Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet activation state and responsiveness to physiological agonists were measured in 65 patients with documented coronary artery disease (54 male and 11 female; mean age, 58 years). Twelve patients (mean age, 52 years), selected at random from the male cohort, were compared with 12 age-matched male control subjects (mean age, 52 years) and with 10 normal, young male subjects (mean age, 25 years). Whole-blood flow cytometry was used to measure platelet activation status ex vivo and platelet responsiveness to physiological agonists in vitro. Peripheral blood samples were analyzed for bound fibrinogen and expression of P-selectin, GPIb, and GPIIb-IIIa at rest and in response to ADP (0.1 to 10 mumol/L) and thrombin (0.02 to 0.32 mu/mL). No significant differences were seen in the basal levels of fibrinogen binding between any of the groups, but P-selectin expression was significantly lower in patients compared with age-matched control subjects (P = .0005). When stimulated with agonists, patients' platelets had significantly decreased fibrinogen binding (P < .03) but no difference in P-selectin expression compared with the age-matched group. Both agonist-induced fibrinogen binding and P-selectin expression were, however, higher in the young subjects compared with either the older control group or the patients (P < .05). GPIb and GPIIb-IIIa expression were lowest in the patients with angina and highest in the young control subjects, with levels in the age-matched control subjects falling between these values. Data from the total patient cohort (n = 65) were identical to those in the smaller cohort (n = 12). In conclusion, atherosclerosis impairs platelet aggregatory responses (fibrinogen binding) over and above the decreased response seen with age. Platelet degranulation (P-selectin expression) is also impaired in patients with coronary artery disease, but only in comparison with younger subjects, not age-matched controls.
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PMID:Altered platelet function detected by flow cytometry. Effects of coronary artery disease and age. 935 70

Platelets play a key role in the pathogenesis of atherosclerosis, acute coronary syndromes and ischaemic complications following percutaneous coronary intervention. More recently, the platelet glycoprotein (GP) IIb/IIIa receptor has been identified as the pivotal mediator of platelet aggregation, leading to thrombus formation. This has led to the emergence of a novel class of potent antiplatelet agent, the GP IIb/IIIa receptor antagonists. These agents show great promise in reducing ischaemic complications of coronary angioplasty and acute coronary syndromes. This review summarizes the current state of knowledge of the biology of GP IIb/IIIa receptor, the different classes of GP IIb/IIIa receptor antagonists, the results of the various trials, and their impact on current clinical practice.
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PMID:Glycoprotein IIb/IIIa platelet receptor inhibitors: a new dimension in cardiology. 939 15

This workshop intended to perform a "state-of-the art" of current research on adhesion molecules in various pathophysiologies, and to determine pharmacological targets. Indeed, recent important progress concerning the cellular and molecular physiology of adhesion molecules led to the development of various integrin antagonists in several domains, like cardiovascular disease, inflammation and cancer. Integrins play a major role in numerous process like embryonic development, tumor growth and metastasis, apoptosis, hemostasis, leucocyte recruitment and activation, and bone resorption. The development of integrin antagonists is well advanced in the cardiovascular domain, since the first marketed drug (abciximax, Reopro) is an antibody directed against the GPIIb/IIIa complex (integrin alpha IIb/beta 3) involved in the final pathway of platelet aggregation. Another active domain of research in pharmacology is 'cardioprotection', i.e. the prevention of cardiac damages induced by the reperfusion of the coronary bed after an ischemia secondary to thrombolysis, angioplasty, of coronary bypass. The pharmacological targets of these antagonists are integrins involved in various process like leucocyte and platelet adhesion and endothelial function. Other potential indications in the cardiovascular field are restenosis after angioplasty, and atherosclerosis.
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PMID:[Cell adhesion molecules and pharmacologic applications. Round Table No 3 at Giens XIII]. 980 7

