celecoxib, Celebrex
[Cost-effectiveness analysis of the use of celecoxib for the treatment of osteoarthritis]

[Article in Spanish]

Moreno A, Vargas E, Soto J, Rejas J.

Servicio de Farmacologia Clinica. Hospital Clinico San Carlos. Madrid. Espana.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), used for the treatment of osteoarthritis, can produce serious gastrointestinal (GI) adverse reactions.Celecoxib, a specific COX-2 inhibitor, has a proven efficacy equivalent to that of traditional NSAIDs with an improved tolerance and safety profile. OBJECTIVE: The objective of this study was to perform a cost-effectiveness analysis on the use of celecoxib versus traditional NSAIDs in the treatment of osteoarthritis. MATERIAL AND METHODS: This cost-effectiveness analysis was designed through a pharmacoeconomic model; each effectiveness unit was defined as each year of life gained after the ingestion of celecoxib or NSAIDs. The probability of different clinical results appearing was obtained from published articles and incorporated assumptions.Only direct medical costs were evaluated (medication, hospitalization, additional tests, analyses, extra visits, etc.) and other costs were excluded.The study perspective was the national health system and the time horizon chosen was 6 months. RESULTS: The additional cost for each year of life gained through the use of celecoxib compared with that of traditional NSAIDs amounted to 8017; (1,333,834 ptas). Sensitivity analysis demonstrated how these values were sensitive to changes in the costs of NSAIDs and gastroprotective agents as well as to the inclusion of younger population groups. CONCLUSION: Celecoxib can be considered as a cost-effective option in the treatment of osteoarthritis because its use prevents deaths and increases survival rate and the additional cost is reasonable and moderate compared with that of NSAIDs. Its efficiency increases in proportion to its use in younger patients and probably in those at high risk for developing GI complications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12605743&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Antenatal administration of celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, appears to improve placental perfusion in the pregnant rabbit.

Hausman N, Beharry K, Nishihara K, Akmal Y, Asrat T.

Division of Maternal-Fetal Medicine, Women's Hospital, Long Beach Memorial Medical Center, 2801 Atlantic Avenue, Long Beach, CA, USA.

To investigate the effects of celecoxib on fetal growth, and placental prostanoid and nitric oxide (NO) production in fetal rabbits, pregnant rabbits received celecoxib (30 mg/kg per day) from 13 to 20 days (Cel-A), from 13 to 28 days (Cel-B), or vehicle from 13 to 28 days gestation. Fetal body and organ weights, and measurements of linear growth were recorded. The placentas were weighed and analyzed for prostaglandins (PGs), NO oxidation products (NOx), and total cellular protein levels. Placental prostaglandin E2 (PGE2) and NOx levels increased (P < or = 0.05), while thromboxane B2 levels were suppressed (P < or = 0.01) in Cel-B group. Tail length and brain weight were greater, while lung weights were lower in the Cel-B group (P < or = 0.05). Maternal administration of celecoxib appears to preferentially increase placental vasodilators and decrease placental TxA2, suggesting that the drug may increase uteroplacental perfusion without adverse fetal outcome.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12611495&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats.

Sairam K, Saravanan KS, Banerjee R, Mohanakumar KP.

Division of Neurosciences, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, 700 032, Calcutta, India.

We evaluated the hydroxyl radical (*OH) scavenging action of nonsteroidal anti-inflammatory drugs (NSAIDs), sodium salicylate (SA), diclofenac and celecoxib in Fenton's reaction and their neuroprotective effects in 1-methyl-4-phenylpyridinium (MPP(+))-induced striatal dopamine (DA) depletion in rats. Salicylate hydroxylation procedure employing HPLC-electrochemistry was used to assay formation of *OH in Fenton's reaction in test tubes. While SA dose- and time-dependently hydroxylated itself and inactivated *OH, celecoxib (up to 10 mM) showed no effect on *OH formation and diclofenac caused a reduction in *OH generation only at high doses (100 microM-10 mM). Administration of the non-selective cyclooxygenase (COX) inhibitor, SA (50, 100 mg/kg, i.p.) significantly attenuated striatal DA depletion caused by intrastriatal infusion of MPP(+) (100 nmol in 4 microl). Treatment with another nonselective, reversible COX inhibitor, diclofenac (5, 10 mg/kg) did not protect against MPP(+)-induced DA depletion. The selective COX-2 inhibitor, celecoxib (2.5-50 mg/kg) treatment exacerbated MPP(+)-induced decrease in DA. Failure of celecoxib or diclofenac to render protection in animals against MPP(+)-induced DA depletion indicates absence of prostaglandin involvement in MPP(+) action. These results also suggest that the neuroprotective ability of SA is independent of prostaglandin mediation. A relationship between inactivation of *OH by SA and its ability to protect DA depletion in the striatum caused by MPP(+) indicates a direct involvement of *OH in the action of this neurotoxin. The present study establishes potent neuroprotective activity of SA and suggests the use of aspirin in adjuvant therapy in Parkinson's disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12618347&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The prevalence of cardiorenal risk factors in patients prescribed nonsteroidal anti-inflammatory drugs: data from managed care.

