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Biomedicine & Pharmacotherapy =... Feb 2023In many countries, valproate is indicated for epilepsy only, whereas its derivative divalproex (DVP) and valpromide (VPM) are indicated for bipolar disorders only. DVP... (Review)
Review
In many countries, valproate is indicated for epilepsy only, whereas its derivative divalproex (DVP) and valpromide (VPM) are indicated for bipolar disorders only. DVP is composed of sodium valproate and valproic acid (VA) in a 1:1 molar ratio and VPM is a prodrug completely hydrolyzed in the gastric tract to VA. Whatever the drug, the absorbed and active substance is the valproate ion. In this article, we reviewed the potential reasons that might justify these different indications. We performed a literature review of comparative studies of efficacy, pharmacokinetic parameters, side effects and costs for VPA, DVP, and VPM. We found only studies comparing VA with DVP. None of the eight efficacy studies found differences in epilepsy or mood disorders. The ten studies of side effects reported a difference in terms of gastrointestinal effects, but inconsistently. The United States (US) summary of product characteristics and kinetic comparison studies reported bioequivalence between DVP and VA, but a longer Tmax for DVP, likely due to its gastro-resistant galenic form. VPM summary of product characteristics and pharmacokinetic studies revealed a lower bioavailability (80% vs. 100% for VA) and a delayed Tmax. There is an additional cost for using DVP or VPM as compared to VA (respectively +177% and +77% in France). The differences in indications between valproate derivatives do not seem justified. Interchangeability between VA and DVP in bipolar disorders seems possible, at identical dosage. VPM would require a closer dosing schedule and a 20% reduction in dosage when switching to valproate.
Topics: Humans; Valproic Acid; Bipolar Disorder; Epilepsy; Drug-Related Side Effects and Adverse Reactions
PubMed: 36521249
DOI: 10.1016/j.biopha.2022.114051 -
Journal of Neurology Dec 2022Hyperammonaemia is a recognised complication of antiseizure treatment but risk factors leading to individual patient susceptibility and outcome remain unclear. (Review)
Review
BACKGROUND
Hyperammonaemia is a recognised complication of antiseizure treatment but risk factors leading to individual patient susceptibility and outcome remain unclear.
OBJECTIVE
To identify risk factors for hyperammonaemia and investigate the impact of its management on clinical outcomes.
METHODS
We carried out a retrospective observational study of adults with epilepsy who had ammonia tested over a 3-year period. Hyperammonaemia was defined as ammonia level > 35 μmol/L. Patients were classified into two groups: hyperammonaemic and non-hyperammonaemic. Association analyses and linear regression analysis were used to identify risk factors for hyperammonaemia.
RESULTS
We reviewed 1002 ammonia requests in total and identified 76 people with epilepsy who had ammonia concentration measured, including 26 with repeated measurements. 59/76 (78%) were found to have hyperammonaemia. There was borderline statistical significance of hyperammonaemia being less common in patients with an established monogenic/metabolic condition than in those with structural or cryptogenic epilepsy (P = 0.05). Drug resistance, exposure to stiripentol and oxcarbazepine were identified as risk factors for hyperammonaemia. We found a dose-dependent association between valproate and hyperammonaemia (P = 0.033). Clinical symptoms were reported in 22/59 (37%) of the hyperammonaemic group. Improved clinical outcomes with concurrent decrease in ammonia concentration were seen in 60% of patients following treatment adjustment.
CONCLUSIONS
Drug resistance and exposure to stiripentol, oxcarbazepine or high-dose valproate are associated with an increased risk of hyperammonaemia. Clinicians should consider symptoms related to hyperammonaemia in patients on high-dose valproate or multiple antiseizure treatments. Prompt identification of hyperammonaemia and subsequent treatment adjustments can lead to improved clinical outcomes.
