celecoxib, Celebrex
The cyclo-oxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca2+-ATPases: a plausible link with its anti-tumour effect and cardiovascular risks.

Johnson AJ, Hsu AL, Lin HP, Song X, Chen CS.

Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington 40536-0082, USA.

Substantial evidence indicates that the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib, a widely prescribed anti-inflammatory agent, displays anti-tumour effect by sensitizing cancer cells to apoptosis. As part of our effort to understand the mechanism by which celecoxib mediates apoptosis in androgen-independent prostate cancer cells, we investigated its effect on intracellular calcium concentration ([Ca(2+)](i)). Digital ratiometric imaging analysis indicates that exposure of PC-3 cells to celecoxib stimulates an immediate [Ca(2+)](i) rise in a dose- and time-dependent manner. Kinetic data show that this Ca(2+) signal arises from internal Ca(2+) release in conjunction with external Ca(2+) influx. Examinations of the biochemical mechanism responsible for this Ca(2+) mobilization indicate that celecoxib blocks endoplasmic reticulum (ER) Ca(2+)-ATPases. Consequently, inhibition of this Ca(2+) reuptake mechanism results in Ca(2+) mobilization from ER stores followed by capacitative calcium entry, leading to [Ca(2+)](i) elevation. In view of the important role of Ca(2+) in apoptosis regulation, this Ca(2+) perturbation may represent part of the signalling mechanism that celecoxib uses to trigger rapid apoptotic death in cancer cells. This Ca(2+)-ATPase inhibitory activity is highly specific for celecoxib, and is not noted with other COX inhibitors tested, including aspirin, ibuprofen, naproxen, rofecoxib (Vioxx), DuP697 and NS398. Moreover, it is noteworthy that this activity is also observed in many other cell lines examined, including A7r5 smooth muscle cells, NIH 3T3 fibroblast cells and Jurkat T cells. Consequently, this Ca(2+)-perturbing effect may provide a plausible link with the reported toxicities of celecoxib such as increased cardiovascular risks in long-term anti-inflammatory therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12076251&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Incidence of outpatient physician claims for upper gastrointestinal symptoms among new users of celecoxib, ibuprofen, and naproxen in an insured population in the United States.

Goldstein JL, Zhao SZ, Burke TA, Palmer R, von Allmen H, Henderson SC.

Department of Medicine, Section of Digestive Diseases and Nutrition, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

OBJECTIVE: The aim of this study was to compare the risk of outpatient medical claims for UGI symptoms among new users of celecoxib versus ibuprofen, and naproxen. METHODS: The study was conducted using LifeLink, an insurance claims database of approximately 1.8 million employees, dependents, and retirees in the United States. Patients newly treated with a prescription of celecoxib, ibuprofen, or naproxen between June 1, 1999, and June 30, 2001, were included. A patient with an upper GI (UGI) symptom was any individual with an outpatient physician claim for dyspepsia (ICD-9 = 536.8), abdominal pain (789.0), or nausea/vomiting (787.0). Incidence was determined using person-time analysis. Multivariate analyses were conducted using Poisson and Cox regression models. RESULTS: The cohort consisted of patients prescribed celecoxib (n = 68,939), ibuprofen (n = 71,456), or naproxen (n = 50,014). At baseline, celecoxib users were older and more likely to have a history of UGI or cardiovascular conditions. The incidence rate of any UGI symptom was 0.46 per 1,000 patient-days for celecoxib, 0.70 for ibuprofen, and 0.62 for naproxen. After adjusting for confounding factors using Poisson regression, the ibuprofen rate was 48% higher than the celecoxib rate (incidence rate ratio (IRR) = 1.48; 95% CI = 1.39-1.58; p < 0.001), whereas the naproxen rate was 40% higher (IRR = 1.40; 95% CI = 1.31-1.49; p < 0.001). The association between drug use and UGI symptoms was confirmed by Cox regression analysis; the hazard ratios were 1.21 (95% CI = 1.13-1.29; p < 0.001) for ibuprofen and 1.15 (95% CI = 1.07-1.23; p < 0.001) for naproxen relative to celecoxib. Younger age, female sex, medical history of UGI, cardiovascular and renal conditions, and higher baseline average healthcare expenditures for the 12-month period preceding the index prescription were also significantly associated with an increased incidence of UGI symptoms. CONCLUSIONS: Celecoxib use is associated with a significantly decreased risk of outpatient physician claims for UGI symptoms compared with commonly used prescription nonspecific nonsteroidal anti-inflammatory drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14687808&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Selective COX-2 inhibition prevents proinflammatory cytokine-induced cartilage damage.

