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PubMed2006

Valproic acid in epilepsy : pregnancy-related issues.

Valproic acid (sodium valproate) is widely used as a first-line antiepileptic agent. As with many antiepileptic drugs, there are a number of consequences associated with the use of valproic acid in women of child-bearing potential. Most pregnancies have a favourable outcome in women with epilepsy, and these women should not be discouraged from becoming pregnant. Unlike many other antiepileptic drugs, valproic acid has no significant pharmacokinetic interactions with the steroid hormones used in oral contraceptives. During pregnancy, the major risks to mother and child result from loss of seizure control on the one hand, and an elevated risk of major congenital malformations due to antiepileptic drug treatment on the other. In particular, an elevated risk of major congenital malformations associated with valproic acid use has been a consistent finding in studies of patient registries and several large case series. In addition, developmental delay, characterised by low verbal IQ, has also been reported in children exposed to valproic acid in utero, although the relative risk is not precisely known. For these reasons, pregnancies in women being treated with valproic acid need to be planned, and the benefit-risk ratios associated with continuing valproic acid or changing treatment need to be discussed with the patient. When treatment with valproic acid is the most appropriate treatment to achieve optimal seizure control, a number of measures can be implemented to minimise risk to the fetus. These include the use of the lowest possible effective dose of valproic acid in monotherapy (ideally <1000 mg/day), appropriate folic acid supplementation and close antenatal monitoring. Regular counselling is a prerequisite for informed planning of pregnancies and optimisation of the probability of a healthy outcome. Future research on valproic acid and pregnancy should involve risk assessment in large, population-based prospective studies.

Abnormalities, Drug-Induced↗

PubMed1995

Relative bioavailability of different valproic acid formulations.

Relative bioavailability of valproic acid after oral administration of 2 Convulsofin (test) tablets each containing 300 mg calcium valproate (263.4 mg valproic acid) was studied versus 2 references (2 dragees each of 300 mg calcium valproate, ref.A, 600 mg sodium valproate in liquid form (258.7 mg valproic acid), ref.B). The controlled, randomized, clinical trial was performed in 16 healthy volunteers (12 males, 4 females, body weight 58-100 kg, Broca index 0.85-1.15) according to a 3-period changeover design with 7 days wash-out between 2 periods. Valproic acid was measured in serum with a GC method. Pharmacokinetic evaluation was done by compartment free methods. Test was considered bioequivalent with ref.A or ref.B with reference to extent of absorption if the 90% confidence interval of their AUC ratio was within the range of 0.80-1.25, and with respect to rate of absorption if the 90% confidence intervals of Cmax/AUC ratios were within 0.70-1.43. The point estimators (90% confidence limits) of the AUC ratios of test/ref.A and test/ref.B were 0.952 (0.882-1.028) and 1.063 (0.989-1.141), respectively. The point estimators (90% confidence limits) of Cmax/AUC ratios were 1.005 (0.923-1.094, test/ref.A) and 0.915 (0.845-0.991, test/ref.B). The following Cmax ratios were calculated: 0.957 (0.866-1.057, test/ref.A) and 0.972 (0.886-1.067, test/ref.B). No serious and unexpected adverse events were observed during the clinical trial. Test was bioequivalent with the 2 reference formulations ref.A and ref.B with respect to extent and rate of absorption. However, according to the secondary criterion tmax test tablets were more rapidly bioavailable than ref.A dragees (tmax-difference: -2.6 (-4.8 to -0.3 h) but more slowly (tmax-difference:+0.8 (-1.3 to +2.9 h) than ref.B juice.

Absorption↗

PubMed1986

The effect of aspirin on valproic acid metabolism.

Urinary valproic acid (VPA) and VPA metabolite profiles were determined before (day 1) and after (day 2) the administration of antipyretic doses of acetylsalicylic acid (ASA) to seven subjects with steady-state levels of VPA. Of the 13 metabolites assayed by GC/MS, levels of (E)-2-ene VPA and 3-keto VPA were significantly decreased on day 2, whereas those of the VPA conjugates (glucuronide) and 4-ene VPA were significantly increased. The beta-oxidation pathway consisting of (E)-2-ene VPA, 3-OH VPA, and 3-keto VPA was decreased from 24.5% +/- 10.3% of total metabolites excreted on day 1 to 8.3% +/- 4.2% on day 2, a decrease of 66% (P less than 0.05). VPA glucuronide content increased from 50.5% +/- 12.6% on day 1 to 65.5% +/- 14% of total excreted on day 2, an increase of 30% (P less than 0.05). The day 2/day 1 ratios of VPA glucuronide correlated significantly with the day 2/day 1 ratios of VPA mean free fraction (r = 0.9424; P = 0.005) in six of the seven subjects. Inhibition of VPA beta-oxidation by salicylate was sufficient to counterbalance the increased elimination of VPA as its conjugates and explains why total clearance of VPA after salicylate remains unchanged even though the free fraction of VPA is increased. Metabolic profiles indicate that salicylate likely inhibits VPA beta-oxidation by reducing valproyl-coenzyme A formation.

