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PubMed2002

Valproate-associated dysmyelopoiesis in elderly patients.

Sodium valproate is widely prescribed for patients with epilepsy and psychiatric disorders. Hematologic toxic effects have been largely described in pediatric patients, and dysmyelopoiesis is reported rarely. We describe 2 elderly patients with valproate-associated dysmyelopoiesis and postulate that this particular side effect may be much more common than currently recognized. A correct diagnosis is important for acute patient anagement and for prognostication.

Anticonvulsants↗

PubMed2001

Intravenous valproate in status epilepticus.

OBJECTIVE: To evaluate the role of intravenous valproate sodium (IV VPA) in the treatment of status epilepticus (SE). DATA SOURCES: A literature search of the English language was performed (MEDLINE 1966-July 2000). Search terms included valproate, valproic acid, and status epilepticus. Bibliographies of articles chosen were reviewed to identify other possible sources. DATA SYNTHESIS: A review of the medical literature was conducted to evaluate the safety and efficacy of IV VPA in the treatment of SE. CONCLUSIONS: Experience with IV VPA in the treatment of SE is too limited to recommend its use as a first-line agent. IV VPA may represent a third- or fourth-line option in cases of SE when other agents are ineffective or contraindicated.

Adult↗

PubMed2005

Teratogenicity of sodium valproate.

The teratogenicity of the widely popular antiepileptic drug (AED) and mood stabiliser sodium valproate (also known as valproate, VPA) has been evidenced by previous research; however, these findings have often been limited by a small population sample of exposed women and a retrospective study design. Many factors contribute to the teratogenicity of VPA. These include the number of drugs that are co-administered, drug dosage, differences in maternal and/or infant metabolism, the gestational age of the fetus at exposure, and hereditary susceptibility. VPA has been associated with a variety of major and minor malformations, including a 20-fold increase in neural tube defects, cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrinological disorders, limb defects, and autism. It has been suggested that polytherapy treatment in epileptic pregnant women increases the risk of teratogenicity in offspring. Furthermore, there is an established relationship between VPA dose and adverse outcome. Large single doses of VPA potentially cause high peak levels in the fetal serum resulting in deleterious effects. Currently there is an increase in the number of national and international pregnancy registries being formed in an effort to better identify the teratogenic effects of AEDs. These efforts hope to enhance our understanding of AEDs and their associated risks by addressing past study limitations.

Abnormalities, Drug-Induced↗

PubMed1983

Sodium valproate and cyproheptadine may independently induce a remission in the same patient with Cushing's disease.

A patient with Cushing's disease was unsuccessfully treated by pituitary surgery and external pituitary irradiation. One year later sodium valproate treatment induced a remission and finally hypocorticism developed. After drug withdrawal hypercoticism recurred. Treatment with cyproheptadine again induced hypocorticism necessitating corticosteroid substitution therapy. Biochemical characteristics of this patient included responsiveness to bromocriptine and cyproheptadine in acute tests. The study demonstrates that sodium valproate and cyproheptadine may both be effective independently in the treatment of the same patient with Cushing's disease. It is proposed that the disease is due to an ACTH producing tumour of pituitary intermediate lobe origin.

Adrenocorticotropic Hormone↗

PubMed1986

No effect of treatment with sodium valproate on plasma growth hormone in bromocriptine unresponsive acromegaly.

Administration of sodium valproate for 6 months at a dose of 300 mg three times daily to 7 bromocriptine unresponsive acromegalic patients who all but one had been treated with pituitary surgery and/or radiotherapy in the past did not result in a significant reduction of the plasma growth hormone (GH) level or in any clinical improvement. It is concluded that sodium valproate is not suitable for the treatment of acromegalic patients who do not show a favourable response to bromocriptine.

Acromegaly↗

PubMed1997

Differential effect of carbamazepine and valproate monotherapy on plasma levels of oestrone sulphate and dehydroepiandrosterone sulphate in male epileptic patients.