Because the beta3-antagonist abciximab (c7E3 Fab) has significantly improved late outcomes after coronary angioplasty, the beta3 integrins have been implicated in the arterial response to injury. However, the mechanisms underlying this benefit are unknown. The observation that c7E3 binds beta3 integrins on vascular cells (alphavbeta3) with affinity equal to that for the platelet glycoprotein IIb/IIIa integrin has led to the hypothesis that c7E3 may act directly on the artery wall to prevent restenosis after angioplasty. To test this hypothesis, we studied the effects of c7E3 on structural changes within the artery wall after angioplasty or stent angioplasty in 23 male cynomolgus monkeys with established atherosclerosis. Animals were randomly assigned to receive either a bolus of c7E3 (0.4 mg/kg IV, n=11) followed by a 48-hour infusion (0. 2 microg. kg-1. min-1) or an equal volume of vehicle (n=12). Animals received weight-adjusted aspirin and heparin and then underwent unilateral iliac artery experimental angioplasty and subclavian artery stent angioplasty (Palmaz). Iliac artery lumen diameter (LD) was determined by angiography at baseline (LDPre), after angioplasty (LDPost), and 35 days later (LDDay35). Arteries were then fixed by perfusion and removed for analysis. Lumen, intima, media, and external elastic lamina (EEL) areas were measured in iliac artery cross sections. Values from each injured iliac artery were normalized to the contralateral uninjured iliac artery to control for interanimal variability in baseline artery size and atherosclerosis extent. Intimal area was also measured in subclavian stent cross sections. c7E3 blocked platelet aggregation and prolonged the bleeding time from 2.8+/-1.1 to 19.8+/-2.5 minutes, P<0.001. Experimental angioplasty increased LDPost an average of 28%, and the initial gain was similar in both groups (P=NS). Despite an anti-platelet effect, c7E3 did not inhibit iliac lumen narrowing (LDDay35-LDPost: c7E3, -0.69+/-0.17 versus vehicle, -0.99+/-.17 mm, P=0.35); intimal hyperplasia (neointima area: c7E3, 1.12+/-.28 versus vehicle, 1.22+/-.20 mm2, P=0.77); or decrease in artery wall size (EEL area [percent of uninjured control]: c7E3, 101+/-7% versus vehicle, 121+/-7%). Stent intimal hyperplasia was also unaltered by c7E3 treatment (neointimal area: c7E3, 1.09+/-0.16 versus vehicle, 1. 28+/-0.11 mm2, P=0.36). These results suggest that the benefits of c7E3 treatment in coronary angioplasty were not from inhibition of intimal hyperplasia or improved artery wall remodeling. Alternative mechanisms should be explored to explain improved late outcomes after angioplasty in patients treated with c7E3.
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PMID:Effects of beta3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates. 981 11

A review of the most important findings published during 1997 in cardiovascular papers is presented: Chlamydia pneumoniae was recognised as a potential risk factor for coronary artery disease (CAD) and possible pathogenic agent for valvular aortic stenosis. Valvular changes similar to the valvular disease reported after ergotamine and methylsergide were also detected in obese women treated with a combination of phentermine and fenfluramine. In CAD, several new laboratory methods were introduced for early diagnosis, such as serum troponin levels, and arbutamine and adenosine stress echocardiography. Laser transmyocardial revascularisation can be performed in patients unsuitable for PTCA and CABG. In patients with end-stage heart failure, implantable ventricular-assist devices can be used, and dynamic cardiomyoplasty or partial ventriculectomy may be useful temporary measures until a suitable heart donor is available. In pharmacotherapy, fluvastatin was registered as an antiatherosclerotic agent, and mibefradil and moxonidin in hypertension and angina. Digoxin was shown to reduce the number of hospitalisations in patients with CHF but still in sinus rhythm. In the future, several improvements in anti-thrombotic therapy are expected: antithrombins, platelet glycoprotein IIb/IIIa receptor blockers and tissue factor inhibitors are all potentially more potent than presently available drugs. Also, efforts are under way to introduce genes directly into the cells of the vascular wall to prevent atherosclerosis and restenosis, as well as to transform cardiac mesenchymal cells into the cardiac myocytes of hearts that have suffered large infarctions.
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PMID:[Cardiology in 1997]. 981 70

