Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and tolerability of etoricoxib, a COX-2 selective inhibitor, in osteoarthritis (OA) patients. METHODS: A double-blind, randomized, multicenter study was conducted in 617 patients with OA of the knee. The base study was 14 weeks in duration and consisted of 2 parts; in Part I (6 weeks), patients were allocated to once daily oral etoricoxib 5, 10, 30, 60, 90 mg or placebo. In Part II (8 weeks); the placebo, etoricoxib 5 and 10 mg groups were reallocated to etoricoxib 30, 60, or 90 mg qd or diclofenac 50 mg t.i.d. Treatment was continued for consecutive 12 and 26 week extensions. Primary efficacy endpoints were the WOMAC VA 3.0 pain subscale and investigator global assessment of disease status. Safety and tolerability were assessed by collecting adverse events throughout the study. RESULTS: Compared with placebo, the etoricoxib groups displayed significant (p < 0.05), dose-dependent efficacy for all primary endpoints in Part I; efficacy was maintained throughout the 52 weeks of the study. During the 46-week active-comparator controlled period, the etoricoxib groups demonstrated clinical efficacy that was similar to that of diclofenac 150 mg and was generally well tolerated, with a lower incidence of gastrointestinal (GI) nuisance symptoms compared with diclofenac (13.1, 14.7, and 13.5% for etoricoxib 30, 60, and 90 mg, respectively compared with 22.5% for diclofenac). CONCLUSION: In this extension study, etoricoxib, at doses ranging from 30 to 90 mg, demonstrated a maintenance of significant clinical efficacy in patients with OA through 52 weeks of treatment. Etoricoxib displayed clinical efficacy similar to diclofenac 150 mg and was generally well tolerated

Lung eQTLs to Help Reveal the Molecular Underpinnings of Asthma

Genome-wide association studies (GWAS) have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL) in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55 × 10(-151)). The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases

Evaluation of the efficacy and safety of etoricoxib in the treatment of hemophilic arthropathy

This 2-part, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of etoricoxib, a COX-2 selective inhibitor, for the treatment of hemophilic arthropathy. In part 1 (6 weeks), 102 patients (≥ 12 years old) with hemophilic arthropathy were randomized to receive 90 mg etoricoxib once daily or placebo (1:1 ratio). In part 2 (6 months), 51 patients taking placebo in part 1 were randomized to receive 90 mg etoricoxib or 25 mg rofecoxib once daily; patients taking etoricoxib in part 1 continued the same treatment. Efficacy end points included Patient Assessment of Arthropathy Pain, Patient Global Assessment of Arthropathy Disease Status, and Investigator Global Assessment of Arthropathy Disease Status. Safety was evaluated at each study visit. Etoricoxib provided significant improvement in all end points versus placebo (P < .001). Fewer patients taking etoricoxib discontinued due to a lack of efficacy versus placebo (P = .048). During part 2, efficacy was maintained; etoricoxib and rofecoxib demonstrated similar results. The most common adverse experiences were upper respiratory infection and headache. The incidence of joint bleeding during part 1 was similar between etoricoxib (66.7%) and placebo (72.6%) and during part 2 between etoricoxib (77.0%) and rofecoxib (78.9%). We conclude that etoricoxib provided superior efficacy versus placebo for the treatment of hemophilic arthropathy and was generally safe and well tolerated

Demographic and clinical characteristics of study cohort.

<p>PreBD, before bronchodilator use; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity.</p>*<p>significantly different among groups at p<0.01 level (Kruskal Wallis and χ² tests were applied to quantitative and categorical traits, respectively).</p

Relative expression of <i>GSDMA</i> and <i>GSDMB</i>.

<p>Primary human airway epithelial cells in monolayer culture were analyzed for; (a) the relative abundance of mRNA for <i>GSDMA</i> and <i>GSDMB</i> (n = 7) and (b) Protein expression of <i>GSDMA</i> and <i>GSDMB</i> by Western blot normalized to expression of β-tubulin (n = 10). (c) Representative image of <i>GSDMA</i> expression in human conducting airway by immunohistochemistry, which shows expression of <i>GSDMA</i> in both basal and apical cells within the airway epithelium.</p

Lung eQTLs found on chromosome 17q21.

<p>(a) The upper panel is a region of chromosome 17q21 from the UCSC browser showing the genes located in this region. The next panel shows the results from the GABRIEL consortium <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003029#pgen.1003029-Moffatt1" target="_blank">[9]</a> (each bar represents a SNP and the y-axis shows −log₁₀<i>P</i> values for association with asthma). The following three panels show the lung eQTL results for expression levels of <i>ORMDL3</i> (blue bars), <i>GSDMB</i> (green bars), and <i>GSDMA</i> (red bars), respectively. The y-axis represents −log₁₀<i>P</i> values derived from the meta-analysis of gene expression. The black horizontal lines are drawn at <i>P</i> = 0.05. (b) Boxplots of lung gene expression levels for GSDMA according to genotype groups for SNPs rs3859192 and rs7216389 in 1,111 subjects.</p