celecoxib, Celebrex
Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage.

Fiorucci S, de Lima OM Jr, Mencarelli A, Palazzetti B, Distrutti E, McKnight W, Dicay M, Ma L, Romano M, Morelli A, Wallace JL.

Clinica di Gastroenterologia ed Endoscopia Digestiva, Dipartimento di Medicina Clinica, Patologia e Farmacologia, Universita degli Studi di Perugia, Perugia, Italy.

BACKGROUND & AIMS: Cyclooxygenase-2 (COX-2) has been implicated as contributing to mucosal defense. Acetylation of COX-2 by aspirin can result in production of an antiinflammatory substance, 15(R)-epi-LXA4. We determined whether aspirin-triggered lipoxin (LX) production via COX-2 diminishes aspirin-induced damage in the rat stomach. METHODS: Rats were treated with aspirin plus or minus celecoxib or rofecoxib. Gastric generation of LXA4 was measured. Effect of exogenous LXA4 or an LXA4 receptor antagonist on gastric resistance to aspirin-induced damage was examined. Aspirin-induced leukocyte adherence in mesenteric venules, and the effects of LXA4, were examined by intravital microscopy. RESULTS: Celecoxib and rofecoxib significantly increased the severity of aspirin-induced gastric damage. Aspirin rapidly up-regulated COX-2 expression in the stomach and caused a significant increase in gastric 15(R)-epi-LXA4 production, which was abolished by celecoxib. LXA4 dose dependently (0.25-2.5 microg/kg, intraperitoneally) reduced the severity of aspirin-induced gastric damage and suppressed aspirin-induced leukocyte adherence, whereas an LXA4 antagonist had the opposite effects. CONCLUSIONS: Aspirin administration results in elevated production of 15(R)-epi-LXA4 via COX-2. LXA4 exerts very potent protective actions on the gastric mucosa. Co-administration of aspirin and a selective COX-2 inhibitor results in substantially more severe gastric injury than is produced with either agent alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404234&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Selective inhibitors of cyclo-oxygenase-2 (COX-2) induce hypoalgesia in a rat paw model of inflammation.

Francischi JN, Chaves CT, Moura AC, Lima AS, Rocha OA, Ferreira-Alves DL, Bakhle YS.

Departamento de Farmacologia, ICB, Universidade Federal de Minas Gerais, Brazil. janettif icb.ufmg.br

1. It is well-established that inhibitors of cyclo-oxygenase (COX) and hence of prostaglandin (PG) biosynthesis reverse inflammatory hyperalgesia and oedema in both human and animal models of inflammatory pain. 2. Paw oedema and hyperalgesia in rats were induced by injecting carrageenan (250 micro g paw(-1)) into a hindpaw. Both inflammatory responses were followed for 24 h after the injection, measuring hyperalgesia by decreased pain threshold in the paws and oedema by plethysmography. 3. Three selective inhibitors of cyclo-oxygenase-2 (COX-2), celecoxib, rofecoxib and SC 236, given systemically in a range of doses, before the inflammatory stimulus, abolished carrageenan-induced hyperalgesia with little reduction of oedema. These inhibitors also induced hypoalgesia, increasing nociceptive thresholds in the inflamed paw above normal, non-inflamed levels. This hypoalgesia was lost at the higher doses of the selective inhibitors, although hyperalgesia was still prevented. 4. In paws injected with saline only, celecoxib, given at the dose inducing the maximum hypoalgesia after carrageenan, did not alter the nociceptive thresholds. 5. Two non-selective inhibitors of COX-2, indomethacin and piroxicam, abolished hyperalgesia and reduced oedema but did not induce hypoalgesia. 6. Celecoxib given locally into the paw also abolished inflammatory hyperalgesia and induced hypoalgesia without reducing oedema. 7. We conclude that hypoalgesia is expressed only over a critical range of COX-2 inhibition and that concomitant inhibition of COX-1 prevents expression of hypoalgesia, although hyperalgesia is still prevented. 8 Our results suggest a novel anti-nociceptive pathway mediating hypoalgesia, involving COX-2 selectively and having a clear peripheral component. This peripheral component can be further explored for therapeutic purposes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411415&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Comparison of the baseline cardiovascular risk profile among hypertensive patients prescribed COX-2-specific inhibitors or nonspecific NSAIDs: data from real-life practice.

Zhao SZ, Burke TA, Whelton A, von Allmen H, Henderson SC.

Pharmacia Corporation, Peapack, New Jersey, USA.

