Serum Thromboxane B2 Production Research Articles

A New Cyclooxygenase‐2 Inhibitor, Rofecoxib (VIOXX®), Did Not Alter the Antiplatelet Effects of Low‐Dose Aspirin in Healthy Volunteers

The present study examined whether rofecoxib (VIOXX), a new specific inhibitor of cyclooxygenase-2 (COX-2), would interfere with the desired antiplatelet effects of aspirin. Thus, the effects of rofecoxib on inhibition of ex vivo serum-generated thromboxane B2 (TXB2) and platelet aggregation by low doses (81 mg) of aspirin were examined in healthy volunteers. This was a double-blind, randomized, placebo-controlled, parallel study of two treatment groups (n = 12 per group) in which subjects received 50 mg of rofecoxib or placebo for 10 days in a blinded fashion. Subjects also received 81 mg aspirin once on each of days 4 through 10 in an open-label fashion. Blood for measurement of serum TXB2 production and platelet aggregation studies was collected on day 1 (prior to rofecoxib/placebo), on day 4 (prior to aspirin), and on day 10 (before and 4 hours following the seventh dose of aspirin). Platelet-derived serum TXB2 (COX-1 assay) was measured in blood clotted for 1 hour at 37 degrees C. Platelet aggregation was independently induced employing 1 mM arachidonic acid and 1 microgram/mL collagen as agonists. Rofecoxib administered alone had no significant effect on serum TXB2 production or platelet aggregation (day 4). TXB2 production was inhibited 98.4% by aspirin coadministered with either rofecoxib or placebo (day 10). Similarly, platelet aggregation induced by arachidonic acid was inhibited 93.7% and 93.5% by aspirin coadministered with either rofecoxib or placebo, respectively (day 10). The comparable values for inhibition of collagen-induced platelet aggregation were 86.8% and 90.8%, respectively. No important clinical or laboratory adverse experiences were observed. In conclusion, rofecoxib alone (50 mg QD for 4 days) did not inhibit serum TXB2 production or platelet aggregation. In addition, rofecoxib (50 mg QD for 10 days) did not alter the antiplatelet effects of low-dose aspirin (inhibition of platelet aggregation and TXB2 production). Rofecoxib was generally well tolerated when administered alone or in combination with low-dose aspirin.

Effects of Ticlopidine Administered to Healthy Volunteers on Platelet Function in Whole Blood

Ticlopidine is thought to be a selective inhibitor of ADP-induced platelet function. Here we have investigated the effects of ticlopidine on platelet function in whole blood induced by ADP and by other platelet agonists. Whole blood was used because it was considered that ADP derived from red cells might act synergistically with other platelet agonists to enhance platelet responses, and that ticlopidine might interfere with this process. Measurements were performed using blood from 16 healthy volunteers before ticlopidine administration, after taking ticlopidine 250 mg daily for 10 days, after taking ticlopidine 250 mg twice daily for a further 10 days, and after 14 days off treatment. Ticlopidine proved to be a very effective inhibitor of the platelet aggregation induced by ADP; it was most effective in enhancing the reversibility of the aggregation response. The drug modestly but significantly reduced streptokinase, adrenaline, collagen, sodium arachidonate, PAF and U46619 - induced platelet aggregation. The drug significantly reduced the extent of the release reaction (14C-5HT release) induced by ADP, streptokinase, PAF, ristocetin and sodium arachidonate, and also reduced the extent of the synergistic 14C-5HT release induced by combinations of ADP and PAF, ADP and adrenaline and PAF and adrenaline. The various inhibitory effects of ticlopidine were evident after treatment with 250 mg daily but were more pronounced after 250 mg twice daily. All values had returned to normal after 14 days off treatment. Ticlopidine had no effect on serum thromboxane B2 production nor on several parameters of coagulation and fibrinolysis. We conclude that ticlopidine is an effective inhibitor of ADP-induced platelet aggregation and also the platelet aggregation and 14C-5HT release induced in whole blood by a number of platelet agonists and combinations of agonists. These latter effects are probably mainly via a selective effect on ADP. The inhibitory effects of the drug are dose-related.