Steroid sulphates such as oestrone sulphate (OE1S) and dehydroepiandrosterone sulphate (DHEAS) have been suggested to be of biological importance in different disease states such as breast cancer and atherosclerosis. Previous studies have shown that drugs such as aminoglutethimide and rifampicin that induce P450-dependent mixed-function oxygenases selectively suppress plasma OE1S levels. The aim of this study was to evaluate the influence of treatment with carbamazepine, an antiepileptic drug known to stimulate mixed-function oxygenases, on plasma levels of OE1S and DHEAS. We measured plasma OE1S and DHEAS together with other plasma oestrogens and androgens in male epileptic patients before and during carbamazepine monotherapy. Patients treated with valproate monotherapy acted as a control group. Treatment with carbamazepine decreased plasma OE1S levels from a mean value of 810.8 to 411.6 pmol/l (mean suppression to 50.7% of pretreatment levels, P < 0.001). Similarly, the ratio of OE1S to OE1 fell to 59.9% of pretreatment levels (P < 0.001)). DHEAS decreased from a mean level of 4.9 mumol/l before treatment to 3.0 mumol/l during carbamazepine therapy (mean reduction to 62.7% of pretreatment levels (P < 0.001), while the ratio of DHEAS to DHEA fell to 63.0% of pretreatment values (P < 0.01). No significant change in plasma levels of the other oestrogens or androgens measured was observed. Treatment with valproate caused a slight decrease in FSH levels (P < 0.05), but no change in any of the other hormones measured was observed. Studies are warranted to evaluate the possible effects of long-term treatment with carbamazepine on the risk of developing endocrine-sensitive tumours and cardiovascular disease and also the possible effects of alterations in plasma DHEAS on epileptic activity.

Adolescent↗

PubMedDate not supplied

Poor correlation between single-dose data and steady-state kinetics for phenobarbitone, primidone, carbamazepine and sodium valproate in children during monotherapy. Possible reasons for the lack of correlation.

An investigation was performed to determine the relationship between the serum drug concentration/dose ratio at 24 hours following a first dose and that at steady-state for phenobarbitone, primidone (as phenobarbitone and as primidone), carbamazepine and sodium valproate, in order to assess the utility of this method in clinical practice. The drugs were given as monotherapy to 63 children for the treatment of epilepsy or febrile convulsions. The correlation between concentration/dose ratios, instead of between serum concentrations, was investigated with the aim of allowing the use of variable doses. The correlation coefficients were: r = 0.30 for phenobarbitone; r = 0.05 for phenobarbitone derived from primidone; r = 0.38 for primidone; r = 0.19 for carbamazepine; and r = 0.52 for sodium valproate. None of these correlation coefficients differed statistically from 0. These low correlation coefficients contrast with the acceptable results found by other authors for other drugs, indicating that several factors may have a greater influence on this correlation than earlier investigations suggest. The poor correlation obtained emphasises the need for clinical verification of mathematical models based on theoretical considerations which do not always apply in practice.

Age Factors↗

PubMed2006

Drug rash with eosinophilia and systemic symptoms induced by valproate and carbamazepine: formation of circulating auto-antibody against 190-kDa antigen.

Drug rash with eosinophilia and systemic symptoms (DRESS) is characterized by fever, rash and internal organ involvement after exposure to certain drugs. Most of the aromatic anticonvulsants, such as phenytoin, phenobarbital, and carbamazepine, can induce DRESS. Cross-sensitivity between not only the aromatic anticonvulsants, but also the aromatic and non-aromatic anticonvulsants, is possible. We report here a case of a Korean woman who had previously tolerated valproate, but developed DRESS due to valproate after carbamazepine intake, which indicates cross-sensitivity. Her skin lesions displayed diffuse oedematous patches on the entire body associated with tense bullae on her arms and legs. Circulating auto-antibody to 190-kDa antigen was detected in the patient's serum by indirect immunofluorescence and immunoblotting, which might contribute to a pathogenic role in DRESS.

Adult↗

PubMed1994

Combining lithium and sodium valproate for bipolar disorder.

We report two cases of severe bipolar disorder in which there was a dramatic response to the combination of lithium and sodium valproate. Both patients had failed to respond to the respective monotherapies. These cases suggest that the combination of lithium and sodium valproate may be more effective than each of these drugs used alone. There is a clear need for controlled outcome studies of the common clinical practice of combining lithium and the anticonvulsants.

Bipolar Disorder↗

PubMedDate not supplied

Interference of high-dose methotrexate in the metabolism of valproate?

A case of tonic-clonic seizure was observed in a child with acute lymphoblastic leukemia a few hours after a 24-hour infusion of high-dose methotrexate (MTX; 5 g/m2). Because of former epileptic symptoms, the child had been treated with valproic acid for several months. During this and the following high-dose MTX infusion, an acute decline of the serum valproate concentration to about 25% of the pre-MTX value was observed. The pathogenesis of the acute decline of serum valproate concentration is discussed.

Child↗

PubMed1989

Sodium valproate does not alter immune competence in mice.

Spleen and thymus weight, delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC), contact hypersensitivity to picryl chloride, anti-sheep red blood cell hemagglutinin titers and plaque-forming cells (PFC), resistance against experimental toxoplasmosis as well as serum total and intestinal specific IgA were investigated in Swiss mice given sodium valproate (250 mg/kg/day) orally for 21 consecutive days. Sodium valproate (SV) did not exert marked effects as only DTH to SRBC and PFC numbers were found to be slightly altered. These results suggest that SV is unlikely to alter immune competence markedly.

