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PubMed1984

Reversal of the anti-conflict action of valproate by various GABA and benzodiazepine antagonists.

The effects of RO 15-1788, RO 5-3663, picrotoxin and bicuculline on the anti-conflict properties of valproate were studied in rats using a modified Vogel 's conflict test procedure. A low dose of the benzodiazepine (BDZ) antagonist, RO 15-1788 (5 mg/kg), blocked the anti-punishment properties of valproate (400 mg/kg), whereas no antagonism was observed after a high dose (25 mg/kg) of the BDZ antagonist. High doses of RO 5-3663 or picrotoxin also reversed the anti-conflict action of valproate. Bicuculline did not change the effects of valproate in this test situation. The suppressive effect of valproate on locomotor activity was reversed by a low dose (5 mg/kg) of RO 15-1788, but not by the other antagonists. RO 5-3663 was the only antagonist which effectively reversed the muscle relaxant effects of valproate observed in a Rotarod performance test. These findings indicate that various pharmacological actions of valproate may be due to a complex interplay with several sites at the GABA-BDZ-receptor complex.

Animals↗

PubMed1990

Effect of the antiepileptic drug sodium valproate on glutamine and glutamate metabolism in isolated human kidney tubules.

We studied the effects of sodium valproate, a widely used antiepileptic drug and a hyperammonemic agent, on L-[1-14C]glutamine and L-[1-14C]glutamate metabolism in isolated human kidney-cortex tubules. Valproate markedly stimulated glutamine removal as well as the formation of ammonia, 14CO2, pyruvate, lactate and alanine, but it inhibited glucose synthesis; the increase in ammonia formation was explained by a stimulation by valproate mainly of flux through glutaminase (EC 3.5.1.2) and to a much lesser extent of flux through glutamate dehydrogenase (EC 1.4.1.3). By contrast, valproate did not stimulate glutamate removal or ammonia formation, suggesting that the increase in flux through glutamate dehydrogenase observed with glutamine as substrate was secondary to the increase in flux through glutaminase. Accumulation of pyruvate, alanine and lactate in the presence of valproate was less from glutamate than from glutamine. Inhibition by aminooxyacetate of accumulation of alanine from glutamine caused by valproate did not prevent the acceleration of glutamine utilization and the subsequent stimulation of ammonia formation. It is concluded from these data, which are the first concerning the in vitro metabolism of glutamine and glutamate in human kidney-cortex tubules, that the stimulatory effect of valproate is primarily exerted at the level of glutaminase in human renal cortex.

Adult↗

PubMed2005

Different effects of valproate on methamphetamine- and cocaine-induced behavioral sensitization in mice.

Repetitive exposure to psychostimulants elicits behavioral sensitization. Accumulating evidence have shown that the central GABAergic system is involved in psychostimulants sensitization. Valproate, a clinically widely used anticonvulsant mood-stabilizing agent, can modulate central GABAergic neurotransmission. Herein, the effects of valproate on the development and expression of behavioral sensitization to methamphetamine (METH) and cocaine was studied in mice. Behavioral sensitization of METH and cocaine was rendered by injection of METH (2.0mg/kg) or cocaine (20mg/kg) once daily for seven days. Locomotor activity was measured by an ambulometer. Single or multiple administration of valproate (37.5, 75, 150 mg/kg) could not decrease acute METH- and cocaine-induced hyperactivity. Co-administration of valproate with METH or cocaine dose-dependently inhibited the development of behavioral sensitization. Single administration of valproate (37.5, 75, 150 mg/kg) did not affect the expression of behavioral sensitization induced by METH and cocaine. Multiple administration of valproate (37.5, 75, 150 mg/kg) dose-dependently inhibited the expression of behavioral sensitization to METH, but not to cocaine. The present results supported that METH- and cocaine-induced behavioral sensitization possesses distinct neural mechanisms, which implies that valproate may have different modulatory effect on METH and cocaine addiction in humans.

Analysis of Variance↗

PubMed2006

Cytoprotection by lithium and valproate varies between cell types and cellular stresses.