OBJECTIVE: To evaluate the baseline cardiovascular (CV) risk of hypertensive patients newly starting cyclooxygenase (COX)-2-specific inhibitors (celecoxib or rofecoxib) or nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: Cross-sectional analysis was performed based on real-life practice data contained in the LifeLink Integrated Claims Solutions employer claims database. Patients who newly received treatment of celecoxib, rofecoxib, ibuprofen, naproxen, or diclofenac between January 1, 1999, and September 30, 2000, were identified from the database. Among them, only those who had a stable hypertensive condition for at least 3 consecutive months before the index prescription were included. Baseline characteristics were determined from claims data at the time of the index prescription. RESULTS: A total of 55 396 index prescriptions were identified, which consisted of 20,915 (37.8%) prescriptions for celecoxib, 12,952 (23.4%) for rofecoxib, 10 789 (19.5%) for ibuprofen, 8,840 (16.0%) for naproxen, and 1,900 (3.4%) for diclofenac. Both univariate and multivariate analyses showed that the patients prescribed COX-2-specific inhibitors were older and more likely to be female than those given nonspecific NSAIDs. Patients prescribed COX-2-specific inhibitors had a significantly higher baseline history of and/or current CV conditions, including ischemic heart disease, heart failure, other forms of heart disease, and cerebrovascular diseases or disorders, than patients prescribed nonspecific NSAIDs. The baseline proportion of patients with rheumatoid arthritis was also higher among COX-2-specific inhibitor users. In addition, COX-2-specific inhibitor users at baseline had higher prescription rates for medications that influence blood pressure, including estrogens, certain types of antidepressants, and corticosteroids. CONCLUSION: COX-2-specific inhibitors were prescribed preferentially to patients who, at the time of their index COX-2-specific inhibitor prescription, were at an increased baseline risk of CV events compared with patients prescribed nonspecific NSAIDs. Researchers aiming to compare the incidence of CV events between COX-2-specific inhibitors and nonspecific NSAIDs using observational study designs should take into account the underlying baseline CV risk of the populations being compared.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12416789&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Blood pressure destabilization and related healthcare utilization among hypertensive patients using nonspecific NSAIDs and COX-2-specific inhibitors.

Zhao SZ, Burke TA, Whelton A, von Allmen H, Henderson SC.

Pharmacia Corporation, Peapack, New Jersey, USA.

OBJECTIVE: To determine the incremental cost of blood pressure (BP) destabilization among patients with stable hypertension who newly initiate therapy with celecoxib, rofecoxib, or 3 commonly used nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen, diclofenac, or naproxen, based on incidence rates of BP destabilization and costs of BP destabilization events obtained from a single observational data source. METHODS: Historical cohort observational analysis was performed based on real-life practice data that are contained in the LifeLink Integrated Claims Solutions employer claims databases. Patients with stable hypertension who had newly initiated therapy with rofecoxib, celecoxib, ibuprofen, diclofenac, or naproxen between January 1, 1999, and September 30, 2000, were identified from the database. The study consists of 3 components. First, the incidence rate of BP destabilization, based on patients' time of exposure to studied drugs, was estimated. Then, the cost of a BP destabilization event was determined by matching all BP destabilization cases with non-BP destabilization cases and following them for 90 days. The differences in the total costs between cases and controls were considered an estimate of the costs associated with managing the BP destabilization event. Last, the drug-specific incremental costs of BP destabilization of using each treatment were estimated in comparison with celecoxib. Incremental costs of BP destabilization were determined by multiplying the specific excess incidence rate of BP destabilization for each of the specific drugs, relative to celecoxib, by the cost of a BP destabilization event. RESULTS: The adjusted incidence rate of outpatient BP destabilization for celecoxib was 2.27 per 1000 patient-days vs 2.66 for rofecoxib (P < .001) or 2.65 for nonspecific NSAIDs (P < .001). The incremental cost of BP destabilization per patient per day of drug utilization for the study drugs compared with celecoxib were $0.18 for rofecoxib and $0.17 for nonspecific NSAIDs. The higher costs of BP destabilization relative to celecoxib were due to the higher incidence of outpatient BP destabilization associated with the other study drugs. The average incremental healthcare cost for an outpatient BP destabilization event within the first 90 days of the event was $459. The incidence of inpatient BP destabilization among rofecoxib users was significantly higher than among celecoxib users (risk rate = 4.17; 95% Cl, 1.86-9.26; P< .001). Incremental cost was not estimated for inpatient BP destabilization because the sample size was too small to provide a stable result. CONCLUSION: The costs of managing BP destabilization were significantly lower for celecoxib compared with rofecoxib and nonspecific NSAIDs. The observed differences among these anti-inflammatory drugs in the costs of BP destabilization will have a significant impact on the total cost of therapy in patients with stable hypertension. In addition to the monetary cost of BP destabilization, the physical cost to the patient regarding development or exacerbation of this serious medical condition should be considered when choosing cyclooxygenase-2-specific inhibitor and nonspecific NSAID therapies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12416790&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cost of heart failure among hypertensive users of nonspecific NSAIDs and COX-2-specific inhibitors.

Zhao SZ, Burke TA, Whelton A, von Allmen H, Henderson SC.

Pharmacia Corporation, Peapack, New Jersey, USA.