Mastbergen SC, Lafeber FP, Bijlsma JW.

Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

OBJECTIVES: This study evaluated the in vitro effect of the selective cyclooxygenase-2 (COX) inhibitor celecoxib on cartilage matrix turnover under normal and inflammatory conditions. METHODS: Healthy human articular cartilage tissue alone, in co-culture with peripheral blood mononuclear cells (PBMC) or in the presence of interleukin 1 (IL-1beta) plus tumour necrosis factor alpha (TNF-alpha) was cultured for 7 days in the presence of celecoxib. Changes in cartilage matrix turnover were measured. RESULTS: No direct effects of celecoxib on healthy normal cartilage were found. Both PBMC and IL-1beta plus TNF-alpha induced strong inhibition of cartilage proteoglycan synthesis and significant enhancement of the release of proteoglycans, diminishing proteoglycan content. Celecoxib was able to reverse these adverse effects up to complete normalization. CONCLUSIONS: The results suggest that, under the influence of inflammation, COX-2 is up-regulated, which results in disturbance of cartilage matrix turnover. Celecoxib, by diminishing COX-2 activity, prevents these adverse effects without having a direct effect on healthy cartilage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12096231&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2 inhibitor celecoxib inhibits promotion of mammary tumorigenesis in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids.

Lu S, Zhang X, Badawi AF, El-Sohemy A, Archer MC.

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Fitzgerald Building 150 College Street, Ont. M5S 3E2, Canada.

The objective of this investigation was to determine whether celecoxib, a highly specific inhibitor of cyclooxygenase-2 (COX-2), inhibits the promotion phase of mammary tumorigenesis in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids (PUFAs) that is known to induce COX-2 expression. Sixty female Sprague-Dawley rats were initially maintained on an AIN-93G diet. At 50 days of age they received a single i.p. injection of methylnitrosourea (MNU). One week later, all rats were switched to a modified AIN-93G diet containing 18% safflower oil plus 3% soybean oil. Half of the rats also began receiving 1500 ppm celecoxib in the diet and the control and experimental diets were continued for a further 23 weeks. Celecoxib significantly decreased both the final tumor incidence (63.3% in the celecoxib group versus 82.2% in the control group, P<0.05) and tumor multiplicity (0.9+/-0.2 tumors/rat in the celecoxib group versus 2.3+/-0.3 tumors/rat in the control group, P<0.05). At the termination of the experiment, body weights were significantly lower in the celecoxib group compared to controls (330.6+/-6.1 versus 401.5+/-10.9 g respectively, P<0.05) although there was no evidence of toxicity and food intakes were not different for the two groups. Fasting serum triglycerides and abdominal adipose tissue accumulation were lower in the celecoxib group compared to controls (49.3+/-4.4 versus 82.8+/-12.6 mg/dL, P<0.05, and 7.2+/-0.3 versus 11.3+/-0.4% of body weight, P<0.01, respectively). These results show that administration of celecoxib to rats in a high fat diet rich in n-6 PUFAs suppresses the promotion of mammary tumorigenesis induced by MNU. This inhibition may be due to the effects of celecoxib on lipid metabolism as well as COX-2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12104042&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Physician-reported management of edema and destabilized blood pressure in cyclooxygenase-2-specific inhibitor users with osteoarthritis and treated hypertension.

Osterhaus JT, Burke TA, May C, Wentworth C, Whelton A, Bristol S.

