celecoxib, Celebrex
Determination of celecoxib in human plasma and rat microdialysis samples by liquid chromatography tandem mass spectrometry.

Brautigam L, Vetter G, Tegeder I, Heinkele G, Geisslinger G.

Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universitat Frankfurt, Frankfurt am Main, Germany.

Methods for the determination of celecoxib in human plasma and rat microdialysis samples using liquid chromatography tandem mass spectrometry are described. Celecoxib and an internal standard were extracted from plasma by solid-phase extraction with C18 cartridges. Thereafter compounds were separated on a short narrow bore RP C18 column (30 x 2 mm). Microdialysis samples did not require extraction and were injected directly using a narrow bore RP C18 column (70 x 2 mm). The detection was by a PE Sciex API 3000 mass spectrometer equipped with a turbo ion spray interface. The compounds were detected in the negative ion mode using the mass transitions m/z 380-->316 and m/z 366-->302 for celecoxib and internal standard, respectively. The assay was validated for human plasma over a concentration range of 0.25-250 ng/ml using 0.2 ml of sample. The assay for microdialysis samples (50 microl) was validated over a concentration range of 0.5-20 ng/ml. The method was utilised to determine pharmacokinetics of celecoxib in human plasma and in rat spinal cord perfusate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11587350&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database.

Zhao SZ, Reynolds MW, Lejkowith J, Whelton A, Arellano FM.

Pharmacia Corporation, Peapack, New Jersey 07977, USA. sean.z.zhao pharmacia.com

BACKGROUND: Two isoforms of cyclooxygenase (COX) have been identified, both of them inhibited by traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-2 has been associated with the therapeutic effects of NSAIDs, whereas inhibition of COX-1 is believed to be the cause of the adverse gastrointestinal effects associated with NSAID therapy. When administered at therapeutic doses, new COX-2-specific inhibitors inhibit only the COX-2 isoform. OBJECTIVE: This study sought to compare renal safety signals between the COX-2-specific inhibitors rofecoxib and celecoxib, based on spontaneous reports of adverse drug reactions (ADRs) in the World Health Organization/Uppsala Monitoring Centre (WHO/UMC) safety database through the end of the second quarter 2000. METHODS: Disproportionality in the association between a particular drug and renal-related ADR was evaluated using a bayesian confidence propagation neural network method in which a statistical parameter, the information component (IC) value, was calculated for each drug-ADR combination. In this method, an IC value significantly greater than 0 implies that the association of a drug-ADR pair is stronger than background; the higher the IC value, the more the combination stands out from the background. The ratio of actual to expected numbers of ADRs was also used to assess disproportionality. RESULTS: As with traditional NSAIDs, both COX-2-specific inhibitors were associated with renal-related ADRs. However, the adverse renal impact of rofecoxib was significantly greater than that of celecoxib. IC values were significantly different for the following comparisons: water retention (1.97 rofecoxib vs 1.18 celecoxib; P < 0.01); abnormal renal function (2.38 vs 0.70; P < 0.01); renal failure (2.22 vs 1.09; P < 0.01); cardiac failure (2.39 vs 0.48; P < 0.01); and hypertension (2.15 vs 1.33; P < 0.01). In an additional analysis, celecoxib was shown to have a similar renal safety profile to that of diclofenac and ibuprofen. CONCLUSIONS: Based on spontaneous ADR reports in the WHO/UMC safety database at the end of the second quarter 2000, this analysis indicates that rofecoxib has significantly greater renal toxicity than celecoxib or traditional NSAIDs. This negative renal impact may have the potential to increase the risk for serious cardiac and/or cerebrovascular events.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11589261&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Chronotherapy and chronotoxicity of the cyclooxygenase-2 inhibitor, celecoxib, in athymic mice bearing human breast cancer xenografts.

Blumenthal RD, Waskewich C, Goldenberg DM, Lew W, Flefleh C, Burton J.

