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PubMedDate not supplied

Clinical and surface EMG characteristics of valproate induced tremors.

PURPOSE: To describe the Clinical and Surface EMG characteristics of Valproate induced Tremors. Sodium Valproate is known to produce tremors as a side effect. We analyzed clinical and surface electromyographic characteristics of tremors in epileptic subjects who presented with tremors while on sodium valproate. METHODS: Neurological examination and surface electromyographic recordings were performed on 20 subjects with sodium valproate induced tremors. Surface electromyographic tremerogram was correlated with clinical presentation of tremors. RESULTS: This study revealed sodium valproate induced tremors involving primarily upper limbs symmetrically. In the present study, all patients presented with action postural tremors except two, who had tremors in the resting position as well. None of these patients had tremors in goal-directed position. The tremors typically were of high frequency (mean 10 Hz), low amplitude, short burst duration and synchronous burst pattern (Synchronous EMG activity in the agonist and antagonistic muscles). CONCLUSIONS: Frequency, amplitude, burst duration and burst pattern of sodium valproate induced tremors resembles benign essential tremors on surface electromyographic recordings.

Adolescent↗

PubMed2005

[Successful treatment with cyclosporine of sodium valproate-induced pure red cell aplasia].

We report a 67-year-old man who developed pure red cell aplasia (PRCA) during therapy for epilepsy with sodium valproate since April 2004. He was admitted to our hospital because of severe anemia (Hb 5.0g/dl, reticulocyte 0.1%) in August 2004. A bone marrow examination showed marked erythroid hypoplasia and a diagnosis of drug-induced PRCA was made. Because the discontinuation of valproate for one month failed to increase the number of reticulocytes and frequent blood transfusions were necessary, cyclosporine therapy was initiated. Within a week, substantial recovery of the numbers of reticulocytes was obtained, the cyclosporine had, however, to be changed to prednisolone due to the refusal of the patient to continue with it, resulting in the exacerbation of his anemia. After three weeks, cyclosporine therapy was resumed, which achieved rapid and remarkable recovery of red blood cells (Hb 8.9g/dl, reticulocyte 4.9%) within one month. Sixteen cases of valproate-induced PRCA have been reported in the literature and all cases except one recovered only by discontinuing or reducing the administration of valproate. However, our case required cyclosporine therapy in addition to the discontinuation of valproate. These results suggest that not only the direct toxic effect on erythropoiesis but also T lymphocyte-mediated immunological mechanism was involved in the pathogenesis of valproate-induced PRCA.

Aged↗

PubMed1990

[Blood level profile of valproate administration under therapeutic conditions in children].

The antiepileptic drug, valproic acid, was administered to 32 children (valproate calcium 8; valproate plus ethosuximide 10; valproate plus phenobarbitone 2; valproate plus primidone 8; valproate plus DPH, primidone and/or carbamazepine 4). They received valproic acid three times daily (8.00 a.m., at noon, 6.00 p.m.). Valproate blood levels were determined. The study revealed that, in contrast to international recommendations, (i) plasma levels were very high, (ii) unnecessary fluctuations occurred, and (iii) obviously valproic acid was too often administered in combined therapy with other antiepileptics.

Adolescent↗

PubMed1989

U.S. experience with valproate in manic depressive illness: a multicenter trial.

Valproic acid and its enteric-coated derivative, divalproex sodium, have been used extensively in a wide variety of seizure disorders. Recent preliminary research demonstrates the effectiveness of valproate in the treatment of manic-depressive illness, including acute mania, prevention of bipolar episodes, and schizoaffective disorder. In uncontrolled and controlled studies, treatment-resistant patients with these disorders have responded well to valproate. Preliminary results of an ongoing community-based open trial of valproate treatment of those affective illnesses reveal that valproate is frequently effective and has a favorable side effect profile. Overall, approximately two out of three patients with refractory bipolar disorder respond to acute therapy with valproate. Response in schizoaffective patients has been moderate, and valproate seems to be less effective in the treatment of depression. Experience suggests the importance of monitoring plasma drug levels to maximize efficacy and minimize potential toxicity.

Adult↗

PubMed1989

The scope and use of valproate in epilepsy.

