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PubMed1985

Effects of valproic acid and ethosuximide on the responding of pigeons maintained under a multiple fixed-ratio fixed-interval schedule of food delivery.

The effects of valproic acid and ethosuximide were examined in pigeons responding under a multiple Fixed-Ratio 50 Fixed-Interval 90-sec schedule of food delivery. When given acutely 30 min prior to behavioral testing, both valproic acid (40, 60, 80, 100, and 120 mg/kg) and ethosuximide (40, 60, 80, 100, and 120 mg/kg) produced generally dose-dependent decreases in responding under both the Fixed-Ratio and Fixed-Interval components. Detailed analysis of drug effects on the temporal distribution of responding under the Fixed-Interval failed to reveal rate-dependent effects for either drug. Varying the presession injection interval from 15 to 120 min indicated that both valproic acid and ethosuximide reduced responding to the greatest extent when given 30 or 60 min before behavioral testing. These results indicate that the anticonvulsants valproic acid and ethosuximide similarly affect schedule-controlled responding, although previous studies have revealed the drugs to have different effects under other procedures.

Animals↗

PubMed1995

A feasibility study of the multiple-peak approach for pharmacokinetic screening: population-based investigation of valproic acid relative clearance using routine clinical pharmacokinetic data.

The multiple-peak approach was used to evaluate the effect of age, body mass, dose and gender on the population estimates of valproic acid relative clearance. Routine clinical pharmacokinetic data (n = 474) was collected from 250 patients receiving valproic acid and no other drug. The data was analysed according to a simple steady-state pharmacokinetic model using NONMEM, a computer program designed for population pharmacokinetic analysis allowing pooling of data. The final regression model for relative clearance (CL, mL kg-1 h-1) was: CL = 18.9 x body weight(-0.276) x daily dose(0.142) x gender where gender = 1 for males, 0.877 for females. NONMEM estimates suggested that the rate of valproic acid clearance decreased nonlinearly with increasing body weight in the maturation process, and increased nonlinearly with increasing valproic acid dose (mg kg-1 day-1). The clearance in females was about 11% less than in males. These estimates were similar to those detected from previous studies.

Adolescent↗

PubMed1991

[Acute pancreatitis and valproic acid].

An 11 year-old epileptic boy, treated with valproic acid developed after 11 months on therapy a severe acute pancreatitis. Pancreatitis recurred 18 months after re-exposure to the same drug. Twenty-four cases of valproic-acid induced acute pancreatitis have been reported in the literature. However, it remains a major anticonvulsant drug whose tolerance is usually excellent. This complication, although exceptional needs to be known so that the treatment can be stopped in due-time if not tolerated or to avoid eventual recurrence.

Acute Disease↗

PubMed1982

In vivo uptake of valproic acid into brain.

The pharmacokinetics of valproic acid (VPA) penetration into the central nervous system of cats were studied. VPA levels in cortical gray matter and plasma were measured at timed intervals after rapid intravenous drug infusion. Brain uptake of the drug was maximal at 1 min postinfusion and decayed rapidly with a mean elimination half-life of 41 min. After a rapid distribution phase, plasma VPA levels remained stable for 90 min. The brain:plasma ratio was maximal at 1 min and also declined rapidly. The volume of distribution was 0.125 1/kg. The small volume of distribution, low brain:plasma ratios and rapid clearance from brain indicate that VPA is not significantly bound in cerebral cortex after a single dose.

Animals↗

PubMed2006

Major malformations with valproic acid.

QUESTION: Increasing numbers of pregnant patients are treated with valproic acid, not just for epilepsy, but also for psychiatric conditions. Are there teratogenic risks other than the risk of spina bifida? ANSWER: It has now become evident that valproic acid might cause more than just neural tube defects (NTDs). In a systematic review of all cohort studies intended to answer this question, higher rates of major malformations (and not just NTDs) were found in most studies. The calculated relative risk was 2.59 when compared with other antiepileptic drugs and was 3.77 when compared with risk in the general population. There is compelling evidence that the risk is dose dependent. The risks appear to begin increasing at doses of 600 mg/d and to become more prominent at doses above 1000 mg/d.

Abnormalities, Drug-Induced↗

PubMed1998

Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy.

