flunarizine and Arteriosclerosis

Topics: Animals; Aorta; Arteries; Arteriosclerosis; Calcinosis; Calcium; Calcium Channel Blockers; Cell Survival; Cholesterol, Dietary; Cinnarizine; Diltiazem; Flunarizine; Humans; Membrane Lipids; Muscle, Smooth, Vascular; Nicardipine; Nifedipine; Propranolol; Rabbits; Verapamil

Thirty-one patients, mean age 60 years (range 45-80 years), with a typical history and objective symptoms of intermittent claudication with a reported maximal walking distance less than 500 m, were included in a cross-over study. After a one month's run-in period on placebo, the patients were randomized into two groups: one group started with flunarizine (5 mg t.i.d.) and the other with pentoxifylline (400 mg t.i.d.). The treatment lasted 3 months, whereafter the medications were changed. The trial followed a double-blind design. The median of the maximal walking distance was 255 m after the placebo period, increasing significantly (p less than 0.01) during both medication periods: by 43% and 18% during flunarizine and pentoxifylline, respectively. No changes were recorded in the ankle systolic blood pressure ratio ( ASBP -ratio) after placebo or either medication period. Red cell rigidity (Pmax), which was initially elevated, decreased significantly (p less than 0.05) during both medication periods, but there were no significant differences between the two drugs. No changes were found in whole blood or plasma viscosity. We conclude that the decrease in red cell rigidity may have contributed to the increased walking distance.

Topics: Aged; Arteriosclerosis; Blood Pressure; Blood Viscosity; Cinnarizine; Clinical Trials as Topic; Double-Blind Method; Erythrocytes; Exercise Test; Flunarizine; Humans; Intermittent Claudication; Leg; Middle Aged; Osmotic Fragility; Pentoxifylline; Physical Exertion; Piperazines; Regional Blood Flow; Rheology; Smoking; Theobromine; Vasodilator Agents

A localized atheromatous plaque was induced in rabbits after transmural electrical stimulation of the carotid and a cholesterol-rich diet (1.33% cholesterol) for 4 weeks. This model was used to investigate the antiatherogenicity of indapamide. The treatment given per os started 14 days before the stimulation period. Animals were divided into six groups: group 1 (control) received gelatin 2%, group 2 received hydrochlorothiazide at 20 mg/kg/day, group 3 was treated with flunarizine at 25 mg/kg/day, and groups 4, 5, and 6 received indapamide at 0.3, 1, and 3 mg/kg/day, respectively. During the experimental period, all rabbits showed similar weight gain, regardless of the treatment. Image analysis showed an antiatherogenic effect for indapamide (0.3 mg/kg/day) characterized by a reduction in the number of cell layers (NCL; 10.5 +/- 1.8 vs. 18.0 +/- 2.9; p < 0.05) and in the intima/media area ratio (I/M; 17.5 +/- 4.5 vs. 42.7 +/- 7.0%; p < 0.01). Indapamide appeared to be more active than the reference drug flunarizine (NCL = 14.2 +/- 2.5, N.S.; I/M = 24.5 +/- 4.3, p < 0.05). The maximum effect occurred at the lowest dose tested (0.3 mg/kg/day). The reason for the loss of antiatherogenic activity of indapamide at higher doses is discussed. Hydrochlorothiazide did not show any effect on the formation of the atheromatous plaque.

Topics: Animals; Arteriosclerosis; Basement Membrane; Body Weight; Carotid Arteries; Cell Division; Cholesterol, Dietary; Disease Models, Animal; Electric Stimulation; Flunarizine; Hydrochlorothiazide; Image Processing, Computer-Assisted; Indapamide; Male; Rabbits; Tunica Intima

A 56-year-old man developed lichen planus while taking flunarizine, a di-fluorinated derivate of cinnarizine. Induction of lichen planus by cinnarizine therapy has been described but the precise etiopathological mechanism is unclear. Although flunarizine is widely prescribed, lichen planus induced (?) by this drug has, to our knowledge, never been reported.

Topics: Arteriosclerosis; Drug Eruptions; Flunarizine; Fluorescent Antibody Technique; Humans; Immunoglobulins; Lichen Planus; Male; Middle Aged

Topics: Animals; Arteriosclerosis; Blood Pressure; Coronary Artery Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Flunarizine; Hypertension; Intracranial Arteriosclerosis; Kidney Diseases; Male; Rats

A densitometric technique was established to investigate quantitative changes in endothelial permeability for horseradish peroxidase (HRP), mol. wt. 40,000 daltons, in rabbit carotid artery. Repeated weak electrical stimulations of rabbit carotid arterial walls with implanted electrodes lead to fibromuscular plaques mainly beneath the anode. It could be demonstrated that there exists a typical growth curve of the plaques dependent on the number of days of electrostimulation, with a fast proliferation rate of smooth muscle cells in the first 2 weeks of electrostimulation, and an increasing retardation of proliferation during the next 4 weeks. Endothelial permeability for HRP increases in close relation to the plaque development. Intravenous applications of single doses of the calcium entry blockers flunarizine or nimodipine are able to inhibit the increased permeability of the endothelial lining covering arteriosclerotic plaques. The intensity of the inhibitory action of these calcium antagonists correlates with the size of the arteriosclerotic plaques in inverse proportion, but nevertheless in large plaques an inhibitory effect is seen.

