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At least 235 records · Page 13Linked to original sources

PubMed2003

Intravenous valproate associated with circulatory collapse.

OBJECTIVE: To report a case of severe circulatory collapse following an intravenous injection of sodium valproate. CASE SUMMARY: A 5-year-old white girl, who was receiving vasopressor support, developed a severe circulatory collapse following an intravenous injection of valproate 480 mg. Her invasive arterial blood pressure dropped after valproate was started, and she went into cardiac arrest requiring full resuscitation including 2 doses of epinephrine. She was successfully resuscitated. DISCUSSION: To the best of our knowledge, this is the first case report of such severe circulatory collapse associated with intravenous valproate. Although hypotension has been reported following the use of intravenous valproate, severe circulatory compromise leading to cardiorespiratory arrest has not been previously described. An objective causality assessment using the Naranjo probability scale revealed that the adverse drug event was highly possible. CONCLUSIONS: In view of this patient's circulatory collapse associated with valproate, intravenous sodium valproate should be used with caution, particularly in hemodynamically unstable patients.

Child, Preschool↗

PubMed1988

The inducing and inhibiting effects of sodium valproate in vivo on the biotransformation systems of xenobiotics in isolated rat hepatocytes.

1. The induction and inhibition of some biotransformation enzymes by valproate have been studied in hepatocytes isolated from rats treated with sodium valproate either i.p. or by subcutaneous implantation of osmotic pumps. 2. When valproate was given i.p., the cytochromes P-450 and b5, and aldrin epoxidase and glutathione S-transferase activities were significantly induced. 3. In contrast, valproate administered by osmotic pumps induced 7-ethoxycoumarin-O-deethylase activity, whereas aldrin expoxidase and glutathione S-transferase activities were significantly inhibited. At a valproate serum concentration of about 100 micrograms/ml for 2 weeks a significant induction of the cytochromes P-450 and b5 was observed. 4. Since there is a large difference between the half-lives of valproate in man and rodent, constant-rate delivery of valproate represents a better model for induction studies than i.p. injection.

7-Alkoxycoumarin O-Dealkylase↗

PubMed2000

Serum valproate levels in 6 breastfeeding mother-infant pairs.

BACKGROUND: Women with bipolar disorder are at high risk for recurrence of an affective episode in the postpartum period, and treatment with a mood stabilizer may be indicated. Few data are available to inform the risk-benefit decision regarding the use of valproate for women with bipolar disorder who elect to breast-feed. METHOD: Serum valproate levels were obtained from 6 breastfeeding mother-infant pairs. All mothers had a diagnosis of bipolar disorder (Research Diagnostic Criteria) and were taking divalproex sodium as prophylaxis for or treatment of a recurrent affective episode. None of the mothers received valproate during pregnancy. RESULTS: The mothers had serum valproate levels near or within the therapeutic range (39.4 to 79.0 microg/mL). Infant serum levels were low, ranging from 0.7 to 1.5 microg/mL (0.9%-2.3% of maternal serum levels). No adverse clinical effects were observed in the infants. CONCLUSION: Serum valproate levels were low in nurslings of mothers treated with valproate. These data can be used to inform clinical decisions regarding the use of valproate during breastfeeding.

Age Factors↗

PubMed2004

[Efficacy and safety of antiepileptic therapy in children (a comparative analysis of valproates and barbiturates)].

