IMPORTANCE p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. DESIGN, SETTING, AND PATIENTS LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22 000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population.

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The disproportionate difficulty in obtaining compelling experimental evidence from 4C-radiolabelling that the indole moiety of the otherwise isoprenoid penitrem A is biosynthesized by Penicillium crustosum directly from tryptophan has been explored. [benzene ring-' 4C]Tryptophan added to the broth beneath the mycelial mat of stationary liquid cultures labelled penitrem A with 1.4% incorporation, only threefold more than that determined for [methylene-14C]tryptophan or [U-14C]tyrosine, incorporation of which could only have been indirect. In contrast, the substituted tryptophan-histidine diketopiperazine roquefortine, biosynthesized concurrently with penitrems by this organism, was labelled with compelling efficiency (23.4% incorporation of [benzene ring-' 4C]tryptophan). In submerged culture, Claviceps paspali concurrently biosynthesized an analogous pair of metabolites, 3-hydroxy-3-methylbutenyl paspalinine and lysergic acid a-hydroxyethylamide. This feature enabled experimental demonstratation of [benzene ring-' 4C]tryptophan incorporation to an extent more consistent with direct contribution of the indole moiety of the indole-diterpenoid paspalinine derivative. The same precursor applied to the sporing surface of P. crustosum stationary cultures also provided stronger evidence for a direct biosynthetic role in the formation of penitrem A. In the absence of competition from any other indolic secondary metabolite, a submerged culture of Penicilliumpaxilfi incorporated 5 % of the [benzene ring-14C]tryptophan given during growth into the indole-diterpenoid paxilline. A double-labelling time-course experiment indicated temporal separation of steps in the biosynthesis of roquefortine. The inadequacy of classical precursor techniques for studying biosynthesis of indole-diterpenoids in P. crustosum is discussed. The more homogeneous submerged culture fermentation system is preferred for experimentation.