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Cellular and Molecular Neurobiology Oct 2021The lack of an effective pharmaceutical agent for spinal cord injury (SCI) is a current problematic situation for clinicians, as the rate of motor vehicle accidents... (Review)
Review
The lack of an effective pharmaceutical agent for spinal cord injury (SCI) is a current problematic situation for clinicians, as the rate of motor vehicle accidents among young adults is on the rise. SCI contributes to the high disability rate. Presently, evidences detailing the precise pathological mechanisms in SCI are limited, compounding to the unavailability of an effective treatment method. Surgery, though not a complete curative method, is useful in managing some of the associated symptoms of secondary SCI. Autophagy and inflammation are contributive factors to both exacerbation and improvement of SCI. The mammalian target of rapamycin (mTOR) signaling pathway is a key player in the regulation of inflammatory response and autophagy. Valproic acid (VPA), a clinically used antiepileptic drug, has been suggested to improve neurological conditions, including SCI. This report reviewed the correlation between mTOR and autophagy, as well as autophagy's role and the therapeutic effects of VPA in SCI. VPA regulates autophagy by potentially inhibiting mTORC1, a complex of mTOR, while also hindering inflammatory response. Conclusively, an effective treatment for SCI could lie in the timely regulation of mTOR signaling pathway, and VPA could be the potential drug that improves SCI owing to its propensity to regulate the mTOR signaling pathway.
Topics: Animals; Autophagy; Recovery of Function; Spinal Cord; Spinal Cord Injuries; TOR Serine-Threonine Kinases; Valproic Acid
PubMed: 32725456
DOI: 10.1007/s10571-020-00929-9 -
BMJ Case Reports Jan 2021
Topics: Anticonvulsants; Cataract; Humans; Lamotrigine; Valproic Acid
PubMed: 33504541
DOI: 10.1136/bcr-2020-240997 -
PloS One 2022The pharmacokinetics of valproic acid have been evaluated in a variety of populations however, the comparison in two different populations was yet to be reported. This...
PURPOSE
The pharmacokinetics of valproic acid have been evaluated in a variety of populations however, the comparison in two different populations was yet to be reported. This study is aimed to compare the pharmacokinetics of valproic acid in Pakistani and South Korean patients.
METHOD
The therapeutic drug monitoring (TDM) data of valproic acid from 92 Pakistani patients with 218 samples was combined with the data of 99 South Korean patients with 335 samples in order to form a pooled dataset of 191 patients with 553 samples. Population pharmacokinetic model was developed on NONMEM® software by using first order conditional estimation method for estimation of pharmacokinetic parameters. The influence of different covariates including ethnicity was evaluated the stepwise covariate modelling. The final model was evaluated for predictive performance and robustness by using goodness of fit plots and bootstrap analysis respectively.
RESULTS
The data was better described by one compartment model with first order elimination. The value for clearance (CL) of valproic in pooled data was 0.931 L/h with 43.4% interindividual variability (IIV) while volume of distribution (Vd) was 16.6 L with 22.3% IIV. In covariate analysis, ethnicity and body weight were significant covariates for CL while body weight was also significant for Vd.
CONCLUSION
A significant difference in CL of valproic acid among Pakistani and South Korean patients was observed. The model can be used for the dose tailoring of valproic acid based on ethnicity and body weight of Pakistani and South Korean patients.
Topics: Body Weight; Humans; Models, Biological; Pakistan; Republic of Korea; Valproic Acid
PubMed: 36001534
DOI: 10.1371/journal.pone.0272622 -
Handbook of Clinical Neurology 2023Though clearly described as far back as the 17th century, chronic migraine has defied precise categorization and has continued to develop as an important diagnostic...
Though clearly described as far back as the 17th century, chronic migraine has defied precise categorization and has continued to develop as an important diagnostic concept with significant societal impact. Worldwide prevalence is estimated to be between 1% and 3%, and these patients form a dynamic group cycling between chronic and episodic migraine. Theories of pathogenesis are developing supported by recent imaging and other findings. Of the many determinants of progression to chronic migraine, overuse of acute abortive headache medications may be one of the most important modifiable factors. Treatment strategies, in addition to educational measures, have included various preventive migraine medications such as topiramate, valproate, and onabotulinumtoxinA. CGRP monoclonal antibodies are efficacious for the management of chronic migraine both with and without medication overuse.
