapy has been used for a long time in an effort to prevent, as well as to treat, thrombotic diseases121314. The multiple pathways of platelet activation limit the effect of specific receptor/pathway inhibitors, resulting in limited clinical efficacy [15,16]. In this way, the best-known inhibitor and turn off signaling in platelet activation is cyclic adenosine monophosphate (cAMP) [17,18]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background The inhibitory effect of adenosine on platelet aggregation is abrogated after the addition of adenosine-deaminase. Inosine is a naturally occurring nucleoside degraded from adenosine. Objectives The mechanisms of antiplatelet action of adenosine and inosine in vitro and in vivo, and their differential biological effects by molecular modeling were investigated. Results Adenosine (0.5, 1 and 2 mmol/L) inhibited phosphatidylserine exposure from 52±4% in the control group to 44±4 (p<0.05), 29±2 (p<0.01) and 20±3% (p<0.001). P-selectin expression in the presence of adenosine 0.5, 1 and 2 mmol/L was inhibited from 32±4 to 27±2 (p<0.05), 14±3 (p<0.01) and 9±3% (p<0.001), respectively. At the concentrations tested, only inosine to 4 mmol/L had effect on platelet P-selectin expression (p<0.05). Adenosine and inosine inhibited platelet aggregation and ATP release stimulated by ADP and collagen. Adenosine and inosine reduced collagen-induced platelet adhesion and aggregate formation under flow. At the same concentrations adenosine inhibited platelet aggregation, decreased the levels of sCD40L and increased intraplatelet cAMP. In addition, SQ22536 (an adenylate cyclase inhibitor) and ZM241385 (a potent adenosine receptor A2A antagonist) attenuated the effect of adenosine on platelet aggregation induced by ADP and intraplatelet level of cAMP. Adenosine and inosine significantly inhibited thrombosis formation in vivo (62±2% occlusion at 60 min [n = 6, p<0.01] and 72±1.9% occlusion at 60 min, [n = 6, p<0.05], respectively) compared with the control (98±2% occlusion at 60 min, n = 6). A2A is the adenosine receptor present in platelets; it is known that inosine is not an A2A ligand. Docking of adenosine and inosine inside A2A showed that the main difference is the formation by adenosine of an additional hydrogen bond between the NH2 of the adenine group and the residues Asn253 in H6 and Glu169 in EL2 of the A2A receptor. Conclusion Therefore, adenosine and inosine may represent novel agents lowering the risk of arterial thrombosis.
    Full-text · Article · Nov 2014
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