Effects of thromboxane synthetase inhibition on arachidonate metabolism and platelet behaviour.

Parry, M.J.

doi:10.1111/j.1365-2125.1983.tb02103.x

Cited by 19 publications

(2 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This metabolite ofarachidonic acid via the cyclo-oxygenase and thromboxane synthetase pathway is a potent platelet agonist and a vasoconstrictor (Needleman et al, 1976a). The physiological role of thromboxane A2 is at present unclear since very few biological effects of selective thromboxane synthetase inhibitors have been described apart from the obvious and usually very marked inhibition of thromboxane production as adjudged by assay of the inert metabolite, thromboxane B2 (Parry, 1983). Due to the complexity of 'To whom correspondence should be sent.…”

Section: Introductionmentioning

confidence: 99%

CGS 12970: a novel, long acting thromboxane synthetase inhibitor

Ambler

Butler

Ku³

et al. 1985

British J Pharmacology

View full text Add to dashboard Cite

1 CGS 12970 is a potent selective inhibitor of human platelet thromboxane synthestase in vitro (IC50 = 12 nM). It is four orders of magnitude less potent as an inhibitor of sheep seminal vesicle cyclooxygenase, bovine aorta prostacyclin synthetase and human leucocyte 15-lipoxygenase. 2 The compound inhibited collagen-induced thromboxane B2 production by human platelets in vitro without an effect on the accompanying platelet aggregation induced by collagen, ADP, platelet activating factor, thrombin, arachidonic acid or the prostaglandin mimetic, U 46619. 3 Administration of CGS 12970 to rats inhibited collagen-induced thromboxane B2 production but had no effect on platelet aggregation ex vivo. It also had no effect on platelet aggregation induced by thrombin or on plasma clotting times. 4 A single oral dose of 1 or 3 mg kg-' to rabbits inhibited thromboxane B2 production in clotting blood ex vivo for 12 or 24 h respectively. 5 CGS 12970 inhibited thromboxane B2 production in vivo induced by intravenous administration of collagen to rats or calcium ionophore to guinea-pigs. In both cases there was a concomitant elevation of immunoreactive 6-keto-prostaglandin Flr. but no effect on the induced thrombocytopenia.6 As with other thromboxane synthetase inhibitors, CGS 12970 prolonged tail bleeding time in the rat. However, CGS 12970 was not as potent as other thromboxane synthetase inhibitors in this test. 7 In addition to these usual effects of thromboxane synthetase inhibitors, CGS 12970 inhibited the thrombocytopenia induced by the Forssman reaction or ADP administration. In these tests the effect of the compound was of short duration. 8 CGS 12970 had no effect on the thrombocytopenia associated with the Arthus reaction which distinguishes it from cyclo-oxygenase inhibitors. It also had no effect on thrombus formation on a cotton thread in an arteriovenous shunt in the rat.

show abstract

Section: Introductionmentioning

confidence: 99%

CGS 12970: a novel, long acting thromboxane synthetase inhibitor

Ambler

Butler

Ku³

et al. 1985

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Some reports suggest that PG endoperoxides or other cyclooxygenase products may be sufficient to induce aggregation by AA, when TXA 2 synthesis is inhibited. 14 ' 15 Therefore, our results suggest that the accumulation and metabolism of pro-aggregatory metabolites differed in each subject. It is unknown, however, whether the diseased condition affects the response to OKY-046.…”

Section: Effect Of Oky-046 Combined With Very Low Dose Of Aspirinmentioning

confidence: 73%

A new approach to antithrombotic therapy--evaluation of combined therapy of thromboxane synthetase inhibitor and very low dose of aspirin.

Nagatsuka¹,

Uyama²,

Nakabayashi³

et al. 1985

Stroke

View full text Add to dashboard Cite

SUMMARY The effect of a selective thromboxane (TX) synthetase inhibitor (OKY-046), alone and in combination with a very low dose of aspirin, on the platelet function was studied in healthy and diseased subjects.A single dose of 100 mg OKY-046 was orally administered to patients with ischemic cerebrovascular disease (CVD) and healthy volunteers. TXB 2 generation and platelet aggregation were measured before and at 1, 4, 6 and 8hr after dosing. In addition, after the administration of a very low dose of aspirin (0.1-0.25 mg/kg/day) for at least one month, a single dose of OKY-046 was given to CVD patients. TXB 2 generation and platelet aggregation were measured in the same manner as OKY-046 alone.The effect of OKY-046 on platelet aggregation induced by arachidonic acid (AA) was different in each subject whereas platelet TXB 2 generation was almost completely inhibited in all of the patients and healthy volunteers. OKY-046 had a slight inhibitory effect on collagen induced aggregation. A combination of OKY-046 with a very low dose of aspirin, on the other hand, produced additional inhibition of the platelet aggregation induced by both AA and collagen.The present results suggest that 1) the accumulation and metabolism of cyclooxygenase products that accumulate when TX synthetase is blocked, differ in each subject, 2) additional inhibition is caused by the combined use of TX synthetase inhibitor and a very low dose of aspirin because the very low dose of aspirin partially reduces the proaggregatory cyclooxygenase products that accumulate when TX synthetase is blocked.We, therefore, believe that the combined use of TX synthetase inhibitor and a very low dose of aspirin may provide a new approach to antithrombotic therapy without the inhibition of prostacyclin production. Stroke Vol 16, No 5, 1985 THROMBOXANE A 2 (TXA 2 ) strongly induced platelet aggregation 1 and contracts vascular smooth muscle.2 On the other hand, prostacyclin (PGI 2 ) inhibits platelet aggregation and relaxes vascular smooth muscle. 34 Because of the potential importance of such a compound in the medication of vascular occlusive events in vivo, there has been a considerable interest in the pharmacological effects attendant to the inhibition of TX biosynthesis in man. Aspirin effectively blocks cyclooxygenase in all tissues and thereby formation of endoperoxides, TXA 2 and PGI 2 . An anti-thrombotic effect of reduced TXA 2 formation might, however, be counteracted by the inhibition of PGI 2 production. Numerous attempts have been made in recent years in order to find an ideal dose of aspirin that would inhibit cyclooxygenase in platelet but not in other tissues, particularly in the vessel wall. 56 However, most human studies have failed to demonstrate the existence of such a "therapeutic window". Therefore, selective inhibitor of TX synthetase is an attractive way to resolve the "aspirin dilemma". 78 However, there is evidence that several compounds completely prevent TXA 2 synthesis but do not inhibit platelet aggregation.9 ' l0 Formation of...

show abstract