Despite much evidence that lithium and valproate, two commonly used mood stabilizers, exhibit neuroprotective properties against an array of insults, the pharmacological relevance of such effects is not clear because most of these studies examined the acute effect of these drugs in supratherapeutic doses against insults which were of limited disease relevance to bipolar disorder. In the present study, we investigated whether lithium and valproate, at clinically relevant doses, protects human neuroblastoma (SH-SY5Y) and glioma (SVG and U87) cells against oxidative stress and endoplasmic reticulum stress in a time-dependent manner. Pretreatment of SH-SY5Y cells for 7 days, but not 1 day, with 1 mM of lithium or 0.6 mM of valproate significantly reduced rotenone and H2O2-induced cytotoxicity, cytochrome c release and caspase-3 activation, and increased Bcl-2 levels. Conversely, neither acute nor chronic treatment of SH-SY5Y cells with lithium or valproate elicited cytoprotective responses against thapsigargin-evoked cell death and caspase-3 activation. Moreover, inhibitors of glycogen synthase kinase-3 (GSK-3), kenpaullone and SB216763, abrogated rotenone-induced, but not H2O2-induced, cytotoxicity. Thus the cytoprotective effects of lithium and valproate against H2O2-induced cell death is likely independent of GSK-3 inhibition. On the other hand, chronic lithium or valproate treatment did not ameliorate cytotoxicity induced by rotenone, H2O2, and thapsigargin in SVG astroglial and U87 MG glioma cell lines. Our results suggest that lithium and valproate may decrease vulnerability of human neural, but not glial, cells to cellular injury evoked by oxidative stress possibly arising from putative mitochondrial disturbances implicated in bipolar disorder.

Antimanic Agents↗

PubMed2006

Valproate prevents MK801-induced changes in brain-derived neurotrophic factor mRNA in the rat brain.

To investigate whether the anticonvulsant valproate influences the changes in brain-derived neurotrophic factor (BDNF) mRNA expression induced by MK801 in rat brain, we injected valproate prior to MK801 and observed the changes in the BDNF expression 3 h later. MK801 significantly increased BDNF expression in the retrosplenial and entorhinal cortex, and these increases were prevented by valproate pretreatment. Valproate pretreatment significantly blocked the MK801-induced increase of BDNF expression in retrosplenial cortex at 3 h, 6 h, and 9 h after MK801 injection, suggesting that valproate pretreatment did not delay the MK801-induced increase of BDNF expression. However, MK801 significantly decreased BDNF expression in the granule cell layer of hippocampus, and valproate pretreatment before MK801 potentiated the MK801-induced decrease in BDNF expression in granule cell layer. These results indicate that valproate pretreatment differentially affects the MK801-induced changes in BDNF expression in a region-selective manner.

Animals↗

PubMedDate not supplied

Valproate activates phosphodiesterase-mediated cAMP degradation: relevance to C6 glioma G1 phase progression.

Forskolin, a diterpene activator of adenylate cyclase, stimulates the production of cyclic adenosine monophosphate (cAMP) in a wide variety of cell types. In C6 glioma, used in this study, the anticonvulsant agent valproic acid (VPA) inhibited forskolin-stimulated cAMP accumulation in intact cells in a concentration-dependent manner. Kinetic studies indicated this valproate effect not to be mediated by direct inhibition of adenylate cyclase activity. The valproate-induced inhibition of cAMP accumulation was partially reversed by the phosphodiesterase (PDE) inhibitor isobutylmethyl xanthine (IBMX). Degradation of cAMP over time was more rapid in valproate-treated cells than in controls, and this effect was also reversed by IBMX. In synchronised C6 glioma, phosphodiesterase type IV (PDE4A1) expression was selectively upregulated during the G1 phase, in tandem with temporal biphasic peaks of cAMP. However, the expression of PDE4 isoforms was not affected by a 48-h exposure to valproate. These findings suggest inhibition of forskolin-stimulated cAMP levels in C6 glioma by valproate to be mediated by increased activation of PDE in the G1 phase. Since the degree of cell cycle arrest induced by valproate is intimately associated with its teratogenic potency, it appears that PDE-mediated inhibition of cAMP may contribute to the molecular mechanisms of valproate-induced teratogenicity.

1-Methyl-3-isobutylxanthine↗

PubMed2002

Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: an open-label, nonrandomized chart review.

