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PubMed1994

[Value of sodium valproate in the treatment of partial epilepsy].

There seems no doubt, in reviewing the literature from controlled randomized studies, that valproate is effective in the treatment of partial epilepsy. There is unanimity amongst a number of large comparative studies that valproate seems as effective as carbamazepine in suppressing secondarily generalized seizures. Controlled studies that have used minimum doses of carbamazepine or valproate in previously untreated patients with partial epilepsy have not suggested that the outcomes with the two drugs are significantly different; however, a Veterans Administrations Study which included over 200 patients who had been previously treated with other antiepileptic drugs suggested the possibility that carbamazepine might be somewhat more effective in suppressing complex partial seizures than valproate. In practice the choice between the two current first-line antiepileptic drugs (carbamazepine and valproate) would seem to be determined by their different adverse effect profiles. Valproate is better tolerated in the shorter term because of the absence of idiosyncratic skin reactions, whilst those patients who tolerate carbamazepine initially may have fewer long-ferm problems and seem less prone to develop weight gain than patients treated with sodium valproate. For patients presenting with seizures that cannot easily be classified, valproate would seem to be the drug of choice because of its broader spectrum of antiepileptic drug activity.

Adolescent↗

PubMed1991

Valproate in the treatment of acute mania. A placebo-controlled study.

We conducted a placebo-controlled, double-blind study of valproate, a drug originally developed as an antiepileptic, in 36 patients with acute manic episodes who had previously failed to respond to or to tolerate lithium carbonate. Treatment duration was 7 to 21 days, with no other psychotropic medications permitted except lorazepam up to 4 mg/d during the first 10 days of treatment. Serum valproate concentrations were measured three times weekly; an unblinded investigator then adjusted dosage to produce serum concentrations between 50 and 100 mg/L. Valproate proved superior to placebo in alleviating manic symptoms. The 17 patients randomized to active drug demonstrated a median 54% decrease in scores on the Young Mania Rating Scale as compared with a median 5.0% decrease among the 19 patients receiving placebo. On the 100-point Global Assessment Scale of overall psychiatric functioning, patients receiving valproate improved by a median of 20 points as compared with a zero-point change with placebo. Significant differences also emerged on the Brief Psychiatric Rating Scale and in the number of supplemental doses of lorazepam required by the patients in each group. Substantial antimanic effects appeared within 1 to 4 days of achieving therapeutic serum valproate concentrations. Adverse effects were infrequent, with no adverse effect appearing significantly more frequently with valproate than with placebo. We conclude that valproate represents a useful new drug for the treatment of manic patients.

Acute Disease↗

PubMed2001

Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures.

BACKGROUND: Phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset (simple partial, complex partial and secondary generalized tonic-clonic seizures) seizures whilst valproate is more effective in generalized onset seizures (generalized tonic-clonic seizures, absence, myoclonus) although there is no evidence from randomized controlled trials to support this belief. The use of individual patient data meta-analysis enabled us to examine time to event outcomes which are important in epilepsy monotherapy trials, and also to examine treatment-covariate interactions. OBJECTIVES: To review the best evidence comparing phenytoin and valproate when used as monotherapy in subjects with partial onset seizures, or generalized onset tonic-clonic seizures with or without other generalized seizure types. SEARCH STRATEGY: Our search strategy included: (i) the Cochrane Epilepsy Group trial register, (ii) MEDLINE 1966-2000, (iii) hand-searching relevant journals, (iv) the pharmaceutical industry, and (v) researchers in the field. SELECTION CRITERIA: Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenytoin monotherapy with valproate monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to (i) withdrawal of allocated treatment, (ii) 12 month remission, (iii) six month remission, and (iv) first seizure post randomization. Data were analysed using stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely on phenytoin. A test for interaction between treatment and seizure type (partial onset versus generalized onset) was also undertaken for each outcome. MAIN RESULTS: Data were available for 669 subjects from five trials, representing 60% of the subjects recruited into the eleven trials that met our inclusion criteria. One important limitation of these data is that in four of the five trials, for patients classified as having generalized onset seizures, tonic-clonic seizures were the only seizure types recorded at follow up, despite the fact that some patients will have been experiencing other generalized seizure types such as absence or myoclonus. Their results for the generalized seizures therefore relate only to generalized onset tonic-clonic seizures. The main overall results were as follows (HR(95% CI), HR>1 indicates a clinical advantage for phenytoin for both remission outcomes and a clinical advantage for valproate for the outcomes time to withdrawal and time to first seizure) (i) time to withdrawal of allocated treatment 1.10(0.79-1.54), (ii) time to 12 month remission 1.04(0.78-1.38), (iii) time to six month remission 0.89(0.71-1.11), and (iv) time to first seizure 0.92(0.74-1.14). The results suggest no overall difference between drugs for these outcomes. The test for an interaction between treatment and seizure type (generalized versus partial onset) was non significant for all outcomes. REVIEWER'S CONCLUSIONS: We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. As generalized seizures such as absence and myoclonus were counted in only one trial, results do not address the treatment of these seizure types. We found no unequivocal evidence to overthrow or support the policy of using valproate in generalized onset tonic-clonic seizures and phenytoin in partial onset seizures.

