Inhalation of Cananga odorata essential oil relieves anxiety behaviors in autism-like rats via regulation of serotonin and dopamine metabolism / 中西医结合学报

OBJECTIVE@#Anxiety is one of the most common symptoms associated with autistic spectrum disorder. The essential oil of Cananga odorata (Lam.) Hook. f. & Thomson, usually known as ylang-ylang oil (YYO), is often used in aromatherapy as a mood-regulating agent, sedative, or hypotensive agent. In the present study, the effects and mechanisms of YYO in alleviating anxiety, social and cognitive behaviors in autism-like rats were investigated.@*METHODS@#The prenatal valproic acid (VPA) model was used to induce autism-like behaviors in offspring rats. The effectiveness of prenatal sodium valproate treatment (600 mg/kg) on offspring was shown by postnatal growth observation, and negative geotaxis, olfactory discrimination and Morris water maze (MWM) tests. Then three treatment groups were formed with varying exposure to atomized YYO to explore the effects of YYO on the anxiety, social and cognitive behaviors of the autistic-like offspring through the elevated plus-maze test, three-chamber social test, and MWM test. Finally, the monoamine neurotransmitters, including serotonin, dopamine and their metabolites, in the hippocampus and prefrontal cortex (PFC) of the rats were measured using a high-performance liquid chromatography.@*RESULTS@#Offspring of VPA exposure rats showed autism-like behaviors. In the VPA offspring, medium-dose YYO exposure significantly elevated the time and entries into the open arms in the elevated plus-maze test, while low-dose YYO exposure significantly enhanced the social interaction time with the stranger rat in session 1 of the three-chamber social test. VPA offspring treated with YYO exposure used less time to reach the platform in the navigation test of the MWM test. YYO exposure significantly elevated the metabolism of serotonin and dopamine in the PFC of VPA offspring.@*CONCLUSION@#YYO exposure showed the effects in alleviating anxiety and improving cognitive and social abilities in the offspring of VPA exposure rats. The role of YYO was related to the regulation of the metabolism of serotonin and dopamine. Please cite this article as: Zhang N, Wang ST, Yao L. Inhalation of Cananga odorata essential oil relieves anxiety behaviors in autism-like rats via regulation of serotonin and dopamine metabolism. J Integr Med. 2023; 21(2): 205-214.

Histone Deacetylase Inhibitors in the in Vitro Expansion of Hematopoietic Stem Cells / 中国医学科学院学报

The self-renewal and differentiation of hematopoietic stem cells(HSCs)are highly regulated by epigenetic modification,in which histone acetylation can activate or silence gene transcription.Histone deacetylase inhibitors(HDACIs)can inhibit the activity of histone deacetylase in HSCs to increase histone acetylation.A variety of HDACIs,such as trichostatin A and valproic acid,are used to expand HSCs in vitro,especially cord blood HSCs,combined with cytokines in serum-free culture to obtain more long-term repopulating cells.HDACIs promote the transcription of pluripotent genes related to stem cell self-renewal and inhibit the expression of genes related to differentiation,so as to promote the expansion and inhibit differentiation of HSCs.The expansion of cord blood HSCs by small molecular HDACIs in vitro is expected to improve the quantity of cord blood HSCs.The further research will focus on high-throughput screening for the most powerful HDACIs and the highly selective HDACIs,exploring the combination of epigenetic modifiers of different pathways.

Optical coherence tomography findings in bipolar disorder: a preliminary receiver operating characteristic analysis on ganglion cell layer volume for diagnosis

Abstract Background Optical coherence tomography (OCT) has been recently used to investigate neuropsychiatric disorders. Objective The aim of this study was to compare the retinal nerve fiber layer thickness (RNFLT) and the ganglion cell layer (GCL) volume in patients with type 1 bipolar disorder (BPD1, diagnosed according to DSM 5) to the values in healthy controls. Methods Eighty consecutive outpatients with a diagnosis of euthymic BPD1 and 80 healthy controls were enrolled in the study. Following assessment with the Sociodemographic Data Form, Structured Clinical Interview for DSM-IV (SCID-I), Hamilton Depression Scale and Young Mania Evaluation Scale, both groups underwent Optical coherence tomography (OCT). Results The mean RNFL thickness and mean GCL volume were significantly lower in the BPD1 group than in the controls (p < 0.05). The GCL global value had a significant and independent effect in distinguishing the BPD1 patients from the controls. A cut-off value of 101 mm3 for global GCL volume was proposed to distinguish BPD1 patients from controls with a sensitivity of 87.5%. Discussion Lower values of GCL volume and RNFLT in patients suffering from BPD1 suggest that neurodegeneration may occur during the course of BPD and that this degeneration can be characterized in particular by a thinning of the GCL volume.

