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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.
Thromb Haemost. 1989 Feb 28; 61(1):43-9.TH

Abstract

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/prostaglandin 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 (greater than or equal to 90% for 48 h), increases serum levels of immunoreactive 6-keto-PGF1 alpha, reduces platelet aggregation in P.R.P. induced by U 46619, collagen (greater than 70% for 8 h), arachidonic acid (greater than 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.

Authors+Show Affiliations

Department of Haematology, Janssen Research Foundation, Beerse, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

2526385

Citation

De Clerck, F, et al. "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." Thrombosis and Haemostasis, vol. 61, no. 1, 1989, pp. 43-9.
De Clerck F, Beetens J, Van de Water A, et al. 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. Thromb Haemost. 1989;61(1):43-9.
De Clerck, F., Beetens, J., Van de Water, A., Vercammen, E., & Janssen, P. A. (1989). 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. Thrombosis and Haemostasis, 61(1), 43-9.
De Clerck F, et al. 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. Thromb Haemost. 1989 Feb 28;61(1):43-9. PubMed PMID: 2526385.
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TY - JOUR T1 - 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. AU - De Clerck,F, AU - Beetens,J, AU - Van de Water,A, AU - Vercammen,E, AU - Janssen,P A, PY - 1989/2/28/pubmed PY - 1989/2/28/medline PY - 1989/2/28/entrez SP - 43 EP - 9 JF - Thrombosis and haemostasis JO - Thromb Haemost VL - 61 IS - 1 N2 - 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/prostaglandin 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 (greater than or equal to 90% for 48 h), increases serum levels of immunoreactive 6-keto-PGF1 alpha, reduces platelet aggregation in P.R.P. induced by U 46619, collagen (greater than 70% for 8 h), arachidonic acid (greater than 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. SN - 0340-6245 UR - https://www.unboundmedicine.com/medline/citation/2526385/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_ DB - PRIME DP - Unbound Medicine ER -