Effects of concurrent administration of phenylbutazone and flunixin meglumine on pharmacokinetic variables and in vitro generation of thromboxane B2 in mares

Summary Flunixin meglumine and phenylbutazone are nonsteroidal anti-inflammatory drugs commonly used for the management of colic, endotoxemia, and musculoskeletal disorders in equids. Although it is not usually recommended, there appears to be an increasing trend to use nonsteroidal anti-inflammatory drugs in combination to enhance or prolong their effects. Therefore, we studied the effect of concurrent administration of flunixin (1.1 mg/kg of body weight, iv) as flunixin meglumine and phenylbutazone (2.2 mg/kg, iv) on the pharmacokinetics of each drug and on in vitro thromboxane B2 production. Pharmacokinetic variables calculated for each drug when given alone and in combination were similar to those reported. Serum thromboxane B2 production was significantly (P = 0.05) suppressed for 12, 8, and 24 hours after administration of flunixin, phenylbutazone, and the drugs in combination, respectively. These results indicate that although concurrent administration of these drugs at the aforementioned dosages does not alter either drug disposition or clearance, it prolongs their pharmacologic effect.

Platelet reactivity and serum thromboxane B 2 production in whole blood in gestational hypertension and pre-eclampsia

Objective— To determine the nature and extent of changes in platelet reactivity in gestational hypertension and pre-eclampsia (using whole blood techniques which may be more physiological than those previously employed). Design— Cross-sectional observational study. Subjects— 8 normal primigravidae, 16 women with gestational hypertension and 12 women with pre-eclampsia, studied at around 36 weeks gestation. Results— Platelet reactivity (aggregation and release reaction) induced by stimulation with adrenaline was decreased in the pre-eclamptic group. Serum thromboxane B2 production was unchanged in both hypertensive groups compared with the control group. Conclusions— In the context of evidence of platelet activation in pre-eclampsia, our findings are interpreted as reflecting platelet exhaustion.

Platelet reactivity and serum thromboxane B2 production in whole blood in gestational hypertension and pre‐eclampsia

To determine the nature and extent of changes in platelet reactivity in gestational hypertension and pre-eclampsia (using whole blood techniques which may be more physiological than those previously employed). Cross-sectional observational study. 8 normal primigravidae, 16 women with gestational hypertension and 12 women with pre-eclampsia, studied at around 36 weeks gestation. Platelet reactivity (aggregation and release reaction) induced by stimulation with adrenaline was decreased in the pre-eclamptic group. Serum thromboxane B2 production was unchanged in both hypertensive groups compared with the control group. In the context of evidence of platelet activation in pre-eclampsia, our findings are interpreted as reflecting platelet exhaustion.

A longitudinal study of platelet behaviour and thromboxane production in whole blood in normal pregnancy and the puerperium

A longitudinal study of platelet behaviour (platelet aggregation and release reaction) in whole blood and of serum thromboxane B2 production was performed before, during and after normal pregnancy. The response of platelets to arachidonic acid and to adrenaline was significantly increased in the third trimester. Six weeks after delivery, values were still modestly increased but return to non-pregnant values was complete by 12 weeks. Serum thromboxane B2 production was unchanged throughout pregnancy and the puerperium.

Selective inhibition of platelet cyclooxygenase with controlled release, low‐dose aspirin

The hypothesis that slow administration of low doses of aspirin may selectively inhibit platelet cyclooxygenase and thromboxane A2 formation was evaluated using controlled release aspirin formulations. In the first study, doses of either 50, 100, 325 and 1,300 mg of these formulations and 300 mg soluble aspirin were ingested daily by healthy volunteers for one week. In the second study, doses of 5, 10, 25 and 50 mg controlled release aspirin, 50 mg soluble aspirin and 100 mg aspirin and glycine formulation were ingested daily for ten days. Platelet function and urinary prostaglandin production were assessed immediately before and on the seventh day of dosing in both studies and in the second study, repeated on the tenth day of dosing. Platelet function and serum thromboxane B2 production were fully inhibited by all formulations of 50 mg aspirin and above, but not by doses of controlled release aspirin below 50 mg doses. The excretion of urinary 6-keto-PGF1 alpha (a major metabolite of prostacyclin) was significantly reduced at controlled release aspirin doses above 100 mg and at all doses of rapidly absorbed aspirin tested. As no significant reduction in the urinary 6-keto-PGF1 alpha production was observed at doses of controlled release aspirin of 50 and 100 mg and below, it appeared that these doses did not inhibit the systemic vascular cyclooxygenase. These data are consistent with a selective inhibition of platelet function by daily doses of 50 and 100 mg of the controlled release formulation of aspirin.