El ácido valproico como agente sensibilizador al tratamiento anticáncer / Valproic acid as a sensitizing agent in anticancer treatment

Resumen El ácido valproico es un fármaco antiepiléptico con más de 50 años de uso clínico. En la década pasada se descubrieron sus efectos anticancerígenos. El análisis de grupos de pacientes que utilizaron este fármaco durante años ha mostrado que disminuye la frecuencia de cáncer de cabeza y cuello. Estudios recientes evidencian el efecto anticáncer al combinar el ácido valproico con la quimioterapia, terapia biológica e inhibidores de sistemas antioxidantes, con resultados excepcionales. En esta revisión se analiza el metabolismo del ácido valproico y su aplicación contra el cáncer.

Abstract Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.

Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Interferon-γ (IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.

Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Valproic acid (VPA), an agent that is used to treat epileptic seizures, can cause spatial memory impairment in adults and children. This effect is thought to be due to the ability of VPA to inhibit neurogenesis in the hippocampus, which is required for learning. We have previously used an animal model to show that VPA significantly impairs hippocampal-spatial working memory and inhibits neuronal generation in the sub-granular zone of the dentate gyrus. As there are patient reports of improvements in memory after discontinuing VPA treatment, the present study investigated the recovery of both spatial memory and hippocampal neurogenesis at two time points after withdrawal of VPA. Male Wistar rats were given intraperitoneal injections of 0.9% normal saline or VPA (300 mg/kg) twice a day for 10 d. At 1, 30, or 45 d after the drug treatment, the novel object location (NOL) test was used to examine spatial memory; hippocampal cell division was counted using Ki67 immunohistochemistry, and levels of brain-derived neurotrophic factor (BDNF) and Notch1 were measured using western immunoblotting. Spatial working memory was impaired 1 and 30 d after the final administration, but was restored to control levels by 45 d. Cell proliferation had increased to control levels at 30 and 45 d. Both markers of neurogenesis (BDNF and Notch1 levels) had returned to control levels at 45 d. These results demonstrate that memory recovery occurs over a period of six weeks after discontinuing VPA treatment and is preceded by a return of hippocampal neurogenesis to control levels.

The alterations of microvasculature, tyrosine phosphorylation, and lipid peroxidation in kidney of rats treated with valproic acid / Alteraciones de la microvasculatura, fosforilación de tirosina y peroxidación lipídica en riñones de ratas tratadas con ácido valproico

SUMMARY: Valproic acid (VPA), an antiepileptic drug, has been demonstrated to damage histology and to change tyrosine phosphorylation patterns with increased oxidative stress in perirenal tissues. This study aimed to investigate the effect of VPA on microstructure, tyrosine phosphorylation, and lipid peroxidation of rat kidney. Adult male rats were divided into control and VPA-treated groups intraperitoneally injected with normal saline and VPA 500 mg/kgBW for 10 consecutive days, respectively (n = 7 each). The blood serum was examined for biochemical levels. The kidney tissues were routinely processed for histological observation. Total proteins from kidney were extracted to assay the malondialdehyde (MDA) levels and phosphorylation expression. The results showed that VPA significantly decreased blood glucose levels while tend to increase urea nitrogen and creatinine. MDA levels in VPA group were significantly higher that of control. Renal cortex of VPA-treated animals revealed vasodilatations. Although the ratio of a renal phosphorylated 72 kDa protein/ beta actin expression seemed to be not different in both groups, VPA significantly decreased the intensity of beta actin. In conclusion, VPA dilates renal microvasculature with increasing of MDA but suppresses the actin expression.

