Therapeutic drug monitoring in pregnancy: Levetiracetam.

OBJECTIVE: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. METHODS: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020-2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1-2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. RESULTS: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope = .85), with no significant change in the 2nd trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (µg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. SIGNIFICANCE: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period.

Neat1 in hematopoietic stem cells.

Hematopoietic Stem Cells (HSCs) generate blood and immune cells through a hierarchical process of differentiation. Genes that regulate this process are of great interest for understanding normal and also malignant hematopoiesis. Surprisingly, however, very little is known about long-non-coding RNAs (lncRNA) in HSCs. Neat1 is a lncRNA that plays a major role in the formation of sub-nuclear structures called paraspeckles, and was reported to regulate proliferation and differentiation in other cells types. We detected Neat1 expression using RNA-seq data and RT-qPCR in HSCs, progenitors and effector immune cells, by specific detection of its isoforms. Neat1 is highly expressed in stem and progenitor cells, yet it shows significant reduction in granulocytes. Microscopically, Neat1 is detected as sharp nuclear foci. Paraspeckle proteins NONO and PSPC1 are detected as aggregated nuclear foci in fresh primary hematopoietic cells, and in cultured cells. Induction of differentiation in vitro was found to enhance Neat1 expression. Taken together, our data demonstrate for the first time the expression of Neat1 and paraspeckles formation in HSCs and along hematopoiesis.