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PubMedDate not supplied

Site-dependent intestinal hydrolysis of valproate and morphine glucuronide in the developing rat.

A previous pharmacokinetic study in developing rats suggested that enterohepatic recirculation of valproic acid was absent prior to weaning. One explanation for this observation is that the rate, extent, and/or primary site of glucuronide hydrolysis in the gastrointestinal tract changes during postnatal development. To test this hypothesis, the hydrolysis of two model glucuronide conjugates, valproate glucuronide and morphine-3-beta,D-glucuronide, was examined in vitro in homogenates of small and large intestine obtained from rats at 5-60 days postpartum. Analysis of initial hydrolysis rates indicated that the principal hydrolytic site for both glucuronide conjugates shifted from the upper to lower intestine as the animals developed. The initial hydrolysis rate (nmol/min/g) for valproate glucuronide decreased from 38.1 +/- 10.2 to 8.25 +/- 2.42 in the small intestine, and increased from 14.2 +/- 2.3 to 105 +/- 22 in the large intestine, as rats developed from 5 to 60 days postpartum, respectively. Likewise, the intestinal hydrolysis rate for morphine-3-beta,D-glucuronide decreased from 3.70 +/- 0.46 to 0.646 +/- 0.165 in the small intestine, and increased from 3.50 +/- 0.48 to 115 +/- 30 in the large intestine, as rats developed from 5 to 60 days postpartum, respectively. If hydrolysis occurs immediately after excretion of conjugate into the intestine in neonatal rats, minimal temporal delay between excretion of conjugate and reabsorption of liberated parent may occur, therefore concealing the secondary increase in serum drug concentrations associated with enterohepatic recirculation. In contrast, the time required for conjugates to reach the primary hydrolytic site in adult animals is sufficient for appearance of secondary peaks in the serum drug concentration-time profile.

Age Factors↗

PubMed1994

Concomitant use of valproate and carbamazepine in bipolar and schizoaffective disorders.

From pharmacy records, the authors identified 17 consecutive patients who were treated with carbamazepine and valproate simultaneously. Twelve patients were diagnosed with bipolar disorder, manic or mixed types; four patients received a diagnosis of schizoaffective disorder, manic type; and one had major depression and posttraumatic stress disorder. All 12 bipolar patients had a moderate to marked response to the combination drug treatment, whereas all 4 schizoaffective patients failed to respond. Only two patients had minor side effects. The authors conclude that the combination of valproate and carbamazepine is usually well tolerated and that it can be effective in bipolar patients who have previously failed to respond to anticonvulsant monotherapy.

Adult↗

PubMed1993

Predictors of valproate response in bipolar rapid cycling.

Multiple regression/discriminant analyses were separately conducted to generate predictors of acute and prophylactic antimanic and depressive outcome in 101 valproate-treated bipolar rapid cyclers. Predictors of good antimanic response included decreasing or stable episode frequencies and nonpsychotic mania. Predictors of good antidepressant response included nonpsychotic mania worsening over the years of the illness and absence of borderline personality disorder comorbidity. This report confirms prior findings that indicate that valproate possesses marked acute and prophylactic antimanic and antimixed effects with only poor to moderate antidepressant properties.

Adult↗

PubMed1993

Rapid cycling bipolar disorder and its treatment with valproate.

A large subgroup of lithium-resistant manic patients are rapid cyclers and as many as 82% of them exhibit poor responses to lithium. Thus, a substantial percentage of poor responses to lithium is accounted for on the basis of rapid cycling. Although controlled trials have demonstrated the efficacy of carbamazepine for the treatment of rapid cycling bipolar disorder, the response to carbamazepine frequently deteriorates. Furthermore, its ability to auto-induce and hetero-induce drug metabolism complicates its routine use. These findings suggest that substantial numbers of rapid cyclers do not respond to either carbamazepine or lithium and that additional mood stabilizers are needed. Our recent findings on 101 rapid cycling bipolar patients continue to support the impression that valproate has marked antimanic efficacy and poor to moderate antidepressant properties. Most patients with mixed states exhibited good antimixed state responses but then became depressed. Predictors of a good antimanic response included decreasing or stable episode frequencies and non psychotic mania. Predictors of a good antidepressant response were non psychotic mania worsening over the years of the illness and absence of borderline personality disorder comorbidity. These open prospective trials, as well as other positive reports of valproate's efficacy in bipolar rapid cycling, await replication with ongoing, controlled maintenance trials.

