Developing a digitally innovative ethics and professionalism curriculum for neonatal-perinatal medicine fellows: a 3-year multicenter pilot study.

OBJECTIVES: The purpose of this study was to develop and regionally pilot a digitally innovative curriculum in ethics and professionalism in neonatology and study the effects on trainee knowledge and confidence. STUDY DESIGN: We developed 13 modules in ethics for neonatology fellows and piloted them at three academic institutions utilizing a flipped-classroom approach. Baseline surveys in ethics knowledge and confidence in approaching ethical dilemmas were compared with repeat surveys after curriculum completion. Pre- and post-tests were also administered for all 13 modules. RESULTS: Forty-four of 49 eligible fellows participated (90% response rate). Pre/post comparisons demonstrated significant improvements in overall knowledge and in 8/13 modules, as well as improvement in overall confidence and individually when navigating 16/22 ethical dilemmas. CONCLUSIONS: After completing this curriculum, participants' knowledge scores and reported confidence in approaching ethical challenges significantly improved. Future steps include assessing the effects of this innovative curriculum via an ongoing international pilot.

Ethics and professionalism education during neonatal-perinatal fellowship training in the United States.

OBJECTIVE: The objectives of this study were to determine the perceived adequacy of ethics and professionalism education for neonatal-perinatal fellows in the United States, and to measure confidence of fellows and recent graduates when navigating ethical issues. STUDY DESIGN: Neonatal-Perinatal Fellowship Directors, fellows and recent graduates were surveyed regarding the quality and type of such education during training, and perceived confidence of fellows/graduates in confronting ethical dilemmas. RESULT: Forty-six of 97 Directors (47%) and 82 of 444 fellows/graduates (18%) completed the surveys. Over 97% of respondents agreed that ethics training is 'important/very important'. Only 63% of Directors and 37% of fellows/graduates rated ethics education as 'excellent/very good' (P=0.004). While 96% of Directors reported teaching of ethics, only 70% of fellows/graduates reported such teaching (P<0.001). Teaching methods and their perceived effectiveness varied widely. CONCLUSION: Training in ethics and professionalism for fellows is important, yet currently insufficient; a more standardized curriculum may be beneficial to ensure that trainees achieve competency.

[Tularemia in Germany]. / Die Tularämie in Deutschland.

The bacterium Francisella tularensis is known for more than 100 years by now as the etiological agent of the disease tularemia, a zoonotic infection with a worldwide distribution in the Northern Hemisphere. The prevalence of tularemia shows a wide geographic variation, being comparably infrequent in Germany. Tularemia can present itself with multiple clinical manifestations including ulceroglandular, glandular, oropharyngeal, oculoglandular, respiratory and typhoidal forms. Due to the low prevalence and the unspecific symptomatology, a rapid diagnosis and early start of an effective therapy are rarely obtained. Thus, in this article we summarize important aspects concerning etiology, ecology and routes of transmission, recent epidemiologic situation, clinical picture, diagnostics and treatment of tularemia, focusing on the situation in Germany.

Evaluation of species-specific score cutoff values of routinely isolated clinically relevant bacteria using a direct smear preparation for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-based bacterial identification.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was introduced a few years ago as a new method for bacterial identification. A variety of studies have been published concerning MALDI-TOF MS-based identification, most of them using culture collections for the validation of the respective databases in a retrospective manner in favor of a parallel investigation. The score cutoff value is of special importance for reliable species identification in the Biotyper database. The score cutoff values suggested by the manufacturer have been validated using a previously published formic acid extraction protocol. In most of the previously published studies investigating the Biotyper database, only little information was given concerning species-specific score values. In addition, the mass spectrometer instruments, the number of replicates, the number of spectra used to calculate a sum-spectrum by the supplied software, and the score cutoff values which have been applied varied within these studies. In this study, we compared a straightforward direct smear preparation and measurement without replicate testing to defined biochemical identifications in a parallel manner. In addition, we described new species-specific score cutoff values for the identification of certain bacteria.

American pain society pain questionnaire and other pain measures in the assessment of osteoarthritis pain: a pooled analysis of three celecoxib pivotal studies.