Topics: Humans; Migraine Disorders; Prescription Drug Overuse; Valproic Acid
PubMed: 38043961
DOI: 10.1016/B978-0-12-823356-6.00008-1 -
The Journal of Antimicrobial... Jul 2020An unexpected drug-drug interaction has been recently reported between dolutegravir, an HIV integrase inhibitor, and valproic acid. Despite there being several potential...
OBJECTIVES
An unexpected drug-drug interaction has been recently reported between dolutegravir, an HIV integrase inhibitor, and valproic acid. Despite there being several potential underlying mechanisms, plasma protein displacement has been suggested. The aim of this study was to assess plasma concentrations of several antiretrovirals when administered with or without valproic acid.
METHODS
We performed a therapeutic drug monitoring registry analysis and identified patients concomitantly taking antiretrovirals and valproic acid and without clinical affecting conditions or interacting drugs.
RESULTS
One hundred and thirty-four patients were identified. Median (IQR) age and BMI were 49.7 years (45-56) and 23.4 kg/m2 (20.8-26.3) and 78 were male (58.2%). Despite small groups, we observed no major effect on antiretroviral exposure, even when considering highly protein-bound compounds (such as etravirine), with the exception of dolutegravir trough concentrations [median (IQR) = 132 ng/mL (62-227) in individuals on valproic acid versus 760 ng/mL (333-1407) in those not receiving valproic acid].
CONCLUSIONS
Valproic acid does not have a major effect on antiretrovirals other than dolutegravir. The mechanism of this unexpected drug-drug interaction may be the combination of protein displacement, reduced absorption and CYP3A4 induction.
Topics: Drug Interactions; HIV Infections; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Male; Oxazines; Pyridones; Valproic Acid
PubMed: 32211890
DOI: 10.1093/jac/dkaa094 -
The Journal of Trauma and Acute Care... Aug 2020The leading causes of death in military conflicts continue to be hemorrhagic shock (HS) and traumatic brain injury (TBI). Most of the mortality is a result of patients... (Review)
Review
The leading causes of death in military conflicts continue to be hemorrhagic shock (HS) and traumatic brain injury (TBI). Most of the mortality is a result of patients not surviving long enough to obtain surgical care. As a result, there is a significant unmet need for a therapy that stimulates a "prosurvival phenotype" that counteracts the cellular pathophysiology of HS and TBI to prolong survival. Valproic acid (VPA), a well-established antiepileptic therapy for more than 50 years, has shown potential as one such prosurvival therapy. This review details how VPA's role as a nonselective histone deacetylase inhibitor induces cellular changes that promote survival and decrease cellular pathways that lead to cell death. The review comprehensively covers more than two decades worth of studies ranging from preclinical (mice, swine) to recent human clinical trials of the use of VPA in HS and TBI. Furthermore, it details the different mechanisms in which VPA alters gene expression, induces cytoprotective changes, attenuates platelet dysfunction, provides neuroprotection, and enhances survival in HS and TBI. Valproic acid shows real promise as a therapy that can induce the prosurvival phenotype in those injured during military conflict.
Topics: Animals; Armed Conflicts; Brain Injuries, Traumatic; Gene Expression; Histone Deacetylase Inhibitors; Humans; Kaplan-Meier Estimate; Military Medicine; Military Personnel; Resuscitation; Shock, Hemorrhagic; Valproic Acid; War-Related Injuries
PubMed: 32282756
DOI: 10.1097/TA.0000000000002721 -
Journal of Pharmacological Sciences May 2020Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible...
Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible side effects including hepatotoxicity. The present study investigated the hepatoprotective effect of ellagic acid against valproic acid-induced hepatotoxicity in rats. Ellagic acid (60 mg/kg/day; p.o) was treated for one week, followed by concomitant injection of valproic acid (250 mg/kg/day; i.p.) for another 14 consecutive days to induce hepatocellular damage in adult Sprague-Dawley rats. Valproic acid showed a marked increase in serum enzyme activities, AST, ALT, ALP and GGT. In addition, it significantly increased MDA and NO along with a marked decline in reduced GSH content. At the same time, valproic acid administration resulted in marked elevation in hydroxyproline, TNF-α production and NF-kB expression. These results were confirmed by histopathological examination. Treatment with ellagic acid markedly attenuated valproic acid-induced hepatic injury in rats.
Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Ellagic Acid; Glutathione; Liver; Male; Nitric Oxide; Oxidative Stress; Phytotherapy; Rats, Sprague-Dawley; Valproic Acid
PubMed: 32139333
DOI: 10.1016/j.jphs.2020.01.007 -
Journal of the College of Physicians... Sep 2021To determine the frequency of hyperglycinemia in epileptic patients taking valproic acid (VPA); and the correlation between therapeutic dose of valproic acid and plasma... (Observational Study)
Observational Study
OBJECTIVES
To determine the frequency of hyperglycinemia in epileptic patients taking valproic acid (VPA); and the correlation between therapeutic dose of valproic acid and plasma glycine levels in epileptic patients.
STUDY DESIGN
Observational, cross-sectional study.
PLACE AND DURATION OF STUDY
Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology Rawalpindi, in collaboration with Combined Military Hospital, Rawalpindi, from August 2020 to January 2021.
METHODOLOGY
Plasma glycine levels were analysed on ion exchange chromatography (IEC)-based instrument, Biochrome 30+ of epileptic patients undergoing treatment with anti-epileptic agents. Therapeutic doses of valproic acid were taken as serum trough levels of valproic acid and analysed on chemiluminescence-based Abbott Architect Plus i1000 SR. Mann-Whitney U-test was applied to compare plasma glycine levels in epileptic patients on valproic acid and those on multiple anti-epileptic agents. Spearman's correlation was used to correlate plasma glycine levels in epileptic patients with trough levels of valproic acid, duration of treatment and frequency of fits/year.
RESULTS
A total of 77 participants, upto 15 years of age, were enrolled. Plasma glycine levels were significantly raised (p <0.001) in those epileptics who were on valproic acid (monodrug therapy), in comparison with those on multiple anti-epileptic agents. There were significant positive correlations between glycine levels and trough valproic acid levels (r = 0.830), duration of treatment (r = 0.525) and frequency of seizures (r = 0.326).
CONCLUSION
Epileptic patients treated with valproic acid (VPA) had raised plasma glycine levels, that increased with therapeutic dose of valproic acid and duration of treatment and was associated with increased frequency of fits in those patients. Key Words: Epilepsy, Seizure, Glycine, Valproic acid.
Topics: Anticonvulsants; Cross-Sectional Studies; Epilepsy; Glycine; Humans; Valproic Acid
PubMed: 34500514
DOI: 10.29271/jcpsp.2021.09.1020 -
Seizure Jul 2019We systematically reviewed studies to provide current evidence about the incidence and risk of alopecia in patients undergoing valproic acid (VPA) therapy. (Meta-Analysis)
Meta-Analysis
PURPOSE
We systematically reviewed studies to provide current evidence about the incidence and risk of alopecia in patients undergoing valproic acid (VPA) therapy.
METHODS
We retrieved relevant publications and gathered data on alopecia in patients taking VPA and other drugs from prospective studies.
RESULTS
Twenty-five articles met the inclusion criteria, and the overall incidence of alopecia in patients receiving VPA therapy was 11% (95% confidence interval (CI): 0.08-0.13). The pooled risk of alopecia showed a significant difference between patients treated with VPA and all other drugs (odds ratio (OR) 5.02, 95% CI: 3.58-7.03), other epileptic drugs (AEDs) (OR 4.82, 95% CI: 3.32-7.00) and other non-AEDs (OR 5.84, 95% CI: 2.67-12.81). Compared to other drugs, VPA increased the risk of alopecia both in patients with migraine headaches (OR 6.05, 95% CI: 2.89-12.63) and patients with epilepsy (OR 5.29, 95% CI: 3.53-7.92), and the increase risk was reported more frequently in patients with migraine. Both lower doses (OR 4.38, 95% CI: 2.32-8.25) and shorter treatments (OR 4.98, 95% CI: 2.41-10.25) with VPA posed a high risk of alopecia compared to other drugs, as did higher doses and longer treatment times.
CONCLUSIONS
Based on our findings, VPA was significantly associated with a risk of alopecia compared to other drugs, and the risk did not depend on the dose and treatment time.
Topics: Alopecia; Anticonvulsants; Epilepsy; Humans; Incidence; Prospective Studies; Valproic Acid
PubMed: 30981051
DOI: 10.1016/j.seizure.2019.04.003 -
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