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Clinical Psychopharmacology and... Nov 2023Epilepsy is a disease characterized by the periodic occurrence of seizures. Seizures can be controlled by antiseizure medications, which can improve the lives of... (Review)
Review
Epilepsy is a disease characterized by the periodic occurrence of seizures. Seizures can be controlled by antiseizure medications, which can improve the lives of individuals with epilepsy when given proper treatment. Therefore, this study aimed to review the scientific literature on brain neuroplasticity after treatment with antiseizure drugs in different regions of the brain. According to the findings, that several antiseizure, such as lamotrigine, diazepam, levetiracetam, and valproic acid, in addition to controlling seizures, can also act on neuroplasticity in different brain regions. The study of this topic becomes important, as it will help to understand the neuroplastic mechanisms of these drugs, in addition to helping to improve the effectiveness of these drugs in controlling the disease.
PubMed: 37859439
DOI: 10.9758/cpn.23.1058 -
Cureus Oct 2023Valproate-induced hyperammonemic encephalopathy (VHE) is a rare and severe side effect that can occur with valproic acid (VPA) therapy, despite therapeutic doses and...
Valproate-induced hyperammonemic encephalopathy (VHE) is a rare and severe side effect that can occur with valproic acid (VPA) therapy, despite therapeutic doses and normal serum levels of valproate. The typical signs of this condition include a sudden onset of impaired consciousness, focal neurologic symptoms, and an increase in seizure frequency. The exact cause of VHE is unknown, but it is believed to be related to the accumulation of toxic VPA metabolites and increased levels of ammonia that can cause swelling of the astrocytes and cerebral edema. We present a case of a 19-year-old male patient with a history of bipolar disorder on valproic acid 250 mg daily, admitted to the hospital after a new-onset seizure. He was found to have elevated levels of ammonia in his blood, despite having therapeutic levels of valproate and no liver dysfunction. His symptoms improved with discontinuation of the medication and his ammonia levels decreased. We discuss possible mechanisms and risk factors leading to encephalopathy while on valproate therapy. VHE should be considered a possibility when patients treated with valproate show signs of impaired consciousness.
PubMed: 38021840
DOI: 10.7759/cureus.47288 -
Drug Metabolism and Disposition: the... Feb 2024Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is... (Observational Study)
Observational Study
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.
Topics: Humans; Anticonvulsants; Chemical and Drug Induced Liver Injury; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Retrospective Studies; Valproic Acid
PubMed: 38195521
DOI: 10.1124/dmd.123.001539 -
Lipids in Health and Disease Nov 2023Roughly 10 -15% of global populace suffer from Chronic Kidney Disease(CKD). A major secondary disease that can progress to end-stage renal disease (ESRD) is...
BACKGROUND
Roughly 10 -15% of global populace suffer from Chronic Kidney Disease(CKD). A major secondary disease that can progress to end-stage renal disease (ESRD) is obesity-associated kidney disease (ORG). Although clinical management strategies are currently available, morbidity and mortality rates are increasing. Thus, new solutions are needed. Intestinal permeability, systemic inflammation, and aberrant intestinal metabolites have all been linked to ORG.
PURPOSE
ACT001 has anti-inflammatory, redox-regulatory and antitumour activities. The current study was designed to examine how ACT001 affects ORG and analyze the fundamental processes.
METHODS
A high-fat diet (HFD) was used to generate ORG in female C57BL/6 J mice. ORG mice were divided into three groups at random: HFD, HFD + ACT001, HFD + polyphosphocholine (PPC). To assess renal and colonic damage, periodic acid-Schiff (PAS) and hematoxylin-eosin (HE) staining were used. Following that, renal inflammation, oxidative stress, lipid deposition, colonic inflammation, and intestinal permeability were evaluated by protein blotting, polymerase chain reaction (PCR), immunohistochemistry, and immunofluorescence staining. Lastly, the SCFAs content was assessed by gas chromatographymass spectrometry.
RESULTS
Mice in the HFD group displayed more severe albuminuria, glomerular hypertrophy, renal oxidative damage, inflammation, and lipid accumulation than mice with the normal diet (ND) group, as well as lower levels of intestinal SCFA valproic acid, colonic inflammation, and tight junction protein downregulation. ACT001 treatment restores the content of valproic acid in intestinal SCFAs, promotes the binding of SCFAs to renal GPR43, activates the AMPK signalling pathway. Therefore, it promotes the Nrf2-Keap1 signalling pathway and inhibits the NF-κB signalling pathway. SCFAs, additionally, augment colonic GPR43 concentrations, diminishing NLRP3 inflammasome expression and restoring ZO-1 and occludin protein levels.
CONCLUSION
This study is the first to look at ACT001's potential as a treatment for obesity-related kidney disease. Regulating GPR43 and AMPK signalling pathways, By controlling the GPR43 and AMPK signalling pathways, ACT001 improves colitis and the intestinal mucosal barrier, decreases renal lipid deposition, and suppresses inflammation and oxidative stress in the kidneys. According to this study, ACT001 could be a viable ORG therapy option.
