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PubMed2000

[Valproic acid in prophylaxis of bipolar disorder. A case of valproate-induced encephalopathy].

A 28-year-old patient with a 5-year history of bipolar disorder developed signs of encephalopathy 2 weeks after the addition of valproic acid to his treatment regimen of doxepine, risperidone, and biperidene. The clinical signs were drowsiness, ataxic gait, asterixis, and a generalized epileptic seizure. Discontinuation of valproic acid gradually resulted in complete remission of these symptoms. Valproate encephalopathy has been described mainly in patients receiving anticonvulsant polytherapy. This complication might become more prevalent in psychiatric pharmacotherapy due to the increasing use of valproic acid.

Adult↗
PubMed2005

Effects of combined lamotrigine and valproate on basal and stimulated extracellular amino acids and monoamines in the hippocampus of freely moving rats.

The antiepileptic drugs sodium valproate (VPA) and lamotrigine (LTG) are increasingly used in combination in patients in whom monotherapy has failed to control seizures. Although these drugs are known to interact pharmacokinetically, several authors have proposed a pharmacodynamic interaction between the two. In order to investigate this we have studied the effects of combined treatment with LTG and VPA on basal and stimulated extracellular aspartate (ASP), glutamate (GLU), taurine (TAU), gamma amino butyric acid (GABA), 5-hydroxytryptamine (5-HT) and dopamine (DA) release in the hippocampus of freely moving rats using microdialysis. Additionally, we measured the possible effect of VPA on LTG in plasma, whole brain and dialysates. Neither LTG (10 mg/kg) nor VPA (300 mg/kg) given alone significantly altered basal levels of ASP, GLU or TAU. When given together, however, the two drugs significantly reduced extracellular ASP and GLU while increasing TAU levels. In the case of GABA, LTG was without effect on basal levels of the transmitter, but these increased following VPA and this persisted with both drugs. When transmitter release was stimulated by 50 muM veratridine, marked increases in the release of all amino acids occurred and this was decreased by LTG in all cases. VPA alone only altered GABA release, increasing it by approximately the same extent as basal GABA. For all of the amino acids studied, however, VPA reversed the decreases in release seen after LTG. VPA and LTG increased and decreased respectively basal 5-HT and DA. When given together the increase in extracellular 5-HT was greatly prolonged, but no effect on DA release was seen. When 5-HT release was evoked by veratridine this was increased by VPA and no other treatment. With DA, however, neither drug alone altered evoked release, but the two combined led to a marked increase. Co-administration of VPA with LTG showed no significant effect of this combination on LTG in any of the three compartments studied indicating that in this case a significant pharmacokinetic contribution to our findings is unlikely, which suggests that there is a probable pharmacodynamic interaction of the two drugs.

Animals↗
PubMed2006

Valproate blocks high-dose methamphetamine-induced behavioral cross-sensitization to locomotion-inducing effect of dizocilpine (MK-801), but not methamphetamine.

RATIONALE: Our group has recently shown that methamphetamine (METH) (2.5 mg/kg) induced delayed increases in glutamate (Glu) levels in the rat nucleus accumbens (NAC), and that its repeated administration leads to behavioral cross-sensitization to a selective uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). OBJECTIVES: The present study aims to examine whether valproate (VPA) would inhibit the delayed increases in Glu levels and prevent METH (2.5 mg/kg)-induced behavioral cross-sensitization to MK-801 (0.2 mg/kg). MATERIALS AND METHODS: We examined the effects of post-treated VPA (50 mg/kg) on METH (2.5 mg/kg)-induced delayed increases in Glu levels. We injected VPA (50 mg/kg) at 120 min after each METH (2.5 mg/kg, once every other day, total of five times) administration and measured locomotor activity induced by challenge with MK-801 (0.2 mg/kg) or METH (0.15 mg/kg) after sufficient withdrawal period. Finally, we measured locomotion induced by MK-801 (0.2 mg/kg) after pretreatment of a competitive NMDA receptor antagonist, CPP (30 mg/kg). Effects of VPA on extracellular Glu levels were examined by using in vivo microdialysis. Locomotor activity was measured by using an infrared sensor. RESULTS: VPA administered 120 min after METH injection had no effect on METH-induced hyperlocomotion, and inhibited METH-induced delayed increases in Glu levels. Repeated VPA administration prevented METH-induced behavioral cross-sensitization to MK-801, but not sensitization to METH. MK-801-induced hyperlocomotion was enhanced when pretreated with the competitive NMDA receptor antagonist, CPP. CONCLUSIONS: These results suggest that VPA inhibits high-dose METH-induced delayed increases in Glu levels to prevent development of behavioral cross-sensitization to an NMDA antagonist, but not sensitization to METH.

