Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For the long-term prevention of thromboembolic events in patients with atherosclerotic vascular disease, aspirin is the preferred antiplatelet drug. Only clopidogrel was shown to be more effective and at least as safe than medium-dose aspirin in direct comparative large-scale trials. Aspirin inhibits the cyclooxygenase dependent pathway of platelet aggregation while ticlopidine and clopidogrel selectively bind to adenosine diphosphate (ADP) receptors on the platelet surface. Compounds which inhibit the synthesis of thromboxane synthase, block the thromboxane receptor or have the dual activity were effective in experimental thrombosis models in animals but not predictive of results in humans. Activation of the platelet glycoprotein (GPIIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GPIIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic as well as non-peptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as two weeks whereas synthetic GPIIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion but have the advantage of being also orally active. In the secondary prevention of atherothrombosis, large scale trials were successfully conducted with aspirin, dipyridamole and clopidogrel. In the first large-scale trials with GPIIb/IIIa inhibitors with abciximab was investigated. In aggregate, this class of platelet inhibitors, combined with aspirin and heparin, was shown to reduce ischaemic events in patients with high- and low-risk coronary intervention, stents, unstable angina and non-Q-wave infarction with long-term preservation of the initial benefit. With synthetic GPIIb/IIIa inhibitors there is no suppression of clinical evident restenosis 6 months after the end of treatment. With the doses presently used, bleeding occurs more often with the synthetic GPIIb/IIIa inhibitors (used for 3 days) than with abciximab (used for 12 hours) but there are no direct comparisons between these drugs.
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PMID:8th Seah Cheng Siang Memorial Lecture: new antithrombotic agents. 1057 18

Naftidrofuryl (Praxilene; NAF) significantly improves claudication distance in patients with peripheral vascular disease (PVD). Endothelin-1 (ET-1) is a powerful endogenous vasoconstrictor and the circulating levels of ET-1 are elevated in patients with vascular disease. Platelet rich plasma (PRP) was prepared from healthy volunteers. NAF at concentrations similar to therapeutic levels (3.5-14 micromol/l), inhibited (P < 0.02) platelet activation (as indicated by a fall in median platelet volume, MPV) induced by ET-1 (0.4 micromol/l) alone. NAF also inhibited (P <0.0001) shape change (PSC; an early phase of platelet activation, characterised by an increase in MPV) induced by ET-1 (0.4 micromol/l) in combination with ADP (0.05-0.15 micromol/l) or serotonin (0.03-0.13 micromol/ l). We assessed the effect of ET(A) (BQ123, 50 nmol/l) or ET(B) (BQ788, 50 nmol/l) receptor antagonists on PSC induced by ET-1 alone. Both antagonists significantly inhibited PSC. We conclude that ET-1 activates human platelets. Both ET(A) and ET(B) receptors probably contribute to this response by a complex mechanism that requires further elucidation. NAF antagonises the action of ET-1 on human platelets. These actions may contribute to the beneficial effects of NAF in PVD.
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PMID:Effect of endothelin-1 on human platelet shape change: reversal of activation by naftidrofuryl. 1103 Apr 61

Percutaneous coronary intervention has had a dramatic impact on the current practice of cardiology. One of its important limitations, however, is the potential for producing unfavorable outcomes such as acute coronary closure following angioplasty or atherectomy or subacute thrombosis following stent implantation. These complications may lead to death, myocardial infarction, or the need for urgent bypass surgery. One mechanism underlying these clinical events is platelet-mediated thrombosis due to arterial trauma. Therapeutically, platelet activation by thromboxane and adenosine diphosphate (ADP), as well as platelet aggregation by glycoprotein IIb/IIIa (GPIIb/IIIa) receptors, has been inhibited with various pharmacologic agents. c7E3 (abciximab), a monoclonal antibody directed against GPIIb/IIIa, has been shown to have potent effects on reducing both acute and subacute complications. Other parenteral GPIIb/IIIa inhibitors, including peptide and small nonpeptide molecules, have also been found to be clinically effective. Oral versions of similar drugs are currently being evaluated, but several have resulted in disappointing efficacy and safety profiles and have failed to show advantages over aspirin. With all antiplatelet agents, in particular GPIIb/IIIa receptor inhibitors, bleeding and vascular complications must be addressed. Inhibition of thromboxane-induced platelet activation with aspirin has been standard therapy for angioplasty and in the global management of vascular disease. Newer agents that block ADP-mediated platelet activation, the thienopyridines, have been found to be synergistic to aspirin in their effects on the complications of coronary intervention. Ticlopidine and, more recently, clopidogrel, in conjunction with aspirin, have become standard therapies for preventing subacute thrombosis after stent implantation. Large-scale clinical trials are ongoing to optimize their use in combination with GPIIb/IIIa inhibitors.
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PMID:Optimizing antiplatelet therapy in coronary interventions. 1112 85

