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PubMedDate not supplied

[Severe vigilance disturbances: a rare complication of sodium valproate treatment (author's transl)].

Severe vigilance disturbances are rarely observed during sodium valproate treatment. Two such cases are reported, with rapid appearance of mental confusion after starting treatment, associated with an overall slowing of the E.E.G. the plasma levels of the different anti-epileptic agents were normal or only slightly raised and could not have caused the phenomenon. Clinical and electrical signs regressed as rapidly after stopping valproate administration as they had appeared after starting treatment.

Adult↗

PubMed2002

Remission of West syndrome associated with valproate hepatotoxicity.

A 6-month-old girl developed West syndrome and it remitted in association with valproate-induced hepatic dysfunction. Plasma -alanine elevated after valproate hepatotoxicity, which seemed to be a possible cause of remission. The patient has been seizure-free with normal electroencephalogram for 12 months without any anticonvulsants. Her developmental milestones were within normal limits at the age of 18 months.

Anticonvulsants↗

PubMed1997

Correlation of in vitro anti-proliferative potential with in vivo teratogenicity in a series of valproate analogues.

The prediction that an anti-proliferative effect coupled with a pro-differentiative action will detect a neural tube teratogen has been validated by comparison of these in vitro endpoints with in vivo teratogenicity in a series of closely allied valproate structural analogues. The majority of the compounds significantly inhibited C6 glioma proliferation, the most potent compounds being ranked as octanoic acid > 2-propylhexanoic acid > or = 2-ethylhexanoic acid > or = valproic acid. The anti-proliferative potency of these compounds did not correlate strictly to their relative in vivo teratogenic potential. Valproic acid exhibited an anti-proliferative IC50 of 1.45 mM, whereas 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid were virtually indistinguishable, exhibiting significantly lower IC50 values of 2.5 and 2.55 mM, respectively. The concanavalin A lectin affinity assay was employed to establish whether an anti-proliferative action was coupled with an increased state of cell differentiation. In this lectin affinity assay, the most potent analogues to significantly attenuate the affinity of exposed C6 glioma cells for concanavalin A lectin-coated plastic included 2-butylhexanoic acid, 2-propyl-4-pentenoic acid, 2-propylhexanoic acid and 2-ethylhexanoic acid in a manner which can be related to their relative teratogenic potencies in vivo. All compounds screened positive in both the anti-proliferative and pro-differentiative assays exhibited in vivo exencephalic rates of 5-44%. These included valproic acid, 2-ethylhexanoic acid, 2-propylhexanoic acid and 2-butylhexanoic acid. It would appear that combined anti-proliferative and pro-differentiative screens provide a promising detection system for teratogenic status in a series of valproate analogues.

Abnormalities, Drug-Induced↗

PubMed2001

Effects of sodium valproate on corticotropin-releasing factor systems in rat brain.

We hypothesized that divalproex sodium, an anticonvulsant effective in the acute treatment of mania, may act upon neuropeptide systems that utilize corticotropin-releasing factor (CRF). Pharmacokinetic studies demonstrated that valproate has an apparent elimination half life of 17 minutes in rats after acute administration and that there is a nonlinear relationship between chronic dose and serum drug concentration. Acute valproate treatment neither altered plasma adrenocorticotropic hormone (ACTH) or corticosterone concentrations nor produced changes in CRF concentration in any of 10 brain regions examined. Subchronic treatment via SC-implanted osmotic minipumps (875 mg/kg/day x 7 days) resulted in decreased CRF concentrations in the median eminence and raphe nuclei. Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus. The benzodiazepine alprazolam, also a positive modulator of GABAergic function, similarly decreases CRF mRNA expression in the CeA. These results suggest that the mood stabilizing effects of valproic acid may be mediated in part by alterations in CRF neuronal activity.

Animals↗

PubMed2003

Valproate unbound fraction and distribution volume following rapid infusions in patients with epilepsy.

