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PubMed2004

Convergent effects of lithium and valproate on the expression of proteins associated with large dense core vesicles in NGF-differentiated PC12 cells.

Lithium and valproate are chemically unrelated compounds that are used to treat manic-depressive illness. Previously, we reported that lithium ions upregulate genes encoding proteins primarily associated with large dense core vesicles (LDCV) in nerve growth factor (NGF)-differentiated PC12 cells, but not in undifferentiated PC12 cells. Moreover, lithium did not alter the expression of proteins associated with small-clear, synaptic-like vesicles (SSV) in these cells. Based on these observations, we investigated whether valproate had actions similar to those of lithium in PC12 cells. Thus, undifferentiated or NGF-differentiated PC12 cells were exposed to lithium (1 mM) or valproate (1 mM) for 48 h. Extracts from these cells were submitted to semiquantitative Northern and Western analyses. In NGF-differentiated cells, both agents increased the expression of proteins associated with LDCV, the vesicular monoamine transporter 1 (VMAT1), and cysteine string protein (CSP). These same treatments did not alter the expression of proteins primarily associated with SSV, the vesicular acetylcholine transporter (VAChT), and synaptophysin (SY). Furthermore, neither drug affected the expression of these proteins in undifferentiated cells. Interestingly, secretion of (3)H-dopamine was increased in cells exhibiting the increase of VMAT1 and csp. Taken together, the convergent effects of these chemically diverse compounds suggest that altered dynamics of LDCV may play a vital role in the biochemical pathway, leading to the relief of the symptoms of manic depression.

Animals↗

PubMed1992

Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo.

The efficacy of sodium valproate (Depalept) versus placebo in the treatment of migraine was evaluated in a double-blind randomized cross-over study in twenty-nine patients. The patients were divided into two groups each of which was alternately given 400 mg of sodium valproate B.I.d or placebo for eight weeks and then crossed over for an additional eight weeks. Our results show that in 86.2% of the patients sodium valproate was effective in preventing migraine or reducing the frequency, severity and duration of the attacks. In general, the drug was well tolerated and proved to be an effective treatment in migraine.

Adolescent↗

PubMed1999

Cholinergic stimulation of early growth response-1 DNA binding activity requires protein kinase C and mitogen-activated protein kinase kinase activation and is inhibited by sodium valproate in SH-SY5Y cells.

Activation of muscarinic receptors in human neuroblastoma SH-SY5Y cells with carbachol stimulated a rapid and large increase in early growth response-1 (Egr-1, also called zif268 and NGF1-A) protein levels and DNA binding activity. Egr-1 DNA binding activity was stimulated within 15 min of treatment with carbachol and maintained a maximum 20-fold increase over basal between 1 and 2 h after treatment, and the EC50 was approximately 1 microM carbachol. Carbachol-stimulated Egr-1 DNA binding activity was dependent on protein kinase C, as it was potently inhibited by GF109203X (IC50 approximately 0.1 microM) and was reduced by 85 +/- 5% by down-regulation of protein kinase C. Inhibitors of increases in intracellular calcium levels reduced carbachol-induced Egr-1 DNA binding activity by 25-35%. Carbachol-stimulated activation of Egr-1 was reduced 35% by genistein, a tyrosine kinase inhibitor, and 60% by PD098059, an inhibitor of mitogen-activated protein kinase kinases 1/2 (MEK1/2) that activates extracellular-regulated kinases 1/2 (ERK1/2). A novel inhibitory action was caused by chronic (7-day) administration of sodium valproate but not by two other bipolar disorder therapeutic agents, lithium and carbamazepine. Valproate treatment reduced carbachol-stimulated Egr-1 DNA binding activity by 60% but did not alter carbachol-induced activation of ERK1/2 or p38 or increases in Egr-1 protein levels. These results reveal that muscarinic receptors activate Egr-1 through a signaling cascade primarily encompassing protein kinase C, MEK1/2, and ERK1/2 and that valproate substantially inhibits Egr-1 DNA binding activity stimulated by carbachol or protein kinase C.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed1999

Long-term valproate treatment induces changes in ovarian morphology and serum sex steroid hormone levels in female Wistar rats.

