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Molecules (Basel, Switzerland) May 2021High performance liquid chromatography with ultra-violet detection (HPLC-UV) and gas chromatography-mass spectrometry (GC-MS) methods were developed and validated for...
High performance liquid chromatography with ultra-violet detection (HPLC-UV) and gas chromatography-mass spectrometry (GC-MS) methods were developed and validated for the determination of chlorambucil (CLB) and valproic acid (VPA) in plasma, as a part of experiments on their anticancer activity in chronic lymphocytic leukemia (CLL). CLB was extracted from 250 µL of plasma with methanol, using simple protein precipitation and filtration. Chromatography was carried out on a LiChrospher 100 RP-18 end-capped column using a mobile phase consisting of acetonitrile, water and formic acid, and detection at 258 nm. The lowest limit of detection LLOQ was found to be 0.075 μg/mL, showing sufficient sensitivity in relation to therapeutic concentrations of CLB in plasma. The accuracy was from 94.13% to 101.12%, while the intra- and inter-batch precision was ≤9.46%. For quantitation of VPA, a sensitive GC-MS method was developed involving simple pre-column esterification with methanol and extraction with hexane. Chromatography was achieved on an HP-5MSUI column and monitored by MS with an electron impact ionization and selective ion monitoring mode. Using 250 µL of plasma, the LLOQ was found to be 0.075 μg/mL. The accuracy was from 94.96% to 109.12%, while the intra- and inter-batch precision was ≤6.69%. Thus, both methods fulfilled the requirements of FDA guidelines for the determination of drugs in biological materials.
Topics: Antineoplastic Combined Chemotherapy Protocols; Calibration; Chlorambucil; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Valproic Acid
PubMed: 34068372
DOI: 10.3390/molecules26102903 -
The Journal of Clinical Psychiatry Oct 2022
Topics: Anticonvulsants; Female; Humans; Reproduction; Valproic Acid
PubMed: 36244029
DOI: 10.4088/JCP.22ed14609 -
Tissue Engineering and Regenerative... Feb 2020Gene therapy shows the ability to restore neuronal dysfunction via therapeutic gene expression. The efficiency of gene expression and delivery to hypoxic injury sites is...
BACKGROUND
Gene therapy shows the ability to restore neuronal dysfunction via therapeutic gene expression. The efficiency of gene expression and delivery to hypoxic injury sites is important for successful gene therapy. Therefore, we established a gene/stem cell therapy system using neuron-specific enolase promoter and induced neural stem cells in combination with valproic acid to increase therapeutic gene expression in hypoxic spinal cord injury.
METHODS
To examine the effect of combined method on enhancing gene expression, we compared neuronal cell-inducible luciferase levels under normoxia or hypoxia conditions in induced neural stem cells with valproic acid. Therapeutic gene, vascular endothelial growth factor, expression with combined method was investigated in hypoxic spinal cord injury model. We verified gene expression levels and the effect of different methods of valproic acid administration in vivo.
RESULTS
The results showed that neuron-specific enolase promoter enhanced gene expression levels in induced neural stem cells compared to Simian Virus 40 promoter under hypoxic conditions. Valproic acid treatment showed higher gene expression of neuron-specific enolase promoter than without treatment. In addition, gene expression levels and cell viability were different depending on the various concentration of valproic acid. The gene expression levels were increased significantly when valproic acid was directly injected with induced neural stem cells in vivo.
CONCLUSION
In this study, we demonstrated that the combination of neuron-specific enolase promoter and valproic acid induced gene overexpression in induced neural stem cells under hypoxic conditions and also in spinal cord injury depending on valproic acid administration in vivo. Combination of valproic acid and neuron-specific enolase promoter in induced neural stem cells could be an effective gene therapy system for hypoxic spinal cord injury.
Topics: Cell Survival; Cell Transplantation; Gene Expression; Genetic Therapy; Humans; Hypoxia; Luciferases; Neural Stem Cells; Neurons; Promoter Regions, Genetic; Spinal Cord Injuries; Valproic Acid; Vascular Endothelial Growth Factor A
PubMed: 32002843
DOI: 10.1007/s13770-019-00223-w -
Valproic acid and sleep apnoea: A disproportionality signal from the WHO pharmacovigilance database.Respirology (Carlton, Vic.) Mar 2020
Topics: Databases, Factual; Humans; Pharmacovigilance; Sleep Apnea Syndromes; Valproic Acid
PubMed: 32000295
DOI: 10.1111/resp.13771 -
Epilepsia Jan 2013Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE) based on 12 months of double-blind therapy. (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE) based on 12 months of double-blind therapy.
METHODS
A double-blind, randomized controlled clinical trial compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed CAE. Study medications were titrated to clinical response, and subjects remained in the trial unless they reached a treatment failure criterion. Maximal target doses were ethosuximide 60 mg/kg/day or 2,000 mg/day, valproic acid 60 mg/kg/day or 3,000 mg/day, and lamotrigine 12 mg/kg/day or 600 mg/day. Original primary outcome was at 16-20 weeks and included a video-electroencephalography (EEG) assessment. For this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video-EEG assessment; differential drug effects were determined by pairwise comparisons. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the month 12 visit.
