Celecoxib (celebrex)

Celebrex, the generic name of which is celecoxib is in many ways a revolutionary anti-inflammatory drug. It was the first of a new class of non-steroidal medicines called COX-2 inhibitors. It restrains the activity of a natural enzyme COX-2, an action known to decrease pain and inflammation. Unlike older drugs of the same kind, though, it does not affect the COX-1 enzyme, which has protective effects on the stomach. This is why it is much safer and exhibits much fewer side effects. Bleeding and ulcers, common adverse side effects of past anti-inflammatory drugs, have not been recorded with celecoxib. The medication can also be used to keep under control the inherited condition FAP (familial adenomatous polyposis). The fact that Celebrex decreases inflammation is very beneficial in treating the symptoms of arthritis. Studies have shown that both rheumatic and osteoarthritis’ symptoms are greatly relieved by just one tablet. So far Celebrex is one of the best choices for the treatment of this disease because of the protective effects it exerts on the stomach.

Curr Med Res Opin. 2005 Jan;21(1):47-60.
Assessing the cost-effectiveness of COX-2 specific inhibitors for arthritis in the Veterans Health Administration.
Schaefer M, DeLattre M, Gao X, Stephens J, Botteman M, Morreale A.
VA Kansas City Healthcare System, Kansas City, MO 64128, USA. Monica.Schaefer@med.va.gov

OBJECTIVE: This study was designed to assess the cost-effectiveness of cyclooxygenase-2 specific (COX-2) inhibitors (rofecoxib and celecoxib) over nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk arthritis patients from the perspective of the Veterans Health Administration (VA). METHODS: This literature-based economic analysis (with data summarized from MEDLINE-indexed and other published sources, FDA reports, and data on file at VA San Diego Healthcare System) compared rofecoxib and celecoxib to NSAIDS in two arthritis patient populations considered at higher risk of developing clinically significant upper gastrointestinal events (CSUGIEs): (1) patients of any age with previous medical history of perforation/ulcer/bleed (PUB); and (2) patients 65 years and older (regardless of history of PUB). Two outcome measures were reported: (1) incremental cost per CSUGIE averted over 1 year; and (2) incremental cost per quality-adjusted life-year (QALY) gained, considering both the mortality and morbidity associated with gastrointestinal (including CSUGIEs) and cardiovascular-related adverse events. When possible, costs were modeled to reflect the VA perspective. Sensitivity analyses were conducted to test the robustness of the analysis. RESULTS: Compared to NSAIDS, rofecoxib and celecoxib increased costs but reduced the incidence of CSUGIE. Cost per CSUGIE avoided were $7476 and $16,379 (in patients with a PUB history) and $14,294 and $18,376 (in patients aged > or = 65 years) for celecoxib and rofecoxib, respectively. In both populations, celecoxib was associated with a cost per QALY less than $50,000. In contrast, rofecoxib was found to cost more and result in a net QALY loss, due in particular to the increase in the risk of cardiovascular complications, and was therefore considered cost-ineffective. Results were most dependent on assumptions about the incidence of cardiovascular events and CSUGIE and the COX-2 inhibitors' acquisition price. CONCLUSIONS: This analysis suggests that COX-2 inhibitors may be cost-effective from the perspective of the VA. However, cost-effectiveness appears to depend less on the specific characteristics of the high-risk target population considered but more on the agent evaluated. Celecoxib appears to be an alternative to traditional NSAIDs in the patient populations studied.

Med Sci Sports Exerc. 2005 May;37(5):712-7.
Effects of indomethacin and celecoxib on renal function in athletes.
Baker J, Cotter JD, Gerrard DF, Bell ML, Walker RJ.
Department of Medical & Surgical Sciences, Dunedin School of Medicine, University of Otago Dunedin, New Zealand.

INTRODUCTION: Strenuous exercise induces a marked reduction in renal hemodynamics. Prostaglandins (PG) play an important role in maintaining renal integrity in the face of hemodynamic changes. Inhibition of cyclooxygenase (COX) and thus PG formation can further compromise renal perfusion. The role of selective COX-2 inhibition on renal hemodynamics during exercise has not been investigated. METHODS: Twelve healthy males (22-47 yr) took part in a randomized placebo controlled study investigating the effects of nonselective COX inhibition (indomethacin) and COX-2 selective inhibition (celecoxib) on renal hemodynamics during exercise. Renal blood flow (RBF), glomerular filtration rate (GFR), and free water clearance were measured using standard clearance techniques. Each experimental session was performed at least a week apart. The medications were taken for 36 h before study with the last dose at 0700 h on the day of study. Following baseline studies, each participant exercised for 30 min at 80% of their maximal aerobic power. Renal function was monitored for 2 h post-recovery. RESULTS: RBF and GFR fell by 40% after exercise with no significant difference between placebo, indomethacin, or celecoxib. Indomethacin (-2.43 +/- 0.95 mL x min(-1), P < 0.007) and celecoxib (-3.88 +/- 0.94 mL x min(-1), P < 0.0001) significantly reduced free water clearance compared with placebo during recovery. CONCLUSION: This study has confirmed that selective and nonselective COX inhibition can induce significant inhibition of free water clearance, indicating that these acute changes are regulated predominantly via COX-2. Acute cerebral edema with hyponatremia has been reported after major endurance sporting events. Identifiable risk factors include excessive hydration and use of NSAID. Impaired free water clearance during exercise potentiated by COX inhibition provides a pathophysiological explanation for these observations.

Hepatology. 2005 Mar;41(3):579-87.
Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites.
Claria J, Kent JD, Lopez-Parra M, Escolar G, Ruiz-Del-Arbol L, Gines P, Jimenez W, Vucelic B, Arroyo V.
DNA Unit, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Nonselective inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs frequently induces renal failure in decompensated cirrhosis. Studies in experimental cirrhosis suggest that selective inhibitors of the inducible isoform COX-2 do not adversely affect renal function. However, very limited information is available on the effects of these compounds on renal function in human cirrhosis. This investigation consists of a double-blind, randomized, placebo-controlled trial aimed at comparing the effects of the selective COX-2 inhibitor celecoxib (200 mg every 12 hours for a total of 5 doses) on platelet and renal function and the renal response to furosemide (40 mg intravenously) with those of naproxen (500 mg every 12 hours for a total of 5 doses) and placebo in 28 patients with cirrhosis and ascites. A significant reduction (P < .05) in glomerular filtration rate (113 +/- 27 to 84 +/- 22 mL/min), renal plasma flow (592 +/- 158 to 429 +/- 106 mL/min) and urinary prostaglandin E(2) excretion (3430 +/- 430 to 2068 +/- 549 pg/min) and suppression of the diuretic (urine volume: 561 +/- 128 to 414 +/- 107 mL/h) and natriuretic (urine sodium: 53 +/- 13 to 34 +/- 10 mEq/h) responses to furosemide were observed in the group of patients treated with naproxen but not in the other two groups. Naproxen, but not celecoxib or placebo, significantly inhibited platelet aggregation (72% +/- 8% to 47% +/- 8%, P < .05) and thromboxane B(2) production (41 +/- 12 to 14 +/- 5 pg/mL, P < .05). In conclusion, our results indicate that short-term administration of celecoxib does not impair platelet and renal function and the response to diuretics in decompensated cirrhosis. Further studies are needed to evaluate the long-term safety of this drug in cirrhosis.