Long-term valproate treatment is associated with polycystic ovaries and endocrine disorders in women with epilepsy. The mechanisms responsible for these effects are unknown, but both the epilepsy itself and the drug per se may be of importance. The aim of this study was to investigate possible effects of the drug on gonadal structure and function in animals with no epileptic disorders. Three groups, each of 15 female Wistar rats, were fed perorally with a valproate mixture (50 mg / kg or 200 mg / kg) or control solution once daily for 90 days, giving mean valproate concentrations within the normal human range. A significant, 20% increase in ovary weight was found in both low- (P = 0.027) and high- (P < 0.001) dose animals together with a significantly increased number of ovarian follicular cysts. Mean serum testosterone concentration was significantly reduced in both low- and high-dose animals. There was a non-significant trend towards reduced estrogen levels, while progesterone levels were unchanged. Even if the hormonal changes are somewhat different from those in humans, the findings demonstrate that changes in gonadal structure and endocrine function also occur in intact animals indicating a drug-specific effect. Our findings encourages further studies using animal models to elucidate possible mechanisms involved in the endocrine side-effects of antiepileptic drugs.

Administration, Oral↗

PubMed2000

Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy.

Lamotrigine is a broad-spectrum antiepileptic drug that blocks sodium channels, thereby inhibiting the pre-synaptic release of excitatory neurotransmitters. The primary aim of the study was to evaluate lamotrigine add-on therapy and consecutive monotherapy in patients with epilepsy whose seizures were not controlled by carbamazepine or valproate. One hundred and twenty six epilepsy patients at 18 centres in Poland were recruited into a lamotrigine substitution study. In all patients, existing seizures were poorly controlled with valproate (n= 63) or carbamazepine (n= 63) monotherapy. The study consisted of four phases: (1) a 4-week lamotrigine dose-escalation phase, (2) an 8-week lamotrigine add-on phase, (3) an 8-week carbamazepine/valproate withdrawal phase, and (4) an 8-week lamotrigine monotherapy phase. Of 126 patients recruited into the study, 107 (85%) completed dose-escalation and add-on therapy with lamotrigine and 85 (68%) completed lamotrigine monotherapy. Fifty percent of patients during add-on therapy and 53% during lamotrigine monotherapy experienced at least 50% reduction in total seizures (responders) compared to the pre-study period. Approximately 20% of patients during add-on therapy and 27% during lamotrigine monotherapy were seizure free. Total well-being was assessed using a Visual Analogue Scale with 62% of patients during add-on therapy and 60% in lamotrigine monotherapy reporting improvement in scores. Lamotrigine was generally well tolerated. Treatment was discontinued in 7% because of adverse events. In conclusion, lamotrigine is an effective AED in add-on therapy and monotherapy, it is safe and well tolerated, and successful conversion from add-on to monotherapy can be achieved in many cases. An additive effect between lamotrigine and valproate was observed.

Adolescent↗

PubMed1991

Reduction of baclofen-, but not sodium valproate-induced growth hormone release in type I diabetic men.

The effects of sodium valproate (a drug enhancing endogenous gamma aminobutyric acid (GABA)-ergic activity) and of the GABA analog baclofen (a GABA B receptor agonist) on serum GH levels was tested in 8 type I diabetic men and 8 normal controls. Sodium valproate (800 mg) or baclofen (10 mg) were given by mouth at 08.30 h on the experimental day. Control tests with a placebo were performed on different occasions. Basal GH levels were similar in controls and diabetic patients. Sodium valproate induced a 7 fold increase in serum GH concentrations in both groups. In contrast, baclofen-induced GH rise was significantly higher in normal controls (mean peak was 3.4 times higher than baseline) than in diabetic patients (mean peak was only 2.1 times higher than basal value). Serum GH levels did not change after placebo administration in any groups. These data suggest the presence of diabetes-induced alterations of a GABAergic pathway mediated by B receptors in the control of GH secretion. Alternatively, the data might indicate a change in diabetic men of other baclofen-sensitive neurotransmissions, different from GABA.

Adult↗

PubMed1998

Combined treatment of schizophrenic psychoses with haloperidol and valproate.

In accordance with a previous study of adjuvant effects of the anticonvulsant carbamazepine (CBZ) on the neuroleptic treatment of schizophrenic psychoses, the effects of valproate (VPA) were tested in a randomly assigned double-blind, placebo-controlled study. Apart from a (statistically nonsignificant) psychopathological deterioration following discontinuation of VPA while on continuous neuroleptic mediation after four weeks and a statistically significant effect on "hostile belligerence", no overall therapeutic effects of the combination of haloperidol (HPD) with VPA were observed under controlled conditions. Unlike the results with CBZ, concomitant use of VPA led to an even higher consumption of haloperidol and biperiden and to a higher rate of extrapyramidal symptoms compared with the corresponding placebo group, although these differences did not attain statistical significance. In regard to use of the sedative neuroleptic chlorprothixene, there was a trend toward lower doses in the VPA group than in the placebo group. From these results, adjuvant effects like those of carbamazepine in the neuroleptic treatment of schizophrenic psychoses could not be confirmed for valproate in the present study. However, the trend toward lower doses of sedative medication and observed effects on "hostile belligerence" may indicate sedative and/or antimanic properties of valproate which have recently been demonstrated in several controlled studies.