RESUMEN: Se ha demostrado que el ácido valproico (AVP), un fármaco antiepiléptico, daña la histología y cambia los patrones de fosforilación de la tirosina con el aumento del estrés oxidativo en los tejidos perirrenales. Este estudio tuvo como objetivo investigar el efecto del AVP en la microestructura, la fosforilación de la tirosina y la peroxidación lipídica del riñón de rata. Se dividieron ratas macho adultas en grupos control y tratados con AVP. Durante 10 días consecutivos fueron inyectadas por vía intraperitoneal con solución salina normal y 500 mg / kg de PC respectivamente (n = 7 cada uno). Se analizó el suero sanguíneo para determinar los niveles bioquímicos. Los tejidos renales se procesaron de forma rutinaria para la observación histológica. Las proteínas totales del riñón se extrajeron para analizar los niveles de malondialdehído (MDA) y la expresión de la fosforilación. Los resultados mostraron que el AVP disminuyó significativamente los niveles de glucosa en la sangre, mientras que tienden a aumentar el nitrógeno ureico y la creatinina. Los niveles de MDA en el grupo de AVP fueron significativamente más altos que los del control. La corteza renal de los animales tratados con AVP reveló vasodilataciones. Aunque la proporción de una expresión de proteína / actina de 72 kDa fosforilada renal no parece ser diferente en ambos grupos, el AVP disminuyó significativamente la intensidad de la actina beta. En conclusión, el AVP dilata la microvasculatura renal al aumentar el MDA, pero suprime la expresión de actina.

Histone deacetylase activity and brain-derived neurotrophic factor (BDNF) levels in a pharmacological model of mania

Objective: In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH) exposure, a well-accepted animal model of acute mania in bipolar disorder (BD), and histone deacetylase (HDAC) inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC) and peripheral blood mononuclear cells (PBMCs) of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF) protein and mRNA levels in these samples. Methods: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li), 200 mg/kg sodium valproate (VPT), 2 mg/kg sodium butyrate (SB), or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. Results: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. Conclusion: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity. .

The prophylactic effects of folic acid and vitamin E against valproic acid during fetal thymus development: an ultrastructural study / Los efectos profilácticos del ácido fólico y la vitamina E contra el ácido valproico durante el desarrollo fetal del timo: un estudio ultraestructural

To evaluate histopathologic differences in the thymus of Wistar Albino rat fetuses prenatally exposed to valproic acid (VPA), folic acid (FA) and vitamin E (Vit-E). VPA (400 mg/kg), FA (400 mcg/kg) and Vit -E (250 mg/kg) were administered to rats on each of gestation days 8, 9 and 10. The fetuses (n:24) were divided into four groups: control, VPA, VPA+Vit-E and VPA+FA groups. On the 20th day of gestation, all pregnant rats were sacrificed and the fetuses were extracted. Thin sections from thymus of live fetuses were stained with uranyl acetate-lead citrate and were examined under transmission electron microscope. The histopathological findings of control group was normal. In VPA group, it showed extensive degenerative changes by VPA were on all tissue compartments when compared to controls. In VPA-FA group, vacuoles, mitochondrial cristalysis and swelling were decreased in cytoplasm. In VPA-Vit-E group, lipid storage and vacuolization were observed. Mitochondrial cristalysis decreased. Our aim in the present study is to analyze histopathological changes which may occur in a high risk experimental model after giving of VPA. In addition, protective roles of the administration of FA and Vit-E are assessed.

Se realizó este estudio para evaluar las diferencias histopatológicas en el timo de fetos de ratas Wistar Albinas expuestas prenatalmente a ácido valproico (VPA), ácido fólico (AF) y vitamina E (Vit-E). VPA (400 mg/kg), FA (400 mcg/kg) y vitamina E (250mg/kg) administradas a ratas en los días 8, 9 y 10 de gestación. Los fetos (n=24) fueron divididos en cuatro grupos: control, APV, APV + vitamina E y VPA + FA. En el día 20 de gestación, todas las ratas preñadas fueron sacrificadas y los fetos fueron extraídos. Se obtuvieron secciones delgadas del timo de los fetos y se tiñeron con citrato de uranilo - acetato de plomo, siendo examinados al microscopio electrónico de transmisión. Los hallazgos histopatológicos del grupo control fueron normales. En el grupo VPA, se observaron cambios degenerativos en todos los compartimentos de tejido en comparación con los controles. En el grupo VPA+FA, las vacuolas, cristalisis mitocondrial e inflamación se redujeron en el citoplasma. En grupo VPA + Vitamina E, se observó el almacenamiento de lípidos y vacuolización. La cristalisis mitocondrial disminuyó. El estudio permitió analizar los cambios histopatológicos que pueden ocurrir en un modelo experimental de alto riesgo después de la administración de VPA, además, las funciones de protección por la administración de AF y vitamina E.