Adolescent↗

PubMed2001

Low serum biotinidase activity in children with valproic acid monotherapy.

PURPOSE: Valproic acid (VPA) is an effective antiepileptic drug (AED), which is associated with dose-related adverse reactions such as skin rash, hair loss (alopecia), etc. Profound as well as partial biotinidase deficiency causes dermatologic manifestations similar these. Therefore, it was of interest to evaluate serum biotinidase activity in patients receiving VPA monotherapy. METHODS: Seventy-five patients with seizures, mean age, 8.6 years (+/-1.9 years) were divided into three groups. Group A (n = 25) was treated with VPA 28.7 +/- 8.5 mg/kg/24 h, group B (n = 25) with 41.6 +/- 4.9 mg/kg/24 h, and group C with 54.5 +/- 5.8 mg/kg/24 h. Their "trough" VPA serum levels were 40.9 +/- 13.2, 86.25 +/- 11.5, and 137 +/- 14.5 microg/ml, respectively. Fifty healthy children were the controls. Patients and controls underwent clinical and laboratory evaluations including liver function data, complete blood counts, NH3, and so on, after 45 days of VPA treatment. Biotinidase serum levels were evaluated fluorometrically. RESULTS: Liver function data were found elevated in the groups B and C. On the contrary, biotinidase activity was significantly statistically lowered (p < 0.001) in groups B and C (1.22 +/- 1.11, 0.97 +/- 0.07 mmol/min/L respectively), as compared with controls (5.20 +/- 0.90 mmol/min/L). Strong inverse correlations were observed between liver enzymes and VPA blood levels with the activity of the enzyme. Additionally, no inhibitory effect on biotinidase activity was found, when the enzyme was incubated in vitro with high (1.2 mM) concentrations of the drug. Skin lesions (seborrheic rash, alopecia) were improved in our patients after biotin (10 mg/day) supplementation. CONCLUSIONS: It is suggested that VPA impairs the liver mitochondrial function, resulting in a low biotinidase activity and or biotin deficiency. Biotin supplementation could restore some of the side effects of the drug.

Amidohydrolases↗

PubMed2005

Acute leukemia associated with valproic acid treatment: a novel mechanism for leukemogenesis?

Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia-like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase.

Acute Disease↗

PubMed2003

Ammonia induced encephalopathy from valproic acid in a bipolar patient: case report.

Valproic acid is widely used as a mood stabilizer. We report a case of an adult with bipolar disorder taking therapeutic doses of valproic acid, who presented to the emergency department with coma related to hyperammonemia as a complication of valproic acid treatment. Valproic acid was discontinued which resulted in rapid clinical recovery. Valproic acid induced coma was likely related to a urea cycle enzymopathy. Clinicians should consider hyperammonemia in all patients who present with coma and other mental status changes while on valproic acid. In such patients, ammonia level should be obtained in addition to liver function tests.

Adult↗

PubMed2002

Valproic acid toxicity: overview and management.

Acute valproic acid intoxication is an increasing problem, accounting for more than 5000 calls to the American Association of Poison Control Centers in 2000. The purpose of this paper is to review the pharmacology and toxicology of valproic acid toxicity. Unlike earlier antiepileptic agents, valproic acid appears to function neither through sodium channel inhibition nor through direct gamma-aminobutyric acid agonism, but through an indirect increase in regional brain gamma-aminobutyric acid levels. Manifestations of acute valproic acid toxicity are myriad, and reflect both exaggerated therapeutic effect and impaired intermediary metabolism. Central nervous system depression is the most common finding noted in overdose, and may progress to coma and respiratory depression. Cerebral edema has also been observed. Although hepatotoxicity is rare in the acute overdose setting, pancreatitis and hyperammonemia have been reported. Metabolic and hematologic derangements have also been described. Management of acute valproic acid ingestion requires supportive care and close attention to the airway. The use of controversial adjunctive therapies, including extracorporeal drug elimination and L-carnitine supplementation, will be discussed.

