celecoxib, Celebrex
Direct evidence for a role of cyclooxygenase 2-derived prostaglandin E2 in human head and neck xenograft tumors.

Zweifel BS, Davis TW, Ornberg RL, Masferrer JL.

Pharmacology/Oncology, Pharmacia Corporation, St. Louis, Missouri 63198, USA.

Both nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX) 2-selective inhibitors such as celecoxib are being reported as having potent anticancer activity in laboratory models. Several reports have suggested that the mechanism of action of these agents in reducing tumor volume/burden is unrelated to their inhibition of prostaglandin synthesis. Many in vitro reports use supraphysiological concentrations of these drugs to demonstrate COX-independent activities on apoptosis or proliferation. In vivo, most murine tumor models express COX-2 only in the vasculature and stroma, unlike human tumors that also express COX-2 in the tumor cells. In general, these models have the limitation of having no measurable, COX-2-derived, prostaglandins, the inhibition of which correlates with antitumor efficacy. We report here that 1483 human head and neck xenograft tumors express COX-2 similar to the pattern observed in human solid tumors and that COX-2 activity produces high levels of prostaglandin E2 (PGE2). Inhibition of COX-2 by celecoxib resulted in loss of intratumor PGE2 levels and reduced tumor growth in a dose-dependent manner. In contrast, a selective COX-1 inhibitor, SC-560, did not measurably reduce tumor prostaglandin levels or tumor growth despite the presence of COX-1 in the host and tumor cells. Celecoxib-treated tumors showed reduced proliferation and increased apoptosis of both tumor and stromal cells compared with vehicle controls. Specific inhibition of PGE2 activity by a neutralizing antibody mimicked the reduced tumor growth observed after celecoxib treatment, suggesting growth is PGE2 mediated. These data indicate that a major antitumor mechanism of action of celecoxib is inhibition of COX-2-derived prostaglandins, particularly PGE2, and suggest celecoxib as a novel therapeutic agent for human head and neck cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12438270&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effect of the antenatal administration of celecoxib during the second and third trimesters of pregnancy on prostaglandin, cytokine, and nitric oxide levels in rabbits.

Hausman N, Beharry KD, Nishihara KC, Akmal Y, Asrat T.

Division of Maternal-Fetal Medicine, Women's Hospital, Long Beach Memorial Medical Center, 2801 Atlantic Avenue, Long Beach, CA 90801-1428, USA.

OBJECTIVE: The purpose of this study was to examine the effects of celecoxib on prostaglandin, cytokine, and nitric oxide synthesis in the pregnant rabbit. STUDY DESIGN: Pregnant rabbits received celecoxib from 13 to 20 days (celecoxib-A), from 13 to 28 days (celecoxib-B), or vehicle from 13 to 28 days by gavage. Blood and tissue were assayed for prostaglandin, cytokine, and nitric oxide oxidation products. RESULTS: Preterm delivery occurred in 4 of 11 controls, 0 of 9 in celecoxib-A, and 0 of 8 in celecoxib-B. Plasma prostaglandin F(2alpha) was reduced in both treated groups at 20 days and at delivery in celecoxib-B. Plasma thromboxane B(2) was suppressed in celecoxib-B at 20 days and delivery. Cervical prostaglandin E(2) was increased; uterine and cervical plasma thromboxane B(2) declined in celecoxib-B. Celecoxib administration suppressed plasma nitric oxide oxidation products at delivery and cervical nitric oxide oxidation products in celecoxib-B. Uterine and cervical interleukin-1beta and interleukin-6 were decreased, and uterine tumor necrosis factor-alpha increased in celecoxib-B. CONCLUSION: Further studies are required to evaluate the therapeutic benefits of cyclo-oxygenase-2 inhibitors in the setting of preterm parturition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14710107&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice.

Cutts C, LaCaze A, Tett S.

