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PubMed1995

Structure-activity relationships of unsaturated analogues of valproic acid.

The principal metabolite of valproic acid (VPA), 2-ene VPA, appears to share most of VPA's pharmacological and therapeutic properties while lacking its hepatotoxicity and teratogenicity, thus making it a useful lead compound for the development of safer antiepileptic drugs. Analogues of 2-ene VPA were evaluated for anticonvulsant activity in mice using the subcutaneous pentylenetetrazole test. Cyclooctylideneacetic acid exhibited a potency markedly exceeding that of VPA itself with only modest levels of sedation. Potency, as either ED50 or brain concentration, was highly correlated (r > 0.85) with volume and lipophilicity rather than with one of the shape parameters calculated by molecular modeling techniques, arguing against the existence of a specific receptor site. Instead, a role for the plasma membrane in mediating the anticonvulsant effect is suggested.

Animals↗
PubMed1986

Effects of valproic acid in cultured mammalian neurons.

Valproic acid (VPA) has been postulated to exert its anticonvulsant effects by interaction with the postsynaptic GABA receptor. To test that hypothesis, we applied VPA in clinically appropriate concentrations to cortical neurons in dissociated cell culture. VPA did not enhance the postsynaptic effect of GABA, but did decrease the generation of sodium-dependent action potentials. VPA may exert anticonvulsant effects by inhibiting spike generation, independent of the GABAergic system.

Action Potentials↗
PubMed1998

Disposition of valproic acid in a case of fatal intoxication.

The case history and toxicological findings of a fatal suicidal valproic acid overdose are presented. Valproic acid concentrations were determined in body tissues and fluids by gas-liquid chromatography (GLC) following both direct extraction and the method of standards addition and quantitative fluorescence polarization immunoassay. The quantitative results obtained by the three procedures were in good agreement. Qualitative identification of valproic acid as its methylated derivative was by ion-trap gas chromatography-mass spectrometry. Toxicological analysis by direct extraction GLC yielded the following valproate concentrations (mg/mL or mg/kg): blood, 1050; bile, 713; brain, 510; heart, 670; kidney, 1580; liver, 985; and vitreous, 516. A total of 15.1 g of valproate was recovered in the stomach contents. These findings far exceed those associated with valproate therapy and are similar to the limited valproate disposition data reported in prior fatal overdoses.

Adult↗
PubMed1978

Valproic acid in epilepsy: clinical and pharmacological effects.

The antiepileptic drug valproic acid was studied in an open clinical trial as adjunct medication for 23 patients with uncontrolled seizures of a generalized or partial type. Two-thirds of the patients experienced reduction in seizure frequency ranging from 25 to 100%. Extensive testing revealed no evidence of serious systemic toxicity due to the drug. Minor side effects (e.g., nausea, vomiting, or sedation) were usually transient. Sodium valproate syrup and valproic acid in capsules gave equivalent mean low (23.3 microgram/ml) and maximum (42.5 microgram/ml) serum concentrations. The drug had a relatively short half-life of 8.7 hours, necessitating administration in divided daily doses. During initiation of valproate therapy there was evidence of a decline in total serum phenytoin concentration (16.5 to 10.2 microgram/ml; p less than 0.001) while the percentage of free phenytoin increased (10.9 to 20%). The quantity of unbound phenytoin was relatively stable throughout. This observation was interpreted as a drug interaction: valproic acid competed with phenytoin for access to plasma protein binding sites.

Adult↗
PubMed1998

Panipenem-betamipron and decreases in serum valproic acid concentration.

Serum concentrations of valproic acid (VPA) were reduced to 0% to 40% of the original levels by concomitant use with panipenem-betamipron (PAM-BP) in three patients. The serum VPA level began to decrease 2 days after the administration of PAPM-BP, and it began to increase within 24 hours of the last dose. The rapid change in the serum VPA level suggests the existence of unique and as yet unknown mechanisms of interaction between VPA and PAPM-BP. Epileptic seizures developed in two of the three patients during PAPM-BP use, which signaled the dangers of PAPM-BP administration to patients concomitantly administered VPA. PAPM-BP should not be used in patients administered VPA.