KEY FINDINGS
A total of 453 children were enrolled and randomized; 7 were deemed ineligible and 446 subjects comprised the overall efficacy cohort. There were no demographic differences between the three cohorts. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. At the month 12 visit, the freedom-from-failure rates for ethosuximide and valproic acid were similar (45% and 44%, respectively; odds ratio [OR]with valproic acid vs. ethosuximide 0.94; 95% confidence interval [CI] 0.58-1.52; p = 0.82) and were higher than the rate for lamotrigine (21%; OR with ethosuximide vs. lamotrigine 3.08; 95% CI 1.81-5.33; OR with valproic acid vs. lamotrigine 2.88; 95% CI 1.68-5.02; p < 0.001 for both comparisons). The frequency of treatment failures due to lack of seizure control (p < 0.001) and intolerable adverse events (p < 0.037) was significantly different among the treatment groups. Almost two thirds of the 125 subjects with treatment failure due to lack of seizure control were in the lamotrigine cohort. The largest subgroup (42%) of the 115 subjects discontinuing due to adverse events was in the valproic acid group. The previously reported higher rate of attentional dysfunction seen at 16-20 weeks in the valproic acid group compared with the ethosuximide or lamotrigine groups persisted at 12 months (p < 0.01).
SIGNIFICANCE
As initial monotherapy, the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine in controlling seizures without intolerable adverse events noted at 16-20 weeks persisted at 12 months. The valproic acid cohort experienced a higher rate of adverse events leading to drug discontinuation as well as significant negative effects on attentional measures that were not seen in the ethosuximide cohort. These 12-month outcome data coupled with the study's prespecified decision-making algorithm indicate that ethosuximide is the optimal initial empirical monotherapy for CAE. This is the first randomized controlled trial meeting International League Against Epilepsy (ILAE) criteria for class I evidence for CAE (or for any type of generalized seizure in adults or children). (NCT00088452.).
Topics: Age Factors; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy, Absence; Ethosuximide; Female; Humans; Lamotrigine; Male; Treatment Outcome; Triazines; Valproic Acid
PubMed: 23167925
DOI: 10.1111/epi.12028 -
Acta Psychiatrica Scandinavica Sep 2021Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We... (Review)
Review
OBJECTIVES
Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research.
METHOD
A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library.
RESULTS
Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone.
CONCLUSIONS
The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.
Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium Compounds; Polypharmacy; Valproic Acid
PubMed: 33960396
DOI: 10.1111/acps.13312 -
European Journal of Pharmaceutical... Jan 2018Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and...
Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and non-neurologic indications. Our study objective was to design and validate a mechanistic model of VPA disposition in adults and children; and evaluate its predictive performance of drug-drug interactions (DDIs). This study expands upon existing physiologically based pharmacokinetic (PBPK) models for VPA by incorporating UGT enzyme kinetics and an advanced dissolution, absorption, and metabolism (ADAM) model for extended-release (ER) formulation. PBPK models for VPA IR and ER formulations were constructed using Simcyp Simulator (Version 15). First-order absorption was used for the immediate-release (IR) formulation and the ADAM model, including a controlled-release profile, for ER. Data from twenty-one published clinical studies were used to assess model performance. The model accurately predicted the concentration-time profiles of IR formulation for single-dose and steady-state doses ranging from 200mg to 1000mg. Similarly profiles were also simulated for ER formulation after a single-dose and steady-state doses of 500mg and 1000mg, respectively. In addition, simulated PK profiles agreed well with the observed data from studies in which VPA ER formulation was given to pediatric patients and VPA IR formulation to adult patients with cirrhosis. The model was further validated with individual adult data from a Phase I clinical trial consisting of eight cohorts after IV infusion of VPA with doses ranging from 15 to 150mg/kg. Co-administrations of VPA as an enzyme-inhibitor with victim drug phenytoin or lorazepam, as well as a substrate with enzyme inducer carbamazepine or phenobarbital, were simulated with the model to evaluate drug-drug interaction. The simulated serum concentration-time profiles were within the 5th and 95th percentiles, and the majority of the predicted area-under-the-curve (AUC) and peak plasma concentration (C) values were within 25% of the reported average values. The comprehensive VPA PBPK model defined by this study may be used to support dosage regimen optimization to improve the safety and efficacy profile of this agent under different scenarios.