Adult↗

PubMed1984

Prevention of recurrent febrile convulsions--a randomized therapeutic assay: sodium valproate, phenobarbital and placebo.

The purpose of this study was to compare three different modes of treatment in the prevention of relapses of febrile convulsions (Phenobarbital = PH, Sodium Valproate = SV, Placebo = PO) in a randomized therapeutic trial. The patients included in the study had shown their first generalized convulsive seizure during a bout of fever (greater than or equal to 38.5 degrees C) and were aged between 6 months and 4 years. They were subsequently followed up as outpatients, and Phenobarbital and sodium valproate levels were measured regularly to ascertain compliance with the treatment and to adjust the dosage accordingly. The patients' families were questioned with respect to the occurrence of feverish bouts and convulsive seizures during the interval between visits, as well as possible adverse reactions. An EEG was carried out yearly. Results were as follows: - 69 patients - 35 boys and 34 girls - with an average age of 24 months were divided into 3 groups according to treatment: 21 cases on PH, 22 cases on SV, and 26 cases on PO. - they were followed up for an average duration of 21 months. - the average number of feverish bouts per child and per year was evaluated at 2.5, no statistically significant difference being noticeable between the various modes of prophylaxis. - 15 relapses of febrile seizures were noted in 14 children, over an average duration of 23 months; on average, relapses occurred after 9 months; among the 14 children who had relapsed, one had been treated with SV, 4 with PH and 9 with PO, leading to estimated relapse rates of 4%, 19%, and 35% respectively. There is a statistically significant difference in the relapse rates between the treated groups (SV and PH) and the Placebo group, and a particularly significant difference between Sodium Valproate and Placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Child, Preschool↗

PubMed1985

Acute valproate intoxication with fatal outcome in an infant.

A healthy twenty-month-old boy ingested a maximal dose of valproate from which about 750 mg/kg were absorbed. Cerebral coma, which lasted for twenty hrs, was followed by an undisturbed period of approximately sixteen hrs. Death from cardiorespiratory failure due to severe bronchopneumonia occurred 46.5 hrs after the ingestion of the drug. The serum valproic acid concentration reached a peak of 1061 micrograms/ml within three hours, and fifteen minutes before death it had fallen to 187 micrograms/ml. The half-life of 16.6 hrs was within the range usually found. Metabolic acidosis, hypernatraemia and hyperosmolarity could be corrected, unlike the hypocalcaemia, which developed later. Bilirubin, GOT, GPT, gamma-GT, alkaline phosphatase, blood glucose, diastase, urea, creatinine, haemoglobin as well as PT and PTT and the platelet count were all normal. Leucopenia with 1,600 per microliter developed only during the bronchopneumonial stage. The histo-pathological findings were acute hypoxic damage of the myocardium, kidneys and certain neurones of vulnerable areas of the brain (neuronal microvesiculation and tigrolysis) in addition to a severe cerebral oedema in the final stage. A morphological substrate of an acute valproate encephalopathy was not demonstrable. The liver showed no necrosis or cholostasis. The vertebral marrow was inconspicuous. All the results indicate that liver function was not impaired in spite of the initial maximal concentration of valproic acid. In all probability the patient might have survived the acute valproate intoxication had it not been for the bronchopneumonia.

Brain↗

PubMed2005

Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo.

Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to accumulative increase in the outgrowth of transformed cells. Furthermore, viral infection also correlates with a blockade of the apoptotic mechanisms concomitant with an apparent latency of the host cell. Conceptually, induction of viral or cellular gene expression could thus also be used as a therapeutic strategy against retroviral-associated leukemia. Here, we provide evidence that valproate, an inhibitor of deacetylases, activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes. In vivo, valproate injection into newly BLV-inoculated sheep did not abrogate primary infection. However, valproate treatment, in the absence of any other cytotoxic drug, was efficient for leukemia/lymphoma therapy in the sheep model leading to decreased lymphocyte numbers (respectively from 25.6, 35.7, and 46.5 x 10(3) cells per mm3 to 1.0, 10.6, and 24.3 x 10(3) cells per mm3 in three leukemic sheep) and tumor regression (from >700 cm3 to undetectable). The concept of a therapy that targets the expression of viral and cellular genes might be a promising treatment of adult T cell leukemia or tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy, diseases for which no satisfactory treatment exists so far.

