Effects Of Cyclooxygenase Research Articles

Effect of cyclooxygenase on “window of implantation” in mouse

The major determinants of uterine receptivity are the ovarian progesterone and estrogen hormones, respectively. Different prostaglandins (PGs) have been elucidated in reproduction and also in this process of implantation in various ways. The blastocyst undergoes implantation on the uterine epithelium in defined hormone prepared period known as “implantation window”. However, any definitive role of PGs in the window of receptivity remains elusive. It is demonstrated herein that selective COX1 inhibitor (SC560) and selective COX2 inhibitor (nimesulide) separately had no significant effect on blastocyst implantation while combination of both inhibitors in lower dose showed partial delay in implantation by more than 24 h and became implanted beyond the window of implantation, i.e. on D6 but these implantation sites were significantly reduced on D10 and the pregnancy is lost in significant number. However, the higher doses of inhibitors in combination completely prevented implantation. Embryos retrieved from these treated mice showed significantly lower number of embryonic cells (77±3.3 and 65.2±3.9) than the optimum number of embryonic cells (93.4±2.6). The lower doses of both the inhibitors reduced uterine PGE 2 and PGI 2 content on D5 but did not inhibit as efficiently as higher doses. In addition, our immunohistochemistry result shows that there was no COX1 and COX2 localization on D5 of treated mice but COX2 begins expressing on D6 like normal D5 of pregnancy. Therefore, we can conclude that embryos implanted after the delay showed defective post-implantation development because of lower number of embryonic cells of implanting blastocyst and implantation beyond the proper time in window of receptivity.

Effects of cyclooxygenase (COX) inhibition on memory impairment and hippocampal damage in the early period of cerebral hypoperfusion in rats

Chronic cerebral hypoperfusion is related to neurological disorders and contributes to a cognitive decline. Its experimental model in rats is permanent, bilateral common carotid artery occlusion. The cyclooxygenase (COX) system plays a pivotal role in the evolution of ischemic brain damage. Several COX inhibitors have proved to be neuroprotective in stroke models. We set out to characterize the effects of COX inhibitors in rats with permanent cerebral hypoperfusion. Some of the animals were exposed to two-vessel occlusion (n=72), while the others served as sham-operated controls (n=54). This was followed by a 3-day post-treatment with the nonselective COX inhibitor indomethacin (3 mg/kg) or with the selective COX-2 inhibitor NS-398 (15 mg/kg) or with the solvent. Some groups of the animals were sacrificed after 3 days, while the remainder were tested in the Morris watermaze for 5 days, and were sacrificed after 2 weeks. Neurons in the hippocampus were subjected to immunocytochemical labeling with cresyl violet, the dendrites with microtubule-associated protein-2, astrocytes with glial fibrillary acidic protein and microglia activation with OX-42 antibody. Two-vessel occlusion induced a learning impairment, mild neuronal damage, marked dendritic injury and moderate astrocytic reaction in the hippocampus. NS-398, but not indomethacin improved the survival rate and abolished the learning disability. However, both drugs increased the proportion of animals displaying neuronal damage. Glial markers revealed a time-dependent elevation in both the sham and the two-vessel occluded group, and were unaffected by the treatments. In summary, NS-398 prevented the hypoperfusion-induced memory impairment, but not by protecting the hippocampal neurons.

Postoperative Ketorolac Tromethamine Use in Infants Aged 6–18 Months: The Effect on Morphine Usage, Safety Assessment, and Stereo-Specific Pharmacokinetics