Evaluación de la función tiroídea en pacientes pediátricos durante el uso de fármacos antiepilépticos / Assessment of thyroid in pediatric patients during the use of antiepileptic drugs

El objetivo principal de este trabajo es evaluar las alteraciones en la función tiroídea de pacientes pediátricos con epilepsia en tratamiento con fármacos antiepilépticos (FAEs). Un segundo objetivo es evaluar la severidad y manifestaciones clínicas de estas alteraciones y los FAEs asociados a ellas. Se revisó las historias clínicas de pacientes de 0-18 años, en control por epilepsia, pertenecientes a la unidad de Neuropsiquiatría Infantil del Hospital Dr. Lautaro Navarro Avaria de Punta Arenas, durante el periodo comprendido entre julio del 2008 y junio del 2009. Criterios de inclusión: estar en tratamiento con FAEs y tener registro de evaluación de función tiroídea en su ficha clínica. De los 59 pacientes que cumplieron con los criterios de inclusión, 21 tenían niveles de hormona tiro-estimulante (TSH) elevados, seis de ellos presentaron manifestaciones clínicas de hipotiroidismo. La mayoría presentó hipotiroidismo subclínico y recibía tratamiento con ácido valproico (VPA) como monoterapia. Es por esto y considerando que el desarrollo cerebral de los niños es altamente sensible a los niveles de tiroxina, parece fundamental el monitoreo de la función tiroídea en niños y adolescentes en tratamiento con FAES.

Our aim was to evaluate severity and clinical manifestations of thyroid function abnormalities in pediatric epileptic patients in therapy with antiepileptic drugs (AED). Medical histories of patients attending to the Pediatric Neuropsychiatric Unit of Dr. Lautaro Navarro Avaria Hospital, Punta Arenas were reviewed. Fifty nine epileptic patients aged between 0-18 years, on AED therapy between July 2008 and June 2009, with evaluation of thyroid function were included. Thyroid-stimulating hormone (TSH) serum levels were high in 21 of the 59 patients, six of them showed clinical signs of hypothyroidism. Most of them exhibited TSH values in the subclinical hypothyroidism range and were on valproic acid (VPA) monotherapy. Considering that children’s brain development is highly sensitive to thyroxine levels, we emphasize the relevance of monitoring thyroid function in children and adolescents receiving antiepileptic treatment.

effect of anticonvulsant drugs [phenobarbital and valproic acid] on the serum level of cholesterol, triglyceride, lipoprotein and liver enzymes in convulsive children

Studies on the effect of various antiepileptic drugs on serum lipids show contradictory results. We aimed to find the effect of Phenobarbital and Sodium Valproate monotherapy on serum lipid profile and liver function tests in epileptic children. This cohort study was concducted in Amirkola Children Hospital. One hundred and ten children with epilepsy were included in this study. Children with hepatic or renal disease, those receiving medications which could alter liver function tests or serum lipid profile were excluded from the study. Patients were allocated into two groups. The first group, including 63 patients, received Phenobarbital and the second group, including 47 patients, received Sodium Valproate, both in divided doses. A venous blood sample was collected after overnight fasting to evaluate serum triglyceride, total cholesterol, LDL, HDL, and liver function tests. Data was analyzed with SPSS version 27. In children receiving Phenobarbital, total cholesterol, LDL, HDL, ALP, SGOT and SGPT increased significantly after treatment, but TG level showed no significant changes. In children receiving Sodium Valproate, HDL, ALP, SGOT, SGPT significantly increased after treatment but there were no statistically significant changes in total cholesterol, LDL and TG. In our study, the plasma levels of LPa elevated significantly after treatment with Phenobarbital and Sodium Valproate [P Value=0.0001]. This increase was more significant in patients receiving Sodium Valproate. Our results suggested a need for monitoring serum total cholesterol, HDL, LDL,and TG levels in patients receiving Phenobarbital and Valproic Acid

Bone morphogenetic protein 4 stimulates neuronal differentiation of neuronal stem cells through the ERK pathway

