Neonatal outcomes of extremely preterm infants exposed to maternal hypertension and cigarette smoking.

OBJECTIVE: To study the outcomes of extremely preterm infants of hypertensive mothers who smoke. STUDY DESIGN: This retrospective cohort study included infants born between 2003 and 2012 at <29 weeks' gestation and admitted to neonatal intensive care units participating in the Canadian Neonatal Network. Infants were divided into four mutually exclusive groups. Infants of hypertensive mothers who smoked; infants of hypertensive, non-smoking mothers; infants of normotensive mothers who smoked; and infants of normotensive, non-smoking mothers. Using infants of normotensive, non-smoking mothers as the reference group, neonatal outcomes were compared between the groups. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariate regression analysis. RESULTS: Of the 12,307 eligible infants, 172 had hypertensive mothers who smoked, 1689 had hypertensive non-smoking mothers, 1535 had normotensive mothers who smoked, and 8911 had normotensive non-smoking mothers. Compared to infants of normotensive non-smoking mothers, infants of hypertensive mothers, regardless of smoking status, had higher odds of developing bronchopulmonary dysplasia (AORs of smokers 1.62; 95% CI 1.12-2.35 and of non-smokers 1.43; 95% CI 1.24-1.64). There was no difference in the odds of mortality and retinopathy of prematurity stage ≥3 between the groups. Infants of hypertensive, non-smoking mothers had decreased odds of intraventricular hemorrhage >grade 2 and higher odds of necrotizing enterocolitis. There was decreased odds of hypertension if the mother was a smoker (AOR 0.71; 95% CI 0.59-0.85). CONCLUSION: Maternal hypertension is associated with increased rates of bronchopulmonary dysplasia, irrespective of smoking status.

A practical synthesis of a gamma-secretase inhibitor.

A practical and scaleable synthesis of the gamma-secretase inhibitor 1 is reported. The inhibitor consists of a central trisubstituted cyclohexane core with appended propionic acid, 2,5-difluorophenyl, and 4-chlorophenylsulfonyl moieties. Two alternative synthetic strategies, proceeding by way of a common disubstituted cyclohexanone derivative 5, were studied. In the preferred route, conjugate reduction of acrylonitrile derivative 4 with L-Selectride configures the desired relative stereochemistry of the cyclohexane core with >99.9:0.1 dr. A second strategy, based on catalyst-controlled hydrogenation of racemic cyclohexene derivative 2, is more convergent but less diastereoselective (up to 75:25 dr). The common cyclohexanone intermediate 5 was constructed by a regioselective Diels-Alder condensation of a 1,1-disubstituted vinyl sulfone 6 with 2-trimethylsiloxybutadiene.

Practical asymmetric synthesis of a gamma-secretase inhibitor exploiting substrate-controlled intramolecular nitrile oxide-olefin cycloaddition.

A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with > or = 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.