vapiprost and Pulmonary-Embolism

We investigated the pharmacological characteristics of Z-335 ((+/-)-sodium[2-[4-(chlorophenylsulfonylaminomethyl)indan-5-yl]ace tate monohydrate), a new indan derivative. Z-335 inhibited the specific binding of [3H]SQ-29548 to human platelets and guinea pig platelet membranes. The IC50 values of Z-335 for human platelets and guinea pig platelet membranes were 29.9 +/- 3.1 nM with a slope of 1.09 +/- 0.05 and 32.5 +/- 1.7 nM with a slope of 1.07 +/- 0.02, respectively. Z-335 inhibited thromboxane A2 receptor-mediated human and guinea pig platelet aggregation in vitro and oral administration of this drug to guinea pigs inhibited U-46619- and collagen-induced platelet aggregation for 24 h. Z-335 dose-dependently prevented the occurrence of U-46619-induced pulmonary thromboembolism in mice and the protective effect of this drug (0.3 and 3 mg/kg, p.o.) lasted for 24 h. These results strongly suggest that Z-335 is a potent, orally active and long-lasting thromboxane A2 receptor antagonist, which may be useful as an antiplatelet drug.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biphenyl Compounds; Cilostazol; Drug Interactions; Fibrinolytic Agents; Guinea Pigs; Heptanoic Acids; Humans; Indans; Male; Mice; Mice, Inbred ICR; Phenylacetates; Platelet Aggregation; Platelet Aggregation Inhibitors; Pulmonary Embolism; Receptors, Thromboxane; Sulfonamides; Tetrazoles; Vasoconstrictor Agents

The inhibitory effects of vapiprost hydrochloride (vapiprost), a novel thromboxane A2 receptor antagonist, on platelet aggregation and ATP release were studied using platelet rich plasma (PRP) of humans, guinea pigs, rabbits and rats. In in vitro experiments with human platelet, vapiprost inhibited the aggregation and ATP release stimulated with U-46619, collagen or arachidonic acid (AA) at an IC50 of less than 2.1 x 10(-8) M. Vapiprost did not inhibit the primary aggregation or ATP release of human platelets stimulated with adenosine 5'-diphosphate (ADP), epinephrine (Epi) or platelet activating factor (PAF), but inhibited the secondary aggregation stimulated with those agonists at an IC50 of less than 1.3 x 10(-7) M. The sensitivity of platelets in various species of animals to vapiprost was in the following order: human > or = guinea pigs > rats > rabbits. In ex vivo experiments with guinea pigs which received a single oral dose of vapiprost, the agent demonstrated strong inhibition of ATP release from platelets stimulated with U-46619, collagen or AA at an ID50 of less than 25.8 micrograms/kg. These inhibitory effects were observed within 30 min and sustained for 24 h at a single dosage of 5 mg/kg of vapiprost. In AA-induced pulmonary infarction models of mice, the sudden death rates decreased significantly with the oral administration of 10 mg/kg or more of vapiprost. These results indicate that vapiprost effectively inhibits the secondary aggregation and ATP release of human platelets stimulated with various agonists, and that guinea pig and human platelets are similar in response to vapiprost. Furthermore, it was demonstrated in ex vivo experiments with guinea pigs that the inhibitory action of vapiprost appears rapidly and lasts for long periods.

Topics: Adenosine Triphosphate; Animals; Arachidonic Acid; Aspirin; Biphenyl Compounds; Blood Platelets; Guinea Pigs; Heptanoic Acids; Humans; Male; Mice; Platelet Aggregation; Platelet Aggregation Inhibitors; Pulmonary Embolism; Rabbits; Rats; Rats, Wistar; Receptors, Thromboxane; Species Specificity; Thromboxane A2