Anticonvulsants↗

PubMed2005

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's Specialised Register (March 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to March 2005) and EMBASE (1988 to March 2005). No language restrictions were imposed. In addition, we 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: (1) proportion of individuals seizure free at 1, 3, 6, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as relative risks (RR) with 95% confidence intervals (95% CI). MAIN RESULTS: Five small trials were found, four of them 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. Another trial compared lamotrigine with sodium valproate, the study lacked power to detect the difference in efficacy. 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. AUTHORS' 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 and did not have sufficient number of participants. More trials of better quality are needed.

Adolescent↗

PubMed1996

Obesity and endocrine disorders in women taking valproate for epilepsy.

We recently reported the frequent occurrence of polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy, especially when the medication was started before the age of 20 years. In the present study we evaluated the association of obesity and hyperinsulinemia with valproate-related polycystic ovaries and hyperandrogenism in women with epilepsy. Sixty-five women participated in the study. Twenty-two received valproate monotherapy and 43 received carbamazepine monotherapy. In addition to clinical examination, vaginal ultrasonography was performed to determine ovarian size, and the concentrations of serum sex hormones, insulin, insulin-like growth factor 1, and the insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) were measured. Fifty-nine percent of the women on valproate were obese, and in a retrospective analysis an indisputable weight gain (mean, 21 kg; range, 8-49 kg) was found in 50% of the women taking valproate. Fourteen (64%) of the women on valproate had polycystic ovaries, hyperandrogenism, or both. These women were obese, and in addition to elevated serum androgen levels, they had high concentrations of fasting serum insulin and low levels of serum insulin-like growth factor-binding protein 1. Valproate therapy for epilepsy is associated with weight gain during treatment in approximately 50% of women patients. The weight gain can be progressive, and is associated with hyperinsulinemia and low serum levels of insulin-like growth factor-binding protein 1, which may lead to hyperandrogenism and polycystic ovaries.

Adult↗

PubMed2006

Valproate enhances imatinib-induced growth arrest and apoptosis in chronic myeloid leukemia cells.

BACKGROUND: The objective of this study was to evaluate the ability of the clinically available histone deacetylase (HDAC) inhibitor valproate to enhance the cytotoxicity of the Bcr-Abl inhibitor imatinib in imatinib-resistant cell lines. METHODS: Interactions between imatinib, and valproate have been examined in imatinib-sensitive and -resistant chronic myeloid leukemia (CML)cell lines (K562, KCL-22, CML-T1) and in bone marrow mononuclear cells (MNCs) derived from imatinib-resistant CML patients. RESULTS: In imatinib-sensitive cell lines, cotreatment with imatinib 0.5 muM and valproate 5 microM for 48 hours potently enhanced imatinib-induced growth arrest and apoptosis. In resistant cell lines and in primary MNCs derived from imatinib-rsistant patients, valproate restored sensitivity to the cytotoxic effects of imatinib. Coexposure of cells to valproate and imatinib was associated with repression of several genes involved in Bcr-Abl transformation. In particular, the combination valproate-imatinib downregulated the expression of Bcr-Abl and the antiapoptotic protein Bcl-2, which is particularly overexpressed in imatinib-resistant clones. CONCLUSIONS: Data from this study suggested that administration of the clinically available HDAC inhibitor valproate may be a powerful strategy to enhance cytotoxic effects of imatinib in those patient resistant to imatinib or in which complete cytogenetic remission has been not reached.

Antineoplastic Agents↗

PubMed2005

Differential effects of chronic lithium and valproate on brain activation in healthy volunteers.

