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

Takahashi T, Ogawa Y, Kitaoka K, Tani T, Uemura Y, Taguchi H, Kobayashi T, Seguchi H, Yamamoto H, Yoshida S.

Department of Orthopaedic Surgery, Ehime University School of Medicine, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. takahast m.ehime-u.ac.jp

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15647833&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Rofecoxib for osteoarthritis.

Garner S, Fidan D, Frankish R, Maxwell L.

Department of Community Health Sciences, St George's Hospital Medical School, Cranmer Terrace, Tooting, London, UK, SW17 0RE.

BACKGROUND: Editor's note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. Further information is available at www.vioxx.com.Osteoarthritis is a chronic disease of the joints, characterised by joint pain, stiffness and loss of physical function. Its onset is age-related and occurs usually between the ages of 50 and 60. It is the commonest cause of disability in those aged over 65, with OA of the knee and/or hip affecting over 20 per cent of the elderly population. OBJECTIVES: To establish the efficacy and safety of rofecoxib in the management of OA by systematic review of available evidence. SEARCH STRATEGY: We searched the following databases up to August 2004: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment Database. The bibliographies of retrieved papers and content experts were consulted for additional references. SELECTION CRITERIA: All eligible randomised controlled trials (RCTs) were included. No unpublished RCTs were included in this edition of the review. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers. A validated checklist was used to score the quality of the RCTs. Comparable trials were pooled using fixed effects model. MAIN RESULTS: Twenty-six RCTs were included. The comparators were placebo, diclofenac, ibuprofen, naproxen, nimesulide, nabumetone, paracetamol, celecoxib and Arthrotec. The evidence reviewed indicated that rofecoxib was more effective than placebo (patient global response RR 1.75 95% CI: 1.35, 2.26) but was associated with more adverse events (RR 1.32 95% CI 1.11, 1.56). There were no consistent differences in efficacy between rofecoxib and any of the active comparators at equivalent doses. Endoscopic studies indicated that compared to ibuprofen 800mg three times a day, rofecoxib caused fewer erosions and gastric ulcers at doses of 25mg and 50mg; the difference in duodenal ulcers was evident only at a dose of 25mg. Rofecoxib 50mg also caused more endoscopically observed ulcers greater than rofecoxib 25mg (RR 2.48 CI: 1.21, 5.11). Very few of the trials reported overall rates of GI adverse events although rofecoxib was found to cause fewer GI events than naproxen. Only one of the nine trials comparing rofecoxib to celecoxib reported on the overall rates of GI events and this was a comparison of the higher recommended dose of rofecoxib with the lower recommended dose of celecoxib. Similarly, the three trials in older hypertensive patients that examined the cardiovascular safety of rofecoxib and celecoxib used non-comparable doses; the results of these studies indicated that rofecoxib caused more patients to have oedema and a clinically significant increase in systolic blood pressure. This difference between rofecoxib and celecoxib was not evident in studies conducted in more general populations. AUTHORS' CONCLUSIONS: Rofecoxib was voluntarily withdrawn from global markets in October 2004 therefore there are no implications for practice concerning its use. There remains a number of questions over both the benefits and risks associated with Cox II selective agents and further work is ongoing.

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celecoxib, Celebrex
Celecoxib does not induce convulsions nor does it affect GABAA receptor binding activity in the presence of new quinolones in mice.

Yoshino T, Noguchi M, Okutsu H, Kimoto A, Sasamata M, Miyata K.

Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. yoshino yamanouchi.co.jp

We sought to determine whether celecoxib would induce convulsions when coadministered with new quinolone antimicrobial agents in mice. The oral administration of celecoxib (500 mg/kg) alone or in combination with enoxacin (500 mg/kg), lomefloxacin (1000 mg/kg), ciprofloxacin (1000 mg/kg), or levofloxacin (1000 mg/kg) induced no convulsions in mice. In contrast, some nonsteroidal anti-inflammatory drugs (NSAIDs), fenbufen (200 mg/kg), indomethacin (500 mg/kg), and naproxen (500 mg/kg) induced convulsions in combination with the majority of the new quinolones tested. gamma-Aminobutyric acid (GABA)(A) receptor blockade-mediated neuronal excitation is assumed to be involved in these toxic convulsions. Enoxacin (100 microM) and lomefloxacin (100 microM) only slightly reduced [3H]muscimol binding to GABA(A) receptors in mouse whole brain membrane. However, these reductions were markedly enhanced by the addition of fenbufen (100 microM), indomethacin (100 microM), or naproxen (100 microM). Conversely, celecoxib (100 microM) had no apparent effect on [3H]muscimol binding when applied alone or in combination with enoxacin or lomefloxacin. These results suggest that celecoxib may be a more desirable anti-inflammatory agent with respect to drug interactions with new quinolones compared with some conventional NSAIDs.

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celecoxib, Celebrex
The effects of selective cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, on experimental colitis induced by acetic acid in rats.

El-Medany A, Mahgoub A, Mustafa A, Arafa M, Morsi M.

Department of Pharmacology, College of Medicine, King Saud University, Riyadh 11461, P.O. Box 22452, Saudi Arabia.

Several mediators may be involved in the pathogenesis of inflammatory bowel disease, as well as in experimental colitis. The present work was conducted to investigate the effects of the two selective cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, on experimentally induced colitis in rats. Rectal instillation of acetic acid was used to induce the colitis. Acetic acid treatment caused haemorrhagic diarrhoea and weight loss in rats. Celecoxib (5 mg/kg) or rofecoxib (2.5 mg/kg), when given twice daily by the oral route, reduced the degree of haemorrhagic diarrhoea and the weight loss produced. In addition, they produced a significant reduction in the degree of colonic injury, the rise in myeloperoxidase (MPO) levels, total nitric oxide synthetase (NOS) activity, platelet-activating factor (PAF), histamine levels and prostaglandin E2 levels. In contrast, there was a significant increase in the levels of reduced glutathione (GSH). Thus, the findings of the present study provide evidence that selective cyclooxygenase-2 inhibitors may be beneficial in patients with inflammatory bowel disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15659320&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Anti-inflammatory effects of selective COX-2 inhibitors.

Suleyman H, Demircan B, Karagoz Y, Oztasan N, Suleyman B.

Ataturk University, Medical Faculty, Department of Pharmacology, Erzurum, Turkey. suleyman atauni.edu.tr.

In this study, effects of rofecoxib, celecoxib, nimesulide on the acute phase of inflammation were studied in the carrageenan-induced paw edema model and their influence on the chronic phase of inflammation was evaluated in the cotton pellet granuloma tests. Additionally, effects of these drugs on capillary vascular permeability were examined in the hyaluronidase test and were compared with that of indomethacin (nonselective COX inhibitor). The results of the study demonstrated that rofecoxib, celecoxib, nimesulide, indomethacin at a dose of 10 mg kg(-1) reduced the volume of paw edema by 40.6% (p < 0.05), 21.6% (p < 0.05), 20.3% (p < 0.05), 64.0% (p < 0.05), respectively. Anti-proliferative effect of rofecoxib was of 29%, while those of celecoxib and nimesulide were of 13.5 and 21.2%, respectively. Indomethacin had an anti-proliferative effect of 44.2%. When the drugs were given at a dose of 25 mg kg(-1) rofecoxib, celecoxib, nimesulide reduced carrageenan-induced paw edema by 50.6% (p < 0.004), 27.9% (p < 0.004) and 33.0% (p < 0.004), respectively. Positive control, indomethacin, reduced the paw edema by 86.1% (p < 0.004). As a result, indomethacin, rofecoxib, celecoxib, nimesulide significantly inhibited both acute and chronic inflammation. While indomethacin, celecoxib, nimesulide significantly reduced capillary vascular permeability, the effect of rofecoxib was insignificant. We could not clarify this observation. Further studies are required to enlighten this effect of rofecoxib.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15662090&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib inhibits ureteral contractility and prostanoid release.

Jerde TJ, Calamon-Dixon JL, Bjorling DE, Nakada SY.

Department of Surgery, Division of Urology, University of Wisconsin Medical School, Madison, Wisconsin 53792, USA.