Harley C, Wagner S.

Ingenix, Economic and Outcomes Research, Eden Prairie, MN 55344, USA. carolyn.harley ingenix.com

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to cause abnormalities in renal function. This is an important concern in patients with cardiorenal risk factors, including hypertension, congestive heart failure, edema, renal impairment, and advanced age. OBJECTIVES: The goals of this study were to determine the prevalence of cardiorenal risk factors in patients with rheumatoid arthritis (RA) or osteoarthritis and ascertain whether these risk factors are associated with prescribing patterns of cyclooxygenase (COX)-2-selective inhibitors and other NSAIDs. METHODS: This was a retrospective, longitudinal claims analysis using data from 19 large independent-practice-model managed care health plans in the United Stated. Three cohorts were identified based on claims for celecoxib, rofecoxib, or other NSAIDs from October 1, 1999, through September 30, 2000. Logistic regression models were used to explore whether baseline cardiorenal risk factors were related to choice of therapy. RESULTS: A total of 77,552 patients received celecoxib (n = 6779 [8.74%]), rofecoxib (n = 7189 [9.27%]), or other NSAIDs (n = 63,584 [81.99%]). Patients prescribed COX-2-selective inhibitors were older than those receiving other NSAIDs and had a diagnosis of RA more often. Overall, 42% of patients had >or=1 cardiorenal risk factor, and approximately one third had hypertension. Cardiorenal risk factors were not related to physicians' prescribing of celecoxib or rofecoxib, but the presence of any cardiorenal risk factor was associated with an increase in the use of COX-2-selective inhibitors compared with other NSAIDs, from 12% for cerebrovascular disease (point estimate, 1.124; P<0.001) to 74% for chronic renal failure/nephritis (point estimate, 1.738; P=0.025). RA and advanced age were associated with the use of celecoxib rather than rofecoxib. CONCLUSIONS: The prevalence of cardiorenal risk factors was found to be similar in patients prescribed celecoxib or rofecoxib for arthritis. Patients with these risk factors were more likely to receive a COX-2-selective inhibitor than other NSAIDs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12637116&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Characterization of celecoxib and valdecoxib binding to cyclooxygenase.

Hood WF, Gierse JK, Isakson PC, Kiefer JR, Kurumbail RG, Seibert K, Monahan JB.

Pharmacia Research and Development, St. Louis, Missouri, USA. william.f.hood pharmacia.com

Two compounds (celecoxib and valdecoxib) from the diarylheterocycle class of cyclooxygenase inhibitors were radiolabeled and used to characterize their binding to cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), several single-point variants of COX-2 (Val523Ile, Tyr355Ala, Arg120Ala, Arg120Gln, Arg120Asn) and one triple-point variant of COX-2 [Val523Ile, Arg513His, Val434Ile (IHI)]. We demonstrate highly specific and saturable binding of these inhibitors to COX-2. Under the same assay conditions, little or no specific binding to COX-1 could be detected. The affinity of [(3)H]celecoxib for COX-2 (K(D) = 2.3 nM) was similar to the affinity of [(3)H]valdecoxib (K(D) = 3.2 nM). The binding to COX-2 seems to be both rapid and slowly reversible with association rates of 5.8 x 10(6)/M/min and 4.5 x 10(6)/M/min and dissociation rates of 14 x 10(-3)/min (t(1/2) = 50 min) and 7.0 x 10(-3)/min (t(1/2) = 98 min) for [(3)H]celecoxib and [(3)H]valdecoxib, respectively. These association rates increased (4- to 11-fold) when the charged arginine residue located at the entrance to the main hydrophobic channel was mutated to smaller uncharged amino acids (Arg120Ala, Arg120Gln, and Arg120Asn). Mutation of residues located within the active site of COX-2 that define a 'side pocket' (Tyr355Ala, Val523Ile, IHI) of the main channel had a greater effect on the dissociation rate than the association rate. These mutations, which modified the shape of and access to the 'side pocket', affected the binding affinity of [(3)H]valdecoxib more than that of [(3)H]celecoxib. These binding studies provide direct insight into the properties and binding constants of celecoxib and valdecoxib to COX-2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12644588&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib acts in a cyclooxygenase-2-independent manner and in synergy with emodin to suppress rat cholangiocarcinoma growth in vitro through a mechanism involving enhanced Akt inactivation and increased activation of caspases-9 and -3.

