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Background: Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor., Methods and Results: In a double-blinded study, 191 patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P<0.0001) in a dose-dependent fashion, with approximately 80% inhibition in >90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291-treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291-treated groups in the 34 of these 60 patients in whom this end point was analyzable (P<0.01)., Conclusions: VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.

Background: Mutations in the cardiac sodium channel gene (SCN5A) can cause one variant of the congenital long-QT syndrome. The effects of some of these mutations on the alpha-subunit channel properties can be blocked by type Ib antiarrhythmic drugs. Recently, we have described a new SCN5A mutation (D1790G) that affects the channel properties in a manner suggesting that sodium blockers of the Ib type will be ineffective in carriers of this mutation. Hence, the ECG effects of flecainide-acetate, a type Ic sodium blocker, were evaluated in carriers of this mutation., Methods and Results: Eight asymptomatic mutation carriers and 5 control subjects were studied. Intravenous lidocaine was tested first in only 2 mutation carriers and had no significant effect on any ECG parameter. Flecainide significantly shortened all heart rate-corrected repolarization duration parameters only in carriers and not in control subjects: QT(c) shortened by 9.5% (from 517+/-45 to 468+/-36 ms, P=0.011), and the S-offset to T-onset interval shortened by 64.7% (from 187+/-88 to 66+/-50 ms, P=0.0092). Flecainide also normalized the marked baseline repolarization dispersion in most mutation carriers. These effects among carriers were maintained during long-term (9 to 17 months) outpatient flecainide therapy with no adverse effects., Conclusions: This report is the first to describe SCN5A mutation carriers who significantly responded to flecainide therapy yet did not respond to lidocaine. These results have important implications for long-QT allele-specific therapeutic strategies.

51Cr-labeled parental strain spleen cells were pretreated in vitro with antithymocyte globulin (ATG) or Fab fragments of ATG before i.v. injection into F1 recipients. Recipients were killed at various intervals after injection and their organs were assayed for radioactivity in order to determine the in vivo distribution pattern of pretreated cells. 51Cr spleen cells pretreated with ATG were almost totally prevented from migrating to spleens, lymph nodes, bone marrow, Peyer's patches, lungs, and peripheral blood of recipients. Pretreatment of 51Cr spleen cells with noncytotoxic Fab of ATG also inhibited localization to these organs and tissues; however, the inhibition was not as complete as that of ATG-treated cells. Localization of Fab-treated 51Cr spleen cells to recipient nodes was inhibited to a greater extent than was localization to recipient spleens. There was no significant difference in the extent of inhibition of ATG-treated 51Cr spleen cells to recipient nodes and spleen. Organ counts from recipients killed at various intervals after injection of Fab-treated 51Cr spleen cells showed that Fab-treated cells do not recover their recirculating potential in vivo.