Adult↗

PubMed1995

[Parkinsonism induced by sodium valproate].

Parkinsonism is a rare side effect of treatment with sodium valproate. We report 2 elderly women who developed parkinsonian syndrome several years after starting valproate therapy, and in whom symptoms disappeared when treatment was withdrawn. These cases, along with others in the literature, may support experimental evidence for the importance of GABAergic modulation in motor control.

Aged↗

PubMedDate not supplied

Antidegenerative effects of Mg(2+)-valproate in cultured cerebellar neurons.

We have investigated in the present study the effect of Mg(2+)-valproate on necrotic degeneration induced by an excitotoxic insult in primary culture of cerebellar neurons, that is an homogeneous population of glutamatergic neurons. Mg(2+)-valproate protected cultures against glutamate-induced neurotoxicity, acting as an indirect N-methyl-D-aspartate (NMDA) receptor antagonist, thus reducing free radical formation and affecting the biochemical parameters (i.e. 45Ca(2+)-influx, cyclic GMP formation, inositol phospholipid hydrolysis and protein kinase C translocation) that undergo modifications following NMDA receptor activation in cerebellar granule cells.

Animals↗

PubMed1996

[Outcome of initial treatment with high-dose vitamin B6, valproate sodium or clonazepam in West syndrome].

We reviewed the outcome (seizures and development) of 25 cases with West syndrome in which antiepileptic drugs (valproate sodium, clonazepam) or high doses of vitamin B6, instead of ACTH therapy, were administered for the initial treatment. Five of 9 cryptogenic cases (56%) and 4 of 16 symptomatic cases (25%) showed complete cessation of spasms. In cryptogenic cases, response to vitamin B6, valproate sodium or clonazepam was not predicted by clinical features (age of onset, seizure type, initial EEG finding or treatment lag). On the other hand, response to these drugs was correlated with some clinical findings in symptomatic cases; all infants with neurocutaneous syndrome (tuberous sclerosis, neurofibromatosis type 1) had controlled infantile spasms, while none of patients with severe neonatal asphyxia or with prior other seizures responded. Twenty of 25 patients have been followed-up. The average age at follow-up was 5 years and 8 months. Prognosis of both cryptogenic and symptomatic "responders" was favorable; all had seizures controlled, and 50% had normal psychomotor development or only mild impairment (DQ > 70). Symptomatic "nonresponders" had the worst prognosis. Our results suggest that choice of drug in the initial treatment of West syndrome should be determined by clinical features (especially etiology).

Anticonvulsants↗

PubMed1996

Valproate as an antidepressant in major depressive disorder.

Thirty-three outpatients who met DSM-IV criteria for major depressive disorder (MDD) with no history of manic or hypomanic symptomatology were enrolled in an 8-week open trial of valproate. By Week 4, 15 of the 28 completers (54%) demonstrated a significant clinical response as defined by a score reduction of 50 percent or more or a total score of 9 or lower on the Hamilton Rating Scale for Depression (HRSD). Mean HRSD scores of the completers decreased 48.8 percent at Week 4 (p < .0001). At Week 8, 19 of the 22 completers (86%) showed a significant response. Mean HRSD scores decreased from 22 +/- 5 at baseline to 7 +/- 4 at Week 8 (p < .0001). With the intent-to-treat analysis at Week 8, 66 percent were responders, and total group mean HRSD scores decreased 55 percent (p < .0001). The data suggest that valproate may be an effective treatment for MDD. Double-blind, placebo-controlled trials are needed to further document its efficacy in the treatment of MDD.

Adult↗

PubMedDate not supplied

[The effect of difenin, valproate and phenobarbital on the development of an epileptiform seizure attack in Krushinskiĭ-Molodkina rats].

The anticonvulsant action of diphenin, sodium valproate, and pentobarbital was studied in Krushinskiĭ-Molodkina (KM) rats subjected to audiogenic seizures. The anticonvulsant effects of the drugs were different and dose-dependent. Valproate in a dose of 120 mg/kg completely eliminated the tonic phase of seizures. Given in a dose of 300 mg/kg it in 50% of cases prevented from the development of the initial seizure stage of motor excitation. The peculiarity of the pentobarbital action consisted in its ability to change the character of motor excitation during sound stimulation from the one-wave reaction for the two-wave.