Topics: Adult; Humans; Hyperammonemia; Valproic Acid; Ammonia; Oxcarbazepine; Epilepsy; Risk Factors; Observational Studies as Topic
PubMed: 35907043
DOI: 10.1007/s00415-022-11304-7 -
Translational Psychiatry May 2023Bipolar disorder (BD) is a distinctly heterogeneous and multifactorial disorder with a high individual and social burden. Immune pathway dysregulation is an important... (Review)
Review
Bipolar disorder (BD) is a distinctly heterogeneous and multifactorial disorder with a high individual and social burden. Immune pathway dysregulation is an important pathophysiological feature of BD. Recent studies have suggested a potential role for T lymphocytes in the pathogenesis of BD. Therefore, greater insight into T lymphocytes' functioning in patients with BD is essential. In this narrative review, we describe the presence of an imbalance in the ratio and altered function of T lymphocyte subsets in BD patients, mainly in T helper (Th) 1, Th2, Th17 cells and regulatory T cells, and alterations in hormones, intracellular signaling, and microbiomes may be potential causes. Abnormal T cell presence explains the elevated rates of comorbid inflammatory illnesses in the BD population. We also update the findings on T cell-targeting drugs as potentially immunomodulatory therapeutic agents for BD disease in addition to classical mood stabilizers (lithium, valproic acid). In conclusion, an imbalance in T lymphocyte subpopulation ratios and altered function may be involved in the development of BD, and maintaining T cell immune homeostasis may provide an overall therapeutic benefit.
Topics: Humans; Bipolar Disorder; T-Lymphocytes; Antimanic Agents; Valproic Acid; Lithium
PubMed: 37156764
DOI: 10.1038/s41398-023-02445-y -
Cells Jun 2023Zebrafish (Danio rerio) assays provide a versatile pharmacological platform to test compounds on a wide range of behaviors in a whole organism. A major challenge lies in...
Zebrafish (Danio rerio) assays provide a versatile pharmacological platform to test compounds on a wide range of behaviors in a whole organism. A major challenge lies in the lack of knowledge about the bioavailability and pharmacodynamic effects of bioactive compounds in this model organism. Here, we employed a combined methodology of LC-ESI-MS/MS analytics and targeted metabolomics with behavioral experiments to evaluate the anticonvulsant and potentially toxic effects of the angular dihydropyranocoumarin pteryxin (PTX) in comparison to the antiepileptic drug sodium valproate (VPN) in zebrafish larvae. PTX occurs in different Apiaceae plants traditionally used in Europe to treat epilepsy but has not been investigated so far. To compare potency and efficacy, the uptake of PTX and VPN into zebrafish larvae was quantified as larvae whole-body concentrations together with amino acids and neurotransmitters as proxy pharmacodynamic readout. The convulsant agent pentylenetetrazole (PTZ) acutely reduced the levels of most metabolites, including acetylcholine and serotonin. Conversely, PTX strongly reduced neutral essential amino acids in a LAT1 (SLCA5)-independent manner, but, similarly to VPN specifically increased the levels of serotonin, acetylcholine, and choline, but also ethanolamine. PTX dose and time-dependent manner inhibited PTZ-induced seizure-like movements resulting in a ~70% efficacy after 1 h at 20 µM (the equivalent of 4.28 ± 0.28 µg/g in larvae whole-body). VPN treated for 1 h with 5 mM (the equivalent of 18.17 ± 0.40 µg/g in larvae whole-body) showed a ~80% efficacy. Unexpectedly, PTX (1-20 µM) showed significantly higher bioavailability than VPN (0.1-5 mM) in immersed zebrafish larvae, possibly because VPN in the medium dissociated partially to the readily bioavailable valproic acid. The anticonvulsive effect of PTX was confirmed by local field potential (LFP) recordings. Noteworthy, both substances specifically increased and restored whole-body acetylcholine, choline, and serotonin levels in control and PTZ-treated zebrafish larvae, indicative of vagus nerve stimulation (VNS), which is an adjunctive therapeutic strategy to treat refractory epilepsy in humans. Our study demonstrates the utility of targeted metabolomics in zebrafish assays and shows that VPN and PTX pharmacologically act on the autonomous nervous system by activating parasympathetic neurotransmitters.