Bone morphogenic protein 4 (BMP4), a member of the TGF-beta superfamily, induced neural differentiation of neural stem cells (NSCs) grown in a medium containing basic fibroblast growth factor (bFGF). The Ras protein level and the activities of the downstream ERKs were increased by transfection of BMP4 or treatment with recombinant BMP4. The effects of BMP4, including activation of the Ras-ERK pathway and induction of the neuron marker beta-tubulin type III (Tuj1), were blocked by co-treatment of the BMP4 antagonist, noggin. The roles of the Ras-ERK pathway in neuronal differentiation by BMP4 were revealed by measuring the effect of the ERK pathway inhibition by dominant negative Ras or PD98059, the MEK specific inhibitor. BMP4 is a transcriptional target of Wnt/beta-catenin signaling, and both the mRNA and protein levels of BMP4 were increased by treatment of valproic acid (VPA), a chemical inhibitor of glycogen synthase kinase 3beta (GSK3beta) activating the Wnt/beta-catenin pathway. The BMP4- mimicking effects of VPA, activation of the Ras-ERK pathway and induction of Tuj1, also were blocked by noggin. These results indicate the potential therapeutic usage of VPA as a replacement for BMP4.

Effects of sodium valproate and carbamazepine on food competition aggression in pigeons

Valproate and carbamazepine (CAR) have been proposed as adjunct alternatives for the control of aggression in psychiatric patients, although no definite conclusions have been reached. We examined the effects of these drugs on food competition offensive aggression and other behaviors in high- and low-aggression food-restricted pigeons. These were divided into pairs containing previously ranked high-aggression (N = 10 pairs) and low-aggression females (N = 10 pairs). In Experiment 1, a pigeon in each pair of high- and low-aggression subjects was treated daily with an oral dose of sodium valproate (50 mg kg-1 mL saline-1) for 15 days. The other animal received the vehicle. On days 1, 7, and 15, food competition trials (10 min) were performed 60 min after treatment. In Experiment 2, one pigeon in each pair was treated daily with an oral dose of CAR (20 mg kg-1 mL saline-1) for 15 days. Each pair was submitted to a food competition trial on days 1, 7, and 15 of treatment. Valproate (15 days of treatment) selectively decreased the time spent in offensive aggression (control: 102.7 ± 9.3 vs valproate: 32.7 ± 9.2 s; P < 0.001, ANOVA-2-TAU) of high-aggression pigeons. This was also the case for 7 and 15 days of CAR treatment (control: 131.5 ± 8.9 vs CAR: 60.4 ± 5.3, P < 0.01, and control: 122.7 ± 7.1 vs CAR: 39.1 ± 5.2; P < 0.001, ANOVA-2-TAU, respectively). Thus, the two anticonvulsive drugs have a similar effect on food competition aggression in pigeons.

Effects of sedium valproate on the replication of herpes simplex virus type 1: an in vitro study

Sodium valproate, an anticonvulsant drug, is reported to stimulate Human Immunodeficiency Virus type 1 and Human cytomegalovirus replication. Since epileptic patients undergoing sodium valproate therapy may suffer from various virus infections, the effect of this drug on replication of viruses especially those affecting neuronal tissues such as Herpes simplex virus type 1 is worthy of investigation. Viral replication was studied by quantal response method. Electron microscopy was also performed on cell monolayers treated with the drug and infected with the virus. Significant reduction in viral infectivity was observed in cell cultures exposed to 0.5-2 mM of sodium valproate either one hr before or after infection. The corresponding electron microscopic examination revealed a very few intracytoplasmic enveloped virions and a marked reduction in the number of intracytoplasmic nucleocapsids in drug-treated virus infected cells compared with those of infected control. However, significant stimulation of virus replication was found upon treatment of cells with 1 mM [p<0.01] and 2 mM [p<0.001] of the drug 24 hours prior to infection. No remarkable change was seen in corresponding electron micrographs. Although the ultimate outcome of this study awaits in vivo assessments, possible stimulation of Herpes simplex virus type 1 replication by sodium valproate should be considered by clinicians prescribing this drug

An experimental evaluation of anticonvulsant activity of Vitex-negundo.

