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Fetal exposure to valproic acid has recently been associated with an increased incidence of neural tube defects. The prenatal detection of a fetus with both hydrocephalus and meningomyelocele after valproic acid exposure is presented and specific recommendations made for antepartum evaluation in future pregnancies.
The pharmacokinetics of valproic acid (VPA) were compared in dogs with those of the prodrugs ethyl valproate (E-VPA), trichloroethyl valproate (T-VPA), and valproyl valproate (V-VPA). Valproic acid, E-VPA, T-VPA, and V-VPA were administered intravenously and orally to six dogs at equimolar doses. The three VPA prodrugs were rapidly converted to VPA. The biotransformation was complete in the case of E-VPA and T-VPA but was only partial in the case of V-VPA. Because of the rapid conversion to the parent drug, after administration of the prodrugs, VPA plasma levels did not yield a sustained-release profile. Further, the anticonvulsant activity of prodrugs was compared in mice to that of VPA and valpromide (VPD). The anticonvulsant activity of E-VPA, T-VPA, and V-VPA was less than that of VPA.
Clearance of valproic acid from brain tissue is believed to occur via a carrier-mediated system(s). The present study was designed to determine whether clearance was capacity-limited (saturable) and whether it occurred primarily at the choroid plexus. Ten rabbits were anesthetized with halothane and surgically prepared for ventriculocisternal perfusion. In group 1 (n = 5) valproic acid was added to blue dextran-containing mock cerebrospinal fluid (CSF) to achieve concentrations of 5, 20, 100, and 500 micrograms.ml-1. The mixture was infused through needles in both cerebral ventricles. The purpose of this group was to determine whether over a large range (100x) of valproic acid concentrations, clearance from CSF was capacity limited (saturable). In group 2 (n = 5) valproic acid concentrations were 3, 10, and 30 microgram.ml-1 and infusion was into the left cerebral ventricle only. The purposes of this group were to determine (a) the magnitude of valproic acid clearance for the "clinical" range of valproic acid in CSF (10-30 micrograms.ml-1), and (b) whether clearance of valproic acid was changed by perfusion across a portion of the choroid plexus surface area (group 2) as compared with perfusion across the entire choroid plexus surface area (group 1). In both groups the percent extraction of valproic acid was calculated from the concentration ratio (valproic acid)out/(valproic acid)in corrected for the rate of CSF formation. In group 1 the percent extraction of valproic acid was 93 +/- 2% (mean +/- SD) at 5 micrograms.ml-1 and stabilized within the range of 58-70% (individual values) at the higher inflow concentrations of valproic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
Valproic acid was administered to a neonate (gestational age of 39 weeks) at 24 days post partum in an initial single dose of 7.5 mg/kg. Multiple serum samples were collected for 24 hours post dose. Valproic acid was continued and the study was repeated in the same child at 6 months of age at which time the dose had been increased to 13.5 mg/kg (27 mg/kg/day). Serum samples were collected for 12 hours post dose in this second study. A one-compartment model was assumed for calculation of the relevant pharmacokinetic parameters. The half-life (t 1/2) at 24 days of age was 17.2 hours, clearance (Cl) 0.18 ml/min/kg, and volume of distribution (Vd) 0.28 liter/kg. This t 1/2 was less than reported values in neonates younger than 10 days but longer than the average t 1/2 in adults. At 6 months of age, clearance had increased to 0.53 ml/min/kg, t 1/2 had decreased to 7.5 hours, while Vd was relatively unchanged (0.34 liter/kg). Factors possibly causing these changes include hepatic enzyme maturation and concomitant administration of anticonvulsant drugs.
Valproic acid (VA) has been reported to be effective in status epilepticus (SE) when given rectally. More recently, intravenous (IV) VA has been demonstrated to be effective and safe. Pharmacokinetic studies and initial clinical experience with IV valproic acid suggest that it may have a useful role in the management of refractory status epilepticus, but the magnitude of its utility is not possible to quantify or compare with phenytoin and phenobarbital. In simple SE, IV VA provides less additional benefit, since standard therapy usually works well. IV VA may be useful as a substitute for standard simple SE therapy, but this is difficult to justify unless adverse reactions to standard therapy are anticipated. The published pediatric experience with IV VA for SE is scant.