The study aimed at a comparative analysis of safety and efficacy of valproic acid (valproate) and barbiturates in the treatment of epilepsy in children. Two hundred and forty children were treated with valproate, 94% being assigned to depakine and depakine chrono, and 210 children received barbiturates. Therapeutic effect (a decrease of seizures frequency by 2 and more times or remission) was detected in 82 of 127 (65 +/- 8.53%) patients for valproate monotherapy and only in 26 of 89 (30 +/- 9.45%) for barbiturates monotherapy. An efficacy of antiepileptic therapy in children was significantly higher (p<0.05) for valproates as compared to barbiturates. A drug withdrawal due to poor tolerability was recorded in 6 of 127 (5 +/- 3.7%) patients treated with valproate in monotherapy and in 14 of 210 (7 +/- 3.45%)--in polytherapy; in 53 of 89 (59 +/- 10.2%) patients treated with barbiturates in monotherapy and in 78 of 121 (65 +/- 8.53%) patients treated with barbiturates in polytherapy. Therefore, adverse effects occurred more often in barbiturates than in valproate treatment both for mono- and polytherapy (p<0.05). The results of the study confirmed the high efficacy and safety of valproates, specifically depakine chrono, in the treatment of epilepsy in children. depakine chrono in-take is associated with lower frequency of adverse effects; side-effects are mostly of dose-dependent character and do not result in the drug withdrawal. The authors do not recommend using barbiturates in the first-line treatment in children, because of the lower efficacy, high frequency of medical complications that might result in the drug withdrawal and reducing of the efficacy of other antiepileptic medications.

Adolescent↗

PubMed2006

Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania.

OBJECTIVE: Previous studies have suggested that oxidative stress may play a role in the pathophysiology of bipolar disorder (BD). Moreover, recent studies indicate that lithium and valproate exert neuroprotective effects against oxidative stress. We studied the effects of the mood stabilizers lithium and valproate on amphetamine-induced oxidative stress in an animal model of mania. METHODS: In the first model (reversal treatment), adult male Wistar rats received d-amphetamine or saline for 14 days, and between the 8th and 14th days, they were treated with lithium, valproate or saline. In the second model (prevention treatment), rats were pretreated with lithium, valproate or saline, and between the 8th and 14th days, they received d-amphetamine or saline. We assessed locomotor activity with the open-field task. We measured thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation, as parameters of oxidative stress, and superoxide dismutase (SOD) and catalase (CAT), the major antioxidant enzymes, in the prefrontal cortex and hippocampus. RESULTS: Lithium and valproate reversed (reversal treatment model) and prevented (prevention treatment model) amphetamine-induced hyperactivity and reversed and prevented amphetamine-induced TBARS formation in both experiments. However, the co-administration of lithium or valproate with amphetamine increased lipid peroxidation, depending on the brain region and treatment regimen. No changes in protein carbonyl formation were observed. SOD activity varied with different treatment regimens, and CAT activity increased when the index of lipid peroxidation was more robust. CONCLUSION: Our findings suggest that lithium and valproate exert protective effects against amphetamine-induced oxidative stress in vivo, further supporting the hypothesis that oxidative stress may be associated with the pathophysiology of BD.

Animals↗

PubMed1995

Valproate-associated pancreatitis and cholecystitis in six mentally retarded adults.

BACKGROUND: Pancreatitis is usually considered a rare side effect of valproate. We describe five cases of pancreatitis and one case of cholecystitis associated with the use of valproate. METHOD: Through chart review, we identified all patients in our facility treated with valproate between 1989 and 1994, and all cases of pancreatitis and cholecystitis identified during that same period in our population of 322 mentally retarded patients. We also searched MEDLINE for all published cases of pancreatitis or cholecystitis associated with valproate treatment. RESULTS: Five (7%) of 72 valproate-treated patients experienced pancreatitis, and one experienced cholecystitis; all recovered fully. This brings the total number of reported cases of valproate-associated pancreatitis to 55. CONCLUSION: Pancreatitis may occur more frequently than previously recognized in mentally retarded adults treated with valproate. Developmentally disabled patients should be carefully monitored for this potentially lethal side effect.

Adult↗

PubMed1996

The use of valproate in an elderly population with affective symptoms.

