celecoxib, Celebrex
Cost-effectiveness of treatment strategies for osteoarthritis of the knee in Taiwan.

Yen ZS, Lai MS, Wang CT, Chen LS, Chen SC, Chen WJ, Hou SM.

Department of Emergency Medicine, National Taiwan University, Taipei, Taiwan.

OBJECTIVE: To evaluate the cost-effectiveness of 3 treatment strategies for osteoarthritis (OA) of the knee: naproxen, celecoxib, and hyaluronan. METHODS: We developed a decision model to estimate the costs and effectiveness of 3 treatment strategies: 250 mg naproxen 3 times daily for 26 weeks, 100 mg celecoxib twice daily for 26 weeks, and 25 mg hyaluronan by intraarticular injection once per week for 5 weeks followed by conventional treatment for 21 weeks. The probabilities and utility data were obtained by surveying the literature and consulting experts. Cost data were obtained from insurance reimbursement data of National Taiwan University Hospital and were converted to 2002 US dollars. The timeframe of the decision tree was 26 weeks. Outcomes were expressed in aggregated costs, quality-adjusted life-years (QALY), and the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed on most variables. RESULTS: The expected total costs for the naproxen, celecoxib, and hyaluronan strategies were US$498.98, US$547.80, and US$678.00, respectively. The ICER of the celecoxib strategy compared with the naproxen strategy was US$21,226 per QALY gained. The ICER of the hyaluronan strategy versus the celecoxib strategy was US$42,000 per QALY gained. The ICER of the hyaluronan strategy decreased to about US$25,000 per QALY gained if the weekly treatment cost of hyaluronan was decreased to US$31. CONCLUSION: Celecoxib treatment results in a reasonable cost-effectiveness ratio for patients with OA of the knee. Hyaluronan treatment, however, may not be an economically attractive choice under the current healthcare scenario in Taiwan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15338503&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Comparison of the anti-proliferation and apoptosis-induction activities of sulindac, celecoxib, curcumin, and nifedipine in mismatch repair-deficient cell lines.

Wei SC, Lin YS, Tsao PN, Wu-Tsai JJ, Wu CH, Wong JM.

Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.

BACKGROUND AND PURPOSE: The adenomatous polyposis coli (APC) and mismatch repair (MMR) pathways are both involved in the tumorigenesis of hereditary colorectal cancers. Chemoprevention focuses on the APC pathway in the absence of information concerning MMR targets. This study compared the anticancer effects of sulindac, celecoxib, curcumin, and nifedipine in MMR-deficient cell lines, in order to determine the most appropriate chemopreventive agent for long-term use in patients with hereditary colorectal cancer. METHODS: Five human colorectal cell lines (SW480, HCT116, LoVo, SW48, and HCT15) and an endometrial cancer cell line (HEC-1-A) were used for susceptibility testing. Tests included assays for growth inhibition, cell-cycle arrest, and apoptosis. RESULTS: Sulindac, celecoxib, curcumin, and nifedipine all displayed dose- and time-dependent anti-proliferation activities. Celecoxib was the most effective anti-proliferative agent, and increased the G0/G1 phase proportion in the cell cycle after treatment more significantly than the other agents in all cell lines. Curcumin displayed a more potent apoptosis-inducing activity than the other agents in treated cells. CONCLUSIONS: The tested drugs were effective against colorectal and endometrial cancer cell lines. Celecoxib is more potent with fewer side effects than sulindac. Nifedipine's observed chemopreventive efficacy may complement its known therapeutic application in patients with hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15340658&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck.

Chen Z, Zhang X, Li M, Wang Z, Wieand HS, Grandis JR, Shin DM.

Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

PURPOSE: Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (Cox-2) contribute to development of squamous cell carcinoma of the head and neck (SCCHN). Simultaneously blocking both EGFR and Cox-2-mediated pathways may be an efficient means of inhibiting cancer cell growth in SCCHN. EXPERIMENTAL DESIGN: A combination of EGFR-selective tyrosine kinase inhibitors (TKIs) AG1478 or ZD1839 (Iressa or gefitinib) with a Cox-2 inhibitor (Cox-2I) celecoxib (Celebrex) was studied for its effects on cell growth, cell cycle progression, and apoptosis in SCCHN cell lines by cell growth assay, clonogenic assay, flow cytometric analysis, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. A potential effect of EGFR TKIs and Cox-2I on angiogenesis was examined by endothelial capillary tube formation assay. Primary and secondary targets of EGFR TKIs and Cox-2I were also examined using immunoblotting and immunoprecipitation after the combined treatment. RESULTS: The combination of AG1478 or ZD1839 with celecoxib either additively or synergistically inhibited growth of the five SCCHN cell lines examined, significantly induced G(1) arrest and apoptosis, and suppressed capillary formation of endothelium. Furthermore, the combination showed strong reductions of p-EGFR, p-extracellular signal-regulated kinase 1/2, and p-Akt in SCCHN cells as compared with the single agents. Both AG1478 and ZD1839 inhibited expression of Cox-2 protein, whereas celecoxib mainly blocked the production of prostaglandin E(2). CONCLUSIONS: These results suggest that cell growth inhibition induced by a combination of EGFR TKIs and Cox-2I is mediated through simultaneously blocking EGFR and Cox-2 pathways. This combination holds a great potential for the treatment and/or prevention of SCCHN.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15355926&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cells.

Hinz B, Ramer R, Eichele K, Weinzierl U, Brune K.

Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nurnberg, Erlangen, Germany. hinz pharmakologie.uni-erlangen.de

Cannabinoids have been implicated in the reduction of glioma growth. The present study investigated a possible relationship between the recently shown induction of cyclooxygenase (COX)-2 expression by the endocannabinoid analog R(+)methanandamide [R(+)-MA] and its effect on the viability of H4 human neuroglioma cells. Incubation with R(+)-MA for up to 72 h decreased the cellular viability and enhanced accumulation of cytoplasmic DNA fragments in a time-dependent manner. Suppression of R(+)-MA-induced prostaglandin (PG) E2 synthesis with the selective COX-2 inhibitor celecoxib (0.01-1 microM) or inhibition of COX-2 expression by COX-2-silencing small-interfering RNA was accompanied by inhibition of R(+)-MA-mediated DNA fragmentation and cell death. In contrast, the selective COX-1 inhibitor SC-560 was inactive in this respect. Cells were also protected from apoptotic cell death by other COX-2 inhibitors (NS-398 [[N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide]] and diclofenac) and by the ceramide synthase inhibitor fumonisin B1, which interferes with COX-2 expression by R(+)-MA. Moreover, the proapoptotic action of R(+)-MA was mimicked by the major COX-2 product PGE2. Apoptosis and cell death by R(+)-MA were not affected by antagonists of cannabinoid receptors (CB1, CB2) and vanilloid receptor 1. In further experiments, celecoxib was demonstrated to suppress apoptotic cell death elicited by anandamide, which is structurally similar to R(+)-MA. As a whole, this study defines COX-2 as a hitherto unknown target by which a cannabinoid induces apoptotic death of glioma cells. Furthermore, our data show that pharmacological concentrations of celecoxib may interfere with the proapoptotic action of R(+)-MA and anandamide, suggesting that cotreatment with COX-2 inhibitors could diminish glioma regression induced by these compounds.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15361550&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death.

Chu K, Jeong SW, Jung KH, Han SY, Lee ST, Kim M, Roh JK.

Stroke and Neural Stem Cell Laboratory, Clinical Research Institute, Department of Neurology, Seoul National University Hospital, Seoul National University, Seoul, South Korea.

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood-injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15362723&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
COX-2 inhibition and prostaglandin receptors in experimental nephritis.

Waldner C, Heise G, Schror K, Heering P.

Heinrich Heine Universitat Dusseldorf, Dusseldorf, Germany.

BACKGROUND: Renal cyclooxygenases (COX) produce the prostaglandins (PG) E2, I2 and thromboxane (TxA2), which interact with distinct G protein-coupled receptors. We investigated the expression of the three EP receptors EP2, EP3 and EP4 and the receptors for PGI2 (IP) and TxA2 (TP) in rats with passive Heymann nephritis (PHN). We studied their regulation by COX-2 inhibition with celecoxib. MATERIALS AND METHODS: Four groups of Wistar rats were studied: healthy rats (group A), healthy rats treated with celecoxib (group B), rats with PHN (group C), and rats with PHN receiving celecoxib (group D). Expression of the mRNA for all receptors in the renal cortex and for the EP3 receptor in cultured mesangial cells (MCs) was determined by semiquantitative reverse transcriptase polymerase chain reaction. Stable prostaglandin metabolites were measured in the urine by radioimmunoassay. RESULTS: Rats with PHN (group C) showed an 1.8-fold increase of cortical EP3 receptor mRNA expression as compared with controls (group A). In celecoxib-treated PHN rats (group D) the mRNA expression of the EP3 and EP4 receptors was significantly reduced to 1.0-fold and 0.7-fold induction, respectively. Furthermore, the excretion of bicyclo-prostaglandin E2 (PGE2) was inhibited by celecoxib. No changes were observed in the expression of the other PG-receptors. In cultured MC, PGE2 enhanced the EP3 mRNA expression. CONCLUSIONS: These data suggest a predominant role of the EP3 receptor in the transduction of PGE2-actions in PHN. It was concluded that COX-2-dependent PGE2 is able to potentiate its effects in the kidney by up-regulating its own receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14636300&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Vitamin E analog alpha-TEA and celecoxib alone and together reduce human MDA-MB-435-FL-GFP breast cancer burden and metastasis in nude mice.

Zhang S, Lawson KA, Simmons-Menchaca M, Sun L, Sanders BG, Kline K.

Division of Nutrition/A2703, University of Texas at Austin, Austin, TX 78712-1097, USA.

Alpha-TEA, a nonhydrolyzable ether analog of vitamin E (RRR-alpha-tocopherol), and celecoxib, a specific COX-2 inhibitor, were delivered separately or in combination to investigate their anticancer properties, using MDA-MB-435-FL-GFP human breast cancer xenografts in nude mice. Liposomal formulated alpha-TEA administered as an aerosol and celecoxib fed at 500 or 1250 mg/kg diet for 31 days separately or in combination significantly reduced tumor volume in comparison to control (p < 0.001 for all treatment groups). Of special note, the combinations of alpha-TEA + celecoxib (1250) inhibited tumor volume significantly better than either single treatment (p < 0.001 and p < 0.001). Average number of macroscopic lung metastases were significantly reduced in all treatment groups in comparison to control, with the exception of celecoxib (500). Mean numbers of microscopic lung and lymph node metastases in all treatment groups were significantly lower than control. Furthermore, the mean number of microscopic lung metastases in the alpha-TEA+celecoxib (1250) group were significantly lower than either separate treatment. Analyses of 5 microm tumor sections showed that all treatments, with the exception of celecoxib (500) alone, significantly enhanced apoptosis (TUNEL) and significantly decreased cell proliferation (Ki-67). alpha-TEA and alpha-TEA + celecoxib (1250) treatments significantly reduced blood vessel density (CD-31) in comparison to control. These data show promise for combination alpha-TEA + celecoxib chemotherapy for breast cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15377836&dopt=Abstract celecoxib, Celebrex