Valproic acid is a commonly used drug for the treatment of epilepsy. Since valproic acid can only be given orally, its absorption from the gastrointestinal (GI) tract especially in patients with short bowel syndrome (SBS) and in neonates is important. The specific sites of absorption for valproic acid in the small intestine and colon have not been investigated. It is currently unknown whether these patients are able to absorb oral valproic acid sufficiently to maintain a therapeutic serum concentration. The primary objectives of the study were to: (a) determine the relative absorption of valproic acid from specific sites in the GI tract; and (b) investigate the influence of intestinal development on valproic acid absorption using the newborn piglet as a model. Two groups were studied: Group I included 5 piglets 18-21 days of age, and Group II included 5 piglets 1-3 days of age. A valproic acid solution was simultaneously perfused through 5 partitioned segments of the gastrointestinal tract: the duodenum, jejunum, ileum, right colon and left colon. Tritiated [3H] polyethylene glycol was co-administered to monitor water movement across the GI mucosa. Following steady state, samples were collected from each segment, and analyzed by a specific enzyme-mediated immunoassay. The absorption rates (micrograms/min/cm) of valproic acid in Group I were as follows: 9.96 +/- 2.8 duodenum; 11.28 +/- 2.79, jejunum; 9.42 +/- 3.34, ileum; 10.88 +/- 3.35, right colon; 10.96 +/- 2.92, left colon.(ABSTRACT TRUNCATED AT 250 WORDS)
Valproic acid serum concentrations predicted by a single-dose prediction model were compared with steady-state serum concentrations measured after the start of therapy in seizure patients. Ten patients receiving valproic acid for the first time or who had not been taking the drug for two or more weeks were entered into the study. The patients' therapies were initiated with the prescribed doses of valproic acid and then maintained on fixed doses and dosing intervals until steady-state trough serum samples were obtained. Initial 5-ml blood samples were collected six to 14 hours after the ingestion of the first dose; a 5-ml steady-state trough sample was drawn in the same manner three to seven days later. Both free and total drug concentrations were determined within 48 hours of sample collection using gas-liquid chromatography. The elimination rate constant was estimated from age-specific population half-life values found in the literature. Six patients (five children, aged four to 16 years) and one adult (aged 87 years) completed the study. There was a statistically significant correlation between predicted and measured steady-state valproic acid serum concentrations for both free and total concentrations. The single-dose prediction model accurately predicted steady-state valproic acid serum concentrations in these seizure patients.
The effects of salicylic acid on the pharmacokinetics of valproic acid were investigated in bile-exteriorized rats. A 50 mg/kg bolus dose of sodium valproate was injected iv to Long Evans rats with and without (control) prior treatment by constant infusion of salicylate to keep it at steady state plasma level (about 250 micrograms/ml). The plasma elimination of valproic acid followed a monoexponential decline in both salicylate-treated and control rats. A significant increase (p less than 0.01) in the disposition rate constant (kel), the volume of distribution (Vd), and the total clearance (Cltot) as well as a significant decrease (p less than 0.01) in the AUC and the elimination half-life (t1/2) were observed in the salicylate-treated rats. In spite of the significantly lowered total plasma level and increased unbound fraction of valproic acid in the salicylate-treated rats, there were no significant differences in unbound valproic plasma levels and unbound valproate pharmacokinetic parameters. The biliary excretion of unchanged and conjugated valproate was not significantly different between the two groups. The in vitro plasma-unbound fractions (fu) of valproic acid were significantly increased (p less than 0.01) in the presence of salicylic acid. The apparent dissociation constant of plasma protein binding for valproic acid was increased from 0.287 to 1.204 mM in the presence of salicylic acid. These findings indicate that the pharmacokinetic changes of valproic acid in the presence of salicylic acid were consistent with the elevation in the plasma-unbound fraction of valproic acid due to displacement from plasma protein-binding sites by salicylic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Valproic acid intoxication is common in North America. Although extra-corporeal therapy has been proposed as beneficial in managing significant exposures, evidence to support its use is limited to isolated case reports. A systematic review has not been performed. METHODS: All cases of valproic acid overdose in Ontario, Canada, reported to the Hospital for Sick Children Poison Information Centre (PIC) between January 1st and July 31st 2002 were reviewed. Patients with valproic acid levels > 100 microg/mL were divided into two groups: those treated with and without extra-corporeal therapy. All hospital-measured valproic acid levels and additional clinical information including elimination half-life and clearance were obtained for patients treated with extra-corporeal therapy. RESULTS: There were 28,362 calls to the PIC, of which 139 related to valproic acid poisoning. Thirty-two patients had peak levels > 100 microg/mL. 26 patients were managed conservatively and 6 with extra-corporeal therapy. Survival was 100% in both groups. Patients who received extra-corporeal therapy had higher peak levels (p=0.005), were more frequently treated with charcoal (P=0.006), required intensive care admission (P=0.019), intubation (P<0.001), and vasopressors (P=0.004). Valproic acid elimination was enhanced about tenfold through extra-corporeal methods. Complications included tonic-clonic seizures in 1 patient who received hemodialysis, and thrombocytopenia in 1 patient who underwent hemoperfusion. CONCLUSION: Hemodialysis and hemoperfusion are safe, effective adjuncts in the management of serious valproic acid intoxication and should be considered for patients with hemodynamic or neurological instability. Further study is needed to determine whether hemodialysis alone versus combined hemodialysis-hemoperfusion is more effective for this condition.
Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC(50) for HDAC1 = 0.4 mm). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.
At 37 degrees C, valproic acid was weakly bound by a PFCE through an interaction with the emulsifiers that was independent of both buffer and PFCE concentration. The binding by PFCE was dependent on valproic acid concentration in 0.1 M buffer, but not in 0.2 M buffer. The addition of PFCE to 4% HSA increased the percent free valproic acid due to both HSA dilution and displacement of HSA bound drug. This displacement was apparently due to an interaction with the PFC liquids and/or intact PFCE droplets, and with the oleic acid component of the PFCE.
To evaluate the effects of valproic acid on the disposition of phenytoin, a single dose of 600 mg valproic acid and multiple doses of valproic acid (200 mg four times a day for 5 days) were administered together with a single oral dose of 600 mg phenytoin to 12 young male volunteers. Fraction of unbound phenytoin and the area under curve (AUC) of the total and unbound phenytoin in plasma were compared with the control phase in which only 600 mg phenytoin was given. Valproic acid increased the unbound fraction of phenytoin in both single- and multiple-dose studies by 15 per cent and 41 per cent, respectively. Single-dose valproic acid increased the total AUC of phenytoin by 11 per cent. Multiple-dose valproic acid decreased the total AUC by 7 per cent. Single- and multiple-dose valproic acid increased the unbound AUC by 25 per cent and 18 per cent, respectively, probably due to the inhibition on the metabolizing enzymes. We concluded that there are at least two mechanisms involved in valproic acid-phenytoin interaction. Whereas valproic acid displacing phenytoin on the plasma protein decreased the total drug concentration of phenytoin, the enzyme inhibition by valproic acid increased both the total and unbound concentration of phenytoin. The two conflicting mechanisms may result in different effects on the total plasma concentration of phenytoin. Therapeutic drug monitoring based on the total concentration of phenytoin may be misleading when valproic acid is co-administered.
Valproic acid, used alone or in combination with other anticonvulsants in 100 children with epilepsy, improved seizure control in all age groups. Mean improvement in seizure control was 82%. Petit mal seizures responded best, but other types of seizures, even with associated mental and physical handicaps, also responded well. A substantial improvement in alertness and behavior often occurred. Leukopenia (27%) and an elevated SGOT value (44%) were frequent but transient. Other side effects included alopecia (1), gastrointestinal distress with vomiting (7), pancreatitis (1), thrombocytopenia (1), edema (2), and coma (2). Three severely retarded children with frequent seizures died while receiving valproic acid, but it is not clear that death was caused by valproic acid. Children must be monitored carefully for potential toxic effects, and drug interactions with other anticonvulsants may cause problems in treatment.
The impact of replacing divalproex sodium with valproic acid on patient outcomes and direct drug costs was studied. Before-and-after medical chart review was performed in a state-supported facility for mentally retarded adults in which a pharmacy and therapeutics (P&T) committee recommended replacement of divalproex with valproic acid. Patients were studied if they had received divalproex for at least three months and if their antiepileptic drug was changed from divalproex to valproic acid between October 1993 and June 1994. Clinical, economic, and prescribing-pattern data were recorded for the periods extending 12 months before and 18 months after the change in therapy. Data for 46 patients were analyzed. Replacing divalproex with valproic acid was effective in 41 (89%) of the patients. There was no significant difference between the divalproex and valproic acid periods in seizure rate or frequency of new drug therapy for GI disorders. Between fiscal year 1992-93 and fiscal year 1995-96 there was a 56% decrease in total direct divalproex plus valproic acid costs, including drug products and packaging materials and labor. The rate of valproic acid prescriptions increased steadily after the replacement was recommended, and then plateaued. Replacing divalproex sodium with valproic acid in a group of institutionalized mentally retarded adults with epilepsy was clinically effective and economically advantageous.