Adjuvants, Immunologic↗

PubMed2000

Clinical and biological findings in a case with 48-hour bipolar ultrarapid cycling before and during valproate treatment.

BACKGROUND: The rare cases of patients with 48-hour ultrarapid cycling allow close investigation of mood cycles in affective disorders, because rhythmic changes in psychopathologic state and biological parameters happen very precisely. METHOD: A 67-year-old white man who had experienced bipolar 48-hour ultrarapid cycling (DSM-IV 296.80) for several years was studied without any medication and then again studied 4 weeks later during treatment with valproate (1800 mg/day). RESULTS: Objective and self ratings revealed pronounced manic states 1 day and depressed states the following day, which were found to be accompanied by rhythmic fluctuations in behavior and electroencephalographic parameters, blood cortisol and growth hormone levels (both elevated on depressive days), and urinary metanephrine (dopamine metabolite) and norepinephrine levels (both elevated on manic days). Using single photon emission computed tomography, regional blood flow in the left thalamus was lower than in the right thalamus on the manic day, while symmetric perfusion of the thalamus was found on the depressive day. Under valproate treatment, the patient remitted completely, and significant rhythmic changes in most of the biological parameters were no longer detectable. CONCLUSION: The biological findings in this patient with bipolar 48-hour ultrarapid cycling, which correspond to those in other types of affective disorders, suggest that disturbances in the diencephalon-pituitary axis may be especially correlated to pathologic changes of mood.

Aged↗

PubMed1999

Differential display PCR reveals novel targets for the mood-stabilizing drug valproate including the molecular chaperone GRP78.

Differential display polymerase chain reaction was used to identify genes regulated by the mood-stabilizing drug valproate (VPA). Four differentially displayed valproate-regulated gene fragments were isolated in rat cerebral cortex after i.p. injection of sodium VPA (300 mg/kg) for 3 weeks, and their expression was confirmed by Northern and slot blot analysis in rat cerebral cortex and C6 glioma cells. Sequencing analysis revealed three previously unidentified cDNA fragments in addition to a sequence with 100% homology with a molecular chaperone, 78-kDa glucose-regulated protein (GRP78). VPA treatment did not increase mRNA expression of 70-kDa heat shock protein, which is a related stress-induced molecular chaperone protein. All four candidate genes, including GRP78, showed similar VPA concentration-dependent increases in mRNA abundance. Another commonly prescribed mood-stabilizing anticonvulsant, carbamazepine, also increased GRP78 mRNA expression in C6 glioma cells, whereas lithium had no effect at doses up to 2 mM. Immunoblotting revealed that GRP78 protein levels were also increased in C6 glioma cells treated with VPA under the same conditions. Nuclear runoff analysis showed that VPA increased GRP78 gene transcription. Because GRP78 possesses molecular chaperone activity, binds Ca2+ in the endoplasmic reticulum, and protects cells from the deleterious effects of damaged proteins, the present findings suggest that VPA (and possibly carbamazepine) treatment may target one or more of these processes.

Animals↗

PubMed1999

Effects of antiepileptic drugs carbamazepine and sodium valproate on fertility of male rats.

The effects of carbamazepine and sodium valproate on fertility of male rats were studied. The tested drugs were given orally to male rats for 30 and 60 consecutive days. Mating performance, sex organs weights, semen quality, plasma concentrations of sexual hormones as well as histopathological findings were the criteria used to evaluate the reproductive efficiency of treated males. Oral administration of carbamazepine and sodium valproate for 30 and 60 consecutive days significantly decreased the testicular weight, sperm cell concentration, live sperms and percentage of progressively motile spermatozoa. Both drugs significantly increased the percentage of morphologically abnormal spermatozoa. A decrease in plasma testosterone, FSH and LH and an increase in prolactin levels were observed in the treated groups. Histopathological examination showed mild to moderate degenerative changes in the testes of the treated rats while the prostate glands and seminal vesicles appeared normal. A recovery period of 30 days was accompanied by marked changes in the tested parameters towards initial values.

Animals↗

PubMed1997

Effect of theophylline on diazepam and sodium valproate protection in pentylenetetrazole - kindled seizures in rats.