Osteoarthritis Cartilage. 2005 Mar;13(3):206-10.
Celecoxib improves the efficiency of the locomotor mechanism in patients with knee osteoarthritis. A randomised, placebo, double-blind and cross-over trial.
Detrembleur C, De Nayer J, van den Hecke A.
Rehabilitation and Physical Medicine Unit, Universite catholique de Louvain, Brussels, Belgium.

OBJECTIVE: To compare the effect of celecoxib vs placebo treatment on clinical and gait variables in knee osteoarthritis (OA) patients; focusing on the efficiency of the locomotor mechanism. METHODS: Study design: A prospective, randomised, double-blind placebo-controlled trial. Patients: Eight adult patients with painful OA of the knee. Outcome measures: Clinical assessment included knee pain assessed by the visual analogue scale, range of knee motion assessed by goniometer, and locomotor function status assessed by a Knee Score Scale. Gait was assessed by means of instrumented analysis including synchronous kinematic, dynamic, electromyographic, and energetic recordings. Statistical analysis: The effect of treatment on the primary variable, the efficiency of the locomotor mechanism, and on secondary clinical and gait variables was assessed by the Hills and Armitage non-parametric approach. RESULTS: Celecoxib treatment improved the efficiency of the locomotor mechanism significantly. Among the secondary outcome measures assessed, celecoxib treatment improved walking cadence and reduced the knee pain significantly. CONCLUSION: This study shows that celecoxib is effective in improving locomotor function and pain in patients with knee OA.

Addiction. 2005 Mar;100 Suppl 1:32-42.
A placebo-controlled screening trial of celecoxib for the treatment of cocaine dependence.
Reid MS, Angrist B, Baker S, Woo C, Schwartz M, Montgomery A, Majewska D, Robinson J, Rotrosen J.
New York University School of Medicine and VA New York Harbor Healthcare System, Department of Psychiatry, New York, NY, USA.

ABSTRACT Aims To conduct a medication screening trial study on the efficacy of celecoxib versus placebo for the treatment of cocaine dependence. Design A modified blinded, parallel group study in an outpatient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design. Setting The study was performed at the New York Medications Development Research Unit (MDRU). Participants All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Twenty-three participants were enrolled in the treatment phase of the study. Intervention After a 2-week screening period, subjects were assigned randomly to receive either celebrex (200 mg/day) or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment. Measurements Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs and extrapyramidal side-effects tests. Results Study retention was similar across both treatment groups and safety measures indicated that celecoxib was moderately tolerated. Cocaine use, as measured by self-report and urine BE levels at end of treatment, indicated weaker improvement in the celecoxib group. Reductions in the intensity of cocaine craving were also weaker in the celecoxib group. Cocaine abstinence rates, global impression scores and all other related psychometric measures did not differ significantly between treatment groups. Conclusion This study does not support the effectiveness of celecoxib for the treatment of cocaine dependence.

Expert Rev Anticancer Ther. 2004 Oct;4(5):725-34.
Celecoxib: a novel treatment for lung cancer.
Abou-Issa H, Alshafie G.
Ohio State University, Division of Surgical Oncology, Department of Surgery, College of Medicine & Public Health, M-260 Starling-Loving Hall, 320 W 10th Ave, Columbus, OH 43210, USA. abou-issa.1@osu.edu.
Lung cancer is by far the leading cause of cancer-related deaths. Overall survival is poor and has not improved substantially over the last 50 years. Therefore, it is clear that novel and more effective treatments are needed to improve the outcome of therapy. Recent attention has been drawn to the role of cyclooxygenase (COX)-2 in the pathogenesis of cancer, and it has been considered as an attractive target for therapeutic and chemopreventive strategies in lung cancer patients. Celecoxib (Celebrex((R)), Pfizer), a selective COX-2 inhibitor and potent anti-inflammatory agent, has been approved for the treatment of osteoarthritis and rheumatoid arthritis. This orally administered agent is generally well tolerated and has almost no gastrointestinal or renal toxicity. Phase II clinical trials suggest that COX-2 inhibition by celecoxib would enhance response to cytotoxic chemotherapy or radiation therapy through interference with cellular proliferation and tumor angiogenic processes, promotion of apoptosis and immune surveillance, or other possible mechanisms. Celecoxib has shown promising antitumor efficacy in lung cancer and a large variety of solid tumors that rely on COX-2-related mechanisms for growth and survival. This article reviews the profile of celecoxib and evidence supporting its role in the therapy of lung cancer.

Biochem Pharmacol. 2004 Sep 15;68(6):1089-100.
Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention.
Chun KS, Surh YJ.
Laboratory of Biochemistry and Molecular Toxicology, College of Pharmacy, Seoul National University, 151-742, South Korea.
Expression of cyclooxygenase-2 (COX-2) has been reported to be elevated in human colorectal adenocarcinoma and other tumors, including those of breast, cervical, prostate, and lung. Genetic knock-out or pharmacological inhibition of COX-2 has been shown to protect against experimentally-induced carcinogenesis. Results from epidemiological and laboratory studies indicate that regular intake of selective COX-2 inhibitors reduces the risk of several forms of human malignancies. Thus, it is conceivable that targeted inhibition of abnormally or improperly elevated COX-2 provides one of the most effective and promising strategies for cancer chemoprevention. The COX-2 promoter contains a TATA box and binding sites for several transcription factors including nuclear factor-kappaB (NF-kappaB), nuclear factor for interleukin-6/CCAAT enhancer-binding protein (NF-IL6/C/EBP) and cyclic AMP response element (CRE) binding protein. Upregulation of COX-2 is mediated by a variety of stimuli including tumor promoters, oncogenes, and growth factors. Stimulation of either protein kinase C (PKC) or Ras signaling enhances mitogen-activated protein kinase (MAPK) activity, which, in turn, activates transcription of cox-2. Celecoxib, the first US FDA approved selective COX-2 inhibitor, initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, has been reported to reduce the formation of polyps in patients with familial adenomatous polyposis. This COX-2 specific inhibitor also protects against experimentally-induced carcinogenesis, but the underlying molecular mechanisms are poorly understood. The present review covers the signal transduction pathways responsible for regulating COX-2 expression as novel molecular targets of chemopreventive agents with celecoxib as a specific example.