Valproate has rapidly advanced as an antiepileptic drug in the last 15 years. This simple branched-chain fatty acid is strikingly different from previous antiepileptic drugs. Numerous clinical studies have found valproate to be highly effective in controlling generalized seizures, particularly as monotherapy. Ideally, valproate is given in three to four doses per day, because the elimination half-life varies from 6 to 15 hours, depending on concomitantly administered drugs and metabolic variations. Increasing the dosage raises the peak serum level and also increases the duration of time during which a minimum effective serum concentration is obtained. Drug interactions occur when valproate is administered with other drugs, especially other antiepileptic drugs. Side effects attributed to valproate include tremor, weight gain, hair loss, hair growth, hepatotoxicity, and neural tube defects in offspring of mothers. Monitoring serum valproate concentrations and seizure frequency are essential aspects of patient follow-up.

Epilepsy↗

PubMed1989

Long-term use of valproate in primary psychiatric disorders.

Thirty-five patients, all with major depressive illness, bipolar disorder, or schizoaffective disorder, were retrospectively identified as having received valproate either alone or in combination with lithium, after having failed to adequately respond to previous lithium and/or carbamazepine treatment. Clinical evaluation and Global Assessment Scale (GAS) scores indicated that at baseline all but 3 of the patients experienced serious psychiatric symptoms, serious impairment in social or professional functioning, or significant impairment in reality testing. Mean GAS scores after a mean duration of at least 1 year of valproate administration improved in 7 of 9 depressed patients, 12 of 12 patients with bipolar disorder, and 11 of 14 patients with schizoaffective states. Mean increases in GAS scores were 27.7 points for depressive disorder patients, 34.5 points for mixed bipolar disorder patients, and 17.1 points for patients with schizoaffective states. For patients with either depressive disorders or mixed bipolar disorders, that mean change represented a level of improvement sufficient to elevate the majority of the patients into the mild symptom range or the virtually asymptomatic state. That improvement was confirmed by the investigator's global evaluation of patient response with regard to affect: valproate administration produced significant affective responses in 7 of 9 depressed patients, 12 of 12 patients with mixed bipolar disorders, and 11 of 14 patients with schizoaffective states. The responses of patients with bipolar and schizoaffective disorders to valproate treatment compared with valproate plus lithium treatment were also evaluated. Patients in both diagnostic categories demonstrated very similar and quite substantial improvement in mean change in GAS ratings and global evaluations, regardless of whether valproate was administered alone or in combination with lithium.

Adult↗

PubMed1978

Serum protein binding and pharmacokinetics of valproate in man, dog, rat and mouse.

The serum protein binding of valproate (di-n-propylacetate) has been determined at therapeutic concentrations by equilibrium dialysis in man (94.8%), dog (78.5%), rat (63.4%) and mouse (11.9%). In dog serum, the binding was found to be independent of the valproate concentration in the range of 5 to about 70 microgram/ml, but fell with higher concentrations. In addition, the kinetics of valproate has been determined in dogs and rats. After intravenous administration, serum concentrations declined biexponentially in both species, the half-life of elimination (T 0.5 (beta)) being 1.7 hours in dogs and 4.6 hours in rats. In comparison with the pharmacokinetics of valproate in man and mouse, it can be assumed that the protein binding of valproate is rate-limiting for its clearance by the liver and may be responsible for the striking differences in the half-lives of the drug in different species. Increased drug binding was associated with a decrease in the total clearance and in all species examined, the calculated hepatic extraction ratios (0.009-0,17) were smaller that the free fraction, indicating that valproate fits into the group of drugs with restrictive and liver blood flow independent elimination, i.e., only the unbound drug can be cleared.

Animals↗

PubMed1985

Valproate hepatotoxicity: a review and report of two instances in adults.

Two patients with severe liver damage induced by sodium valproate are described. Both were adults. One had taken valproate for longer than one year before complications developed. The other, in whom the disorder was fatal, had a predominantly 'hepatic' pattern of liver damage with centrilobular necrosis and he also developed pancreatitis. The first patient, who recovered following cessation of valproate intake, manifested a predominantly cholestatic illness with portal tract inflammation. In addition he had a degree of reversible renal failure. Neither subject had microvesicular steatosis on liver biopsy. This report indicates that valproate hepatotoxicity is not always confined to children, that it may develop much later in the course of valproate therapy than has been previously recognized, that it is not necessarily fatal if valproate intake is ceased early enough, and that it may be associated with reversible renal insufficiency.

Adolescent↗

PubMed1984

Genetic influences on the central nervous system depressant and membrane-disordering actions of ethanol and sodium valproate.

