celecoxib, Celebrex
Improvement of physical stability and dissolution rate of celecoxib suspensions by complexation with beta-cyclodextrins.

Chandra Sekhara Rao G, Satish Kumar M, Mathivanan N, Bhanoji Rao ME.

Pharmaceutics Division, Roland Institute of Pharmaceutical Sciences, Berhampur, Orissa, India. gonuguntac yahoo.co.in

Solid dispersions of celecoxib with beta-cyclodextrins were prepared by physical mixing, slugging and kneading methods at 1:1 and 1:2 molar ratios and characterized by differential scanning calorimetry. Celecoxib suspensions were formulated employing its solid dispersions with sodium carboxymethylcellulose as the suspending agent. Stability studies were conducted by subjecting all the suspensions to freeze-thaw cycling. The suspensions were evaluated for particle size, sedimentation volume, viscosity, redispersibility and dissolution rate initially and after stability testing. Celecoxib suspensions formulated employing its solid dispersions exhibited good physical stability and gave higher dissolution rates than those formulated with celecoxib alone. The suspension prepared from solid dispersions (1:2) by the kneading method gave the highest improvement in dissolution rate and efficiency. Celecoxib in the inclusion complex with beta-cyclodextrin produced suspensions of better physical stability and dissolution rate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15378853&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumour activity of doxorubicin?

Awara WM, El-Sisi AE, El-Sayad ME, Goda AE.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31111, Egypt. wagawara yahoo.com

The potential anti-tumour activity of non-steroidal anti-inflammatory drugs (NSAIDS) has been previously discussed. This study was undertaken to assess the possible anti-tumour activity of the cyclooxygenase-2 (COX-2) inhibitor; celecoxib in an animal model of mammary carcinoma; the solid Ehrlich carcinoma (SEC). The possibility that celecoxib may modulate the anti-tumour activity of doxorubicin on the SEC was also studied. Some of the possible mechanisms underlying such modulation were investigated. The anti-tumour activity of celecoxib (25 mg kg(-1)), diclofenac (12.5 mg kg(-1)) and doxorubicin (2 mg kg(-1)) either alone or in combination were investigated on SEC in vivo through the assessment of tumour growth delay (TGD) and tumour volume (TV), changes in tumour DNA content and nitric oxide (NO) levels, immunohistochemical staining of the tumour suppressor gene product; p53 histopathological examination and determination of apoptotic index of SEC. In addition, the influence of these drugs on the DNA fragmentation pattern of Ehrlich carcinoma cells (ECC) was studied. It was found that both celecoxib and diclofenac lack the anti-tumour activity on SEC. In addition there was a significant increase in doxorubicin anti-tumour activity when administered in combination with celecoxib. Moreover, it was found that both celecoxib and diclofenac have the potential to inhibit the function of P-glycoprotein (P-gp) in ECC using rhodamine uptake and efflux assays. Therefore, the current study suggested the chemosensitizing potential of celecoxib in the SEC animal model of mammary tumour, which could be explained in part on the basis of inhibition of P-gp function, with possible enhancement of doxorubicin anti-tumour activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15458769&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effects of celecoxib on high-sensitivity C-reactive protein in chronic peritoneal dialysis patients.

Kim SB, Kim SH, Chang JW, Lee SK, Min WK, Chi HS, Park JS.

Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.

To evaluate the effects of celecoxib, a cyclooxygenase-2 inhibitor, on the level of high-sensitivity C-reactive protein (hs-CRP), D-dimer, von Willebrand factor (vWF) and troponin-T, 46 chronic peritoneal dialysis (CPD) patients with hs-CRP equal or greater than 0.25 mg/dL were randomized to the treatment group who took 200 mg of celecoxib daily for 4 weeks or to the control group who did not take the medication. The levels of hs-CRP, albumin, D-dimer, vWF and troponin-T were measured at baseline and at 4 weeks of the study. Baseline values of all the parameters were not significantly different between the two groups. In the control group, the levels of hs-CRP, albumin, D-dimer, vWF and troponin-T did not change. In the treatment group, administration of celecoxib for 4 weeks significantly reduced hs-CRP from median 0.77 (range 0.25-7.08) to 0.39 mg/dL (range 0.11-5.22, p<0.05). The levels of albumin, D-dimer, vWF and troponin-T levels were not affected by the administration of celecoxib. These results showed that celecoxib had an antiinflammatory effect in usual dosage in CPD patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15462105&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Prevention by celecoxib of secondary hyperalgesia induced by formalin in rats.