Garden State Cancer Center, Belleville, New Jersey 07109, USA. rblumenthal.gscancer att.net

PURPOSE: Inhibition of the enzyme cyclooxygenase with celecoxib is cytotoxic in a variety of solid tumor cell lines. Previous work has shown that by charting circadian rhythms, it has been possible to find optimal times to deliver a dose of drug, such that it is most efficacious in killing cancer cells and least harmful to normal tissues. Therefore, we examined the time dependence of toxicity (chronotoxicity) and of antitumor effects (chronotherapy) of celecoxib to determine optimal time of day for dosing with respect to light-dark cycles. EXPERIMENTAL DESIGN: Celecoxib was administered i.p. for 10 days (5 days on, 2 days off, 5 days on) to nude mice bearing s.c. breast xenografts. Body weight, peripheral blood cells, clinical chemistry, and tumor growth were monitored. RESULTS: The highest tolerance (100% survival) was found at 7 HALO and the least occurred at 17 h after light onset (HALO; 10% survival). Chronotherapy at a 20-mg/kg dose varied between the seven HALO evaluated and between the three breast tumors (MCF-7, ZR-75-30, and MDA-MB-468) studied. When the maximum tolerated dose (MTD) of celecoxib was optimized for each HALO, we found that at 7-10 HALO, the MTD was 25 mg/kg, whereas at 17-20 HALO; the MTD was only 10 mg/kg. Tumor regression was observed when dosing was done at 23 HALO to 7 HALO (5 a.m. to 1 p.m.), whereas no therapeutic response was observed when dosing was done at 10-13 HALO (4 p.m. to 7 p.m.), and rapid tumor growth was noted when dosing was done at 17 HALO (11 p.m.). CONCLUSIONS: Tumor growth response to the MTD at each HALO revealed that there was no clear relationship between dose administered and therapeutic response. COX-2 expression was not able to explain either the chronotherapy or the chronotoxicity results obtained.

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celecoxib, Celebrex
Acute gastrointestinal permeability responses to different non-steroidal anti-inflammatory drugs.

Smecuol E, Bai JC, Sugai E, Vazquez H, Niveloni S, Pedreira S, Maurino E, Meddings J.

Small Intestinal Section, Clinical Service, C Bonorino Udaondo Gastroenterology Hospital, del Salvador University, Buenos Aires, Argentina.

BACKGROUND AND AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage both in the upper and lower gastrointestinal tract. New anti-inflammatory drugs have been developed in an attempt to improve their gastrointestinal side effect profile. Our objective was to compare the effect on gastrointestinal permeability of acute equieffective doses of four different NSAIDs; three were designed to reduce gastrointestinal mucosal injury. MATERIALS: Healthy volunteers underwent sugar tests in a randomised fashion, 15 days apart, at: (1) baseline; (2) after two days of 75 mg slow release (microspheres) indomethacin; (3) after two days of 7.5 mg oral meloxicam which preferentially inhibits cyclooxygenase 2; and (4) after two days of 750 mg naproxen. A subgroup of subjects was tested after two days of 200 mg celecoxib. In each test, subjects ingested a solution containing sucrose, lactulose, and mannitol and sucralose, to evaluate gastroduodenal, intestinal, and colonic permeability, respectively. RESULTS: Gastric permeability was significantly affected by naproxen (p<0.05) but not by slow release indomethacin, meloxicam, or celecoxib. Intestinal permeability was significantly increased by the first three NSAIDs (p<0.05) but not by celecoxib. Abnormal lactulose/mannitol ratios were observed in 42% of meloxicam treatments, in 62% during indomethacin, and in 75% of subjects treated with naproxen. Finally, colonic permeability, as measured by sucralose, was not significantly increased by any of the four drugs. CONCLUSION: Our study provides evidence that the newly developed NSAIDs reduce gastric mucosal permeability significantly. However, most produced significant alteration of small intestinal permeability. In contrast, our results suggest that celecoxib seems to exhibit the most desirable gastrointestinal side effect profile.

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celecoxib, Celebrex
COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib.

Grosch S, Tegeder I, Niederberger E, Brautigam L, Geisslinger G.

pharmazentrum frankfurt, Klinikum der Johann Wolfgang Goethe-Universitat Frankfurt, 60590 Frankfurt am Main, Germany.