Valproic acid is widely used for the treatment of epilepsy and mood disorders, but its mode of action is unclear. Treatment of neuronal cells with valproic acid promotes neurite sprouting, is neuroprotective and drives neurogenesis; however its effects on non-neuronal brain cells are less clear. We report that valproic acid induces apoptosis in the mouse microglial cell line, BV-2, at concentrations within the therapeutic range. When BV-2 cells were incubated for 24 h with 500-1000 microM valproic acid we observed a reduction in cell number, the appearance of apoptotic morphology and increased caspase 3 cleavage. Exposure of a macrophage cell line (RAW 264.7) to similar concentrations of valproic acid also led to reduced cell number but no caspase 3 cleavage, suggesting these cells responded to valproic acid with reduced proliferation rather than apoptosis. This was confirmed using bromodeoxyuridine incorporation studies. Similar concentrations of valproic acid added to Neuro-2a, SK-N-SH and C6 cell lines as well as human NTera-2 astrocytes did not evoke cell death. The caspase 3 inhibitor DEVD-CHO inhibited valproic acid-induced apoptosis in BV-2 cells whereas the MEK inhibitor U0126 potentiated valproic acid-mediated apoptosis. These results demonstrate that valproic acid selectively induces apoptosis in BV-2 cells by way of a caspase 3-mediated action. As activated microglia secrete neurotoxins in neurodegenerative diseases such as Alzheimer's, Parkinson's, and HIV dementia, valproic acid may alleviate these diseases by selectively killing microglia.
Valproic acid is an anticonvulsant that has been associated with open neural tube defects. We report a family in which the maternal use of valproic acid, and other anticonvulsants, during pregnancy resulted in different malformations in two siblings, one of which had a lipomyelomeningocele. The association of valproic acid and closed neural tube defects has not previously been reported. A brief review of the teratogenic effects of valproic acid is included as well as the implications for early surgical management of lipomyelomeningocele.
OBJECTIVE: To determine whether valproic acid (VPA) influences urinary levels of 15-F2t -isoprostane (15-F2t -IsoP), a marker of oxidative stress, in children. STUDY DESIGN: Morning urine samples were collected from children with epilepsy receiving VPA (n = 25), carbamazepine (n = 16), or clobazam (n = 12) for > or = 4 weeks and from age-matched control subjects (n = 39). Urinary 15-F2t -IsoP levels were determined by enzyme-linked immunosorbent assay. RESULTS: The mean (+/- standard deviation) urine 15-F2t -IsoP levels (nmol/mmol Cr) were: valproic acid (0.36 +/- 0.15); carbamazepine (0.24 +/- 0.10); clobazam (0.23 +/- 0.10); control group (0.20 +/- 0.09). Patients treated with VPA had significantly elevated 15-F2t -IsoP levels when compared with the control, carbamazepine, and clobazam groups (P < .05). Multiple linear regression analysis demonstrated that younger patient age and exposure to second-hand smoke were significant predictors of elevated urine 15-F2t -IsoP levels within the control group (r2 = 0.261, P = .05 and P = .01, respectively). Subjects not exposed to second-hand smoke receiving valproic acid therapy had a significantly elevated mean urine 15-F2t -IsoP level compared to subjects not exposed to second-hand smoke in the carbamazepine, clobazam and control groups (P < .05). CONCLUSIONS: These data demonstrate that treatment of children with VPA is associated with higher urinary levels of 15-F2t -IsoP, a marker of oxidative stress.
Carbamazepine and valproic acid are used together in the treatment of epilepsy. It is therefore, relevant to investigate the possibility of a carbamazepine effect on valproic acid disposition, particularly since carbamazepine is known to induce enzymes. We gave valproic acid orally to 6 normal subjects, 250 mg twice daily for 4 wk. Carbamazepine, 200 mg once daily, was begun after 4 days on valproic acid. Serum drug concentrations were measured during 4 dosing intervals, once before and 3 times after beginning carbamazepine. Minimum steady-state concentrations of valproic acid declined after carbamazepine from 34.4 +/- 5.1 to 27.1 +/- 4.4 mug/ml (p less than 0.0005). Clearance rose from 6.46 +/- 0.80 to 8.48 +/- 2.28 ml/hr/kg (p less than 0.01). The increase in clearanace and decrease in minimum steady-state levels was apparent only after 2 wk on carbamazepine. The elimination rate constant (KE) during the dosing interval did not rise during carbamazepine administration (0.0623 +/- 0.0168 hr--1 before and 0.0573 +/- 0.0168 hr--1 after, p greater than 0.25), raising the possibility of an increase in distribution volume.