cardiovascular-agents and motapizone

Ten healthy subjects took single oral doses of placebo, 8.8 +/- 1.8 mg motapizone, 40 +/- 13 mg captopril, 25 mg dihydralazine, 20 mg nifedipine and 4.5 +/- 1.1 mg prazosin in random order, and, as the last preparation 500 mg acetylsalicylic acid. Thrombocyte aggregation induced "ex-vivo" with collagen, ADP and adrenaline was measured before and after 60 min. Immediately before each dose, the "threshold concentration" of each agent was determined in each subject, i.e. the concentration producing about 90% of maximal aggregation. After the preparation had been taken, aggregation was induced with 1-, 2- and 4-times the threshold concentration. Both motapizone and also acetylsalicylic acid caused marked inhibition of aggregation at up to 4-times the threshold concentration; the dose ratio was about 1:50. Motapizone produced greater inhibition of the aggregation induced by ADP and acetylsalicylic acid than of that due to collagen. The inhibitory actions after captopril, dihydralazine, nifedipine and prazosin were weak and did not significantly differ from placebo.

Topics: Adult; Antihypertensive Agents; Aspirin; Cardiovascular Agents; Female; Fibrinolytic Agents; Humans; Male; Platelet Aggregation; Pyridazines

Murine resident peritoneal macrophages were stimulated with lipopolysaccharide and treated with phosphodiesterase (PDE) inhibitors zardaverine, rolipram and motapizone. The PDE inhibitors suppressed the formation of tumor necrosis factor (TNF) by macrophages. The mono-selective PDE IV inhibitor rolipram and the dual-selective PDE III/IV inhibitor zardaverine had equal inhibitory potency, whereas the PDE III inhibitor motapizone was of lower inhibitory potency. All PDE inhibitors acted in synergy with the adenylate cyclase activators prostaglandin E2 and CG 4203, a prostacyclin analog, and super-additive effects of combinations were observed. The PDE inhibitors also blocked the formation of leukotriene C4 (LTC4); however, substantially higher doses were needed than for blockade of TNF synthesis. Furthermore, no additive or synergistic effects were observed upon combined treatment with adenylate cyclase activators. It is suggested that the suppression of TNF formation by PDE inhibitors is mediated mainly by a PDE isoenzyme of type IV. The effect of PDE inhibitors on LTC4 synthesis appears to be mediated by a different mechanism.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cardiovascular Agents; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 4; Epoprostenol; Isoenzymes; Lipopolysaccharides; Macrophages; Male; Mice; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Platelet Aggregation Inhibitors; Pyridazines; Pyrrolidinones; Rolipram; SRS-A; Tumor Necrosis Factor-alpha

Single doses of motapizone 1 to 10 mg were given to 12 healthy subjects. Before and up to 8 h after each dose the blood pressure and heart rate were measured, as well as thrombocyte aggregation "ex vivo" with collagen, ADP and adrenaline. Motapizone produced a dose-dependent reduction in diastolic blood pressure and an increase in heart rate. These effects were demonstrated with individual variations after 1 to 3 mg and as a rule they were very marked after more than 6 mg. With the highest dose (mean 7.7 +/- 2.3 mg) the diastolic pressure fell by an average of 23% 1 h after medication as compared to with the baseline values. At the same time there was marked inhibition of thrombocyte aggregation, which also became apparent after about 3 mg and increased in proportion to the dose. The inhibition of aggregation peaked after 2 h and had disappeared within 8 h. The inhibition of ADP-induced aggregation was particularly marked.

Topics: Adult; Blood Pressure; Cardiovascular Agents; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Heart Rate; Humans; Male; Platelet Aggregation; Pyridazines