OBJECTIVES: To evaluate the efficacy and potency of clinically available celecoxib for inhibition of ureteral contractility and prostanoid release. We have previously reported that the selective cyclooxygenase (COX)-2 inhibitor NS-398 inhibits ureteral contractility. METHODS: We evaluated the release of prostaglandin (PG) E2, F2alpha, D2, thromboxane B2 (a thromboxane2 metabolite), and 6-keto-PGF1alpha (a prostacyclin metabolite) by gas chromatography-mass spectrometry from porcine ureters in the presence and absence of tumor necrosis factor-alpha (TNF-alpha), a putative cyclooxygenase (COX)-2 inducer. PGE2 and PGF2alpha were the prostanoids released in greatest quantity in response to TNF-alpha. We subsequently measured spontaneous contractility and prostanoid release in porcine ureters treated with 0.1, 1.0, or 10 microM concentrations of indomethacin (nonselective COX inhibitor), NS-398, celecoxib, or 0.1% dimethyl sulfoxide (vehicle) for 2 hours. Ureteral contractility and prostanoid release were measured every 15 minutes after the addition of the various compounds. We also treated ureters with 10 ng/mL TNF-alpha and all three COX inhibitors or dimethyl sulfoxide for 2 and 4 hours and measured the PGE2 and PGF2alpha release. RESULTS: Celecoxib, indomethacin, and NS-398 inhibited ureteral contractility and prostanoid release with similar efficacy and potency. All three compounds also reduced TNF-alpha-induced prostanoid release to control levels at concentrations as low as 0.1 microM. CONCLUSIONS: Our data have indicated that celecoxib and indomethacin inhibit PG release by the ureter to a similar degree, even in the presence of COX-2 induction. Animal experiments and clinical trials evaluating the safety and efficacy of celecoxib for the treatment of symptomatic ureteral obstruction are warranted.

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celecoxib, Celebrex
Effect of Maternal Administration of Selective Cyclooxygenase (COX)-2 Inhibitors on Renal Size, Growth Factors, Proteinases, and COX-2 Secretion in the Fetal Rabbit.

Hartleroad JY, Beharry KD, Hausman N, Stavitsky Y, Asrat T, Modanlou HD.

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Irvine Medical Center, University of California, Orange, Calif., USA.

Background: Selective cyclooxygenase (COX)-2 inhibitors are currently being considered for management of preterm labor. COX-2 is an important regulator of fetal renal growth and function. Its inhibition may lead to congenital oligonephropathy. Objectives: We investigated whether maternal administration of a selective COX-2 inhibitor would adversely affect fetal renal growth. Methods: Three groups of timed pregnant rabbits at 13 days gestation were examined. Group 1 received oral celecoxib (30 mg/kg/day) from 13 to 20 days gestation (Cel-A); group 2 received celecoxib from 13 to 28 days gestation (Cel-B), and group 3 received equivalent volumes of the vehicle from 13 to 28 days gestation. The fetuses were delivered by cesarean section at 29 days gestation. The kidneys were weighed and analyzed for vascular endothelial growth factor (VEGF) and its soluble receptors, matrix metalloproteinase (MMP)-2 and -9, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, COX-2, and total cellular protein levels. Sections from the cortex and medulla were assessed histologically. Results: Fetal kidney size was unaffected. VEGF levels were elevated in the Cel-B group. Soluble VEGF receptors, MMP-2, TIMP-1 and COX-2 levels remained unchanged. MMP-9 levels were suppressed in both treated groups, which resulted in significantly lower MMP-9/TIMP-1 ratios. Although TIMP-2 secretion was enhanced in the Cel-B group, MMP-2/TIMP-2 ratios were unaffected. No significant histological changes were detected. Conclusions: We conclude that maternal administration of therapeutic doses of celecoxib does not adversely affect fetal renal growth. MMP-9 is increased in various nephropathies, but may also have protective effects therefore its suppression by COX-2 inhibitors needs further study. Copyright (c) 2005 S. Karger AG, Basel.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15668523&dopt=Abstract celecoxib, Celebrex