Acoustic Stimulation↗

PubMed1997

gamma-Hydroxybutyrate conversion into GABA induces displacement of GABAB binding that is blocked by valproate and ethosuximide.

gamma-Hydroxybutyrate (GHB) has been reported to be a ligand for GABAB receptor(s), although with low or very low affinity (IC50 = 150-796 microM). In addition, several reports argue for a role of GHB via GABAB receptors in both in vivo and in vitro electro-physiological experiments. In the present study, we demonstrate that the inhibition of GHB's conversion into GABA by rat brain membranes blocks the ability of GHB to interfere with GABAB binding. In particular, the inhibition of GHB dehydrogenase by valproate or ethosuximide and the blockade of GABA-T by aminooxyacetic acid induce the disappearance of the GABA-like effect of GHB at GABAB, but also at GABAA, receptors. This finding could explain the misinterpretation of in vitro or in vivo experiments where GHB possesses a GABA-like effect. But in addition, it is postulated that the normal metabolism of GHB in brain induces GABAB mechanisms that could be blocked by the administration of valproate or ethosuximide.

4-Aminobutyrate Transaminase↗

PubMed1998

Influence of caffeine on pharmacokinetic profile of sodium valproate and carbamazepine in normal human volunteers.

The present study evaluates effect of pharmacokinetic interaction between caffeine (300 mg) in three divided doses with sodium valproate (400 mg) and carbamazepine (200 mg) given as single doses, in normal human volunteers, using a open cross over design. Both the serum concentration of sodium valproate and pharmacokinetic parameters remained unaltered, as against significant reduction in plasma concentration and area under the concentration curve of carbamazepine following the coadministration of caffeine. Also, the plasma t 1/2 (of carbamazepine was prolonged by two folds and bioavailability reduced by about 32% in presence of caffeine. The results are of clinical significance as xanthine consumption may have to be restricted in patients on carbamazepine therapy and this aspect may need further investigation.

Anticonvulsants↗

PubMed2026

Valproate vs levetiracetam in juvenile myoclonic epilepsy: systematic review and meta-analysis.

INTRODUCTION: Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy syndrome with onset typically in adolescence and a chronic course requiring long-term antiseizure medications (ASMs). Valproate (VPA) is the most effective treatment for seizure control in JME but use is limited by metabolic, cognitive, and teratogenic adverse effects (AEs). Levetiracetam (LEV) is an alternative ASM when VPA is contraindicated or not tolerated. Comparisons of the efficacy and long-term tolerability of VPA and LEV remain limited. METHODS: We conducted a systematic review and meta-analysis using PRISMA guidelines and the Cochrane Handbook. We searched PubMed, Embase, and the Cochrane Library from inception through January 2026 for studies in JME patients comparing LEV and VPA, and included randomized controlled trials and comparative observational studies with ≥ 6 months of follow-up. Primary outcomes were seizure remission and ASM failure or treatment discontinuation. Secondary outcomes included, memory impairment, weight gain or obesity, dizziness, and overall AEs. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Heterogeneity was assessed using the I2 statistic. RESULTS: Seven studies encompassing 1,009 patients were included. VPA was associated with higher pooled seizure remission rates compared with LEV (344 of 574 vs. 169 of 390; RR 1.44, 95% CI 1.27-1.63); however, substantial heterogeneity (I2 = 88.4%) limits confidence in this finding. VPA was associated with a lower risk of drug failure or treatment discontinuation (RR 0.68, 95% CI 0.54-0.86), with no heterogeneity (I2 = 0.0%). VPA was also associated with a higher risk of memory impairment (RR 5.37, 95% CI 2.05-14.04; I2 = 74.5%) and weight gain or obesity (RR 6.40, 95% CI 3.64-11.26; I2 = 35.9%). No significant differences were observed between treatments regarding dizziness (RR 0.91, 95% CI 0.61-1.37; I2 = 21.2%). Sensitivity analyses confirmed the robustness of the pooled estimates. CONCLUSION: VPA was associated with higher seizure remission rates and lower treatment discontinuation compared with LEV; however, these findings must be interpreted with caution given the substantial heterogeneity, the predominance of observational studies, and the serious risk of bias identified in most included studies VPA also demonstrated lower rates of treatment discontinuation, despite a higher burden of cognitive impairment and weight gain. No relevant differences were observed regarding dizziness. Large-scale randomized trials with standardized outcome definitions and longer follow-up are needed to define the comparative risk-benefit profiles of LEV and VPA in JME.

Humans↗

PubMed1977

Valproate sodium in Huntington chorea.

