rs-5186 and ozagrel

Thromboxane A2 (TXA2) causes bronchoconstriction and bronchial hyperresponsiveness. Two types of TXA2 modifiers, one synthase inhibitor and one receptor antagonist, are widely used for the treatment of asthma in Japan. Although the target of TXA2 modifiers is to inhibit bioactivity of TXA2, the pharmacological properties are somewhat different between these drugs. We studied the inhibitory effects of the TXA2 synthase inhibitor CS-518 and the TXA2 receptor antagonist S-1452 alone and in combination on antigen-induced bronchoconstriction in passively sensitized guinea pigs treated with diphenhydramine. Both CS-518 and S-1452 inhibited the antigen-induced bronchoconstriction dose-dependently with the plateau. The combination of these drugs at the maximal inhibitory doses did not have any more effect compared with each single dosing. The combination at the submaximal doses tended to show an additive effect, but the effect was not significant. These findings suggest that other prostanoids such as PGE2, PGI2, PGD2 and PGF2alpha may not take an important role in the antiasthmatic effects of TXA2 modifiers.

Topics: Animals; Antigens; Bridged Bicyclo Compounds; Bronchoconstriction; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Guinea Pigs; Male; Methacrylates; Receptors, Thromboxane; Thiophenes; Thromboxane-A Synthase

The anti-asthmatic effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a specific thromboxane A2 (TXA2) synthase inhibitor, were investigated in the ovalbumin-sensitized guinea pig asthmatic model. Although CS-518 slightly inhibited (about 25%) whole bronchoconstriction, it significantly inhibited the antigen-induced bronchoconstriction mediated by slow-reacting substance of anaphylaxis (SRS-A), which was not reduced by chlorpheniramine, a histamine H1 antagonist. On the other hand, indomethacin, a cyclooxygenase inhibitor, potentiated the SRS-A-mediated constriction. CS-518 strongly, and indomethacin slightly, suppressed the leukotriene D4-induced bronchoconstriction. CS-518 clearly inhibited the antigen-induced airway hyperresponsiveness, but this compound had no effect on the airway hyperresponsiveness induced by U-46619, a TXA2-mimetic agent, and propranolol. These results suggest that CS-518 suppresses the development of bronchoconstriction and airway hyperresponsiveness in asthmatic models by inhibition of TXA2 synthesis with the concomitant increase in bronchodilating prostaglandins such as prostaglandin E2 and prostaglandin I2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Chlorpheniramine; Disease Models, Animal; Guinea Pigs; Indomethacin; Male; Methacrylates; Ovalbumin; Propranolol; Prostaglandin Endoperoxides, Synthetic; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

The in vitro properties of CS-518 (RS-5186; sodium 2-(1-imidazolylmethyl)- 4,5-dihydrobenzo[b]thiophene-6-carboxylate, CAS 113817-57-5), a new thromboxane (TX) synthetase inhibitor, as an antiplatelet agent were investigated. Incubation of clotting whole blood from man, rabbits, and dogs with CS-518 resulted in a concentration-dependent reduction of TXB2 production and an increase in 6-keto-PGF1 alpha. Similar properties were also observed for ozagrel and isbogrel, but both agents were less effective on TXB2 production. CS-518 inhibited arachidonic acid (AA)- or collagen-induced platelet aggregation in platelet rich plasma (PRP) from man, rabbits and dogs. In addition, antiaggregatory effects of CS-518 were confirmed in whole blood by two methods: impedance method and free platelet count method. TXA2 formation in washed canine platelets in response to AA (0.1 mmol/l) was dose-dependently inhibited by incubation with CS-518. This inhibition by CS-518 was gradually attenuated after platelets were subsequently washed with drug-free buffer, but a dose-dependent inhibition was still observed with platelets that had been washed three times. Ozagrel also inhibited TXB2 formation when incubated with platelets, whereas this inhibition disappeared with platelets only washed once. In contrast, platelets treated with acetylsalicylic acid, an irreversible inhibitor of cyclooxygenase showed a comparable inhibition before and after they were washed three times. These results indicate that CS-518 exerts antiplatelet effects in vitro via potent, selective, and long-lasting but reversible inhibition on TX synthetase.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Aspirin; Dogs; Humans; Imidazoles; In Vitro Techniques; Male; Methacrylates; Platelet Aggregation; Platelet Aggregation Inhibitors; Rabbits; Thiophenes; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes