celecoxib, Celebrex
Serum proteomic profiles suggest celecoxib-modulated targets and response predictors.

Xiao Z, Luke BT, Izmirlian G, Umar A, Lynch PM, Phillips RK, Patterson S, Conrads TP, Veenstra TD, Greenwald P, Hawk ET, Ali IU.

Laboratory of Proteomics and Analytical Technologies and Advanced Biomedical Computing Center, SAIC-Frederick Inc., National Cancer Institute at Frederick, Frederick, Maryland, USA.

Cyclooxygenase-2 is a valid target for cancer prevention and treatment. This has been shown in preclinical and clinical cancer prevention studies by using a cyclooxygenase-2 inhibitor, celecoxib. When used in a randomized cancer prevention clinical trial on patients with the inherited autosomal dominant condition, familial adenomatous polyposis, celecoxib proved efficacious. However, a remarkable heterogeneity in patients' responses to the chemopreventive effects of celecoxib was observed. Proteomic profiling of sera from these patients identified several markers, the expression of which was specifically modulated after treatment with celecoxib. A decision tree algorithm identified classifiers for response to celecoxib with relatively high sensitivity but moderate to low specificity. In particular, a spectral feature at m/z 16,961.4 was identified as a strong discriminator between response and nonresponse to celecoxib at the highest dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15087410&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults.

Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, Avorn J.

Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, 1620 Tremont St, Suite 3030, Boston, Mass 02120, USA. dhsolomon partners.org

BACKGROUND: Although cyclooxygenase-2 inhibitors (coxibs) were developed to cause less gastrointestinal hemorrhage than nonselective nonsteroidal antiinflammatory drugs (NSAIDs), there has been concern about their cardiovascular safety. We studied the relative risk of acute myocardial infarction (AMI) among users of celecoxib, rofecoxib, and NSAIDs in Medicare beneficiaries with a comprehensive drug benefit. METHODS AND RESULTS: We conducted a matched case-control study of 54 475 patients 65 years of age or older who received their medications through 2 state-sponsored pharmaceutical benefits programs in the United States. All healthcare use encounters were examined to identify hospitalizations for AMI. Each of the 10 895 cases of AMI was matched to 4 controls on the basis of age, gender, and the month of index date. We constructed matched logistic regression models including indicators for patient demographics, healthcare use, medication use, and cardiovascular risk factors to assess the relative risk of AMI in patients who used rofecoxib compared with persons taking no NSAID, taking celecoxib, or taking NSAIDs. Current use of rofecoxib was associated with an elevated relative risk of AMI compared with celecoxib (odds ratio [OR], 1.24; 95% CI, 1.05 to 1.46; P=0.011) and with no NSAID (OR, 1.14; 95% CI, 1.00 to 1.31; P=0.054). The adjusted relative risk of AMI was also elevated in dose-specific comparisons: rofecoxib < or =25 mg versus celecoxib < or =200 mg (OR, 1.21; 95% CI, 1.01 to 1.44; P=0.036) and rofecoxib >25 mg versus celecoxib >200 mg (OR, 1.70; 95% CI, 1.07 to 2.71; P=0.026). The adjusted relative risks of AMI associated with rofecoxib use of 1 to 30 days (OR, 1.40; 95% CI, 1.12 to 1.75; P=0.005) and 31 to 90 days (OR, 1.38; 95% CI, 1.11 to 1.72; P=0.003) were higher than >90 days (OR, 0.96; 95% CI, 0.72 to 1.25; P=0.8) compared with celecoxib use of similar duration. Celecoxib was not associated with an increased relative risk of AMI in these comparisons. CONCLUSIONS: In this study, current rofecoxib use was associated with an elevated relative risk of AMI compared with celecoxib use and no NSAID use. Dosages of rofecoxib >25 mg were associated with a higher risk than dosages < or =25 mg. The risk was elevated in the first 90 days of use but not thereafter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15096449&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
(214) Rofecoxib Provides Superior Relief of Pain in Osteoarthritis (OA) Compared to Celecoxib.

Kivitz AJ, Schnitzer TJ, Greenwald M, In Medicine A, Matzura-Wolfe D, Polis AB, Dixon ME, Dobbins TW, Geba GP.

Altoona Clinical Research.

We performed a randomized, double-blind, clinical trial to evaluate pain relief efficacy of rofecoxib and celecoxib at highest indicated once daily doses in osteoarthritis. 1082 patients meeting entry criteria for OA, responsive to NSAIDs, were randomized 3:3:1 to treatment with rofecoxib 25 mg QD (n = 471), celecoxib 200 mg QD (n = 460) or placebo (n = 151). Efficacy was assessed over the first 6 days of therapy and at weeks 2, 4 and 6 by WOMAC questionnaire and patient global assessment of response to therapy (PGART). Demographics were well balanced. Significantly more patients on placebo discontinued prematurely compared to both active groups (p < 0.001) mainly due to lack of pain relief efficacy. Rofecoxib provided statistically superior relief of night pain (p = 0.023), morning stiffness (p = 0.002), rest pain (p = 0.023), and walking pain (p = 0.005) compared to celecoxib. Rofecoxib was significantly superior to celecoxib on all WOMAC subscales including pain (p = 0.008), stiffness (p = 0.001) and physical function (p = 0.01). Rofecoxib was superior to celecoxib in % of patients with good or excellent PGART over 6 weeks (p = 0.014) and provided quicker onset of pain relief as assessed by time to first report of good or excellent response (p < 0.001). Both active groups were superior to placebo on efficacy endpoints. Incidence of clinical AEs, drug related AEs, serious AEs, and discontinuations due to AEs was similar between active groups. In this study, once daily doses of rofecoxib provided superior relief of pain and other related symptoms in OA compared to celecoxib and placebo. All treatments were generally well tolerated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15102275&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Isoflurane produces delayed preconditioning against myocardial ischemia and reperfusion injury: role of cyclooxygenase-2.

Tanaka K, Ludwig LM, Krolikowski JG, Alcindor D, Pratt PF, Kersten JR, Pagel PS, Warltier DC.

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.

BACKGROUND: Whether volatile anesthetics produce a second window of preconditioning is unclear. The authors tested the hypothesis that isoflurane causes delayed preconditioning against infarction and, further, that cyclooxygenase (COX)-2 mediates this beneficial effect. METHODS: Rabbits (n = 43) were randomly assigned to receive 0.9% intravenous saline, the selective COX-2 inhibitor celecoxib (3 mg/kg intraperitoneal) five times over 2 days before coronary artery occlusion and reperfusion, or isoflurane (1.0 minimum alveolar concentration) 24 h before acute experimentation in the absence or presence of celecoxib pretreatment. Two additional groups of rabbits received a single dose of celecoxib either 30 min before or 21.5 h after administration of isoflurane. Rabbits were then instrumented for measurement of hemodynamics and underwent 30 min of coronary occlusion followed by 3 h of reperfusion. Myocardial infarct size was measured using triphenyltetrazolium staining. Western immunoblotting to examine COX-1 and COX-2 protein expression was performed in rabbit hearts that had or had not been exposed to isoflurane. RESULTS: Isoflurane significantly (P < 0.05) reduced infarct size (22 +/- 3% of the left ventricular area at risk) as compared with control (39 +/- 2%). Celecoxib alone had no effect on infarct size (36 +/- 4%) but abolished isoflurane-induced cardioprotection (36 +/- 4%). A single dose of celecoxib administered 2.5 h before coronary occlusion and reperfusion also abolished the delayed protective effects of isoflurane (36 +/- 4%), but celecoxib given 30 min before exposure to isoflurane had no effect (22 +/- 4%). Isoflurane did not alter COX-1 and COX-2 protein expression. CONCLUSIONS: The results indicate that the volatile anesthetic isoflurane produces a second window of preconditioning against myocardial ischemia and reperfusion injury. Furthermore, COX-2 is an important mediator of isoflurane-induced delayed preconditioning.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15108964&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2 mediates ischemic, anesthetic, and pharmacologic preconditioning in vivo.

Alcindor D, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR.

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.

BACKGROUND: Cyclooxygenase-2 (COX-2) mediates the late phase of ischemic preconditioning (IPC), but whether this enzyme modulates early IPC, anesthetic-induced preconditioning (APC), or other forms of pharmacologic preconditioning (PPC) is unknown. The authors tested the hypothesis that COX-2 is an essential mediator of IPC, APC, and PPC in vivo. METHODS: Barbiturate-anesthetized dogs (n = 91) were instrumented for measurement of hemodynamics and randomly assigned to receive IPC (four 5-min coronary occlusions interspersed with 5-min reperfusions), APC (1.0 minimum alveolar concentration of isoflurane for 30 min), or PPC (selective mitochondrial K(ATP) channel opener diazoxide, 2.5 mg/kg intravenous) in the presence or absence of pretreatment with oral aspirin (650 mg), the selective COX-2 inhibitor celecoxib (200 mg), or acetaminophen (500 mg) administered 24, 12, and 2 h before experimentation in 12 separate experimental groups. All dogs were subjected to a 60-min coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size and coronary collateral blood flow were quantified with triphenyltetrazolium staining and radioactive microspheres, respectively. Myocardial 6-keto-prostaglandin F1alpha, a stable metabolite of prostacyclin, was measured (enzyme immunoassay) in separate experiments (n = 8) before and after isoflurane administration, in the presence or absence of celecoxib. RESULTS: No significant differences in baseline hemodynamics or the left ventricular area at risk for infarction were observed between groups. IPC, isoflurane, and diazoxide all decreased myocardial infarct size (9 +/- 1, 12 +/- 2, and 11 +/- 1%, respectively) as compared with control (30 +/- 1%). Celecoxib alone had no effect on infarct size (26 +/- 3%) but abolished IPC (30 +/-3%), APC (30 +/- 3%), and PPC (26 +/- 1%). Aspirin (24 +/- 3%) and acetaminophen alone (29 +/- 2%) did not alter infarct size or abolish APC-induced protection (18 +/- 1 and 19 +/- 1%, respectively). Isoflurane increased myocardial 6-keto-prostaglandin F1alpha to 463 +/- 267% of baseline in the absence but not in the presence (94 +/- 13%) of celecoxib. CONCLUSIONS: The results indicate that COX-2 is a critical mediator of IPC, APC, and PPC in dogs. The role of cyclooxygenase enzymes as obligatory mediators of myocardial protection produced by diverse preconditioning stimuli may have implications for the clinical use of COX-2 inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15108967&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Drug utilization review of celecoxib in Ontario.

LeLorier J, Fitzsimon C, Keresteci M, Stewart D, Lavoie F.

Pharmacoepidemiology and Pharmacoeconomics, Research Unit, Centre hospitalier de l'Universite de Montreal, Quebec, Canada.

Cyclooxygenase (COX)-2-specific inhibitors were developed to circumvent the gastrointestinal toxicity of non-specific non-steroidal anti-inflammatory drugs while maintaining efficacy. However, the higher acquisition cost of COX-2-specific inhibitors has resulted in the implementation of a programme for cost containment in the Ontario public drug program. This programme consists of limited use (LU) criteria that need to be met for drug reimbursement of patients with osteoarthritis (OA) or rheumatoid arthritis (RA). Determining the proportion of patients eligible for reimbursement for celecoxib according to the LU criteria (based on prior treatment failure and the presence or history of serious ulcer-related gastrointestinal complications) can provide an indication of the extent of adherence to suggested guidelines. Using a patient-based survey and an analysis of the Ontario Drug Benefit Program database, the proportion of patients prescribed celecoxib who met rigorous or pragmatic definitions of the LU criteria was determined. The extent of coprescription of gastroprotective agents among patients taking celecoxib was also determined. Using the pragmatic definition, the majority of patients in the patient-based survey (53% for OA and 81% for RA) met the LU criteria. Similarly, in the database analysis, the majority of patients (76% for OA and 78% for RA) met the LU criteria. These data suggest that physician prescribing of celecoxib is consistent with the LU criteria. Concomitant prescription of gastroprotective agents in patients taking celecoxib was approximately 40%. It is recommended that further investigations be performed to determine the long-term impact of LU criteria on clinical and economic outcomes, since these criteria may also serve to restrict use in patients who may benefit from taking COX-2-specific inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14585913&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Gastric effects of the selective cyclooxygenase-2 inhibitor, celecoxib, in the rat.

Coppelli G, Guaita E, Spaggiari S, Coruzzi G.

Pharmacology Section, Department of Human Anatomy, Pharmacology and Forensic Medicine, Medical Faculty, University of Parma, Via Volturno, 39, 43100 Parma, Italy.

BACKGROUND: Recent studies have revealed that cyclooxygenase-2 is involved in the protection of the damaged gastric mucosa, mediating, in particular, the acceleration of ulcer healing and angiogenesis; therein, it has been suggested that selective cyclooxygenase-2 inhibitors, although safe in healthy stomach, may have deleterious effects on the injured gastric mucosa. Moreover, no information is available about direct effects of these drugs on gastric surface epithelium. AIMS: To investigate the gastric effects of the selective cyclooxygenase-2 inhibitor, celecoxib, in healthy and damaged rat gastric mucosa. METHODS: Gastric toxicity was studied in the rat by measuring gastric potential difference and mucosal lesions. Celecoxib was administered intragastrically, either in basal conditions or in combination with damaging (acetylsalicylic acid and ethanol) or protective (sodium nitroprusside and lipopolysaccharides from Escherichia coli) agents. The anti-inflammatory activity was evaluated in the carrageenan-induced paw oedema assay. The non-selective inhibitors indomethacin and acetylsalicylic acid were used for comparison. RESULTS: In conscious rats celecoxib, indomethacin and acetylsalicylic acid significantly reduced the paw oedema induced by carrageenan. While acetylsalicylic acid and indomethacin significantly reduced basal gastric potential difference and caused gastric mucosal lesions, celecoxib was ineffective; moreover, it did not aggravate the direct damaging effect of intragastric ethanol or aspirin. Pretreatment with the non-selective nitric oxide synthase inhibitor N-nitro-L-argynine methyl ester did not significantly change the gastric effects of celecoxib. Both celecoxib and indomethacin prevented the gastroprotective effects induced by sodium nitroprusside (nitric oxide donor) or by bacterial lipopolysaccharides (inducer of nitric oxide synthesis). CONCLUSIONS. These data indicate that the selective cyclooxygenase-2 inhibitor celecoxib did not alter gastric mucosal barrier nor induced mucosal lesions in the healthy or nitric oxide-deficient rat gastric mucosa. However, cyclooxygenase-2 inhibition impaired nitric oxide-dependent gastroprotection, indicating that cyclooxygenase-2 derived prostaglandins may be involved in the gastric mucosal defence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15115339&dopt=Abstract celecoxib, Celebrex