Animals↗

PubMed1999

[Should folic acid be given to women treated with valproic acid and/or carbamazepine? Folic acid and pregnancy in epilepsy].

Fetal exposure to valproic acid or carbamazepine increases the risk of neural tube defect (NTD). The risk of a mother having a baby with spina bifida has been estimated at 1-2 p. 100, close to the rate of risk of recurrent cases. No study has evaluated the effect of folic acid in neonates of women treated with valproic acid or carbamazepine although the protective effect against NTD has been proven in other populations. Periconceptional folic acid supplementation, 0.4 to 1 mg/day, for at least one month prior to conception and until the date of the second missed menstrual period or later decreases the incidence of a first occurrence of neural tube defect. Periconceptional folic acid supplementation, 4 mg/day, decreases the recurrence of NTD in women who had previously had a child with NTD. It seems pertinent to recommend periconceptional folic acid supplementation in women treated with carbamazepine or valporic acid. There are very few data in women on which to base a decision to advise taking 4 mg/day (as used in recurrence prevention) or low doses of 0.4 mg/day (used in primary prevention).

Anticonvulsants↗

PubMed1985

Pharmacological evaluation of various metabolites and analogues of valproic acid. Anticonvulsant and toxic potencies in mice.

Thirty-two metabolites and analogues of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) were tested for anticonvulsant and toxic effects in mice, in an attempt to find out if any of these compounds were superior to valproic acid. Valproic acid and ethosuximide, another clinically established antiepileptic drug, were included in these studies for comparison. After intraperitoneal administration, the anticonvulsant potency of the various drugs was determined in three seizure tests: the threshold for maximal electroconvulsions, the maximal electroshock seizure test and seizures induced by subcutaneous injection of pentylenetetrazol. For the most potent compounds, median minimal neurotoxic doses (TD50S) and LD50S (after i.p. and i.v. injection) were determined. Valpramide, the primary amide of valproic acid, proved to be the most potent compound in the three seizure tests, used, being 2-5 times as potent as valproic acid, but valpramide was also considerably more sedative and toxic than valproic acid or ethosuximide. Of the metabolites of valproic acid tested, the unsaturated compounds 4-en-valproic acid (4-en-VPA) and the trans-isomer of 2-en-valproic acid (2-en-VPA) were most potent and, depending on the seizure test used, reached 60-100% of the efficacy of the parent drug. Both metabolites had LD50 values which were similar or greater than those of valproic acid but they were more sedative than the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Formation of a free acyl adenylate during the activation of 2-propylpentanoic acid. Valproyl-AMP: a novel cellular metabolite of valproic acid.

A study of the activation of valproic acid (2-n-propylpentanoic acid) by a soluble extract of rat liver mitochondria in the presence of ATP, CoASH, and MgCl2 revealed that, in addition to valproyl-CoA, an unknown UV-absorbing compound is formed which is the sole product when CoASH is omitted from the incubation mixture. The unknown compound, which was purified by high performance liquid chromatography, was identified as valproyl adenylate (valproyl-AMP) by mass spectrometry and by its enzymatic conversion to valproyl-CoA in the presence of CoASH. Valproyl-AMP exists, at least partially, in a free, not-enzyme-bound form. Its rate of formation is linear with time and increases 5-fold when the pH is decreased from 8 to 6.8. Valproyl-AMP was also identified when the metabolism of valproate was investigated with rat liver mitochondria and rat hepatocytes. Since the synthesis of valproyl-AMP is inhibited by octanoate, medium-chain acyl-CoA synthetase (EC. 6.2.1.2) may be responsible for its formation. This study establishes that during the activation of valproic acid to valproyl-CoA free valproyl-AMP is formed which is a novel cellular metabolite of valproic acid.

Acyl Coenzyme A↗

PubMed1996

High-dose versus low-dose valproic acid as a prophylactic medication.