Topics: Anticonvulsants; Caco-2 Cells; Computer Simulation; Dose-Response Relationship, Drug; Drug Interactions; Humans; Models, Biological; Monte Carlo Method; Tissue Distribution; Valproic Acid
PubMed: 29030176
DOI: 10.1016/j.ejps.2017.10.009 -
Folia Biologica 2007Valproic acid (2-propyl pentanoic acid) is a drug used for the treatment of epilepsy and bipolar disorder. Although very rare, side effects such as spina bifida and... (Review)
Review
Valproic acid (2-propyl pentanoic acid) is a drug used for the treatment of epilepsy and bipolar disorder. Although very rare, side effects such as spina bifida and other defects of neural tube closure indicate that valproic acid interferes with developmental regulatory pathways. Recently obtained data show that valproic acid affects cell growth, differentiation, apoptosis and immunogenicity of cultured cancer cells and tumours. Focused studies uncovered the potential of valproic acid to interfere with multiple regulatory mechanisms including histone deacetylases, GSK3 alpha and beta, Akt, the ERK pathway, the phosphoinositol pathway, the tricarboxylic acid cycle, GABA, and the OXPHOS system. Valproic acid is emerging as a potential anticancer drug and may also serve as a molecular lead that can help design drugs with more specific and more potent effects on the one side and drugs with wide additive but weaker effects on the other. Valproic acid is thus a powerful molecular tool for better understanding and therapeutic targeting of pathways that regulate the behaviour of cancer cells.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Teratogens; Valproic Acid
PubMed: 17448293
DOI: No ID Found -
Antiviral Research Aug 2019Herpes simplex virus type 1 (HSV-1) is a ubiquitous infectious agent that can establish latency in neurons, and in some cases, viral retrograde transport results in...
Herpes simplex virus type 1 (HSV-1) is a ubiquitous infectious agent that can establish latency in neurons, and in some cases, viral retrograde transport results in infection of the central nervous system (CNS). Several antivirals have been identified with the ability to inhibit HSV-1 replication in human cells to a greater or lesser degree, most of which are nucleoside analogues that unfortunately exhibit teratogenic potential, embryotoxicity, carcinogenic or antiproliferative activities and resistances in immunocompromised patients, specially. In the present study, we assessed two amidic derivatives of valproic acid (VPA) - valpromide (VPD) and valnoctamide (VCD) - which are already used in clinic treatments, as feasible HSV-1 antivirals in glial cells. Both VPD and VCD have exhibited increased efficacy in bipolar disorders and as anticonvulsant drugs compared to VPA, while being less teratogenic and hepatotoxic. Cytotoxicity assays carried out in our laboratory showed that VPD and VCD were not toxic in a human oligodendroglioma cell line (HOG), at least at the concentrations established for human treatments. Infectivity assays showed a significant inhibition of HSV-1 infection in HOG cells after VPD and VCD treatment, being more pronounced in VPD-treated cells, comparable to the effects obtained with acyclovir. Furthermore, the same antiherpetic effects of VPD were observed in other oligodendrocytic cell lines and rat primary oligodendrocytes (OPCs), confirming the results obtained in HOG cells. Altogether, our results allow us to propose VPD as a potential antiherpetic drug that is able to act directly on oligodendrocytes of the CNS.
Topics: Amides; Animals; Antiviral Agents; Cell Survival; Cells, Cultured; Herpesvirus 1, Human; Humans; Molecular Structure; Oligodendroglia; Rats; Valproic Acid; Viral Proteins; Virus Internalization; Virus Replication
PubMed: 31132386
DOI: 10.1016/j.antiviral.2019.05.006 -
Biological & Pharmaceutical Bulletin 2012Therapeutic drug monitoring of valproic acid (VPA) is essential to prevent toxicity, but the correlation between plasma ammonia level and serum VPA concentration remains...
Therapeutic drug monitoring of valproic acid (VPA) is essential to prevent toxicity, but the correlation between plasma ammonia level and serum VPA concentration remains unclear. We examined the correlation of plasma ammonia level with VPA dose and serum trough concentrations of total and free VPA in Japanese patients with epilepsy. Thirty-eight data sets from 19 Japanese patients with epilepsy were analyzed. The relations of VPA dose and serum total and free VPA concentrations with plasma ammonia level, and the breakpoints of VPA parameters predicting hyperammonemia (plasma ammonia higher than 60 µmol/L) were analyzed. A significant positive correlation was observed between plasma ammonia level and VPA dose (r(s)=0.56, p=0.00062), serum trough total VPA concentration (r(s)=0.55, p=0.00086) and serum trough free VPA concentration (r(s)=0.58, p=0.00041). The breakpoints predicting hyperammonemia were VPA dose of 30.4 mg/kg, serum trough total VPA concentration of 90.9 µg/mL, and serum trough free VPA concentration of 8.65 µg/mL, with impurity reductions at 1.35, 1.35 and 2.02, respectively. These findings suggest that serum trough concentration of free VPA is the most reliable predictor for hyperammonemia, and that the risk of developing hyperammonemia may increase in patients with serum trough free VPA concentrations higher than 8.65 µg/mL.
Topics: Adolescent; Adult; Ammonia; Anticonvulsants; Asian People; Child; Child, Preschool; Epilepsy; Female; Humans; Infant; Infant, Newborn; Male; Valproic Acid; Young Adult
PubMed: 22687541
DOI: 10.1248/bpb.35.971