Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin.
BACKGROUND
The antithrombotic efficacy of aspirin is attributed to its inhibition of the enzyme prostaglandin G/H synthase, which is necessary for the formation of thromboxane A2 in platelets. Thromboxane A2 is a potent vasoconstrictor and platelet agonist. However, the formation of prostacyclin by vascular endothelium also requires prostaglandin G/H synthase, and prostacyclin exerts opposite effects on platelet function and vascular tone. We wanted to see whether controlled-release aspirin would affect the formation of thromboxane A2 but not prostacyclin by reducing the aspirin concentration that reaches the posthepatic circulation.


METHODS
A controlled-release formulation containing 75 mg of aspirin, designed to release 10 mg per hour, was developed to inhibit prostaglandin G/H synthase in platelets in the prehepatic circulation. The effects of the controlled-release preparation on plasma levels of aspirin and salicylate, serum levels of thromboxane B2, and urinary dinor metabolites of prostacyclin and thromboxane B2 (measured by gas chromatography-mass spectrometry) were compared with those of conventional immediate-release aspirin in normal volunteers. Prostacyclin release was stimulated by intravenous bradykinin.


RESULTS
Steady-state inhibition of serum thromboxane B2 required two to four days and appeared slower with 75 mg of controlled-release than with the same amount of immediate-release aspirin. Maximal inhibition was achieved rapidly by adding a single loading dose of 162.5 mg of immediate-release aspirin to the regimen. Over a 28-day period, suppression of thromboxane A2 with this regimen was comparable to that with immediate-release aspirin taken either as 162.5 mg daily or as 325 mg on alternate days, despite the minimal systemic bioavailability of controlled-release aspirin. Bleeding time was prolonged to a similar degree with each of the three regimens. The five- to sixfold increase in the prostacyclin metabolite induced by bradykinin was depressed by pretreatment for four days with 75 mg of immediate-release aspirin, but not by 75 mg of controlled-release aspirin.


CONCLUSIONS
Maximal inhibition of platelet thromboxane A2 production was sustained during long-term dosing with controlled-release aspirin, whereas basal prostacyclin biosynthesis fell only slightly and systemic synthesis of prostacyclin stimulated by bradykinin was preserved. Controlled-release aspirin may facilitate determination of the clinical importance of preserving prostacyclin during platelet inhibition in humans.
Clarke
R J
RJ
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232.
Mayo
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Price
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FitzGerald
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D000293:Adolescent; D000328:Adult; D001241:Aspirin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D003692:Delayed-Action Preparations; D003864:Depression, Chemical; D004334:Drug Administration Schedule; D011464:Epoprostenol / Q000096:biosynthesis* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D012459:Salicylates / Q000097:blood; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000652:urine
D003692:Delayed-Action Preparations; D012459:Salicylates; D013928:Thromboxane A2; D011464:Epoprostenol; D001241:Aspirin; D001920:Bradykinin