OBJECTIVE: To determine the costs of heart failure in hypertensive patients receiving celecoxib, rofecoxib, and nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs) in clinical practice. METHODS: Stable hypertensive patients without a history of heart failure and newly treated with celecoxib, rofecoxib, ibuprofen, naproxen, or diclofenac between January 1, 1999, and September 30, 2000, were identified from the LifeLink Integrated Claims Solutions employer database. The incidence rate of inpatient and outpatient heart failure claims was determined based on patients' time of exposure to study drugs after adjusting for confounding factors. The heart failure costs of managing inpatient and outpatient events were estimated as the total healthcare costs for patients with heart failure claims minus the total healthcare costs among matched control groups without heart failure claims. Healthcare costs were computed for the 0 to 30 days and 31 to 90 days following the initial outpatient or inpatient claim. Finally, the excess incidence rate of patients with inpatient and outpatient heart failure claims, relative to celecoxib, were multiplied by the heart failure cost of an inpatient and outpatient event to determine the incremental costs of heart failure associated with each of the study drugs relative to celecoxib. RESULTS: Among 50 940 patients, 707 patients had outpatient heart failure claims and 229 patients had inpatient heart failure claims. In this study, rofecoxib-treated patients were 26% more likely to have an outpatient claim (rate ratio [RR] = 1.26; 95% confidence interval [CI], 1.06-1.48; P= .007) and 52% more likely to have an inpatient claim (RR = 1.52; 95% Cl, 1.15-2.02; P = .003) for heart failure than celecoxib-treated patients. The adjusted RR of heart failure claims was similar between celecoxib and NSAIDs. The average cost of outpatient heart failure was $1054 within 30 days and $221 for the period 31 to 90 days after the initial claim (total 90-day cost of $1275). The cost for a patient with inpatient heart failure was $5966 during the hospitalization. The 90-day posthospitalization heart failure cost was $245 (total 90-day cost of $6,211 for hospitalization and follow-up). The total heart failure-related incremental cost per patient per day of use was $0.15 for rofecoxib and $0.04 for nonspecific NSAIDs relative to celecoxib. CONCLUSION: The additional heart failure costs associated with the use of rofecoxib significantly add to its cost in patients with stable hypertension, relative to celecoxib and nonspecific NSAIDs. The higher heart failure costs of rofecoxib were attributable to the higher incidence of patients with inpatient and outpatient heart failure claims relative to celecoxib and nonspecific NSAID populations being compared.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12416791&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Selective cyclooxygenase-2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells.

Yamazaki R, Kusunoki N, Matsuzaki T, Hashimoto S, Kawai S.

Institute of Medical Science, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki-shi, Kanagawa, Japan.

Although the influence of selective cyclooxygenase (COX)-2 inhibitors on the proliferation of colon adenocarcinoma cells have been the subject of much investigation, relatively little research has compared the effects of different COX-2 inhibitors. Celecoxib strongly suppressed the proliferation of COX-2 expressing HT-29 cells at 10-40 microM. NS-398 and nimesulide also inhibited cell proliferation, whereas rofecoxib, meloxicam, and etodolac did not. Only celecoxib induced apoptosis of HT-29 cells, as detected on the basis of DNA fragmentation, TUNEL positivity, and caspase-3/7 activation. DNA fragmentation was also increasd in COX-2 non-expressing cell lines (SW-480 and HCT-116) by exposure to celecoxib for 6-24 h. All six COX-2 inhibitors suppressed the production of prostaglandin E(2) by HT-29 cells, suggesting that the pro-apoptotic effect of celecoxib was unrelated to inhibition of COX-2. Inactivation of Akt might explain the differential pro-apoptotic effect of these selective COX-2 inhibitors on colon adenocarcinoma cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12417326&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Positive patch test reactions to celecoxib may be due to irritation and do not correlate with the results of oral provocation.

Kleinhans M, Linzbach L, Zedlitz S, Kaufmann R, Boehncke WH.

Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt, Germany.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among those therapeutics most frequently causing pseudoallergic and sometimes allergic cutaneous adverse reactions. Coxibs preferentially inhibiting cyclooxygenase-2 are increasingly propagated as alternatives in NSAID-sensitive patients. We evaluated the tolerability of celecoxib in NSAID-sensitive patients. In 14 consecutive patients (6 males, 8 females, age 18-72 years), scratch and patch tests with homogenized Celebrex were performed, followed by single-blind, placebo-controlled oral provocation (maximal single dose: 200 mg; cumulative dose: 350 mg). 8 of the first 10 patients showed erythematous reactions to celecoxib on patch testing after 2 days with decrescendo kinetics between then and day 3. 9 patients with no history of NSAID intolerance showed similar reactions. When the patch tests were repeated with homogenized Celebrex at final concentrations of 5% and 10% in petrolatum, no reaction was observed in any patient. Subsequent oral provocation was tolerated without adverse effects by all individuals. We conclude that patch tests with high concentrations of celecoxib cause irritant reactions and do not correlate with the outcome of oral provocation tests. Therefore, these tests should be performed with lower concentrations of celecoxib (Celebrex). Celecoxib itself seems to be a valuable alternative drug in NSAID-sensitive patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12423408&dopt=Abstract celecoxib, Celebrex