The availability of an intravenous formulation now makes possible rapid administration of valproate (VPA) loading doses, but estimates of key VPA pharmacokinetic parameters in patients have limited the use of this approach. VPA disposition was characterized in 112 epilepsy patients, with or without enzyme inducing comedications, randomized to either 3.0 or 1.5mg/kg/min infusions of valproate sodium injection. Maximum dose was </=15mg/kg per infusion. Total and unbound plasma VPA concentrations were determined from blood samples obtained prior to and for 6h following the infusion. Analyses of covariance assessed the effect of induction, weight, age, gender, albumin, creatinine, and infusion rate on pharmacokinetics. Maximum total and unbound VPA concentrations were 94 and 14mg/l, respectively. Total concentration fell below 50mg/l within 3h in induced and 6h in uninduced patients. VPA unbound fraction decreased from 15% at maximum concentration to 9% at 45mg/l. The mean (S.D.) distribution volume was 0.21 (0.044)l/kg. Induction status, albumin concentration, and infusion rate significantly affected pharmacokinetics. Measurement of unbound VPA may be useful when alterations in binding are suspected. Infusions up to 3mg/kg/min produce predictable total VPA concentrations when induction status and albumin levels are considered.

Adolescent↗

PubMed1998

Effects of new valproate derivatives on epileptiform discharges induced by pentylenetetrazole or low Mg2+ in rat entorhinal cortex-hippocampus slices.

The effects of four valproic acid derivatives were studied on pentylenetetrazole-induced epileptiform discharges in combined entorhinal cortex hippocampus slices. The two new sugar-esters of valproic acid, dimethylenexylitol valproate (VDMX, 0.5 mM) and glucose valproate (VG, 2 mM) abolished the epileptiform activity. These two new derivatives were compared to two clinically used anticonvulsant drugs, valpromide (2 mM) which suppressed the activity and valproic acid (2 mM), which was ineffective. The new drugs VDMX and VG were also tested on different patterns of epileptiform activity induced by lowering of [Mg2+]0. A 1 mM concentration of VDMX and 2 mM VG, reversibly suppressed the recurrent short discharges in area CA1 and the seizure-like events in the entorhinal cortex. A concentration of 2 mM VDMX was required to abolish the late recurrent discharges in entorhinal cortex. VG at 2 mM reduced the frequency of these discharges by 58.5+/-9.5%.

Animals↗

PubMed1993

Temporary abolition of seizure activity by flumazenil in a case of valproate-induced non-convulsive status epilepticus.

We report on a 33-year-old female suffering from frequent complex-partial seizures who developed a non-convulsive status epilepticus after one week of antiepileptic therapy with valproate (VPA) which had been added to a basic medication with barbexaclone (BBC) in rapidly increasing dosage. The electroencephalogram (EEG) showed continuous rhythmic generalized sharp and slow wave activity with a frontal maximum. Intravenous administration of 3.0 mg of the benzodiazepine (BZ) receptor antagonist flumazenil under monitoring with video-EEG led to an immediate and marked electroclinical improvement, whereas 6.0 mg of the BZ receptor agonist midazolam was followed by a deterioration both clinically and in the EEG. We discuss the concept of VPA-encephalopathy and the possible mechanisms of the action of flumazenil on VPA-induced as well as on other toxic and metabolic encephalopathies. Flumazenil might antagonize increased benzodiazepine receptor activity with agonistic and even convulsive properties in these encephalopathic syndromes. Further investigations are needed concerning the relation of drug-induced or metabolic encephalopathies and central benzodiazepine receptor activity. We recommend a therapeutic trial with flumazenil, if stupor or decreased seizure control develop in patients treated with valproate.

Adult↗

PubMed1998

Pathological laughter following intravenous sodium valproate.

BACKGROUND: Pathological laughter can be a sign of epilepsy, psychiatric illness, effect of toxins or psychotropic drugs or of structural brain disease. METHOD: Case Studies. RESULT: Two patients developed inappropriate uncontrollable laughter following intravenous sodium valproate for treatment of epilepsy. CONCLUSION: Pathological laughter can be a side effect of intravenous sodium valproate.