Queensland Rural Medical Support Agency, 467 Enoggera Road, Alderley, Queensland 4051, Australia. christopher qrmsa.com.au

AIMS: The new cyclooxygenase-2 (COX-2) selective inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx), have been widely prescribed since their launch. No reviews currently appear in the literature of prescribing patterns in Australia. This paper describes a self-audit of the clinical use of selective COX-2 inhibitor therapy undertaken with rural general practitioners (GPs) in Australia. METHODS: A structured audit form was developed and distributed to interested GPs. The form was self-administered and focused on issues about COX-2 inhibitors and the types of patients who were receiving them, e.g. indications, patient demographics, risk factors and drug interactions. RESULTS: A total of 627 patients were recruited (569 celecoxib and 58 rofecoxib). A range of doses was prescribed. Osteoarthritis was the most common indication (68.1%). Risk factors known for the nonselective nonsteroidal anti-inflammatory drugs were identified in 65.1% of patients, with the most common being advanced age, hypertension and previous peptic ulcer disease. Potential drug interactions were common. A variety of reasons for initiation of therapy was identified; these included perceived increased efficacy, safety and failure of other treatment. CONCLUSIONS: These results show that COX-2 inhibitors are being prescribed for patients with multiple risk factors that may place the patient at increased risk of adverse drug reactions to a COX-2 inhibitor. The perception of improved safety and efficacy was common and is of concern. Limitations of the study include the reliance on self-reporting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12445032&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Simultaneous determination of celecoxib, hydroxycelecoxib, and carboxycelecoxib in human plasma using gradient reversed-phase liquid chromatography with ultraviolet absorbance detection.

Stormer E, Bauer S, Kirchheiner J, Brockmoller J, Roots I.

Institute of Clinical Pharmacology, University Medical Center Charite, Humboldt University Berlin, Schumannstrasse 20/21, 10098, Berlin, Germany. elke.stoermer charite.de

A new HPLC method for the simultaneous determination of celecoxib, carboxycelecoxib and hydroxycelecoxib in human plasma samples has been developed. Following a solid-phase extraction procedure, the samples were separated by gradient reversed-phase HLPC (C(18)) and quantified using UV detection at 254 nm. The method was linear over the concentration range 10-500 ng/ml. The intra-assay variability for the three analytes ranged from 4.0 to 12.6% and the inter-assay variability from 4.9 to 14.2%. The achieved limits of quantitation (LOQ) of 10 ng/ml for each analyte allowed the determination of the pharmacokinetic parameters of the analytes after administration of 100 mg celecoxib.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12450540&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Arthritis treatment in Hong Kong--cost analysis of celecoxib versus conventional NSAIDS, with or without gastroprotective agents.

You JH, Lee KK, Chan TY, Lau WH, Chan FK.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong. joyceyou cuhk.edu.hk

BACKGROUND: Selective cyclo-oxygenase-2 inhibitors have been reported to cause fewer gastrointestinal complications when compared with conventional, non-selective, non-steroidal anti-inflammatory drugs (NSAIDs). AIM: To analyse the cost of celecoxib (selective cyclo-oxygenase-2 inhibitor) and conventional NSAID regimens for the treatment of osteoarthritis and rheumatoid arthritis from the perspective of a public health organization in Hong Kong. METHODS: A decision tree was used to analyse the cost of celecoxib, NSAID alone, NSAID plus histamine2-receptor antagonist, NSAID plus misoprostol and NSAID plus proton pump inhibitor over 6 months. Model outcomes were no gastrointestinal toxicity, gastrointestinal discomfort, symptomatic ulcer, anaemia with occult bleeding and serious gastrointestinal complications. The clinical probabilities were estimated from clinical trials. Resource utilization for gastrointestinal events was determined locally. Sensitivity analysis was performed. RESULTS: The 6-month costs per base-case analysis were as follows: NSAID plus histamine2-receptor antagonist, 1404 HK dollars (1 US dollar = 7.8 HK dollars); celecoxib, 1545 HK dollars; NSAID alone, 1610 HK dollars; NSAID plus misoprostol, 2213 HK dollars; NSAID plus proton pump inhibitor, 2857 HK dollars. The model was sensitive to the patients' underlying gastrointestinal risk scores, daily cost of NSAID regimen, risk ratio of NSAID plus histamine2-receptor antagonist for symptomatic ulcer, daily cost of celecoxib and daily cost of histamine2-receptor antagonist. CONCLUSIONS: Celecoxib appeared to be the least costly alternative in patients with intermediate to high gastrointestinal risk for the treatment of osteoarthritis and rheumatoid arthritis in Hong Kong.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12452942&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Response of fetal prostanoids, nitric oxide, and ductus arteriosus to the short- and long-term antenatal administration of celecoxib, a selective cyclo-oxygenase-2 inhibitor, in the pregnant rabbit.