RATIONALE: Previous functional imaging studies have shown altered brain activity during cognitive task performance in bipolar patients. However, the fact that these patients are often on medication makes it unclear to what extent these changes reflect treatment effects. OBJECTIVES: This study aims to identify regional brain activity changes occurring following lithium and valproate treatment 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 14 days of treatment with valproate, lithium or placebo. The changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after treatment were compared between the groups using a one-way ANOVA for each task followed by a post-hoc multiple comparisons correction. RESULTS: A significant group effect was noted in the change in BOLD signal magnitude from baseline to post-treatment, in all three tasks (working memory p< 0.000; spatial attention task p = 0.003; word generation paradigm p = 0.030). In the working memory task, the lithium group had a significant decrease in BOLD signal change, compared with the control group (p< 0.000). A decrease in BOLD signal change was also noted in the valproate group, in the spatial attention task (p = 0.004). Both lithium and valproate groups had a decreased BOLD signal in the verbal task, following treatment, compared with the placebo group (p = 0.061 (lithium approached significance); p = 0.050 (valproate)). CONCLUSIONS: These findings suggest that lithium and valproate have independent effects on brain activation that vary in a task and region-dependent manner.

Adult↗

PubMed2005

Sodium valproate inhibits glucose transport and exacerbates Glut1-deficiency in vitro.

Anticonvulsant sodium valproate interferes with brain glucose metabolism. The mechanism underlying such metabolic disturbance is unclear. We tested the hypothesis that sodium valproate interferes with cellular glucose transport with a focus on Glut1 since glucose transport across the blood-brain barrier relies on this transporter. Cell types enriched with Glut1 expression including human erythrocytes, human skin fibroblasts, and rat astrocytes were used to study the effects of sodium valproate on glucose transport. Sodium valproate significantly inhibited Glut1 activity in normal and Glut1-deficient erythrocytes by 20%-30%, causing a corresponding reduction of Vmax of glucose transport. Similarly, in primary astrocytes as well as in normal and Glut1-deficient fibroblasts, sodium valproate inhibited glucose transport by 20%-40% (P < 0.05), accompanied by an up to 60% downregulation of GLUT1 mRNA expression (P < 0.05). In conclusion, sodium valproate inhibits glucose transport and exacerbates Glut1 deficiency in vitro. Our findings imply the importance of prudent use of sodium valproate for patients with compromised Glut1 function.

Animals↗

PubMed1993

Valproate and sodium currents in cultured hippocampal neurons.

Cultured rat hippocampal neurons with short processes were investigated using the whole cell voltage clamp under conditions appropriate for isolating Na+ currents. After incubation of the neuron culture for a period of 15-30 min in 1 mM sodium valproate, several parameters of the Na+ current were changed. The peak Na+ conductance gp, measured using hyperpolarizing prepulses, was reduced by valproate in a voltage-dependent manner. In the membrane voltage range from -30 to +20 mV, this reduction showed a linear dependence on voltage, increasing from about zero to approximately 30% of gp, the maximum peak Na+ conductance of the neuron. At the holding voltage of -70 mV, the inactivation parameter h infinity decreased from 0.88 in the control to 0.64 in the valproate solution. This reduction originated mainly from a 10 mV shift in the sigmoid relation between h infinity and membrane voltage along the voltage axis to hyperpolarizing potentials. The decay of the maximum peak Na+ current (inactivation) could be fitted by a biexponential function. Time constants of the fast and slow component at -20 mV decreased in valproate by about 50%. Valproate also retarded the recovery from inactivation, as determined at the holding voltage. The sigmoid recovery from inactivation could reasonably be described by an exponential function with time constant tau r and delay time delta t. Both tau r and delta t increased more than 200% in valproate. Our results indicate that valproate affected the Na+ current in hippocampal neurons in a way that contributed to a considerable depression of Na+ reactivation.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1981

Effect of sodium valproate on motor function regulated by the activation of GABA receptors.

Sodium valproate is an anticonvulsant which elevates GABA levels in the brain. GABA interacts with dopamine functionally in certain areas of the brain involved in motor behavior such as the nucleus accumbens and the substantia nigra. In order to determine whether GABA can play a functional role in the pharmacological effects of valproate, both valproate and GABA were injected directly into these two brain areas and the effects of these compounds on motor function were studied. Both GABA and sodium valproate inhibited in a dose dependent manner the hyperactivity induced by the bilateral injection of dopamine into the nucleus accumbens. Picrotoxin, a GABA antagonist, blocked the inhibitory effect of valproate. When injected into the pars reticulata of the substantia nigra, both sodium valproate and GABA enhanced apomorphine-induced circling in rats with a unilateral lesion of lateral hypothalamus caused by 6-hydroxydopamine. This effect was blocked by the systemic administration of picrotoxin. These observations suggest that sodium valproate can produce effects that result from the activation of GABA receptor sites in the brain.