BACKGROUND: Subsets of psychiatric patients gain excess body weight while receiving mood-stabilizing agents such as lithium carbonate or valproate sodium. Patients who gain excess weight may discontinue therapy, with severe consequences. Among the newer anticonvulsant agents, topiramate is a candidate agent for bipolar disorder and is associated with weight loss when used as adjunctive treatment. OBJECTIVE: This open-label, nonrandomized, chart-review study assessed changes in body weight and body mass index (BMI) in patients receiving topiramate, lithium, or valproate. METHODS: Data were extracted from the medical charts of patients admitted in 1999 and 2000 to a state psychiatric hospital with either schizophrenia, schizoaffective disorder, bipolar disorder, or other psychiatric diagnoses who were prescribed valproate, lithium, or topiramate and were reviewed for changes in body weight and BMI. The use of concomitant psychotropic medicines was recorded (eg, antipsychotic agents, antidepressant agents, other mood stabilizers such as gabapentin or carbamazepine). Continuous variables were analyzed using a factorial analysis of variance and the Student t test. Contingency statistics were used to analyze categorical variables. RESULTS: A total of 214 patients were included in the chart review (123 men, 91 women; mean age, 39.4 years). Significantly more women than men received topiramate (P = 0.004). Patients receiving either lithium or valproate gained a mean (SD) of 6.3 (9.0) kg and 6.4 (9.0) kg, respectively, whereas patients receiving topiramate lost a mean 1.2 (6.3) kg (F = 11.54, df = 2,198; P < 0.001). Lithium- or valproate-treated patients experienced an increase in BMI (mean, 2.1 [3.0] for both groups), whereas topiramate-treated patients experienced a reduction in BMI (mean, -0.5 [2.4]); this result was statistically significant (F = 11.40, df = 2,198; P < 0.001). Finally, lithium- or valproate-treated patients gained >8% of their baseline body weight (8.2% [11.5%] for lithium-treated patients and 8.5% [11.9%] for valproate-treated patients), whereas topiramate-treated patients lost 0.7% (7.2%) of their body weight (F = 9.93, df= 2,198; P < 0.001). CONCLUSIONS: Controlled studies for the efficacy of topiramate therapy in various psychiatric conditions are awaited. These data indicate that patients receiving topiramate experience body weight loss and a reduction in BMI. This advantage of topiramate may promote long-term adherence to treatment among psychiatric patients and possibly decrease the medical risks associated with obesity.

Adult↗

PubMed1997

Effects of subchronic treatment with valproate on L-5-HTP-induced cortisol responses in mania: evidence for increased central serotonergic neurotransmission.

The mechanisms underlying the acute and prophylactic antimanic properties of valproate have remained elusive. There are some reports that treatment with valproic acid may increase brain serotonergic neurotransmission in the rodent. This study was carried out in order to investigate the effects of subchronic therapy with valproate on central serotonin metabolism in manic patients. Toward this end, the authors examined plasma cortisol responses to 200 mg (orally) L-5-hydroxy-tryptophan (L-5-HTP) in 10 manic patients both before and after subchronic treatment with valproate. Administration of L-5-HTP resulted in significantly increased cortisol responses both before and after treatment with valproate. The L-5-HTP-induced cortisol responses were significantly higher after treatment with valproate than before treatment. It is suggested that valproate may increase central serotonergic neurotransmission and that this stimulation may play a role in the antimanic effects of valproate.

5-Hydroxytryptophan↗

PubMed2003

Sodium valproate induces apoptosis in the rat hepatoma cell line, FaO.

Sodium valproate (VPA) is clinically employed as an anti-convulsant and, to a lesser extent, mood stabilizer. While the incidence of toxicity associated with the clinical use of valproate is low, serious hepatotoxicity makes up a significant percentage. Rats treated with high doses of sodium valproate are subject to hepatotoxicity, and the study of the molecular mechanisms underlying this phenomenon may shed further light on the human situation. Exposure to sodium valproate results in the down regulation in rat liver of several transcripts whose products are involved in cellular energy homeostasis, resulting in time-dependent fluctuations in cellular ATP, possibly resulting in cell death. To further examine this, classical markers of apoptosis were examined in the rat hepatoma cell line FaO following sodium valproate exposure. Concentrations greater than 300 microM sodium valproate resulted in a transient wave of apoptosis, as assessed by chromatin condensation and DNA fragmentation assay. Analysis indicated that Fas-ligand and caspase-11 expression were increased at the transcriptome level, while caspase-3 was activated at the proteome level during the exposure period. These data demonstrates that sodium valproate causes cell death through apoptosis in a rat liver cell line, and provides information on the possible molecular mechanisms underlying this phenomenon in vivo.