Nonsteroidal antiinflammatory drugs have been useful for treating postoperative pain in children. The only parenteral nonsteroidal antiinflammatory drug currently available in the United States is ketorolac tromethamine with cyclooxygenase-1 and cyclooxygenase-2 effects. Information on the pharmacokinetics of ketorolac in infants is sparse, making dosing difficult. Ketorolac is administered as a racemic mixture with the S(-) isomer responsible for the analgesic effect. In this study, we describe the population pharmacokinetics of ketorolac in a group of 25 infants and toddlers who received a single IV administration of racemic ketorolac and evaluate the potential influence of patient covariates on ketorolac disposition. In this double-blind, placebo-controlled study, ketorolac pharmacokinetic, safety, and analgesic effects were studied in 37 infants and toddlers (aged 6-18 mo) postoperatively. On postoperative day 1, infants were randomized to receive placebo, 0.5, or 1 mg/kg ketorolac as a 10-min IV infusion. Blood samples were collected up to 12-h after dosing. The data were analyzed using noncompartmental and compartmental (nonlinear mixed-effects model) means. The patient covariates, including body weight, age, and surgical procedure, were analyzed in a stepwise fashion to identify their potential influence on ketorolac pharmacokinetics. The data were best described by a two-compartmental model. Inclusion of covariates did not significantly decrease the nonlinear mixed-effects model objective function values and between-subject variability in the pharmacokinetic parameters of nested models. The mean and standard error of the estimates of the R(+) isomer were central volume of distribution 1200 +/- 163 mL (coefficient of variation of interindividual variability, 13.6%), peripheral volume of distribution 828 +/- 108 mL (13.0%), clearance from the central compartment 7.52 +/- 0.7 mL/min (9.3%), and extrapolated elimination half-life 238 +/- 48 min. Those of the S(-) isomer were 2320 +/- 34 (14.6%), 224 +/- 193 mL (86.2%), 45.3 +/- 5.5 mL/min (12.1%), and 50 +/- 42 min respectively. Dosing simulations, using population pharmacokinetic parameters, showed no accumulation of S(-) ketorolac but steady increases in R(+) ketorolac. Safety assessment showed no adverse effects on renal or hepatic function tests, surgical drain output, or continuous oximetry between placebo and ketorolac groups. Cumulative morphine administration showed large interpatient variability and was not different between groups. The stereo-isomer-specific clearance of ketorolac in infants and toddlers (aged 6-18 mo) shows rapid elimination of the analgesic S(-) isomer. No adverse effects on surgical drain output, oximetry measured saturations, renal or hepatic function tests were seen. Simulation of single dosing at 0.5 or 1 mg/kg every 4 or 6 h does not lead to accumulation of S(-) ketorolac, the analgesic isomer, but does result in increases in R(+) ketorolac. Shorter dose intervals may be needed in infants older than 6 mo.

Effects of cyclooxygenase (COX) and nitric oxide (NO) in radiocontrast‐induced nephropathy (RCN)

Radiocontrast-induced nephropathy (RCN) is a well-known cause of acute renal failure. However, the pathogenesis of RCN has remained poorly understood. In the present study we determined the roles of cyclooxygenase (COX) and nitric oxide (NO) in RCN by administering the radiocontrast agents iothalamate or iomeprol (4ml/kg as bolus injection) to mice deficient in COX-1 (COX-1−/−), COX-2 (COX-2 −/−), eNOS (eNOS−/−), or bNOS (bNOS−/−) and monitoring total renal blood flow (RBF) as well as superficial (SBF) and deep renal cortical blood flow (DBF). At 90 minutes after the injection, both iothalamate and iomeprol caused decreases of RBF, SBF and DBF in all mice with effects being particularly strong in eNOS −/− and COX-2 −/− mice. Since recent reports showed that renal tubular cell apoptosis is a feature of RCN, we determined an apoptotic marker in kidneys after treatment with either iothalamate or iomeprol. 24 hours after the injection we collected urine and serum samples, and utilized in situ terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining to detect apoptosis in fixed kidneys. Degrees of apoptosis in the renal medulla were more severe in eNOS −/− and COX-2 −/− than wild type mice. Especially in the renal papilla of COX-2 −/− mice apoptotic cells amounted to over 50% in the iothalamate injection group. Nevertheless, no significant differences of serum creatinine were observed between mouse strains. These findings suggest that COX and NO strongly affect progression of RCN. COX-2 protects against the papillary toxicity of radiocontrast agents.