Animals↗

PubMed1993

Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain.

Valproate is currently one of the major antiepileptic drugs in clinical use. Because of its wide spectrum of anticonvulsant activity against different seizure types, it has repeatedly been suggested that valproate acts through a combination of several mechanisms. As shown in this review, there is substantial evidence that valproate increases GABA turnover and thereby potentiates GABAergic functions in some specific brain regions, such as substantia nigra, thought to be involved in the control of seizure generation and propagation. Furthermore, valproate seems to reduce the release of the epileptogenic amino acid gamma-hydroxybutyric acid and to block cell firing induced by NMDA-type glutamate receptors. In addition to effects on amino acidergic neurotransmission, valproate presumably exerts a direct action on ion channels, thereby limiting sustained repetitive neuronal firing. Recent microdialysis data suggest that valproate also alters dopaminergic and serotonergic functions. These diverse effects of valproate might explain why the drug not only exerts anticonvulsant activity but also other pharmacodynamic and pharmacotherapeutic actions, such as antipsychotic and antidystonic efficacy.

Amino Acids↗

PubMed1992

Pharmacokinetics of valproate in pregnancy: mother-foetus-newborn.

An increased risk of seizures during and immediately after labour has been observed in epileptic women, and it is recognized that serum levels of antiepileptic drugs may decrease in pregnancy. Several studies have suggested that total valproate levels fall, but that free fractions increase during pregnancy. Recent findings suggest that the actual metabolism of valproate is not altered by pregnancy and that the changes of the plasma clearance are due primarily to decreased protein binding. The levels of free drug will not change significantly as pregnancy advances. However, dose reduction after delivery may be necessary to avoid toxicity. Valproate and its metabolites undergo placental transfer. In the foetus the plasma level of valproate and the protein binding are higher than in maternal plasma, and the half-life of valproate following placental transfer is considerably longer than in adults. Only small amounts of valproate appear in breast milk and those are not likely to cause any problems. During pregnancy and the first month after delivery preferably both total and free valproate serum levels should be closely monitored to determine the lowest effective dose.

Anticonvulsants↗

PubMed1999

Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal symptoms and taper outcome.

Recent uncontrolled research suggested that trazodone and sodium valproate may be helpful in benzodiazepine (BZ) discontinuation. We therefore undertook a double-blind study to assess whether trazodone and valproate, as compared to placebo, would attenuate withdrawal and facilitate discontinuation in BZ-dependent patients with a minimum of 1 year daily BZ use. Seventy-eight patients, taking a mean dose of 19+/-17 mg/day of diazepam (or its equivalent), were stabilized for several weeks on their BZ (16 diazepam, 25 lorazepam, 37 alprazolam) and then for 1-2 weeks, pretreated with trazodone, sodium valproate or placebo before being tapered at 25% per week. All treatments were continued for 5 weeks post-taper. BZ-free status was assessed after 5 and 12 weeks post-taper. Neither trazodone nor valproate had any significant effect on withdrawal severity. Peak physician withdrawal checklist change from baseline to peak severity was 16.4 for trazodone, 18.04 sodium valproate and 18.24 placebo (F = 0.10; NS). Taper success rates were significantly effected by both active agents at the 5-week, but not 12-week, assessment. At 5 weeks post-taper, 79% of sodium valproate and 67% of trazodone, but only 31% of placebo patients were BZ-free (chi2 = 7.34; df 2; P<0.03). Major adverse events for trazodone were sedation and dry mouth, and for valproate, diarrhea, nausea and headaches.

Adult↗

PubMed1988

Comparison of monotherapy with valproate and other antiepileptic drugs in the treatment of seizure disorders.

Comparative data strongly suggest that valproate is the drug of choice for patients with primary and secondarily generalized epilepsies and that it is as effective as other antiepileptic drugs in the treatment of less clearly defined or partial epilepsies beginning in adult life. In simple absence epilepsy, several studies found no significant difference in efficacy between valproate and ethosuximide. In all primary generalized epilepsies, valproate has in many studies produced an excellent response, with one comparative study showing that valproate was as effective as phenytoin. Infantile spasms responded as well to valproate as to adrenocorticotropic hormone in several studies, while valproate produced fewer side effects. More long-term studies designed to compare the efficacy of monotherapy with valproate with that of other antiepileptic drugs are needed, and several are underway in both Europe and the United States.