Anaesthesia. 2004 Sep;59(9):876-80.
The effect of celecoxib on intrathecal morphine-induced pruritus in patients undergoing Caesarean section.
Lee LH, Irwin MG, Lim J, Wong CK.
Department of Anaesthesiology, Universiy of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. libbylee@hkucc.hku.hk
Pruritus associated with intrathecal opioid administration is particularly common in pregnancy. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the severity of this pruritus but have undesirable side effects. The recent development of drugs that can specifically inhibit the cyclooxygenase 2 isoenzyme have become an attractive alternative. This study was designed to evaluate the efficacy of such a drug (celecoxib) in reducing intrathecal opioid-induced pruritus in a randomised double-blinded study of 60 women undergoing Caesarean section. All of them received spinal anaesthesia with 3 ml of 0.5% hyperbaric bupivacaine and 0.3 mg preservative-free morphine. After delivery of the baby, they received either oral celecoxib 200 mg or placebo. Visual analogue scores for pain and pruritus were measured at 30 min, 2, 4, 8, and 24 h. There was no difference in the severity and onset of pain and pruritus between the two groups. Timing of administration, inadequate dosing and possible altered pharmacokinetics in pregnancy may explain the lack of efficacy.

Clin Cancer Res. 2004 Sep 1;10(17):5930-9.
Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck.
Chen Z, Zhang X, Li M, Wang Z, Wieand HS, Grandis JR, Shin DM.
Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
PURPOSE: Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (Cox-2) contribute to development of squamous cell carcinoma of the head and neck (SCCHN). Simultaneously blocking both EGFR and Cox-2-mediated pathways may be an efficient means of inhibiting cancer cell growth in SCCHN. EXPERIMENTAL DESIGN: A combination of EGFR-selective tyrosine kinase inhibitors (TKIs) AG1478 or ZD1839 (Iressa or gefitinib) with a Cox-2 inhibitor (Cox-2I) celecoxib (Celebrex) was studied for its effects on cell growth, cell cycle progression, and apoptosis in SCCHN cell lines by cell growth assay, clonogenic assay, flow cytometric analysis, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. A potential effect of EGFR TKIs and Cox-2I on angiogenesis was examined by endothelial capillary tube formation assay. Primary and secondary targets of EGFR TKIs and Cox-2I were also examined using immunoblotting and immunoprecipitation after the combined treatment. RESULTS: The combination of AG1478 or ZD1839 with celecoxib either additively or synergistically inhibited growth of the five SCCHN cell lines examined, significantly induced G(1) arrest and apoptosis, and suppressed capillary formation of endothelium. Furthermore, the combination showed strong reductions of p-EGFR, p-extracellular signal-regulated kinase 1/2, and p-Akt in SCCHN cells as compared with the single agents. Both AG1478 and ZD1839 inhibited expression of Cox-2 protein, whereas celecoxib mainly blocked the production of prostaglandin E(2). CONCLUSIONS: These results suggest that cell growth inhibition induced by a combination of EGFR TKIs and Cox-2I is mediated through simultaneously blocking EGFR and Cox-2 pathways. This combination holds a great potential for the treatment and/or prevention of SCCHN.

Gan To Kagaku Ryoho. 2004 Sep;31(9):1407-10.
A case report of metastatic pancreatic cancer that responded remarkably to the combination of thalidomide, celecoxib and irinotecan
Hada M, Mizutari K.
Dept. of Gastroenterological, Ashitaka Hospital.
The prognosis of pancreatic cancer with metastases or recurrence is quite poor. Chemotherapy has not resulted in a significant survival benefit; median survival is 3-6 months. Various chemotherapeutic agents have been evaluated and the standard chemotherapy of pancreatic cancer is gemcitabine. The response rate, however, is low at 13%. Thalidomide and celecoxib have different mechanisms of action and activity in various malignant tumors. Both have been evaluated and shown to demonstrate activity against solid tumors. Thalidomide decreased the stability of TNF-mRNA and COX-2 mRNA. COX-2 is a bifunctional enzyme possessing both cyclooxygenase and peroxidase activities. Although celecoxib inhibits PG biosynthesis, most do not affect the peroxidase activity of COX, which can generate proximate carcinogens. Because thalidomide does not completely inhibit COX-2 expression or PG biosynthesis, a therapeutic strategy combining celecoxib with thalidomide might be more effective than using either agent alone. Differences in the mechanism of action of gemcitabine and irinotecan suggest that a change of gemcitabine to irinotecan could provide clinically efficacious outcomes. In order to accomplish new treatment strategies, we have been using thalidomide, celecoxib and irinotecan in low-doses. We believe this combination represents a viable treatment for patients of pancreatic cancer with recurrence or metastases.

Ann Rheum Dis. 2004 Aug;63(8):931-9. Epub 2004 Apr 13
Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis.
Pincus T, Koch G, Lei H, Mangal B, Sokka T, Moskowitz R, Wolfe F, Gibofsky A, Simon L, Zlotnick S, Fort JG.
Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. t.pincus@vanderbilt.edu
BACKGROUND: Acetaminophen (paracetamol) is recommended as the initial pharmacological treatment for knee or hip osteoarthritis. However, survey and clinical trial data indicate greater efficacy for non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 specific inhibitors. DESIGN: Two randomised, double blind, placebo controlled, crossover multicentre clinical trials, Patient Preference for Placebo, Acetaminophen or Celecoxib Efficacy Studies (PACES).Patients: Osteoarthritis of knee or hip.Intervention: "Wash out" of treatment; randomisation; 6 weeks of celecoxib 200 mg/day, acetaminophen 1000 mg four times a day, or placebo; second "wash out;" crossover to 6 weeks of second treatment.Measurements: Western Ontario McMaster Osteoarthritis Index (WOMAC), visual analogue pain scale, patient preference between two treatments. RESULTS: Celecoxib was more efficacious than acetaminophen in both periods in both studies; WOMAC and pain scale scores differed at p<0.05 in period II and both periods combined of PACES-a and in periods I and II and both periods combined in PACES-b, but not in period I of PACES-a. Acetaminophen was more efficacious than placebo, generally p<0.05 in PACES-b, and >0.05 in PACES-a. Patient preferences were 53% celecoxib v 24% acetaminophen in PACES-a (p<0.001) and 50% v 32% in PACES-b (p = 0.009); 37% acetaminophen v 28% placebo in PACES-a (p = 0.340) and 48% v 24% in PACES-b (p = 0.007). No clinically or statistically significant differences were seen in adverse events or tolerability among the three treatment groups. CONCLUSIONS: Greater efficacy was seen for celecoxib v acetaminophen v placebo, while adverse events and tolerability were similar. Variation in results and statistical significance in the two different trials are of interest.

Carcinogenesis. 2004 Aug;25(8):1449-58. Epub 2004 Mar 19.
Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms.
Won YK, Ong CN, Shi X, Shen HM.
Department of Community, Occupational, and Family Medicine, Faculty of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
Parthenolide (PN) is a major sesquiterpene lactone of feverfew (Tanacetum parthanium) with known anti-inflammatory activity. However, the anticancer effects of PN have not been well studied. In the present investigation, we examined the cancer chemopreventive property of PN using a combination of in vivo and in vitro approaches. We first tested the anticancer effect of PN in UVB-induced skin cancer model. Mice fed with PN (1 mg/day) showed a delayed onset of papilloma incidence, a significant reduction in papilloma multiplicity (papilloma/mouse) and sizes when compared with the UVB-only group. To our surprise, neither PN nor the known cyclooxygenase (COX)-2 inhibitor celecoxib inhibit UVB-induced COX-2 expression and epidermal prostaglandin E2 (PGE2) production. We next investigated the molecular mechanism(s) involved in its anticancer effects using cultured JB6 murine epidermal cells. Non-cytotoxic concentrations of PN significantly inhibited UVB-induced activator protein-1 DNA binding and transcriptional activity. In addition, PN pre-treatment also inhibited c-Jun-N-terminal kinase (JNK) and p38 kinase activation. More importantly, we found that impaired AP-1, JNK and p38 signaling led to the sensitization of JB6 cells to UVB-induced apoptosis. Data from our study for the first time confirm the anticancer property of PN in an animal model, and provide evidence that the inhibitory effects on AP-1 and mitogen-activated protein kinases serve as one of the underlying mechanisms for the cancer chemopreventive property of PN.

J Cereb Blood Flow Metab. 2004 Aug;24(8):926-33.
Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death.
Chu K, Jeong SW, Jung KH, Han SY, Lee ST, Kim M, Roh JK.
Stroke and Neural Stem Cell Laboratory, Clinical Research Institute, Department of Neurology, Seoul National University Hospital, Seoul National University, Seoul, South Korea.
The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood-injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.

Immunol. 2004 Aug 1;173(3):2011-22.
Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis.
Shishodia S, Koul D, Aggarwal BB.
Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-kappa B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-kappa B. In the present study, we investigated the effect of this drug on the activation of NF-kappa B by a wide variety of agents. We found that celecoxib suppressed NF-kappa B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1 beta. Celecoxib inhibited TNF-induced I kappa B alpha kinase activation, leading to suppression of I kappa B alpha phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-kappa B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-kappa B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with I kappa B alpha kinase (IKK). Celecoxib abrogated the NF-kappa B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-kappa B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-kappa B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-kappa B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-kappa B activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.

Mini Rev Med Chem. 2004 Aug;4(6):597-601.
First and second generations of COX-2 selective inhibitors.
de Leval X, Julemont F, Benoit V, Frederich M, Pirotte B, Dogne JM.
Natural and Synthetic Drugs Research Centre, Laboratory of Medicinal Chemistry, University of Liege, 1 av. de l'Hopital, tour 4(+5) Sart-Tilman, B-4000 Liege, Belgium. xdeleval@ulg.ac.be
The identification and characterization of the inducible form of cyclooxygenases (COX-2) stimulated the investigations to develop efficient, non-steroidal anti-inflammatory drugs (NSAIDs) with reduced side effects (essentially gastro-intestinal toxicity) compared to classical NSAIDs. This review focuses on the chemical and pharmacological properties (pre-clinical data) of marketed COX-2 inhibitors.

Pharmazie. 2004 Aug;59(8):627-30.
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.

Biochem Pharmacol. 2004 Jul 15;68(2):341-50.
Effects of the selective COX-2 inhibitors celecoxib and rofecoxib on human vascular cells.
Niederberger E, Manderscheid C, Grosch S, Schmidt H, Ehnert C, Geisslinger G.
Pharmazentrum frankfurt, Klinikum der Johann Wolfgang Goethe-Universitat Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. e.niederberger@em.uni-frankfurt.de
Rheumatoid arthritis (RA) is associated with a reduced life expectancy considered to be partly caused by cardiovascular events. A growing concern is that accelerated atherosclerosis is driven by inflammatory mechanisms similar to those responsible for RA. Therefore, selective COX-2 inhibitors, which are widely used for the symptomatic treatment of pain and inflammation in RA, may have an impact on atherosclerotic processes. Their anti-inflammatory properties might provoke anti-atherogenic effects but on the other hand, selective inhibition of anti-thrombotic prostacyclin and COX-2 independent effects might promote the risk of increased prothrombotic activity. In the current study, the effects of the presently marketed selective COX-2 inhibitors celecoxib and rofecoxib on vascular cells have been investigated. Celecoxib inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. At high concentrations, it induced apoptosis and the modulation of inhibitory cell cycle proteins. In contrast rofecoxib-even at high concentrations-had no effect on cell proliferation, apoptosis or cell cycle distribution indicating that celecoxib and rofecoxib do not affect the same signal transduction pathways in endothelial cells. Both drugs did not affect apoptosis induction or cell cycle proliferation in human vascular smooth muscle cells. The observed effects on endothelial cells appear to be COX-independent since both drugs selectively inhibited COX-2-activity and the applied concentrations lay beyond the IC(50) for inhibition of prostacyclin production. Regarding endothelial apoptosis as a relevant event in the initiation and progression of atherosclerosis the present data put forward the hypothesis that the presently marketed COX-2 inhibitors have a different impact on atherosclerotic processes.

Cancer Res. 2004 Jul 15;64(14):5004-12.
Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates activation of cigarette smoke-induced nuclear factor (NF)-kappaB by suppressing activation of IkappaBalpha kinase in human non-small cell lung carcinoma: correlation with suppression of cyclin D1, COX-2, and matrix metalloproteinase-9.
Shishodia S, Aggarwal BB.
Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, bladder, and lung; all are known to overexpress the nuclear factor-kappaB (NF-kappaB)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 inhibitor, celecoxib, approved for the treatment of colon carcinogenesis and rheumatoid arthritis, affects CS-induced NF-kappaB activation is not known, although the role of NF-kappaB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-kappaB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-kappaB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-kappaB activation. Celecoxib was effective even when administered 12 h after CSC treatment. This effect, however, was not cell type-specific. The activation of inhibitory subunit of NF-kappaB kinase (IkappaB), as examined by immunocomplex kinase assay, IkappaB phosphorylation, and IkappaB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-kappaB-dependent reporter gene expression. CSC-induced NF-kappaB reporter activity induced by NF-kappaB inducing kinase and IkappaB alpha kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-kappaB-regulated proteins, COX-2, cyclin D1, and matrix metalloproteinase-9, and celecoxib abolished the induction of all three. The COX-2 promoter that is regulated by NF-kappaB was activated by CSC, and celecoxib suppressed its activation. Overall, our results suggest that chemopreventive effects of celecoxib may in part be mediated through suppression of NF-kappaB and NF-kappaB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.