Mechanisms of adrenosensitivity in capsaicin induced hyperalgesia

It is well known that iontophoresis of norepinephrine in capsaicin treated skin is followed by an increase in thermal hyperalgesia. It is unclear if this action on nocicepitive afferents involves the release of prostaglandins. The aim of the present study was to determine: (1) the effect of norepinephrine iontophoresis on spontaneous and evoked pain in the human skin after topical application of capsaicin; (2) the effect of cyclooxygenase (COX) inhibition on changes in pain perception induced by norepinephrine application. Methods Ten volunteers were included in the study. Iontophoresis of norepinephrine or saline was performed in a randomized cross over design on the volar aspect of the forearm after topical application of capsaicin. In the second part of the study single iv. injections of saline or acetylsalicylic acid were performed in a randomized double blind cross over design. After the injection norepinephrine iontophoresis was performed on the skin treated with topical capsaicin. Spontaneous pain, mechanical hyperalgesia as well as warm and heat pain thresholds were measured before and after each iontophoresis. Results Norepinephrine did enhance spontaneous pain and mechanical and thermal hyperalgesia in capsaicin treated skin. Inhibition of COX I and II had no effect on the norepinephrine induced changes in pain perception. Conclusion The results do not support the assumption that in human skin sensitized by topical capsaicin application of norepinephrine acts on nociceptive afferents via the release of prostaglandins. Thus, a direct action of norepinephrine on adrenergic receptors in the membrane of the afferent fibers is most likely.

Review: Rofecoxib increases renal events and arrhythmia, but a COX-2-inhibitor class effect does not exist

Source Citation Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA. 2006;296:1619-32. 16968832

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials

Is elevated cardiovascular risk a class effect of cyclo-oxygenase 2 inhibitors?

Is elevated cardiovascular risk a class effect of cyclo-oxygenase 2 inhibitors?

P-832: Prostaglandin E2 (PGE2) up regulates epidermal growth factor- like factors biosynthesis in human granulosa cells: New insights of the coordination between PGE2 and luteinizing hormone in ovulation

To evaluate whether PGE2 induces amphiregulin (Ar) and epiregulin (Ep) biosynthesis in human granulosa cells in a similar way to luteinizing hormone (LH), as well as the effect of cyclooxygenase-2 (COX-2) inhibition on Ar and Ep biosynthesis.

Cyclooxygenase-2 inhibition normalizes arterial blood pressure in CYP1A1-REN2 transgenic rats with inducible ANG II-dependent malignant hypertension

The present study was performed to determine the effects of cyclooxygenase (COX)-1 and COX-2 inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats (n = 7) were fed a normal diet containing the aryl hydrocarbon, indole-3-carbinol (I3C; 0.3%), for 6-9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats during control conditions, following administration of the COX-2 inhibitor nimesulide (3 mg/kg iv), and following administration of the nonspecific COX inhibitor meclofenamate (5 mg/kg iv). Rats induced with I3C had higher MAP than noninduced rats (n = 7; 188 +/- 6 vs. 136 +/- 4 mmHg, P < 0.01). There was no difference in renal plasma flow (RPF) or glomerular filtration rate (GFR) between induced and noninduced rats. Nimesulide elicited a larger decrease in MAP in hypertensive rats (188 +/- 6 to 140 +/- 8 mmHg, P < 0.01) than in normotensive rats (136 +/- 4 to 113 +/- 8 mmHg, P < 0.01). Additionally, nimesulide decreased GFR (0.9 +/- 0.13 to 0.44 +/- 0.05 ml.min(-1).g(-1), P < 0.05) and RPF (2.79 +/- 0.27 to 1.35 +/- 0.14 ml.min(-1).g(-1), P < 0.05) in hypertensive rats but did not alter GFR or RPF in normotensive rats. Meclofenamate further decreased MAP in hypertensive rats (to 115 +/- 10 mmHg, P < 0.05) but did not decrease MAP in normotensive rats. Meclofenamate did not alter GFR or RPF in either group. These findings demonstrate that COX-1- and COX-2-derived prostanoids contribute importantly to the development of malignant hypertension in Cyp1a1-Ren2 transgenic rats. The data also indicate that COX-2-derived vasodilatory metabolites play an important role in the maintenance of RPF and GFR following induction of malignant hypertension in Cyp1a1-Ren2 transgenic rats.