BACKGROUND: Little is known about the efficacy and tolerability of valproate in the elderly population with affective disorders. This pharmacoepidemiologic study was undertaken to determine the side effect profile and efficacy of valproate in an elderly population with psychiatric symptomatology. METHOD: This was a retrospective chart review of all elderly inpatients at McLean Hospital who received valproate between May 8, 1989, and May 8, 1992. Charts were reviewed to determine gender, discharge diagnosis, indication for the agent, and length of time on each medication. Charts were also reviewed for abnormalities in liver function tests, blood cell dyscrasias, sedation, nausea and vomiting, weight gain, impairment of cognition, tremor, and hair loss. The efficacy of the medication was also determined. RESULTS: Thirty-five elderly subjects who suffered from an affective disorder and who had received valproate were identified. The mean age was 71.3 years. The mean length of time the patient received valproate was 32.7 days. The mean dose was 743 mg/day, and the mean blood drug level was 52.9 mg/L. The valproate was rated as efficacious in 18 (62%) of the 29 patients who had had an adequate drug trial at discharge. Overall the medication was well tolerated. There were no reports of liver function test abnormalities. One patient experienced transient leukopenia. Other adverse events included two reports of nausea, two reports of sedation, and one complaint of confusion. None of the variables examined were found to be statistically significant in regard to efficacy. CONCLUSION: Valproate was well tolerated and efficacious in this elderly population with affective disorders. Further controlled studies are needed to confirm our results.

Affective Disorders, Psychotic↗

PubMed1998

Cerebral blood flow effects of sodium valproate in drug combinations in the baboon model.

Sodium valproate (CAS 1069-66-5, Epilim) has been used in the management of epilepsy during the last three decades. Although important information on the pharmacological actions and efficacy of sodium valproate has accrued to date, limited research has been conducted on its effects on cerebral blood flow. In recent years, with the aid of SPECT (single photon emission computed tomography) and PET (positron emission tomography) it has been shown that marked cerebral blood flow changes occur in epileptic patients. Furthermore it was established recently that sodium valproate influences the cerebral blood flow in children by decreasing the flow significantly. The present study investigated the effects of sodium valproate on the cerebral blood flow, using 99mTc-HMPAO (hexamethylpropylene amino oxime) and SPECT, in a primate model, as well as the effects of its drug interactions with therapeutic agents that influence cerebrovascular dynamics, e.g. sumatriptan, nimodipine and acetazolamide. The current study using single dose treatment with sodium valproate did not detect a decrease or increase of the cerebral blood flow when compared with control baseline results. Drug interaction between sodium valproate and nimodipine may occur as a reduction of 25% in cerebral blood flow from the baseline control was observed in this case. The effects observed for the combinations of sodium valproate respectively with sumatriptan and acetazolamide are attributed to the influences of the sumatriptan (decrease) and acetazolamide (increase) alone. The cerebral blood flow effects of these drugs and possible interactions during an acute epileptic seizure need to be investigated.

Acetazolamide↗

PubMed1996

Effect of valproate on cognitive functioning. Comparison with carbamazepine. The Department of Veterans Affairs Epilepsy Cooperative Study 264 Group.

OBJECTIVE: To assess the effects of carbamazepine vs valproate sodium on cognitive functioning in patients with epilepsy compared with normal control subjects. DESIGN: Patients with recently diagnosed, previously unmedicated seizures participated in a prospective randomized double-blind Department of Veterans Affairs multicenter study of the efficacy and toxicity of carbamazepine vs valproate. MAIN OUTCOME MEASURE: A behavioral toxicity battery was administered prior to treatment and again 6 and 12 months after the initiation of antiepileptic medication. RESULTS: There were no significant differences in the effect of carbamazepine vs valproate on motor speed and coordination, memory, or concentration and mental flexibility, and there was no significant decline in neuropsychological performance from pretreatment baseline levels for either drug. No significant differences in performance were found between patients with low (mean, 52.8 micrograms/mL) vs high (mean, 94.4 micrograms/mL) serum valproate levels within the therapeutic range. Patients treated with either carbamazepine or valproate did not show practice effects experienced by normal controls, a finding that may reflect a subtle compromise in cognitive functioning. CONCLUSION: The impact of carbamazepine and valproate monotherapy on cognitive functioning is similar: both drugs produce minimal negative effects compared with pretreatment baseline performance.