J Med Chem. 2004 Jul 15;47(15):3777-87.
Pruned receptor surface models and pharmacophores for three-dimensional database searching.
Sutherland JJ, O'Brien LA, Weaver DF.
Departments of Chemistry and Pathology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
A pharmacophore represents the 3D arrangement of chemical features that are shared by molecules exhibiting activity at a protein receptor. Pharmacophores are routinely used in 3D database searching for identifying potential lead compounds. The lack of shape constraints causes the query to identify compounds that could not fit into the active site. In the absence of structural information, a receptor surface model (RSM) can be used to represent the active site. The RSM consists of a surface that envelops a set of known actives after these have been aligned using their common features. When used for database searching, a RSM is overconstraining as it restricts access to regions that could be occupied by ligands, such as the solvent-protein interface or unexplored pockets. We describe a protocol for developing pruned RSMs using information gleaned from 3D quantitative structure-activity relationship (QSAR) models. We examined the performance of queries that consist of pharmacophores used alone or with pruned or unpruned RSMs by performing searches on six databases containing known actives distributed among inactives. The pruned RSMs yield an average selectivity 1.8 times greater than that for pharmacophore queries, compared to 1.6 times for unpruned RSMs. However, the pruned RSMs retrieve on average 73% of the actives identified using the pharmacophores, compared to 40% for the unpruned RSMs. As such, pruned RSMs represent a useful compromise between the high sensitivity of pharmacophores and the high selectivity of unpruned RSMs.

Acta Pharmacol Sin. 2004 Jul;25(7):943-9.
Effects of cyclooxygenase 2 inhibitors on biological traits of nasopharyngeal carcinoma cells.
Chen PY, Long QC.
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, China. peiyichen@163.net
AIM: To investigate effects of cyclooxygenase 2 (COX-2) inhibitors on nasopharyngeal carcinoma (NPC) cells and on angiogenesis in vitro. METHODS: Human NPC cell lines (CNE1, CNE2 and SUNE) were treated with nimesulide or celecoxib. MTT assay and colony formation assay were performed to observe antiproliferation activity of COX-2 inhibitors to NPC cell lines. Cell cycle arrest and apoptosis of NPC cell strains were tested by flow cytometry assay, microscopic morphology observation, and DNA fragmentation assay. The effect of COX-2 inhibitor on angiogenesis was tested by chick chorioallantoic membrane (CAM) model. RESULTS: Nimesulide (Nim) and celecoxib (Cel) could antiproliferate NPC cell lines with IC50 182 micromol/L(Nim-SUNE), 78 micromol/L(Nim-CNE1), 175 micromol/L(Nim-CNE2), 7.2 micromol/L(Cel-SUNE), 8.1 micromol/L(Cel-CNE1), and 7.6 micromol/L(Cel-CNE2). The antiproliferation presented dose-dependent (Nim 5-400 micromol/L, Cel 0.5-80 micromol/L) and time-dependent manner (Nim IC50 562 micromol/L(24 h), 316 micromol/L(48 h), 50.1 micromol/L(240 h)). Nim and Cel arrested SUNE and CNE1 cell cycle at phase G2/M (cell aggregation rate 28.9%-45.1%(Nim 25-200 micromol-12 h-SUNE), 18.9%-26.2%(Nim 25-200 micromol-24 h-SUNE), 28.8%-35.6%(Nim 25-200 micromol-48 h-SUNE), 30.4%-16.4%(Cel 25-100 micromol-12 h-SUNE), 21.2%-19.7%(Cel 25-100 micromol-24 h-SUNE), 31.1%-19.9%(Cel 25-100 micromol-24 h-SUNE), 20.5%-34.1%(Nim25-200 micromol-12 h-CNE1), 25.2%-26.9%(Nim 25-200 micromol-24 h-CNE1), 11.5%-7.1% (Nim 25-200 micromol-48 h-CNE1)). Apoptosis shape and apoptosis strap displayed in NPC cells after treatment with Nim and Cel. Nim had a feature of anti-angiogenesis on CAM model. CONCLUSION: Nim and Cel could suppress proliferation of squamous epithelium NPC cell (SUNE, CNE1 and CNE2) through blocking cell cycle and inducing cell apoptosis. Nim could apparently suppress CAM angiogenesis induced by SUNE cell.

Cancer. 2004 Jul 1;101(1):189-97.
The cost-effectiveness of aspirin versus cyclooxygenase-2-selective inhibitors for colorectal carcinoma chemoprevention in healthy individuals.
Hur C, Simon LS, Gazelle GS.
Institute for Technology Assessment, Massachusetts General Hospital, 101 Merrimac Street, 10th Floor, Boston, MA 02114, USA. chur@mgh-ita.org
BACKGROUND: Aspirin therapy is accepted widely for secondary prevention in patients with documented cardiovascular disease, but there is a growing trend among healthy individuals to use aspirin as primary chemoprevention for both cardiovascular and oncologic diseases. Accruing evidence suggests that cyclooxygenase-2-selective inhibitors (coxibs) may be effective for colorectal carcinoma (CRC) chemoprevention but would not provide the primary cardiac benefit of aspirin. METHODS: A computer-based Markov model simulated hypothetical cohorts of healthy men age 50 years who took either 325 mg of enteric-coated aspirin daily or celecoxib at a dose of 400 mg twice a day. Patients in both cohorts could develop drug-related complications that would lead to its discontinuation. The aspirin group also was modeled to have a decreased rate of coronary ischemic events; however, decreased CRC mortality was not modeled in either group based on the assumption that the two treatments were effective equally in this regard. Data sources included published literature and the Centers for Medicare and Medicaid Services. Endpoints used to compare the two strategies included quality-adjusted life years (QALYs), mortality and complication rates, and cost. The analysis was from a societal perspective with a time horizon of 10 years from age 50 years. Extensive sensitivity analyses were performed. RESULTS: Aspirin therapy resulted in 0.03 more QALYs and cost $23,000 less than coxib therapy over a 10-year period. Compared with the aspirin group, the coxib group had 3.877% more complications and 0.17% more deaths. Alternatively stated, coxib therapy resulted in 1 patient complication or death for every 26 or 588 patients treated with coxibs, respectively. CONCLUSIONS: Assuming equal efficacy in CRC prevention over a 10-year period, aspirin was both more effective and less costly than coxib therapy when used for primary chemoprevention of CRC. Copyright 2004 American Cancer Society.

