celecoxib, Celebrex
[Safety of celecoxib administration]

[Article in Croatian]

Babic-Naglic D.

Klinika za reumatske bolesti i rehabilitaciju, KBC Zagreb, Kispaticeva 12, 10000 Zagreb.

Celecoxib is selective cylooxygenase-2 (COX-2) inhibitor with equal efficacy like conventional non-steroidal antiinflammatory drugs (NSAIDs). The main advantage is safer gastrointestinal (GI) profile. All other adverse effects of celecoxib are comparable with NSAIDs adverse reactions. Clinical studies in thousands of patients show convincing evidence of GI safety in total number of GI events. The serious GI complications could not be excluded regarding safety. There is no antithrombotic effect and caution is required in elderly, hypertension, oedema, vascular and ulcer diseases. Cardioprotective aspirin therapy may be indicated in persons with cardiovascular risk. Celecoxib is contraindicated in people with known allergy on sulfonamides. The caution is needed in any NSAIDs allergy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12476757&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Spherical crystallization of celecoxib.

Paradkar AR, Pawar AP, Chordiya JK, Patil VB, Ketkar AR.

Department of Pharmaceutics, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Erandwane, Pune 411 038, Maharashtra, India. arparadkar rediffmail.com

Celecoxib exhibits poor flow properties and compressibility. Spherical crystallization of celecoxib was carried out using the solvent change method. An acetone:dichloromethane (DCM):water system was used where DCM acted as a bridging liquid and acetone and water as good and bad solvent, respectively. Hydroxypropylmethylcellulose (HPMC) was used to impart strength and sphericity to the agglomerates. The effect of amount of bridging liquid and speed of agitation was studied using 3(2) factorial design. Primary properties of the agglomerates were evaluated by infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The effect of variables on micromeritic, mechanical, compressional, and dissolution behavior was evaluated by response surface methodology. Particle size, bulk density, mean yield pressure (MYP), and drug release were found to be significantly affected by either of the two variables. Interaction of variables significantly affected the MYP.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12476867&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Induction of apoptosis in rheumatoid synovial fibroblasts by celecoxib, but not by other selective cyclooxygenase 2 inhibitors.

Kusunoki N, Yamazaki R, Kawai S.

St. Marianna University School of Medicine, Kawasaki, Japan.

OBJECTIVE: Selective cyclooxygenase 2 (COX-2) inhibitors are now being used as antiinflammatory agents that cause fewer gastrointestinal complications, compared with other antiinflammatory drugs, in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether selective COX-2 inhibitors could induce apoptosis of RA synovial fibroblasts (RASFs). METHODS: RASFs were exposed to selective COX-2 inhibitors, i.e., celecoxib, etodolac, meloxicam, nimesulide, N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide, and rofecoxib, under various conditions. Cell proliferation and cell viability were assessed by incorporation of 5-bromo-2'-deoxyuridine and by the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, respectively. Apoptosis was detected by identifying DNA fragmentation. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) was measured by the luciferase reporter gene assay with a PPAR response element-driven luciferase reporter plasmid and a PPARgamma expression plasmid. RESULTS: Celecoxib strongly inhibited the proliferation of RASFs, whereas other selective COX-2 inhibitors had little or no effect. In addition, celecoxib reduced the viability of RASFs by induction of apoptosis, in a concentration-dependent manner. This action was abolished by addition of caspase inhibitors. Interleukin-1beta had a weak enhancing effect on celecoxib-induced apoptosis in RASFs. In contrast, other selective COX-2 inhibitors at concentrations up to 100 microM did not induce apoptosis of RASFs. Indomethacin, a nonselective COX inhibitor, activated PPARgamma transcription, while celecoxib did not. CONCLUSION: Celecoxib suppressed the proliferation of RASFs by COX-2-independent and PPARgamma-independent induction of apoptosis. Although the mechanism involved remains unclear, celecoxib may have not only antiinflammatory activity, but also a disease-modifying effect on rheumatoid synovial proliferation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12483719&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Chemopreventive effect of celecoxib and expression of cyclooxygenase-1 and cyclooxygenase-2 on chemically-induced rat mammary tumours.