Adult↗

PubMed2000

Carbamazepine versus valproate monotherapy for epilepsy.

BACKGROUND: Carbamazepine and valproate are drugs of first choice for epilepsy. Despite the lack of hard evidence from individual randomized controlled trials, there is strong clinical belief that valproate is the drug of choice for generalized epilepsies and carbamazepine for partial epilepsies. OBJECTIVES: To overview the best evidence comparing carbamazepine and valproate monotherapy SEARCH STRATEGY: Our search strategy included: (a) MEDLINE 1966-99, (b) The Cochrane Library 1999 issue 4, (c) The trial register of the Cochrane Epilepsy Group (d) the pharmaceutical industry. SELECTION CRITERIA: Randomized controlled trials comparing carbamazepine and valproate monotherapy for epilepsy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcome measures were time to withdrawal of allocated treatment, time to 12 month remission, and time to first seizure post randomization. Data were analysed using the stratified Logrank test with results expressed as hazard ratios (HR) (95% CI), where HR>1 indicates an event is more likely on valproate. A test for an interaction between treatment and epilepsy type (partial versus generalized) was also undertaken. MAIN RESULTS: Results Data were available for 1265 patients from five trials, representing 85% of the patients recruited into the eight trials that met our inclusion criteria. The main overall results (HR 95% CI) were: Time to treatment withdrawal 0.97 (0.79-1.18), 12 month remission 0.87 (0.74-1.02), first seizure 1.09 (0.96-1.25) suggesting no overall difference for these outcomes. The test for an interaction between treatment and epilepsy type was non significant for time to treatment withdrawal and 12 month remission, but significant for time to first seizure. The age distribution of adults classified as having a generalized epilepsy indicate that significant numbers of patients may have had their epilepsy misclassified. REVIEWER'S CONCLUSIONS: We have found some evidence to support the policy of using carbamazepine as the first treatment of choice in partial epilepsies, but no evidence to support the choice of valproate in generalized epilepsies, but confidence intervals are too wide to confirm equivalence. Misclassification of patients may have confounded our results, and has important implications for the design and conduct of future trials.

Adult↗

PubMed2003

Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents.

BACKGROUND: Absence seizures are brief epileptic seizures which present in childhood and adolescence. They are characterised by sudden loss of awareness and an electroencephalogram (EEG) typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of anticonvulsant for a child with typical absence seizures. OBJECTIVES: To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures, when compared with placebo or each other. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register, the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 1, 2003), MEDLINE (January 1966 to March 2003) and EMBASE (1988 to March 2003). We also contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. SELECTION CRITERIA: Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with absence seizures: ethosuximide; sodium valproate; lamotrigine or placebo. DATA COLLECTION AND ANALYSIS: Outcome measures were: (i) proportion of individuals seizure free at 1, 6 and 18 months post randomisation; (ii) people with a 50% or greater reduction in seizure frequency; (iii) normalisation of EEG and/or negative hyperventilation test and (iv) adverse effects. Data were independently extracted by two reviewers. Results are presented as relative risks (RR) with 95% confidence intervals (95% CI). MAIN RESULTS: Four small trials were found, which were of poor methodological quality. One trial (29 participants) compared lamotrigine with placebo using a response conditional design. Individuals taking lamotrigine were significantly more likely to be seizure free than participants taking placebo during this short trial. Three studies compared ethosuximide, but because of diverse study designs and populations studied, we decided not to pool results in a meta-analysis. None of these studies found a difference between valproate and ethosuximide with respect to seizure control, but confidence intervals were wide and the existence of important differences could not be excluded. REVIEWER'S CONCLUSIONS: Although ethosuximide, lamotrigine and valproate are commonly used to treat people with absence seizures we have insufficient evidence to inform clinical practice, and the few trials included in this review were of poor methodological quality. More trials of better quality are needed.