Animals↗

PubMed1988

Effect of valproate on renal metabolism in the intact dog.

Valproate is an antiepileptic drug known to induce hyperammonemia in humans. This hyperammonemia might result from a reduced detoxification of ammonium in the liver and/or from an accelerated renal ammoniagenesis. Six dogs with normal acid-base equilibrium and eight dogs with chronic metabolic acidosis were infused with valproate directly into their left renal artery in order to obtain arterial concentrations around 3 to 4 mM. The arterial ammonium concentration rose only in chronically acidotic dogs, whereas the lactate concentration and the lactate/pyruvate ratio increased in both groups. The urinary excretion of lactate and pyruvate increased markedly but the urinary excretion of other relevant metabolites remained minimal. Renal glutamine utilization and ammonium production were not changed by valproate administration in normal dogs but increased modestly in acidotic dogs. However, renal lactate utilization was drastically reduced and in fact, changed into a net production of lactate. Valproate strikingly reduced the renal cortical concentrations of glutamine, glutamate, alphaketoglutarate and citrate, and more modestly those of malate, oxaloacetate, aspartate, alanine and ATP. By contrast, the tissue lactate concentration and the lactate/pyruvate ratio were markedly increased. In experiments with brush border membrane vesicles, valproate inhibited the lactate transporter. These results suggest that high concentrations of valproate drastically inhibited the proximal reabsorption and the proximal and distal oxidation of lactate and pyruvate. Valproate probably became itself a significant energetic substrate for the kidney.

Acid-Base Equilibrium↗

PubMed1998

Increases in metabolism of valproate and excretion of 6beta-hydroxycortisol in patients with traumatic brain injury.

AIMS: The objectives of this study were to determine the effect of brain trauma on the multiple pathways of metabolism of valproate and to evaluate the use of the urinary 6beta-hydroxycortisol to cortisol ratio in predicting changes in hepatic metabolism induced by brain injury. METHODS: Fourteen patients with severe head injuries received a 15 mg kg(-1) loading dose and a maintenance dose of valproate to maintain therapeutic plasma concentrations. A minimum of one steady state trough blood sample and one dosage interval urine were collected during days 3-6 and during days 7-14 post-injury. Total and unbound valproate plasma concentrations were determined by gas chromatography-flame ionization detection (GC-FID) with and without ultrafiltration. Urinary valproate metabolites were measured by gas chromatography/mass spectrometry (GC-MS) (n = 10). Urinary 6beta-hydroxycortisol and cortisol concentrations were determined by high performance liquid chromatography (h.p.l.c.) (n = 14). Total intrinsic clearance (CL[int]) for valproate and individual formation clearances (CL[f]) to its major metabolites were calculated. Data obtained during baseline (days 3-6) were averaged for each patient and were compared with averaged data obtained from days 7 to 14 using a paired t-test. RESULTS: Statistically significant increases in the CL(int), CL(f) of VPA glucuronide, 2-ene-VPA, and 4-OH-VPA pathways and the 6beta-hydroxycortisol to cortisol ratio were found. The percent change in the 6beta-hydroxycortisol to cortisol ratio correlated significantly with the changes in the CL(int) of valproate. CONCLUSIONS: Brain trauma results in induction of multiple pathways of valproate metabolism and increases in the 6beta-hydroxycortisol to cortisol ratio, suggesting a non-specific enzyme induction in response to head injury.

Adult↗

PubMed2002

Fanconi syndrome caused by sodium valproate: report of three severely disabled children.

We report three severely disabled children with epilepsy, a 4-year-old boy, 8-year-old girl and 14-year-old girl, who were treated with sodium valproate from the age of 2 months, 3 months and 7 years, respectively, and who developed Fanconi syndrome. All three patients were bed-ridden and fed by means of a nasogastric or gastrostomy tube. Since Fanconi syndrome was considered to be caused by sodium valproate, it was stopped. After the discontinuation of sodium valproate, renal involvement improved in all patients in 2-12 months. Severely handicapped children may be at risk for sodium valproate-induced renal involvement. Although among the adverse effects of sodium valproate, renal involvement is uncommon, Fanconi syndrome due to valproate therapy has rarely been reported. We have to pay attention to Fanconi syndrome in epileptic children treated with sodium valproate, especially in severely disabled children.