Veiga AP, Duarte ID, Avila MN, da Motta PG, Tatsuo MA, Francischi JN.

Departamento de Farmacologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, Campus da Pampulha, CEP31270-901, Belo Horizonte, Minas Gerais, Brazil.

Administration of formalin in rat paws results in stimulation of nociceptive pathways, which leads to an increase in the excitability of neurons present in dorsal horn. This increased neuron excitability, described as central sensitization, may result in development of inflammatory pain at a distant site of injury application, known as secondary hyperalgesia. The aim of the present study was to verify whether formalin injection in rat paws would lead to secondary hyperalgesia development, as measured by the tail-flick test. We also aimed to investigate whether celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, would affect secondary hyperalgesia. Formalin injected into the rat paws significantly reduced the latency for a flick response in the rat tail, which characterized development of secondary hyperalgesia. In addition, formalin-induced secondary hyperalgesia was locally prevented by pre-but not post-celecoxib treatment. However, celecoxib administered spinally inhibited formalin-induced secondary hyperalgesia, either administered previously or following formalin. In contrast, piroxicam, an unspecific COX inhibitor which displays an increased selectivity towards COX-1, only prevented secondary hyperalgesia to formalin at a high dose following spinal administration. Taken together, these results suggest that COX-2 plays an important role both in the central and in the peripheral nerve sensitization following formalin administration in rat paws. They also suggested that once central sensitization starts it can no longer be blocked by a specific COX-2 inhibitor administered locally. Notwithstanding, spinal administration of a specific COX-2 inhibitor still blocks ongoing sensitization and prevents maintenance of central sensitization. Copyright 2004 Elsevier Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15464832&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis.

Chen X, Wang S, Wu N, Sood S, Wang P, Jin Z, Beer DG, Giordano TJ, Lin Y, Shih WC, Lubet RA, Yang CS.

Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA. xiaochen rci.rutgers.edu

PURPOSE: Aberrant arachidonic acid (AA) metabolism, especially through the cyclooxygenase (Cox) and 5-lipoxygenase (5-Lox) pathways, has been suggested to play an important role in the development of esophageal adenocarcinoma (EAC). The purpose of this study was to investigate the expression of 5-Lox in EAC of a rat model and in human samples as well as the chemopreventive effects of zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor) in the rat EAC model. EXPERIMENTAL DESIGN: 5-Lox expression in EAC of a rat esophagogastroduodenal anastomosis model and of humans was examined with immunohistochemistry. A chemoprevention study was designed to test whether zileuton and celecoxib could suppress aberrant AA metabolism and esophageal adenocarcinogenesis. RESULTS: With immunohistochemistry, we found that 5-Lox was overexpressed during esophageal adenocarcinogenesis in our rat model and in humans. In the chemoprevention study, EAC incidence was reduced in a dose-dependent manner from 68.8% (11 of 16) to 44.4% (8 of 18; P > 0.05) and 31.3% (5 of 16; P < 0.05) by 500 and 1,000 ppm zileuton, respectively, and to 33.3% (7 of 21; P < 0.05) and 20% (3 of 15; P < 0.05) by 500 and 1,000 ppm celecoxib, respectively. With isobolographic analysis, zileuton and celecoxib, both at a dose of 500 ppm, had an additive effect by reducing the tumor incidence to 16.7% (3 of 18, P < 0.01). Leukotriene B4 and prostaglandin E2 levels in the esophageal tissues were also significantly reduced by zileuton and celecoxib. CONCLUSIONS: This study clearly demonstrated that 5-Lox and Cox2 play important roles in the development of EAC. Both zileuton and celecoxib had inhibitory effects on esophageal adenocarcinogenesis through inhibition on their respective enzymes of AA metabolism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15475461&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The spectrum of gastrointestinal toxicity and effect on disease activity of selective cyclooxygenase-2 inhibitors in patients with inflammatory bowel disease.