Valproic acid has been shown to be effective in migraine prophylaxis. Its method of action is believed to be the inhibition of gamma-aminobutyric acid transaminase. The therapeutic dose needed to prevent migraine headaches has been examined in several studies, yet the optimum dose has not been found. In this case report, valproic acid was given to a 24-year-old woman with chronic headaches at 1000 mg per day. Her headaches resolved for 2 months. She tapered herself off of the medication, and her headaches returned. She was restarted at 500 mg per day of valproic acid and again, her headaches resolved. She preferred being on the lower dose which she found as effective as the higher dose. Her case makes two interesting points. The first is that lower dosages of valproic acid may be as effective as higher ones in headache prophylaxis. The second is that more studies looking at dose ranges are needed to correlate effectiveness with daily requirements.

Adult↗

PubMed1984

Pancreatitis associated with valproic acid therapy.

Four patients had pancreatitis associated with valproic acid therapy. Three patients received valproic acid at usual doses, and all were free of other symptoms of toxic reactions, with serum levels of valproic acid in the usual therapeutic range. Two patients underwent exploratory laparotomy prior to diagnosis. Complications included pseudocyst, pericardial effusion, laparotomy wound infection, and coagulopathy. All patients recovered with discontinuation of valproic acid therapy and enteral feeding and administration of intravenous fluids. After recovery, a valproic acid regimen was restarted uneventfully (in one patient). All were asymptomatic with normal serum amylase levels after five to 14 months. Pancreatitis is a serious complication of valproic acid therapy that must be considered in any patient receiving valproic acid who experiences severe abdominal pain and vomiting.

Abdomen↗

PubMed2001

Septo-optic dysplasia as a manifestation of valproic acid embryopathy.

BACKGROUND: The use of valproic acid during pregnancy has been associated with adverse fetal outcomes, including major and minor congenital malformations, intrauterine growth retardation (IUGR), hyperbilirubinemia, hepatotoxicity, transient hyperglycemia, and fetal and neonatal distress. In addition, intrauterine exposure to valproic acid has been associated with an increased risk of central nervous system abnormalities, primarily neural tube defects. Optic nerve hypoplasia has been reported in association with other prenatal anticonvulsant exposures, but the occurrence of septo-optic dysplasia as a manifestation of valproic acid embryopathy has not been reported previously. RESULTS: We report on a woman who received Depakote (valproic acid) throughout her pregnancy for the treatment of a seizure disorder. The patient presented with features typical of valproic acid embryopathy, including bitemporal narrowing, hypertelorism, short palpebral fissures, epicanthal folds, microphthalmia, a flat broad nasal bridge, small mouth, hypoplastic nails, mild clinodactyly, and camptodactyly. MRI showed hypoplasia of the optic chiasm and absence of the septum pellucidum. CONCLUSIONS: We report the first case of septo-optic dysplasia associated with maternal exposure to valproic acid throughout pregnancy. This case expands the clinical phenotype of valproate embryopathy.

Abnormalities, Drug-Induced↗

PubMed1996

Displacement of valproic acid and carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions.

Displacement of valproic acid (90-95% bound to albumin) and carbamazepine (80% bound to albumin) by salicylate, leading to higher concentrations of pharmacologically active free drugs, has been reported. We studied the possibility of displacement of valproic acid and carbamazepine by other strongly albumin-bound nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen. We observed statistically significant displacement of carbamazepine from protein binding in uremic serum at higher therapeutic concentrations of all three antiinflammatory drugs we studied, whereas in normal serum, we observed statistically significant displacement only with 75 micrograms/ml of naproxen. For valproic acid, we observed significant displacement even at lower therapeutic concentrations with all three drugs when the study was conducted using a normal serum pool. In the uremic serum pool, we observed significant displacements only with tolmetin and ibuprofen, whereas we observed no significant displacement of valproic acid even with higher concentrations of naproxen. We conclude that tolmetin, naproxen, and ibuprofen can displace both carbamazepine and valproic acid from protein binding, but uremic serum contains an inhibitor that blocks valproic acid-naproxen interaction.

Binding, Competitive↗

PubMed1999

Cytotoxicity induced by the combination of valproic acid and tumor necrosis factor-alpha: implication for valproic acid-associated hepatotoxicity syndrome.