Animals↗
PubMed2000

Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder.

RATIONALE: Search for alternatives to lithium therapy for mood disorders commenced with anticonvulsants, carbamazepine (CBZ) and valproic acid (VPA), in the late 1970s. The comparative safety and efficacy data of CBZ and VPA monotherapy in patients with bipolar disorder remain to be established. OBJECTIVES: The main objectives of the study were to assess the relative antimanic efficacy and safety of CBZ and VPA; to study the feasibility of using either, as a first line anti-manic agent; to investigate and generate clinically relevant parameters involving therapeutic drug monitoring of the two drugs. METHODS: After a 2-day screening period, suitable patients (n = 30) were randomly assigned to treatment with CBZ or VPA. Both the drugs were started with an average dose of approximately 20 mg/kg body weight per day. Further increment in dose was carried out at weekly intervals, guided by clinical improvement, serum levels and treatment emergent adverse events. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. A favourable clinical response was defined a priori as a decrease of more than 50% from baseline in Young Mania Rating Scale total score. RESULTS: Both CBZ and VPA were found to be efficacious as single first-line anti-manic agents, however VPA proved to be better. Using the intent-to-treat analysis, the VPA group showed a significant fall in YMRS total scores after week 1 while the CBZ group showed a significant fall after week 2. In the primary efficacy analysis, valproate group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the CBZ group. Of the VPA treated patients, 73% showed a favourable clinical response while 53% of the patients on CBZ responded favourably. In the CBZ group, significantly more patients received rescue medication during the week 2 and the requirement was quantitatively more as compared to the VPA group. The steady state serum concentration (Css) of CBZ ranged from 3 to 9 micrograms/ml; however, it did not appear to correlate with the dose or clinical response. The Css of VPA ranged from 50 to 100 micrograms/ml; a linear correlation was found between the dose and serum levels of VPA as well as between weekly rise in serum levels and clinical response. Weekly dose escalations of VPA also correlated positively with corresponding rise in serum levels. Significantly more patients in the CBZ group reported adverse events, including nausea, vomiting and dizziness, than VPA. CONCLUSIONS: The findings from this study suggest that both CBZ and VPA monotherapy is feasible for treatment of acute mania; however, VPA is more efficacious in terms of its early onset of action, lesser requirement for rescue medication and better tolerability. Further work needs to be undertaken to characterise the manic patients in terms of their differential psychopharmacologic response profile.

Adolescent↗
PubMed2000

Steady-state dispositions of valproate and diflunisal alone and coadministered to healthy volunteers.

