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PubMed1981

Anticonvulsant activity of metabolites of valproic acid.

Eight metabolites of valproic acid (VPA), i.e. 2-en-VPA, 3-hydroxy VPA, 3-keto-VPA, 4-en-VPA, 5-hydroxy-VPA, 2-n-propylglutaric acid, 3-en-VPA, and 4-hydroxy-VPA, were examined for their effects on the thresholds for the maximal electroconvulsion and the pentetrazole convulsion in mice. All metabolites gave rise to significant threshold elevations but were less potent than VPA itself. Among the metabolites studied, the unsaturated compounds 2-en-VPA and 4-en-VPA were most active showing 50 to 90% of the potency of VPA. Taking the different anticonvulsant potencies of VPA and its metabolites into consideration, VPA seems responsible for more than 80% of the antiepileptic effect during chronic therapy in man.

Animals↗

PubMed1985

Depression of hippocampal low calcium field bursts by the antiepileptic drug valproic acid.

The antiepileptic drug valproic acid (VPA) reduces the occurrence of the rhythmic and synchronous bursts produced by hippocampal neurons maintained 'in vitro' and bathed in Ringer-containing low-Ca2+ (0.2 mM), high-Mg2+ (4.0 mM). In this medium, synaptic transmission is blocked, thus demonstrating an action of VPA unrelated to potentiation of GABAergic phenomena. This conclusion is reenforced by the persistence of VPA effects in the presence of bicuculline. Also, the VPA doses effective in reducing the low-calcium synchronous burst in the hippocampal slice are similar to the free plasma levels of VPA observed to exert anticonvulsant effects in kindled rats.

Animals↗

PubMed1976

Valproic acid: reversibly acting drug?

Valproic acid [dipropylacetic acid (DPA)] was evaluated in an alumina-gel monkey model (N = 12) by constant-rate intravenous infusion. The data indicated: (a) a statistically significant decrease in seizure frequency the first 2 days of drug Step I (45-55 mug/ml) and drug Step II (90-110 mug/ml) which was temporary, lasting 2 days only; (b) a later, more permanent decrease in siezure frequency which was not apparent until drug Setp III (130-170 mug/ml); and a delayed return of the seizure frequency to predrug levels for 2 weeks after drug administration was discontinued, with no DPA detectable in plasma after the initial postdrug day. Whether DPA will behave as a reversibly acting drug was discussed.

Animals↗

PubMed1991

Induction of metallothionein in mouse liver by valproic acid.

Intraperitoneal injection of valproic acid (VPA) induces metallothionein (MT) in mouse liver. There was a clear-cut dose-dependency and the maximal amount of MT induced by VPA was about 6 times the basal level. The hepatic MT level reached the peak value at 24 h after VPA injection. Neither Cu nor Zn concentrations showed any significant changes after VPA administration in either the whole liver, or in the mitochondrial or supernatant fractions of the liver homogenate. Gel filtration profiles for the supernatant of the liver homogenate of the VPA-treated mice, however, clearly showed that induced MT was chiefly Zn-thionein. Therefore, Zn molecules necessary for the elevated MT levels seem to originate mainly from cytosolic Zn-containing proteins except for MT.

Animals↗

PubMed1990

Valproic acid and panic disorder.

Valproic acid (VA), an anticonvulsant which increases GABAergic transmission was given to patients suffering from recurrent panic attacks. Ten consecutive outpatients were included in this study. After a seven day placebo washout period, patients were given a dose of 500 mg/day, which was gradually increased to a maximum of 2250 mg/day. A significant improvement was found in the symptomatology of patients as measured on the Clinical Global Impression Scale for panic severity (p less than 0.001), the Hamilton Psychiatric Rating Scale for Anxiety (p less than 0.001) and the panic factor of the SCL-90 (p less than 0.05). These findings support the hypothesis that VA is useful in the treatment of panic disorders. Further research should be carried out to assess its efficacy and safety.

Adult↗

PubMedDate not supplied

Choleretic effect of valproic acid in the rat.