Lai GH, Zhang Z, Sirica AE.

Division of Cellular and Molecular Pathogenesis, Department of Pathology, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia 23298-0297, USA.

Emodin, a tyrosine kinase inhibitor, effectively blocked tyrosine phosphorylation of p185(neu) overexpressed in cultured rat C611B cholangiocarcinoma (ChC) cells and in neu-transformed WB-F344 rat-liver epithelial stem-like cells (WBneu cells). Celecoxib, a cyclooxygenase-2 inhibitor, markedly decreased prostaglandin (PG) levels overproduced by these respective neoplastically transformed liver cell types but was without effect in inhibiting PG production by untransformed WB-F344 cells that do not express detectable cyclooxygenase-2 protein. Notably, in combination, emodin (30 micro M) and celecoxib (35 micro M) acted synergistically to significantly suppress anchorage-dependent and -independent growth of C611B ChC cells and of WBneu cells over treatments with either agent alone. This prominent suppression of cell growth correlated with significant increases in the activation of caspases-9 and -3 and induction of apoptosis in the combination-treated cells, which was associated with an enhanced suppression of Akt activation. Here it is important to note that the concentration of celecoxib needed to suppress growth and induce apoptosis in the C611B and WBneu cells was markedly higher than that needed to effectively inhibit PG production by these malignant cell types. Thus, our data indicate that celecoxib is acting independently of its ability to inhibit cyclooxygenase-2 activity in suppressing growth of C611B and WBneu cells in vitro. Furthermore, our findings strongly suggest that increased inhibition of the antiapoptotic kinase Akt activation produced by the emodin/celecoxib combination treatment plays a key role in the mechanism by which this drug combination acts to enhance cell growth suppression and apoptosis in cultured C611B ChC cells and WBneu cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12657721&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Chemoprevention of gastric cancer by celecoxib in rats.

Hu PJ, Yu J, Zeng ZR, Leung WK, Lin HL, Tang BD, Bai AH, Sung JJ.

Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

BACKGROUND: Overexpression of cyclooxygenase 2 (COX-2) is frequently detected in gastric cancer and is believed to play a crucial role in gastric carcinogenesis. Aim: We examined the chemopreventive effect of a COX-2 inhibitor in an animal model of stomach carcinogenesis. METHODS: Eighty six male Wistar rats were divided into six different treatment groups: group A, water alone (n = 5); group B, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG 100 micro g/ml) (n = 16); group C, indomethacin (3 mg/kg/day) (n = 16); group D, celecoxib (5 mg/kg/day) (n = 17); group E, celecoxib (10 mg/kg/day) (n = 16); and group F, celecoxib (20 mg/kg/day) (n = 16). Group B-F animals were treated with 10% sodium chloride (in the initial six weeks) and MNNG in drinking water to induce adenocarinoma in the stomach. All animals received treatment for 40 weeks, and were sacrificed after death or at 48 weeks. Gastric neoplasm was evaluated by histology. RESULTS: The incidences of gastric cancer were 0% in group A, 75% in group B, 68.8% in group C, 70.6% in group D, 18.8% in group E, and 31.3% in group F (p = 0.002, ANOVA). Compared with MNNG controls, treatment with celecoxib 10 mg/kg/day also showed lower tumour multiplicity (0.19 (0.40) v 1.00 (0.73); p = 0.004) and lower mean tumour volume (2.4 v 2805 mm(3); p = 0.02). Although tumours had significantly higher COX-2 expression than their adjacent normal tissues (p<0.02), there was no significant difference in COX-2 levels among tumours in the different treatment groups. The lowest tumour prostaglandin E(2) level was found in the indomethacin treated group, suggesting that the chemopreventive effect of celecoxib may be mediated by a COX independent pathway. CONCLUSION: While treatment with indomethacin had no significant effect on tumour development, treatment with celecoxib reduced gastric cancer incidence and growth in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14724149&dopt=Abstract celecoxib, Celebrex