Faculty Bibliography

BACKGROUND:Most nonsteroidal anti-inflammatory drugs (NSAIDs) are non-selective cyclooxygenase-1 (COX-1) and COX-2 inhibitors and are associated with upper gastrointestinal (GI) dyspeptic symptoms often resulting in GI co-medication usage or treatment discontinuation. OBJECTIVE:To compare the rates of new use of gastroprotective agents and discontinuations due to dyspepsia with the COX-2 selective inhibitor etoricoxib compared with non-selective NSAIDs. RESEARCH DESIGN AND METHODS/METHODS:This pre-specified combined analysis used data from nine randomized, double-blind, controlled, clinical trials with etoricoxib in patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis. The cumulative incidences of (1) new use (new prescription or increased dose) of gastroprotective agents (GPA) and (2) discontinuation due to dyspeptic symptoms were compared among patients treated with etoricoxib (60 mg, 90 mg, or 120 mg daily) vs. non-selective NSAIDs (diclofenac 50 mg. t.i.d. or naproxen 500 mg. b.i.d.). RESULTS:The overall rates/100 patient-years for new use of GPAs were 9.1 and 13.0 for etoricoxib and NSAIDs, respectively (RR = 0.75; 95% confidence interval [CI] 0.64, 0.89; p < 0.001). A benefit with etoricoxib was seen in the first 6 months when most new GPA usage occurred; after 6 months new use of GPAs was similar between etoricoxib and NSAIDs. The rates/100 patient-years of treatment discontinuation due to dyspeptic symptoms with etoricoxib and NSAIDs were 1.5 and 2.7, respectively (RR = 0.60; 95% CI 0.41, 0.87; p = 0.007). Analyses of placebo-controlled treatment periods showed significantly more new GPA use and more discontinuations due to dyspeptic symptoms with NSAIDs vs. placebo, but not with etoricoxib vs. placebo. CONCLUSION/CONCLUSIONS:In this combined analysis of clinical trials of patients with OA, RA, chronic low back pain, or AS, new use of gastroprotective agents was significantly lower with etoricoxib than with the comparator non-selective NSAIDs during the initial 6 months of treatment and similar thereafter. There were significantly fewer discontinuations for dyspeptic symptoms with etoricoxib than with NSAIDs over the entire follow-up period.

OBJECTIVES/OBJECTIVE:Mitogen-activated protein kinases (MAPK) are important intermediates in the signal transduction pathways involved in neuronal dysfunction following cerebral ischemia-reperfusion injury. One subfamily, extracellular regulated kinase 1/2, has been heavily implicated in the pathogenesis of post-ischemic neuronal damage. However, the contribution of extracellular regulated kinase 1/2 to neuronal damage following deep hypothermic circulatory arrest and low flow cardiopulmonary bypass is unknown. We attempted to correlate the extent of neuronal damage present following deep hypothermic circulatory arrest and low flow cardiopulmonary bypass with phosphorylated extracellular regulated kinase 1/2 expression in the cerebral vascular endothelium. METHODS:Piglets underwent normal flow cardiopulmonary bypass (n=4) deep hypothermic circulatory arrest (n=6) and low flow cardiopulmonary bypass (n=5). Brains were harvested following 24 h of post-cardiopulmonary bypass recovery. Cerebral cortical watershed zones, hippocampus, basal ganglia, thalamus, cerebellum, mesencephalon, pons and medulla were evaluated using hematoxylin and eosin staining. A section of ischemic cortex was evaluated by immunohistochemistry with rabbit polyclonal antibodies against phosphorylated extracellular regulated kinase 1/2. RESULTS:Compared to cardiopulmonary bypass controls, the deep hypothermic circulatory arrest and low flow cardiopulmonary bypass piglets exhibited diffuse ischemic changes with overlapping severity and distribution. Significant neuronal damage occurred in the frontal watershed zones and basal ganglia of the deep hypothermic circulatory arrest group (P<0.05). No detectable phosphorylated extracellular regulated kinase 1/2 immunoreactivity was found in the cardiopulmonary bypass controls; however, ERK 1/2 immunoreactivity was present in the cerebral vascular endothelium of the deep hypothermic circulatory arrest and low flow cardiopulmonary bypass groups. CONCLUSIONS:Our results indicate that phosphorylated extracellular regulated kinase 1/2 may play a prominent role in early cerebral ischemia-reperfusion injury and endothelial dysfunction. The pharmacologic inhibition of extracellular regulated kinase 1/2 represents a new and exciting opportunity for the modulation of cerebral tolerance to low flow cardiopulmonary bypass and deep hypothermic circulatory arrest.