Wasatch Health Outcomes, Park City, Utah 84060, USA. jtosterhaus mindspring.com

BACKGROUND: The addition of a nonsteroidal anti-inflammatory drug to the regimen of a patient with treated hypertension can cause a destabilization of blood pressure. OBJECTIVE: The aim of this study was to describe physician-reported management of clinically significant edema and/or destabilized blood pressure in patients with osteoarthritis (OA) and hypertension when initiating therapy with rofecoxib or celecoxib. METHODS: A cross-sectional survey was administered to physicians who attended one of several arthritis consultant programs sponsored by Pharmacia Corporation, with attendees selected by local sales representatives. Each program included a clinical presentation by a physician concerning the cardiorenal safety of celecoxib, followed by a consultative presentation and session led by a Pharmacia Clinical Education Manager. RESULTS: A total of 828 physicians in the following specialties completed the survey: family practice (33.0%), internal medicine (25.0%), orthopedics (15.2%), and rheumatology (11.4%). Responding physicians expected that the majority of patients who experienced edema would contact them (68.4%). They reported that they schedule follow-up visits for blood pressure monitoring 65.6% of the time after initiating a cyclooxygenase-2 (COX-2)-specific inhibitor, with family practitioners and internists most likely to indicate that they would do so and orthopedists least likely. Responding physicians indicated that the presence of edema and destabilized blood pressure generally led to discontinuation of the COX-2-specific inhibitor (58%-82% of the time). Internists and family practitioners were most likely to report that they treat edema by initiating or modifying diuretic therapy (33%-51% of the time). For destabilized blood pressure, an antihypertensive drug was reported to be initiated or modified 40% to 55% of the time by family practitioners and internists, whereas orthopedists indicated that they referred patients to the primary care provider. The COX-2-specific inhibitor prescribed resulted in management differences: physicians indicated that they were more likely to switch from rofecoxib to celecoxib in the event of edema or destabilized blood pressure, whereas they were more likely to adjust the celecoxib dose than the rofecoxib dose. Because the data were captured from convenience samples of physicians attending sponsored meetings, it is possible that respondents provided the answers they thought the sponsor would want. Because this was a cross-sectional survey, reported behavior was not compared with actual behavior. CONCLUSIONS: A significant percentage of physicians reported that they monitor patients with OA and hypertension for the occurrence of destabilized blood pressure and edema after initiation of a COX-2-specific inhibitor. Physicians indicated that they would nearly always intervene when either event is identified.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12117086&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effect of cyclooxygenase inhibitors in postoperative ileus: an experimental study.

Shafiq N, Malhotra S, Pandhi P.

Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

The aim of our study was to investigate the effect of various cyclooxygenase (COX) inhibitors (namely, indomethacin [a nonselective COX inhibitor], nimesulide [a partially selective COX inhibitor] and celecoxib [a highly selective COX inhibitor]) on postoperative ileus in rats. Equianalgesic doses of the three drugs were determined previously by formalin-induced hyperalgesia. Three comparative doses of the drugs were taken. After overnight fasting, a standardized laparotomy was performed on the rats. Bowel motility was determined by the charcoal meal test. The distance traveled by the charcoal meal was expressed as a percentage of the total length of the small intestine. The animals were pretreated intraperitoneally with either indomethacin (2.5, 5.0 and 10 mg/kg), nimesulide (10.0, 20.0 and 40 mg/kg), celecoxib (10.0, 20.0 and 40 mg/kg) or vehicle 1 h prior to the experiment. The lowest doses at which an increase in postoperative bowel motility occurred were 10 mg/kg of indomethacin and 20 mg/kg for both nimesulide and celecoxib. For equianalgesic doses it was noted that celecoxib was more effective than nimesulide or indomethacin in increasing postoperative bowel motility (52.15 +/- 1.08, 55.11 +/- 0.87 and 60.65 +/- 1.22 at the highest doses of indomethacin, nimesulide and celecoxib, respectively).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12168503&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Pharmacology of celecoxib in rat brain after kainate administration.

Ciceri P, Zhang Y, Shaffer AF, Leahy KM, Woerner MB, Smith WG, Seibert K, Isakson PC.

Pharmacia Discovery Research, St. Louis, Missouri, USA.

Prostaglandin E(2) (PGE(2)) is the major prostaglandin produced both centrally and in the periphery in models of acute and chronic inflammation, and its formation in both locations is blocked by cyclooxygenase-2 (COX-2) inhibitors such as celecoxib. In animal models of inflammation, PGE(2) inhibition in the brain may occur secondarily to a peripheral action by inhibiting local PG formation that elicits increased firing of pain fibers and consequent activation of PG synthesis in the central nervous system (CNS). Celecoxib was studied in the kainate-induced seizure model in the rat, a model of direct central prostaglandin induction, to determine whether it can act directly in the CNS. In the kainate-treated rat brain there was increased PGE(2), PGF(2alpha), and PGD(2) production, with COX activity and PGE(2) formation increased about 7-fold over normal. We quantitated mRNA levels for enzymes involved in the prostaglandin biosynthetic pathways and found that both COX-2 and PGE synthase (PGEs) mRNA levels were increased in the brain; no changes were found for expression of COX-1 or PGD synthase mRNA. By Western blot analysis, COX-2 and PGEs were induced in total brain, hippocampus, and cortex, but not in the spinal cord. Immunohistological studies showed that COX-2 protein expression was enhanced in neurons. Dexamethasone treatment reduced the expression of both COX-2 and PGEs in kainate-treated animals. Celecoxib reduced the elevated PGE(2) levels in brain of kainate-treated rats and inhibited induced COX activity, demonstrating the ability of this compound to act on COX-2 in CNS. Doses of celecoxib that inhibited brain COX-2 were lower than those needed for anti-inflammatory activity in adjuvant arthritis, demonstrating a potent direct central action of the compound.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12183639&dopt=Abstract celecoxib, Celebrex