Valproic acid (VPA) is an anticonvulsant agent which produced marked choleresis in the rat. Bile flow rate increased from 50 to 60 microliter per min per kg to 120 to 145 microliter per min per kg immediately after i.v. injection of VPA (37.5 to 150 mg per kg; 2 ml per kg) in male Sprague-Dawley rats. The duration of maximal bile flow was dose-dependent and increased from 30 min (37.5 mg VPA per kg) to approximately 2 hr (150 mg VPA per kg). Choleresis diluted the biliary concentrations of bile acids, Cl-, cholesterol, and phospholipids. VPA did not change the bile/plasma ratio for erythritol suggesting that the increased bile flow is of canalicular origin. VPA did not influence the excretion of bile acids or their osmotic activity, whereas bile salt-independent flow doubled in rats treated with 150 mg VPA per kg. The bile/plasma, bile/liver, and liver/plasma concentration ratios for VPA were 11.7, 1.6, and 7.3, respectively. Approximately 90% of VPA appearing in bile was biotransformed, primarily as a glucuronide. Bile flow correlated with VPA excretion; 16 microliter of bile was produced per micromole VPA which suggests that choleresis is primarily due to the osmotic activity of VPA metabolites in bile. VPA enhanced the excretion of inorganic ions which may also contribute to choleresis. Biliary excretion of phenol-3,6-dibromophthalein disulfonate and ouabain was unaffected. Thus, VPA is an effective choleretic which stimulates bile salt-independent flow of canalicular origin largely as a consequence of the osmotic properties of VPA conjugates in bile.

Animals↗

PubMedDate not supplied

Hepatotoxicity in rat following administration of valproic acid.

Chronic injections of valproic acid (VPA), VPA with phenobarbital (PB), and PB were studied for their effects on liver mitochondrial morphology and carnitine metabolism in rats. Mitochondrial enlargement was induced by the administration of VPA (500 mg/kg/day) for a period of 7 consecutive days. The administration of VPA (500 mg/kg/day)-plus-PB (20 mg/kg/day) for 7 days, however, did not induce megamitochondrial formation, but in these livers an unusual increase was observed in the number of liver mitochondria, microvesicular steatoses, and myeloid bodies. VPA-treated rats had significantly lower levels of serum-free and total carnitine and higher levels of acylcarnitine and acyl to free ratio than those of the controls. The free carnitine concentrations in serum and liver of the rats treated with VPA-plus-PB were much lower as compared with those treated with either VPA or PB. These morphological and biochemical results, especially of carnitine metabolism, suggest that inhibition of beta-oxidation in liver mitochondria occurred in rats treated with VPA and PB and that, in particular, polytherapy with VPA-plus-PB could be clinically hazardous in causing hepatic injury.

Animals↗

PubMed1990

The effects of phenytoin and carbamazepine on serum concentrations of mono-unsaturated metabolites of valproic acid.

Serum concentrations of valproic acid (VPA) and its mono-unsaturated metabolites, 2-propyl-2-pentenoic acid (2-en), 2-propyl-3-pentenoic acid (3-en) and 2-propyl-4-pentenoic acid (4-en), were measured in 36 epileptic patients. The subjects were divided into three subgroups, i.e., receiving VPA alone (n = 20: VPA group), VPA with phenytoin (n = 9: VPA + DPH group), and VPA with carbamazepine (n = 7: VPA + CBZ group). In the VPA group, the correlations between the serum concentration of VPA and those of the metabolites were significantly positive (r = 0.693, P less than 0.01 for 2-en; r = 0.584, P less than 0.01 for 3-en; and r = 0.868, P less than 0.001 for 4-en). The concentration/dose ratio of VPA was significantly lower, and the 4-en/VPA ratio was significantly higher in the VPA + CBZ group than in the VPA group (P less than 0.05). However, DPH had less effect on the concentration/dose ratio of VPA and the 4-en/VPA ratio than CBZ. This may be due partly to the relatively smaller therapeutic dose of DPH. These results suggest a correlation between the serum concentration of VPA and that of 4-en, and an increased metabolic conversion of VPA to 4-en by coadministration of CBZ. High serum concentrations of VPA and concomitant use of CBZ resulted in an elevation of the serum concentration of 4-en, which has been reported to be the most toxic metabolite of VPA.

Adult↗

PubMed2004

Polycomb homologs are involved in teratogenicity of valproic acid in mice.