1. Antiplatelet drugs have been demonstrated to reduce the incidence of recurrent events in patients with symptomatic vascular disease. However, there is no experimental data indicating the effects of these agents when given together on platelets and leukocytes. We investigated the ability of aspirin (an inhibitor of cyclo-oxygenase), dipyridamole (an inhibitor of phospodiesterases and adenosine uptake) and AR-C69931 (a direct acting P(2T) antagonist with effects similar to those of clopidogrel which can be used in vitro) when used alone or in combination to inhibit platelet and leukocyte function. 2. Measurements of platelet and leukocyte function were performed in blood taken from normal volunteers, and the inhibitory effects of aspirin (100 micromol l(-1)), dipyridamole (10 micromol l(-1)) and AR-C66931 (100 nmol l(-1)) were determined. Platelet aggregation was induced by stirring blood with and without adenosine diphosphate (ADP) or platelet activating factor (PAF) and measured by platelet counting. Platelet P-selectin expression, platelet-leukocyte conjugate formation, and leukocyte activation were determined by flow cytometry. 3. Dipyridamole, AR-C69931, dipyridamole and AR-C69931, dipyridamole and aspirin, AR-C69931 and aspirin, and all three agents together inhibited platelet aggregation induced by stirring, ADP and PAF (P<0.01). However, it was only the combination of all three agents inhibited P-selectin expression (P<0.01). Similarly, it was the combination of all three antiplatelet agents that most consistently inhibited platelet-monocyte and platelet-neutrophil conjugate formation and monocyte and neutrophil activation. 4. Since both platelets and leukocytes are thought to contribute to arterial thrombosis and atherosclerosis, it is possible that combinations of different antiplatelet agents with different mechanisms of action may afford better protection than individual or pairs of agents used on their own.
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PMID:Effects of combining three different antiplatelet agents on platelets and leukocytes in whole blood in vitro. 1156 53