Specific oxidative metabolites of valproic acid (VPA) have been associated with the clinically defined toxicity of the drug. To investigate the role of enzymatic detoxification in clinical toxicity, we compared activities of five antioxidant enzymes in 15 patients with a serious adverse experience (SAE) related to VPA therapy, to enzyme activities measured in 35 patients with good clinical tolerance of VPA, and 50 healthy, age-matched subjects. These enzymes included glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione transferase, superoxide dismutase, and catalase in erythrocytes; and GSH-Px in plasma. We also determined levels of Se, Cu, and Zn, trace elemental cofactors for these enzymes, in plasma from each individual. In patients with a VPA-associated SAE, GSH-Px was significantly depressed and GSSG-R was significantly elevated relative to values for the other groups. Selenium and zinc concentrations were lower in SAE patients than in controls. These findings may indicate a role for selenium dependent antioxidant activity in individual susceptibility to an SAE related to VPA therapy.

Analysis of Variance↗

PubMed1977

Disposition of valproic acid in man.

The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9 +/- 2.6 h in the single dose and 17.3 +/- 3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064 +/- 0.0011 l/kg X h. The apparent volume of distribution was small at 0.15 +/- 0.2 l/kg. The mean steady state plasma concentration (Css) reached after 4 days was 81.3 +/- 13.0 microgram/ml. Css observed was lower than Css predicted (99.2 +/- 14.7 microgram/ml) from single dose kinetics (p less than 0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7 +/- 0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.

Adult↗

PubMed2005

Valproic acid monotherapy induces DNA oxidative damage.

Valproic acid (VPA) and 8-hydroxy-2-deoxyguanosine (8-OHdG) are implicated with the free radicals production. We aimed to evaluate total oxidant status (TOS) and 8-OHdG in children on VPA monotherapy. Fifty patients with seizures, mean age 8.5+/-3.6 years, were divided into group A (N=26) and group B (N=24) with VPA serum levels 81.0+/-8.0 and 114+/-9.7 microg/mL, respectively. Thirty healthy children were the controls. Liver function tests and lipids were determined with routine methods, TOS and 8-OHdG with commercial kits, after 60 days on VPA therapy. Liver function parameters, lipids, TOS (647+/-43 micromol/L) and 8-OHdG (0.49+/-0.08 ng/mL) were significantly higher in group B than those in group A (580+/-40 micromol/L, 0.37+/-0.04 ng/mL, p<0.001) and controls (124+/-30 micromol/L, 0.11+/-0.04 ng/mL, p<0.001, respectively). Significant correlation coefficients were found between 8-OHdG versus TOS (r=0.67, p<0.001) and 8-OHdG versus VPA (r=0.60, p<0.001) levels. It is suggested that VPA impairs the liver function resulting in free radicals production. The latter seems to produce DNA oxidative damage in liver cells, not excluding neuronal cells, as evidenced by the measured remarkably increased 8-OHdG serum levels. 8-OHdG evaluation may be a useful biomarker to follow up the increased risk of degeneration process in VPA patients.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2001

Analysis of the musculoskeletal system in children and adolescents receiving anticonvulsant monotherapy with valproic acid or carbamazepine.

OBJECTIVE: To examine bone development in children and adolescents who have uncomplicated idiopathic epilepsy and had received monotherapy with carbamazepine or valproic acid for at least 1 year. METHODS: Thirty-nine patients from 6 to 19 years of age (18 girls) were studied. Total bone mineral content (BMC) and trabecular volumetric bone mineral density were measured at the distal radius using peripheral quantitative computed tomography. Maximum isometric grip force was determined with a standard dynamometer. Alkaline phosphatase activity and deoxypyridinoline (a marker of bone resorption) were assessed in serum and urine, respectively. RESULTS: Trabecular volumetric bone mineral density was significantly decreased in the entire group (z score mean +/- standard deviation: -0.62 +/- 1.04) and in the subgroup using valproic acid (-0.75 +/- 1.18). In the carbamazepine subgroup, there was a similar but nonsignificant trend (-0.50 +/- 0.90). Total BMC and isometric maximum grip force were normal in the entire study population (0.10 +/- 1.22) and in the 2 subgroups. The relationship between BMC and grip force was similar between patients and healthy participants. Urinary levels of deoxypyridinoline were significantly elevated above normal in the whole study population (1.35 +/- 2.00) and in both the valproic acid and the carbamazepine subgroups. CONCLUSIONS: Bone turnover can be increased, but bone mass is adequate in children and adolescents who have uncomplicated idiopathic epilepsy and who receive monotherapy with carbamazepine or valproic acid.