BACKGROUND: Valproic acid (VPA) is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its teratogenic mechanisms are unknown. We have attempted to describe a fundamental role of the Polycomb group (Pc-G) in VPA-induced transformations of the axial skeleton. METHODS: Pregnant NMRI mice were given a single subcutaneous injection of vehicle or VPA (800 mg/kg) on gestation day (GD) 8. The expression of genes encoding Polycomb and trithorax groups was measured by quantitative real-time RT-PCR using total RNA isolated from the embryos exposed to vehicle or VPA for 1, 3, and 6 hr. In addition, the use of two less teratogenic antiepileptic chemicals valpromide (VPD) and valnoctamide (VCD) provide reliable evidence to support the relationship between VPA teratogenicity and the Polycomb group. RESULTS: At a teratogenic level, VPA inhibits the expression of the Polycomb group genes, including Eed, Ezh2, Zfp144, Bmi1, Cbx2, Rnf2, and YY1 in the mouse embryos. In contrast, neither VPD nor VCD have significant effects on the expression of those genes affected by VPA. The trithorax group (trx-G) gene MLL, which is known to be required to maintain homeobox gene expression such as the Polycomb gene, is not affected by a teratogenic dose of VPA. CONCLUSIONS: We propose that, during embryonic development, VPA may affect the gene silencing pathway mediated by the Polycomb group complex. The epigenetic mechanism of VPA teratogenicity on anteroposterior patterning is suspected.

Abnormalities, Drug-Induced↗

PubMed2002

An in ovo chicken model to study the systemic and localized teratogenic effects of valproic acid.

BACKGROUND: The antiepileptic valproic acid (VPA) is a teratogen whose embryopathic mechanism(s) remain uncertain. Elucidating potential cellular and molecular effects of VPA is complicated by systemic application paradigms. We developed an in ovo model to reproduce the teratogenic effects of VPA and a localized VPA application procedure to determine whether VPA can selectively effect abnormal development in one region of the embryo. METHODS: VPA was applied topically to chicken embryos in ovo at different embryonic stages. Embryos were later evaluated for gross and skeletal anomalies. Pax-2 and Pax-6 protein expression in the developing eye was also evaluated because VPA-induced eye anomalies are similar to those seen by the disruption of Pax-2 and Pax-6. For localized application, a thin sheet of the synthetic polymer Elvax was impregnated with VPA. A small piece of the VPA-impregnated polymer was applied directly to the presumptive wing bud region in Stage 10-17 embryos. Embryos were examined for gross and skeletal anomalies. Sham controls were employed for all experiments. RESULTS: Chicken embryos exposed to VPA in ovo demonstrated increased mortality, growth delay and anomalies similar to ones previously seen in humans: neural tube, cardiovascular, craniofacial, limb and skeletal. Pax-2 and Pax-6 protein expression was qualitatively diminished in the eye. Localized wing bud VPA exposure caused structural abnormalities in the developing wing in the absence of other anomalies in the embryos. These wing defects were similar to those observed after topical whole-embryo VPA application. CONCLUSIONS: These results indicate that at least one mechanism for the teratogenicity of VPA involves a direct effect on developing tissue. The nature of the abnormalities observed implies that this effect may be mediated by disruption of genes that regulate pattern formation.

Animals↗

PubMed1994

Bone marrow suppression induced by high dose valproic acid.

A girl with intractable epilepsy who received high dose valproic acid showed bone marrow suppression, which improved after the end of valproic acid treatment and the administration of supportive treatments. Valproic acid markedly suppressed the in vitro colony growth in this patient. It is believed that high dose valproic acid treatment directly suppressed the growth of haematopoietic progenitors, resulting in bone marrow failure.

Anemia↗

PubMed1991

Pattern- and age-dependency of the antiepileptic effects induced by valproic acid in the rat hippocampus.