Animals↗

PubMed1997

The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates.

Valproic acid and lithium are effective antibipolar drugs. We recently showed that lithium stimulated the release of glutamate in monkey and mouse cerebral cortex slices, which, through activation of the N-methyl-D-aspartate receptor, increased accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. We show here that valproate behaves similarly to lithium in that at therapeutic concentrations it stimulates glutamate release and Ins(1,4,5)P3 accumulation in mouse cerebral cortex slices. The fact that these two effects are a common denominator for two structurally unrelated antibipolar drugs suggests that these effects are important in their antibipolar action. The effects of maximal concentrations of lithium and valproate on glutamate release are additive, suggesting different mechanisms for release, which are discussed. The additivity of the two drugs on glutamate release is consistent with the clinical benefit of combining the two drugs in the treatment of subsets of bipolar patients, e.g., in rapid cycling manic-depression. Unlike lithium, valproate does not increase accumulation of inositol monophosphates, inositol bisphosphates, or inositol 1,3,4-trisphosphate. This is additional evidence against the "inositol depletion" hypothesis, which states that, by trapping inositol in the form of inositol monophosphates and certain inositol polyphosphates, lithium exerts its antimanic action by inhibiting resynthesis of phosphoinositides with resultant blunting of Ins(1,4,5)P3 signaling.

Animals↗

PubMed2004

Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study.

BACKGROUND: Various drugs are effective in the management of painful diabetic neuropathy, but none is completely satisfactory. We previously found sodium valproate to be effective and safe in a short-term study. AIM: To test the effectiveness and safety of sodium valproate in the management of painful diabetic neuropathy over 3 months. DESIGN: Randomized double-blind placebo-controlled study. METHODS: Consecutive attending patients with type 2 diabetes mellitus with painful neuropathy were asked to participate in the trial: 48 agreed. Five were excluded: three with HbA(1c) > 11, one with too low a pain level and one who withdrew consent. The remaining 43 were given either drug (group A) or placebo (group B). Each patient was assessed clinically. Quantitative assessment of pain was done by McGill Pain Questionnaire, Visual Analogue Score and Present Pain Intensity, at the beginning of the study, after 1 month and after 3 months. Motor and sensory nerve conduction velocities were measured initially and after 3 months. Liver function tests and other adverse drug-related effects were assessed periodically. RESULTS: Of the 43 patients, four dropped out: one in group A and three in group B. There was significant improvement in pain score in group A, compared to group B, at 3 months (p < 0.001). Changes in electrophysiological data were not significant. The drug was well-tolerated by all patients, except one, who had raised serum AST and ALT levels after 1 month of treatment, and whose treatment was discontinued. DISCUSSION: Sodium valproate is well-tolerated, and provides significant subjective improvement in painful diabetic neuropathy.

Adult↗

PubMed2000

Blepharoptosis and central nervous system abnormalities in combined valproate and hydantoin embryopathy.

PURPOSE: To report a case of intrauterine anticonvulsant exposure with subsequent ocular adnexal manifestations. METHODS: Case report. RESULTS: An 18-month-old child with known anticonvulsant embryopathy was referred for the management of bilateral congenital blepharoptosis. Physical examination confirmed ocular and nonocular external manifestations of valproate and hydantoin embryopathies. Cavum septum pellucidum, mild sulcation defects, and cerebellar atrophy were identified on neuroimaging. CONCLUSIONS: To our knowledge, our patient represents the second reported case of anomalous septum pellucidum after intrauterine valproate exposure. Clinicians evaluating patients with craniofacial features associated with intrauterine valproate exposure should recognize that concomitant anomalies of the central nervous system, including the septum pellucidum, might exist.

Abnormalities, Drug-Induced↗

PubMed1993

Parkinsonian syndrome in childhood after sodium valproate administration.

Among the side effects attributed to sodium valproate administration, the production of a parkinsonian syndrome is very uncommon, particularly in children. We report a 12-year-old girl with secondary epilepsy; 7 days after the initiation of valproate therapy she developed parkinsonism that disappeared completely when valproate was replaced by carbamazepine. We discuss the possible role of alterations in GABAergic neurotransmission in the extrapyramidal syndrome that developed.

Child↗

PubMed1992

Algorithm for patient management of acute manic states: lithium, valproate, or carbamazepine?