Topics: Female; Mice; Animals; AMP-Activated Protein Kinases; Kelch-Like ECH-Associated Protein 1; Diet, High-Fat; Valproic Acid; Mice, Inbred C57BL; NF-E2-Related Factor 2; Kidney; Inflammation; Kidney Diseases; Obesity
PubMed: 37978497
DOI: 10.1186/s12944-023-01949-2 -
Cureus Apr 2024Hyponatremia is an adverse effect of many antiseizure medications (ASMs). It occurs with interference with the normal balance of electrolytes within the body. Various... (Review)
Review
Hyponatremia is an adverse effect of many antiseizure medications (ASMs). It occurs with interference with the normal balance of electrolytes within the body. Various risk factors associated with the development of hyponatremia in patients taking these medications include age, gender, dosage, and combinations with other drugs. ASMs such as carbamazepine (CBZ), oxcarbazepine (OXC), and valproic acid have a higher risk of hyponatremia. Hyponatremia induced by an antiseizure medication can occur through various mechanisms depending on the drug's specific mechanism of action. Hyponatremia can be a potentially fatal side effect. Patients taking these medications need to be monitored closely for the signs and symptoms of hyponatremia. Acute hyponatremia, defined as developing in <48 hours, is more likely to show symptoms than chronic hyponatremia. Signs of acute hyponatremia include delirium, seizures, decerebrate posturing, and cerebral edema with uncal herniation. Chronic hyponatremia, defined as developing in >48 hours, can cause lethargy, dizziness, weakness, headache, nausea, and confusion. Hyponatremia is associated with longer hospital stays and increased mortality. Treatment varies based on the degree of severity of hyponatremia. Choosing a treatment option should include consideration of the drug causing the electrolyte disturbance, the patient's risk factor profile, and the severity of symptoms as they present in the individual patient. Healthcare providers should be aware of hyponatremia as a potential side effect of ASMs, the signs and symptoms of hyponatremia, the different treatment options available, and the potential complications associated with rapid correction of hyponatremia.
PubMed: 38707045
DOI: 10.7759/cureus.57535 -
Pediatric Neurology Sep 2023Sodium channel genes, especially SCN1A, were reported to play an important role in the treatment outcomes of antiseizure medications. The aim of this study was to...
BACKGROUND
Sodium channel genes, especially SCN1A, were reported to play an important role in the treatment outcomes of antiseizure medications. The aim of this study was to explore the association of SCN1A polymorphisms with efficacy and adverse drug reactions (ADRs) related to valproic acid (VPA) among Chinese children with epilepsy.
METHODS
A total of 126 children with epilepsy treated with VPA for at least 12 months were enrolled in this study. Three single nucleotide polymorphisms (SNPs) of SCN1A including rs2298771, rs10167228, and rs3812718 were genotyped using Sequenom MassArray system. Bioinformatics tools were used to explore the potential targets and pathways of SCN1A in VPA-related ADRs.
RESULTS
The three SNPs in this study were found to be closely associated with treatment outcomes for VPA. Carriers of SCN1A rs3812718 TT genotype tended to be seizure-free with VPA treatment (P = 0.007). AA genotype of rs10167228 and TT genotype of rs2298771 might be protective factors for weight gain induced by VPA, whereas TA genotype of rs10167228 and CT genotype of rs2298771 increased the risk. TAT haplotype carriers were found to respond better to VPA treatment (P = 0.017), whereas CTC haplotype might be a risk factor for VPA-induced weight gain (P = 0.035). Bioinformatics analysis suggested that SCN1A might play a role in VPA-induced weight gain by regulating gated channel activity and GABAergic synapse pathway.
CONCLUSION
This study revealed that SCN1A rs2298771, rs10167228, and rs3812718 polymorphisms and haplotypes might affect the treatment outcomes of VPA in Chinese children with epilepsy.
Topics: Child; Humans; Anticonvulsants; East Asian People; Epilepsy; Genotype; Haplotypes; NAV1.1 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide; Treatment Outcome; Valproic Acid
PubMed: 37451178
DOI: 10.1016/j.pediatrneurol.2023.06.010 -
CNS Neuroscience & Therapeutics Apr 2024Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity...
INTRODUCTION
Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive.
METHODS
The cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection.
RESULTS
In this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes.
CONCLUSION
HDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.
Topics: Animals; Rats; Cauda Equina; Ferroptosis; Inflammation; Pain; Rats, Sprague-Dawley; Reproducibility of Results; RNA; Valproic Acid; Histone Deacetylase 2
PubMed: 38105511
DOI: 10.1111/cns.14524 -
Frontiers in Pharmacology 2024Valproic acid (VPA) has been widely used as an antiepileptic drug for decades. Although VPA is effective and well-tolerated, long-term VPA treatment is usually...
