6-ketoprostaglandin-f1-alpha and nimesulide

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.. 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).. 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).. 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.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Analgesics, Opioid; Cyclooxygenase 2 Inhibitors; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Morphine; Pain Measurement; Pain, Postoperative; Prospective Studies; Prostaglandin-Endoperoxide Synthases; Sternum; Sulfonamides; Thoracotomy; Time Factors; Treatment Outcome

Prostaglandins (PGs) generated in the spinal cord may play a major role in pain perception. Consequently, the suppression of spinal cyclooxygenase (COX) and PG formation may contribute to the analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in pain following surgery. Which isoform of COX is responsible for postsurgical pain and, consequently, should be targeted, is unclear.. Prospective randomized blinded study.. University teaching hospital.. Thirty patients undergoing thoracotomy for lobectomy were recruited.. Patients were randomized to receive the COX-2 selective inhibitor nimesulide, 100 mg orally twice daily, or ibuprofen (nonselective), 400 mg orally three times daily, in an open-label study. In addition, there was a randomized control group that received no NSAIDs. Cerebrospinal fluid (CSF) was analyzed for 6-keto-PGF(1)alpha, the principle metabolite of prostacyclin. COX-1 and COX-2 activity was determined by measuring serum thromboxane (TX) B(2) and endotoxin-induced PGE(2) generation in whole blood.. Pain perception was measured by visual analog scores, and blinded assessment of opioid analgesic requirements and expiratory peak flow measurements were performed.. At the doses used, nimesulide was selective for COX-2, while ibuprofen was nonselective based on serum TXB(2) levels. The mean (+/- SEM) levels of 6-keto-PGF(1)alpha in CSF increased following surgery from 32 +/- 4.9 to 127 +/- 29 pg/mL (p < 0.001), and this was suppressed by nimesulide (49 +/- 9.3 pg/mL; p = 0.0025) but not by ibuprofen (122 +/- 35 pg/mL). Pain scores (p < 0.001), morphine requirement (p = 0.0175), and the fall in peak expiratory flow rate (p < 0.001) were significantly lower in the nimesulide group.. Increases in spinal PG synthesis after thoracotomy are repressed by a selective COX-2 inhibitor. This suggests that the inducible COX-2 mediates central PG synthesis, which may be important in the generation of pain, as the use of nimesulide also resulted in significant decreases in postoperative pain perception.

Topics: 6-Ketoprostaglandin F1 alpha; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Ibuprofen; Isoenzymes; Pain, Postoperative; Perception; Pneumonectomy; Prospective Studies; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Spinal Cord; Sulfonamides; Thoracotomy

Patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E syndrome/antenatal Bartter syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E(2), thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase-2 (COX-2) specific inhibitor nimesulide to patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome blocked renal prostaglandin E(2) formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B(2) synthesis resulting from platelet COX-1 activity and complete inhibition of urinary 6-keto-prostaglandin F(1alpha), reflecting endothelial COX-2 activity, indicate preferential inhibition of COX-2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX-2 may play an important pathogenetic role in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Moreover, on the basis of our data we postulate that COX-2-derived prostaglandin E(2) is an important mediator for stimulation of the renin-angiotensin-aldosterone system in the kidney.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Bartter Syndrome; Blood Platelets; Child; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Humans; Indomethacin; Isoenzymes; Kidney; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Sulfonamides; Thromboxane B2

The formation of prostacyclin (PGI(2)), thromboxane (TX) A(2), and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis.. The study population consisted of 42 patients with atherosclerosis who were undergoing surgical revascularization. COX-2 mRNA was detected in areas of atherosclerosis but not in normal blood vessel walls, and there was evidence of COX-1 induction. The use of immunohistochemical studies localized the COX-2 to proliferating vascular smooth muscle cells and macrophages. Twenty-four patients who did not previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours before surgery and then for 3 days. Eighteen patients who were receiving aspirin were continued on a protocol of either aspirin alone or a combination of aspirin and nimesulide. Urinary levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha), metabolites of TXA(2) and PGI(2), respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211+/-533 versus 679+/-63 pg/mg creatinine, P<0.001; 594+/-156 versus 130+/-22 pg/mg creatinine, P<0.05, respectively), as was the level of the isoprostane 8-iso-PGF(2alpha). Nimesulide reduced 2, 3-dinor-6-keto-PGF(1alpha) excretion by 46+/-5% (378.3+/-103 to 167+/-37 pg/mg creatinine, P<0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB(2) before (2678+/-694 to 2110+/-282 pg/mg creatinine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the addition of nimesulide. None of the treatments influenced urinary 8-iso-PGF(2alpha) excretion.. Both COX-1 and -2 are expressed and contribute to the increase in PGI(2) in patients with atherosclerosis, whereas TXA(2) is generated by COX-1.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arteriosclerosis; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Epoprostenol; F2-Isoprostanes; Female; Humans; Isoenzymes; Macrophages; Male; Membrane Proteins; Microscopy, Fluorescence; Muscle, Smooth, Vascular; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Thromboxane A2; Thromboxane B2