The aim of this study was to evaluate the utility of the American Pain Society (APS) questionnaire in the assessment of osteoarthritis (OA) pain and to determine the onset of action of celecoxib in the treatment of acute flare pain in patients with OA of the knee or hip. Pooled data from three pivotal, randomized, double-blind, placebo-controlled, 12-week trials of patients with OA who exhibited a flare of disease activity after withdrawal of nonsteroidal anti-inflammatory drug or analgesic therapy were evaluated. Patients completed the APS Pain Measure Questionnaire, which evaluates pain intensity and quality of life, at baseline and daily for the first 7 days of therapy. In addition, patients underwent a range of standard OA assessments to evaluate the analgesic efficacy of celecoxib up to 12 weeks. Three thousand two hundred fifty-eight patients were enrolled in the three studies, of whom 2041 completed the APS questionnaire (1010 received celecoxib, 513 received naproxen, and 518 received placebo). Within the first 24 hours, celecoxib at a dose of 200 or 400 mg/d significantly reduced the amount of acute pain experienced compared with placebo for four of the five measures, and statistical significance for the remaining parameter, "pain in the last 24 hours," was achieved on day 2. Celecoxib at a dose of 200 to 400 mg/d provided similar efficacy to naproxen at a dose of 1000 mg/d. The pain relief observed with celecoxib was maintained for the APS evaluation period. Long-term efficacy assessments showed the efficacy of 200 mg/d of celecoxib to be continuous and maintained for at least the 12 weeks of the study and that it was equivalent to 400 mg/d of celecoxib and 1000 mg/d of naproxen. This study demonstrates that the APS questionnaire is a useful measure of pain and therapeutic response in OA. Celecoxib furthermore seems to be an effective acute and chronic analgesic in OA.

Dyspepsia tolerability from the patients' perspective: a comparison of celecoxib with diclofenac.

AIM: To compare celecoxib (800 mg/day, n=1997) with diclofenac (150 mg/day, n=1996) on dyspepsia-related tolerability. METHODS: In one of the two protocols comprising the Celecoxib Long-Term Arthritis Safety Study, a randomized double-blind trial, patients completed the Severity of Dyspepsia Assessment Questionnaire at baseline and at weeks 4, 13, 26 and 52 for the following three scales: Pain Intensity, Non-Pain Symptoms and Satisfaction with Dyspepsia-Related Health. RESULTS: For the Pain Intensity scale, patients given diclofenac had significantly higher (worsening dyspepsia) mean changes, defined as follow-up minus baseline, than patients given celecoxib (P < 0.001, at all assessments). The mean changes in the Pain Intensity scale (scale, 2-47; higher score is higher pain intensity) were 0.99 (95% confidence interval (CI): 0.50, 1.48) for celecoxib and 2.76 (95% CI: 2.28, 3.25) for diclofenac at 4 weeks. Satisfaction was superior with celecoxib at all assessments (P < 0.001). At 4 weeks, the mean changes in the Satisfaction scale (scale, 7-35; higher score is higher satisfaction) were 0.02 (95% CI: - 0.26, 0.29) for celecoxib and - 0.72 (95% CI: - 1.00, - 0.45) for diclofenac. Diclofenac patients had significantly higher Non-Pain Symptoms at 4 weeks (P=0.005). CONCLUSIONS: Celecoxib, at two to four times the recommended dose, demonstrated a superior dyspepsia-related tolerability and satisfaction compared with standard dosages of diclofenac.

Upper gastrointestinal tolerability of celecoxib compared with diclofenac in the treatment of osteoarthritis and rheumatoid arthritis.

OBJECTIVE: To compare the upper gastrointestinal (UGI) tolerability of celecoxib (a cyclooxygenase-2 specific inhibitor) and diclofenac using data from three randomised, double-blind clinical trials in osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: Patients in two OA studies received either celecoxib 100 mg BID (n = 545), diclofenac 50 mg BID or TID (n = 540), or placebo (n = 200) for 6 weeks. In the RA study, patients received celecoxib 200 mg BID (n = 326) or diclofenac 75 mg BID (n = 329) for 24 weeks. The cumulative incidence of abdominal pain, dyspepsia, nausea or any of these events (UGI tolerability composite endpoint) after the first 6 weeks was estimated using time-to-event analysis. RESULTS: In the pooled OA trials, the cumulative incidence of the composite endpoint was significantly higher with diclofenac (17.6%; 95% CI: 14.4-20.9%) than celecoxib (11.1%; 95% CI: 8.4-13.8%; p = 0.002) and comparable with placebo (13.3%; 95% CI: 8.1-18.4%; p = 0.157). In the PA trial, the cumulative incidence of the UGI tolerability composite endpoint was also significantly higher with diclofenac (20.7%; 95% CI: 16.3-25.1%) than celecoxib (15.9%; 95% CI: 11.9-20.0%; p = 0.013). Celecoxib was also better tolerated than diclofenac in this trial in terms of the cumulative incidences of abdominal pain (p = 0.031) and dyspepsia (p = 0.062). The results of the UGI tolerability composite endpoint analysis were confirmed using the Cox proportional hazards model to controlfor other predictors of UGI adverse events. CONCLUSION: The UGI tolerability of therapeutic dosages of celecoxib was significantly better than diclofenac in patients with RA or OA.

Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac.

It has been hypothesized that cyclooxygenase 2 specific inhibitors may increase the risk of cardiovascular (CV) thromboembolic events because of their inhibition of vascular prostacyclin synthesis and lack of an effect on platelet thromboxane A(2) production and aggregation. Thus, we analyzed the data for celecoxib and nonsteroidal anti-inflammatory drugs (NSAIDs) from the Celecoxib Long-term Arthritis Safety Study to determine the incidences of serious CV thromboembolic events. This trial included 3,987 persons randomized to celecoxib 400 mg twice daily (2,320 person-years of exposure) and 3,981 persons randomized to either ibuprofen 800 mg 3 times daily or diclofenac 75 mg twice daily (2,203 person-years). Because acetylsalicylic acid (ASA) use for CV risk prophylaxis (< or =325 mg/day) was permitted, separate analyses were performed for all patients and those not taking ASA. The incidences of serious CV thromboembolic events (myocardial infarction, stroke, CV deaths, and peripheral events) were similar, and not significantly different, between celecoxib and NSAID comparators (combined or individually) for all patients as well as the subgroup of patients not taking ASA. This observation was true both for all serious CV thromboembolic events, as well as for individual events. No increase in myocardial infarction was apparent, even in patients not taking ASA who were candidates for secondary prophylaxis for myocardial infarction. The relative risks for celecoxib versus NSAIDs for serious CV thromboembolic events were 1.1 for all patients and 1.1 for the subgroup of patients not taking ASA (95% confidence interval 0.7 to 1.6 and 0.6 to 1.9, respectively). In addition, the incidences of adverse CV events such as hypertension, edema, and congestive heart failure were similar to, or significantly lower than, NSAID comparators regardless of the use of ASA. Thus, these analyses demonstrate no increased risk of serious CV thromboembolic events associated with celecoxib compared with conventional NSAIDs and therefore do not support the hypothesis of a class adverse effect of cyclooxygenase 2 specific inhibitors on the CV system.

Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis.

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin production by inhibiting cyclooxygenase (COX); they are believed to cause gastroduodenal damage by inhibiting the COX-1 isoform and to have analgesic and anti-inflammatory effects by inhibiting the COX-2 isoform. As compared to conventional NSAIDs, celecoxib, a COX-2 specific inhibitor, has been shown in previous single posttreatment endoscopy studies to be associated with lower gastroduodenal ulcer rates. In response to concerns that such studies may under-represent ulceration rates, the present serial endoscopy study was designed to compare cumulative gastroduodenal ulcer rates associated with the use of celecoxib to those of naproxen, a conventional NSAID. METHODS: In this double-blind, parallel-group, multicenter study, 537 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were randomized to treatment with celecoxib 200 mg b.i.d. (n = 270) or naproxen 500 mg b.i.d. (n = 267) for 12 wk. Gastroduodenal damage was determined from esophagogastroduodenoscopy after 4, 8, and 12 wk of therapy. Arthritis efficacy was evaluated with Patient's and Physician's Global Assessments. RESULTS: Gastroduodenal ulcer rates after celecoxib and naproxen treatment were 4% versus 19% in the 0-4 wk interval (p < 0.001), 2% versus 14% in the 4-8 wk interval (p < 0.001), and 2% versus 10% in the 8-12 wk interval (p < 0.001), respectively. After 12 wk of treatment, the cumulative incidence of gastroduodenal ulcers was 9% with celecoxib and 41% with naproxen. In the celecoxib group, gastroduodenal ulcers were significantly associated with Helicobacter pylori status (p < 0.05), concurrent aspirin usage (p = 0.001), and a history of ulcer (p = 0.010), but not with disease type (OA/RA), age, gender, other relevant medical histories, or concurrent corticosteroid or disease-modifying antirheumatic drugs usage (p > 0.05). Celecoxib produced a significantly lower incidence rate of both gastric (p < 0.001) and duodenal (p < 0.030) ulcers. The two agents produced similar improvements in Patient's and Physician's Global Assessments of arthritis efficacy. The incidence of adverse events and withdrawal rates did not differ significantly between treatments. CONCLUSIONS: As compared to naproxen (500 mg b.i.d.), use of celecoxib (200 mg b.i.d.), a COX-2 specific agent, at the recommended RA dose and twice the most frequently prescribed OA dose, was associated with lower rates of gastric, duodenal, and gastroduodenal ulcers but had comparable efficacy, in patients with OA and RA.