Adolescent↗

PubMed2005

Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation.

BACKGROUND: Previous studies have suggested that both lithium and valproate may decrease phosphoinositol second messenger system (PI-cycle) activity. There is also evidence that dextroamphetamine may increase PI cycle activity. It was previously demonstrated that dextroamphetamine administration in volunteers causes a region and task dependent decrease in brain activation in healthy volunteers. The current study assessed the effect of 14 days pretreatment with lithium and valproate on these dextroamphetamine-induced changes in regional brain activity in healthy volunteers. METHODS: This was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n = 12), 900 mg lithium (n = 9) or placebo (n = 12). Functional images were acquired using functional magnetic resonance imaging (fMRI) while subjects performed three cognitive tasks, a word generation paradigm, a spatial attention task and a working memory task. fMRI was carried out both before and after administration of dextroamphetamine (25 mg). Changes in the number of activated pixels and changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after dextroamphetamine administration were then determined. RESULTS: In keeping with previous findings dextroamphetamine administration decreased regional brain activation in all three tasks. Pretreatment with lithium attenuated changes in the word generation paradigm and the spatial attention task, while pretreatment with valproate attenuated the changes in the working memory task. CONCLUSIONS: These results suggest that both lithium and valproate can significantly attenuate dextroamphetamine-induced changes in brain activity in a task dependent and region specific manner. This is the first human evidence to suggest that both lithium and valproate may have a similar effect on regional brain activation, conceivably via similar effects on PI-cycle activity.

Adult↗

PubMed1995

A model for estimating individualized valproate clearance values in children.

To evaluate the population pharmacokinetics of valproic acid in children, 97 steady-state serum valproate concentration measurements were gathered during normal, routine, outpatient care of 52 children with epilepsy (1.2-16 years of age). Levels were obtained from patients receiving valproate monotherapy (49%) or valproate with concomitant carbamazepine (32%), phenytoin (11%), or phenobarbitone (8%). A one-compartment model was used to fit the data with the Nonlinear Mixed Effects Model (NONMEM) computer program. The final model for clearance (L/hr) was CL = [EXP (0.022WT-1.38)] X M, where EXP = the base of the natural logarithm, WT = patient weight (kg) and M = a scaling factor for concomitant medication with a value of 1 for patients on valproate monotherapy and 1.61 for those receiving concomitant carbamazepine. Although phenytoin and phenobarbitone also were expected to increase valproate clearance, this could not be demonstrated, possibly because of the small number of samples taken from patients receiving these agents. Weight-adjusted values of valproate clearance decreased with increasing age. The actual mean value of 0.021 L/hr/kg for children taking monotherapy was slightly higher than values shown in most previously published reports, whereas the mean value of 0.028 L/hr/kg for patients taking concomitant carbamazepine was similar to those found previously in children taking other antiepileptic drugs.

Administration, Oral↗

PubMed1990

Teratogenic effects on the neuroepithelium of the CD-1 mouse embryo exposed in utero to sodium valproate.