Theophylline is well known for its convulsant and proconvulsant action. Some experimental studies also suggest that theophylline and other methylxanthines may impair the protection of antiepileptic drugs. The interaction of theophylline and the antiepileptic drugs diazepam and sodium valproate was studied in pentylenetetrazole (PTZ) - kindled seizures in rats. Pretreatment with both diazepam 4 mg/kg and sodium valproate 300 mg/kg, i.p., showed protection against PTZ kindled seizures. Theophylline, 50 mg/kg, i.p., when given before the antiepileptic drugs, failed to reverse their protection. Since theophylline has an adenosine receptor antagonist activity which may be responsible for its convulsant potential, the results indicate non-involvement of adenosinergic mechanisms in the mechanisms of actions of these antiepileptic drugs.

Animals↗

PubMed1999

[A case of fetal valproate syndrome with intractable wheezing due to submucosal tumor below the vocal cord].

A full-term baby was born to an epileptic mother treated with two anti-epileptic drugs, sodium valproate and phenobarbital, throughout the pregnancy. She was given no information about the risk of teratogenesis of these drugs. At birth the patient was hypotonic and had clinical features specific for the fetal valproate syndrome. After a viral infection at three months of age, he had intractable and persistent wheezing. Suspecting the presence of congenital respiratory tract abnormality, we performed tracheobronchoscopy, which revealed a relatively big submucosal tumor on the left trachial wall below the vocal cord. Dyspnea and wheezing were remarkably improved by tracheolaryngotomy, but he died suddenly and unexplainedly at seven months of age.

Abnormalities, Drug-Induced↗

PubMed2000

Pathomorphological changes in mouse liver and kidney during prolonged valproate administration.

Mice given sodium valproate 0.71% weight/volume in drinking water for 7, 14 and 21 days were assessed for pathomorphological changes in liver and kidney tissues at certain time points. This treatment caused a marked alteration in liver and kidney cell morphology, which was proportional to the period of treatment. This treatment induced fatty degeneration of hepatocytes, increased the number of Kupffer cells and caused them to swell. These changes were irregular after days 7 and 14 of treatment but with time increased in intensity, producing inflammation of the portal tracts, albuminous degeneration and necrosis of septa. Precirrhotic conditions, cirrhosis, acidophilic degeneration of hepatocytes and glassy eosinophilic homogenous cytoplasm were a constant feature after 21 days' treatment. In some cases the portal area was invaded by small, round inflammatory cells. Hepatocytes in this group were swollen, with large nuclei and increased amounts of condensed chromatin. The kidney sections of the same animals revealed severe morphological changes, indicated by significant epithelial necrosis and sloughing of tubules, as well as cast formation and mild lymphocytic infiltrate after 21 days' treatment. The results suggest that the histopathologic changes induced by sodium valproate are dependent upon the duration of exposure of these organs to the drug. Prolonged use of this drug should be carefully assessed.

Animals↗

PubMedDate not supplied

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

UNLABELLED: Lamotrigine is a broad-spectrum antiepileptic drug which is thought to act in part via a use-dependent blockade of voltage-sensitive sodium channels to stabilise the neuronal membrane. This results in the inhibition of the excessive release of excitatory amino acids, such as glutamate, during epileptic activity. An open, multicentre, prospective trial of lamotrigine was carried out in adult patients with drug-resistant epilepsy on monotherapy with carbamazepine or valproate. The primary aim of the study was to assess add-on lamotrigine withdrawing to monotherapy. 28-week clinical trial was divided into 4 phases: (1) Dose escalation period (4 weeks), (2) Add-on period (8 weeks), (3) Standard AED withdrawal period (8 weeks), (4) Lamotrigine monotherapy (8 weeks). Thirty-three patients were previously treated with valproate, 44 with carbamazepine. Of 77 patients recruited into the study, 64 patients (83%) completed add-on therapy, 49 patients (64%) completed lamotrigine monotherapy. 44% of all patients during the add-on phase and 48% during lamotrigine monotherapy had a reduction in seizure frequency of at least 50% compared with pre-study period. 13% of all patients achieved seizure freedom during add-on therapy and 18% during monotherapy. Improvement of Visual Analogue Scale (VAS) scores was observed in 65% and 57% patients respectively. A significant proportion of patients could be successfully converted to lamotrigine monotherapy. Lamotrigine was also generally well tolerated. 23 patients (30%) had at least one adverse event (AE), but only 1/4 of all AEs might be reasonably regarded as an effect of the medication. 7 patients (9%) discontinued prematurely from the study due to adverse event. More AEs were observed in add-on therapy than in lamotrigine monotherapy. The safety profile was consistent with that seen during other clinical trials with lamotrigine. CONCLUSIONS: 1. Lamotrigine is effective AED in add-on and monotherapy (responders rate--44% and 48% respectively). 2. In most cases conversion from add-on therapy to monotherapy can be done successfully. 3. Lamotrigine is a safe and well-tolerated drug.

Adult↗