celecoxib, Celebrex
Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice.

Kisley LR, Barrett BS, Dwyer-Nield LD, Bauer AK, Thompson DC, Malkinson AM.

Department of Pharmaceutical Sciences, University of Colorado Cancer Center, Denver CO 80262, USA.

Cyclooxygenase (COX) enzyme expression is elevated in human and rodent lung tumors, and non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin reduce lung tumor formation in mice. These observations, along with the well-characterized protection that NSAID treatment engenders for colon cancer, have prompted clinical trials testing whether celecoxib, a COX-2-specific inhibitor, can prevent lung cancer development in populations at high risk. Protection by celecoxib in murine models of pulmonary inflammation and lung tumorigenesis has not yet been evaluated, however, and we now report such studies. Chronic administration of butylated hydroxytoluene (BHT) to mice stimulates pulmonary inflammation characterized by vascular leakage and macrophage infiltration into the air spaces, increased PGE2 production, and translocation of 5-lipoxygenase (5-LO) from the cytosol to the particulate fraction. Dietary celecoxib limited macrophage infiltration, abrogated PGE2 production and reduced particulate 5-LO content. Celecoxib and aspirin were ineffective at preventing lung tumorigenesis in a two-stage carcinogenesis protocol in which 3-methylcholanthrene administration is followed by chronic BHT. Celecoxib also did not reduce the multiplicity of lung tumors after induction by urethane; lung tumors in celecoxib-treated mice were larger than those in mice that did not receive celecoxib. Tumors induced in celecoxib-fed mice contained 60% less PGE2 than tumors in mice fed control diets, so reducing lung PGE2 levels was insufficient to prevent lung tumor formation. As the production of eicosanoids in addition to PGE2 is also inhibited by celecoxib, and as celecoxib has COX-independent interactions, its effects on tumor formation may vary in different organ systems.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12376474&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The effect of cyclooxygenase-2 inhibitors on spinal fusion.

Long J, Lewis S, Kuklo T, Zhu Y, Riew KD.

Department of Othopaedic Surgery, Barnes-Jewish Hospital at Washington University St Louis, Missouri 63110, USA.

BACKGROUND: Spine surgeons discourage the use of nonsteroidal anti-inflammatory drugs following spine arthrodesis because of their inhibitory effect on bone-healing. To our knowledge, there are no data on the effects of the new cyclooxygenase-2 inhibitors on bone-healing. We undertook this study to determine the effects of these more selective nonsteroidal anti-inflammatory drugs on spinal fusion in a rabbit model. METHODS: Seventy-two New Zealand White rabbits underwent a posterolateral intertransverse process arthrodesis with use of autologous iliac crest bone. Sixty-six rabbits survived the surgical procedure and the perioperative period and had an uneventful postoperative course. These rabbits were randomly divided into three groups. One group received 10 mg/kg of celecoxib orally, the second group received 10 mg/kg of indomethacin orally, and the third group (the control group) received 1 cm (3) of saline solution orally. The rabbits received the treatment daily for eight weeks, after which they were killed and the lumbar spine was harvested. The specimens were palpated for motion, radiographed, and prepared for histological analysis. The quality of the fusion was graded at each level by assigning a histological score of 0 to 7. RESULTS: Gross inspection and palpation revealed that 64% (fourteen) of the twenty-two control spines and 45% (ten) of the twenty-two spines in the rabbits treated with celecoxib were fused. With the numbers available, this difference was not significant (p = 0.224). Of the twenty-two spines in the indomethacin-treated rabbits, 18% (four) were fused, and this percentage was significantly different from the control value (p = 0.002). On radiographic assessment, the spine segment was deemed to be fused in 82% (eighteen) of the twenty-two controls, 86% (nineteen) of the twenty-two rabbits treated with celecoxib, and 41% (nine) of the twenty-two indomethacin-treated animals. Only the difference between the indomethacin-treated and control groups was significant (p = 0.004). The histological scores averaged 5.2, 4.8, and 3.5 for the control, celecoxib, and indomethacin groups, respectively. There was a significant difference between the control and indomethacin groups (p = 0.002) but not between the celecoxib and control groups (p = 0.161). CONCLUSIONS: These results suggest that celecoxib does not significantly inhibit the rate of spinal fusion in rabbits. They also suggest that the inhibitory effects of nonsteroidal anti-inflammatory drugs on bone-healing are likely mediated by inhibition of cyclooxygenase-1 and that celecoxib is the better choice if treatment with nonsteroidal anti-inflammatory drugs is deemed necessary following spinal arthrodesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12377905&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Renal effects of cyclooxygenase-2 inhibition in fetal lambs.