Cancer. 2004 Jul 1;101(1):133-8.
Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma.
Milella M, Gelibter A, Di Cosimo S, Bria E, Ruggeri EM, Carlini P, Malaguti P, Pellicciotta M, Terzoli E, Cognetti F.
Divisions of Medical Oncology "A" and "C", Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy. milella@ifo.it
BACKGROUND: Cyclooxygenase-2 (COX-2) is up-regulated frequently and may constitute a promising therapeutic target in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients with advanced PDAC who had progressive disease after gemcitabine-based chemotherapy were eligible for this pilot study. Treatment was comprised of oral celecoxib (400 mg twice daily) and protracted intravenous (i.v.) infusion 5-fluorouracil (5-FU) (200 mg/m(2) per day), both given continuously for a maximum of 9 treatment months, in the absence of disease progression or unacceptable toxicity. Patients were examined weekly for toxicity and were restaged every 6-8 weeks for tumor assessment. RESULTS: Seventeen patients entered the study. Asymptomatic transaminase elevation was the most common toxicity and reached NCI-CTC (version 3.0) Grade 3-4 in 4 of 133 treatment weeks. No other hematologic or nonhematologic toxicity > Grade 2 was observed. Four patients discontinued celecoxib due to upper gastrointestinal tract toxicity. Two confirmed partial responses (durations of 23 weeks and 68 weeks, respectively) and 2 patients with stable disease (durations of 10 weeks and 13 weeks, respectively) were observed for an overall response rate of 12% (95% confidence interval, 0-27%) in the intent-to-treat population. A significant decrease (> or = 50%) in serum CA 19.9 levels was observed in 3 of 9 evaluable patients. The median time to disease progression was 8 weeks, and the median overall survival was 15 weeks. CONCLUSIONS: The combination of oral celecoxib and 5-FU by protracted i.v. infusion was found to be feasible and well tolerated, and was capable of inducing durable objective responses, even in patients with far advanced, gemcitabine-resistant/refractory PDAC. Further exploration of COX-2 inhibitor/fluropyrimidine combinations is warranted. Copyright 2004 American Cancer Society.

Clin J Sport Med. 2004 Jul;14(4):225-31.
Efficacy of celecoxib, a COX-2-specific inhibitor, and naproxen in the management of acute ankle sprain: results of a double-blind, randomized controlled trial.
Petrella R, Ekman EF, Schuller R, Fort JG.
Canadian Center for Activity and Aging, London, Ontario, Canada. petrella@julian.uwo.ca
OBJECTIVE: To assess the efficacy and safety of celecoxib and naproxen in the treatment of acute ankle sprain. DESIGN: Double-blind, parallel-group, randomized trial. SETTING: Multicenter outpatient. PATIENTS: Adult patients (n = 397) with acute first-degree or second-degree ankle sprain. INTERVENTIONS: Patients randomized to celecoxib 200 mg b.i.d. (n = 198) or naproxen 500 mg b.i.d. (n = 198) for 7 days. MAIN OUTCOME MEASURES: Primary measures of efficacy were Patient's Assessment of Ankle Pain Visual Analogue Scale (VAS) and Patient's Global Assessment of Ankle Injury. Secondary efficacy measures included Physician's Global Assessment of Ankle Injury, Patient's Return to Normal Function/Activity, and Patients' and Physicians' Satisfaction Assessments. Adverse events (AEs) were reported by investigators during the study. RESULTS: For the primary endpoints at day 4, the mean pain VAS scores were 31.9 mm +/- 1.96 for celecoxib and 29.0 mm +/- 1.91 for naproxen, and the responder rate for Patient's Global Assessment of Ankle Injury was 71% in the celecoxib group and 72% in the naproxen group, differences that were not statistically significant. In addition, noninferiority analysis demonstrated treatment differences that were within prespecified minimal clinical important differences. Gastrointestinal AEs were the most common AE, accounting for 14% in the celecoxib group and 21% in the naproxen group. The incidence of dyspepsia was 3% for celecoxib compared with 12% for naproxen (P = 0.032). CONCLUSIONS: Celecoxib is as effective as naproxen in treating acute first-degree or second-degree ankle sprains but causes significantly less dyspepsia.

Prog Neuropsychopharmacol Biol Psychiatry. 2004 Jul;28(4):715-21.
Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia.
Yokota O, Terada S, Ishihara T, Nakashima H, Kugo A, Ujike H, Tsuchiya K, Ikeda K, Saito Y, Murayama S, Ishizu H, Kuroda S.
Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, 700-8558, Japan. oyokota1@yahoo.co.jp
Several types of evidence suggesting that the inflammatory response system is associated with pathophysiology of schizophrenia have been accumulated. Recently, a prospective double-blind study demonstrated that supplementary treatment with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, produced significantly greater improvement in scores on the Positive and Negative Syndrome Scale (PANSS) and on all subscales during the acute phase in patients with schizophrenia compared with risperidone alone therapy. The therapeutic effect of celecoxib on the psychopathology of schizophrenia is speculated to be based on COX activity inhibition; however, the detailed pharmacological mechanisms are unclear. To clarify whether or not COX-2 expression is altered in schizophrenia, we examined neuronal COX-2 expression in the hippocampus from cases of schizophrenia (n = 17), normal controls (n = 22), and cases of Alzheimer's disease (AD) as a positive control (n = 17). Quantitative immunohistochemical analysis demonstrated that neuronal COX-2 expression was significantly up-regulated in each CA1-4 region in Alzheimer's disease compared with controls, and that the mean COX-2 immunointensity in CA1-4 was significantly correlated with Abeta load in cases of Alzheimer's disease. In contrast, COX-2 expression was not up-regulated in any subdivision of the hippocampus in the schizophrenia group. These results suggest that celecoxib may affect the pathophysiology of schizophrenia through COX-2-independent actions rather than by inhibiting activity of up-regulated COX-2 protein.

World J Gastroenterol. 2004 Jul 1;10(13):1971-4.
Anti-cancer effects of COX-2 inhibitors and their correlation with angiogenesis and invasion in gastric cancer.
Fu SL, Wu YL, Zhang YP, Qiao MM, Chen Y.
Department of Gastroenterology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China. fusuolin@163.com
AIM: To observe the anti-cancer effects of COX-2 inhibitors and investigate the relationship between COX-2 inhibitors and angiogenesis, infiltration or metastasis in SGC7901 cancer xenografts. METHODS: Thirty athymic mice xenograft models with human stomach cancer cell SGC7901 were established and divided randomly into 3 groups of 10 each. Sulindac, one non-specific COX inhibitor belonging to non-steroidal anti-inflammatory drugs (a series of COX inhibitors known as NSAIDs) and celecoxib, one selective COX-2 inhibitor (known as SCIs) were orally administered to mice of treatment groups. Immunohistochemistry was used to examine the expression of PCNA, CD44v6 and microvessel density (MVD). Apoptosis was detected by using TUNEL assay. RESULTS: Tumors in sulindac and celecoxib groups were significantly smaller than those in control group from the second week after drug administration (P<0.01). In treatment group, the cell proliferation index was lower (P<0.05) and apoptosis index was higher (P<0.05) than those in control groups. Compared with the controls, microvessel density was reduced (P<0.01) and expression of CD44v6 on tumor cells was weakened (P<0.05) in treatment groups. CONCLUSION: COX-2 inhibitors have anticancer effects on gastric cancer. They play important roles in angiogenesis and infiltration or metastasis of stomach carcinoma. The anticancer effects of COX-2 inhibitors may include inducing apoptosis, suppressing proliferation, reducing angiogenesis and weakening invasiveness.