To test the effect of selective and non-selective inhibitors of prostaglandin H synthase-2 (PGHS-II) on basal and cytokine-stimulated prostaglandin (PG) production by the immortalized human myometrial cell line, UTLRp16.. UTLRp16 cells were treated with interleukin (IL)-1beta (0.1, 1, 10ng/ml) and tumor necrosis factor (TNF)-alpha (1, 3, 10ng/ml) in the presence or absence of indomethacin, etodolac, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2 (5H)-furanone (DFU) or nimesulide for 16h (1.6-1000nM). PG production was then measured by radioimmunoassay.. IL-1beta and TNF-alpha both stimulated production of PGE(2) and 6-keto-PGF(1alpha) in a concentration-dependent manner. DFU showed the most PGHS-II selectivity with IL-beta-stimulated PG production, with a IC(50)(basal)/IC(50)(stimulated) ratio of 177.8, followed by nimesulide (122.5), etodolac (23.5) and indomethacin (2.7). DFU was not as selective in TNF-alpha stimulated cells (ratio 99.5).. PGHS-II-selective inhibitors may be effective in the prevention of cytokine-driven myometrial PG production associated with preterm labor.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Transformed; Cyclooxygenase Inhibitors; Cytokines; Dinoprostone; Enzyme Inhibitors; Etodolac; Female; Furans; Humans; Indomethacin; Interleukin-1; Prostaglandins; Sulfonamides; Tumor Necrosis Factor-alpha

The initial phase of zymosan-induced peritonitis involves an increase of vascular permeability (peak at 30 min) that is correlated with high levels of vasoactive eicosanoids, namely, prostaglandins (PGI2 and PGE2) of cyclooxygenase-1 origin (as estimated by RT-PCR) and cysteinyl-leukotrienes. Previously, we showed that the increase of vascular permeability can be attributed only partially to mast cells and their histamine, as seen in mast cell-deficient WBB6F1-W/Wv mice. Thus we aimed to identify the major cellular source(s) that mediate vasopermeability, as well as particular vasoactive mediators operating in this model. For this purpose, some mice were selectively depleted of either peritoneal macrophages or mast cells, and/or they were treated with several pharmacologic inhibitors of cyclooxygenase- and lipoxygenase-metabolic pathways. More-over, macrophage-depleted mast cell-deficient WBB6F1-W/Wv mice and their controls (+/+) were used. The macrophage depletion always caused a profound decrease of both vascular permeability and lipid-mediator levels, which was particularly pronounced for leukotrienes, whereas the effects of mast-cell depletion were less severe. The macrophage/mast-cell co-mediation of vasopermeability was also revealed in thioglycolate-induced peritonitis, as well as the macrophage origin of cysteinyl-leukotrienes. Taken together, these findings demonstrate that the resident peritoneal macrophages are in fact the main contributors to the vasopermeability at the early stages of zymosan-induced peritonitis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Leak Syndrome; Capillary Permeability; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cysteine; Diterpenes; Eicosanoids; Enzyme Induction; Ginkgolides; Histamine Release; Indoles; Indomethacin; Isoenzymes; Lactones; Leukotriene C4; Leukotrienes; Lipoxygenase Inhibitors; Macrophages, Peritoneal; Male; Mast Cells; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Nitrobenzenes; Peritonitis; Phospholipid Ethers; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Quinolines; Sulfonamides; Thioglycolates; Zymosan

The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Artery Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Epoprostenol; Female; Indomethacin; Isoenzymes; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin-Endoperoxide Synthases; Receptors, LDL; Sulfonamides; Thromboxane B2