Matuk R, Crawford J, Abreu MT, Targan SR, Vasiliauskas EA, Papadakis KA.

Department of Medicine, Division of Gastroenterology, Cedars-Sinai Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

The safety and toxicity associated with the use of selective cyclooxygenase-2 (COX-2) inhibitors in patients with inflammatory bowel disease (IBD) has not been extensively studied. Thirty-three patients with IBD who were prescribed celecoxib or rofecoxib were identified from questionnaire during their clinic visit at the Cedars-Sinai IBD Center between 1999 and 2002. Twenty-six had Crohn's disease (CD), 6 had ulcerative colitis (UC), and 1 had indeterminate colitis (IC). Twenty-one received rofecoxib, 10 celecoxib, and 2 received both medications at different time points. Overall, 13 (39%) patients experienced disease exacerbation, 7 of which had received celecoxib and six rofecoxib. IBD exacerbation associated with COX-2 treatment did not correlate with age, disease activity, or use of immunosuppressive medications. All patients experienced flare-up of their underlying IBD within 6 weeks of initiating COX-2 therapy. Five of 13 (38%) patients had resolution of their symptoms after discontinuing the COX-2 inhibitor, but the remaining patients required additional medical therapy to control their disease. Six other patients (18%) experienced GI side effects not associated with their underlying IBD. Five developed abdominal pain, and one developed a duodenal ulcer and a circumferential ileo-colonic ulceration with GI bleeding. Treatment with COX-2 inhibitors is associated with a high incidence of exacerbation of the underlying IBD and GI-related complications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15475742&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effect of chronic intake of NSAIDs and cyclooxygenase 2-selective inhibitors on esophageal cancer incidence.

Bardou M, Barkun AN, Ghosn J, Hudson M, Rahme E.

Division of Gastroenterology, Department of Medicine, McGill University and McGill University Health Center, Montreal, Quebec, Canada. marc.bardou u-bourgogne.fr

BACKGROUND & AIMS: A rising incidence and a poor survival rate make esophageal cancer a major health issue, hence the need for chemoprevention. We investigated the effects of the selective cyclooxygenase 2 inhibitors (coxibs), rofecoxib and celecoxib, the nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin on esophageal cancer. METHODS: This nested case-control study used data from a government-run insurance database on patients 66 years and older who underwent esophageal imaging (esophagogastroduodenoscopy or barium swallow) between January 1999 and September 2002. Logistic regression models were used to determine the effect of chronic exposure, by using as proxy at least 30 days of use of the drugs of interest in the past year, on the occurrence of esophageal cancer. RESULTS: The study included 251 cases and all 86,644 eligible control subjects. Patients more likely to have esophageal cancer (odds ratio, 95% confidence interval) were men (3.42, 2.62-4.48) and older subjects (those 75-84 years and those > or =85 years: 1.40, 1.08-1.82 and 1.69, 1.05-2.72, respectively). Chronic exposure to coxibs or NSAIDs was associated with a significant risk reduction for esophageal cancer (0.63, 0.40-0.98 and 0.47, 0.24-0.93, respectively). Assessed separately, the point estimates were slightly lower for rofecoxib than for celecoxib when examining a possible duration-response effect, although all 95% confidence intervals overlapped (celecoxib: 0.51, 0.27-0.98; 0.30, 0.11-0.82; 0.39, 0.14-1.05; rofecoxib: 0.39, 0.16-0.96; 0.37, 0.12-1.16; 0.33, 0.08-1.36 for exposures of > or =30, > or =60, and > or =90 days, respectively). CONCLUSIONS: Chronic intake of rofecoxib and celecoxib and of nonselective NSAIDs appears to be associated with a decreased incidence of esophageal cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15476151&dopt=Abstract celecoxib, Celebrex