Adult↗
PubMed1984

Aspects of the metabolism of valproic acid.

The metabolic routes of valproic acid (VPA) were studied by i.p. administration of the mono-unsaturated and hydroxylated metabolites to rats. Conjugation with glucuronic acid was a major metabolic route for VPA and its metabolites. Conjugation with glycine was a minor route for VPA, but was of more importance with the unsaturated metabolites. The hydroxylated metabolites, which were further oxidized to oxo-derivatives and subsequently to the dicarboxylic acids, were not metabolically dehydrated to form unsaturated metabolites. Multiple metabolic pathways, including dehydrogenation, isomerization, hydration, hydroxylation, reduction and epoxidation were inferred from the metabolites obtained after dosage of the unsaturated metabolites. Six dien-VPA metabolites were detected in VPA-treated rats, four of which are present in patients. It was concluded that 3-en-VPA and 4-en-VPA pathways, originating through dehydrogenation, are distinct from the omega- and omega-1-hydroxylation pathways. Enzyme induction from co-administration of phenobarbital caused enhancement of the minor omega-1-oxidation pathway, yet the largest effect on clearance came from increases in glucuronidation. Mitochondrial processes were unaffected, resulting in decreased contribution to the total clearance.

Animals↗
PubMed2006

Molecular approaches to developmental malformations using analogous forms of valproic acid.

The teratogenic potential of valproic acid has been well established both in experimental models and in human clinical studies. Evidence from many previous studies has shown that VPA is an appropriate drug model for studying chemical structure-teratogenicity relationships. Using molecular techniques of DNA microarray (GeneChip system) or quantitative real-time polymerase chain reaction with low teratogenic VPA analogs as comparative control drugs, we attempted to identify the genes involved with the molecular mechanisms of VPA teratogenicity in the neural tube and the axial skeleton of the mouse embryo. The recent development of DNA microarray enables a genome-wide approach to the identification of genes correlated with the teratogenicity of chemicals (teratogenomics). The VPA-induced changes in gene expression seen during mouse embryogenesis provides information for understanding how VPA disrupts normal embryonic development, and also provides leads for the development of safer medicines.

Animals↗
PubMed2004

Simple and sensitive fluorimetric liquid chromatography method for the determination of valproic acid in plasma.

A simple and sensitive liquid chromatographic method is described for the analysis of valproic acid in human plasma. The method is based on the derivatization of valproic acid extracted from acidified plasma with 2-(2-naphthoxy)ethyl 2-(piperidino)ethanesulfonate. The resulting derivative is highly responsive to a fluorimetric detector (excitation at 230 nm and emission at 350 nm), giving a low detection limit of 0.6 microM (S/N = 3, 10 microl injected). The relative standard deviations of the method for intra- and inter-day analyses (n = 5) are below 3.3 and 4.1%, respectively. Toluene was used for the extraction of valproic acid from plasma and the toluene extract obtained was subjected to subsequent derivatization without solvent replacement. The simple method was applied to the analysis of valproic acid in plasma of dosed patients using only small amount of sample (10-50 microl plasma).

Adult↗
PubMed2003

Acute pancreatitis in children from Valproic acid: case series and review.

Valproic acid (VPA) is a commonly prescribed medication approved for use in the United States for epilepsy, migraine, and bipolar disorder. Although the common adverse effects associated with VPA are typically benign, less common but more serious adverse effects can occur. These include hepatotoxicity, teratogenicity, possible polycystic ovaries with the potential for sterility or carcinogenesis, and pancreatitis. A characteristic clinical profile has been determined for several of these adverse effects. We report four children with VPA-induced pancreatitis, one of which was fatal, and review the literature. Three of these children presented within a 4-year period (1995-1999) at the same institution. Because previous reviews have included either a small number of patients, or both pediatric and adult patients, we reviewed only pediatric cases to minimize any effect from adults with more serious co-existing medical illnesses. We attempted to determine the following: (1) if there are any characteristics that are predictive of pancreatitis and whether it will be fatal; (2) whether different clinical and laboratory characteristics exist for nonfatal vs fatal cases; and (3) if a specific pediatric patient profile, similar to that with VPA associated hepatotoxity or polycystic ovary-androgenism syndrome, could be identified.