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

Division of Maternal-Fetal Medicine, Women's Hospital, Long Beach Memorial Medical Center, 2801 Atlantic Avenue, Long Beach, CA 90801-1428, USA.

OBJECTIVE: The purpose of this study was to test the hypothesis that the maternal administration of therapeutic doses of celecoxib would not affect ductus arteriosus patency or alter renal and hepatic prostanoids in the fetal rabbit. STUDY DESIGN: Pregnant rabbits received celecoxib from 13 to 20 days (celecoxib-A), from 13-28 days (celecoxib-B), or vehicle from 13 to 28 days by gavage. Fetal serum and lung tissue were analyzed for nitric oxide oxidation products. Fetal plasma, liver, and kidney were analyzed for prostaglandin levels. RESULTS: The ductus arteriosus was patent in both treatment groups. Celecoxib induced elevations of plasma prostaglandin E(2) production. In celecoxib-B liver and kidney, the 6-keto-prostaglandin F(1alpha) and prostaglandin F(2alpha) levels were increased, and the prostaglandin E(2) and thromboxane B(2) levels were decreased substantially. CONCLUSION: This preliminary evaluation demonstrates that the maternal administration of celecoxib does not influence fetal ductus arteriosus patency adversely in rabbits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14710108&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents.

Zhu J, Song X, Lin HP, Young DC, Yan S, Marquez VE, Chen CS.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210-1291, USA.

BACKGROUND: The cyclooxygenase-2 (COX-2) inhibitor celecoxib is thought to act as a chemopreventive agent by sensitizing cancer cells to apoptotic signals. Other COX-2 inhibitors, such as rofecoxib, are two orders of magnitude less potent than celecoxib at inducing apoptosis. The molecular structures of celecoxib and rofecoxib were used as starting points to examine the structural features that contribute to this discrepancy. METHODS: We used a systematic chemical approach to modify the structures of celecoxib and rofecoxib to produce a series of compounds that were tested for their effects on the viability of human prostate cancer PC-3 cells and their ability to induce apoptosis in these cells. Cell viability was measured by the trypan blue dye exclusion assay, and apoptosis was measured by an enzyme-linked immunosorbent assay that quantifies DNA cleavage and by western blot detection of poly(ADP-ribose) polymerase (PARP) cleavage. Western blotting was used to monitor the effects of the compounds on phosphorylation of the serine/threonine kinase Akt and extracellular signal-regulated kinase 2 (ERK2), two components of celecoxib-induced apoptosis signaling. Monte Carlo simulations were used to molecularly model the surface electrostatic potential and electron density of selected compounds. All statistical tests were two-sided. RESULTS: The structural requirements for the induction of apoptosis in PC-3 cells were different from those for COX-2 inhibition. Structure-function analysis indicated that the induction of apoptosis by compounds derived from COX-2 inhibitors required a bulky terminal phenyl ring, a heterocyclic system with negative electrostatic potential, and a benzenesulfonamide or benzenecarboxamide moiety. These derivatives mediated apoptosis by facilitating the dephosphorylation of Akt and ERK2, irrespective of their COX-2 inhibitory activities. CONCLUSION: A new class of compounds that induce apoptosis by targeting Akt and ERK2 signaling pathways in human prostate cancer cells can be synthesized by modifying existing COX-2 inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12464646&dopt=Abstract celecoxib, Celebrex