Insulin resistance is associated with an increased risk of atherothrombotic vascular disease, but the mechanisms are poorly understood. We determined how insulin in vivo regulates platelet activation in nonobese and obese subjects by using methods mimicking thrombus formation. Twelve nonobese (aged 42+/-2 years, body mass index 24.0+/-0.4 kg/m(2)) and 14 obese (aged 43+/-1 years, body mass index 37.2+/-1.5 kg/m(2)) subjects were studied under euglycemic hyperinsulinemic (3-hour insulin infusion of 1 mU. kg(-1). min(-1)) conditions. Before and at the end of hyperinsulinemia, the following were determined: (1) platelet-related early hemostasis (shear rate of approximately 4000 s(-1)) by platelet function analysis; (2) platelet deposition to collagen during whole-blood perfusion (shear rate of 1600 s(-1)); (3) aggregation responses to collagen, thrombin receptor-activating peptide, ADP, and epinephrine; and (4) platelet cGMP concentrations. Insulin action on glucose metabolism was 69% lower in the obese subjects (1.6+/-0.2 mg. kg(-1). min(-1)) than in the nonobese subjects (5.4+/-0.4 mg. kg(-1). min(-1), P<0.0001). The in vivo insulin infusion inhibited platelet deposition to collagen from 4.3+/-0.6x10(6) to 3.5+/-0.4x10(6) per square centimeter in the nonobese subjects (P<0.05) but failed to do so in the obese subjects (5.2+/-0.8x10(6) versus 5.5+/-0.7x10(6) per square centimeter, P=NS; P<0.01 versus nonobese subjects). Epinephrine- and ADP-primed closure times by platelet function analysis were prolonged by insulin in the nonobese but not the obese subjects (P<0.05 for between-group difference). In the nonobese subjects, insulin decreased aggregation to all agonists and significantly increased platelet cGMP concentrations (2.5+/-0.3 versus 3.2+/-0.5 pmol/10(9) for before versus after insulin, respectively; P<0.01). In the obese subjects, insulin did not alter collagen-induced aggregation or cGMP concentrations (1.9+/-0.2 versus 1.8+/-0.1 pmol/10(9) for before versus the end of in vivo hyperinsulinemia, respectively; P=NS). These data demonstrate that normal in vivo insulin action inhibits platelet interaction with collagen under conditions mimicking thrombus formation and reduces aggregation to several agonists. These platelet-inhibitory actions of insulin are blunted or absent in obese subjects and could provide 1 mechanism linking insulin resistance to atherothrombotic disease.
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PMID:Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. 1178 78

Patients with peripheral arterial disease (PAD) are at increased risk of generalized atherothrombotic events. Epidemiologic data shows a high rate of co-prevalence of PAD and atherosclerosis in other vascular beds. Aggressive risk-factor modification and antiplatelet therapy has become the cornerstone of treatment to prevent ischaemic events associated with PAD. Recent clinical trials have confirmed the clinical benefit of clopidogrel and ticlopidine in patients with PAD, agents that irreversibly inhibit the binding of adenosine diphosphate to its platelet receptor. In the clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) trial, clopidogrel was associated with an overall risk reduction of 8.7% (compared with aspirin, P=0.043) in myocardial infarction (MI), ischaemic stroke and vascular death. These results demonstrated that long-term administration of clopidogrel was effective in preventing ischaemic events in patients with atherosclerotic vascular disease including PAD. Aspirin and/or clopidogrel are the antiplatelet agents of choice for the reduction of atherothrombotic events in patients with PAD.
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PMID:Preventing atherothrombotic events in peripheral arterial disease: the use of antiplatelet therapy. 1188 78

Acetylsalicylic acid inhibits thromboxane A2 production and reduces the risk of vascular occlusive events by 20% to 25%. Ticlopidine inhibits ADP-dependent platelet aggregation and reduces the same risk by 30% to 35%, but produces some adverse effects. Clopidogrel is a ticlopidin-related antiplatelet drug, with the same mechanism of action; it reduces the expression of the glycoprotein IIb/IIIa, the fibrinogen receptor on the platelet surface. Clopidogrel has the same clinical efficacy of ticlopidin and has a decreased incidence of adverse effects. The effect of one daily dose of 75 mg of clopidogrel on platelet function in 90 subjects was evaluated; 41 with coronary artery disease and 49 with cerebral vascular disease. Before treatment and after 6 and 12 weeks, bleeding time and fibrinogen plasma concentration were also evaluated. There was a reduction in 5-microM ADP-induced platelet aggregation of 38%+/-27% at 6 weeks and 44%+/-29% at 12 weeks in patients with coronary artery disease; 35%+/-41%, 29%+/-59% in the cerebral vascular disease group; and 36%+/-36% and 35%+/-49% in the total group. Reduction of 20 microg/mL collagen-induced platelet aggregation was not significant in any group. Plasma fibrinogen levels did not vary during treatment. Bleeding time was significantly prolonged in all studied groups. There were no hemorrhagic complications; only digestive discomfort in less than 3% of patients. Clopidogrel efficiently reduces ADP-induced platelet aggregation and prolongs bleeding time and is a safe and efficacious antiplatelet drug.
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PMID:Effect of clopidogrel on platelet aggregation and plasma concentration of fibrinogen in subjects with cerebral or coronary atherosclerotic disease. 1251 89

