2-3-dinor-6-ketoprostaglandin-f1alpha and Cardiovascular-Diseases

Nonsteroidal anti-inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase-2 (COX-2)-dependent biosynthesis of prostacyclin (PGI(2)). CG100649 is a novel NSAID proposed to inhibit both COX-2 and carbonic anhydrase (CA)-I/-II. We compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX-2. In a controlled, double-blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3-dinor-6-keto-PGF(1α) (PGI-M); the effect of CG100649 was dose-dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX-1-dependent prostanoid formation. CA inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX-2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Asian; Black People; Carbonic Anhydrase Inhibitors; Cardiovascular Diseases; Celecoxib; Cross-Over Studies; Cyclooxygenase 2 Inhibitors; Double-Blind Method; Epoprostenol; Female; Furans; Humans; Male; Middle Aged; Prostaglandin Antagonists; Prostaglandins; Pyrazoles; Risk Assessment; Sulfonamides; Thromboxane B2; White People; Young Adult

Activated platelets have been implicated in both acute thrombus formation and atherogenesis. Because smoking is a risk factor for cardiovascular disease in men and women and male smokers have biochemical evidence of increased platelet activation, we found it of interest to study whether smoking augments platelet activity in women as well.. Data on smoking habits and a urinary sample were obtained from 125 healthy female nonsmokers and an equal number of smokers, stratified by age in five groups from 18 to 59 years old. Urinary samples were analyzed with gas chromatography/mass spectrometry for the 2,3-dinormetabolites of thromboxane A2 (Tx-M), reflecting platelet activity, and prostacyclin (PGI-M), representing platelet/vessel wall interaction. Urinary Tx-M in smokers was higher than in nonsmokers (p < 0.001), increasing with the number of cigarettes smoked per day and with age. In nonsmokers, there was no difference in Tx-M between the age groups. Urinary PGI-M in smokers was higher than that in nonsmokers (p < 0.001) and decreased with age in nonsmokers but not in smokers. There was no difference in Tx-M between previous smokers and lifelong nonsmokers.. The elevated Tx-M in women who smoke cigarettes indicates an increased platelet activity that is dependent on smoking intensity. In parallel, PGI-M is augmented, suggesting that platelet/vessel wall interaction is stimulated. Quitting smoking is an effective means to restore platelet function. We propose that the observed increase in platelet activity in women who smoke cigarettes may be related to subsequent development of cardiovascular disease and that quitting smoking should be considered a high-priority medical target also in this sex.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Age Factors; Cardiovascular Diseases; Female; Gas Chromatography-Mass Spectrometry; Humans; Middle Aged; Platelet Activation; Risk Factors; Smoking; Smoking Cessation; Thromboxane B2