Valproic acid (VPA) has been widely used as an antiepileptic drug for decades. Although VPA is effective and well-tolerated, long-term VPA treatment is usually associated with hepatotoxicity. However, the underlying mechanisms of VPA-caused hepatotoxicity remain unclear. In this study, a total of 157 pediatric patients with epilepsy were recruited and divided into normal liver function (NLF, 112 subjects) group and abnormal liver function (ABLF, 45 subjects) group. We observed that A1298C and C677T variants may be linked to VPA-induced liver dysfunction ( = 0.001; = 0.023, respectively). We also found that the A1298C polymorphism was associated with a higher serum Hcy level ( = 0.001) and a lower FA level ( = 0.001). Moreover, the serum Hcy levels was strongly correlated with the GSH and TBARS concentrations (r = -0.6065, < 0.001; r = 0.6564, < 0.001, respectively). Furthermore, logistic analysis indicated that A1298C/C677T polymorphisms and increased Hcy concentrations may be risk factors for VPA-induced liver dysfunction. These results suggested that individual susceptibility to VPA-induced liver dysfunction may result from A1298C/C677T polymorphisms and increased Hcy levels. This study may be helpful for the prevention and guidance of VPA-induced liver dysfunction.
PubMed: 38464726
DOI: 10.3389/fphar.2024.1358262 -
The Journal of Trauma and Acute Care... Nov 2023It has previously been shown that administration of valproic acid (VPA) can improve outcomes if given within an hour following traumatic brain injury (TBI). This short...
BACKGROUND
It has previously been shown that administration of valproic acid (VPA) can improve outcomes if given within an hour following traumatic brain injury (TBI). This short therapeutic window (TW) limits its use in real-life situations. Based upon its pharmacokinetic data, we hypothesized that TW can be extended to 3 hours if a second dose of VPA is given 8 hours after the initial dose.
METHOD
Yorkshire swine (40-45 kg; n = 10) were subjected to TBI (controlled cortical impact) and 40% blood volume hemorrhage. After 2 hours of shock, they were randomized to either (1) normal saline resuscitation (control) or (2) normal saline-VPA (150 mg/kg × two doses). First dose of VPA was started 3 hours after the TBI, with a second dose 8 hours after the first dose. Neurologic severity scores (range, 0-36) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day 3.
RESULTS
Hemodynamic and laboratory parameters of shock were similar in both groups. Valproic acid-treated animals had significantly less neurologic impairment on days 2 (16.3 ± 2.0 vs. 7.3 ± 2.8) and 3 (10.9 ± 3.6 vs. 2.8 ± 1.1) postinjury and returned to baseline levels 54% faster. Magnetic resonance imaging showed no differences in brain lesion size on day 3. Pharmacokinetic data confirmed neuroprotective levels of VPA in the circulation.
CONCLUSION
This is the first study to demonstrate that VPA can be neuroprotective even when given 3 hours after TBI. This expanded TW has significant implications for the design of the clinical trial.
Topics: Swine; Animals; Valproic Acid; Shock, Hemorrhagic; Saline Solution; Disease Models, Animal; Brain Injuries, Traumatic; Resuscitation
PubMed: 37314445
DOI: 10.1097/TA.0000000000004022 -
European Journal of Hospital Pharmacy :... Sep 2023Total plasma levels of valproic acid (VPA) may mask an increased risk of adverse effects in hypoalbuminaemic patients since, in these patients, the free fraction is... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
OBJECTIVES
Total plasma levels of valproic acid (VPA) may mask an increased risk of adverse effects in hypoalbuminaemic patients since, in these patients, the free fraction is higher. The aim of this study is to analyse the relationship between plasma levels of total and free VPA (VPA) in hypoalbuminaemic patients and define an equation that allows the estimation of VPA concentration, as well as to validate the obtained equation.
METHODS
This is a retrospective observational study conducted between January 2015 and January 2020. Hypoalbuminaemic adult patients with normal renal function were included. Serum VPA levels were determined using an automated enzyme immunoassay technique with a pre-treatment of the sample by ultrafiltration for the quantification of VPA. Patients' determinations were randomised into two groups: first, to calculate the VPA estimation equation (regression group) by multiple linear regression analysis; and second to validate the equation (validation group), calculating the agreement between experimental and estimated VPA concentrations using Lin's coefficient and a Bland and Altman analysis.
RESULTS
We included 51 determinations, corresponding to 33 patients: 26 in the regression group, and 25 in the validation group. The multiple linear regression analysis showed a statistically significant relationship between VPA concentration (Y), total VPA concentration (X) and albumin level (X), explained by the equation Y=11.882 + 0.216*X-4.722*X. Pearson's correlation coefficient was 0.798 (p<0.001). Lin's coefficient was 0.82 (95% CI 0.63 to 0.92). The Bland and Altman analysis showed a bias of 0.32 mg/L, and the concordance limits were between -3.80 and 4.44.
CONCLUSIONS
The calculated equation adequately predicts VPA concentration, with a high degree of correlation between the variables. Despite Lin's coefficient outcome, Bland and Altman analysis showed a minimum bias that slightly underestimates VPA concentration, positioning the calculated equation as a useful and validated estimation tool in hypoalbuminaemic patients with normal renal function.
Topics: Valproic Acid; Hypoalbuminemia; Retrospective Studies; Immunoenzyme Techniques; Albumins; Humans; Anticonvulsants
PubMed: 34750247
DOI: 10.1136/ejhpharm-2021-003092