The effects of the two central nervous system (CNS) depressant drugs ethanol and sodium valproate were compared using two pairs of mouse lines that had been selected from a heterogeneous stock for differential sensitivity to ethanol. The LS/SS lines differ in sensitivity to ethanol-induced sedation, and the WSP/WSR lines differ in the severity of their withdrawal convulsions after chronic ethanol treatment. We used these lines to test the hypothesis that ethanol and valproate act by the same mechanism. CNS depressant action was assessed by determining the brain drug concentration at which the mice lost their ability to balance on a stationary wooden dowel. LS mice were about twice as sensitive as SS mice to valproate-induced ataxia, in agreement with their reported relative sensitivity to ethanol. The WSR and WSP mice did not differ significantly in sensitivity to ethanol or valproate in this test. The intrinsic order and sensitivity to disordering of synaptosomal plasma membranes prepared from the four lines were measured using fluorescence polarization with the probe 1,6-diphenyl-1,3,5-hexatriene and EPR spectroscopy with 5-doxylstearic acid. No differences in the intrinsic membrane order of the four lines were detected with either technique. The sensitivities of the membranes from the four lines to ethanol- or valproate-induced disordering were not significantly different when measured by fluorescence polarization, but EPR spectroscopy revealed line differences in disordering sensitivity that correlated with the relative sensitivity of the four lines to the CNS depressant action of these drugs. These studies show that genetic factors modulate sensitivity to ethanol and valproate in a similar manner both in vivo and in vitro, suggesting that these drugs act by the same membrane-disordering mechanism.

Animals↗

PubMed1995

Valproate in the treatment of acute bipolar affective episodes complicated by substance abuse: a pilot study.

BACKGROUND: Bipolar disorder is commonly complicated by comorbid substance dependence. Little is known about treatment of this important subpopulation of patients with bipolar disorder. The following study was designed to preliminary explore the use of valproate in a group of patients with comorbid bipolar disorder and substance dependence. METHOD: Nine patients with bipolar disorder, as defined by DSM-III-R, and concurrent substance dependence (five alcohol, three polysubstance abuse, one cocaine) were treated with valproate in an open-label, nonblinded trial. Subjects were followed for a mean of 16 weeks. Ratings included measures of affective state (Young Mania Rating Scale, Hamilton Rating Scale for Depression [HAM-D]) as well as substance use (Time-Line Follow-Back). RESULTS: Patients tolerated valproate well with minimal reports of side effects and no liver toxicity or increase in liver function tests noted. The mean +/- SD maintenance dose of valproate was 1583 +/- 204 mg/day. Subjects evidenced significant decreases in both depression (HAM-D score 17.8 vs. 10.4, p < or = .005) and mania (Young Mania Rating Scale score 12.0 vs. 4.9, p < or = .001) ratings by Week 4, which were sustained throughout the study period. There was a significant decrease in number of days of substance use (t = 4.7, p < or = .005) as well as the amount of substances used during the follow-up period as compared with the month before valproate treatment. CONCLUSION: While limited by the open-label, nonblinded nature of the design, this study provides preliminary evidence for the efficacy of valproate in the acute treatment of bipolar episodes complicated by concomitant substance dependence. The medication was well tolerated, and no unacceptable elevations in liver function tests were seen.

Acute Disease↗

PubMed1997

[Acidosis and hyperlactatemia in acute sodium valproate poisoning].

OBJECTIVES: We searched for signs of metabolic acidosis and associated hyperlactatemia in case of sodium valproate overdose. PATIENTS AND METHODS: A retrospective study was conducted in the toxicology intensive care unit at the Fernand Widal hospital from 1990 to 1995. Patients retained for study had sodium valproate levels above the therapeutic range (> 600 mumol/l). Data collected included past history, intubation for mechanical ventilation, administration of catecholamines and infusion of bicarbonate or sodium lactate, and blood pressure. Laboratory tests included serum sodium valproate, pH, PCO2, bicarbonate, anion balance and lactate. RESULTS: The study included 22 consecutive patients. None had a history of liver disease. Thirteen patients were intubated before admission to intensive care. Two received catecholamines. None of the patients received bicarbonate or sodium lactate. Mean blood pressure was 118 +/- 16 mmHg, mean serum sodium valproate was 2668 +/- 2437 mumol/l, mean pH was 7.41 +/- 0.08, mean PO2 35.6 +/- 8.0, mean anion imbalance 23.2 +/- 6.0 mmol/l and mean lactate 5.0 +/- 2.1 mmol/l. There was a significant correlation between lactase and pH (p < 0.003). CONCLUSION: We found metabolic acidosis with major anion imbalance and high lactate levels in patients with acute sodium valproate intoxication. Hyperlactatemia could be due to the direct effect of sodium valproate or to an unknown mechanism.