Adolescent↗

PubMed1999

Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures.

Preclinical studies suggested valproate increased brain gamma-aminobutyric acid (GABA) with no major effects on brain glutamate or glutamine. Valproate increased human cerebrospinal fluid GABA and glutamine in some studies; others reported no effect. In vivo measurements of glutamate, glutamine, and GABA were made of a 14 cm3volume in the occipital cortex using a1H spectroscopy with a 2.1 Tesla magnetic resonance spectrometer and an 8 cm surface coil. Ten control subjects and 14 patients with refractory complex partial seizures were examined. Brain glutamine concentrations were above normal in three of five patients taking valproate and two of nine taking carbamazepine or phenytoin. Mean glutamine levels of patients taking valproate were higher than control subjects and patients taking carbamazepine or phenytoin. Brain glutamate concentrations were above normal in four of nine patients taking phenytoin or carbamazepine and two of five taking valproate. Brain GABA levels were below normal in four of nine patients taking carbamazepine or phenytoin and one of five taking valproate. Above normal glutamate or below normal GABA was present in nine of 14 patients and may contribute to their refractory epilepsy. Increased brain glutamine associated with valproate therapy may reflect mild hyperammonemia.

Adult↗

PubMed2002

Reversible valproate-induced choreiform movements.

Valproate is an anticonvulsive drug whose mechanism of action is based on GABAergic systems. One of the infrequent adverse effects of valproate is choreiform movements. In our study, we report a patient having head trauma history with partial and secondary generalized seizures taking 1500 mg/day valproate. During the second month of the therapy, generalized chorea was observed. Since other aetiologic causes of chorea were excluded, acutely occurring chorea in the patient was thought to be related with valproate usage because of persistence of choreiform movements for days without any fluctuation. Valproate was stopped slowly and lamotrigine was added at a dose of 400 mg/day. Within a two-month period after cessation of the valproate, choreiform movements had disappeared. We thought that the history of head trauma and another antiepileptic drug usage were the risk factors for the occurrence of valproate-induced choreiform movements.

Adult↗

PubMed1992

A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group.

BACKGROUND: Valproate is approved for use primarily in patients with absence seizures, but the drug has a broad spectrum of activity against seizures of all types. Partial or secondarily generalized tonic-clonic seizures are often difficult to control adequately with standard treatment, usually carbamazepine or phenytoin. METHODS: We conducted a multicenter, double-blind trial that compared valproate with carbamazepine in the treatment of 480 adults with complex partial seizures (206 patients) or secondarily generalized tonic-clonic seizures (274 patients). The patients were randomly assigned to treatment with carbamazepine or divalproex sodium (valproate) at doses adjusted to achieve blood levels in the middle of the therapeutic range. Patients were followed for one to five years or until seizures became uncontrollable, treatment had unacceptable adverse effects, or both these events occurred. RESULTS: For the control of secondarily generalized tonic-clonic seizures, carbamazepine and valproate were comparably effective (in 136 patients and 138 patients, respectively). For complex partial seizures, four of five outcome measures favored carbamazepine (100 patients) over valproate (106 patients): the total number of seizures (2.7 vs. 7.6, P = 0.05), the number of seizures per month (0.9 vs. 2.2, P = 0.01), the time to the first seizure (P less than 0.02), and the seizure-rating score (P = 0.04). Carbamazepine was also superior according to a composite score that combined scores for the control of seizures and for adverse effects (P less than 0.001). Valproate was associated more frequently than carbamazepine with a weight gain of more than 5.5 kg (12 lb) (20 percent vs. 8 percent, P less than 0.001), with hair loss or change in texture (12 percent vs. 6 percent, P = 0.02), and with tremor (45 percent vs. 22 percent, P less than 0.001). Rash was more often associated with carbamazepine (11 percent vs. 1 percent, P less than 0.001). CONCLUSIONS: Valproate is as effective as carbamazepine for the treatment of generalized tonic-clonic seizures, but carbamazepine provides better control of complex partial seizures and has fewer long-term adverse effects.