Topics: Humans; Animals; Pentylenetetrazole; Valproic Acid; Zebrafish; Vagus Nerve Stimulation; Serotonin; Acetylcholine; Tandem Mass Spectrometry; Seizures; Anticonvulsants; Choline
PubMed: 37296660
DOI: 10.3390/cells12111540 -
Molecules (Basel, Switzerland) Mar 2021A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell...
A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell research, drug discovery, and disease modeling. While this forced genetic expression represents an advantage, there will always be an issue with genomic instability and transient pluripotency genes reactivation that might preclude their clinical application. During the reprogramming process, a somatic cell must undergo several epigenetic modifications to induce groups of genes capable of reactivating the endogenous pluripotency core. Here, looking to increase the reprograming efficiency in somatic cells, we evaluated the effect of epigenetic molecules 5-aza-2'-deoxycytidine (5AZ) and valproic acid (VPA) and two small molecules reported as reprogramming enhancers, CHIR99021 and A83-01, on the expression of pluripotency genes and the methylation profile of the OCT4 promoter in a human dermal fibroblasts cell strain. The addition of this cocktail to culture medium increased the expression of OCT4, SOX2, and KLF4 expression by 2.1-fold, 8.5-fold, and 2-fold, respectively, with respect to controls; concomitantly, a reduction in methylated CpG sites in OCT4 promoter region was observed. The epigenetic cocktail also induced the expression of the metastasis-associated gene S100A4. However, the epigenetic cocktail did not induce the morphological changes characteristic of the reprogramming process. In summary, 5AZ, VPA, CHIR99021, and A83-01 induced the expression of OCT4 and SOX2, two critical genes for iPSC. Future studies will allow us to precise the mechanisms by which these compounds exert their reprogramming effects.
Topics: Cell Differentiation; Cell Line; Decitabine; Epigenesis, Genetic; Fibroblasts; Gene Expression; Humans; Kruppel-Like Factor 4; Pyrazoles; Pyridines; Pyrimidines; Thiosemicarbazones; Valproic Acid
PubMed: 33805347
DOI: 10.3390/molecules26071909 -
PloS One 2022Valproic acid (VPA) has shown beneficial effects in vitro against SARS-CoV-2 infection, but no study has analyzed its efficacy in the clinical setting.
Exposure to valproic acid is associated with less pulmonary infiltrates and improvements in diverse clinical outcomes and laboratory parameters in patients hospitalized with COVID-19.
BACKGROUND
Valproic acid (VPA) has shown beneficial effects in vitro against SARS-CoV-2 infection, but no study has analyzed its efficacy in the clinical setting.
METHODS
This multicenter, retrospective study included 165 adult patients receiving VPA at the time of admission to hospital, and 330 controls matched for sex, age and date of admission. A number of clinical, outcome and laboratory parameters were recorded to evaluate differences between the two groups. Four major clinical endpoints were considered: development of lung infiltrates, in-hospital respiratory worsening, ICU admissions and death.
RESULTS
VPA-treated patients had higher lymphocyte (P<0.0001) and monocyte (P = 0.0002) counts, and lower levels of diverse inflammatory parameters, including a composite biochemical severity score (P = 0.016). VPA patients had shorter duration of symptoms (P<0.0001), were more commonly asymptomatic (P = 0.016), and developed less commonly lung infiltrates (65.8%/88.2%, P<0.0001), respiratory worsening (20.6%/30.6%, P = 0.019) and ICU admissions (6.1%/13.0%, P = 0.018). There was no difference in survival (84.8%/88.8%, P = 0.2), although death was more commonly related to non-COVID-19 causes in the VPA group (36.0%/10.8%, P = 0.017). The cumulative hazard for developing adverse clinical endpoints was higher in controls than in the VPA group for infiltrates (P<0.0001), respiratory worsening (P<0.0001), and ICU admissions (P = 0.001), but not for death (0.6). Multivariate analysis revealed that VPA treatment was independently protective for the development of the first three clinical endpoints (P = 0.0002, P = 0.03, and P = 0.025, respectively), but not for death (P = 0.2).