The effect of CV-4151, a selective inhibitor of thromboxane synthetase, on prostanoid formation and platelet aggregation in humans.

The pharmacokinetics and pharmacologic effects of a potent, selective inhibitor of thromboxane synthetase, CV-4151 [(E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid] on prostanoid formation and platelet aggregation were studied in 42 healthy male volunteers. The drug was well tolerated. After oral administration of 10 to 100 mg of CV-4151, peak plasma levels of 1-6 micrograms/mL were reached in a dose-dependent manner within 1 hour. Elimination followed first-order fashion with elimination half-life of about 1 hour. Serum levels of thromboxane B2 reduced to 4% to 15% of control at 2 hours after drug ingestion dose-dependently. Serum levels of 6-keto-prostaglandin F1 alpha increased to about four to six times basal levels. Platelet aggregation induced by collagen and arachidonate was inhibited in most cases. Such pharmacologic effects outlasted serum drug levels. In repeated administration, stable inhibition of serum thromboxane B2 production and platelet aggregation in proportion to the enhancement of serum 6-keto-prostaglandin F1 alpha production was observed although no drug accumulation was found. These results indicate that CV-4151 may be suitable for clinical trials in cardiovascular diseases in which imbalance between thromboxane and prostacyclin may be involved in the pathogenesis.

Platelet aggregation and thromboxane B2 release in patients with acute myocardial infarction--their relation to coronary patency.

Platelet function in the aortic blood in 39 patients who underwent intracoronary thrombolysis with urokinase was evaluated in the acute stage of myocardial infarction and after 4 weeks. The patients were classified into 2 groups according to the patency of the infarct vessel shown by coronary arteriography before urokinase administration. In the acute stage, 26 patients with completely occluded infarct vessel (group 1) showed a decreased level of platelet aggregation induced by adenosine diphosphate or arachidonic acid as compared with 13 patients with patent infarct vessel (group 2). The platelet aggregation in group 1 increased 4 weeks later and both groups showed similarly enhanced platelet aggregation levels as compared with normal controls. Like platelet aggregation, serum thromboxane B2 production in group 1 was lower than that in group 2 in the acute stage. Plasma thromboxane B2 levels in the aorta in both groups were significantly elevated in the acute stage, and were normalized after 4 weeks. This elevation of thromboxane B2 seems to be due to its washout from the infarct vessel, because plasma thromboxane B2 levels were significantly higher in the great cardiac vein than those in the aorta after successful reperfusion in group 1 or group 2. In conclusion, despite a significant elevation in plasma thromboxane B2 levels, platelet aggregation and serum thromboxane B2 production relatively decrease in patients with totally occluded infarct vessel. The patency of the infarct vessels should be taken into account when evaluating platelet function in acute myocardial infarction.

Plasma concentrations of platelet-specific proteins and serum thromboxane B2 production in response to treatment with dipyridamole. A pilot study of 27 post-myocardial infarction patients

In the present study 27 post-myocardial infarction patients were treated with Persantin capsules (Depot-Kapseln, sustained release form), containing 200 mg dipyridamole, b.i.d. over a period of 3 weeks. Baseline levels for plasma beta-thromboglobulin (BTG), platelet factor 4 (PF4), and serum thromboxane B2 (TXB2) were obtained on day 0 and subsequently on days 1, 3, 5, 7, 14 and 21. The baseline levels for plasma BTG and PF4 as well as for serum TXB2 significantly exceeded those for a control group consisting of healthy subjects. The plasma values for BTG and PF4 remained unchanged during the whole study period. During the first week of study the levels for serum X TXB2 were unchanged; however, on days 14 and 21 the means for TXB2 dropped significantly. There is experimental work to suggest that dipyridamole may exert an inhibitory effect on platelet thromboxane biosynthesis. The present results support this concept.