Multitechnical non-invasive procedures were used to assess the arteriolar effects of cinnarizine and its difluoroderivative, flunarizine, in 20 normal volun teers and in 43 elderly patients with occlusive disease of the extremities due to arteriosclerosis, 22 of whom had intermittent claudication. The trial involved six separate studies of which three were double-blind cross-over, one was a 6- month open study followed by a 6-month double-blind study and two were open studies. Significant drug-related effects were obtained by venous occlusion plethysmometry, differentiated pulse plethysmometry, oscillometry, claudicom eter, postexercise arm-ankle pressure gradients and exercise tolerance measure ments, but not by light plethysmometry and skin temperature measurements. The results indicated that cinnarizine and flunarizine improved vascular disten sion and blood flow in normal volunteers, as well as in patients with occlusive disease of the extremities due to arteriosclerosis. The patients also showed increased postexercise arm-ankle pressure gradients, improved arterial pulsa tions and better exercise performance and tolerance. The drugs were devoid of effects on sympathetic reflexes, resting blood pressure and pulse rate; they were devoid of side-effects and were well tolerated also by patients treated with antihypertensives and cardiac glycosides. Flunarizine was at least as effective as its parent compound at two to three times lower dose levels.
Platelet aggregation in response to 5-hydroxytryptamine was investigated in 40 normal subjects, in 45 patients with acute myocardial infarction, and in 65 patients with peripheral arterial obstructive disease. It was found that of the 110 patients with cardiovascular disease, 40% had a biphasic irreversible platelet aggregation, whereas this phenomenon occurred in only 7.5% of the normal population. A double-blind placebo-controlled study further showed that a subacute treatment with ketanserin, a selective 5-HT2-receptor antagonist both on platelets and on vascular tissue, efficiently abolished the irreversible platelet aggregation in patients hyperreactive to 5-hydroxytryptamine. In an additional open study, including 10 patients with peripheral arterial obstructive disease, a chronic treatment with ketanserin 40 mg t.i.d. for a period of 3 months significantly suppressed the primary platelet aggregation to 5-HT at 2 X 10(-5) M and at 2 X 10(-6) M and significantly lowered the plasma beta thromboglobulin levels. Since 5-HT is a potent mediator of vasospasm, treatment with ketanserin might be of therapeutic value in atherosclerotic diseases, where platelet activation is thought to be involved.
Controversy still exists about the exact role of platelets in the pathogenesis of atherosclerosis. However, patients with cardiovascular (CV) diseases have been reported to have enhanced platelet activity and to show hyperaggregability in response to common aggregators. Very little is known on 5-hydroxytryptamine (5-HT)-induced platelet aggregation in these patients. In a previous preliminary study we observed an increased sensitivity of platelets in response to 5-HT in patients with CV diseases. We further showed that ketanserin, a selective 5-HT receptor antagonist both on platelets and vascular tissue, abolished the 5-HT dependent hyperreactivity of platelets in patients with CV diseases. In a prospective study we investigated platelet aggregation in response to 5-HT at 2 x 10-5Mol in 405 patients with various CV diseases as compared with an age-matched control group of 110 apparently healthy donors. Evaluation of the results was based on the presence of a second irreversible aggregation in response to 5-HT. The control subjects responded to 5-HT with a shape change and a weak, reversible aggregation, except for 9 of the 110 volunteers, where a second irreversible wave occurred (8%). In contrast, it was found that 119 out of 405 patients with CV diseases had a biphasic irreversible aggregation (29%) (Chi-square test : p < 0.0001). From these 405 patients 129 patients suffered from an acute myocardial infarction (AMI), between 4 and 14 days after the onset of symptoms, 78 patients suffered from ischemic heart disease (IHD), 99 patients from peripheral arterial obstructive disease (PAOD) and 99 patients from diabetes, without clinical symptoms of atherosclerosis. A secondary irreversible platelet aggregation to 5-HT was observed in 36% of patients with AMI, in 22% of patients with IHD, in 25% of patients with PAOD and in 31% of patients with diabetes, all the subgroups being significantly different from the control subjects (p <0.01). These findings suggest that platelets may play a role in the propagation and manifestations of CV diseases and that in diabetes the enhanced platelet activity may be a contributing risk factor in de development of atherosclerosis. Finally, since 5-HT is a potent mediator of vasospasm, treatment with ketanserin might be of therapeutic value in atherosclerosis, where platelet activation is thought to be involved.
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