Aminophylline increases seizure length during electroconvulsive therapy

Electroconvulsive therapy (ECT) is considered to be one of the most effective treatments for patients with major depression and persistent psychosis. Seizure characteristics probably determine the therapeutic effect of ECT; as a consequence, short seizures are accepted as one of the factors of poor outcome. During most ECT courses seizure threshold increases and seizure duration decreases. Methylxanthine preparations, caffeine, and theophylline have been used to prolong seizure duration. The use of aminophylline, more readily available than caffeine, has not been well documented. The objective of this study was to test the effects of aminophylline on seizure length. Fourteen drug-free patients with diagnoses of affective disorder or psychotic episode receiving ECT participated in this study. Seizure length was assessed clinically and per EEG. Statistical comparisons were done using paired t tests. A significant increase (p < 0.04) in seizure length was achieved and maintained on three subsequent treatments with aminophylline. No adverse events were noted from the addition of aminophylline.     

Regional brain volume abnormalities and long-term cognitive outcome in preterm infants

CONTEXT: Preterm infants have a high prevalence of long-term cognitive and behavioral disturbances. However, it is not known whether the stresses associated with premature birth disrupt regionally specific brain maturation or whether abnormalities in brain structure contribute to cognitive deficits. OBJECTIVE: To determine whether regional brain volumes differ between term and preterm children and to examine the association of regional brain volumes in prematurely born children with long-term cognitive outcomes. DESIGN AND SETTING: Case-control study conducted in 1998 and 1999 at 2 US university medical schools. PARTICIPANTS: A consecutive sample of 25 eight-year-old preterm children recruited from a longitudinal follow-up study of preterm infants and 39 term control children who were recruited from the community and who were comparable with the preterm children in age, sex, maternal education, and minority status. MAIN OUTCOME MEASURES: Volumes of cortical subdivisions, ventricular system, cerebellum, basal ganglia, corpus callosum, amygdala, and hippocampus, derived from structural magnetic resonance imaging scans and compared between preterm and term children; correlations of regional brain volumes with cognitive measures (at age 8 years) and perinatal variables among preterm children. RESULTS: Regional cortical volumes were significantly smaller in the preterm children, most prominently in sensorimotor regions (difference: left, 14.6%; right, 14.3% [P<.001 for both]) but also in premotor (left, 11.2%; right, 12.6% [P<.001 for both]), midtemporal (left, 7.4% [P =.01]; right, 10.2% [P<.001]), parieto-occipital (left, 7.9% [P =.01]; right, 7.4% [P =.005]), and subgenual (left, 8.9% [P =.03]; right, 11.7% [P =.01]) cortices. Preterm children's brain volumes were significantly larger (by 105. 7%-271.6%) in the occipital and temporal horns of the ventricles (P<. 001 for all) and smaller in the cerebellum (6.7%; P =.02), basal ganglia (11.4%-13.8%; P相似文献   

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.