Topics: Animals; Arteriosclerosis; Capillary Permeability; Carotid Arteries; Densitometry; Electric Stimulation; Endothelium, Vascular; Flunarizine; Horseradish Peroxidase; Male; Nimodipine; Rabbits

Flunarizine is a calcium entry blocker active in the treatment of peripheral vascular disease. The present study was performed to evaluate the effect of flunarizine on cerebral blood flow (CBF) and lipidic patterns in rabbits with dietary experimental atherosclerosis. Since it is well known that there is only a slight correlation between the severity of atheromatous lesions ascertained at necroscopy and the severity of clinical symptoms of cerebral vascular disease, the effect of the drug was assessed by measuring the CBF and compartmental distribution of blood flow in unanaesthetized rabbits by the intracarotid Xe-133 clearance method; blood pressure, plasma lipids and tissue fat infiltration were also checked. An atherogenic diet brings about significant impairment of CBF. Flunarizine is inactive in normal rabbits if chronically administered at the daily dose of 10 mg/kg p.o. In atherosclerotic rabbits chronic treatment with flunarizine induced a pronounced increase in cerebral haemodynamic parameters. Arterial pressure and blood pCO2 were not significantly modified. Lipidic patterns were not markedly improved by flunarizine treatment in comparison with values for atherosclerotic animals. These data demonstrate that flunarizine treatment counteracts the haemodynamic effects of cerebral atherosclerosis. The pronounced activity on the cerebral vessels is accompanied by a weak antilipaemic effect.

Topics: Animals; Arteriosclerosis; Cerebrovascular Circulation; Cinnarizine; Diet, Atherogenic; Flunarizine; Hypolipidemic Agents; Lipids; Male; Rabbits

Repeated weak electrical stimulations of rabbit carotid artery walls with implanted electrodes cause intimal proliferations of smooth muscle cells (SMC) and lead to fibromuscular plaques beneath the anode. If the animals receive a cholesterol-enriched diet the plaques become typical atheromas. The endothelial lining is maintained. The procedure for the production of an atheroma with 11 +/- 4 layers of SMC lasts 4 weeks. Addition of the calcium antagonist Flunarizine to the food during the stimulation periods inhibits the growth of the plaque. The inhibition is dose-dependent. Whether the drug inhibits atherogenesis by direct action on SMC or via an effect on permeation of macromolecules through the endothelium has been studied by measurement of (1) peroxidase (MW 40,000 dalton) permeability through the stimulated endothelium of the artery and (2) the inhibitory effects of Flunarizine on cultures of arterial SMC. Endothelial permeability increases for some hours after stimulation mainly beneath the anode. Flunarizine inhibits the permeation of peroxidase through the endothelial lining for the most part by its action on intercellular transport. The drug also inhibits the growth of SMC in mass cultures and clone cultures. The inhibition of proliferation is not specific for SMC. Skin fibroblasts obtained from the same animals as the artery smooth muscle cells are also inhibited in mass cultures and clone cultures. From the results it can be concluded that Flunarizine exerts its inhibitory action not only by its effect on the permeation through the endothelial lining but by a combined action on permeability and proliferation of cells in the artery wall.

Topics: Animals; Arteriosclerosis; Carotid Arteries; Cell Division; Cells, Cultured; Cinnarizine; Disease Models, Animal; Electric Stimulation; Endothelium; Fibroblasts; Flunarizine; Horseradish Peroxidase; Male; Muscle, Smooth, Vascular; Rabbits; Vasodilator Agents

Topics: Aged; Arteriosclerosis; Cinnarizine; Female; Flunarizine; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Ultrasonography

We tested the effects of the calcium antagonists lanthanum, diltiazem, and flunarizine on the development of atherosclerosis in rabbits fed a 2% cholesterol diet. The drugs were given orally and were well tolerated. In the cholesterol control animals, 52.2% of the thoracic aortic intimal surface was Sudan IV positive. This was reduced by 37% (p less than 0.05) with lanthanum, 37% (p less than 0.05) with diltiazem, and 34% (p less than or equal to 0.06) with flunarizine. In all cholesterol-fed animals, the intramural, but not subepicardial, coronary arteries were severely diseased. The extent and distribution of this disease were not altered by the various drug interventions. Thus, the calcium antagonists lanthanum, diltiazem, and flunarizine suppress atherogenesis of the rabbit aorta but have no effect on the extent or distribution of atherosclerosis in the intramural coronary arteries.

Topics: Animals; Aortic Diseases; Arteriosclerosis; Calcium Channel Blockers; Cholesterol, Dietary; Cinnarizine; Coronary Disease; Diltiazem; Female; Flunarizine; Lanthanum; Organ Size; Rabbits