[Action mechanism and clinical indications for thrombocyte aggregation inhibitors].
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Abstract:
The mechanisms of action of three most commonly used antiplatelet agents (aspirin, sulfinpyrazone, dipyridamole) are briefly discussed. Aspirin inhibits the prostaglandin synthetase of platelets irreversibly and thereby blocks the production of prostaglandin endoperoxides and thromboxane A2, which stimulate platelet aggregation. A daily aspirin dose of 200--300 mg is sufficient to achieve this effect. Sulfinpyrazone appears to interfere with the adhesion of platelets to subendothelial structures and atherosclerotic plaques. Dipyridamole increases cyclic AMP in platelets and thus reduces platelet response to aggregating agents. A few of the satisfactorily performed studies on the clinical effectiveness of antiplatelet agents are mentioned. Sulfinpyrazone treatment of patients with myocardial infarction (Killip--classification I and II), starting 25--35 days after the acute myocardial infarction, reduces cardiac mortality and incidence of sudden death for a period of two years. The efficacy of aspirin treatment in coronary artery disease is not yet definitely established. In patients with transient ischemic attacks, particularly males with appropriate carotid lesions, aspirin therapy reduces the frequency of transient ischemic attacks and possibly the incidence of stroke and death. Sulfinpyrazone is ineffective in these patients. Sulfinpyrazone and aspirin are of value in the prevention of thrombosis in straight arterio-venous shunts. Aspirin reduces the frequency of deep venous thrombosis after total hip replacement in males but not in females. In patients with recurrent venous thrombosis, sulfinpyrazone treatment is effective in preventing thrombosis.Keywords:
Sulfinpyrazone
Dipyridamole
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Sulfinpyrazone
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Sulfinpyrazone
Dipyridamole
Prostaglandin E1
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Platelets play an important role in atherogenesis. This has given rise to the speculation that inhibitors of platelet function may prevent atherosclerotic changes. Two distinct therapeutic goals might be achieved by the use of inhibitors of platelet function in vascular disease - one, the prevention of thrombosis and, two, the prevention of atherosclerosis. The choice of inhibitor may well determine the goal achieved. Thus far, the data available indicate that inhibitors of platelet aggregation, such as aspirin, are the most effective in the prevention of thrombosis, while inhibitors of platelet adherence, such as dipyridamole, are likely to be the most effective in the prevention of atherosclerosis.
Dipyridamole
ATHEROSCLEROTIC VASCULAR DISEASE
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Sulfinpyrazone
Dipyridamole
Coronary thrombosis
Ticlopidine
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In order to evaluate the pathogenetic importance of platelet aggregates in cerebrovascular disease, a platelet count ratio method was used to study 66 patients with transient ischemic attacks (TIAs). Thirty normal subjects and 22 patients without thromboembolic disorders were also included as controls. The mean platelet aggregate ratio of the TIA group was 0.75 ± 0.03 SEM which was significantly lower than that of normal subjects (0.90 ± 0.02) or patient controls (0.88 ± 0.01) (P < 0.01). Seventeen patients with TIA were then treated with aspirin (1,200 mg) and dipyridamole (200 mg) daily. The platelet aggregate ratios were normalized in 13 patients. Of four patients who did not respond to this regimen, one did respond to sulfinpyrazone. When sulfinpyrazone was discontinued, recurrence of symptoms was preceded by an increase in platelet aggregates. These findings suggest that platelet aggregates may play an important role in the pathogenesis of cerebrovascular insufficiency. The determination of platelet aggregates appears useful in selecting patients for antiplatelet therapy.