Comparison of once-daily and twice-daily administration of celecoxib for the treatment of osteoarthritis of the knee.

OBJECTIVE: The purpose of this study was to compare the efficacy and tolerability of a celecoxib 200 mg QD regimen with a 100 mg BID regimen in patients with osteoarthritis (OA) of the knee. METHODS: Patients enrolled in this prospective, double-blind, placebo-controlled, parallel-group, multicenter study were randomly assigned to receive celecoxib 100 mg BID, celecoxib 200 mg QD, or placebo for 6 weeks. Assessments of OA severity (Patient's and Physician's Global Assessments of Arthritis, Patient's Assessment of Arthritis Pain-Visual Analog Scale, Lequesne Osteoarthritis Severity Index, and the Western Ontario and McMaster Universities Osteoarthritis Index) were performed at baseline and at week 2 and/or 6. Patients who discontinued treatment underwent assessments at the time of withdrawal from the study. RESULTS: Of the 718 patients enrolled, 243 received celecoxib 100 mg BID, 231 received celecoxib 200 mg QD, and 244 received placebo. For all measures of efficacy, at all assessments, improvements from baseline in both celecoxib groups were superior to that seen in the placebo group (P < 0.05). No significant differences in efficacy between the celecoxib groups were observed. The overall incidence of adverse events was similar in the 2 celecoxib treatment groups. CONCLUSIONS: Dosing regimens of celecoxib 200 mg QD and 100 mg BID are equally effective and well tolerated in patients with OA of the knee. The availability of 2 effective regimens provides patients and physicians with increased flexibility in the selection of an appropriate dosing regimen for celecoxib therapy.

Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults.

BACKGROUND: Current outpatient management of postoperative pain includes the use of oral opioid analgesics or nonsteroidal anti-inflammatory drugs; however, both types of medications are associated with side effects that can limit their usefulness in the outpatient setting. OBJECTIVE: Two studies with identical protocols assessed the single- and multiple-dose analgesic efficacy and tolerability of celecoxib, a specific cyclooxygenase-2 inhibitor, in the treatment of acute pain after orthopedic surgery. METHODS: These were multicenter, randomized, placebo- and active-controlled, double-blind, parallel-group trials conducted between January and June 1998. Both consisted of a single-dose assessment period (SDAP) and a multiple-dose assessment period (MDAP). In the SDAP, patients who had undergone orthopedic surgery received a single oral dose of celecoxib 200 mg, hydrocodone 10 mg/acetaminophen 1000 mg, or placebo within 24 hours after the end of anesthesia, with pain assessments conducted over the following 8-hour period. In the MDAP, extending from 8 hours after the first dose of study medication up to 5 days, patients who had received < or =1 dose of rescue medication during the SDAP continued on study medication (placebo recipients were rerandomized to active treatment), which could be taken up to 3 times a day as needed. RESULTS: A total of 418 patients were enrolled in the 2 trials. During the SDAP, 141 patients received celecoxib, 136 received hydrocodone/acetaminophen, and 141 received placebo. During the MDAP, 185 patients received celecoxib and 181 received hydrocodone/acetaminophen. When the combined data were analyzed, mean pain intensity difference (PID) scores generally favored the active treatments over placebo from 1 to 6 hours (with the exception of 1.5 hours) after dosing (P < or = 0.016) and favored celecoxib over the other treatments at 7 and 8 hours after dosing (P < 0.001). The active treatments demonstrated superior summed PID scores through 8 hours (P < 0.001), significantly shorter median times to onset of analgesia (P < 0.05), and significantly longer median times to first use of rescue medication (P < 0.05). During the MDAP, more hydrocodone/acetaminophen-treated patients (20%) than celecoxib-treated patients (12%) required rescue medication (P < 0.05), and the celecoxib group had significantly lower maximum pain intensity scores (P < 0.001, days 2-5), required fewer doses of study medication (P < or = 0.01, days 3-5), and had superior scores on a modified American Pain Society Patient Outcome Questionnaire (P < or = 0.013). In addition, a significantly lower proportion of celecoxib-treated patients experienced adverse events (43%) compared with hydrocodone/acetaminophen-treated patients (89%; P < 0.001). CONCLUSIONS: Over 8 hours, patients with moderate to severe pain after orthopedic surgery experienced comparable analgesia with single doses of celecoxib and hydrocodone/acetaminophen. Over a 5-day period, oral doses of celecoxib 200 mg taken 3 times a day demonstrated superior analgesia and tolerability compared with hydrocodone 10 mg/acetaminophen 1000 mg taken 3 times a day. Most patients required no more than 2 daily doses of celecoxib 200 mg for the control of their postorthopedic surgical pain.