005 The effect of cyclooxygenase (COX) enzyme blockers on the implantation and outgrowth rates of three dimensional endometriosis and endometrial cancer cells in vitro

005 The effect of cyclooxygenase (COX) enzyme blockers on the implantation and outgrowth rates of three dimensional endometriosis and endometrial cancer cells in vitro

Decrease of Endothelin Receptor Subtype ETB and Release of COX-Derived Products Contribute to Endothelial Dysfunction of Porcine Epicardial Coronary Arteries in Left Ventricular Hypertrophy

Alterations in the regulation of coronary circulation play a major role in the enhanced susceptibility to ischemic injury of the myocardium in left ventricular hypertrophy (LVH). The present study was designed to assess the role of endothelium-dependent contracting factors and endothelin receptors in the coronary endothelial dysfunction in LVH, occurring 2 months after aortic banding in a swine model. Hemodynamic and morphologic analyses were performed in LVH and control groups. Vascular reactivity studies were performed in rings from control and aortic banding groups to assess the contribution of endothelin (ET-1) receptor subtypes to the contraction induced by ET-1 and IRL-1620 (an ETB receptor agonist), with and without endothelium. The effects of cyclooxygenase (COX)-derived products induced by ET-1, serotonin (5-HT), and bradykinin (BK) were evaluated, with or without indomethacin (a COX antagonist). ET-1 receptor density was assessed by confocal microscopy and Western blot experiments. The wall-to-lumen ratio, determined in digital planimetry, was increased in the LVH group with no significant changes in coronary perfusion pressures. There was a significant increase in contractions to ET-1 in the LVH group, which were reduced by exposure to indomethacin and daltroban (thromboxane A2 [TXA2] receptor antagonist). Relaxations to 5-HT and BK were improved by indomethacin in the LVH group. There was no significant change in ETA receptor density (3.113 +/- 0.389 vs 3.594 +/- 0.314) but a decrease in ETB receptor density (6.435 +/- 0.265 vs 4.588 +/- 0.089; P < 0.001) in the LVH group. The coronary endothelial dysfunction of swine epicardial coronary arteries in LVH secondary to 2 months of aortic banding involves both relaxing and contracting factors. ETA receptors and COX-derived products are preferentially implicated in the increased contractions to ET-1. Strategies aimed at decreasing ET-1 effects with ET-1 antagonists selective for ETA receptors could improve the coronary endothelial dysfunction in LVH.

Effects of Introducing Silicon Isosteres in COX-2 Inhibitors: A Preliminary In Silico Evaluation

Since the discovery that the anti-inflammatory effects of cyclooxygenase (prostaglandin endoperoxide H(2) synthetase; COX) inhibitors were dependent on their selectivity for the inducible COX-2 isoform over the constitutive COX-1, many efforts have been devoted towards the design of compounds displaying improved COX-2 selectivity. Classical bioisosteres such as CH-CF and CH(2)-S/O substitutions have been extensively used in the design of the classical COX-2 inhibitors, although silicon isosteres have been so far overlooked. The replacement of a carbon by a silicon atom can have beneficial effects in this particular family of compounds, because the increased bond lengths and altered bond angles brought by the sila-substitution might modify their binding mode to the COX enzymes. In order to evaluate such possible benefits, several well-characterized model inhibitors were selected and docked in the murine COX-2 and COX-1 binding sites. The binding energies for the interaction of each model compound with the respective isoenzymes were derived from the docking data. As in previous publications, these were found to correlate closely (r(2) = 0.66 and 0.75 for COX-2 and COX-1, respectively) with experimental inhibitory activities towards the recombinant enzymes gathered from the literature. These relationships allowed the prediction of the inhibitors activity towards both enzyme isoforms, which further permitted the prediction of their selectivity for COX-2 with an acceptable accuracy (cross-validated squared correlation coefficient q(2) = 0.64). These model compounds were theoretically modified by substituting selected carbon atoms by an sp(3) silicon, and further docked in both COX-2 and COX-1 binding sites in order to derive their predicted inhibitory activity for both isoforms. Except in a few cases, the sila-substitution did not significantly increase the inhibitory activity towards COX-2. In most cases however, it produced a significant decrease in the inhibitory activity towards COX-1. These results indicate that isosteric sila-substitutions could be of value in the design of COX inhibitors with improved selectivity for COX-2.