Anticonvulsants↗

PubMed1988

Pharmacologic interactions between valproate and other drugs.

Valproate is often administered with other antiepileptic drugs, a practice that can lead to clinically significant pharmacologic interactions. Concomitant administration of such enzyme-inducing antiepileptic drugs as carbamazepine, phenobarbital, primidone, or phenytoin will markedly accelerate the metabolic conversion of valproate, particularly in children. In response to the effects of enzyme induction, valproate dosage may need to be doubled to maintain therapeutic serum levels. Valproate does not appear to induce enzymatic drug metabolism, but rather acts as a metabolic inhibitor. Because of this inhibition, phenobarbital dosage must often be reduced after valproate is added to the therapeutic regimen. Valproate also may markedly increase concentrations of the active epoxide metabolite of carbamazepine. The interaction between phenytoin and valproate results primarily from displacement from plasma proteins. The resulting increase in the free fraction of phenytoin alters the relationship between total phenytoin concentration and the drug's pharmacologic effect. Thus, clinical evidence of toxicity may be present at concentrations usually considered to be in the therapeutic range.

Anticonvulsants↗

PubMed1981

Effect of sodium valproate on hypothalamic neurons in vivo and in vitro.

The effects of sodium valproate on extracellularly recorded spontaneous neuronal activity and its interaction with GABA-induced inhibition were assessed in the rat medial basal hypothalamus both in situ and in explant culture. In situ, valproate enhanced the spontaneous rate in 14 of 20 neurons sampled, 6 neurons were unaffected. In vitro, valproate had an inconsistent effect on firing rate; the spontaneous rate was decreased in 6 cells, elevated in 1, while 17 either were unchanged or demonstrated no consistent pattern of response. Both in vivo and in vitro, valproate produced a variable effect on GABA induced inhibition. In vivo, the modal response of valproate on GABA inhibition was antagonism whereas the response in vitro was less consistent, favoring no change in GABA inhibition. The results of this study suggest that valproate exerts an inconsistent action on hypothalamic neurons. These findings are in contrast to those from the cerebral cortex, suggesting that the action of valproate in the brain may be regionally specific.

Animals↗

PubMed1992

Kindled rats are more sensitive than non-kindled rats to the behavioural effects of combined treatment with MK-801 and valproate.

The effects of combined treatment with low doses (0.025-0.05 mg/kg i.p.) of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. MK-801, 0.05 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 100 mg/kg i.p. However, the increase in anticonvulsant activity was paralleled by a marked increase in adverse effects such as motor impairment and hyperactivity, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, MK-801 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. Combined treatment with MK-801 and valproate induced much less marked adverse effects in non-kindled rats than in kindled rats. The competitive NMDA receptor antagonist, CGP 37849 1 mg/kg i.p., did not alter the effects of valproate in kindled rats. The data on combined treatment with MK-801 and valproate substantiate the conclusion that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events.

2-Amino-5-phosphonovalerate↗

PubMed1993

Competitive antagonists of NMDA receptors, CGP 37849 and CGP 39551, enhance the anticonvulsant activity of valproate against electroconvulsions in mice.

Two novel N-methyl-D-aspartic acid (NMDA) competitive antagonists, CGP 37849 (1.25 and 2.5 mg/kg) and CGP 39551 (10 mg/kg), significantly raised the threshold for electroconvulsions in mice. CGP 37849 in doses of 0.125-1.0 mg/kg and CGP 39551 in doses of 0.625-5 mg/kg i.p. considerably potentiated the protective activity of magnesium valproate against maximal electroshock-induced convulsions. The anticonvulsant activity of sodium valproate was potentiated by CGP 37849 (1 mg/kg) to a similar degree, which suggests that magnesium is not involved in the observed interaction. Neither CGP agent influenced the plasma level of valproate, so a pharmacokinetic interaction, in terms of total plasma levels, is not probable. Furthermore, the performance of mice injected with magnesium valproate (91 mg/kg) and CGP 37849 (0.25 mg/kg), which provided 50% protection against maximal electroshock-induced convulsions, in the long-term memory test and chimney test did not differ significantly from that of the control animals. The combination of magnesium valproate and CGP 39551 had a neurotoxic potential comparable to that of valproate alone. The results suggest that a combined treatment of valproate and some competitive NMDA antagonists may be important from a clinical point of view.

2-Amino-5-phosphonovalerate↗