The effects induced by the antiepileptic drug valproic acid were studied in the CA3 subfield of in vitro hippocampal slices obtained from young (16- to 27-day-old) and adult (over 60-day-old) rats. Spontaneous epileptiform discharges were induced by the addition of the convulsant 4-aminopyridine to the medium. Valproic acid (0.5 mM) selectively blocked the ictal epileptiform discharges in slices obtained from young rats. Interictal epileptiform discharges disappeared during perfusion with higher doses of valproic acid (2 mM). This blockade of interictal epileptiform activity was not observed when valproic acid (0.5-5 mM) was tested in hippocampal slices from adult rats. Thus, in the hippocampus of young rats, 4-aminopyridine-induced ictal activity is more sensitive to valproic acid than are interictal discharges. Moreover, valproic acid is effective in controlling interictal discharges in the young, but not in the adult rat hippocampus.

4-Aminopyridine↗

PubMed1984

Protein binding of valproic acid in maternal and umbilical cord serum.

The serum valproic acid levels of 18 maternity patients at the time of delivery were compared with the valproic acid levels in the umbilical cord serum. The levels in the umbilical cord serum were 1.1-4.6 times higher than those in the maternal serum, with a mean value of 1.38. One explanation for this difference apparently is an increased protein binding of valproic acid in the infant's serum. Protein binding was determined in nine patients, in six by equilibrium dialysis and in three by ultrafiltration. The median value of the free fraction of valproic acid was 9.1% (range, 5.8-16.4%) in the umbilical cord serum (equilibrium dialysis) and 15% (range, 12.7-35.3%) in the maternal serum. The difference between the infant and the maternal serum is significant.

Adolescent↗

PubMed1999

The adverse effect profile and efficacy of divalproex sodium compared with valproic acid: a pharmacoepidemiology study.

BACKGROUND: Divalproex sodium has been reported to be better tolerated than valproic acid. To our knowledge, no study has examined whether significant differences in the tolerability and efficacy exist between these preparations in psychiatric patients. The objective of the present study was to compare the tolerability and efficacy of divalproex sodium with those of valproic acid in psychiatric inpatients. METHOD: Information gathered retrospectively from the medical records of 150 patients treated with divalproex sodium was compared with that of 150 patients treated with valproic acid. These medical records were photocopied, and any mention of divalproex sodium or valproic acid treatment was concealed. A series of demographic and clinical characteristics were compared. RESULTS: Patients treated with divalproex sodium compared with patients treated with valproic acid were less likely to have gastrointestinal side effects (14.7% vs. 28.7%, p = .003), specifically anorexia (6.0% vs. 14.7%, p = .012), nausea or vomiting (6.7% vs. 16.7%, p = .007), and dyspepsia (11.3% vs. 22.0%, p = .013). Divalproex sodium-treated patients compared with valproic acid-treated patients were less likely to have discontinued their medication because of side effects (4.0% vs. 12.7%, p = .0066). Twelve (63.2%) of 19 patients who discontinued valproic acid because of gastrointestinal side effects were subsequently treated with divalproex sodium, of whom only 2 continued to have gastrointestinal side effects. There were no differences in efficacy between the 2 drugs. CONCLUSION: Divalproex sodium was better tolerated than valproic acid in inpatients with a variety of diagnoses and taking concomitant medications. Patients treated with divalproex sodium compared with patients treated with valproic acid were less likely to experience gastrointestinal side effects and to have discontinued their medication because of an adverse event.

Adolescent↗

PubMed1997

Effectiveness of valproic acid on destructive and aggressive behaviours in patients with acquired brain injury.

Valproic acid, a primary anticonvulsant drug, has recently been studied for purported effectiveness in disparate disorders of mood and behaviour. The psychopharmacological treatment of patients with acquired brain injury frequently includes numerous trials of psychotherapeutic drugs such as antipsychotics, benzodiazepines, antidepressants, and lithium, in an effort towards affective and behavioural improvement. In this report we describe and graphically depict the striking efficacy of valproic acid in reducing and improving destructive and aggressive behaviours in five patients with acquired brain injury. In all cases valproic acid was effective after other pharmacological interventions were not. Also, the addition of valproic acid was followed by neurobehavioural improvement rather quickly, often within 1-2 weeks. Advantages of valproic acid, in addition to its possible unique efficacy, include a lower propensity towards sedation and cognitive impairment, and thus a more robust potential for rehabilitation participation. Behaviours associated with affective disorders ranging along the affective spectrum from depression to dysphoric mania may be particularly amenable to valproic acid. The drug may also be beneficial in some cases in which another psychotropic anticonvulsant, carbamazepine, was not.

