thromboxane-b2 and 7-hydroxy-5-11-dioxotetranorprostane-1-16-dioic-acid

The renin-angiotensin system plays a critical role in cardiovascular function, but little is known about the effects of specific cyclooxygenase 2 (COX-2) inhibition on this system in healthy humans under physiologic conditions.. Twenty-one healthy female volunteers received, in a randomized, double-blind, crossover study, celecoxib 200 mg twice a day, indomethacin 50 mg three times a day, or placebo for 4 days and a single dose, each, on day 5. On day 5 of each treatment, the following parameters were assessed with subjects in an upright position before and after administration of 20 mg furosemide intravenously: plasma renin activity (PRA), plasma aldosterone, serum and urine electrolytes, and creatinine. Index metabolites of prostanoids were analyzed by gas chromatography-tandem mass spectrometry in 24-hour urine on day 4 and in 2-hour urines before and after furosemide administration.. Baseline and furosemide-stimulated PRA were reduced to a similar degree by celecoxib and indomethacin. Plasma aldosterone and urinary excretion of potassium showed changes consistent with the alteration of PRA. Urinary excretion rates of prostaglandin E(2), (PGE(2)), 7alpha-hydroxy-5, 11-diketotetranor-prosta-1,16-dioic acid (PGE-M), and 2,3-dinor-thromboxane B(2) (TxB(2)) were not reduced by celecoxib, whereas indomethacin led to a decrease of 40%, 45%, and 80%, respectively. Both active treatments inhibited urinary excretion of 2,3-dinor-6-keto-PGF(1alpha) and 6-keto-PGF(1alpha) by 60% and 40%, respectively.. Renin-release in healthy humans with normal salt intake is COX-2 dependent. While COX-1 is critical for renal and systemic PGE(2) production, renal prostacyclin synthesis is apparently COX-2 dependent. Finally, the previously demonstrated shift of the thromboxane-prostacyclin balance toward prothrombotic thromboxane by specific COX-2 inhibition is confirmed.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aldosterone; Body Weight; Celecoxib; Creatinine; Cross-Over Studies; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Diuretics; Female; Furosemide; Humans; Indomethacin; Kidney; Potassium; Prostaglandins; Pyrazoles; Renin; Sodium; Sulfonamides; Thromboxane B2

Meloxicam is a new NSAID with selectivity for the inducible cyclooxygenase (COX-2) in vitro. We compared the effects of therapeutically equivalent doses of meloxicam and indomethacin, a preferential inhibitor of the constitutive cyclooxygenase (COX-1), on platelet aggregation and platelet thromboxane formation, which are exclusively COX-1 dependent, physiological renal, and total body prostaglandin E2 (PGE2) production.. In a randomized cross-over design, 14 healthy female volunteers received meloxicam 7.5 mg per day for 6 days or indomethacin 25 mg three times per day for 3 days; the wash-out period was 5 days, and drug intake was adapted to the menstrual cycle. On the day before treatment and on the last day of each treatment period the following parameters were evaluated: maximum platelet aggregation and thromboxane B2 (TXB2) formation in response to 1.0 mmol/L arachidonic acid; 24-hour urinary excretion of PGE2 and 7 alpha-hydroxy-5, 11-diketo-tetranor-prosta-1, 16-dionic acid (PGE-M), the index metabolites of renal and total body PGE2 synthesis, respectively, were assessed by gas chromatography/tandem mass spectrometry.. Maximum platelet aggregation and TXB2 formation were almost completely inhibited by indomethacin (-87% and -99%, respectively; p < 0.001, each) as compared to control (100%), but remained unaffected by meloxicam (-1% and +4%, respectively). Meloxicam showed no significant effects on urinary PGE2 excretion (-13%) and only slight effects on PGE-M excretion (-22%; p < 0.05), whereas indomethacin reduced urinary PGE2 excretion (-43%; p < 0.05) as well as PGE-M excretion (-36%; p < 0.001).. Our data show, that meloxicam 7.5 mg per day is COX-1 sparing in humans in vivo.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Cross-Over Studies; Cyclooxygenase Inhibitors; Dinoprostone; Female; Humans; Indomethacin; Meloxicam; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Therapeutic Equivalency; Thiazines; Thiazoles; Thromboxane B2

In the present randomized, fourway crossover study we determined the effects of two oral doses each of ketoprofen and ibuprofen on platelet aggregation and prostanoid formation in man.. Twelve healthy female volunteers received for 2 consecutive days, followed by a 5-day drug-free interval, one of the following: ketoprofen 3 x 25 mg per day, or ketoprofen 3 x 50 mg per day, or ibuprofen 3 x 200 mg per day, or ibuprofen 3 x 400 mg per day. The response criteria, determined before and on the 2nd day of each treatment period, were: maximal platelet aggregation in response to 1.0 mmol.l-1 arachidonic acid measured by the method of Born and Cross, thromboxane B2 (TXB2) concentration in platelet-rich plasma after aggregation measured by radioimmunoassay, and PGE-M, the index metabolite of total body prostaglandin E2 (PGE2) production, assessed by gas chromatography/tandem mass spectrometry using 18O2-PGE-M as internal standard.. Platelet aggregation was significantly reduced by ketoprofen 3 x 25 mg per day (-57%) and ketoprofen 3 x 50 mg per day (-85%) as compared to control, whereas ibuprofen 3 x 200 mg per day (-3%) and ibuprofen 3 x 400 mg per day (-22%) had no significant effects. TXB2 synthesis was significantly decreased by ketoprofen 3 x 25 mg per day (-72%), ketoprofen 3 x 50 mg per day (-97%) and ibuprofen 3 x 400 mg per day (-48%) as compared to control; ibuprofen 3 x 200 mg per day did not reduce TXB2 formation significantly (-23%). All four treatments reduced 24-h urinary excretion of PGE-M significantly in the range of -39% (ketoprofen 3 x 25 mg per day) to -53% (ibuprofen 3 x 400 mg per day) without significant differences between treatments.. Our data show that both ketoprofen dosages were more effective in inhibition of platelet aggregation and platelet thromboxane synthesis than ibuprofen in low or high dosage. Total body synthesis of the E-prostaglandins was inhibited by all drug schedules without significant differences between treatments.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Cross-Over Studies; Female; Humans; Ibuprofen; Ketoprofen; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins; Thromboxane B2

In an isotope dilution assay, prostaglandin (PG) E2, 6-keto-PGF1 alpha, thromboxane (Tx) B2 and their metabolites PGE-M (11 alpha-hydroxy-9,15-dioxo-2,3,4,5,20-pentanor-19-carboxyprostano ic acid), 2,3-dinor-6-keto-PGF1 alpha, 2,3-dinor-TxB2 and 11-dehydro-TxB2 were determined in urine by gas chromatography-triple stage quadrupole mass spectrometry (GC-MS-MS). After addition of deuterated internal standards, the prostaglandins were derivatized to their methoximes and extracted with ethyl acetate-hexane. The sample was further derivatized to the pentafluorobenzylesters and purified by thin-layer chromatography (TLC). Three zones were scraped from the TLC plate. The prostanoid derivatives were converted to their trimethylsilyl ethers and the products were quantified by GC-MS-MS. In each run, two or three prostanoids were determined.

Topics: 6-Ketoprostaglandin F1 alpha; Chromatography, Thin Layer; Dinoprostone; Gas Chromatography-Mass Spectrometry; Humans; Prostaglandins; Thromboxane B2