Acute Disease↗
PubMed1977

Time-dependent kinetics III: diurnal oscillations in steady-state plasma valproic acid levels in rhesus monkeys.

Valproic acid was administered by constant rate intravenous infusion to catheterized chained rhesus monkeys for 8-10 weeks under controlled environmental conditions. Steady-state plasma levels were monitored at 2-hr intervals for 26 hr (10 am-12 noon on the following day), 1 day/week for 6 weeks. Individual steady-state plasma concentration-time plots exhibited the following characteristics. During Period A (10 am-6 pm), plasma levels remained stable or decreased. During Period B (6 pm-6 am), plasma levels increased, reached a maximum, and remained markedly higher than during Period A. The maximum concentrations were 40-140% higher than the observed minimum concentrations. During Period C (6 am-noon), plasma levels tended to decline from the maximum concentrations achieved in Period B. In most cases, plasma concentrations at 10 am and 12 noon of the 2nd experimental day fell within 10% of their respective values on the previous day. The mean (+/- SD) periods obtained by cross-correlation analysis of individual plasma concentration-time plots were 30.7 (+/- 3.7) and 22.8 (+/- 3.6) hr for Animals 903 and 923, respectively. The corresponding mean (+/- SD) amplitudes were 27.3 (+/- 12.6) and 17.4 (+/- 2.3)%. A circadian rhythm in total body clearance was hypothesized, and its pharmacokinetic implications are discussed.

Animals↗
PubMed1990

Analysis of the factors influencing anti-epileptic drug concentrations--valproic acid.

The factors that influence valproic acid (VPA) serum concentrations and level:dose ratios were evaluated, retrospectively, on 51 consecutive routine VPA determinations from 50 chronically treated epileptic patients. The influence of co-medicated anti-epileptic drugs (phenytoin, phenobarbital, carbamazepine), alone or in combination, on total and free levels of VPA was studied. Furthermore, the possible influence of certain physiological and/or pathophysiological factors (age, weight, sex and clinical laboratory data) was considered. The total level:dose ratio was lower when VPA was given in combination with phenytoin or with carbamazepine than when VPA was given alone. The free level:dose ratio also decreased during concomitant treatment with phenytoin. The free fraction of VPA was unaltered when in combination with phenytoin or with carbamazepine, whereas it was decreased by a combination with phenytoin plus carbamazepine. As a whole, strong, positive, correlations existed between the VPA dose (mg/kg/day) and the total and free serum levels of VPA in the range of less than 15 mg/kg/day, but both levels of VPA tended to flatten out at the range of more than 15 mg/kg/day. These findings should therefore be considered when defining dosage regimens or interpreting serum drug concentrations. Stepwise multivariate regression analysis (MVR) showed that the VPA dose, simultaneous carbamazepine intake, serum glutamic oxalacetic transaminase (SGOT) and serum albumin concentration were important determinants of VPA serum concentrations.

Adolescent↗
PubMed1988

Marked increase in anticonvulsant activity but decrease in wet-dog shake behaviour during short-term treatment of amygdala-kindled rats with valproic acid.

The anticonvulsant activity of valproic acid (VPA) was determined in amygdala-kindled rats after single and repeated (total of 7 injections given 3 times per day) administration of 200 mg/kg i.p. After a single injection, VPA significantly reduced the severity and duration of the kindled seizures and decreased the duration of after-discharges recorded from the stimulated amygdala, but only 12% of the animals were totally protected from seizures. The percentage of animals totally protected increased to 88% after 7 doses. This pronounced increase in the anticonvulsant activity was not related to alterations in the plasma concentrations of VPA or its major active metabolites. Furthermore, determination of VPA and its metabolites in the substantia nigra after a single and repeated administration yielded the same data, again indicating that the increase in the anticonvulsant activity was not due to drug accumulation. In contrast to the marked increase in the anticonvulsant efficacy of VPA during short-term treatment, wet-dog shake behaviour induced by a single injection of the drug was significantly attenuated after repeated dosing, indicating that the anticonvulsant effect of VPA and the wet-dog shake behaviour induced by the drug were not mediated by the same mechanism. This was substantiated by experiments with one of the major metabolites of VPA in rat plasma, trans-2-en-VPA, which had approximately the same anticonvulsant efficacy as VPA but did not induce wet-dog shakes in rats.