Kajino H, Roman C, Clyman RI.

Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.

We used late gestation fetal lambs to examine the effects of a selective COX-2 inhibitor (celecoxib) on fetal renal function. After a 2-hour baseline period, each fetus was exposed to either saline (control, n = 10), 'low-dose' celecoxib (plasma concentration 0.47 microg/ml, n = 4), or 'high-dose' celecoxib (1.4 microg/ml, n = 8) during a 5-hour study period. High-dose celecoxib (but not low-dose celecoxib) caused a significant decrease in urine volume, free water clearance, arterial pH, and an increase in blood lactate compared with the control group. There were no significant differences in creatinine clearance, fractional excretion of sodium and potassium, or in renal blood flow between the 3 groups. These effects are similar to those reported for the nonselective COX-1/-2 inhibitor, indomethacin. COX-2 appears to play an important role in promoting free water excretion in the fetal lamb. Copyright 2002 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12381934&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib (celebrex) increases canine lower esophageal sphincter pressure.

de la Fuente SG, McMahon RL, Clary EM, Harris MB, Lawson DC, Reynolds JD, Eubanks WS, Pappas TN.

Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.

BACKGROUND: Prostaglandins inhibit the contraction of gastrointestinal smooth muscle and may decrease lower esophageal sphincter tone. The purpose of this study was to determine whether the cyclooxygenase-2 inhibitor celecoxib (Celebrex) could increase lower esophageal pressure (without affecting gastric emptying) compared to placebo and cisapride (Prepulsid), a compound previously used to treat reflux disease. MATERIALS AND METHODS: Six mongrel dogs were assigned to receive celecoxib, cisapride, and placebo using a randomized cross-over design with a 1-week washout period between treatments. Prior to dosing, each dog underwent an esophagopexy to provide access to the esophagus and stomach. On the fourth day of dosing, sphincter tone was measured in awake unsedated dogs using radial manometry. In a different set of six dogs, liquid and solid gastric emptying rates were scintigraphically determined. RESULTS: Celecoxib significantly increased mean and average maximum lower esophageal pressures compared to placebo without affecting the gastric emptying rate. The magnitudes of these increases were similar to that produced by cisapride. CONCLUSIONS: Celecoxib had a positive effect on canine lower esophageal sphincter tone. This finding, combined with the drug's low incidence of gastrointestinal toxicity, suggests that celecoxib may warrant consideration and investigation as a pharmacotherapy for human reflux disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12384079&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11.

Trifan OC, Durham WF, Salazar VS, Horton J, Levine BD, Zweifel BS, Davis TW, Masferrer JL.

Oncology Pharmacology, Pharmacia Corp., Chesterfield, Missouri 63198, USA. ovidiu.c.trifan pharmacia.com

Combining anticancer drugs with different mechanisms of action has the potential to enhance antitumor effect. CPT-11 (Camptosar, irinotecan), a topoisomerase I inhibitor, has been shown to be highly effective in the treatment of a variety of cancers. However, its clinical usage is often complicated by late diarrhea. A number of studies have shown that cyclooxygenase (COX)-2 is overexpressed in many forms of human tumors, suggesting that COX-2 inhibition may be useful in the treatment of cancer. In this study, we used two mouse tumor models (HT-29 and colon-26 cells) to evaluate the effect of combining CPT-11 with celecoxib on tumor growth. We also assessed the involvement of COX-2 in the pathogenesis of CPT-11-induced late diarrhea using a rat model. Results indicate that celecoxib enhances the antitumor effect of CPT-11 and reduces the severity of late diarrhea in a dose-dependent manner. The extended benefits of combining celecoxib with CPT-11 may significantly improve the outcome of cancer patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12384538&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase.

Sandberg M, Yasar U, Stromberg P, Hoog JO, Eliasson E.

Division of Clinical Pharmacology, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden.

