Association of Valproic Acid and Its Main Metabolites' Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring.

Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 µg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 µg/mL versus 4.83 µg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.

LC-MS/MS quantification of levetiracetam, lamotrigine and 10-hydroxycarbazepine in TDM of epileptic patients.

BACKGROUND: To minimize drug-related toxicity and monitor dosing regimens, an ultra-sensitive, simple and high-throughput analytical method for therapeutic drug monitoring is required. A novel LC-MS/MS bioassay of levetiracetam, lamotrigine and 10-hydroxycarbazepine in human plasma was established. The analytes were separated on a Hypersil GOLD™ C18 column under a 2.5 min isocratic elution after one-step protein precipitation. MS detection was performed under electrospray ionization positive-mode fitted with selected reaction monitoring. The validated ranges were 0.1-20 µg/ml for LTG, 0.3-60 µg/ml for 10-hydroxycarbazepine and levetiracetam. The intra- and inter-batches of precision and accuracy was within ±15%. The novel method met all other criteria. CONCLUSION: This method can be used to monitor drug concentrations and decision-making in epileptic patients.

Hollow heterostructure design enables self-cleaning surface for enhanced polysulfides conversion in advanced lithium-sulfur batteries.

Constructing interpenetrating heterointerface with reasonable interface energy barriers to improve electron/ion transport and accelerate the deposition/decomposition of lithium sulfide (Li2S) is an effective method to improve the electrochemical performance of lithium-sulfur (Li-S) batteries. Herein, NiCoO2/NiCoP heterostructures with hollow nanocage morphology are prepared for efficient multifunctional Li-S batteries. The hollow nanocage structure exposes abundant active sites, traps lithium polysulfides and inhibits the shuttle effect. The NiCoO2/NiCoP heterostructure, combing strong adsorption capacity of NiCoO2 and excellent catalytic ability of NiCoP, facilitates the process of anchoring-diffusion-transformation of polysulfides. The successful construction of heterostructures reduces the reaction barrier, accelerating the lithium ion (Li+) diffusion rate and thus effectively enhancing the redox reaction kinetics. More importantly, NiCoO2/NiCoP heterostructure plays a role in self-cleaning that minimizes solid sulfur species accumulation to maintain surface clean during long cycling for a continuously catalysis of the polysulfides conversion reactions. With the merit of these features, the NiCoO2/NiCoP modified separator exhibits excellent cycling stability with a low capacity decay of 0.043% per cycle up to 1000 cycles at 2 C. The design of NiCoO2/NiCoP hollow nanocage heterostructures offers a new option for high-performance electrochemical energy storage devices.