Pharmacokinetic assessment of alprazolam-induced neonatal abstinence syndrome using physiologically based pharmacokinetic model.

Sustained benzodiazepine use during pregnancy can induce neonatal abstinence syndrome (NAS). In this study, the association between NAS and plasma alprazolam concentration was examined using the measured neonatal concentrations in the time series as well as simulated plasma concentrations of pregnant woman and neonate by physiologically based pharmacokinetic (PBPK) modeling. A neonate born to a mother taking alprazolam daily throughout pregnancy exhibited symptoms such as apnea and vomiting from 9 h to 4 days after birth. Finnegan score was 7 at birth and decreased to 0 by day 4. Apnea improved by 24 h post-delivery and gastrointestinal symptoms disappeared by day 4. The plasma alprazolam concentration in the neonate was 15.2 ng/mL immediately after birth and gradually decreased over 3 days. Measured neonate and estimated maternal plasma alprazolam concentrations were within the 90% prediction intervals of each concentration by PBPK simulation using "pregnancy" and "pediatrics" population parameters including in Simcyp population-based ADME simulator. In conclusion, NAS symptoms such as apnea and digestive events disappeared in parallel with the decrease of the neonate's plasma alprazolam concentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data.

Interruption of env gene expression depending on the length of the SV40 early region used for the polyA signal.

In order to invent a screening system to check in vivo gene function and the efficiency of gene transfer mediated by a retroviral vector system, we established a novel packaging cell, PacNIH/A8, based on the neuropathogenic retrovirus A8-V. To construct the expression vector, pA8(Psi-), which expresses the genes gag, pol and env derived from A8-V, the SV40 early region was used for the polyadenylation signal (polyA signal). When a 0.85 kbp fragment in the SV40 early region was employed for the expression vector (pA8(Psi-)beta), env expression was abolished. This abolition was rescued by shortening the SV40 early region to 0.14 kbp (pA8(Psi-)delta). The NHI3T3 cells transfected with pA8(Psi-)delta showed expressions of both env and gag genes.