AIMS: Celecoxib is a novel selective cyclooxygenase-2 inhibitor, which is subject to extensive hepatic metabolism. The aims of the present in vitro investigation were 1) to compare the rate of celecoxib hydroxylation by different genetic variants of cytochrome P450 2C9 (CYP2C9), and 2) to identify the enzyme(s) involved in the formation of the major metabolite carboxycelecoxib. METHODS: Hydroxycelecoxib formation was studied in human liver microsomes from 35 genotyped livers, as well as in yeast microsomes with recombinant expression of different P450 variants. Carboxycelecoxib formation was studied in liver microsomes incubated in the absence or presence of liver cytosol. The metabolites were identified and quantified by h.p.l.c. In addition, hydroxycelecoxib oxidation by different variants of recombinant human alcohol dehydrogenase (ADH1-3) was analysed by spectrophotometric monitoring of NADH generation from NAD+. RESULTS: The intrinsic clearance of celecoxib hydroxylation was significantly lower for yeast-expressed CYP2C9.3 (0.14 ml min-1 nmol-1 enzyme) compared with CYP2C9.1 (0.44 ml min-1 nmol-1 enzyme). In human liver microsomes, a significant 2-fold decrease in the rate of hydroxycelecoxib formation was evident in CYP2C9*1/*3 samples compared with CYP2C9*1/*1 samples. There was also a marked reduction (up to 5.3 times) of hydroxycelecoxib formation in a liver sample genotyped as CYP2C9*3/*3. However, the CYP2C9*2 samples did not differ significantly from CYP2C9*1 in any of the systems studied. Inhibition experiments with sulphaphenazole (SPZ) or triacetyloleandomycin indicated that celecoxib hydroxylation in human liver microsomes was mainly dependent on CYP2C9 and not CYP3A4. The further oxidation of hydroxycelecoxib to carboxycelecoxib was completely dependent on liver cytosol and NAD+. Additional experiments showed that ADH1 and ADH2 catalysed this reaction in vitro with apparent K m values of 42 micro m and 10 micro m, respectively, whereas ADH3 showed no activity. CONCLUSIONS: The results confirm that CYP2C9 is the major enzyme for celecoxib hydroxylation in vitro and further indicate that the CYP2C9*3 allelic variant is associated with markedly slower metabolism. Furthermore, it was shown for the first time that carboxycelecoxib formation is dependent on cytosolic alcohol dehydrogenase, presumably ADH1 and/or ADH2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12392591&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
COX-2-specific inhibitors: prescribing patterns in a large managed care health system and strategies to minimize costs.

Weideman RA, Kelly KC, Kelley CL, Cryer B.

Department of Veterans Affairs, North Texas Health Care System, Dallas 75216, USA. Rick.Weideman med.va.gov

OBJECTIVE: To determine the relative costs associated with the exclusive use of celecoxib versus rofecoxib in a large managed care system. STUDY DESIGN: A retrospective review of all calendar year 2000 prescriptions dispensed for celecoxib and rofecoxib in the Veterans Affairs (VA) system. METHODS: The primary data points included drug strength, quantity dispensed, and days supply for the prescription. The cost minimization model described in Federal Practitioner (1999;16[4]:41-44) was used to calculate the cost savings. The mean once-daily dosing rates and their 95% confidence intervals were determined by binomial data analysis. Calendar year 2001 utilization and cost projections were derived by linear regression trend analysis. RESULTS: Current VA system costs per dose are celecoxib 100 mg $0.66; celecoxib 200 mg $1.32; rofecoxib (12.5 or 25 mg) $1.32; rofecoxib 50 mg $2.14. During calendar year 2000, the VA spent $13.8 million and $4.2 million on celecoxib and rofecoxib, respectively. The percentage of once-daily or less than once-daily dosing was celecoxib 100 mg (17%), celecoxib 200 mg (67%), celecoxib overall (49%), rofecoxib 12.5 mg (86%), rofecoxib 25 mg (94%), rofecoxib 50 mg (100%), and rofecoxib overall (93%). Based on current utilization, if all celecoxib prescriptions were changed to rofecoxib, the VA would have realized annual cost savings of $2.1 million in calendar year 2000. In calendar year 2001, projected cost savings could total $5.2 million. This potential savings is largely due to the high prevalence of twice-daily celecoxib dosing. CONCLUSION: The results of the cyclooxygenase-2 cost minimization analysis provide a compelling argument for the preferred use of rofecoxib in the VA system, and potentially in other managed care systems.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12395955&dopt=Abstract celecoxib, Celebrex