Amygdala↗
PubMed1998

Cell motility is inhibited by the antiepileptic compound, valproic acid and its teratogenic analogues.

Valproic acid (VPA) is an established human teratogen that causes neural tube defects in 1-2% of human foetuses exposed to the drug during early pregnancy. In this study, individual cell motility was evaluated using short- and long-term time-lapse video-recording and computer assisted image analysis, and it was found that VPA and selected VPA-analogues inhibited individual cell motility of L-cells in a dose-dependent manner. The compounds caused a decrease in the root-mean-square speed, S, and in the rate of diffusion, R, but an increase in the time of persistence in direction, P. Using short-term recordings and measurements of mean-cell speed, the reduction in the motile behaviour was shown to correlate with the teratogenic potency of the tested compounds. The observed effects of VPA on cell motility was independent of the employed L-cell clone, and could be reproduced in cells containing the neuronal marker NCAM and in the neuronal cell line N2a. Furthermore, the observed effect was independent of culture substratum, being observed for L-cells grown on fibronectin as well as on plastic. Immunofluorescence microscopy revealed that VPA-treatment of mouse L-cells caused a redistribution of F-actin and of a series of focal adhesion proteins, indicating that the effect of VPA on cell motility may be causally related to increased cell-substratum interactions or to alterations in the organisation or dynamics of the actin cytoskeleton.

Animals↗
PubMed2006

Myo-inositol enhances teratogenicity of valproic acid in the mouse.

BACKGROUND: Valproic acid (VPA) is an anticonvulsant drug that is widely used therapeutically for a variety of neurological conditions. VPA is also well known for its teratogenic potential in both humans and experimental animal models. The typical malformations observed following VPA exposure include neural tube defects (NTDs) and craniofacial and skeletal malformations. Nevertheless, the mechanisms underlying VPA's anticonvulsant efficacy or its teratogenicity remain to be elucidated. It was recently suggested that a relationship exists between VPA exposure and the cellular depletion of myo-inositol (INO). Furthermore, INO has been shown to rescue NTDs in the curly tail mouse. The aim of this study was to investigate the interactions of VPA and INO in the developing embryo. METHODS: For this purpose, 2 strains of mice were used: SWV/Fnn (known to be sensitive to VPA) and LM/Bc (known to be resistant to VPA-induced NTDs). Pregnant females were randomly assigned to 4 experimental groups: control, VPA (600 mg/kg), INO (400 mg/kg), and VPA plus INO. VPA was injected IP at 8.5 days postcoitum (dpc). INO was administered PO twice a day from 6.5 to 10.5 dpc. At term the dams were killed, the uteri were removed, and all of the general toxicological parameters (number of implants, resorptions, dam weight, and fetus weight) were recorded and statistically analyzed. RESULTS: Postimplantation loss in the SWV/Fnn strain and NTDs in the LM/Bc strain were significantly increased after the coadministration of VPA and INO. CONCLUSIONS: This work clearly indicates that INO enhances VPA-induced teratogenicity in the mouse.

Abnormalities, Drug-Induced↗
PubMed2006

Teratology study of derivatives of tetramethylcyclopropyl amide analogues of valproic acid in mice.