Acidosis↗

PubMedDate not supplied

Valproate versus flunarizine in migraine prophylaxis: a randomized, double-open, clinical trial.

The aim of this study was to compare the efficacy and safety of valproate versus flunarizine in migraine prophylaxis in a randomized double-open clinical trial. Twenty-two migraine sufferers were treated with valproate (1 g per day) for 8 weeks; a parallel group of 22 migraine sufferers was treated with flunarizine (10 mg per day). The main admission criterion was a minimum of 3 migraine (with, or without aura) attacks per month. The major clinical parameters evaluated were the frequency of headache attacks, the frequency of use of drugs for the acute management of migraine, the patients' opinion of treatment and the Hamilton anxiety and depression rating scales. During the study 3 patients dropped out (1 from the valproate and 2 from the flunarizine groups). Fifteen patients (71.4%) from the valproate group responded to therapy, compared to 14 patients (65%) from the flunarizine group. In the valproate group 12 patients (57.1%) reported various side effects (prevalently gastric symptoms) versus 10 patients (47.6%) in the flunarizine group (prevalently somnolence). The patients who were treated with flunarizine showed an increase in the mean score of the 21-item Hamilton rating scale for depression, but the difference was not significant; morning dysthymia however, was significantly more often observed in the flunarizine patients, compared to the valproate patients. These results suggest that both drugs are effective and safe in migraine prophylaxis.

Adult↗

PubMed1998

A case of severe hyperammonemia and unconsciousness following sodium valproate intoxication.

Although valproic acid has gradually gained its popularity in the treatment of various seizure disorders, overdose of valproate is not common. An 18-y-old man with a history of epilepsy controlled by sodium valproate and clonazepam attempted suicide with an ingestion of 45 g sodium valproate. He presented to our service with drowsiness and irritability. Extremely high serum ammonia (623 ug/dL) and elevated serum valproate concentration (575 ug/mL) were found on admission. Several metabolic abnormalities, including hypernatremia, hypocalcemia and metabolic acidosis, as well as, increased serum transaminase levels were also recorded. With supportive measures, he became clear 24 h later and was discharged 6 d after ingestion. Serial follow-up of his serum valproate and ammonia levels disclosed a close relationship between these 2 measurables. After acute overdose of valproic acid, patients usually present with mild and generally reversible depression of the central nervous system. However, impairment of liver function, hyperammonemia, fluid-electrolyte disturbances, coma, seizures, hypotension and even death may occur following valproate overdose. Symptomatic and supportive measures are the mainstay in the treatment of valproic acid overdose. With prompt diagnosis and early institution of treatment, a complete recovery should be anticipated.

Adolescent↗

PubMed1979

Comparative trial of valproate sodium and clonazepam in chronic epilepsy.

A crossover comparative study of valproate sodium and clonazepam in the treatment of 32 adult epileptic patients receiving multiple drug therapy is described. Serum concentrations of other anticonvulsant drugs were unchanged by the addition of clonazepam. However, patients receiving high doses of other anticonvulsant drugs had lower serum concentrations of clonazepam (p less than .01). With valproate sodium, phenobarbital concentrations increased (P less than .05) in patients receiving phenobarbital but not significantly in patients receiving primidone. Phenytoin concentrations were reduced (P less than .05) during treatment with valproate sodium. Both drugs significantly reduced the frequency of minor seizures, with valproate sodium having the greater effect. However, it is important to monitor serum concentrations of other anticonvulsant drugs during treatment with valproate sodium since changes in these may influence seizure control or cause side effects.

Adult↗

PubMed1993

Effect of infusion duration on valproate pharmacokinetics.