OBJECTIVES/OBJECTIVE:Etoricoxib is a selective cyclooxygenase inhibitor that in clinical studies has improved the signs and symptoms of osteoarthritis and rheumatoid arthritis and reduced the potential for GI injury. The incidence of endoscopically detected ulcers and of clinically important upper GI events (perforations, ulcers, and bleeding episodes) was compared in patients taking etoricoxib or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS:Upper GI endoscopy was performed at intervals over 12 wk in 680 patients taking etoricoxib 120 mg once daily, ibuprofen 800 mg three times daily, or placebo in a randomized, parallel-group, double-blind study. Survival analysis was used to analyze time-to-event data for the incidence of gastric or duodenal ulcers (> or =3 mm and > or =5 mm), and the log rank test was used to compare the cumulative incidence between treatment groups. A combined analysis of upper GI events in all 10 Phase II/III clinical trials of etoricoxib (60, 90, or 120 mg) versus nonselective NSAIDs (naproxen, ibuprofen, or diclofenac) for osteoarthritis, rheumatoid arthritis, and chronic low back pain was conducted. Investigators reported potential events for adjudication by an external, blinded committee, using prespecified criteria to confirm events. All events that occurred during active treatment periods (maximum 792 days) or within 14 days of stopping treatment were included in the analysis. Time to first event was evaluated using survival analysis; the Kaplan-Meier method was used to determine the cumulative incidence, and relative risk was estimated with the Cox proportional hazards model. RESULTS:In the endoscopy study, the cumulative incidence of ulcers >/=3 mm at 12 wk in the ibuprofen group (17%) was significantly higher than in the etoricoxib group (8.1%, p < 0.001); similar results were seen for ulcers >/=5 mm. In the placebo group, the rate of ulcers >/=3 mm was 1.86%. Of 3142 patients treated with once-daily etoricoxib and 1828 patients treated with a nonselective NSAID (ibuprofen, naproxen, or diclofenac), 82 patients with investigator-reported upper GI events (71 confirmed) were eligible for the combined analysis. For etoricoxib versus NSAIDs, the rate per 100 patient-yr for confirmed events was 1.16 versus 3.05 (relative risk = 0.44, 95% CI = 0.27-0.72, p < 0.001), whereas that for investigator-reported events was 1.35 versus 3.42 (relative risk = 0.47, 95% CI = 0.30-0.74, p = 0.001). Results were driven primarily by studies with naproxen as the comparator. CONCLUSIONS:The incidence of endoscopically detected ulcers was significantly lower with etoricoxib 120 mg than with ibuprofen 2400 mg. Treatment with etoricoxib reduced the incidence of investigator-reported and confirmed adverse upper GI events by approximately 50% compared with treatment with nonselective NSAIDs.

BACKGROUND:Cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs are intended to preserve cyclo-oxygenase-1-mediated gastroprotection and platelet function, whilst inhibiting cyclo-oxygenase-2-mediated inflammation. AIM/OBJECTIVE:To assess the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib vs. non-selective non-steroidal anti-inflammatory drugs. METHODS:Two randomized, double-blind, placebo- and active-controlled studies were performed: (i) daily faecal red blood cell loss was measured in 62 subjects receiving etoricoxib (120 mg once daily), ibuprofen (800 mg t.d.s.) or placebo for 28 days; (ii) the incidence of endoscopically detectable gastric/duodenal ulcers was determined in 742 osteoarthritis or rheumatoid arthritis patients receiving etoricoxib (120 mg once daily), naproxen (500 mg b.d.) or placebo over 12 weeks. RESULTS:In the first study, the between-treatment ratio of faecal blood loss for etoricoxib vs. placebo (1.06) was not significantly different from unity; however, the ratios for ibuprofen vs. placebo (3.26) and etoricoxib (3.08) were significantly greater than unity (P < 0.001). In the second study, the incidence of ulcers of > or = 3 mm with naproxen (25.3%) was significantly higher than that with etoricoxib (7.4%) or placebo (1.4%; P < 0.001); the results were similar for ulcers of > or = 5 mm. CONCLUSIONS:The reduced toxicity of etoricoxib (less faecal blood loss and fewer endoscopically detectable lesions) suggests that use of this drug will may be associated with a reduced incidence of gastrointestinal perforations, ulcers and bleeds.

