Integrating metabolomics and lipidomics revealed a decrease in plasma fatty acids but an increase in triglycerides in children with drug-refractory epilepsy.

OBJECTIVE: The drug-refractory epilepsy (DRE) in children is commonly observed but the underlying mechanisms remain elusive. We examined whether fatty acids (FAs) and lipids are potentially associated with the pharmacoresistance to valproic acid (VPA) therapy. METHODS: This single-center, retrospective cohort study was conducted using data from pediatric patients collected between May 2019 and December 2019 at the Children's Hospital of Nanjing Medical University. Ninety plasma samples from 53 responders with VPA monotherapy (RE group) and 37 non-responders with VPA polytherapy (NR group) were collected. Non-targeted metabolomics and lipidomics analysis for those plasma samples were performed to compare the potential differences of small metabolites and lipids between the two groups. Plasma metabolites and lipids passing the threshold of variable importance in projection value >1, fold change >1.2 or <0.8, and p-value <0.05 were regarded as statistically different substances. RESULTS: A total of 204 small metabolites and 433 lipids comprising 16 different lipid subclasses were identified. The well-established partial least squares-discriminant analysis (PLS-DA) revealed a good separation of the RE from the NR group. The FAs and glycerophospholipids status were significantly decreased in the NR group, but their triglycerides (TG) levels were significantly increased. The trend of TG levels in routine laboratory tests was in line with the lipidomics analysis. Meanwhile, cases from the NR group were characterized by a decreased level of citric acid and L-thyroxine, but with an increased level of glucose and 2-oxoglutarate. The top two enriched metabolic pathways involved in the DRE condition were biosynthesis of unsaturated FAs and linoleic acid metabolism. SIGNIFICANCE: The results of this study suggested an association between metabolism of FAs and the medically intractable epilepsy. Such novel findings might propose a potential mechanism linked to the energy metabolism. Ketogenic acid and FAs supplementation might therefore be high-priority strategies for DRE management.

Association between serum vitamin D status and the anti-seizure treatment in Chinese children with epilepsy.

Objective: To compare the serum 25-OH-VitD levels, the major marker of vitamin D (VitD) status, between healthy children and children with epilepsy before initiation of and during anti-seizure medications (ASMs) treatment and to evaluate the potential influence factors on 25-OH-VitD levels. Another major aim was to assess the potential role of VitD supplementation. Methods: For comparison, we finally enrolled and collected data from 6,338 healthy children presenting to Health Care Department and 648 children visiting primary care pediatricians with symptoms of epilepsy in Children's Hospital of Nanjing Medical University from January 2019 to June 2021. The demographic and biochemical characteristics of each child were extracted from the hospital information system. Results: Serum 25-OH-VitD levels in 648 children with epilepsy were significantly lower than those of 6,338 healthy children (P < 0.0001), and the percentage of VitD insufficiency and deficiency status in pediatric patients was 49.19%. Of note, the serum 25-OH-VitD levels in children with newly diagnosed epilepsy before receiving any ASMs treatment were also significantly lower than those in healthy controls. Interestingly, ASMs therapy, alone or in combination, did not consistently reduce baseline serum VitD levels in children with epilepsy. The lower serum VitD levels in pediatric patients than those in healthy children might be related to the disease itself, rather than the ASMs treatment. As expected, VitD supplementation substantially increased the serum 25-OH-VitD levels (P < 0.0001). More critically, children with epilepsy receiving VitD supplementation achieved good seizure control in our study. Significance: In this retrospective study, the childhood epilepsy before initiation of and during ASMs treatment decreased the serum 25-OH-VitD concentrations, suggesting a clear association between epileptic disease and the risk of VitD deficiency. ASMs coadministration and long-term valproic acid treatment did not worse VitD-deficiency status, but in the small group receiving VitD supplementation, there was a significant improvement in reduction of seizure frequency. Therefore, pediatric clinicians are urged to raise public awareness of epilepsy-associated VitD deficiency.

Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update.

BACKGROUND: Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed. METHODS: We searched in PubMed for manuscripts published in English, combining terms such as "Valproic acid", "hepatotoxicity", "liver injury", and "mechanisms". The data of screened papers were analyzed and summarized. RESULTS: The formation of VPA reactive metabolites, inhibition of fatty acid ß-oxidation, excessive oxidative stress and genetic variants of some enzymes, such as CPS1, POLG, GSTs, SOD2, UGTs and CYPs genes, have been reported to be associated with VPA hepatotoxicity. Furthermore, carnitine supplementation and antioxidants administration proved to be positive treatment strategies for VPA-induced hepatotoxicity. CONCLUSION: Therapeutic drug monitoring (TDM) and routine liver biochemistry monitoring during VPA-therapy, as well as genotype screening for certain patients before VPA administration, could improve the safety profile of this antiepileptic drug.

Potential Pharmacokinetic Herb-Drug Interactions: Have we Overlooked the Importance of Human Carboxylesterases 1 and 2?

BACKGROUND: Herbal products have grown steadily across the globe and have increasingly been incorporated into western medicine for healthcare aims, thereby causing potential pharmacokinetic Herb-drug Interactions (HDIs) through the inhibition or induction of drug-metabolizing enzymes and transporters. Human Carboxylesterases 1 (CES1) and 2 (CES2) metabolize endogenous and exogenous chemicals including many important therapeutic medications. The growing number of CES substrate drugs also underscores the importance of the enzymes. Herein, we summarized those potential inhibitors and inducers coming from herbal constituents toward CES1 and CES2. We also reviewed the reported HDI studies focusing on herbal products and therapeutic agents metabolized by CES1 or CES2. METHODS: We searched in PubMed for manuscript published in English after Jan 1, 2000 combining terms "carboxylesterase 1", "carboxylesterase 2", "inhibitor", "inducer", "herb-drug interaction", "inhibitory", and "herbal supplement". We also searched specific websites including FDA and EMA. The data of screened papers were analyzed and summarized. RESULTS: The results showed that more than 50 natural inhibitors of CES1 or CES2, including phenolic chemicals, triterpenoids, and tanshinones were found from herbs, whereas only few inducers of CES1 and CES2 were reported. Systemic exposure to some commonly used drugs including oseltamivir, irinotecan, and clopidogrel were changed when they were co-administered with herb products such as goldenseal, black cohosh, ginger, St. John's Wort, curcumin, and some Chinese compound formula in animals. CONCLUSION: Nonclinical and clinical studies on HDIs are warranted in the future to provide safety information toward better clinical outcomes for the combination of herbal products and conventional drugs.