Heart rate-corrected QT interval in men increases during winter months.

BACKGROUND: Sudden cardiac death increases during winter months in both men and women. The heart rate-corrected QT (QTc) interval exhibits circadian variation. However, little is known about QTc interval variation with month of year. OBJECTIVE: We sought to determine whether the QTc interval varies with month of year. METHODS: We retrospectively analyzed a database of 24,370 electrocardiograms (ECGs) to determine seasonal variation in QTc intervals. The analysis data set included 7,976 baseline ECGs, one each for 3,700 men and 4,276 women. ECGs selected for analysis were normal, recorded in regions north of the equator, and taken on subjects >or=18 years old. The QT correction for heart rate (HR) was performed using QTc = QT*(HR/60)(0.4). The monthly mean QTc intervals were compared, for men and women separately, using a one-way analysis of variance with the Bonferroni correction for multiple comparisons. RESULTS: Subject ages ranged from 18 to 95 years. The monthly mean QTc intervals were consistently greater for women than for men by 5.2 +/- 2.3 ms. After correction for multiple comparisons, the difference between the greatest and least monthly mean QTc interval was 6.1 +/- 1.5 ms (P <.01) for men and 3.5 ms (nonsignificant) for women. The maximum monthly mean QTc interval of 413 +/- 18 ms (n = 560; P <.05) occurred in October for men and of 417 +/- 16 ms (n = 350) in March for women, but it was not significant. CONCLUSIONS: Significant seasonal variation in QTc interval exists among male subjects >or=18 years of age with normal baseline ECGs, with the QTc interval being longest in October. No significant variation was seen for women.

Impact of a soluble phospholipase A2 inhibitor on inhaled allergen challenge in subjects with asthma.

The possible roles of secretory phospholipases A2 (sPLA2) in asthma include the release of arachidonic acid from cellular membranes, generation of lysophospholipids, sPLA2-mediated activation of cPLA2 with increased leukotriene production, and surfactant degradation. LY333013 is a potent inhibitor of sPLA2. This study examined the impact of two doses of LY333013 vs. placebo on allergen-induced bronchoconstriction following inhaled allergen challenge in atopic asthmatics. Fifty subjects were randomly assigned to treatment, and 40 subjects completed the study. A double-blind, placebo-controlled, random order, crossover study design was used. LY333013 had no impact on the primary outcome variables of the areas under the FEV1 response curve early (0-3 hours) (AUC(early)) and late (3-8 hours) (AUC(Iate)) following inhaled allergen challenge. No significant drug-related adverse effects were observed. The response to inhaled allergen challenge was reproducible and confirms the utility of this technique as a model in which to screen compounds for further testing in asthmatic patients.

A randomized, double-blinded, placebo-controlled clinical trial of LY333013, a selective inhibitor of group II secretory phospholipase A2, in the treatment of rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and safety of a selective inhibitor of secretory phospholipase (sPLA2), LY333013, in the treatment of rheumatoid arthritis (RA). METHODS: Two hundred and fifty-one patients with active RA despite treatment with one or more disease modifying antirheumatic drugs (DMARD) received oral doses of LY333013 (50, 250, and 1000 mg) or placebo once daily for 12 weeks. Concomitant low-dose glucocorticoids (< or = 10 mg/day prednisone equivalent) were allowed. Clinical improvement was assessed using the response criteria of the American College of Rheumatology (ACR20), and safety was evaluated with respect to adverse events and laboratory test abnormalities. RESULTS: The demographic characteristics of the treatment groups were similar. Dose-response relationships were found for ACR20 responses (p = 0.058) and reductions in C-reactive protein (p = 0.058) at week 1. The proportions of patients with an ACR20 response subsequently increased in all study groups including the placebo group at weeks 4 and 8, and the initial treatment benefit was lost. Adverse events were generally mild in severity and not associated with treatment. CONCLUSION: Treatment with LY333013 for 12 weeks was well tolerated but ineffective as an adjunct to DMARD treatment of active RA.