CONCLUSIONS
VPA-treated patients seem to develop less serious COVID-19 than control patients, according to diverse clinical endpoints and laboratory markers.
Topics: Aged; Blood Cell Count; COVID-19; Female; Hospitalization; Humans; Inflammation; Lung; Male; Middle Aged; Retrospective Studies; SARS-CoV-2; Severity of Illness Index; Spain; Treatment Outcome; Valproic Acid; COVID-19 Drug Treatment
PubMed: 35085321
DOI: 10.1371/journal.pone.0262777 -
CNS Neuroscience & Therapeutics Jan 2023Resistance to valproic acid (VPA) is a major challenge for epilepsy treatment. We aimed to explore the mechanism underlying this resistance.
AIMS
Resistance to valproic acid (VPA) is a major challenge for epilepsy treatment. We aimed to explore the mechanism underlying this resistance.
METHODS
Pentylenetetrazol-induced chronic epileptic rats were administered VPA (250 mg/Kg) for 14 days; rats with controlled seizure stages (seizure score ≤0) and latent time (latent time ≥0) were considered VPA-responsive, while the others were considered nonresponsive. Differentially expressed genes (DEGs) between the VPA-responsive and nonresponsive rat hippocampus transcriptomes were identified, and their functions were evaluated. The roles of postsynaptic density (PSD) and Homer1 were also determined. Furthermore, a subtype of Homer1 (Homer1b/c) was overexpressed or silenced in HT22 cells to determine its effect on VPA efficacy. Moreover, the membrane levels of mGluR1/5 directly bound to Homer1b/c were assessed.
RESULTS
Overall, 264 DEGs commonly enriched in the PSD between VPA-responsive and nonresponsive rats. Among them, Homer1 was more highly expressed in the hippocampus of nonresponses compared to that of responses. Overexpression of Homer1b/c interrupted VPA efficacy by increasing reactive oxygen species production, lactate dehydrogenase release, and calcium content. Furthermore, it induced the overexpression of mGluR1 and mGluR5.
CONCLUSION
Overexpression of Homer1b/c influenced VPA efficacy, revealing it could be a target to improve the efficacy of this treatment.
Topics: Animals; Rats; Anticonvulsants; Epilepsy; Pentylenetetrazole; Receptor, Metabotropic Glutamate 5; Seizures; Valproic Acid; Mice
PubMed: 36353757
DOI: 10.1111/cns.14008 -
Missouri Medicine 2022Bipolar Affective Disorder (BPAD) is frequently encountered in the primary care office and must be considered in the differential diagnosis of all patients with mood...
Bipolar Affective Disorder (BPAD) is frequently encountered in the primary care office and must be considered in the differential diagnosis of all patients with mood dysregulation. Appreciation for the range of bipolar illness has evolved in recent years, and the overlap of bipolar illness with trauma-based diagnosis such as Post-Traumatic Stress Disorder (PTSD) and Borderline Personality Disorder must be considered. Treatment of BPAD is divided into manic, depressive, and maintenance phases, each with different pharmacologic considerations. First line agents for the acute manic phase include lithium, valproic acid, and second generation antipsychotics (SGAs). First line agents for depressive phase include lamotrigine, lithium, and the SGAs lurasidone and quetiapine. For bipolar maintenance therapy, lamotrigine, valproic acid, and lithium are first line options. Finally, nonpharmacologic interventions including psychoeducation can be extremely helpful for patients and their families to successfully participate in the management of their disease.
Topics: Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Humans; Lamotrigine; Lithium; Primary Health Care; Valproic Acid
PubMed: 36035565
DOI: No ID Found -
Behavioural Neurology 2022The glutamate system plays a major role in the development of neuropsychiatric disorders such as addiction, epilepsy, dementia, and psychosis. MK-801 (dizocilpine), an...
