Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Association of race/ethnicity with emergency department wait times.

OBJECTIVE: To determine whether wait times for children treated in emergency departments (EDs) nationally are associated with patient race/ethnicity. METHODS: Data were obtained from the National Hospital Ambulatory Medical Care Survey, which collects information on patient visits to EDs throughout the United States. We examined data for patients < or =15 years of age who presented to EDs during the 4-year period of 1997-2000. Sample weights were applied to the identified patient records to yield national estimates. For the purposes of this study, race/ethnicity was analyzed for 3 major groups, ie, non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic white (HW). RESULTS: During the 4-year study period, 20633 patient visits were surveyed, representing a national sample of 92.9 million children < or =15 years of age. The race/ethnicity distribution included 9019 NHW children (59.5%), 3910 NHB children (23.9%), and 2991 HW children (16.6%). The wait time for all groups was 43.6 +/- 1.7 minutes (mean +/- SEM). There were significant unadjusted intergroup differences in wait times (38.5 +/- 1.6 minutes, 48.7 +/- 0.5 minutes, and 54.5 +/- 0.1 minutes for NHW, NHB, and HW children, respectively). Visit immediacy (triage status), when reported, was categorized as <15 minutes for 2203 children (17.1%), 15 to 60 minutes for 5324 (41.4%), 1 to 2 hours for 3010 (25.1%), and >2 to 24 hours for 1910 (16.4%). There were significant unadjusted differences in triage status according to race, with 14.6% of NHW patients being placed in the >2-hour immediacy range, compared with 18.8% of NHB patients and 20.0% of HW patients. In a linear regression analysis with logarithmically transformed wait time as a dependent variable and with adjustment for potential confounders, including hospital location, geographic region, and payer status, both NHB and HW patients waited longer than NHW patients, although the results were statistically significant only for HW patients. CONCLUSIONS: These nationally representative data suggest that children who come to EDs have wait times that vary according to race/ethnicity. There are several potential explanations for this observation, including discrimination, cultural incompetence, language barriers, and other social factors. These data and similar data from the National Hospital Ambulatory Medical Care Survey are useful in identifying nonclinical influences on the delivery of pediatric emergency care.