Adolescent↗

PubMed1998

Effect of valproate on the pharmacokinetics of free and total plasma bilirubin in experimental hyperbilirubinemia in guinea pigs.

The effects of valproate (VPA) on free and total bilirubin concentrations in plasma were studied in guinea pigs. Steady-state hyperbilirubinemia (around 2.5-3.0 mg/100 mL) was induced by constant intravenous (i.v.) infusion of bilirubin followed by an i.v. bolus dose of sodium valproate (VPA-Na) of 50 (n = 4) or 200 (n = 5) mg/kg. Steady-state plasma total bilirubin concentration was lowered by 40% and 55% and the unbound fraction (fu) increased by 1.9- and 4.9-fold at the respective doses of 50 mg/kg and 200 mg/kg VPA-Na. Free bilirubin was not significantly changed by 50 mg/kg VPA-Na, but did show a significant transient elevation with the 200 mg/kg dose. In another experiment, guinea pigs (n = 3) were given a constant i.v. infusion of VPA-Na to maintain a steady-state plasma concentration (58 micrograms/mL), followed by an i.v. bolus dose of bilirubin (2 mg/kg). A control study (n = 3) was performed simultaneously using normal saline instead of VPA. Free bilirubin was detectable only following induction of hyperbilirubinemia in either group. A higher volume of distribution and lower elimination rate constant of bilirubin were observed in the VPA-treated than in the control animals. The displacement effect of VPA on bilirubin-plasma binding in vitro was studied by adding serial concentrations of VPA-Na to bilirubin-plasma solution. VPA displaced bilirubin from the high-affinity plasma protein binding site, with a binding constant (KD) of 5.7 x 10(-2)/microM. Similar displacement of bilirubin plasma protein binding was observed in vivo. These results suggest that VPA reduces plasma protein binding and slows the elimination rate of bilirubin. The principal mechanism for decreased plasma concentrations of total bilirubin by administration of VPA is caused by decreased plasma binding, as opposed to metabolic induction.

Animals↗

PubMed2000

Apparent autoinduction of valproate beta-oxidation in humans.

AIMS: The study aimed to show whether autoinduction of valproate (VPA) along its beta-oxidation pathway occurred upon chronic dosing in humans. METHODS: Twelve young volunteers without active illness took sodium valproate (NaVPA) 200 mg orally 12 hourly for 3 weeks. On days 7 and 21, serial blood samples and all urine passed over an interdosing interval from 08.00 to 20.00 h were collected for analysis of VPA and certain metabolites. RESULTS: Plasma AUC(0,12 h) of VPA was significantly lower on day 21 than on day 7 (2.40 vs 2.84 micromol ml-1 h, 95% CI for the difference 0.13-0.81 micromol ml-1 h). Significant differences in plasma AUC(0,12 h) of the beta-oxidation metabolites E-2-en-VPA and 3-oxo-VPA were not found. However, formation clearances of plasma VPA to urinary E-2-en-VPA and 3-oxo-VPA were significantly increased from day 7 to day 21 (0. 010 vs 0.024 and 2.57 vs 3.60 ml kg-1 h-1, respectively, 95% CI for the differences -0.025 to -0.004 and -1.72 to -0.34 ml kg-1 h-1, respectively). Formation clearances to VPA-glucuronide (0.534 vs 0. 505 ml kg-1 h-1) and 4-OH-VPA (0.112 vs 0.110 ml kg-1 h-1) were not significantly different. CONCLUSIONS: Regular low dose VPA intake in humans over a period of 3 weeks appears to be associated with a small induction of its metabolism by the beta-oxidation pathway, but not by glucuronidation or 4-hydroxylation.

Adolescent↗

PubMed2003

Lithium and valproate decrease the membrane phosphatidylinositol/phosphatidylcholine ratio.