Brain Res Mol Brain Res. 2004 Jun 18;125(1-2):113-9.
Nonsteroidal anti-inflammatory drugs increase expression of inducible COX-2 isoform of cyclooxygenase in spinal cord of rats with adjuvant induced inflammation.
Hsueh SF, Lu CY, Chao CS, Tan PH, Huang YW, Hsieh SW, Hsiao HT, Chung NC, Lin SH, Huang PL, Lyu PC, Yang LC.
Department of life Science, National Tsing Hua University, Hsinchu, Taiwan.
Several lines of evidence have accumulated that release of excitatory amino acids, nitric oxide and prostaglandin E2 (PGE2) play a critical role in the development of peripheral tactile and thermal hypersensitivity in chronic inflammatory pain models. Synthesis of PGE2 is controlled by cyclooxygenase (COX), either the COX-1 or COX-2 isoform. COX-2 plays a central role in the inflammatory reactions. The relationship between central sensitization of a complete Freund's adjuvant (CFA) induced inflammation and expressions of COX-2 were assessed in a rat model of CFA injection induced inflammation. Moreover, the time course of analgesia and spinal COX-2 expression following intrathecal (IT) injection with a nonspecific COX inhibitor (ketorolac) and COX-2 inhibitor (celecoxib) were determined using Western blot and immunohistochemistry. COX-2 protein was slightly increased in the lumbosacral spinal cord at 24 h following subcutaneous injection of CFA in the plantar surface of the left hindpaw (p > 0.05). COX-1 was not detected in normal and CFA injection rats. Surprisingly, IT ketorolac or celecoxib significantly increased spinal COX-2 levels at 1 h post-IT injection (p < 0.05) both in inflamed and non-inflamed rats. Then, spinal COX-2 levels declined at 3 and 6 h post-IT injection. These results provide strong in vivo evidence that COX-2 activity but not level may play a central role in the Freund's adjuvant-induced inflammation. However, spinal COX-2 level was upregulated following IT ketorolac and celecoxib injection. These data implies that suppression of PGE2 activity may induce the expression of spinal COX-2 in Freund's adjuvant-induced pain model. Our study concludes that IT administration of COX-2 inhibitor or nonspecific COX inhibitor is associated with significant short-term increase in spinal COX-2 expression.

Cancer Res. 2004 Jun 15;64(12):4309-18.
From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors.
Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, Shaw YJ, Kulp SK, Chen CS.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, 43210, USA.
The blockade of Akt activation through the inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1) represents a major signaling mechanism whereby celecoxib mediates apoptosis. Celecoxib, however, is a weak PDK-1 inhibitor (IC(50), 48 microM), requiring at least 30 microM to exhibit discernable effects on the growth of tumor cells in vitro. Here, we report the structure-based optimization of celecoxib to develop PDK-1 inhibitors with greater potency in enzyme inhibition and growth inhibition. Kinetics of PDK-1 inhibition by celecoxib with respect to ATP suggest that celecoxib derivatives inhibit PDK-1 by competing with ATP for binding, a mechanism reminiscent to that of many kinase inhibitors. Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells. Docking of potent compounds into the ATP-binding site of PDK-1 was performed for lead optimization, leading to two compounds, OSU-03012 and OSU-03013, with IC(50) values in PDK-1 inhibition and apoptosis induction in the low microM range. Exposure of PC-3 cells to these agents led to Akt dephosphorylation and inhibition of p70 S6 kinase activity. Moreover, overexpression of constitutively active forms of PDK-1 and Akt partially protected OSU-03012-induced apoptosis. Screening in a panel of 60 cell lines and more extensive testing in PC-3 cells indicated that the mean concentration for total growth inhibition was approximately 3 microM for both agents. Considering the conserved role of PDK-1/Akt signaling in promoting tumorigenesis, these celecoxib analogs are of translational relevance for cancer prevention and therapy.

Allerg Immunol (Paris). 2004 Jun;36(6):215-8.
Tolerability of three selective cyclo-oxygenase-2 inhibitors, meloxicam, celecoxib and rofecoxib in NSAID-sensitive patients.
Senna G, Bilo MB, Antonicelli L, Schiappoli M, Crivellaro MA, Bonadonna P, Dama AR.
Unita Operativa di Allergologia, Ospedale Civile Maggiore di Verona, Verona, Italy.
BACKGROUND: Patients with aspirin-sensitive respiratory and cutaneous diseases experience cross reactions to all nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit cyclo-oxigenase (COX) enzymes. As are now available drugs which selectively inhibit COX-2, questions are raised whether cross-reactivity occurs between aspirin and these COX 2 inhibitors. OBJECTIVE: The aim of this study was to evaluate the tolerability of three COX-2 inhibitors (meloxicam, celecoxib and rofecoxib) in subjects with previous pseudoallergic respiratory and cutaneous reactions to NSAIDs. METHODS: 76 subjects with documented previous cutaneous and respiratory pseudoallergic reactions to aspirin and/or other NSAIDs underwent a single blind challenge with celecoxib, meloxicam and rofecoxib. RESULTS: All subjects with previous respiratory reactions tolerated all drugs. Three subjects with multiple-drug induced urticaria complained of a generalized reaction after challenge (Two due to celecoxib and one due to meloxicam). Among the group of patients with NSAIDs-induced urticaria five complained of a relapse of the disease due to rofecoxib (one subject), celecoxib (two subjects and meloxicam (two subjects). CONCLUSIONS: According to these results the cross-reactivity between aspirin and these COX-2 inhibitors does not occur in subjects with previous respiratory pseudoallergic reactions. A good safety profile was also demonstrated in patients with cutaneous reactions, being few reactions observed. However for this reason a controlled oral challenge with these drugs is useful for the proper management of patients sensitive to classic NSAIDs.