The present study examined the inhibitory profiles of NS-398 and nimesulide against prostaglandin (PG) formation in inflammatory and non-inflammatory sites, and compared them with those of aspirin and indomethacin. In vitro, indomethacin inhibited PGH synthase (PGHS)-1 and PGHS-2 almost equally, while NS-398 and nimesulide inhibited only PGHS-2. NS-398 (1, 10 mg/kg) and nimesulide (3 mg/kg) slowed the rate of plasma exudation and thus the exudate accumulation in rat carrageenin-induced pleurisy. Aspirin (30, 100 mg/kg) and indomethacin (10 mg/kg) also reduced this rate. NS-398 and nimesulide reduced the PGE2 more potently than TXB2 and 6-keto-PGF1 alpha in the exudate. However, aspirin and indomethacin did not exhibit this selectivity. The levels of PGE2 correlated significantly with the plasma exudation rate. Moreover, nimesulide (3 mg/kg) did not affect PGE2 formation in rat stomachs injected with 1 M NaCl solution, while indomethacin (10 mg/kg) reduced it. Thus, NS-398 and nimesulide exhibit different inhibitory profiles from aspirin and indomethacin against PG formation. These results suggest that PGE2 may be produced by PGHS-2 in the inflammatory site, and may play a more prominent role than PGI2 in plasma exudation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Gastric Juice; Indomethacin; Isoenzymes; Male; Membrane Proteins; Nitrobenzenes; Pleurisy; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Sprague-Dawley; Sodium Chloride; Sulfonamides; Thromboxane B2

Pretreatment of mice with lipopolysaccharide for 16 h enhanced the number of acetic acid-induced writhing reactions by 2 to 3-fold. In the peritoneal exudates at 10 min after acetic acid injection, 6-keto-prostaglandin F1alpha was detected as a major prostanoid, and this level increased by several-fold by the pretreatment with lipopolysaccharide. The writhing reaction and the prostaglandin formation were almost completely suppressed by indomethacin. However, the lipopolysaccharide-induced enhancement of writhing reaction and an increment of 6-keto-prostaglandin F1alpha level were diminished by the administration of cyclooxygenase-2-selective inhibitors, such as NS-398, nimesulide, or L-745337, to a level similar to the mice that did not receive lipopolysaccharide. Cyclooxygenase-2 protein in the exudates became detectable at 5-48 h after the lipopolysaccharide-pretreatment. These results suggest that the increased prostaglandin production by cyclooxygenase-2 could be responsible for enhancement of the acetic acid-induced writhing reaction by lipopolysaccharide pretreatment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Enzyme Induction; Exudates and Transudates; Indans; Indomethacin; Isoenzymes; Male; Mice; Mice, Inbred ICR; Nitrobenzenes; Pain; Pain Measurement; Peritoneum; Prostaglandin-Endoperoxide Synthases; Sulfonamides

Rat carrageenin-induced pleurisy was used to clarify the role of prostaglandin H synthase (PGHS)-2 in acute inflammation. Intrapleural injection of 0.2 ml of 2% lambda-carrageenin induced accumulation of exudate and infiltration of leukocytes into the pleural cavity. When PGHS-1 and -2 proteins in the pleural exudate cells were analyzed by Western blot analysis, PGHS-2 was detectable from 1 hr after carrageenin injection. Its level rose sharply, remained high from 3 to 7 hr after injection, and then fell to near the detection limit. PGHS-1 was also detected, but kept almost the same level throughout the course of the pleurisy. Levels of prostaglandin (PG) E2 and thromboxane (TX) B2 in the exudate increased from hour 3 to hour 7, and then declined. Thus, the changes of the level of PGE2 were closely paralleled those of PGHS-2. The selective PGHS-2 inhibitors NS-398, nimesulide and SC-58125 suppressed the inflammatory reaction and caused a marked decrease in the level of PGE2 but not in those of TXB2 and 6-keto-PGF 1 alpha. These results suggest that the PGHS-2 expressed in the pleural exudate cells may be involved in PGE2 formation at the site of inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Azo Compounds; Blotting, Western; Carrageenan; Cell Count; Cells, Cultured; Coloring Agents; Cyclooxygenase Inhibitors; Dexamethasone; Dinoprostone; Excipients; Inflammation; Isoenzymes; Leukocytes; Male; Nitrobenzenes; Pleura; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Thromboxane B2; Trypan Blue