BACKGROUND: Although valproic acid (VPA) is used extensively for treating various kinds of epilepsies, it is well known that it causes neural tube and skeletal defects in both humans and animals. The amide and urea derivatives of the tetramethylcylcopropyl VPA analogue, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (N-methoxy-TMCD) and 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMC-urea), were synthesized and shown to have a more potent anticonvulsant activity than VPA. The objective of this study was to investigate the teratogenic effects of these compounds in NMRI mice. METHODS: Pregnant NMRI mice were given a single subcutaneous injection of either VPA, N-methoxy-TMCD, or TMC-urea at 1.8 and 3.6 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18. First, the live fetuses were examined to detect any external malformations, then their skeletons were double-stained for bone and cartilage and subsequently examined. RESULTS: Significant increases in fetal losses and neural tube defects were observed with administration of VPA at 3.6 mmol/kg when compared to the vehicle control. In contrast, upon cesarean section, there were no significant differences between either N-methoxy-TMCD or TMC-urea and the control groups for any parameter. Skeletal examination revealed that a number of the abnormalities were induced by VPA dose-dependently at high rates of incidence. These abnormalities were mainly at the axial skeletal level. However, lower frequencies of skeletal abnormality were observed with N-methoxy-TMCD and TMC-urea than with VPA. CONCLUSIONS: In addition to their more potent antiepileptic activity, these findings clearly indicate that N-methoxy-TMCD and TMC-urea are distinctly less teratogenic than VPA in NMRI mice.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Diurnal variations in steady-state plasma concentrations of valproic acid in epileptic patients.

Patients on long term valproate treatment exhibit unusual fluctuations in steady-state plasma levels of valproic acid. In order to delineate the underlying mechanisms of these fluctuations, 2 studies were undertaken. In the oral study, 6 epileptic patients received enteric-coated sodium valproate tablets (on a bid regimen for at least 1 month) and plasma levels were monitored on an hourly basis during 24 hours. In the intravenous study, 5 patients received first an intravenous bolus dose (800mg) of sodium valproate followed a week later by a combination intravenous loading dose/constant rate infusion for 36 hours. Plasma valproic acid concentrations were monitored hourly during the infusion study. In the oral study, valproic acid concentrations in all subjects continued to decay for 5 to 6 hours following the 8pm dose. The mean fluctuation in concentrations during 24 hours was 112.8 +/- 31.6%. Consecutive fasting levels were not reproducible. In the intravenous study, small but significant oscillations were present at steady-state; fluctuations ranged from 22 to 34%. However, no circadian rhythm was apparent. On the basis of these findings, it appears that the value of a single fasting sample during therapeutic monitoring of valproic acid is questionable. For an accurate evaluation of valproic acid plasma levels, an average concentration based upon several daily determinations should be performed.

Administration, Oral↗
PubMed1981

Serial free and plasma valproic acid and phenytoin monitoring and drug interactions.

In 12 institutionalized epilepsy patients who had been treated 19 months (SD +/- 5) with valproic acid, 27.0 mg/kg (SD +/- 11.9), phenytoin, 6.33 mg/kg (SD +/- 1.36), and co-anticonvulsants, the mean percentage of daily free valproic acid was 11.72 (SD +/- 2.10) and of phenytoin 20.39 (SD +/- 3.32). By serial within-day blood samplings for a.m., noon, and p.m. periods, the diurnal variation of percentage free valproic acid and phenytoin was determined for each patient. For morning and noon periods the variations in the percentages of free valproic acid and phenytoin were independent of each other, correlation coefficients (r) being zero for each period. In contrast, for early p.m. the correlation coefficient was highly significant at r = 0.894 (p less than 0.01). It is apparent that diurnal variations in the percentages of free valproic acid and phenytoin occur even in patients who have been treated with these compounds for more than a year.

Adolescent↗
PubMed1989

The effect of valproic acid on 65Zn distribution in the pregnant rat.

The effect of valproic acid on the distribution of gavaged 65Zn in maternal and embryonic tissue of Sprague-Dawley rats was examined 24 h after gavaging of the drug on d 13 of pregnancy. Valproic acid treatment resulted in a significantly higher retention of 65Zn in maternal liver and lower amounts in uterus, placenta and embryos than in controls. Compared to controls, gel chromatography of maternal liver from valproic acid-treated dams showed higher 65Zn counts associated with a protein peak of molecular weight of 6,500, the approximate molecular weight of the Zn-binding protein metallothionein. These results support the idea that the teratogenicity of valproic acid is in part due to an induction of embryonic Zn deficiency secondary to a drug-induced sequestering of Zn into maternal liver that results in a decrease in maternal plasma Zn and subsequent reduction in embryonic Zn uptake.

Abnormalities, Drug-Induced↗