Jang TJ, Jung HG, Jung KH, O MK.

Department of Pathology, Dongguk University College of Medicine, Kyongju, Kyongbuk, Korea. taejung mail.dongguk.ac.kr

We investigated the chemopreventive effect of celecoxib on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumours and also the expression and immunolocalization of cyclooxygenase-1 (COX-1) and COX-2 in the various stages of rat mammary carcinogenesis. Rats were divided into normal control group, DMBA-control group, 500 p.p.m. celecoxib-treated group, and 1500 p.p.m. celecoxib-treated group. Both incidence and multiplicity values of tumour for rats treated with celecoxib were less than those in rats of the DMBA-control group. The level of prostaglandin E2 was higher in tumours of the DMBA-control and both celecoxib-treated groups compared to normal mammary glands of each group. In Western blot analysis, all tumours of the DMBA-control group expressed COX-1, whereas normal mammary glands showed insignificant expression. COX-2 expression was observed in 67% of the DMBA-control group and 20% of both celecoxib-treated groups and was absent in normal mammary glands. COX-1 protein was localized in the nuclear membrane and cytoplasm of epithelial tumour cells abutting on glandular lumen, stromal cells, and endothelial cells. COX-2 protein was detected in the perinuclear cytoplasm of tumour cells bordering on glandular lumen and surrounding stroma, stromal cells, and vascular smooth muscle. In the DMBA-control group, invasive carcinoma cells showed higher positive immunoreactivity of COX-2 than carcinomas in situ and atypical tumours. Tumours displayed an increased number of mast-like cells with COX-2 expression in comparison to carcinomas in situ. Our results suggest that COX-1 and COX-2 expression in tumour cells and stromal cells play an important role in the various stages of DMBA-induced rat mammary carcinogenesis. In addition, we reconfirm that celecoxib reduces the growth of DMBA-induced rat mammary tumours.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12485462&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Insulin-like growth factor-I antagonizes the antiproliferative effects of cyclooxygenase-2 inhibitors on BxPC-3 pancreatic cancer cells.

Levitt RJ, Pollak M.

Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada, H3T 1E2.

Cyclooxygenase (COX)-2 inhibitors demonstrate modest antineoplastic activity in experimental models of human malignancies, but little is known about factors that may confer resistance to their antiproliferative actions. We observed that fetal bovine serum antagonizes growth inhibition and G(1) arrest induced by two COX-2 inhibitors (NS-398 and celecoxib) on BxPC-3 pancreatic cancer cells. We investigated the hypothesis that insulin-like growth factor I (IGF-I), a major survival factor present in serum, mediates these effects. Treatment of BxPC-3 cells with 25 micro M celecoxib in 1% fetal bovine serum-containing medium for 48 h resulted in a approximately 40% decrease in cell viability. Coincubation of BxPC-3 cells with 25 micro M celecoxib and 50 ng/ml IGF-I resulted in complete attenuation of the celecoxib-associated decrease in cell viability. Cell cycle analysis revealed that this IGF-I-induced increase in cell viability was correlated with an IGF-I-induced inhibition of celecoxib-mediated G(1) arrest. Similar results were observed when another COX-2 inhibitor (50 micro M NS-398) was used. When IGF-binding protein-3 (an inhibitor of IGF-I bioactivity) was added in combination with 25 micro M celecoxib, enhanced growth inhibition was observed (approximately 60% decrease in cell viability). Treatment of BxPC-3 cells with a higher dose (50 micro M) of celecoxib for 24 h resulted in the induction of apoptosis, as assayed by flow cytometry and poly(ADP-ribose) polymerase cleavage. Addition of 50 ng/ml IGF-I resulted in a complete attenuation of celecoxib-induced apoptosis. The protection from celecoxib-induced apoptosis by IGF-I correlated with an increase in the levels of the activated antiapoptotic protein Akt. These results suggest that alterations of IGF-I levels or IGF-I receptor signal transduction modulate the antineoplastic actions of COX-2 inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12499282&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Inhibition of cyclooxygenase-2 by celecoxib reverses tumor-induced wasting.

