SummaryThe ability of platelets to synthesize thromboxane B2 (TxB2) from arachidonic acid (AA) or prostaglandin H2 (PGH2) was studied in 26 control subjects, 40 patients with essential hypertension, 20 patients with cerebrovascular disease (CVD) not taking aspirin and 11 patients with CVD taking aspirin. The activity of platelets to form TxB2 from AA or PGH2 was measured using 1 — 14C arachidonic acid or 1—14C PGH2 as a substrate. There was no significant difference in TxB2 generation from AA or PGH2 among the platelets collected from the control subjects, hypertensive patients and CVD patients not taking aspirin.In CVD patients taking aspirin, marked suppression was observed in TxB2 synthesis from AA, but no suppression in TxB2 synthesis from PGH2. At least 750 mg aspirin per day were required for nearly complete suppression of TxB2 generation from AA.

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The effect of the selective thromboxane A2 synthetase inhibitor OKY-1581, a pyridine derivative [sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methyl-2-propenoate], on thromboxane B2 and 6-keto-prostaglandin F,, levels and platelet aggregation was studied in human volunteers. To clarify its effectiveness as an enzyme inhibitor, OKY-1581, at doses of 17, 83, 167, 417, 833, and 1667 gig/kg (n = S for each group), was injected intravenously, or was infused (10 ,ug/kg/min; n = 5) over 3 hr on 3 successive days. OKY-1580 (OKY-1581 free acid) was rapidly converted to its main ,Boxidized product, OKY-1565, and its reduced form, OKY-1558. During the study, plasma thromboxane B2 levels, inhibition of thromboxane B2 production in serum, and inhibition of rabbit platelet thromboxane A2 synthetase were monitored continuously. Twenty-five minutes after the injection of the above doses, plasma thromboxane B2 levels decreased by 4 + 7%, 40 + 14%, 57 + 7%, 68 6%, 93 + 5%, and 96 + 5% (mean SD), respectively. Thromboxane B2 production in serum was decreased by 2 + 8%, 70 + 10%, 75 8%, 81 + 10%, 95 10%, and 96 ± 8%, respectively, and rabbit platelet thromboxane A2 synthetase by 2 ± 7%, 52 + 8%, 79 ± 10%, 80 ± 9%, 96 + 8%, and 95 ± 7%. These parameters returned to the control levels 24 hr after the injection. During infusion of OKY-1581 at a rate of 10 gg/kg/min for 3 hr, plasma thromboxane B2 levels decreased significantly, and inhibition of thromboxane B2 production in serum and of rabbit platelet thromboxane A2 synthetase was also significant. Intravenous infusion of this drug reduced platelet aggregation induced by arachidonate (2 mM) significantly. In serum of incubated whole blood, after the treatment with OKY-1581, serum 6-keto-prostaglandin F,, production was increased significantly. OKY-1581 caused no untoward symptoms or changes in hemodynamic parameters or electrocardiographic or laboratory results, including those for bleeding time and coagulation. In cardiovascular diseases in which thromboxane A2 may be involved in the pathogenesis, this selective inhibitor of thromboxane A2 synthetase may become a useful drug because it inhibits thromboxane A2 production and arachidonate-induced platelet aggregation.

In our country, FOY[Etryl-p-(6-guanidinohexanoyloxy )benzoate methanesulfonate], a newly developed protease Inhibitor, has been used in the treatment of DIC with promising result It has been postulated that FOY may possess certain effect en platelet function, besides its proved action on coagulation and fibrinolysis system. Therefore, in vitro effect or FOY on platelet aggregation was Investigated, utilizing aggregometer and human PRP.When PRP was preincubated with FOY UOQug/ml in final concentration), the secondary aggregation by ADP (4μg/ml) was completely Inhibited. However, FOY did not exhibit any inhibitory effect m primary aggregation Induced by lower concentration of ADP even with higher amount of FOY (up to 362μg/mn). FOY completely Inhibited aggregation Induced by thrombin (0.5 U/ml), when it was preincubated with PRP for 2 minutes. 30 μg/ml of FOY caused disaggregation when it was added to the mixture or PRP and thrcmbln immedlately after aggregation was Initiated. The Dremixture of thrombin and FOY did not cause aggregation of PRP. 10μg/ml of FOY completely inhibited aggregation induced by 0.7 mN of arachldonate, when It was preincubated with PRP for 2 minutes. Also, 100μg/ml of FOY exhibited similar Inhibitory effect on aggregation induced by collagen. It was not surprising for FOY to Inhibit platelet aggregation induced by thrombin, since it was round to possess competitive inhibition arainst thrcefcin. However, it is interesting for FOY to Inhibit the secondary platelet agfreration by ADP and by arachldonate.