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Stroke
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Following a myocardial infarction, patients are usually started on long term antiplatelet therapy with aspirin in a dose of 80-150 mg/day. However, there are no quick and easy methods to assess the efficacy of the antiplatelet activity of aspirin.We studied 60 consecutive patients (men, < 40 years of age) 8-10 weeks after they had had acute myocardial infarction. These patients were receiving 100 mg aspirin daily orally with or without b-blockers. We measured P-selectin expression and fibrinogen binding by flowcytometry at least 3 times over a period of 2 years in all the patients. We also studied 100 age- and sex-matched controls.Of the 60 patients, 30 (50%) showed both increased P-selectin and fibrinogen binding by platelets, suggesting platelet activation. Fourteen other patients had increased fibrinogen binding but normal P-selectin expression. Sixteen patients and all the controls had normal results of both tests.Our data show evidence of platelet activation in at least 50% of patients receiving 100 mg of aspirin daily. Flowcytometry for P-selectin expression and fibrinogen binding to platelets can be used to monitor antiplatelet therapy with aspirin following acute myocardial infarction.
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Platelet survival (PS) may be decreased in some thromboembolic disorders. Treatment of patients with drugs that suppress platelet function may or may not be associated with normalisation of PS. It is uncertain, however, whether a lack of influence on PS necessarily indicates lack of an antithrombotic effect. We have examined this problem in an arterial thrombosis model in rabbits. A non-occlusive mural thrombus was produced in the aortic arch and PS studied using 51Cr-labelled homologous platelets. Thrombus size was assessed by measuring 51Cr accretion. Three groups of 15 animals were studied as follows:group A - thrombus induced 30 min prior to start of PS, group B- as for group A but animals treated with SUL (25 mg/Kg) and ASA (25 mg/Kg) prior to thrombus induction and 12 hrly thereafter and group C- sham operated controls. Animals in group B showed a 45% reduction in thrombus size when compared with group A (p<0.05). The platelet Tl/2 in groups A, B, and C were 25.7, 25.6, and 33.8 hrs respectively. The difference between groups A and C and between groups B and C was significant (p<0.01).Thus, treatment with SUL and ASA reduced thrombus size but did not modify the change in PS associated with thrombus induction. Re-examination of PS data by 7 different analytical methods established that all were equally sensitive in discriminating thrombosis but all failed to detect a drug effect. It is concluded that failure to modify platelet survival does not necessarily exclude an antithrombotic effect and that this apparent lack of sensitivity does not relate to the method of data analysis used.
Sulfinpyrazone
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Eighteen patients with ischaemic peripheral vascular disease were treated for a 5-week period with either 20 mg aspirin daily, 75 mg dipyridamole three times daily or a combination of these two treatments. Before and after 4 weeks' treatment autologous platelet labelling with 111 In was carried out and sites of active vascular platelet uptake monitored, and platelet half-life measured. Neither aspirin nor dipyridamole alone had any effect on platelet uptake or on platelet half-life. The combination of aspirin and dipyridamole resulted in a significant decrease in platelet uptake and a nonsignificant trend towards prolongation of platelet half-life. These findings suggest that this combined therapy may be of benefit in the treatment of atherosclerosis in man.
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Numerous drugs and chemicals affect the function of human blood platelets. The mechanism of action of some medications is partly understood. Aspirin is the most frequently involved drug. It appears to interfere with the platelet release reaction by acetylation of a platelet membrane protein which may be involved in the synthesis of prostaglandins. Other anti-inflammatory drugs, including indomethacin, phenylbutazone, ibuprophen (Motrin) and clonixin, also interfere with the release reaction but have a shorter acting course than aspirin. Some drugs stimulate adenylcyclase (gliclazide) or block phosphodiesterase, (dipyridamole, caffeine) both of which actions lead to an increase in adenosine cyclic 3':5' monophosphate (cAMP) and decrease aggregation by adenosine diphosphate (ADP). These interactions should be known to clinical scientists since patients using these medicaments may manifest abnormal platelet function tests in the laboratory and mild hemorrhagic syndromes in the clinic.
Sulfinpyrazone
Dipyridamole
Mechanism of Action
Adenosine diphosphate
Cyclic adenosine monophosphate
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