Adolescent↗

PubMed1996

3-Hydroxymethylphenytoin valproic acid ester, a new prodrug combining two anticonvulsant drugs.

3-Hydroxymethylphenytoin valproic acid ester (VAL-PHT) was designed as a new prodrug combining valproic acid and phenytoin, two anticonvulsant drugs with different pharmacological profiles. The compound was hydrolyzed by rat plasma esterases in vitro but exhibited only activity in the maximal electroshock seizure test (MES test) after intraperitoneal administration to mice. The compound did not protect against pentylenetetrazole-induced seizures. It is concluded that VAL-PHT acts as a prodrug displaying the anticonvulsant profile of phenytoin.

Animals↗

PubMed1994

Isaac's syndrome: report of a case responding to valproic acid.

Isaac's syndrome is an uncommon, but distressing, condition of spontaneous abnormal muscle activity caused by neuronal hyperexcitability possibly due to damage to slow potassium channels. The underlying aetiology may be peripheral nerve damage from a wide variety of causes, including autoimmune disease. We report a case that failed to respond to carbamazepine or phenytoin but responded dramatically to valproic acid. Thus, valproic acid may be an effective treatment for Isaac's syndrome where these other drugs have failed.

Biopsy↗

PubMedDate not supplied

[Comparative study of valproic acid and sodium valproate (author's transl)].

The action of valproic acid prescribed instead of sodium valproate in strictly identical conditions was analysed in 11 epileptic children and 24 adults. No change in therapeutic effect was observed in a large proportion of cases. However, blood tests showed an increase in serum levels in most cases. Thus, valproic acid can be of help in cases hitherto treated with sodium valproate, on the same basis as diphenylhydantoin; the acid form sometimes offers an advantage over the use of the sodium salt.

Adolescent↗

PubMed1993

Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid.

The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4-butanediol divalproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4-butanediol.

Animals↗

PubMedDate not supplied

Levonantradol potentiates the anticonvulsant effects of diazepam and valproic acid in the kindling model of epilepsy.

The anticonvulsant effects of the cannabinoid derivative levonantradol and its ability to potentiate the anticonvulsant effects of diazepam and valproic acid were studied in rats with previously established amygdala-kindled seizures. Levonantradol administered in doses of 100 to 400 micrograms/kg did not block any components of the motor seizure. However, levonantradol did increase the latency of appearance of fully kindled seizures at the 400 micrograms/kg dose. Administration of diazepam at doses of 1 or 2 mg/kg or valproic acid at doses of 100 or 200 mg/kg produced seizure control as measured by a reduction in motor components of the seizure or a reduction in afterdischarge length or both. The anticonvulsant effects of diazepam and valproic acid were potentiated by administration of 100 microgram/kg levonantradol without apparent increases in sedation. Although the mechanism underlying this potentiation of the antiepileptic effects of valproic acid and diazepam remains unknown, levonantradol may have potential as adjunctive therapy in the treatment of complex partial seizures.

Animals↗

PubMed1979

Stupor following administration of valproic acid to patients receiving other antiepileptic drugs.

Stupor is an unusual complication following the addition of valproic acid to other antiepileptic drugs. We report four such cases. Stupor occurred acutely in 3 patients and insidiously in the fourth. In the cases of acute toxicity, neither toxic levels of valproate nor significant elevations in blood levels of the other drugs occurred. In the fourth patient, stupor occurred concomitantly with a rise in the phenobarbital level. The electroencephalograms of all 4 patients revealed generalized high-amplitude rhythmic bisynchronous delta activity. Recovery occurred following discontinuation of valproic acid or other antiepileptic drugs. These observations suggest that stupor may occur as a result of drug interactions after the addition of valproic acid to other antiepileptic drugs.

Adolescent↗

PubMed1982

Systemic interaction between valproic acid and free fatty acids in rhesus monkeys.

