Evaluation of the clinical use of magnesium sulfate for cerebral palsy prevention.

OBJECTIVE: Clinical trials support the efficacy and safety of magnesium sulfate for cerebral palsy prevention. We evaluated the implementation of a clinical protocol for the use of magnesium for cerebral palsy prevention in our large women's hospital, focusing on uptake, indications, and safety. METHODS: We performed a review of selected gravidas with threatened or planned delivery before 32 weeks of gestation from October 2007 to February 2011. The primary study outcome was the change in the rate of predelivery administration of magnesium sulfate over this time period. RESULTS: Three hundred seventy-three patients were included. In 2007, before guideline implementation, 20% of eligible gravidas (95% confidence interval [CI] 9.1-35.6%) received magnesium before delivery compared with 93.9% (95% CI 79.8-99.3%) in the final 2 months of the study period (P<.001). Dosing did not vary significantly over the 4 study years: the median number of treatments was one, the total predelivery median dose ranged from 15 to 48 g, and the median duration of therapy ranged from 3 to 12 hours. After 3 years, magnesium administration was almost universal among patients diagnosed with preeclampsia, preterm labor, or preterm premature rupture of membranes (95.4%), whereas patients delivered preterm for fetal growth restriction were significantly less likely to receive predelivery magnesium (44%, P<.001). No maternal or perinatal magnesium-attributable morbidity was noted. Among patients eligible for the protocol who received magnesium, 84.2% delivered before 32 weeks of gestation. CONCLUSION: It is feasible to implement a magnesium sulfate cerebral palsy prevention protocol into clinical practice. LEVEL OF EVIDENCE: III.

A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system.

OBJECTIVE: Accumulation of amyloid-beta (Abeta) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Abeta production or clearance in the human CNS. The objective of this study was to determine the effects of a gamma-secretase inhibitor on the production of Abeta in the human CNS. METHODS: We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Abeta production during treatment of a gamma-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Abeta production in healthy men (age range, 21-50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group). RESULTS: LY450139 significantly decreased the production of CNS Abeta in a dose-dependent fashion, with inhibition of Abeta generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Abeta clearance. INTERPRETATION: Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009.