Maximal electroshock seizures (MES) in albino rats and pentylenetetarazole (PTZ) induced seizures in albino mice were used to study anticonvulsant activity of Vitex-negundo leaf extract. The ethanolic leaf extract of Vitex-negundo was administered orally in graded doses (250, 500 and 1000 mg/kg p.o) in both the experimental models and the effects were compared with diphenylhydantoin in MES method and valporic acid in PTZ induced seizures method as standard control respectively. The Vitex-negundo in the doses (250, 500 and 1000 mg/kg, p.o) did not show protection against MES to any significant extent but significant post-ictal depression was observed in the dose of 1000 mg/kg body weight in comparison to control. However, sub-protective dose of test drug (100 mg/ kg, p.o) potentiated the anticonvulsant action of diphenylhydantoin. The test drug in the dose (1000 mg/kg, po) showed 50% protection in clonic seizures and 24-hour mortality against PTZ induced seizures. It also decreased number and duration of convulsions significantly. Vitex-negundo potentiated anticonvulsant activity of valporic acid. The anticonvulsant activity of Vitex-negundo has not been found equi-effective with standard drugs. These findings suggest that Vitex-negundo possesses anticonvulsant activity particularly against PTZ induced convulsions. Moreover, the potentiation of diphenylhydantoin and valporic acid by Vitex-negundo indicates that it may be useful as an adjuvant therapy along with standard anticonvulsants and can possibly lower the requirement of diphenylhydantoin and valporic acid.

Morphological and morphometric alterations induced by valproic acid on rat fetuses' meckel's cartilage, lingual musculature, and submandibular gland

El acido valproico es una droga antiepileptica, bien conocida como agente teratogenico; su principal órgano blanco es el tubo neural, aunque malformaciones de otros órganos tambien han sido descritas. El propósito del trabajo fue analizar los efectos del acido valproico en las estructuras orales embriofetales: Cartilago de Meckel, músculos de la lengua y glándula submandibular. Las ratas recibieron una inyección diaria intraperitoneal de acido valproico (300 mg/Kg), durante 10 dias de su gestación. Las ratas hembras fueron sacrificadas al 20 dia post coito y fueron examinados los fetos. No fueron observadas malformaciones macroscópicas. Fueron observadas las siguientes malformaciones: bajo peso del cuerpo y de la placenta; cordón umbilical corto; parenquima de la glandula submandibular menos diferenciada con gran cordón celular y ramificaciones terminales e incremento del volumen nuclear; las fibras de los músculos de la lengua desorganizados y de menor tama¤o y de volumen nuclear peque¤o; cartilago de Meckel rudimentario, con peque¤os condrocitos y muy abundante matriz. Estos datos sugieren que alteraciones en el tejido oral, inducidos por acido valproico, como resultado de un efecto directo de la droga en los tejidos, provoca una diferenciación retardada de ellos.

Sodium valproate-induced potentiation of antiherpetic effect of acyclovir

Sodium valproate [VPA], an anticonvalsant drug, has been reported to stimulate viral replication. A combination therapy with VPA and acyclovir [ACV] is used for the treatment of herpesvirus encephalitis, the commonest sporadic encephalitis of viral origin. To determine a possible interaction between VPA and ACV leading to a modification of antiviral activity of ACV. Cultured Hela cells were treated with 5 micro M of ACV and various concentrations of VPA followed by infection with herpes simplex virus type 1 [HSV-1]. Virus replication was monitored by quantal assay. Further investigations comprised electron microscopy, immunoperoxidase and immunoblot procedures. Possible chemical interaction between VPA and ACV was studied by nuclear magnetic resonance [NMR] spectrometer. Combined treatment of infected cells with ACV and VPA revealed 50- to 250-fold potentiation of antiviral activity of ACV by increasing VPA concentrations. Examination by NMR spectrometer showed a strong chemical interaction between amino groups of ACV and carboxyl part of VPA. The present in vitro studies should be paralleled by appropriate in vivo investigations, and if substantiated, a combination therapy with ACV and VPA may supersede single ACV therapy for herpesvirus encephalitis. Further studies are thus needed to establish which of VPA metabolites or newly-formed compounds is accountable for augmentation of antiviral effect of ACV

O papel do divalproato de sodio no tratamento dos transtornos do humor: eficacia, tolerabilidade e seguranca / Treatement of mood disorders with divalproex sodium: efficacy, tolerability and safety

O divalproato de sodio e um medicamento antiepileptico que vem sendo usado frequentemente nos transtornos do humor. Existem fortes evidencias de eficacia em mania aguda e algumas evidencias de...