Davis TW, Zweifel BS, O'Neal JM, Heuvelman DM, Abegg AL, Hendrich TO, Masferrer JL.

Oncology, PTC Therapeutics, South Plainfield, NJ 07080, USA. tdavis ptcbio.com

There have been a number of reports suggesting inhibition of prostaglandin production may impact tumor-mediated wasting and levels of associated humoral factors such as hypercalcemia. These reductions were achieved using traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which are often contraindicated in cancer patients. This is especially true during chemotherapeutic regimens due to concerns of bleeding from gastrointestinal and hematopoietic toxicities associated with inhibition of the housekeeping cyclooxygenase enzyme COX-1. Here, we report that celecoxib, one of the new class of selective COX-2 inhibitors, has the potential to reverse tumor-mediated wasting and associated humoral factors such as interleukin (IL)-6 and hypercalcemia in preclinical models of cachexia. Tumor bearing mice in late stage cachexia regained weight within days of the start of celecoxib treatment. Two models were tested. The first was the Colon 26 (Col26) syngeneic murine model that induces high levels of circulating IL-6 and hypercalcemia. The second was the human head and neck 1483 HNSCC xenograft model, which is less inflammatory and produces less prostaglandin than Col26. Despite the observation that no significant impact on tumor growth was observed between vehicle and celecoxib-treated animals over the course of the studies, celecoxib rapidly reversed weight loss in both cachectic models. With the added safety of celecoxib over traditional NSAIDs, these results suggest a possible therapeutic use for celecoxib for treating tumor-mediated wasting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14711936&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model.

Ayalasomayajula SP, Kompella UB.

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-6025, USA.

Overexpression of vascular endothelial growth factor (VEGF) is implicated in the development of vascular leakage and retinal neovascularization in diabetic subjects. The objective of this study was to determine whether celecoxib, a selective cyclooxygenase-2 enzyme inhibitor, reaches ocular tissues following oral administration and inhibits the retinal VEGF expression and vascular leakage in a streptozotocin-induced diabetic rat model. After administering a single intraperitoneal injection of streptozotocin (60 mg/kg) to Sprague-Dawley rats and ensuring the induction of diabetes at the end of 24 h, celecoxib was administered b.i.d. by oral gavage (50 mg/kg). On day 8, the animals were sacrificed and the retinal VEGF and cyclooxygenase-2 mRNA levels, ocular tissue celecoxib concentrations, and the vitreous/plasma protein ratio were determined. In diabetic rats, the retinal VEGF mRNA expression was 2.3-fold compared to controls, with a corresponding increase in cyclooxygenase-2 mRNA expression. Celecoxib treatment inhibited VEGF mRNA expression without any significant reduction in cyclooxygenase-2 mRNA. Furthermore, the retinal vascular leakage estimated as vitreous to plasma protein ratio increased in diabetic animals from 0.35+/-0.1 to 1.1+/-0.1 and celecoxib treatment significantly decreased this ratio to 0.4+/-0.1. Celecoxib levels were 24.8+/-6.6, 1.9+/-1, 1.7+/-0.8, and 6.9+/-0.9 ng/mg in the retina, vitreous, lens, and cornea, respectively. The plasma celecoxib levels were 85+/-24 ng/ml. Thus, celecoxib reaches the retina after oral administration and reduces diabetes-induced retinal VEGF mRNA expression and vascular leakage by inhibiting the activity of cyclooxygenase-2 enzyme.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12504784&dopt=Abstract celecoxib, Celebrex