A causal association has now been recognized between the use of the anticonvulsant drug sodium valproate during pregnancy and the increased incidence of spina bifida in the human population. The objective of this study was to investigate the teratogenic effects of sodium valproate on the cephalic 1) neuroepithelium, 2) extracellular matrix, and 3) embryonic protein content in the CD-1 mouse embryo. Nulliparous female CD-1 mice were dosed intraperitoneally on day 8 of gestation with 340 mg/kg of sodium valproate. On day 10 of gestation, females were killed by cervical dislocation, and all live embryos were assigned to one of the following groups and processed accordingly for: 1) head measurements, 2) scanning electron microscopy, 3) total protein determination, 4) two-dimensional polyacrylamide gel electrophoresis, 5) immunohistochemistry, and 6) light microscopy. Exposure to sodium valproate at the selected dosage resulted in a 30% incidence of neural tube defects in the cranial region of these embryos. Treated embryos showed a significant reduction in head size, indicating a drug-induced microcephaly. No major differences were seen in the total embryonic protein patterns between control and treated embryos. Immunoreactivity to laminin and fibronectin showed a similar distribution in control and treated embryos except in the vasculature pattern of the hindbrain neuroepithelium. The neuroepithelium of the treated embryos showed marked disorganization when it was examined histologically, particularly in the forebrain region. Cells were disoriented, and there was a noticeable loss of intercellular adhesion in the juxtaluminal region. Increased cellular blebbing was apparent at the ependymal surface, and large protrusions of cells were seen invading the neural tube lumen. The lumen was distorted in shape and frequently contained blood cells. Irregularities and gaps were observed in the underlying basal lamina. These results suggest that treatment with sodium valproate during a critical time in neurogenesis in the CD-1 mouse embryo alters the normal architecture of the neuroepithelium, with a loss of integrity at both the basal and apical surfaces. The alterations seen in the neuroepithelium at any of these sites in this animal model could help explain the increased incidence of spina bifida seen in children of epileptic mothers receiving sodium valproate.

Abnormalities, Drug-Induced↗

PubMed1992

Pharmacokinetics, anticonvulsant efficacy, and adverse effects of trans-2-en-valproate after acute and chronic administration in amygdala-kindled rats.

The trans isomer of 2-en-valproate (trans-2-en-VPA), an unsaturated metabolite of the clinically established antiepileptic valproate (VPA), was examined in the kindling model of epilepsy. As in the case of VPA, trans-2-en-VPA exerted potent anticonvulsant effects against partial seizures and secondarily generalized clonic seizures in amygdala-kindled rats after i.p. administration of acute doses. The anticonvulsant potency of trans-2-en-VPA appeared to be higher than that of VPA, especially in the case of secondarily generalized seizures. However, as previously reported for effects of valproate in the kindling model, trans-2-en-VPA exerted anticonvulsant effects against kindled seizures only at doses which were associated with motor impairment. Pharmacokinetic experiments with trans-2-en-VPA indicated non-linear kinetics with dose-dependent elimination rate and enterohepatic recirculation. According to the initial rapid decline in plasma concentrations of trans-2-en-VPA, the duration of anticonvulsant action in kindled rats was short-lasting so that an experimental protocol with 3 daily administrations was chosen for chronic experiments with this drug. During chronic treatment of kindled rats with 3 times daily injection of 100 mg/kg trans-2-en-VPA for 2 weeks, there was a marked reduction of anticonvulsant activity during the second week of treatment. This loss of anticonvulsant activity was not due to metabolic tolerance, i.e. reduction of drug levels by increased drug metabolism. Furthermore, additional experiments with altered experimental protocol indicated that the loss of anticonvulsant activity was not due to contingent tolerance, i.e. involvement of learning processes due to too frequent drug testing. However, the size of chronic treatment dose was important for the rate and degree of tolerance development, since an increase of dosage to 150 mg/kg 3 times daily resulted in significant anticonvulsant effects throughout the period of treatment with almost no indication of tolerance. The date indicate that trans-2-en-VPA is as effective as valproate in the kindling model. In view of previously reported experimental evidence that trans-2-en-VPA might have a lower hepatotoxic and teratogenic potential as valproate, the present study substantiates that trans-2-en-VPA might be an interesting alternative to valproate in antiepileptic therapy.

Amygdala↗

PubMed1994

Differential effects of vigabatrin, gamma-acetylenic GABA, aminooxyacetic acid, and valproate on levels of various amino acids in rat brain regions and plasma.

