Effects of two preparations of 75-mg extended-release aspirin on platelet aggregation, prostanoids and nitric oxide production in humans.
OBJECTIVE
The lowest dose of aspirin shown to be effective in the secondary prevention of thrombotic accidents is 75 mg/day. Presystemic acetylation of cyclooxygenase and the formation of salicylic acid in the liver are fundamental to ensure optimum antithrombotic effects of aspirin. This study was designed to compare the effects of two forms of extended-release aspirin (at 75 mg/day) on prostanoid and nitric oxide synthesis in healthy volunteers.


METHODS
The participants in this single-blind cross-over study (n = 6) were randomly assigned to receive one of three different formulations: plain-formulated aspirin (PF), extended-release aspirin that released acetylsalicylic acid steadily over 5 h (EX5) or an extended-release formulation that released 49% of the drug during the first 2 h after intake (EX2) and the rest of the dose during the subsequent 5 h. Laboratory analyses were done for platelet aggregation and thromboxane B2 (in whole blood), 6-keto-prostaglandin F1alpha (in leucocytes), neutrophil nitric oxide production and plasma nitrite/ nitrate levels.


RESULTS
The PF and EX2 formulations inhibited platelet aggregation by 97% with no significant difference in effect between the two. In contrast, maximum inhibition of aggregation by the EX5 formulation was only 30%. Similar effects were found for platelet thromboxane production: PF and EX2 led to 99% inhibition, whereas EX5 led to 76% inhibition (P < 0.05). The inhibition of prostacyclin production differed in all three treatments (63% for PF, 40% for EX2 and 24% for EX5). The increase in leucocyte nitric oxide production also differed in all three treatments (1.01-fold the basal value with PF, 1.4-fold with EX5 and 3.6-fold with EX2). Both extended-release formulations maintained high levels of nitric oxide production 24 h after the last dose, whereas in the PF period nitric oxide concentration had returned to basal values after this time. The changes in plasma nitrite concentrations in each period of treatment were similar to those seen for leucocyte nitric oxide.


CONCLUSIONS
The pharmacodynamic profile of the extended-release formulations was better than that of plain-formulated aspirin in terms of thromboxane/prostacyclin balance and nitric oxide production. However, the EX2 formulation inhibited platelet function more effectively than did the EX5 formulation.
de la Cruz
J P
JP
Department of Pharmacology and Therapeutics, School of Medicine, University of Málaga, Spain. jpcruz@uma.es
Guerrero
A
A
González-Correa
J A
JA
Márquez
E
E
Nacle
I
I
Sánchez de la Cuesta
F
F
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000328:Adult; D016718:Arachidonic Acid / Q000097:blood / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage* / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002214:Capsules; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D010979:Platelet Function Tests; D011453:Prostaglandins / Q000097:blood*; D016037:Single-Blind Method
D002214:Capsules; D003692:Delayed-Action Preparations; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D016718:Arachidonic Acid; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D001241:Aspirin; D002118:Calcium