thromboxane-b2 and methyl-salicylate

Oral acetylsalicylic acid (aspirin) is the primary antiplatelet therapy in the treatment of acute myocardial infarction and acute coronary syndrome. Methyl salicylate (MS; oil of wintergreen) is compounded into many over-the-counter antiinflammatory muscle preparations and has been shown to inhibit platelet aggregation locally and to be absorbed systemically.. To assess the ability of topically applied MS to inhibit systemic platelet aggregation for patients who are unable to tolerate oral drug therapy.. A randomized, prospective, blinded, crossover study was conducted in 9 healthy men, aged 30-46 years. All subjects ingested 162 mg of aspirin or applied 5 g of 30% MS preparation to their anterior thighs. There was a minimum 2-week washout period between study arms. Blood and urine were collected at baseline and at 6 hours. An aggregometer measured platelet aggregation over time against 5 standard concentrations of epinephrine, and a mean area under the curve (AUC) was calculated. Urinary metabolites of thromboxane B(2) were measured by a standard enzyme immunoassay. Differences in and between groups at baseline and 6 hours were tested by the Wilcoxon signed-rank test.. Baseline platelet aggregation did not differ significantly between the 2 arms of the study (median AUC [% aggregation(*)min]; binominal confidence intervals): aspirin 183; 139 to 292 versus MS 197; 118 to 445 (p = 0.51). Both aspirin and MS produced statistically significant platelet inhibition; aspirin decreased the AUC from 183; 139 to 292 to 85; 48 to 128 (p = 0.008) and MS decreased the AUC from 197; 118 to 445 to 112; 88 to 306 (p = 0.011). No significant difference was detected between baseline and 6-hour thromboxane levels for either aspirin (p = 0.779) or MS (p = 0.327).. Topical MS and oral aspirin both significantly decrease platelet aggregation in healthy human volunteers.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Area Under Curve; Aspirin; Cross-Over Studies; Double-Blind Method; Epinephrine; Humans; Immunoenzyme Techniques; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Salicylates; Statistics, Nonparametric; Thromboxane B2; Time Factors

Human platelets pre-exposed to arachidonic acid (AA) (0.1-1 mM) or to the endoperoxide analogue U46619 (1-3 microM) and then washed and resuspended, failed to respond with aggregation or secretion to a second challenge by either agonist. The response to thrombin at low (0.04-0.1 u ml-1) but not at high (2.5 u ml-1) concentrations was also inhibited by pre-exposure to AA and U46619. The ability of platelets to synthesize thromboxane (Tx) B2 from AA or upon challenge with thrombin persisted despite platelet desensitization. In the presence of the reversible cyclo-oxygenase (CO) inhibitors methyl salicylate (MS) or L8027, pre-exposure to AA had no effect on subsequent challenge by the same agonist or by U46619, whereas platelet desensitization by pre-exposure to U46619 persisted. However, platelet activation by, and desensitization to AA and U46619, was prevented by trimetoquinol and compound L636499, two thromboxane/endoperoxide receptor antagonists. In contrast to the CO inhibitors, the thromboxane synthetase inhibitor dazoxiben, which in 3 'responders' out of 5 subjects suppressed aggregation, secretion, and Tx formation induced by AA, failed to prevent AA-induced desensitization. Compared to quiescent cells the distances between platelets desensitized after re-exposure to AA were reduced in electron microscopy, but the tight connections associated with aggregated cells were not observed. Degranulation was also not observed and cell morphology resembled that of normal quiescent platelets. In conclusion, (a) AA and U46619 desensitize human platelets at a similar site sensitive to prostaglandin/thromboxane receptor antagonists, and show cross-desensitization; (b) desensitization by AA appears to be mediated by a CO-dependent metabolite, as CO inhibitors prevent desensitization by AA but not to U46619; (c) the failure of dazoxiben to prevent desensitization by AA suggests that a metabolite other than TxA2, possibly the endoperoxides, mediates the phenomenon; (d) desensitization does not involve inactivation of CO or thromboxane synthetase enzymes.

Topics: Adenosine Triphosphate; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cyclooxygenase Inhibitors; Humans; Imidazoles; Indoles; Microscopy, Electron; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Salicylates; Thrombin; Thromboxane B2