Lithium remains the mainstay of pharmacologic therapy for the majority of patients with bipolar disorder; however, significant numbers of patients with both classical bipolar disorder and syndromal variants fail to respond to lithium therapy. The discussion that follows outlines subgroups of patients who are likely to be nonresponsive to or have poor tolerance for lithium therapy either because of disease type (rapid cyclers and schizoaffectives) or patient characteristics (the elderly or those with psoriasis or organic brain syndrome). Alternate therapy with valproate and carbamazepine is discussed. The relative efficacy of lithium versus valproate is briefly evaluated through a retrospective review of current case material. Algorithms for patient management are presented based on experience in our center for mood disorders. Valproate and carbamazepine were found to have an important clinical role for the treatment of bipolar spectrum disorders with the initial preference for treatment based on broad clinical phenomena.

Acute Disease↗

PubMed2000

Comprehensive review of the psychiatric uses of valproate.

The therapeutic effects of valproate in psychiatric conditions are most substantially recognized in bipolar disorder. However, this well-tolerated medication may be beneficial in the treatment of other mental illnesses. In this article, the authors comprehensively review studies of valproate as treatment for psychiatric conditions, including bipolar, depressive, anxiety, and psychotic disorders; alcohol withdrawal and dependence; tardive dyskinesia; agitation associated with dementia; and borderline personality disorder. Valproate shows the most promising efficacy in treating mood and anxiety disorders, with possible efficacy in the treatment of agitation and impulsive aggression, and less convincing therapeutic response in treating psychosis and alcohol withdrawal or dependence. The authors conclude with a brief summary of its mechanism of action and therapeutic spectrum.

Anticonvulsants↗

PubMed1984

Clinical implications of serum protein binding in epileptic children during sodium valproate maintenance therapy.

Steady-state serum levels of total and unbound valproic acid as well as unbound fraction in epileptic children were studied in a clinical setting. Valproic acid binding parameters were analyzed and compared with in vitro findings. Daily dose of sodium valproate ranging from 29 to 73 mg/kg/day were administered per os. Considerable variation in total and unbound concentrations and unbound fractions within and between subjects was observed. In subjects evaluated in this study, serum level of total and unbound valproic acid ranged from 279 to 1,196 mumol/L and from 37 to 410 mumol/L, respectively. The unbound fraction ranged from 10.32 to 48.39%. In vivo binding parameters obtained from clinical material were as follows: association constant, Ka = 4.984 L/mmol; total binding sites, NP = 1.451 mmol/L, where P is the molar concentration of albumin; number of binding sites per molecule of albumin, N = 2.48. Using spiked sera, binding parameters of Ka = 8.032 L/mmol, NP = 1.262 mmol/L, and N = 1.86 were found in the in vitro study. The association constant obtained from in vivo and in vitro studies were not significantly different (p greater than 0.05) from each other. The unbound fraction of valproic acid was concentration dependent even within the therapeutic range. An equation for estimating unbound concentration (Cf') or unbound fraction (fp') from total concentration (Ct) of valproic acid is derived. The ratio of observed unbound fraction to the estimated unbound fraction (fp/fp') was used to evaluate the variation in valproate serum binding of that clinical sample. Nine samples from hospitalized patients whose medication and diet were closely supervised showed an fp/fp' ratio very close to 1 (mean +/- SD 1.04 +/- 0.24). It is suggested that a clinical sample showing a value of fp/fp' greater than 1.76 (mean + 3 SD) should be evaluated for the cause of the decrease in serum binding and for the associated pharmacokinetic alterations. Therefore, in clinical monitoring of valproate, determination of both total and unbound drug levels was preferable to determination of either one alone. Furthermore, an understanding of the unbound fraction of valproic acid would significantly contribute to the effective management of epileptic patients.

Adult↗

PubMedDate not supplied

Psychotropic drug interactions with valproate.

Valproate is a well-established anticonvulsant that is increasingly being employed, often in combination with other psychotropics, for its mood-stabilizing properties. This compound is metabolized by conjugation, beta-oxidation, and cytochrome P450 oxidation (CYP2C9, CYP2C19, and CYP2A6) and also acts as a broad-spectrum inhibitor of a variety of hepatic enzymes including glucoronyltransferase, epoxide hydrolase, and the CYP2C enzymes. In addition, it exhibits saturable protein binding and competes with many drugs for protein binding sites. It is therefore not surprising that valproate has been noted to interact with psychotropic medications of all classes. This article provides an overview of the noted pharmacokinetic psychotropic interactions with valproate, with a particular focus on the mechanisms of these interactions and potential clinical consequences.

Anticonvulsants↗