OBJECTIVE: The effects of coadministration of the non-steroidal anti-inflammatory drug diflunisal (DF) on glucuronidation and beta-oxidation of the antiepileptic agent valproic acid (VPA), and of VPA on DF glucuronidation, were studied in human volunteers. METHODS: Seven healthy male volunteers received sodium valproate (NaVPA, 200 mg) orally twice daily for 7 days, after which all drug intake ceased for 1 month. The volunteers then took DF (250 mg) orally twice daily for 7 days. Both drugs were then taken (at the same doses as previously) twice daily for 7 days. On day 7 of each dosing phase, serial blood samples and all urine passed over the 12-h inter-dosing interval were collected. VPA, DF and selected metabolites were analysed using validated methods. Statistical comparisons of pharmacokinetic parameters were made using paired Student's t-tests. RESULTS: Mean plasma concentrations of total VPA were lower and apparent plasma clearances significantly higher during DF coadministration. This was associated with a significant 20% increase in the unbound fraction of VPA (from 6.6+/-1.3% to 7.9+/-1.8%). The apparent clearance of unbound VPA was not different. There was no evidence of any significant effect of DF coadministration on VPA metabolism: urinary recoveries of and formation clearances to urinary VPA-glucuronide, E-2-en-VPA, 3-oxo-VPA and 4-en-VPA were not significantly altered. However, there was a highly significant 35% increase in the area under the plasma concentration-time curve from 0-12 h (AUC0-12h) of 3-oxo-VPA and its renal clearance was lower, though not significantly so. VPA coadministration had no effect on DF pharmacokinetics or formation clearances of DF to its acyl glucuronide (DAG), phenolic glucuronide (DPG) or sulfate (DS) conjugates. However, plasma AUC0-12h values of the glucuronides were significantly lower and their renal clearances higher (though significantly so only in the case of DPG) during VPA coadministration. CONCLUSIONS: Steady-state coadministration of VPA and DF leads to a significant displacement of VPA from plasma protein binding sites. There was no evidence of competition for glucuronidation capacity or other metabolic interactions. Rather, the interactions detected appeared to be renal in nature, with renal clearance of 3-oxo-VPA being reduced by DF coadministration, and renal clearance of DPG and perhaps DAG being increased by VPA coadministration.

Adult↗
PubMed2002

Non convulsive status epilepticus after replacement of valproate with lamotrigine.

PURPOSE: Lamotrigine (LTG) and valproate (VPA) are widely used in the treatment of generalized epilepsies. Nevertheless seizure aggravation with LTG has been reported in juvenile myoclonic epilepsy and epilepsy with myoclonic absences. The aim of this study was to describe clinical features and EEG findings in patients with non convulsive status epilepticus (NCSE) after replacement of VPA with LTG. METHOD: Retrospective analysis of three identified patients in a large university hospital. RESULTS: We describe three adult patients aged 39, 50 and 75 years, who developed non-convulsive status epilepticus (NCSE) after replacement of VPA with LTG. The episodes of NCSE presented as an acute confusional state with mild myoclonus. Ictal EEG showed generalized spike-wave or polyspike wave activity. The clinical symptoms and the EEG responded promptly to IV benzodiazepines and patients remained well controlled with dose reduction of LTG (in one patient) or discontinuation of LTG (in two patients). CONCLUSION: The reported episodes of NCSE in these patients with generalized epilepsy may be either due to a possible paradoxical reaction to LTG or due to a withdrawal effect of VPA.

Adult↗
PubMed2002

Low dose sodium valproate in the treatment of juvenile myoclonic epilepsy.

Fourteen patients with juvenile myoclonic epilepsy (JME) were treated with a single low dose of a sustained-release preparation of sodium valproate (VPA, 500 mg daily). The mean age of the onset of the low dose treatment was 19.2 years (range 14-26). Before this treatment, six patients had been treated with high dose VPA for a period of more than 2 years, three patients for 1 to 2 years, three patients less than 1 year and two patients initiated the treatment from the beginning with a low dose. The mean duration of low dose treatment is 35.6 months (range 25-59 months). (All patients are still under medication). Generalized tonic-clonic and absence seizures were controlled in all patients. Myoclonic jerks relapsed only in one patient, a young mother who was looking after her newly born baby and was deprived of sleep. No adverse reactions have been reported. We suggest that JME patients can effectively be treated with single low VPA dose (500 mg daily), while at the same time seizure precipitating factors, such as sleep deprivation and alcohol ingestion, should be avoided.

Adolescent↗
PubMed2005

Secondary renal Fanconi syndrome caused by valproate therapy.