The pharmacokinetics of intravenously administered valproic acid (VPA) were investigated in 16 healthy male volunteers in a single-dose, fasting, four-period, randomized, double-blind, placebo-controlled, parallel design study. Subjects were randomly assigned to be infused a single dose of sodium valproate equivalent to 1000 mg VPA or placebo over each of four different time periods. Valproate concentrations in plasma were determined using gas chromatography with flame ionization detection. The pharmacokinetic parameters were determined by both non-compartmental and model-dependent techniques. Analyses of variance (ANOVAs) were performed to detect any statistical differences among the regimens. Overall, the pharmacokinetic of valproate were similar after infusions of 5, 10, 30, and 60 min, with an average terminal-phase half-life of 15.9 h. There were modest differences in overall clearances among the regimens, with the 5 min infusion producing a mean area under the plasma concentration-time curve (AUC; 1877 micrograms.h ml-1) that was significantly (13 to 16 per cent) higher than the means for the longer infusions (1614-1656 micrograms.h ml-1). Differences in distribution were also noted as a function of infusion duration. The shortest duration produced a significantly smaller terminal volume of distribution (12.8 vs 14.2-15.1 l) and more rapid tissue equilibration. The alpha-phase rate constant declined from a mean of 5.1 h-1 after the 5 min infusion to a mean of 0.9 h-1 after the 60 min infusion. The distributional differences are almost certainly related to the saturable protein binding of valproate. However, the lower clearance after the 5 min infusion indicates that there may have also been partial saturation of one of the metabolic pathways of valproate during the distributive phase, and that the increase in fu was smaller than the decrease in CL'int, such that the product of fu.CL'int showed a net decrease.

Adolescent↗

PubMed2007

Valproate-induced Parkinsonism in epilepsy patients.

We systematically examined 226 epilepsy patients in a tertiary-referral center and found 6 (5.04%) to have valproate-induced Parkinsonism. There was a significantly higher prevalence of patients with Parkinsonism in the group of patients treated with valproate compared to those who were on other antiepileptic drugs (6 [5.04%] of 119 vs. 0 [0%] of 107; chi2 = 5.54; P = 0.025). These six patients had been on valproate for more than 3 years (mean, 75.67 +/- 25.32 months) at an average dose of 750 +/- 273.86 mg/day. The valproate doses were decreased or discontinued with supplementation from another antiepileptic medication. The mean UPDRS motor score significantly improved from 10.67 +/- 5.1 to 4.75 +/- 2.75 (P < 0.05). There was no relapse of seizures. Clinicians working in tertiary-referral centers should have a high index of suspicion for valproate-induced Parkinsonism. Early recognition and switching into another antiepileptic medication may help reduce unnecessary suffering in these patients.

Adult↗

PubMed1997

Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder: time dependence of peroxidative injury.

Mice fed with sodium valproate for 7, 14 and 21 days were evaluated for hepatotoxicity and renal tubular disorder. The drug was administered as an aqueous solution with an increasing concentration up to five days gradually reaching up to 0.71% w/v, which persisted throughout the study period. Mice fed with sodium valproate for 7, 14 and 21 days showed, marked hepatic injury and renal tubular disorder, evidenced by increased levels of malondialdehyde as a measure of lipid peroxidation. Administration of sodium valproate affected the glutathione contents both in liver and kidney tissue at all the three time points. However, this reduction in glutathione concentration was more pronounced in kidney when compared to control group. These results support the hypothesis that lipid peroxidation mediates the effect of sodium valproate on liver and kidney. Furthermore, the valproate induced toxicity is time related and the increase in lipid peroxide levels and depletion of glutathione occur time dependent even if the dose is clinically appropriate.

Animals↗

PubMed1998

Effect of non-steroidal anti-inflammatory drugs on the anticonvulsive activity of valproate and diphenylhydantoin against maximal electroshock-induced seizures in mice.

Prostaglandins and their inhibitors may affect convulsive phenomena. Thus, the aim of this study was to examine possible interactions between non-steroidal anti-inflammatory drugs and two conventional antiepileptic drugs in terms of their anticonvulsive activity and side-effects. Also, the plasma levels of antiepileptics were measured in order to delineate possible pharmacokinetic interactions. The following non-steroidal anti-inflammatory drugs (NSAIDs) were studied: acetylsalicylic acid, ibuprofen, indomethacin, metamizole, paracetamol and piroxicam. None of these drugs affected the threshold for electroconvulsions. However, all NSAIDs studied enhanced the protective activity of valproate magnesium against maximal electroshock-induced seizures. Only ibuprofen and piroxicam enhanced the anticonvulsive activity of diphenylhydantoin. Ibuprofen decreased the ED50 value of valproate (for the induction of motor impairment) in the rotorod test, whilst piroxicam reduced the ED50 value of valproate in rotorod and chimney tests. Diphenylhydantoin combined with either ibuprofen or piroxicam did not cause any motor impairment in these tests. The total plasma level of valproate and free plasma level of diphenylhydantoin remained unchanged in the presence of all studied NSAIDs. These data demonstrate that NSAIDs could enhance the protective activity of antiepileptics. However, in case of valproate it may be associated with the severe side effects.

Animals↗