While a consensus definition of the clinical parameters important in asthma control exists, an adequate objective definition of a response to asthma treatment and parameters for prediction of that response remain undefined. Given that asthma is a complex biological disease and that different parameters may measure dissimilar aspects of the disease status, this study assessed the relationship among several end-points of asthma control, and attempted to select a combination of variables measured before (baseline characteristics) or early in asthma therapy which would be predictive of a long-term clinical response. Data from two previously reported clinical studies which included montelukast, inhaled beclomethasone, and placebo in mild-to-moderate asthmatics (n=1,576) were analysed. The forced expiratory volume in one second (FEV1), daily symptoms score (DSS), beta-agonist use, and morning peak expiratory flow (PEFAM) were recorded during the baseline period and throughout the 12-week treatment period. For the long-term response, as measured during the last 9 weeks of treatment, there was a large within-patient variability and no more than a moderate correlation between the changes in FEV1 and PEFAM; DSS and FEV1; and DSS and beta-agonist use. The overall predictive values for FEV1 and DSS were 70-80%. The results showed that multiple measurements over a length of time are needed to establish a more complete profile of response, and that demographic and early treatment responses had a small but inadequate ability to predict future response. This study demonstrates the complex relationship among asthma end-points and the difficulty of reliably estimating long-term response using common, surrogate clinical markers of asthma control.

In many epidemiologic studies, the first indication of an environmental or genetic contribution to the disease is the way in which the diseased cases cluster within the same family units. The concept of clustering is contrasted with incidence. We assume that all individuals are exchangeable except for their disease status. This assumption is used to provide an exact test of the initial hypothesis of no familial link with the disease, conditional on the number of diseased cases and the distribution of the sizes of the various family units. New parametric generalizations of binomial sampling models are described to provide measures of the effect size of the disease clustering. We consider models and an example that takes covariates into account. Ascertainment bias is described and the appropriate sampling distribution is demonstrated. Four numerical examples with real data illustrate these methods.

BACKGROUND:Peak expiratory flow (PEF) is an important measure of airway functin in asthma. PEF variability (PEFvar) assessment is described in asthma treatment guidelines as another means of evaluating patient status and response to therapy. OBJECTIVE:The goal of this study was to determine the clinical effect of oral montelukast, a leukotriene receptor antagonist, on PEFvar in asthmatic patients and to assess the relationship of PEFvar with other clinical measures. METHODS:This was a retrospective analysis of data from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, details of which have been published previously. Eligible patients had chronic stable asthma, had a forced expiratory volume in 1 second (FEV1) that was 50% to 85% of the predicted value, used inhaled beta-agonists, had at least 15% improvement in absolute FEV1 after inhaled beta-agonist administration, and showed a minimal predefined level of daytime asthma symptoms. Treatment consisted of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period (montelukast 10 mg or matching placebo once daily at bedtime). RESULTS:Six hundred eighty-one patients (age range, 15-79 years) were randomized to treatment at 50 centers. Baseline PEFvar was 11.44% +/- 6.55% and 10.62% +/- 6.48% in the montelukast and placebo groups, respectively. PEFvar decreased 20.1% and 7.5% from baseline in the montelukast and placebo groups, respectively. The between-group difference was significant (P < 0.001). PEFvar had low correlation with other clinical measures. CONCLUSIONS:Over 12 weeks of treatment, montelukast significantly reduced PEFvar compared with placebo, indicating improved asthma control. The relative reduction in PEFvar was similar in patients with different degrees of variability at baseline. PEFvar did not correlate highly with other outcome variables and may measure different aspects of the disease.

Vaginal candidiasis (VC) is a common concern for women living with HIV infection. The authors evaluated the effectiveness of two self-care approaches to prophylaxis of VC among HIV-infected women, weekly intravaginal application of Lactobacillus acidophilus or weekly intravaginal application of clotrimazole tablets, in a randomized, double-blind, placebo-controlled trial. VC was defined as a vaginal swab positive for Candida species in the presence of signs/symptoms of vaginitis and the absence of a diagnosis of Trichomonas vaginalis or bacterial vaginosis. Thirty-four episodes of VC occurred among 164 women followed for a median of 21 months. The relative risk of experiencing an episode of VC was 0.4 (95% CI = 0.2, 0.9) in the clotrimazole arm and 0.5 (95% CI = 0.2, 1.1) in the Lactobacillus acidophilus arm. The estimated median time to first episode VC was longer for clotrimazole (p = .03, log rank test) and Lactobacillus acidophilus (p = .09, log rank test) compared with placebo. Vaginal yeast infections can be prevented with local therapy. Education about self-care for prophylaxis of VC should be offered to HIV-infected women.