celecoxib, Celebrex
Renal effects on a solitary kidney of specific inhibition of cyclooxygenease-2 after 24 h of complete ureteric obstruction in rats.

Ozturk H, Ozdemir E, Otcu S, Buyukbayram H, Ihsan Dokucu A.

Department of Pediatric Surgery, Dicle University Hospital, 21280 Diyarbakir, Turkey. ozturkhayrettin hotmail.com

The purpose of this study is to show whether selective (celecoxib) and non-selective (piroxicam) inhibitors of COX-2 can alter the morphological and functional changes after the release of a 24 h complete ureteric obstruction in tissue from solitary rat kidney. Forty male Sprague-Dawley rats weighing 225-250 g were used. The animals were divided into four groups. In group 1 rats (control, n=10), only right nephrectomy was performed. Group 2 rats (untreated, n=10) underwent right nephrectomy and the left ureter was completely obstructed. In group 3 rats (celecoxib), the same operation was performed as described for group 2 and than celecoxib was administered by gavage for a period of 24 h. Group 4 rats (piroxicam) underwent the same operation as described for group 2, then piroxicam was administered intramuscularly at least 1 h before the release of the for 24 h complete ureteric obstruction. All animals were then prepared for functional and histopathological studies. The administration of celecoxib produced a significant decrease in blood urea nitrogen levels when compared to the animals receiving piroxicam and the animals with no treatment. Moreover, celecoxib caused a significant decreased in creatinine levels when compared to the untreated group. Urine volume and the urinary sodium values were increased in the celecoxib group when compared with the other groups. The administration of celecoxib and piroxicam caused a significant decrease in the number of interstitial macrophages when compared to the untreated group. The Bowman space was significantly increased in the untreated group when compared with the celecoxib and the piroxicam groups. These studies indicate that celecoxib may be an important factor affecting renal morphological and functional changes after the release of a 24 h complete ureteric obstruction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12202939&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The cyclooxygenase-2 inhibitor, celecoxib, prevents the development of mammary tumors in Her-2/neu mice.

Lanza-Jacoby S, Miller S, Flynn J, Gallatig K, Daskalakis C, Masferrer JL, Zweifel BS, Sembhi H, Russo IH.

Department of Surgery, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA. Susan.Lanza-Jacoby mail.tju.edu

Evidence is now available showing that cyclooxygenase (COX)-2, which is involved in prostaglandin production, is overexpressed in many types of tumors including breast. Several reports have indicated that HER-2/neu-positive breast tumors are associated with an increased amount of COX-2 protein. In this study, we evaluated the effectiveness of the select COX-1 and COX-2 inhibitors in preventing mammary tumor development in HER-2/neu transgenic mice. At 4 weeks of age, female HER-2/neu mice were fed a #5020 rodent diet supplemented with 900 ppm celecoxib, a COX-2 inhibitor, 64 ppm of SC560, a COX-1 inhibitor, or the unsupplemented #5001 diet (control). The incidence of mammary tumors was significantly lower in the celecoxib-fed mice (71%; P = 0.001 versus control) than in the control mice (95%) or in the SC560-fed mice (91%). Celecoxib-treated mice also developed fewer tumors (1.3 +/- 1.1 SD; P = 0.039 versus control) than the control mice (2.2 +/- 1.2) or the SC560 treated mice (2.3 +/- 1.3). The median time to tumor development was 266 days in the control group versus 291 days in the celecoxib-treated group (P = 0.003 versus control). Lung metastasis was also reduced by treatment with celecoxib. The COX-1 inhibitor SC560 had no protective effect. The protection offered by celecoxib was associated with significantly lower concentrations of prostacyclin and prostaglandin E(2) in mammary tumors and their adjacent mammary glands. Our findings provide additional preclinical evidence to support the clinical studies to investigate the potential effectiveness of COX-2 inhibitors in protecting woman who are at high risk for breast cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14693742&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance.

Ma L, del Soldato P, Wallace JL.

Mucosal Inflammation Research Group, Department of Pharmacology and Therapeutics, University of Calgary, Calgary, AB, Canada T2N 4N1.

Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet/serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib- or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti- and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro- and antiangiogenic growth factors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12232050&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase inhibition in nerve-injury- and TNF-induced hyperalgesia in the rat.

Schafers M, Marziniak M, Sorkin LS, Yaksh TL, Sommer C.

Department of Neurology, University of Wurzburg, 97080 Wurzburg, Germany. schaefers_m klinik.uni-wuerzburg.de

After nerve injury, cyclooxygenase-2 (COX-2) is upregulated in spinal cord and peripheral nerve, the latter being dependent on tumor necrosis factor-alpha (TNF). Here we asked whether COX inhibitors attenuate pain behavior induced by chronic constrictive sciatic nerve injury (CCI) or intraneural injection of TNF (2.5 pg/ml). Rats received either 0.9% saline, the nonselective COX inhibitor ibuprofen (40 mg/kg) or the selective COX-2 inhibitor celecoxib (10 or 30 mg/kg) twice daily by gavage started 2 days before, 12 h or 7 days after surgery. Mechanical allodynia and thermal hyperalgesia induced by CCI was moderately, but consistently attenuated by early (day -2 or 12 h after CCI), but not late (7 days after CCI) ibuprofen and celecoxib treatment. Mechanical allodynia, but not thermal hyperalgesia induced by intraneural TNF, was reduced by ibuprofen, but not by celecoxib treatment 5 and 7 days after injection. Sciatic nerves, lumbar dorsal root ganglia (DRG) and spinal cords from rats with treatment started 12 h after surgery were analyzed for prostaglandin E2 (PGE2) levels 10 days after CCI. In injured nerves and ipsilateral DRG, PGE2 levels were increased. Ibuprofen treatment reversed PGE2 levels in injured nerves and DRG, whereas celecoxib blocked increased PGE2 levels only in nerves. In spinal cord, no change in PGE2 levels was observed. In contrast to the marked inhibition of nerve-injury-induced upregulation of PGE2 by COX inhibitors, the effect on pain behavior was modest. Nerve-injury- and TNF-induced pain-related behavior seem to be only partly dependent on peripheral prostaglandins.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14697327&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs.

Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G, Austin PC, Laupacis A.

Institute for Clinical Evaluative Sciences, 2075 Bayview Avenue-G215, Toronto, Ontario, Canada. muhammad.mamdani ices.on.ca

OBJECTIVE: To compare rates of upper gastrointestinal haemorrhage among elderly patients given selective cyclo-oxygenase-2 (COX 2) inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: Observational cohort study. SETTING: Administrative data from Ontario, Canada, used from 17 April 2000 to 31 March 2001 to identify population based, NSAID-naive cohorts of patients. PATIENTS: Subjects aged > or =66 years who started taking non-selective NSAIDs (n=5391), diclofenac plus misoprostol (n=5087), rofecoxib (n=14 583), or celecoxib (n=18 908) and a randomly selected control cohort not exposed to NSAIDs (n=100 000). MAIN OUTCOME MEASURES: Rate ratios of hospital admission for upper gastrointestinal haemorrhage in each drug cohort with adjustment for potential confounders. RESULTS: Relative to controls, the multivariate model revealed an increased short term risk of upper gastrointestinal haemorrhage for users of non-selective NSAIDs (adjusted rate ratio 4.0 (95% confidence intervals 2.3 to 6.9)), diclofenac plus misoprostol (3.0 (1.7 to 5.6)), and rofecoxib (1.9 (1.3 to 2.8)) but not celecoxib (1.0 (0.7 to 1.6)). Relative to celecoxib, significantly higher risks of upper gastrointestinal haemorrhage were observed for non-selective NSAIDs (4.4 (2.3 to 8.5)), diclofenac plus misoprostol (3.2 (1.6 to 6.5)), and rofecoxib (1.9 (1.2 to 2.8)). Relative to rofecoxib, non-selective NSAID users were at significantly higher risk of upper gastrointestinal haemorrhage (1.9 (1.0 to 3.5)). CONCLUSIONS: This population based observational study found a lower short term risk of upper gastrointestinal haemorrhage for selective COX-2 inhibitors compared with non-selective NSAIDs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12242172&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effect of selective cyclooxygenase-2 inhibition on the development of ligature-induced periodontitis in rats.

Holzhausen M, Rossa Junior C, Marcantonio Junior E, Nassar PO, Spolidorio DM, Spolidorio LC.

Department of Periodontology, Araraquara Dental School, State University of Sao Paulo (UNESP) Araraquara, Brazil.

BACKGROUND: The purpose of this study was to evaluate the effect of a selective cyclooxygenase-2 inhibitor on the progression of alveolar bone loss in an experimental periodontitis model in rats. METHODS: One hundred eighty (180) Wistar rats were separated into 3 experimental groups. Cotton ligatures were placed at the gingival margin level of lower right first molars. The rats were randomly assigned to one of the following groups that received: a daily oral dose of 10 mg/kg body weight of celecoxib (Ce1); 20 mg/kg body weight of celecoxib (Ce2); or 10 ml/kg of saline solution (C). Serum levels of celecoxib and white blood cell count were determined. Standardized digital radiographs were taken after sacrifice at 3, 5, 10, 18, and 30 days to measure the amount of bone loss around the mesial root surface of the first molar tooth in each rat. RESULTS: Two-way analysis of variance (ANOVA) indicated that groups treated with celecoxib had significantly less bone loss compared to controls (P < 0.0001) and that there was a significant interaction between treatment with celecoxib and time (P < 0.03). Post-hoc comparisons showed that in both groups treated with celecoxib, the bone loss became significant only after 10 days of ligature placement, while in the control group it was already significant after 5 days. However, differences in mean bone loss between control and Ce1 were significant only at 18 days and, between control and Ce2, at 5 and 18 days. There was no significant difference in bone loss among experimental groups at the end of the experimental period. CONCLUSION: These data provide evidence that systemic therapy with celecoxib can modify the progression of experimentally induced periodontitis in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12296588&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer.

Howe LR, Subbaramaiah K, Patel J, Masferrer JL, Deora A, Hudis C, Thaler HT, Muller WJ, Du B, Brown AM, Dannenberg AJ.

Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10021, USA. lrhowe med.cornell.edu

Cyclooxygenase 2 (HER-2) (Cox-2), an inducible form of Cox, is overexpressed in HER-2/neu-positive human breast cancers. The aim of this study was to determine whether celecoxib, a selective Cox-2 inhibitor, protected against HER-2/neu-induced experimental breast cancer. Cox-2 protein was detected in breast carcinomas from mouse mammary tumor virus (MMTV)/neu mice. Treatment with celecoxib (500 ppm) significantly reduced the incidence of mammary tumors in MMTV/neu mice (P = 0.003) and caused about a 50% reduction in mammary prostaglandin E2 (PGE2) levels. Because mammary glands from MMTV/neu mice expressed all four PGE2 receptor subtypes, we speculate that signaling through PGE2 receptors is important for mammary tumorigenesis. These results strengthen the rationale for developing clinical trials to determine whether selective Cox-2 inhibitors possess anticancer properties in humans at risk for breast cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12359744&dopt=Abstract celecoxib, Celebrex