Although renal Fanconi syndrome resulting from valproate (VPA) has occasionally been reported, the detailed clinical characteristics of this disease remain unclear. To clarify the clinical features of patients with VPA-induced Fanconi syndrome, we analyzed the clinical and laboratory data of seven affected patients. All patients were children, were severely disabled and required tube feeding. Five patients required treatment with multiple anticonvulsant agents. Hypophosphatemia and hypouricemia were found in all patients. Mild proteinuria, increased excretion of urinary beta2-microglobulin (beta2MG) and generalized hyperaminoaciduria were present in all patients. The renal biopsy of one patient exhibited tubulointerstitial nephritis without any structural abnormalities of the mitochondria in proximal renal tubular cells. All patients recovered from the Fanconi syndrome after the cessation of VPA therapy without any long-term renal sequellae. These results indicate that young age and being severely disabled with tube feeding and anticonvulsant polytherapy are contributory factors to the development of VPA-induced Fanconi syndrome. Serum phosphate and uric acid concentrations and urinary beta2MG levels in addition to serum electrolytes and urinalysis should be examined regularly in patients receiving VPA therapy, especially in those with the contributory factors outlined above. Patients with Fanconi syndrome caused by VPA have a favorable renal outcome.

Adolescent↗
PubMed2006

A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate.

Autism symptoms, including impairments in language development, social interactions, and motor skills, have been difficult to model in rodents. Since children exposed in utero to sodium valproate (VPA) demonstrate behavioral and neuroanatomical abnormalities similar to those seen in autism, the neurodevelopmental effects of this antiepileptic agent were examined in mice following its pre- or postnatal administration. Exposed pups were evaluated in a battery of neurodevelopmental procedures designed to assess VPA-induced retardation (wherein a behavior fails to mature on schedule), regression (wherein a behavior does mature on time but then deteriorates), or intrusions (wherein normal behaviors are overshadowed by stereotypic or self-injurious behaviors). The resulting observations were interpreted in the context of this new strategy to model autism.

Animals↗
PubMed1988

Side effects of valproate.

In the management of epilepsy, selecting an antiepileptic drug appropriate for each individual patient requires matching the patient's clinical needs with the agent's specific pharmacologic attributes. In many situations, the final choice of an antiepileptic drug is based upon an agent's side-effect profile. Because side-effect profiles emerge gradually as the number of patients treated expands from the thousands to the hundreds of thousands, it is helpful to periodically update our perspective of side effects of antiepileptic drugs. For valproate, the frequency of side effects has been reduced by monitoring serum levels, using improved formulations, and limiting use in patients who have been identified as having a high risk for the development of a serious side effect.

Behavior↗
PubMed1988

Protective effect of D,L-carnitine on valproate-induced hyperammonemia and hypoketonemia in primary cultured rat hepatocytes.

The effect of D,L-carnitine on sodium valproate (VPA)-induced hyperammonemia and hypoketonemia was investigated in primary cultures of rat hepatocytes. Administration of VPA (0.1 to 1.0 mM) resulted in an increase of ammonia and a decrease of ketone bodies in culture medium. When D,L-carnitine was added with VPA to the medium, the level of ammonia decreased significantly and that of ketone bodies increased. A significant negative relationship was found between the concentrations of ammonia and the ketone bodies in the medium following administration of D,L-carnitine. Our results suggested that VPA suppressed the urea cycle metabolism and that a protective effect of D,L-carnitine on ketone metabolism was probably due to the reversal of the inhibition of beta-oxidation.

Ammonia↗
PubMed1992

Cytochrome aa3 depletion is the cause of the deficient mitochondrial respiration induced by chronic valproate administration.

Liver mitochondria from rats fed 1% (w/w) valproic acid for 75 days displayed an approximate 30% decrease in coupled respiration rates with substrates entering the respiratory chain at complexes I and II. Uncoupling the respiration from proton-pumping, or measuring the respiration without complex IV removed this inhibition. The treatment induced a loss of activity of cytochrome oxidase consistent with a decrease in the mitochondrial content of cytochrome aa3. The inhibition induced by long lasting administration of valproate is apparently located at the site of the proton-pumping activity of complex IV. Furthermore, the capacity of electron transport through complex IV, being far in excess of that required for normal functioning in coupled mitochondria, seems to be controlled by the coupling to proton-pumping in which cytochrome aa3 appears to play a major role.

Animals↗
PubMed1986

Growth hormone response to sodium valproate in chronic schizophrenia.