Adolescent↗

PubMed2004

Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania.

This exploratory analysis was performed to compare the efficacy and tolerability of risperidone when added to two different mood stabilizers (lithium or valproate) for mania in bipolar disorder. Patients receiving lithium or valproate at baseline were drawn from the database of a 12-week, open-label risperidone study. The primary efficacy measure was the Young Mania Rating Scale (YMRS). Other assessments included the Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression (CGI) of improvement, and safety measures. The analysis included 33 patients on lithium plus risperidone and 46 patients on valproate plus risperidone. Both subgroups had comparable baseline YMRS scores (lithium 28.2, valproate 28.7) and both had significant reductions in score by week 1 (P<0.0001). Comparable reductions in score continued for both subgroups until the end of the study (YMRS scores at week 12: lithium 4.6 and valproate 6.7). There were no significant differences in response rates (> or =50% improvement on YMRS) or remission rates (YMRS score < or = 8) between the two subgroups. At week 12, 88% of the lithium plus risperidone patients and 80% of the valproate plus risperidone patients were in remission. Similarly, HAM-D scores were significantly and comparably reduced in both subgroups, and improvement in CGI was the same. There was no difference between subgroups in the incidence of adverse events or weight gain. These data suggest that risperidone can be safely combined with either lithium or valproate, and that the efficacy is similar regardless of the mood stabilizer used.

Adolescent↗

PubMed2005

Effect of valproate on plasma levels of interleukin-6 in healthy male humans.

Valproate exerts many biochemical and physiological effects and may have a modulating effect on the immune system. The present study aimed to determine whether there is a treatment effect of valproate on plasma levels of the pro-inflammatory cytokine, interleukin (IL)-6, in healthy male humans. Plasma levels of IL-6 were measured in 10 healthy male humans before and after 7 days of treatment with 1000 mg per day of valproate (i.e. 500 mg in the morning and 500 mg in the evening). All the healthy subjects had no past or current psychiatric disorder. They reported to the outpatient clinic at 09.00 h for baseline sampling. Subsequently, they were commenced on valproate 1000 mg per day for 7 days. They took the last dose of valproate at 22.00 h on the day 7, and post-treatment blood sampling for plasma levels of IL-6 was carried out on day 8. An additional blood sample was also taken from each subject at the same time to measure plasma levels of valproic acid for drug compliance. We found a significant increase in plasma levels of IL-6 after the 7 days of valproate treatment in healthy male subjects. Furthermore, there was a significant positive correlation between the changes in plasma IL-6 and blood levels of valproic acid. The findings of this study are consistent with previous studies on subjects with epilepsy, suggesting a modulating effect of valproate on the pro-inflammatory cytokine IL-6 in humans. However, studies with a larger number of participants and employing a double-blind, placebo-control group are required to confirm the findings, and also the levels of other cytokines should be measured to generalize the effect to the immune system.

Adult↗

PubMed1992

Valproate use associated with persistent hyperammonemia and mitochondrial injury in a child with Down's syndrome.

Valproate is a commonly prescribed anticonvulsant drug that may cause potentially fatal hepatotoxicity, bone-marrow toxicity, and pancreatitis. Toxicity usually resolves, though, after discontinuation of the medication. We report a 9-year-old boy who had Down's syndrome and who developed valproate-associated bone marrow toxicity, and hepatotoxicity that persisted greater than 2 years after discontinuation of valproate therapy. Three years after starting valproate, he developed erythrocyte aplasia with a severe, normochromic, macrocytic anemia requiring several blood transfusions. Several months later while still receiving valproate, he developed progressive hyperammonemia and decreased hepatic synthetic function. The macrocytic anemia resolved and hepatic synthetic function improved after discontinuation of valproate therapy. However, hyperammonemia, steatosis, mitochondrial injury, and marked hepatic iron accumulation persisted greater than 2 years after the valproate was discontinued. The persistent hyperammonemia was responsive to lactulose therapy. A decrease in hepatic iron content by serial phlebotomies did not result in any improvement in the hyperammonemia or hepatic synthetic function. This is the first report of persistent hyperammonemia and hepatic mitochondrial injury after valproic acid therapy.

Ammonia↗