Generalized atherosclerosis and coronary artery disease (CAD) are associated with endothelial dysfunction and during acute myocardial ischemia platelet activation has been reported. Activated platelets exert activated fibrinogen receptors (GP IIb/IIIa) and express CD 62p being regarded as reliable marker for platelet activation. Patients with angiographically proven CAD performed a bicycle exercise test until the onset of angina or ST-segment depression. We studied the ischemia-induced alterations in fibrinogen binding to activated platelet GP IIb/IIIa receptors and CD 62p expression. Therefore, the basal fibrinogen binding to GP IIb/IIIa and CD 62p expression and the thrombin-concentration for half-maximal platelet activation before and after exercise testing were determined. Additionally, inhibition of thrombin-induced platelet activation by increasing concentrations of the prostacyclin-analog iloprost and the NO-donor SIN-1 was examined. In patients with CAD, a significantly reduced basal activation and a highly significant reduction in sensitivity towards thrombin was measured. The thrombin-induced expression of GP IIb/IIIa and CD 62p was significantly diminished in patients with CAD after physical exercise and their platelets were significantly more sensitive towards the inhibitory effects of iloprost and SIN-1. These data demonstrate a significant reduction in platelet activation in response to physical exercise in patients with CAD and advanced atherosclerosis. Despite exercise induced myocardial ischemia as evidenced by angina and ECG-changes, the platelets are not generally activated, as it could be expected. Thus, patients with myocardial ischemia experienced a reduced platelet activity and enhanced sensitivity towards prostacyclin (PGI2) and nitric oxide, probably due to an augmented release of endogenous platelet inhibitory mediators.
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PMID:Increased platelet sensitivity toward platelet inhibitors during physical exercise in patients with coronary artery disease. 995 Feb 58

Aspirin is the most widely prescribed agent to reduce the platelet-mediated contributions to atherosclerosis, coronary thrombosis and restenosis after angioplasty. While aspirin treatment has led to significant reductions in morbidity and mortality in many clinical trials, there are several scenarios in which aspirin may fail to provide a full antithrombotic benefit. The cyclic flow model of experimental coronary thrombosis suggests that elevations of plasma catecholamines, high shear forces acting on the platelets in the stenosed lumen and the presence of multiple, input stimuli can activate platelets through different mechanisms that may lead to thrombosis despite aspirin therapy. Aspirin therapy is limited because it only blocks some of the input stimuli, leaving aspirin-independent pathways through which coronary thrombosis can be precipitated. These include thrombin and thrombogenic arterial wall substrates such as tissue factor. New agents that block the adenosine diphosphate (ADP) receptor, or regulate platelet free cytosolic calcium, such as direct nitric oxide donors, may be more potent overall than aspirin. Agents that block the platelet integrin GPIIb-IIIa receptor inhibit the binding of fibrinogen to platelets regardless of which input stimuli activate the platelet and, thus, as demonstrated in the cyclic flow model, would be much more potent than aspirin as an antithrombotic agent. The cyclic flow model has been useful in predicting which agents are likely to be of benefit in clinical trials.
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PMID:A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials. 997 6