Drugs which elevate brain levels of the inhibitory amino acid neurotransmitter GABA by inhibiting the GABA catabolizing enzyme GABA transaminase (GABA-T) have been developed for treatment of brain disease, such as epilepsy. Among all GABA-T inhibitors available, vigabatrin is thought to be the most selective compound, and this drug is the only GABA-T inhibitor in clinical use. However, some previous studies have indicated that vigabatrin might affect the metabolism of several amino acids not directly linked to the GABA shunt. In the present study, various amino acids, involving inhibitory and excitatory neurotransmitters, were determined in 12 brain regions and plasma of rats after treatment with anticonvulsant doses of vigabatrin and the less selective GABA-T inhibitors aminooxyacetic acid (AOAA) and gamma-acetylenic GABA (GAG). Furthermore, the antiepileptic drug valproate, which is also thought to act via the GABA system, was included for comparison. The GABA-T inhibitors markedly enhanced GABA levels in all brain regions examined, while valproate induced only moderate increases in some regions. All drugs, including valproate, significantly decreased aspartate in the brain to a similar extent, and the GABA-T inhibitors but not valproate decreased levels of glutamate. The decreases in aspartate and glutamate levels were not correlated with the different magnitudes of GABA increase produced by GABA-T inhibitors, suggesting that these effects were not simply due to the altered GABA degradation. In addition to glutamate and aspartate, alanine levels were decreased by GABA-T inhibitors but not valproate in several regions. Brain levels of glutamine were decreased by GAG and vigabatrin but increased by valproate and partly also by AOAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkynes↗

PubMed1991

"In vivo" administration of valproate decreases t-[35S]butylbicyclophosphorothionate binding in the rat brain.

The effect of the "in vivo" administration of sodium valproate on t-[35S]butylbicyclophosphorothionate (35S-TBPS) binding measured "ex vivo" in the rat cerebral cortex was investigated. Sodium valproate produced a decrease of 35S-TBPS binding. The maximal effect (-32%) was reached with the dose of 400 mg/kg i.p., 60 min after the administration of the drug. Saturation experiments revealed that the effect of sodium valproate was due to a decrease in the total number of binding sites with no changes in the affinity constant. A small dose of diazepam (0.5 mg/kg, i.p.), which per se does not modify 35S-TBPS binding, markedly potentiated the inhibitory effect of sodium valproate on 35S-TBPS binding. Moreover, the "in vitro" addition of sodium valproate to cortical membranes failed to modify 35S-TBPS binding, indicating that the effect of the "in vivo" administration of this drug is not due to its direct interaction with the chloride associated binding sites. These results strongly suggest that this drug enhances the function of GABAergic synapses at the level of the GABA-coupled chloride channel. This conclusion supports the hypothesis that an enhancement of GABAergic transmission plays a role in the molecular mechanism involved in the antiepileptic action of sodium valproate.

Animals↗

PubMed1984

Sodium valproate: effects on social behaviour and physical development in the mouse.

Sodium valproate given in drinking fluid at 600 mg/l (160-180 mg/kg daily) to breeding mice did not affect fertility, birth weights or physical development of pups. Postnatal and postweaning administration of this dose also had no effects upon development or weight gain. The offspring ingested 103-158 mg/kg valproate daily after weaning. Behaviour was examined in a neutral enclosure by ethological methods. Offspring exposed to valproate in utero and throughout postnatal life showed no behavioural changes at 5 weeks, although at 15 weeks Immobility was reduced in females and Social Investigation increased. At 25 weeks when encountering mice of the opposite sex, treated males showed increase in Social Investigation and treated females increases in Other Non-social Activity. Postnatal and postweaning treatment with valproate caused behavioural changes both in juveniles and adults. After postnatal exposure, reduced Immobility with increased Social Investigation and Explore and Scan occurred at 5 and 15 weeks, at 25 weeks valproate increased Social Investigation in males encountering females and at 30 weeks enhanced Aggression in pair-housed males. Stimulation of Social Investigation was the only significant behavioural effect after postweaning exposure. Overall valproate appears to enhance behaviour stimulated by the test situation; urinary pheromones do not appear to play a part in this behavioural action.

Animals↗