Activities of Daily Living↗

PubMed1990

Zinc concentrations in mouse embryo and maternal plasma. Effect of valproic acid and nonteratogenic metabolite.

The effect of a single teratogenic dose of the antiepileptic drug valproic acid and its nonteratogenic metabolite, 2-en-valproic acid, on zinc concentrations in mouse plasma, embryo, and decidua on d 9 of gestation was investigated. The substances were injected subcutaneously (sc) as their sodium salts. In this mouse model, valproic acid induced between 20% (400 mg/kg dose) and 60% (600 mg/kg dose) incidence of exencephaly in living fetuses; 2-en-valproic acid was not teratogenic at these dose levels. The zinc concentrations in plasma were significantly increased 1 and 2 h after administration of both substances. The embryonic zinc concentrations were increased 2 and 4 h after application of both substances. The concentrations of zinc in the decidua were not affected. The similarity of effects of valproic acid and its nonteratogenic analog on zinc concentrations in maternal plasma and embryo suggests that the teratogenicity of a single administration of valproic acid in the mouse is not owing to interference with the zinc metabolism in this species.

Animals↗

PubMed1998

Valproic acid treatment of agitation in dementia.

OBJECTIVE: Valproic acid, an anticonvulsant medication that enhances GABAergic neurotransmission, has been shown to be helpful in treating behavioural disturbances associated with dementia in several small case series. In an attempt to further document its effectiveness and safety, valproic acid was used to treat a group of elderly patients with dementia and severe agitation. METHOD: Sixteen patients, aged 68 to 95 years, who were previously unresponsive to other pharmacotherapeutic interventions, were treated prospectively with open-label divalproex sodium. Effectiveness was measured with the Behave AD (B-AD), the Cohen-Mansfield Agitation Inventory (CMAI), and the Clinical Global Impression Scale (CGIS). Doses ranged from 750 to 2500 mg, divided, per day, with levels of 184 to 742 mumol/L. RESULTS: Scores on the CMAI declined from 68.8 to 61.0 (P < 0.005), and scores on the B-AD declined from 15.8 to 12.3 (P < 0.004). On the CGIS, 1 patient was rated as very much improved, 3 patients were much improved, 4 patients were minimally improved, and 8 patients were unchanged. The drug was prematurely discontinued in only 1 patient because of side effects. CONCLUSION: Valproic acid was shown to be well tolerated with modest effectiveness.

Aged↗

PubMed2002

Protein binding of valproic acid in Japanese pediatric and adult patients with epilepsy.

The binding of valproic acid to serum proteins in pediatric and adult patients was studied. Serum samples were obtained from 48 Japanese pediatric patients with epilepsy (group A) and 48 Japanese adult patients with epilepsy (group B) receiving valproic acid monotherapy. The patients' age ranged from 1 to 15 years for the pediatric patients and from 18 to 44 years (group B--younger) and 45 to 63 years (group B--older) for the adult patients. The serum concentrations of total and unbound valproic acid were measured by fluorescence polarization immunoassay, and the unbound serum fraction of valproic acid was analyzed by ultrafiltration. The mean association constant, K, and total concentration of binding sites, n(P), were as follows: group A, K = 0.016 L/mumol, n(P) = 1077 microM; group B, K = 0.011 L/mumol, n(P) = 1365 microM; group B--younger, K = 0.013 L/mumol, n(P) = 1291 microM; and group B--older, K = 0.006 L/mumol, n(P) = 1827 microM. Significant differences between groups A and B were observed in the serum free fatty acid concentration and the serum concentration ratio of free fatty acids to albumin. However, no significant differences between the two groups were observed in the binding of valproic acid to serum proteins. Group A's serum concentration ratio of free fatty acids to albumin was significantly lower than in group B--older and was lower than in group B--younger. However, there were no significant differences in binding between group A and groups B--younger and B--older. The serum concentration of albumin was significantly higher in group B--younger than in group B--older. Consequently, there was a significant difference in binding between groups B--younger and B--older. The serum protein binding of valproic acid was similar in pediatric and adult patients with epilepsy, but binding characteristics differed between younger and older adults.

Adolescent↗