Cox-2-specific inhibitors: definition of a new therapeutic concept.

Nonsteroidal anti-inflammatory drugs have been a mainstay in the treatment of inflammatory diseases such as rheumatoid arthritis. However, these agents can result in severe and occasionally life-threatening adverse effects that can limit therapeutic benefit. Progress toward safer anti-inflammatory therapy was aided by the discovery that cyclooxygenase (COX) exists as two isozymes, COX-1 and COX-2. Both isozymes form prostaglandins that support physiologic functions; however, the formation of proinflammatory prostaglandins is catalyzed by COX-2. Inhibition of COX-2 accounts for the anti-inflammatory and analgesic action of NSAIDs; however, concurrent inhibition of COX-1 inhibits prostaglandin-dependent mechanisms such as gastroduodenal mucosal defense and platelet aggregation. This inhibition is the basis of the gastrointestinal toxicity and bleeding characteristic of these drugs. These findings led to the hypothesis that agents that selectively inhibit COX-2 would possess anti-inflammatory and analgesic action but would spare COX-1, thereby avoiding adverse effects in the gastrointestinal tract and platelets. Selective COX-2 inhibitors are now available. The novelty of these agents has raised questions in the medical community as to what constitutes selectivity for COX-2. This review outlines the criteria that must be met to characterize a compound as COX-2-specific. Clinical evidence of clear improvement in gastrointestinal tolerability and safety must be demonstrated in addition to complementary evidence of COX-2 selectivity obtained from enzyme, biochemical, and clinical pharmacology evaluations.

Celecoxib versus diclofenac in the management of osteoarthritis of the knee.

OBJECTIVE: A clinical trial was conducted in 600 patients with OA of the knee to test the hypothesis that the specific COX-2 inhibitor, celecoxib, has equivalent efficacy and a superior tolerability/safety profile when compared to diclofenac, the current worldwide standard of care. METHODS: Patients were administered celecoxib 100 mg BID, diclofenac 50 mg TID or placebo for 6 weeks in a multicentre, double-blind. placebo-controlled trial. RESULTS: Primary efficacy measures (index joint pain by VAS, WOMAC index) indicated statistically significant improvement versus placebo for both celecoxib and diclofenac and no statistically significant differences between celecoxib and diclofenac. American Pain Society (APS) measures to assess the rapidity of onset of action showed statistically significant and comparable pain relief versus placebo within 24 h for both celecoxib and diclofenac. More diclofenac patients reported GI side effects than patients treated with either placebo or celecoxib. Diclofenac-treated patients experienced statistically significant elevations in mean hepatic transaminases and serum creatinine and reductions in haemoglobin concentration when compared to placebo, events not observed with celecoxib. CONCLUSION: Celecoxib 200 mg daily is as effective as diclofenac 150 mg daily for relieving signs and symptoms of OA of the knee, including pain, and has a rapid onset of action. However, celecoxib appears to have a superior safety and tolerability profile.