Cigarette smoking is a well-known risk factor for atherosclerotic disorders. Several authors have suggested that platelet aggregability is important in smoking-induced vascular injury. When platelet-rich plasma is stirred at 37 degrees C in the absence of chemical stimulants, small aggregates of platelets may be formed, but it was difficult to detect small aggregates by conventional aggregometer using optical density. Recent technological advances have made it possible to detect small aggregates by using a newly developed assay system that employs laser light scattering. In the present study, we attempted to measure platelet aggregation by this method, using laser light scattering in 54 nonsmoking healthy males and 51 healthy male habitual smokers who were age matched. In smokers, blood was obtained after 10 hours of smoking abstinence. No significant difference in platelet aggregation was induced by 1 microM or 5 microM of ADP between smokers and nonsmokers. In smokers, plasma fibrinogen levels and the number of small aggregates formed in the absence of chemical stimulants was significantly higher than in nonsmokers. Small aggregates formed in the absence of stimulants correlated positively with the concentrations of von Willebrand factor (vWF) antigen (r=0.2654, p<0.01) and of fibrinogen (r=0.2834, p<0.01). The formation of these small aggregates was inhibited by monoclonal antibody against GPIIb/IIIa blocking fibrinogen binding to GPIIb/IIIa but not inhibited at all by monoclonal antibody against GPIb blocking vWF binding to GPIb. From these results, enhanced platelet aggregability in smokers was confirmed, and it was suggested that GPIIb/IIIa is concerned in platelet spontaneous aggregation, although vWF may not directly influence on the platelet spontaneous aggregation. Since the mechanism of spontaneous aggregation and the effect of increased spontaneous aggregability on the progression of atherosclerosis remains unclear, further study was considered necessary.
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PMID:Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers. 1009 68

The antithrombotic effect of abciximab is believed to be primarily due to its blockade of platelet glycoprotein IIb/IIIa receptors, leading to the inhibition of platelet aggregation. Studies have, however, identified that antibody 7E3, the parent molecule of abciximab, and/or abciximab itself, binds to both "activated" alphaMbeta2 receptors and alphaVbeta3 receptors. Because alphaMbeta2 receptors are present on granulocytes and monocytes, cells that have been implicated in contributing to atherosclerosis, intimal hyperplasia after vascular injury, reperfusion injury, and thrombin generation, it is possible that some of abciximab's effects relate to this reactivity. Similarly, because alphaVbeta3 has been implicated in platelet adhesion to osteopontin, intimal hyperplasia after vascular injury, and platelet-mediated thrombin generation, it is possible that some of abciximab's beneficial effects relate to this reactivity. Blockade of alphaVbeta3 receptors may also be beneficial in other disease states because, in animal models, such blockade inhibits tumor angiogenesis and sickle cell adhesion to blood vessel endothelium. Despite these intriguing observations, there are no direct data to support any beneficial roles or any unwanted side effects related to the reactivities of abciximab with "activated" alphaMbeta2 or alphaVbeta3 receptors.
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PMID:Potential non-glycoprotein IIb/IIIa effects of abciximab. 1038 84

Platelet active drugs are part of the antithrombotics. Their biological effect is not assessed in current practice. Their clinical efficacy has been firmly established in randomised controlled trials. Aspirin has been the most widely tested drug and is effective in various forms of coronary artery disease and in the secondary prevention after a first ischaemic stroke; in these settings, aspirin reduces the incidence of myocardial infarction, stroke and cardiac death; aspirin has been tested in various daily doses from 30 to 1300 mg: best evidence has been gathered for dosages between 75 and 300 mg; good clinical practice is to use the lowest effective dose. Ticlopidine and clopidogrel have been shown to be superior to aspirin in 2 trials where the incidence of myocardial infarction has been lowered by the new drugs; nevertheless the superiority is apparent only in patients with lower limb atherosclerosis and after stroke. The combination of dipyridamole and aspirin has been proven to be superior to aspirin in the secondary prevention of stroke in one trial contrasting with the other trials performed with other combinations of those two drugs. Glycoprotein GP IIb/IIIa antagonists have been tested in coronary angioplasty and in acute coronary syndromes and only in short intravenous administration; these drugs reduce the incidence of myocardial infarction without any effect on 6-month mortality.
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PMID:[Indications for antiplatelet medications]. 1058 93


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