R 68 070: Thromboxane A2 Synthetase Inhibition and Thromboxane A2/Prostaglandin Endoperoxide Receptor Blockade Combined in One Molecule - II. Pharmacological Effects In Vivo and Ex Vivo

F De Clerck; J Beetens; A Van de Water; E Vercammen; P A J Janssen

doi:10.1055/s-0038-1646524

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1989; 61(01): 043-049
DOI: 10.1055/s-0038-1646524

Original Article

Schattauer GmbH Stuttgart

R 68 070: Thromboxane A₂ Synthetase Inhibition and Thromboxane A₂/Prostaglandin Endoperoxide Receptor Blockade Combined in One Molecule - II. Pharmacological Effects In Vivo and Ex Vivo

F De Clerck

The Department of Haematology, Janssen Research Foundation, Beerse, Belgium

,

J Beetens

The Department of Haematology, Janssen Research Foundation, Beerse, Belgium

,

A Van de Water

¹The Department of Cardiovascular Pharmacology, Janssen Research Foundation, Beerse, Belgium

,

E Vercammen

²The Department of Clinical Research, Janssen Research Foundation, Beerse, Belgium

,

P A J Janssen

The Department of Haematology, Janssen Research Foundation, Beerse, Belgium

› Author Affiliations

Abstract

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Summary

R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid (Janssen Research Foundation, Belgium), a newly developed compound, combining specific thromboxane A₂ (TXA₂) synthetase inhibition with TXA₂/pros- taglandin endoperoxide receptor blockade in one molecule, is active in vivo in man and in experimental animals.

In man (n = 5), a single oral 400-mg dose of R 68 070 produces deep and protracted inhibition of platelet TXA₂ synthetase activity (≥90% for 48 h), increases serum levels of immuno- reactive 6-keto-PGF_1α, reduces platelet aggregation in RR.R induced by U 46619, collagen (>70% for 8 h), arachidonic acid (>90% for 18 h) and prolongs template bleeding times significantly, without affecting plasma coagulation or fibrinolysis.

In rats, R 68 070 (1.25 mg/kg orally, –2 h) singly prolongs tail bleeding times as much as a combination of TXA₂ synthetase inhibition (dazoxiben 10 mg/kg) and TXA₂/prostaglandin endoperoxide receptor blockade (BM 13177 40 mg/kg). In dogs, the compound reduces coronary thrombosis induced by electrical damage (1.25 mg/kg i. v.) and prevents the evolution of occlusion/ reperfusion-induced arrhythmias into ventricular fibrillation (2.5 mg/kg i.v.). R 68 070 thus may be an appropriate pharmacological tool to analyze the roles and interactions of agonistic (TXA₂, prostaglandin endoperoxides) and antagonistic (PGD2, PGE₂, PGI₂) metabolites of arachidonic acid in experimental and human pathologies.

Key words

R 68 070 - TXA₂-synthetase - Receptor blockade - Man - Experimental models

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References

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