Comparative efficacy and safety of celecoxib and naproxen in the treatment of osteoarthritis of the hip.

Osteoarthritis (OA) is responsible for more disability of the lower extremities in the elderly than any other disease in the US. The pain associated with OA is the primary symptom leading to disability in these patients. Current ACR guidelines recommend consideration of acetaminophen for mild-to-moderate pain and conventional non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 specific inhibitors for moderate-to-severe OA symptoms. The aim of this study was to compare the efficacy and safety of the COX-1 sparing, COX-2 specific inhibitor, celecoxib, with the conventional NSAID naproxen, and placebo, in the treatment of OA of the hip. In this multicenter, randomized, placebo-controlled trial, 1061 patients with symptomatic OA of the hip were randomized to receive celecoxib at doses of 100 mg, 200 mg, or 400 mg/day; naproxen 1000 mg/day; or placebo, for 12 weeks. Patients were evaluated using standard measures of efficacy at baseline, 2-4 days after discontinuing previous NSAID or analgesic therapy, and after 2, 6, and 12 weeks of treatment. All doses of celecoxib and naproxen significantly improved the symptoms of OA, at all time points compared with placebo. This sustained treatment effect of celecoxib was dose dependent. In terms of pain relief and improvement in functional capacity, celecoxib 200 mg/day and 400 mg/day were similarly efficacious and were comparable to naproxen. Both drugs were generally well tolerated. Celecoxib at a dose of 200 mg/day is as effective as a standard therapeutic dose of the conventional NSAID, naproxen, in reducing the pain associated with OA of the hip.

Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.

CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (

Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor.

OBJECTIVE: The aim of this study was to assess the rate of upper gastrointestinal (UGI) ulcer complications (bleeding, perforation, or gastric outlet obstruction) associated with celecoxib, a specific COX-2 inhibitor, compared with the rate associated with nonspecific, nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: A pooled analysis was conducted of 14 multicenter, double-blind, randomized, controlled trials (RCTs) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis. The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2-24 wk; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr. In the RCTs, patients were randomly assigned to receive placebo (n = 1,864; 208 patient-years), celecoxib 25-400 mg b.i.d. (n = 6,376; 1,020 patient-years), or a comparator NSAID (n = 2,768; 535 patient-years); NSAIDs were naproxen 500 mg b.i.d., diclofenac 50 or 75 mg b.i.d., or ibuprofen 800 mg t.i.d.). In the long-term, open-label trial, patients received celecoxib 100-400 mg b.i.d. for up to 2 yr (n = 5,155; 5,002 patient-years). The principal outcome measure of this analysis was development of a UGI ulcer complication, which was prospectively defined as bleeding, perforation, or gastric outlet obstruction. Ulcer complications were assessed and adjudicated by persons blinded to the patient's treatment assignment or the study in which the patient participated. RESULTS: In the RCTs, UGI ulcer complications occurred in no placebo patients (0 of 1,864 patients), in 2 of 6,376 celecoxib patients (0.03%), and in 9 of 2,768 patients receiving an NSAID (0.33%), corresponding to annual incidences of 0.20% for celecoxib (p > 0.05 vs placebo) and 1.68% for NSAIDs (p = 0.002 vs celecoxib and placebo). In the long-term open-label trial, nine UGI ulcer complications occurred, for an incidence of 0.17% and an annualized incidence of 0.18%. CONCLUSIONS: The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs. The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs, and to that in non-NSAID users reported in the literature.

Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo.