J Pain Symptom Manage. 2004 Jan;27(1):85-95.
Effects of celecoxib, medroxyprogesterone, and dietary intervention on systemic syndromes in patients with advanced lung adenocarcinoma: a pilot study.
Cerchietti LC, Navigante AH, Peluffo GD, Diament MJ, Stillitani I, Klein SA, Cabalar ME.
Supportive Care Division (L.C.A.C., A.H.N.), Translational Research Unit (L.C.A.C.), Internal Medicine Department (A.H.N., M.E.C.), and Experimental Cancer Department (G.D.P., M.J.D., I.S., S.A.K.), Angel H. Roffo Cancer Institute, University of Buenos Aires, Buenos Aires, Argentina
Systemic syndromes characterized by a persistent activity of circulating mediators (cytokines) are frequently present with advanced cancer. We grouped under the general heading of "Systemic Immune-Metabolic Syndrome (SIMS)" a particular variety of distressing systemic syndrome characterized by dysregulation of the psycho-neuro-immune-endocrine homeostasis, with overlapping clinical manifestations. SIMS may include cachexia, anorexia, nausea, early satiety, fatigue, tumor fever, cognitive changes and superinfection. The aim of this study was to ameliorate some of the SIMS symptoms in a homogeneous group of lung adenocarcinoma patients using a multitargeted therapy. Fifteen patients with evidence of SIMS were studied. SIMS was defined as the presence of weight loss, anorexia, fatigue performance status>/=2 and acute-phase protein response. Patients received medroxyprogesterone (MPA) (500 mg twice daily), celecoxib (200 mg twice daily), plus oral food supplementation for 6 weeks. After treatment, 13 patients either had stable weight (+/- 1%) or had gained weight. There were significant differences in improvement of body-weight-change rate, nausea, early satiety, fatigue, appetite and performance status. Patients who had any kind of lung infection showed higher levels of IL-10 compared to non-infected patients (P=0.039). Our results suggest that patients with advanced lung adenocarcinoma, treated with MPA, celecoxib and dietary intervention, might have considerable improvement in certain SIMS outcomes. This multitargeted symptomatic approach deserves further study.

J Urol. 2004 Feb;171(2):S59-S63.
Nonsteroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Selective Inhibitors for Prostate Cancer Chemoprevention.
Basler JW, Piazza GA.
SUMMARY: PURPOSE There is increasing evidence that using nonsteroidal anti-inflammatory drugs decreases the incidence of clinically apparent prostate cancer. We review the potential mechanisms of cancer reduction with cyclooxygenase (COX)-2 inhibitors and the clinical evidence suggesting their effectiveness.MATERIALS AND METHODS A literature review using MEDLINE was conducted of animal, observational, and clinical studies of nonsteroidal anti-inflammatory drugs in cancer, specifically prostate cancer. The Physician Data Query database was searched for current studies of COX-2 inhibitors for chemoprevention of prostate cancer.RESULTS Research suggests that COX-2 inhibiting medications are determinants in lower cancer incidence rates. Other studies have suggested up-regulation of the COX-2 enzyme in prostate cancer compared with normal prostate tissue. Selective COX-2 inhibitors are currently under study to evaluate their potential roles in preventing prostate cancer in high-risk patients (rofecoxib) or the recurrence of bladder cancer (celecoxib). Agents such as exisulind, which is a selective apoptotic antineoplastic drug, are also under investigation.CONCLUSION COX-2 inhibitors are promising agents for the chemoprevention of prostate cancer but further research is needed.

Arthritis Care Res. 2000 Apr;13(2):112-21.
Zhao SZ, Fiechtner JI, Tindall EA, Dedhiya SD, Zhao WW, Osterhaus JT, Yu SS.
Global Health Outcomes, IL, USA.
Evaluation of health-related quality of life of rheumatoid arthritis patients treated with celecoxib.
To study the functional status and health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA) after treatment with celecoxib, compared with placebo and naproxen. This was a prospective, randomized, double-blind, parallel group trial conducted at 79 sites in the United States and Canada over a 12-week treatment period. Patients were randomly assigned to 5 groups: placebo, 100 mg twice a day of celecoxib, 200 mg twice a day of celecoxib, 400 mg twice a day of celecoxib, and 500 mg twice a day of naproxen. The Health Assessment Questionnaire (HAQ) disability index was used to measure functional status. The Medical Outcomes Study Short Form 36 (SF-36) was used to measure general HRQOL. Enrollees were 1,149 patients with diagnosed and active RA. At the end of the treatment period, patients in the 4 active treatment groups had significant improvement in both functional status and overall HRQOL in comparison with the placebo group. Patients in the twice-daily 100 mg celecoxib group significantly differed from placebo at weeks 2 and 6 on HAQ scores and at week 12 on 5 domains and both summary scores of the SF-36. Patients treated with twice-daily 200 mg celecoxib had significantly better functional status than placebo at all times of testing with the HAQ, and also had significantly better function than those treated with naproxen after 2 and 12 weeks of treatment. Patients in the twice-daily 200 mg and 400 mg celecoxib groups showed similar improvement in HRQOL as determined by the 8 domain scores and 2 summary scores of the SF-36. Celecoxib was better than placebo and comparable with naproxen in improving functional status and overall HRQOL among RA patients.

Nietert PJ, Ornstein SM, Dickerson LM, Rothenberg RJ.
Center for Health Care Research, Department of Medicine, Medical University of South Carolina, USA.
Comparison of changes in blood pressure measurements and antihypertensive therapy in older, hypertensive, ambulatory care patients prescribed celecoxib or rofecoxib.
To determine if changes in blood pressure and changes in class or dosing of antihypertensive drugs were significantly different in patients treated with celecoxib versus rofecoxib, two cyclooxygenase (COX)-2 inhibitors. DESIGN: Retrospective cohort study. Thirty-one ambulatory care practices that shared an electronic medical record. Nine hundred sixty men and women over age 55 years with stable hypertension. Patients had to have at least a 30-day supply of celecoxib or rofecoxib (any dose) prescribed between July 1, 1999, and June 30, 2000. Patients were followed for 6 months, and logistic regression and survival models were used to compare outcomes between groups while adjusting for confounders. Baseline characteristics of 517 patients receiving celecoxib and 443 receiving rofecoxib were similar. No significant differences were observed, regardless of the COX-2 inhibitor prescribed, in the proportion of patients whose systolic blood pressure increased by 20 mm Hg, whose diastolic blood pressure increased by 15 mm Hg, or who were prescribed a new class of antihypertensive drug. Compared with patients taking celecoxib, those taking rofecoxib were significantly more likely (odds ratio 1.68, 95% confidence interval 1.09-2.60) to have had the dosage of their antihypertensive drug increased and also the dosage increased sooner (p<0.05). New-onset cardiac and renal comorbidity, number of physician visits, and changes in body weight and laboratory values were not significantly different between the groups. No significant differences in blood pressure changes or in the proportion of patients who were prescribed a new class of antihypertensive drug were found between rofecoxib- and celecoxib-treated patients. However, significantly more rofecoxib-treated patients had the dosage of their existing antihypertensive drug increased compared with those receiving celecoxib.