The Effects of Cyclooxygenase-2 [COX-2] Inhibitors and Nonsteroidal Anti-inflammatory Therapy on 24-Hour Blood Pressure in Patients With Hypertension, Osteoarthritis, and Type 2 Diabetes Mellitus—Correction

The Effects of Cyclooxygenase-2 [COX-2] Inhibitors and Nonsteroidal Anti-inflammatory Therapy on 24-Hour Blood Pressure in Patients With Hypertension, Osteoarthritis, and Type 2 Diabetes Mellitus—Correction

Selective COX-2 inhibitor regulates the MAP kinase signaling pathway in human osteoarthritic chondrocytes after induction of nitric oxide

The purpose of this study was to examine the effect of cyclooxygenase-2 (COX-2) inhibitors on the mitogen-activated protein (MAP) kinase signaling pathway and synthesis of glucosaminoglycan after nitric oxide (NO) induction in articular human chondrocytes. After NO induction, the cells were divided into three groups that were treated with either ethanol (control); a selective COX-2 inhibitor (Celecoxib), or no additive, and evaluated. There were no differences in the effect of the selective COX-2 inhibitor on mitochondrial membrane potential or Annexin V levels. However, Celecoxib significantly decreased prostaglandin E2 (PGE2) production. Celecoxib also decreased the phosphorylation state of p38 and p44/42 of MAP kinase. The ratio of chondroitin-6 sulfate (C6S)/C4S was increased in response to the exposure to Celecoxib. Celecoxib did not affect apoptosis, but decreased the activation of MAP kinase in osteoarthritic chondrocytes after NO induction. NO-induced OA chondrocytes were associated with the p38 and the p44/42 MAPK signaling pathways, in a pathway that is distinct from PGE2-mediated apoptosis.

The role of cyclooxygenase inhibition in the effect of α-melanocyte-stimulating hormone on reactive oxygen species production by rat peritoneal neutrophils

The effect of α-MSH on reactive oxygen species (ROS) production by rat peritoneal neutrophils and the effect of cyclooxygenase (COX) inhibition were investigated using the chemiluminescence (CL) technique. Cells were obtained by peritoneal lavage 4 h after administration of oyster glycogen to rats and were stimulated with lipopolysaccharide (LPS) from Salmonella enderitidis and phorbol 12-myristate 13-acetate (PMA). The increasing concentrations of α-MSH (10 –12–10 –6 M) were added to stimulated cells alone or along with the COX inhibitors indomethacin, ketorolac or nimesulide (10 −8–10 −5 M). Luminol and lucigenin CL levels were significantly increased in cells stimulated with LPS and PMA compared to unstimulated ones. α-MSH significantly reduced lucigenin CL values and this effect was completely reversed in the presence of indomethacin (10 −8 and 10 −7 M). In conclusion, α-MSH inhibits the production of superoxide radicals by activated rat peritoneal neutrophils and COX contributes to this effect.

Effect of cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors on short-chain fatty acids induced tight junction permeability changes in intestinal monolayer cells

Effect of cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors on short-chain fatty acids induced tight junction permeability changes in intestinal monolayer cells

Effects of cyclooxygenase-2 on angiogenesis in pancreatic carcinoma

Effects of cyclooxygenase-2 on angiogenesis in pancreatic carcinoma

Differential effects of cyclooxygenase and nitric oxide inhibition on endothelium-dependent responses in coronary arteries from juvenile and adult male pigs

Differential effects of cyclooxygenase and nitric oxide inhibition on endothelium-dependent responses in coronary arteries from juvenile and adult male pigs