A previous study showed that valproic acid (VPA) and tumor necrosis factor-alpha (TNF-alpha) exhibit synergistic toxicity (lethality) in Sprague-Dawley and Wistar rats. The present study investigated a possible mechanism for this synergy using an in vitro system. Incubation of human U937 cells with 1 mM VPA or with 0.001 ng/mL of TNF-alpha alone had a negligible effect on cytotoxicity (less than 7%). However, the combination of the two drugs significantly increased the cytotoxicity up to 34%. Chronic treatment of U937 cells with VPA or TNF-alpha for 48 hr reduced protein kinase C (PKC) activity. Further, the PKC selective inhibitor Gö6976 potentiated VPA-induced cytotoxicity and TNF-alpha-induced cytotoxicity, whereas the PKC activator phorbol-12-myristate-13-acetate provided a significant protection against the cytotoxicity associated with VPA or TNF-alpha. These results suggest that the synergism in cytotoxicity exhibited by the combination of VPA and TNF-alpha may be mediated through attenuation of PKC activity.

Animals↗

PubMed1983

Influence of valproic acid on hepatic carbohydrate and lipid metabolism.

Valproic acid (dipropylacetic acid), an antiepileptic agent known to be hepatotoxic in some patients, caused inhibition of lactate gluconeogenesis, fatty acid oxidation, and fatty acid synthesis by isolated hepatocytes. The latter process was the most sensitive to valproic acid, 50% inhibition occurring at ca. 125 microM with cells from meal-fed female rats. The medium-chain acyl-CoA ester fraction was increased whereas coenzyme A (CoA), acetyl-CoA, and the long chain acyl-CoA fractions were decreased by valproic acid. The increase in the medium chain acyl-CoA fraction was found by high-pressure liquid chromatography to be due to the accumulation of valproyl-CoA plus an apparent CoAester metabolite of valproyl-CoA. Salicylate inhibited valproyl-CoA formation and partially protected against valproic acid inhibition of hepatic metabolic processes. Octanoate had a similar protective effect, suggesting that activation of valproic acid in the mitosol is required for its inhibitory effects. It is proposed that either valproyl-CoA itself or the sequestration of CoA causes inhibition of metabolic processes. Valproyl-CoA formation also appears to explain valproic acid inhibition of gluconeogenesis by isolated kidney tubules. No evidence was found for the accumulation of valproyl-CoA in brain tissue, suggesting that the effects of valproic acid in the central nervous system are independent of the formation of this metabolite.

Acyltransferases↗

PubMed2000

High-flux hemodialysis without hemoperfusion is effective in acute valproic acid overdose.

OBJECTIVE: To report a case of valproic acid overdose treated successfully with high-flux hemodialysis without the addition of charcoal hemoperfusion. CASE SUMMARY: A 25-year-old white woman with a history of multiple suicide attempts and schizophrenia presented after ingesting an unknown amount of valproic acid. She became comatose and developed hypotension and lactic acidosis as valproic acid concentrations increased to > 1200 micrograms/mL (therapeutic concentration 50-100). High-flux hemodialysis was performed for four hours; the calculated elimination rate constant (kel) during the procedure was 0.2522 h-1 with a half-life (t1/2) of 2.74 hours compared with posthemodialysis kel of 0.0296 h-1 and t1/2 of 23.41 hours, suggesting that high-flux hemodialysis effectively eliminates valproic acid. The patient's hemodynamic status and mental function improved in conjunction with the acute reduction in valproic acid concentrations. Her subsequent hospital course was complicated only by transient thrombocytopenia. DISCUSSION: Most literature reports of valproic acid overdose have described the use of charcoal hemoperfusion alone or in combination with hemodialysis to accelerate valproic acid clearance at toxic concentrations. However, the pharmacokinetic properties of valproic acid indicate that hemodialysis alone would be effective therapy for an acute valproic acid overdose. CONCLUSIONS: We suggest that toxic concentrations of valproic acid can be effectively reduced with high-flux hemodialysis without the addition of charcoal hemoperfusion and its attendant risks.

Acidosis, Lactic↗

PubMed1990

Neurophysiological and biochemical changes evoked by valproic acid in the central nervous system.

(1) Valproic acid is an anticonvulsant agent widely used in the management of various forms of epilepsy, including absence, myoclonic and tonic-clonic seizures. (2) It also has anticonvulsant potency in a wide variety of animal models of epilepsy. (3) This action is generally thought to be exerted through modulation of the activity of the endogenous inhibitory neurotransmitter, gamma-aminobutyric acid. (4) Evidence that valproic acid interacts with the gamma-aminobutyric acid system is presented. (5) Interactions of valproic acid with other neurotransmitters, i.e. aspartate, glutamate, taurine, serotonin, as well as with cyclic nucleotides and hormones are also considered. (6) Direct effects of valproic acid on excitable membranes and its relationships with analgesia are outlined.

Animals↗