OBJECTIVE
The glutamate system plays a major role in the development of neuropsychiatric disorders such as addiction, epilepsy, dementia, and psychosis. MK-801 (dizocilpine), an uncompetitive -methyl-D-aspartate (NMDA) receptor antagonist, could increase locomotor activity and stereotyped neurobehaviors mimicking schizophrenic-like features in the mouse model. The study would explore the neuropharmacological differences of risperidone and valproic acid on the MK-801-induced neurobehavioral changes.
METHODS
The subjects were male C57BL/6J mice obtained from the National Laboratory Animal Center. Drug effects were assessed using the open field with a video-tracking system and gaiting tests. After habitation, risperidone (0, 0.1 mg/kg) or valproic acid (0, 200 mg/kg) was injected and ran locomotion for 30 mins. Sequentially, mice were followed by intraperitoneal injection (i.p.) with MK-801 (0, 0.2 mg/kg) and ran locomotion for 60 mins. Gaiting behaviors such as step angles, stride lengths, and stance widths were measured following the study drugs.
RESULTS
The results showed that risperidone and valproic acid alone could not alter the locomotor activities. Following the MK-801 injection, the travelled distance and speed in the entire open field dramatically increased. The dose 0.1 mg/kg of risperidone could totally inhibit the MK-801-induced hyperlocomotion compared with that of the saline-injected group ( < 0.001). The valproic acid (200 mg/kg) partially suppressed the hyperlocomotion which is induced by MK801.
CONCLUSION
The more dominant effect of risperidone to rescue MK-801 induced hyperlocomotion compared with that of valproic acid. The partial suppression of valproic acid may imply the psychopharmacological evidence as adjuvant effect to treat psychotic patients through tuning glutamatergic neurotransmission.
Topics: Animals; Dizocilpine Maleate; Locomotion; Male; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate; Risperidone; Valproic Acid
PubMed: 35251367
DOI: 10.1155/2022/1048463 -
Epilepsy Research Sep 2023Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We aimed to evaluate the long-term effects of intravenous phenobarbital on adult patients with GCSE.
METHODS
This randomized clinical trial with a 12-month follow-up was performed in Xuanwu Hospital, Capital Medical University (Beijing, China) between February 2011 and December 2021. After the failure of intravenous diazepam treatment, adult patients with GCSE were randomized to receive either intravenous phenobarbital or valproate. Neurological outcome within 12-month was dichotomized as good (modified Rankin scale, mRS 0-2) or poor (mRS 3-6). Cognitive function was measured by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) were tested for mood disorders.
RESULTS
We consecutively recruited 166 patients with GCSE. After excluding individuals with termination after intravenous diazepam (n = 61), and with other exclusion criteria (n = 7), 98 patients were included and 88.0% (66/75) of survivors achieved seizure freedom at 12-month. Forty-five patients (45.92%) had good outcomes at 3-month and 57 patients (58.16%) had good outcomes at 12-month. And 46.67% (35/75) of survivors showed mRS improvement at 12-month (phenobarbital group, n = 17 vs. valproate group, n = 18, P = 0.321). Despite there was no significant difference with respect to good outcomes at 3-month (54.0% vs. 37.5%, P = 0.101), the rate of good outcomes in phenobarbital group was higher than valproate group at 12-month (68.0% vs. 47.92%, P = 0.044). A total of 43 patients successfully participated cognitive and emotional tests. Mild cognitive impairment was found in 7.14% of phenobarbital group and 50.0% in valproate group (P = 0.026). In addition, there were no significant differences with respect to anxiety (36.36% vs. 38.10%) and depression (31.82% vs. 47.62%) between the phenobarbital and valproate groups.
CONCLUSIONS
Combined with long term conventional therapy, intravenous phenobarbital group had more good outcomes than intravenous valproate group in Chinese adult patients with GCSE up to 12-month follow-up. This finding may prompt the option of intravenous phenobarbital especially in patients with limited access to new antiseizure drugs.
Topics: Humans; Adult; Valproic Acid; Anticonvulsants; Follow-Up Studies; Treatment Outcome; Status Epilepticus; Phenobarbital; Diazepam
PubMed: 37467704
DOI: 10.1016/j.eplepsyres.2023.107187