Formation of platelet-leukocyte aggregates via the CD62 ligand represents an important mechanism by which leukocytes contribute to thrombotic events. In a cross-sectional study, we investigated platelet-leukocyte aggregate formation and markers indicative for platelet, leukocyte, and endothelial activation (CD62, activated fibrinogin receptor glycoprotein IIb/IIIA [PAC-1], CD11b/CD18 [MAC-1], and soluble intercellular adhesion molecule 1) in 44 patients with atherosclerotic vascular disease and peripheral occlusions receiving clopidogrel (n = 12), aspirin (n = 17), their combination (n = 8), or no treatment (n = 7), as well as in a group of healthy subjects (n = 9). Whole-blood flow cytometry was performed before (baseline) and after stimulation with thrombin receptor-activating peptide or adenosine diphosphate. Both at baseline and after stimulation, untreated patients and those receiving aspirin monotherapy exhibited significantly higher levels of platelet CD62 expression (baseline CD62: untreated, 22% [median]; with aspirin, 16%) and had higher rates of platelet-leukocyte aggregate formation (monocyte-platelet-leukocyte aggregates at baseline: untreated, 27%; with aspirin, 16%) when compared with patients receiving clopidogrel alone (baseline CD62: 10% [P <.05]; monocyte-platelet-leukocyte aggregates: 13% [P <.05]) or combined with aspirin (baseline CD62: 5% [P <.05]; monocyte-platelet-leukocyte aggregates: 7% [P <.05]). Up-regulation of MAC-1 on monocytes after stimulation with thrombin receptor-activating peptide and adenosine diphosphate was significantly lower in patients treated with clopidogrel and aspirin. Plasma levels of soluble intercellular adhesion molecule 1 were significantly lower in the group of healthy subjects (median, 186 ng/mL) when compared with those in untreated patients (median, 352 ng/mL) (P <.05), whereas intercellular adhesion molecule 1 levels in treated patients were similar for any antiplatelet regimen (aspirin, 262 ng/mL; clopidogrel, 274 ng/mL; combination therapy, 273 ng/mL) but significantly lower than those in untreated patients. This is the first report showing that platelet-leukocyte aggregate formation is enhanced in atherosclerotic vascular disease but was found to be reduced in patients receiving clopidogrel.
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PMID:Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. 1262 88

We report a case of a 76-year-old-man who developed spontaneous hemarthrosis of his right knee following clopidogrel-aspirin treatment. Clopidogrel is an ADP receptor antagonist and in combination with aspirin widely used in patients with atherosclerotic vascular disease to reduce the incidence of ischemic events. To date, no case of spontaneous hemarthrosis following clopidogrel-aspirin therapy has been reported. Prompt aspiration after discontinuing the ADP receptor antagonist-aspirin combination therapy can assist early diagnosis and may prevent further damage to the joint. In conclusion, spontaneous hemarthrosis is a possible complication following clopidogrel-aspirin therapy and is recommended to be evaluated when appropriate clinical symptoms (e.g., intraarticular effusion) present.
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PMID:Spontaneous hemarthrosis of the knee associated with clopidogrel and aspirin treatment. 1262 8

Platelets play a key role in the development of ischemic complications in the arterial circulation. Antiplatelet therapy has proven effective in the treatment and prevention of ischemic events. Numerous clinical studies have confirmed the therapeutic efficacy of aspirin to such a point that this antiplatelet agent has become the gold standard in clinical practice. Clopidogrel is a thienopyridine compound that inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors. Results of a large, double-blind, randomized study (CAPRIE) confirm that administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction or vascular death. The present article highlights the importance of activation of platelets through ADP receptors and reviews the pharmacology and clinical studies of clopidogrel, a selective inhibitor of these mechanisms.
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PMID:Clopidogrel: a selective inhibitor of platelet ADP receptors. 1287 16


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