Lithium and valproate, two structurally different anti-bipolar drugs, cause decreased intracellular inositol in the yeast Saccharomyces cerevisiae and an in-crease in expression of a structural (INO1) and a regulatory (INO2) gene for phospholipid synthesis that responds to inositol depletion (Vaden, D., Ding, D., Peterson, B., and Greenberg, M.L., 2001, J Biol Chem 276: 15466-15471). We report here that both drugs decrease the relative rate of membrane phosphatidylinositol synthesis and, to a lesser but still significant degree, the steady state relative phosphatidylinositol composition. In addition, both drugs increase the rate of phosphatidylcholine (PC) synthesis. Finally, valproate, but not lithium, increases expression of phosphatidylcholine pathway genes CHO1 and OPI3. The overall effect on membrane phospholipid composition is a reduction in the phosphatidylinositol/phosphatidylcholine ratio by both drugs. Because maintenance of the appropriate phosphatidylinositol/phosphatidylcholine ratio is required for secretory vesicle formation, a decrease in this ratio may have far-reaching implications for understanding the therapeutic mechanisms of action of these drugs.

Cell Membrane↗

PubMed1989

Sodium valproate in the treatment of cluster headache: an open clinical trial.

The effect of prophylactic treatment with sodium valproate in cluster headache was investigated in an open pilot study. Fifteen cluster headache patients were studied of whom two suffered from chronic cluster headache and thirteen from the episodic type. The dose used was between 600 and 2000 mg per day in two divided doses. Eleven out of the fifteen patients (73.3%) reacted favorably to the treatment. Nine reported a complete disappearance of pain and two, a marked improvement. Sodium valproate appears to be an effective drug in the treatment of cluster headache. A double-blind controlled study is needed for further evaluation.

Adult↗

PubMed2000

Valproate prophylaxis for migraine induced by selective serotonin reuptake inhibitors.

We report the successful use of valproate in a 44-year-old woman with migraine induced by selective serotonin reuptake inhibitors. Valproate should be considered for those patients who develop serious migraine for the first time, or worsening of previous migraine, after the initiation of treatment with selective serotonin reuptake inhibitors and for whom continued treatment with this class of drugs is important.

Adult↗

PubMed2002

Acute pancreatitis coincident with valproate use: a critical review.

PURPOSE: Acute pancreatitis has been associated with a number of medications, including valproate (VPA). Valproate-coincident pancreatitis is uncommon and is usually associated with other risk factors; however, the United States Food and Drug Administration has issued a box warning for risk of acute pancreatitis with VPA products. We reviewed cases of pancreatitis in VPA-treated patients from the clinical database of VPA/divalproex trials and compared the incidence of elevated amylase levels between VPA- and placebo-treated patients. METHODS: Report rates of acute pancreatitis coincident with VPA use in 34 clinical trials were calculated. Incidence rates of amylase elevations above the normal range in three clinical placebo-controlled migraine trials were compared between VPA- and placebo-treated patients. RESULTS: Among 3,007 VPA-treated patients in 34 clinical trials, two reports of pancreatitis were considered by investigators to be probably related to VPA. Both patients recovered. Similar rates of amylase elevations were observed in VPA- (5.9%) and placebo-treated (6.1%) patients in the three migraine headache trials. CONCLUSIONS: VPA-coincident acute pancreatitis is uncommon and idiosyncratic. Checking amylase levels in the absence of other clinical signs and symptoms provides little value for predicting pancreatitis. Physicians should be guided by clinical symptoms of pancreatitis to identify cases.

Acute Disease↗

PubMed2002

Pro- and anticoagulatory factors under sodium valproate-therapy in children.