The interaction between valproic acid (VPA) and free fatty acids (FFA) was investigated at a systemic level in eight rhesus monkeys. Intralipid emulsion (I.L.) was infused to increase plasma FFA levels. During I.L. treatment, plasma FFA levels were elevated in all cases (12 cases) with increases ranging from 38 to 525% (median, 102%). Valproate free fraction (fp) was elevated in 11 of 12 cases, with increases ranging between 7 and 100% (median, 18%). A positive correlation between the relative increase in FFA and the corresponding increase in fp of VPA was obtained. Intralipid infusion was associated with changes in the systemic clearance of VPA (an increase in five cases and a decrease in seven cases). The intrinsic clearance (Clint) of VPA was decreased in 9 of 12 cases with decreases ranging from 13 to 78% (median, 22%). Urinary excretion of valproate glucuronide was decreased in three of four monkeys during I.L. treatment. A significant positive correlation (p less than 0.05) between the relative increase in FFA levels and the decrease in Clint of VPA were also observed. The mechanism of interaction between VPA and FFA in rhesus monkey is more complex than a simple protein binding displacement and involves at least one metabolic inhibition component such as glucuronidation.

Animals↗

PubMedDate not supplied

Metabolic conversion of 2-propylpentanal acetals to valproic acid in vitro. Model prodrugs of carboxylic acid agents.

As part of an investigation to test the feasibility of using acetals as precursors of acidic drugs, the dimethyl, diethyl, [2H10]diethyl, and diisopropyl acetals of 2-propylpentanal were synthesized and their metabolic conversion to the anticonvulsant, valproic acid (2-propylpentanoic acid), was investigated. The acetals were incubated with either 10,000g supernatant or microsomes isolated from rat liver. Data from the measurement of the metabolite, valproic acid, with selected ion monitoring gas chromatography/mass spectrometry indicated that the dimethyl, diethyl, [2H10]diethyl, and diisopropyl acetals were substrates. The amount of valproic acid produced from the incubation of 2-propylpentanal diethyl acetal with 10,000g supernatant was reduced by the cytochrome P-450 inhibitor, SKF-525A. The production of acid was also decreased by lack of NADPH or oxygen. These data are consistent with a cytochrome P-450 mediated reaction. 2-Propyl-1-pentanol was the major metabolite identified from microsomal preparations free of soluble fraction enzymes. A deuterium isotope effect calculated as the ratio of the amount of valproic acid produced from unlabeled and [2H5]ethyl-labeled substrate was 1.2. Failure to detect an ester as a metabolite of 3-phenylpropanal diethyl acetal along with the results of the isotope effect studies suggest that the mechanistic pathway of acyclic acetal metabolism involves oxidation of an ether methylene and not oxidation at the acetal carbon.

Acetals↗

PubMed1989

Asymmetric synthesis and enantioselective teratogenicity of 2-n-propyl-4-pentenoic acid (4-en-VPA), an active metabolite of the anticonvulsant drug, valproic acid.

Previous studies indicated that the enantiomers of thalidomide and its analogue EM12 exhibit differing teratogenic potencies. Unfortunately, these substances proved to be unstable and racemised considerably, so that the intrinsic teratogenic potencies of the pure enantiomers were difficult to elucidate. We have therefore studied the teratogenicity of the enantiomers of 2-n-propyl-4-pentenoic acid (4-en-VPA), a metabolite of the human and animal teratogen valproic acid (VPA). Both enantiomers were prepared via asymmetric synthesis using (R)- and (S)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP: SAMP). The determination of the absolute configuration and of the optical purities is described. They were administered as single intraperitoneal injections during early organogenesis in the mouse (day 8 of gestation), a period shown to be highly susceptible to interference with neural tube closure by VPA. S-(-)-4-en-VPA was significantly more teratogenic (formation of exencephaly) and embryotoxic (incidence of embryolethality and fetal growth retardation) than R-(+)-4-en-VPA. The rate of neural tube defects (exencephaly) produced by the S-enantiomer was about 4 times higher than that produced by the R-enantiomer. The S-enantiomer of 4-en-VPA is the first analogue of VPA with higher teratogenic potency than the parent drug. Our results show that racemic mixtures may consist of enantiomers with greatly differing teratogenic potencies. These findings may lead to the development of clinically useful drug enantiomers with low teratogenic potencies, and assist in studies of molecular mechanisms in drug and chemical teratogenesis.

Abnormalities, Drug-Induced↗