Cytotoxicity, genotoxicity and mutagenicity of mixed ternary mononuclear Mg complex based on valproic acid with 1,10-phenanthroline in Saccharomyces cerevisiae and V79 cells.

Valproic acid (VA) is a widely used drug for the treatment of diseases affecting the central nervous system. Due to its epigenetic modulatory potential, it has been studied for possible therapeutic application in anticancer therapies. However, the VA exhibits different side effects in its application. Thus, synthetic coordination complexes with valproate can generate promising candidates for new active drugs with reduced toxicity. In this sense, we investigated the genotoxic and mutagenic potential of the sodium valproate and of the mixed ternary mononuclear Mg complex based on VA with 1,10-phenanthroline (Phen) ligand - [Mg (Valp)2Phen], in Saccharomyces cerevisiae and V79 cells. The MTT and clonal survival assays in V79 cells indicated that the Mg complex has higher cytotoxicity than sodium valproate. A similar cytotoxicity profile is observed in yeast. This fact is possibly due to the intercalation capacity of [Mg(Valp)2Phen], inducing DNA strand breaks, as observed in the comet assay and micronucleus test. In this sense, members of the NER, HR, NHEJ and TLS repair pathways are required for the repair of DNA lesions induced by [Mg(Valp)2Phen]. Interestingly, BER proteins apparently increase the cytotoxic potential of the drug. Furthermore, the [Mg(Valp)2Phen] showed higher cytotoxicity in V79 cells and yeast when compared to sodium valproate indicating applicability as a cytotoxic agent.

Sodium Valproate-Induced Chromatin Remodeling.

Valproic acid/sodium valproate (VPA), a drug originally prescribed as an anticonvulsant, has been widely reported to act on epigenetic marks by inducing histone acetylation, affecting the DNA and histone methylation status, and altering the expression of transcription factors, thus leading to modulation of gene expression. All these epigenetic changes have been associated with chromatin remodeling effects. The present minireview briefly reports the main effects of VPA on chromatin and image analysis and Fourier transform infrared (FTIR) microspectroscopy in association with molecular biology methodological approaches to investigate the VPA-induced changes in chromatin structure and at the higher-order supraorganizational level.

Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy

Pediatric epilepsy comprises chronic neurological disorders characterized by recurrent seizures. Sodium valproate is one of the common antiseizure medications used for treatment. Glucuronide conjugation is the major metabolic pathway of sodium valproate, carried out by the enzyme uridine 5′-diphosphate (UDP) glucuronosyl transferase (UGT) whose gene polymorphisms may alter the clinical outcome. The objective of this study was to assess the association between UGT1A6 genetic polymorphism and clinical outcome in terms of efficacy and tolerability in pediatric epileptic patients on sodium valproate monotherapy. Pediatric epileptic patients (n=65) aged 2-18 years receiving sodium valproate monotherapy for the past one month were included. Genetic polymorphism patterns of UGT1A6 (T19G, A541G, A552C) were evaluated by PCR-RFLP. Clinical outcome was seizure control during the 6 months observation period. Tolerability was measured by estimating the hepatic, renal, and other lab parameters. Out of 65 patients, TT (40%), TG (57%), and GG (3%) patterns were observed in UGT1A6 (T19G) gene, AA (51%), AG (40%), and GG (9%) in (A541G) gene, and AA (43%), AC (43%), and CC (14%) in (A552C) gene. No statistical difference in clinical outcome was found for different UGT1A6 genetic polymorphism patterns. We concluded that different patterns of UGT1A6 genetic polymorphism were not associated with the clinical outcome of sodium valproate in terms of efficacy and tolerability. Sodium valproate was well-tolerated among pediatric patients with epilepsy and can be used as an effective antiseizure medication.

Results of an open label feasibility study of sodium valproate in people with McArdle disease.

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VO2peak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VO2peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile.

Sodium valproate (VPA) interactions with DNA and histones.

Valproic acid/sodium valproate (VPA) constitutes a widely prescribed drug for the treatment of seizure disorders and is a well-known epigenetic agent, inducing the acetylation of histones and affecting the methylation status of DNA and histones, with consequences on gene expression. Because this drug has been recently reported to exert affinity for histone H1, and to a minor degree for DNA, in this work, we investigated a possible interaction of sodium valproate with DNA and histones H1 and H3 using high-performance polarization microscopy and Fourier-transform infrared (FTIR) microspectroscopy. The preparations under examination consisted of hemispheres resulting from drop-casting samples containing VPA-DNA and VPA-histone mixtures. The results indicated that VPA may interact with DNA and histones, inducing changes in the textural superstructure and molecular order of the DNA possibly through van der Waals forces, and in histone H1 and H3 conformations, probably as a result of electrostatic binding between the drug and protein amino acid residues. These results contribute to a better understanding of the pharmacological potential of VPA. The precise sites and mechanisms involved in these interactions would certainly benefit from investigations provided by complementary methodologies.

