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Purpose: This study aims to evaluate the associations between genetic polymorphisms and the effect of sodium valproate (VPA) therapy in children with generalized seizures.Methods: A total of 174 children with generalized seizures on VPA therapy were enrolled. Steady-state trough plasma concentrations of VPA were analyzed. Seventy-six single nucleotide polymorphisms involved in the absorption, metabolism, transport, and target receptor of VPA were identified, and their associations with the therapeutic effect (seizure reduction) were evaluated using logistic regression adjusted by various influence factors.Results: rs7668282 (UGT2B7, T > C, OR = 2.67, 95% CI: 1.19 to 5.91, P = 0.017) was more prevalent in drug-resistant patients than drug-responsive patients. rs2242480 (CYP3A4, C > T, OR = 0.27, 95% CI: 0.095 to 0.79, P = 0.017) and rs10188577 (SCN1A, T > C, OR = 0.40, 95% CI: 0.17 to 0.94, P = 0.035) were more prevalent in drug-responsive patients compared to drug-resistant patients.Conclusion: In children with generalized seizures on VPA therapy, polymorphisms of UGT2B7, CYP3A4, and SCN1A genes were associated with seizure reduction. Larger studies are warranted to corroborate the results. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study is to evaluate the association between genetic polymorphisms and valproic acid (VPA) concentration to dose ratio in children with epilepsy on VPA monotherapy.Methods: A total of 137 children, aged 3.5-18 years, (89 males and 48 females) with epilepsy on sustained-release VPA monotherapy were enrolled. Trough plasma concentrations of VPA at steady-state were measured using an AXSYM automatic immunity analyzer. The values were divided by body weight and total daily dose to calculate concentration to dose ratio of VPA (CDRV). Forty-eight single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system. The logarithmic transformed CDRV (lnCDRV) was normally distributed, and PLINK software was used to evaluate the association between genetic polymorphisms and lnCDRV using linear regression adjusted for gender and seizure type.Results: rs28898617 (UGT1A3/4/5/6/7/8/9/10, BETA=0.32, P=0.0089) was significantly associated with higher lnCDRV. No other associations were found.Conclusions: In pediatric patients taking VPA monotherapy, rs28898617 was associated with a higher normalized VPA plasma concentration. Further studies are warranted to confirm the results. [ABSTRACT FROM AUTHOR]

The use of organophosphate esters (OPEs) as flame retardants, which has increased over the past two decades, raises concerns that OPEs may be harmful to humans, especially children. Animal studies and some human studies have reported that OPEs may adversely impact brain development, but few human studies evaluated OPE exposure during early childhood and neurodevelopmental outcomes. We aimed to fill this knowledge gap with the present study on urinary OPE metabolite concentrations at ages 1–5 years and cognitive abilities at 8 years. We used data of 223 children from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio. The point estimates for bis-2-chloroethyl-phosphate (BCEP) and bis(1,3-dichloro-2-propyl)-phosphate (BDCIPP) in association with IQ tended to be small and positive, while the point estimates for diphenyl-phosphate (DPHP) were small and negative, with 95% CIs including the null. However, we did find that socioeconomic status (SES) variables modified associations between OPEs and child IQ, with adverse OPE-IQ associations being stronger in socioeconomically disadvantaged children than in others. We identified an additional 1- to 2-point decrease in Full Scale IQ for every log-unit increase in BDCIPP, BCEP, and DPHP among those with lower maternal education, non-white race, lower income, or living in more deprived neighborhoods. We observed similar results for the Perceptual Reasoning, Verbal Comprehension, and Working Memory Index Scores. We suspect that there is residual confounding related to socioeconomic disadvantage, which was not captured with the available SES variables typically used in epidemiologic studies. • This cohort study examines OPEs at ages 1–5 years and cognition at age 8 years. • In child urine, BCEP was detected at 90–95%, BDCIPP at 99%, and DPHP at 99–100%. • Point estimates for OPEs and cognition were small, and 95% CIs included the null. • SES variables modified associations; disadvantaged children have worse outcomes. [ABSTRACT FROM AUTHOR]

Organophosphate esters (OPEs), widely used as flame retardants and plasticizers for commercial and residential purposes, are suspected of being neurotoxic. We aimed to assess exposure to an OPE mixture in early life and its relationship to parent-reported child behavior. We measured urinary concentrations of three OPE metabolites, bis-2-chloroethyl phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP), at pregnancy (16 and 26 weeks of gestation and delivery) and postnatal time points (ages 1, 2, 3, and 5 years) in the Health Outcomes and Measures of the Environment Study, a longitudinal pregnancy and birth cohort in Cincinnati, Ohio, USA (enrolled 2003–2006, n = 219). We used latent variable analysis in structural equations models and quantile g-computation to investigate associations of a mixture of the three OPE metabolites with parent-reported child behaviors at 3 and 8 years, measured using the Behavioral Assessment System for Children, Second Edition. Higher log-transformed urinary OPE latent variable values at 16 weeks were associated with fewer externalizing problem behaviors (ß = −5.74; 95% CI = −11.24, −0.24) and fewer overall behavioral problems at age 3 years (ß = −5.26; 95% CI = −10.33, −0.19), whereas having higher OPEs at delivery was associated with poorer overall behavioral problems at age 3 years (ß = 2.87; 95% CI = 0.13, 5.61). OPE latent variable values at 16 weeks, 26 weeks, and delivery were not associated with child behavior at 8 years. However, higher OPE latent variable values at 3 years were associated with fewer externalizing behaviors at 8 years (ß = −2.62; 95% CI = −5.13, −0.12). The quantile g-computation estimates had directions largely consistent with the latent variable analysis results. Pregnancy and postnatal urinary OPE metabolite mixtures were associated with child internalizing, externalizing, and overall negative behaviors at 3 and 8 years, but we did not identify a consistent pattern in terms of the direction of the effects or a particularly sensitive time point. • We studied pregnancy and postnatal OPEs and child behavior in a longitudinal cohort. • We used latent variable analysis and quantile g-computation to assess OPE mixtures. • Pregnancy OPEs were associated with child behavior at 3 years. • The direction of associations and vulnerable time points were inconsistent. [ABSTRACT FROM AUTHOR]