Ridogrel Inhibits Systemic and Renal Formation of Thromboxane A2 and Antagonizes Platelet Thromboxane A2/Prostaglandin Endoperoxide Receptors upon Chronic Administration to Man

C Weber; J R Beetens; F Tegtmeier; P Van Rooy; E Vercammen; L Wouters; F De Clerck

doi:10.1055/s-0038-1656351

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1992; 68(02): 214-220
DOI: 10.1055/s-0038-1656351

Original Article

Schattauer GmbH Stuttgart

Ridogrel Inhibits Systemic and Renal Formation of Thromboxane A₂ and Antagonizes Platelet Thromboxane A₂/Prostaglandin Endoperoxide Receptors upon Chronic Administration to Man

C Weber

⁴The Janssen Research Foundation, Neuss (Rosellen), Germany

,

J R Beetens

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

,

F Tegtmeier

⁴The Janssen Research Foundation, Neuss (Rosellen), Germany

,

P Van Rooy

²The Clinical Pharmacology, Janssen Research Foundation, Beerse, Belgium

,

E Vercammen

³The Clinical R & D, Janssen Research Foundation, Beerse, Belgium

,

L Wouters

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

,

F De Clerck

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

› Author Affiliations

Abstract

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Summary

The effects of ridogrel, a dual thromboxane A₂ (TXA₂) synthase inhibitor and TXA₂/prostaglandin (PG) endoperoxide receptor antagonist, on systemic and renal production of prostaglandins and on platelet TXA₂/PG endoperoxide receptors was evaluated upon chronic administration (300 mg b. i. d. orally, for 8 and 29 days) to man. Such a medication with ridogrel inhibits the systemic as well as the renal production of TXA₂ as measured by the urinary excretion of 2,3-dinor-TXB₂ and TXB₂ respectively without inducing significant changes in systemic or renal PGI₂ production. Simultaneously with the latter effects, the production of TXB₂ by spontaneously coagulated whole blood ex vivo is inhibited (>99%) while that of PGE₂ and PGF_2α is largely increased. Administration of ridogrel causes a three- to five-fold shift to the right of concentration-response curves for U46619 in eliciting platelet aggregation; no tachyphylaxis is observed after 29 days of treatment in this respect. Apart from a reduction of serum uric acid levels with a concomitant increase in urinary uric acid excretion during the first days of treatment, no clinically significant changes in hematological, biochemical, hemodynamic and coagulation parameters occur during the 8 days or 29 days study. The study demonstrates that ridogrel is a potent inhibitor of the systemic as well as renal TXA₂ synthase and an antagonist of platelet TXA₂/PG endoperoxide receptor in man, covering full activity during 24 h at steady-state plasma level conditions without tachyphylaxis during 29 days of medication. The compound is well tolerated, at least during 1 month of administration.

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References

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