An open trial of valproate sodium in 14 patients suffering from Huntington chorea showed that the drug was ineffective in the two treatment schedules employed.

Adolescent↗

PubMed1979

Postanoxic action myoclonus (Lance-Adams syndrome) responding to valproate.

A patient with postanoxic action myoclonus (Lance-Adams syndrome) was severely disabled with this movement disorder. Valproate sodium was administered orally, with complete resolution of the myoclonus. This favorable response has been maintained for two years. Excessive yawning, the only side effect encountered, was dose related and was abolished with the addition of pimozide to the drug regimen.

Adult↗

PubMed1981

Dissociation between free and bound phenytoin levels in presence of valproate sodium.

A dissociation of free vs bound phenytoin levels is frequently observed in the presence of therapeutic doses of valproate sodium. This leads at times to symptoms and signs of phenytoin intoxication despite "therapeutic" plasma levels. The importance of supplementing bound levels with free levels is stressed when combined therapy of this type is used in epileptic patients.

Adult↗

PubMed1996

Dose-dependent distribution volumes of total and unbound valproate in guinea-pigs: consequence of non-linear plasma protein binding.

The response of steady-state distribution volume (Vdss for total and Vdssu for unbound drug) of valproate (VPA) to dose-dependent plasma protein binding was studied in guinea-pigs. Various steady-state plasma concentrations of VPA were achieved by intravenous constant infusion. The concentrations of VPA in plasma (Css for total and C(uss) for unbound drug) and various tissues (CT) were determined. The Vdss and the Vdssu were estimated based upon the apparent tissue-to-plasma concentration ratio of VPA. The results showed that the plasma unbound fraction (fu) of VPA increased significantly with dose. The Vdss was significantly increased with, while the Vdssu was significantly decreased against the increasing dose. The increase in Vdss with dose indicated an increase in tissue-to-plasma concentration ratio, which may be attributed to the increase in distribution of unbound drug from plasma to tissues subsequent to non-linear plasma protein binding. The decrease in Vdssu against the increasing dose indicated a decrease in tissue-to-unbound plasma concentration ratio, which suggests that the extravascular distribution of unbound VPA might be capacity limited and the tissue binding of VPA negligible.

Animals↗

PubMed1984

The fetal valproate syndrome.

We evaluated seven children who had been exposed to sodium valproate (or valproic acid) in utero. A consistent facial phenotype was observed in all seven in addition to other birth defects in four. The facial changes consisted of epicanthal folds which continued inferiorly and laterally to form a crease or groove just under the orbit, flat nasal bridge, small upturned nose, long upper lip with a relatively shallow philtrum, a thin upper vermillion border, and downturned angles of the mouth. Hypospadias, strabismus, and psychomotor delay were found in two males; two children had nystagmus and two had low birth weight.

Epilepsy↗

PubMed1988

Verification of the fetal valproate syndrome phenotype.

We have evaluated 19 children who were exposed to valproic acid (VPA) in utero to look for manifestations of a fetal valproate syndrome (FVS), as proposed by Di Liberti et al. [1984]. We found no consistent alterations of pre- or postnatal growth with exposure to VPA monotherapy. Postnatal growth deficiency and microcephaly were present however, in two thirds of children exposed to VPA in combination with other anticonvulsants. Developmental delay or neurologic abnormality was found in 71% of those exposed to VPA monotherapy, and in 90% of those exposed to VPA and other anticonvulsants. Craniofacial anomalies, which can be seen with other anticonvulsant exposures, including midface hypoplasia, short nose with a broad and/or flat bridge, epicanthal folds, minor abnormalities of the ear, philtrum or lip, and micrognathia were also found in infants whose mothers used VPA. Prominent metopic ridge and outer orbital ridge deficiency or bifrontal narrowing and certain major anomalies such as tracheomalacia, talipes equinovarus (with intact spine) and lumbosacral meningomyelocele seem to be peculiar to infants with VPA exposure. Other defects such as urogenital anomalies, inguinal or umbilical hernias, and minor digital anomalies that are common to other prenatal anticonvulsant exposures are also occasionally found in those exposed to VPA. Heart defects have been found in infants exposed to nearly every class of anticonvulsant although the types of defects associated with maternal VPA use may be clarified when classified by pathogenetic mechanism. Our findings overall are in agreement with the report of Di Liberti et al. [1984].

Abnormalities, Drug-Induced↗