OBJECTIVE: To determine the upper gastrointestinal (GI) tolerability of celecoxib, naproxen, and placebo in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: An analysis of 5, 12-week, randomized, double blind, parallel group, placebo controlled clinical trials was conducted. In these trials, patients were randomized to: naproxen 500 mg bid (n = 1,099), placebo (n = 1,136), celecoxib 50 mg bid (n = 690) (subtherapeutic dose), celecoxib 100 mg (n = 1,131) or 200 mg bid (n = 1,125) (therapeutic dose), or celecoxib 400 mg bid (n = 434) (supratherapeutic dosage). The incidence and time until moderate to severe abdominal pain, dyspepsia, nausea, and any of the aforementioned 3 upper GI symptoms (composite endpoint) were determined using time-to-event analysis. RESULTS: The cumulative incidences of moderate to severe abdominal pain, dyspepsia, or nausea (composite endpoint) were: naproxen 500 mg (12.0%; 95% CI 9.9%-14.0%), celecoxib 50 mg bid (7.1%; 95% CI 5.0%-9.2%), celecoxib 100 mg bid (7.8%; 95% CI 6.0%-9.5%), celecoxib 200 mg bid (8.1%; 95% CI 6.4%-9.9%), celecoxib 400 mg bid (6.0%; 95% CI 3.6%-8.4%), and placebo (8.5%; 95% CI 6.5%-10.8%). After controlling for independent predictors of the composite endpoint, relative risks (RR) for the various treatments relative to naproxen 500 mg bid were: celecoxib 50 mg (RR 0.54; 95% CI 0.37-0.77; p < 0.001), celecoxib 100 mg (RR 0.60; 95% CI 0.45-0.80; p < 0.001), celecoxib 200 mg bid (RR 0.63; 95% CI 0.47-0.83; p = 0.001), celecoxib 400 mg bid (RR 0.56; 95% CI 0.35-0.89; p = 0.015), and placebo (RR 0.63; 95% CI 0.47-0.85; p = 0.002). After controlling for independent predictors of the composite endpoint, celecoxib treatment group patients did not differ from placebo patients when reporting the composite endpoint, with p values ranging from 0.40 to 0.96. CONCLUSION: The upper GI tolerability of celecoxib is superior to naproxen. A dose-response relationship between celecoxib and upper GI symptoms was not apparent.

Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects.

The objective of this study was to determine the effects of celecoxib, an anti-inflammatory/analgesic agent that primarily inhibits COX-2 and not COX-1 at therapeutic doses, on the steady-state pharmacokinetic profile and hypoprothrombinemic effect of racemic warfarin in healthy volunteers. Twenty-four healthy adult volunteers on maintenance doses of racemic warfarin (2-5 mg daily), stabilized to prothrombin times (PT) 1.2 to 1.7 times pretreatment PT values for 3 consecutive days, were randomized to receive concomitant celecoxib (200 mg bid) or placebo for 7 days in an open-label, multiple-dose, randomized, placebo-controlled, parallel-group study of warfarin pharmacokinetics and PT. Steady-state exposure of S- and R-warfarin (area under the curve [AUC]) and maximum plasma concentration (Cmax) in subjects receiving celecoxib were within 2% to 8% of the warfarin AUC and Cmax in subjects receiving placebo during the concomitant treatment period. In addition, PT values were not significantly different in subjects receiving warfarin and celecoxib concomitantly compared with subjects receiving warfarin and placebo. In conclusion, concomitant administration of celecoxib has no significant effect on PT or steady-state pharmacokinetics of S- or R-warfarin in healthy volunteers.

Effects of celecoxib and naproxen on renal function in the elderly.

OBJECTIVE: To compare the effects of celecoxib, a cyclooxygenase 2-specific inhibitor, with the nonspecific cyclooxygenase 1 and 2 inhibitor naproxen on renal function in 29 healthy elderly subjects in a single-blind, randomized, crossover study. METHODS: Subjects received either celecoxib, 200 mg twice daily, for 5 days followed by celecoxib, 400 mg twice daily, for the next 5 days, or they received naproxen, 500 mg twice daily, for 10 days. After a 7-day washout, subjects were crossed over to receive the other regimen. RESULTS: After the first dose, the trend was for a greater decrease in glomerular filtration rate with naproxen (-5.31 mL/min per 1.73 m2) compared with celecoxib (-0.86 mL/min per 1.73 m2). The treatment difference became statistically significant on day 6 (-7.53 vs -1.11 mL/min per 1.73 m2 for naproxen and celecoxib, respectively; P=.004). Urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion was significantly reduced from baseline across the treatment interval with both celecoxib and naproxen (P< or =.04). There were no significant differences in prostaglandin excretion between these 2 agents (P> or =.07). Small, transient decreases (P<.05) in urinary sodium excretion were observed after the initiation of both celecoxib and naproxen treatment. Sodium excretion values returned to baseline by the end of the study. CONCLUSIONS: The results indicate that cyclooxygenase 2-specific inhibition in healthy elderly subjects may spare renal hemodynamic function, although the effects on sodium excretion, as well as urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion, appear to be similar to those of nonspecific cyclooxygenase inhibitors such as naproxen.