Celio-mesenteric trunk associated with giant omphalocele: surgical consequences / Tronco celíaco-mesentérico asociado con onfalocele gigante: consecuencias quirúrgicas

We report the first case of a newborn presenting with a celio-mesenteric trunk variation associated with a giant omphalocele. The celio-mesenteric trunk was unexpected and unseen during the staged surgical closure. After partial reintegration of the liver, the newborn presented refractory hypovolemia with anuria, leading to redo surgery. This procedure revealed ischemia of the liver and necrosis of the entire gastrointestinal tract except the colon. Despite treatment, including liver externalization, the infant did not survive. The autopsy revealed a celio-mesenteric trunk, a rare anomaly characterized by a common origin of the celiac axis and the superior mesenteric artery from the aorta. This association may explain the dramatic consequences of the staged closure procedure. Awareness of the association of celio-mesenteric trunk and omphalocele would allow the surgeon to take extra care during this delicate surgery.

Presentamos el primer caso de un recién nacido que presenta una variación del tronco celíaco-mesentérico asociada con un onfalocele gigante. El tronco celíaco-mesentérico fue inesperado y no se vio durante las etapas del cierre quirúrgico. Después de la reintegración parcial del hígado, el recién nacido presentó hipovolemia refractaria con anuria, lo que condujo a la repetición de la cirugía. Este procedimiento reveló isquemia del hígado y necrosis de todo el tracto gastrointestinal excepto el colon. A pesar del tratamiento, incluyendo la externalización hepática, el bebé no sobrevivió. La autopsia reveló un tronco celíaco-mesentérico, una rara anomalía caracterizada por un origen común del tronco celíaco y la arteria mesentérica superior, a partir de la aorta. Esta asociación puede explicar las dramáticas consecuencias del procedimiento durante las etapas del cierre. El conocimiento de la asociación de tronco celíaco-mesentérico y onfalocele permitiría al cirujano tomar especial cuidado durante esta delicada cirugía.

Protective effect of vitamin E on sperm motility and oxidative stress in valproic acid treated rats.

Long-term administration of valproic acid (VPA) is known to promote reproductive impairment mediated by increase in testicular oxidative stress. Vitamin E (VitE) is a lipophilic antioxidant known to be essential for mammalian spermatogenesis. However, the capacity of this vitamin to abrogate the VPA-mediated oxidative stress has not yet been assessed. In the current study, we evaluated the protective effect of VitE on functional abnormalities related to VPA-induced oxidative stress in the male reproductive system. VPA (400 mg kg(-1)) was administered by gavage and VitE (50 mg kg(-1)) intraperitoneally to male Wistar rats for 28 days. Analysis of spermatozoa from the cauda epididymides was performed. The testes and epididymides were collected for measurement of oxidative stress biomarkers. Treatment with VPA induced a decrease in sperm motility accompanied by an increase in oxidative damage to lipids and proteins, depletion of reduced glutathione and a decrease in total reactive antioxidant potential on testes and epididymides. Co-administration of VitE restored the antioxidant potential and prevented oxidative damage on testes and epididymides, restoring sperm motility. Thus, VitE protects the reproductive system from the VPA-induced damage, suggesting that it may be a useful compound to minimize the reproductive impairment in patients requiring long-term treatment with VPA.

Evaluation of the efficacy of sodium valproate in convulsive status epilepticus following to ıschemic stroke / Avaliação da eficácia do valproato de sódio no status epilepticus convulsivo devido ao acidente vascular cerebral isquêmico

Objective : Convulsive status epilepticus (CSE) is very rarely observed after ischaemic stroke. Sodium valproate (SV) is one of the agents used in the treatment of CSE, but its role still controversial, and its degree of efficacy in treating CSE that develops following stroke is unclear. Method : We evaluated 19 patients who were treated with intravenous (IV) SV (20 mg/kg, 2 mg/kg/h-12h) after diazepam. Patients’ modified Rankin scores (mRS), SE types, and changes in biochemical parameters after treatment were assessed. Results : CSE was successfully treated in 12 (63.15%) patients. Side effects such as hypotension and allergic reactions were observed in two patients. Refractory SE development was observed in 5 (29.4%) patients with high mRS (˃ 3). No significant deterioration in patients’ laboratory evaluations, conducted before and after status, was observed. Conclusion : SV may be safe and effective in the treatment of CSE observed after ischaemic stroke, especially in patients with low mRS. .

Objetivo : Status epilepticus convulsivo (SEC) é muito raramente observado após acidente vascular cerebral isquêmico. Valproato de sódio (VS) é um dos agentes utilizados no tratamento do SEC, mas seu papel ainda é controverso e seu grau de eficácia não é claro no SEC pós acidente vascular. Método Avaliamos 19 pacientes que foram tratados com AV endovenoso (EV) (20 mg/kg, 2 mg/kg/h-12h) após diazepam. Valores da escala modificada de Rankin (mRS) dos pacientes, tipos de SE e mudanças nos parâmetros bioquímicos foram avaliados. Resultados SEC foi tratado com sucesso em 12 pacientes (63,15%). Efeitos colaterais como hipotensão e reações alérgicas foram observados em dois pacientes. Desenvolvimento de SE refratário foi observado em cinco pacientes (29,4%) com altos valores de mRS (˃ 3). Não houve deterioração significativa nas avaliações laboratoriais dos pacientes feitas antes ou depois do status. Conclusão AV pode ser eficaz no tratamento do SEC observado após acidente vascular cerebral isquêmico, especialmente nos pacientes com baixo mRS. .