OBJECTIVE: To evaluate sodium valproate-induced hemostatic side effects in children. METHODS: A variety of both pro- and anticoagulatory parameters were longitudinally investigated in 80 children before therapy and up to 720 days after initiation of sodium valproate (VPA) therapy. RESULTS: VPA caused a significant reduction in platelet count (309,000/ micro l +/- 122,000 before treatment to 261,000/ micro l +/- 150,000 under VPA therapy, p = 0.007). However platelet function was not impaired. While vWF antigen was reduced during VPA therapy (1.05 U/ml +/- 0.4 U/ml before therapy, 0.95 +/- 0.4 U/ml under VPA therapy), the in vivo activity of vWF (ratio between function and antigen concentration) increased significantly (1.06 +/- 0.2 before therapy, 1.36 +/- 0.3 under VPA therapy, p = 0.01). Both procoagulatory and anticoagulatory factors were significantly reduced (fibrinogen: 264.5 +/- 64.5 mg/dl before therapy, 221.4 +/- 47.5 mg/dl under therapy, p = 0.001; protein C: 81.3 % +/- 18 before therapy, 65.6 % +/- 21.4 under VPA therapy, p = 0.005, antithrombin: 122.7 % +/- 23.7 before therapy, 101.7 % +/- 18 under VPA therapy, p = 0.04). With the exception of fibrinogen, these effects were identical in children treated either with monotherapy or with polytherapy. CONCLUSIONS: Besides already known alterations of a variety of procoagulatory parameters, a relevant influence of VPA on the anticoagulatory system is demonstrated. We hypothesize that this additional alteration of anticoagulatory parameters might reduce the absolute bleeding risk of children treated with VPA.

Adolescent↗

PubMed2005

Risperidone-associated transient diabetic ketoacidosis and diabetes mellitus type 1 in a patient treated with valproate and lithium.

UNLABELLED: A 37-year-old man treated with valproate and lithium for bipolar affective disorder since 1999 and with risperidone since March 2003 was admitted to our clinic due to metabolic acidosis. Serum glucose was 647 mg/dL and urine ketones were positive. The patient was accepted as diabetic ketoacidosis (DKA). Risperidone, valproate, and lithium were immediately stopped, and the patient was treated with insulin and i.v. fluid replacement. Serum insulin and C-peptide levels were too low, and islet cell antibody and anti-GAD antibody were positive. We accepted him as type 1 diabetes mellitus (DM type 1). After the intensive treatment of diabetes, insulin requirements decreased gradually and diabetes mellitus disappeared completely within three months. CONCLUSION: Risperidone may lead to transient DM type 1 and DKA.

Adult↗

PubMed1996

Addition of lamotrigine to valproate may enhance efficacy in the treatment of bipolar affective disorder.

The new antiepileptic lamotrigine has been shown to be effective in the treatment of focal epilepsies with or without secondary generalization and has also been suggested to be efficacious in the treatment and prophylaxis of affective disorders. Therefore, we analyzed its possible benefit in a patient with refractory bipolar affective disorder. Lamotrigine (up to 150 mg/d) was added to valproate (2700 mg/d), substituting previously administered neuroleptics. A considerable improvement of the patient's condition was achieved several days after the beginning of lamotrigine co-administration, and lasted over the total follow-up period of more than one year. The plasma concentrations after total remission were in the range of 1.9 to 6.2 mg/l for lamotrigine and 57.1 to 95.2 mg/l for valproate. This positive action of lamotrigine is discussed in the context of the drug's elementary effects on sodium and calcium channels.

Adult↗

PubMed1999

[Encephalopathies caused by valproate].

Valproic acid (VPA)-induced encephalopathy is a rarely considered side effect, with somnolence, reduced motor activity and severe deterioration of cognitive and behavioural abilities. In accordance with the increasing clinical importance of valproate clinical symptoms, causes and possibilities of treatment are reviewed by reporting on two cases of valproate-induced encephalopathy. In comparison to VPA intoxication, which is associated to increased VPA blood levels, the mechanisms of encephalopathy may include interactions of the hepatic enzymes, a direct toxic effect on the cerebral receptors, as well as drug interactions, a paradoxical epileptogenic effect and metabolic interactions. In most cases withdrawal of VPA produces regression of the symptoms within a few days; the role of L-carnitin or citrullin supplementation in clinical treatment remains unclear.

Adult↗