Nimesulide 90 mg orally twice daily does not influence postoperative morphine requirements after major chest surgery.

BACKGROUND: Cyclooxygenase 2 inhibition has proven analgesic efficacy in a variety of surgical procedures. We postulated that perioperative cyclooxygenase 2 inhibition significantly reduces postoperative morphine requirements after major thoracic surgery and investigated the site of this potential analgesic effect. METHODS: Ninety-two patients participated in this single-center, double-blind, randomized, placebo-controlled, parallel-group trial. Patients between the ages of 18 and 80 yr undergoing a thoracotomy or median sternotomy were randomized to receive either nimesulide or placebo in combination with a standard analgesic regimen perioperatively. Nimesulide was administered orally the evening before surgery and at 12-h intervals for 5 days postoperatively. The primary efficacy variables were morphine consumption and pain scores for the first 48 h postoperatively. The secondary efficacy variable was the effect of nimesulide on cyclooxygenase activity in cerebrospinal fluid (CSF). RESULTS: Pain scores at rest or with movement, and total morphine consumption for the first 48 h postoperatively, were not statistically different between the groups. The mean difference in total morphine consumption up to 48 h postoperatively between the nimesulide and placebo group was a 9.0 mg reduction (95% CI: -28.9 to 10.9 mg) (P = 0.37). Adjusted mean (se) CSF 6-keto-PGF1alpha (6-keto-PGF1alpha) concentrations increased by 54.7 (25.7) pg/mL from preoperatively to Day + 2 postoperatively in the placebo group, whereas adjusted mean (se) CSF 6-keto-PGF1alpha concentration decreased by 0.6 pg/mL (18.2 pg/mL) in the nimesulide group. These changes were not statistically different between the groups (P = 0.095). CONCLUSION: Nimesulide, at a dose of 90 mg twice daily in combination with a standard analgesic regimen, does not influence pain scores, morphine requirements, or CSF prostaglandin levels after major thoracic surgery.

Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers.

BACKGROUND AND PURPOSE: Aspirin resistance may be relatively common and associated with adverse outcome. Meta-analysis has clearly shown that 75 mg plain aspirin is the lowest effective dose; however, it is not known whether the recent increased use of enteric-coated aspirin could account for aspirin resistance. This study was designed to determine whether enteric-coated aspirin is as effective as plain aspirin in healthy volunteers. METHODS: Seventy-one healthy volunteers were enrolled in 3 separate bioequivalence studies. Using a crossover design, each volunteer took 2 different aspirin preparations. Five aspirin preparations were evaluated, 3 different enteric-coated 75-mg aspirins, dispersible aspirin 75 mg and asasantin (25-mg standard release aspirin plus 200-mg modified-release dipyridamole given twice daily). Serum thromboxane (TX) B2 levels and arachidonic acid-induced platelet aggregation were measured before and after 14 days of treatment. RESULTS: All other aspirin preparations tested were inferior to dispersible aspirin (P<0.001) in their effect on serum TXB(2) level. Treatment failure (<95% inhibition serum TXB2 formation) occurred in 14 subjects, none of whom were taking dispersible aspirin. Mean weight for those demonstrating treatment failure was greater than those with complete TXB2 (>99%) inhibition (P<0.001). Using logistic regression analysis an 80-kg subject had a 20% probability of treatment failure. Asasantin was the most potent preparation in terms of inhibition of platelet aggregation. CONCLUSIONS: Equivalent doses of the enteric-coated aspirin were not as effective as plain aspirin. Lower bioavailability of these preparations and poor absorption from the higher pH environment of the small intestine may result in inadequate platelet inhibition, particularly in heavier subjects.

The impact of genetic variation in the region of the GPIIIa gene, on Pl expression bias and GPIIb/IIIa receptor density in platelets.

Some studies have suggested that genetic variability in the glycoprotein (GP) IIIa gene modulates expression of platelet GPIIb/IIIa (alpha(2b)beta(3)). We sought to determine as to whether combinations of genetic variants within the GPIIIa gene (haplotypes) influenced the expression of GPIIIa RNA and protein levels in human platelets. Three promoter polymorphisms, Pl(A1/A2) genotype and platelet receptor densities were determined in 207 acute coronary syndrome (ACS) patients. Allele-specific quantitative reverse transcription-polymerase chain reaction of platelet RNA from Pl(A1/A2) heterozygotes identified a greater expression of Pl(A2) bearing transcripts among heterozygotes. Among the patients studied, the ratio of Pl(A1)/Pl(A2) RNA expression was significantly influenced by promoter haplotype (P < 0.01). However, this effect reflected carriership of rare not common haplotypes (P = 0.2). There was a threefold variation between subjects in the number of GPIIb/IIIa receptors expressed per platelet, although no association between receptor density and the Pl(A2) (P = 0.93) or promoter polymorphisms was demonstrated (-468A, P = 0.52; -425C, P = 0.59; -400A, P = 0.52). Among common haplotypes, Pl(A1)/Pl(A2) RNA expression was negatively correlated with adjusted GPIIb/IIIa receptor density (P = 0.04). The overall trend towards higher expression of Pl(A2) bearing message in Pl(A1/A2) heterozygotes, and the existence of rare haplotypes with more pronounced changes indicate the existence of cis-acting genetic factors that remain to be identified.

Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease.

OBJECTIVES: We investigated whether use of low-dose enteric-coated (EC) aspirin for secondary prevention of cardiovascular events has sufficient bioavailability to achieve complete platelet cyclooxygenase (COX) inhibition in all individuals. BACKGROUND: Aspirin reduces cardiovascular morbidity and mortality in patients with pre-existing vascular disease; however, there is variability in the way individuals respond. Persistent normal platelet function despite therapy, referred to as "aspirin resistance," is associated with an increased risk of major cardiovascular events. METHODS: We studied 131 stable cardiovascular patients between March and September 2002 who were taking 75 mg EC aspirin. Serum thromboxane (TX) B2 levels were assayed as a measure of COX activity. Mean arachidonic acid (AA)-induced platelet aggregation > or =20% was deemed evidence of persistent platelet activity and an incomplete aspirin response. RESULTS: Patients of median age 63 years (61% men) were enrolled. Forty-four percent of patients had elevated serum TX B2 levels (>2.2 ng/ml). Arachidonic acid-induced platelet aggregation occurred more frequently in these patients (21% vs. 3%; p = 0.004). In all cases addition of exogenous aspirin during the assay abolished platelet aggregation. Patient weight and age were significant independent predictors of an incomplete response to EC aspirin (p = 0.025 and p < 0.001, respectively). These patients were also more likely to have a history of myocardial infarction (MI) (p = 0.038). CONCLUSIONS: Many patients who are prescribed low-dose EC aspirin for secondary prevention of cardiovascular events have persistent uninhibited platelet COX activity. Younger and heavier patients and those with a previous MI are most likely to have an inadequate response to treatment.