The regular use of various nonsteroidal anti-inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX-independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX-dependent and COX-independent mechanisms further, we assessed the effects of celecoxib (selective COX-2 inhibitor) and SC560 (selective COX-1 inhibitor) on cell survival, cell cycle distribution, and apoptosis in three colon cancer cell lines, which differ in their expression of COX-2. Both drugs induced a G0/G1 phase block and reduced cell survival independent of whether or not the cells expressed COX-2. Celecoxib was more potent than SC560. The G0/G1 block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin-dependent kinase-1 and an increased expression of the cell cycle inhibitory proteins p21Waf1 and p27Kip1. In addition, celecoxib, but not SC560, induced apoptosis, which was also independent of the COX-2 expression of the cells. In vivo, celecoxib as well as SC560 reduced the proliferation of HCT-15 (COX-2 deficient) colon cancer xenografts in nude mice, but both substances had no significant effect on HT-29 tumors, which express COX-2 constitutively. Thus, our in vitro and in vivo data indicate that the antitumor effects of celecoxib probably are mediated through COX-2 independent mechanisms and are not restricted to COX-2 over-expressing tumors.

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celecoxib, Celebrex
Formation and antiproliferative effect of prostaglandin E(3) from eicosapentaenoic acid in human lung cancer cells.

Yang P, Chan D, Felix E, Cartwright C, Menter DG, Madden T, Klein RD, Fischer SM, Newman RA.

Pharmaceutical Development Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77054, USA.

We investigated the formation and pharmacology of prostaglandin E(3) (PGE(3)) derived from fish oil eicosapentaenoic acid (EPA) in human lung cancer A549 cells. Exposure of A549 cells to EPA resulted in the rapid formation and export of PGE(3.) The extracellular ratio of PGE(3) to PGE(2) increased from 0.08 in control cells to 0.8 in cells exposed to EPA within 48 h. Incubation of EPA with cloned ovine or human recombinant cyclooxygenase 2 (COX-2) resulted in 13- and 18-fold greater formation of PGE(3), respectively, than that produced by COX-1. Exposure of A549 cells to 1 microM PGE(3) inhibited cell proliferation by 37.1% (P < 0.05). Exposure of normal human bronchial epithelial (NHBE) cells to PGE(3), however, had no effect. When A549 cells were exposed to EPA (25 microM) or a combination of EPA and celecoxib (a selective COX-2 inhibitor), the inhibitory effect of EPA on the growth of A549 cells was reversed by the presence of celecoxib (at both 5 and 10 microM). This effect appears to be associated with a 50% reduction of PGE(3) formation in cells treated with a combination of EPA and celecoxib compared with cells exposed to EPA alone. These data indicate that exposure of lung cancer cells to EPA results in a decrease in the COX-2-mediated formation of PGE(2), an increase in the level of PGE(3), and PGE(3)-mediated inhibition of tumor cell proliferation.

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celecoxib, Celebrex
Celecoxib, a selective cyclo-oxygenase-2 inhibitor reduces the severity of experimental colitis induced by dinitrobenzene sulfonic acid in rats.

Cuzzocrea S, Mazzon E, Serraino I, Dugo L, Centorrino T, Ciccolo A, Sautebin L, Caputi AP.

Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valera, Gazzi, 98100, Messina, Italy. salvator www.unime.it

Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, upregulation of the expression of intercellular adhesion molecule 1 (ICAM-1) and upregulation of P-selectin in the colon. Here, we investigate the effects of the selective cyclo-oxygenase-2 inhibitor, celecoxib, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhoea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology, as well as an increase in myeloperoxidase activity in the mucosa) was associated with upregulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed intense staining in the inflamed colon. Celecoxib (5 mg/kg twice a day orally) significantly reduced the degree of hemorrhagic diarrhoea and the weight loss caused by administration of DNBS. Celecoxib also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that a selective cyclo-oxygenase-2 inhibitor celecoxib reduces the degree of colitis caused by DNBS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11716847&dopt=Abstract celecoxib, Celebrex