The hypothesis of a gamma-aminobutyric acid (GABA) involvement in the pathophysiology of schizophrenia has been recently proposed but not confirmed. As GABA has been shown to affect basal growth hormone (GH) secretion in humans, the assessment of plasma GH response to a GABAergic drug, such as sodium valproate (SV), in schizophrenic subjects might be a tool with which to investigate central GABA activity in this illness. For this purpose, we administered orally 800 mg of SV or placebo to 13 chronic schizophrenics and to 10 normal controls, and measured plasma GH levels before and after the drug administration. SV enhanced basal GH secretion in healthy male volunteers, but not in chronic schizophrenics. These results suggest a defect of the endogenous GABA system in chronic schizophrenia. Whether the reduced responsiveness observed represents a primary defect or a secondary alteration of the GABA system in schizophrenia is as yet unknown.

Adult↗
PubMed1985

Therapeutic levels of sodium valproate inhibit mitotic indices in cells of neural origin.

Sodium valproate (VPA) inhibited the mitotic index of neuroblastoma (Neuro-2A) and glioma (C6) cells with an IC50 of 0.5 and 1.0 mM, respectively. Continued exposure of these cell lines to 1 mM VPA induced differentiation and increased adhesiveness. These observations are characteristic of putative teratogens and this implication for VPA is discussed.

Animals↗
PubMed1986

The action of valproate on spontaneous epileptiform activity in the absence of synaptic transmission and on evoked changes in [Ca2+]o and [K+]o in the hippocampal slice.

The effects of valproate (VPA) on neuronal excitability and on changes in extracellular potassium ([K+]o) and calcium ([Ca2+]o) were investigated with ion selective-reference electrode pairs in area CA1 of rat hippocampal slices. Field potential responses to single ortho- and antidromic stimuli were unaltered by VPA (1-5 mM). The afferent volley evoked in the Schaffer-commissural fibers was also unaffected. In contrast, VPA (1 mM) depressed frequency potentiation and paired pulse facilitation markedly. Decreases in [Ca2+]o induced either by repetitive stimulation or by application of the excitatory amino acids N-methyl-D-aspartate and quisqualate were reduced, and the latter results suggest that VPA interferes with postsynaptic Ca2+ entry. When synaptic transmission was blocked by lowering [Ca2+]o (0.2 mM) and elevating [Mg2+]o (7 mM), prolonged afterdischarges elicited by antidromic stimulation were blocked by VPA. VPA also suppressed the spontaneous epileptiform activity seen when [Ca2+]o was lowered to 0.2 mM, without elevating [Mg2+]o. The amplitudes of the rises in [K+]o induced by repetitive orthodromic stimulation were only slightly depressed and those elicited by antidromic stimulation were generally unaltered by VPA, as were laminar profiles of stimulus-evoked [K+]o signals. These results indicate that VPA has membrane actions in addition to known effects on excitatory and inhibitory transmitter pools.

Animals↗
PubMed1988

The anticonvulsant sodium valproate specifically induces the expression of a rat glial heat shock protein which is identified as the collagen type IV receptor.

A potential mechanism for valproate (VPA)-induced increases in glial cell-substratum adhesivity has been demonstrated. Metabolically labelled glioma (C6) and primary astrocytes showed a statistically significant accumulation of protein when cultured in the presence of therapeutic concentrations of VPA (1 mM). This was mainly accounted for by a 10-fold increase in the production of a single polypeptide of 43 kDa molecular weight. Fractionation studies and metabolic labelling with N-acetyl-D-mannosamine showed this to be a sialoglycoprotein which was plasma membrane-bound. VPA-induction of the polypeptide was apparently specific to glioma and primary astrocytes and was not observed in neuroblastoma (neuro-2a), fibroblasts (3T3), pituicytes (GH3) and epithelial cells (NCTC). The 43 kDa component of glia was demonstrated to be the receptor for type IV collagen by binding metabolically labelled and solubilised cells to Sepharose beads which had been individually coated with laminin, fibronectin and type IV collagen. The protein has also been shown to be a heat shock product as metabolically labelled glioma showed a 10-fold increase in its expression when cultured at 42 degrees C. This heat shock induced expression was transient and was in marked contrast to that seen with VPA where it increased with time and was sustained. The expression of 43 kDa is suggested to arise by VPA and heat shock induced delays in cell cycle progression and this is discussed in relation to teratogenic action.

Anticonvulsants↗