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At least 19 recordsLinked to original sources
PubMed1981

Effect of di-N-propylacetic acid (valproic acid) on the TSH response to TRH--a presumptive role for gamma aminobutyric acid.

The effect of di-n-propylacetic acid (valproic acid), an inhibitor of gamma aminobutyric acid (GABA) transaminase, was studied with reference to its effect on the serum concentration of thyroid hormones, baseline serum TSH concentration and TRH stimulated TSH release, in seven normal controls and six patients with primary hypothyroidism. All volunteers took 250 mg of valproic acid administered orally, four times daily for 3 days. Baseline serum T4 and TSH concentrations were unaffected by valproic acid administration (p less than 0.05) while serum T3 concentrations fell in all volunteers (p less than 0.001). Serum T3 concentration (mean +/- SD) fell from 116.3 +/- 18 ng/dl to 101.7 +/- 15 ng/dl in the control group and from 94.2 +/- 47.9 ng/dl to 81.5 +/- 43.2 ng/dl in the hypothyroid group. Valproic acid produced a decline in stimulated serum TSH concentrations (delta TSH--maximum increment above baseline) in all controls and patients studied (p less than 0.01). delta TSH (mean +/- SD) declined from 16.1 +/- 4.7 microunits/ml to 10.5 +/- 5.8 microunits/ml in the control subjects and from 43.1 +/- 25.4 microunits/ml to 29.7 +/- 18 microunits/ml in the hypothyroid patients. Based on the data presented, it is postulated that GABA plays an inhibitory role either by acting directly on the pituitary gland inhibiting TSH release, or by inducing the secretion of a hypothalamic TSH-inhibitory factor. The data do not exclude a direct pharmacological effect of valproic acid on pituitary TSH release. Decrease in serum T3 following valproic acid may be due to peripheral mechanisms.

4-Aminobutyrate Transaminase↗
PubMed2003

Amino acid conjugates: metabolites of 2-propylpentanoic acid (valproic acid) in epileptic patients.

In this study, spectroscopic and chromatographic evidence is presented for the identification and characterization of the metabolites, valproyl glutamate (2-propylpentanoyl glutamate, VPA-GLU) and valproyl glutamine (2-propylpentanoyl glutamine, VPA-GLN) in the urine, serum, and cerebrospinal fluid (CSF) of patients on valproic acid (VPA) therapy. Moreover, the identification of valproyl glycine (2-propylpentanoyl glycine, VPA-GLY) in the serum and urine of patients on VPA, albeit in trace concentrations, is also reported here. The three amino acid conjugates excreted in urine accounted for about 1% of the VPA dose in four patients who were on VPA therapy chronically and had reached steady state. VPA-GLU was quantitatively the most prominent metabolite (0.66-13.1 microg/mg creatinine) compared with VPA-GLN (0.78-9.93 microg/mg creatinine) and VPA-GLY (trace-1.0 microg/mg creatinine) in overnight urine samples of all patients studied (n = 29). The relatively low serum concentrations of the three amino acid conjugates of VPA in six patients suggest that the metabolites are readily excreted once formed. In contrast, whereas VPA GLY was absent in the CSF of one patient on VPA, the concentrations of VPA-GLU and VPA-GLN in this CSF sample were 9 and 5 times, respectively, their corresponding serum concentrations.

Adolescent↗
PubMed2003

Axial skeletal and Hox expression domain alterations induced by retinoic acid, valproic acid, and bromoxynil during murine development.

Retinoic acid (RA) alters the developmental fate of the axial skeletal anlagen. "Anteriorizations" or "posteriorizations," the assumption of characteristics of embryonic areas normally anterior or posterior to the affected tissues, are correlated with altered embryonal expression domains of Hox genes after in utero RA treatment. These "homeotic" changes have been hypothesized to result from alterations of a "Hox cod" which imparts positional identity in the axial skeleton. To investigate whether such developmental alterations were specific to RA, or were a more general response to xenobiotic exposure, CD-1 pregnant mice were exposed to RA, valproic acid (VA), or bromoxynil (Br) during organogenesis. Additionally, the expression domains of two Hox genes, Hoxa7 and Hoxa10, were examined in gestation day (GD) 12.5 embryos obtained from control, RA, VA, or Br, treated gravid dams exposed on GD 6, 7, or 8. The anterior expression boundary of Hoxa7 is at the level of the C7/T1 vertebrae and that of Hoxa10 is at L6/S1. Compound-induced changes in the incidence of skeletal variants were observed. These included supernumerary cervical ribs (CSNR) lateral to C7, 8 vertebrosternal ribs, supernumerary lumbar ribs (LSNR) lateral to L1, extra presacral vertebrae, and the induction of vertebral and/or rib malformations. RA and VA administration on GD 6 caused posteriorization in the cervico-thoracic region (CSNR) while GD 8 exposure to any of the three compounds resulted in anteriorizations in the thoraco-lumbar area (LSNR and an increase in the number of presacral vertebrae). These effects occurred across regions of the axial skeleton. Analysis of gene expression demonstrated changes in the anterior boundaries of Hoxa7 expression domains in embryos treated on GD 6 and 8 with RA. VA and Br did not induce any statistically significant alterations in Hoxa7 and none of the compounds caused alterations in Hoxa10 expression domains. The studies indicate that RA GD 6 treatment-induced Hoxa7 shifts were rostral (posteriorization) while the RA-induced GD 8 anterior expression boundary shift was caudal (anteriorization), correlating with the axial skeletal changes noted. These data suggest that xenobiotic compounds such as VA and Br may induce similar axial skeletal changes by affecting different components of the developmental processes involved in the patterning of the axial skeleton.

Abnormalities, Drug-Induced↗
PubMed1990

Inactivation of beef brain alpha-ketoglutarate dehydrogenase complex by valproic acid and valproic acid metabolites. Possible mechanism of anticonvulsant and toxic actions.

The anticonvulsant valproic acid (VPA, 2-n-propylpentanoic acid) causes inhibition of the citric acid cycle and elevations of central nervous system (CNS) gamma-aminobutyric acid (GABA) levels, which correlates with anticonvulsant action. No unifying mechanism for these actions of VPA has won general acceptance. alpha-Ketoglutarate dehydrogenase complex (KDHC) is a critical control enzyme in the CNS. We hypothesized that VPA may be an inhibitor of this enzyme since decreased KDHC activity would reduce substrate flux through the citric acid cycle and may increase flux into GABA synthesis. To test this hypothesis, inhibition of purified beef brain KDHC by VPA and its metabolites 2-n-propylpent-2-enoic acid (delta 2,3 VPE) and their coenzyme A (CoA) derivatives were studied. Preincubation of the NADH-reduced enzyme with delta 2,3 VPE, VPA-CoA, and delta 2,3 VPE-CoA caused time-dependent inactivation, reversible by addition of CoA. Under steady-state conditions, delta 2,3 VPE and VPA-CoA were competitive inhibitors of KDHC and delta 2,3 VPE-CoA was a mixed inhibitor. These observations have implications for the molecular mechanisms of VPA action. VPA derivatives cause inactivation and inhibition of KDHC, which may explain the anticonvulsant and some toxic actions of VPA.

Animals↗
PubMed2006

Serum and liver tissue biotinidase enzyme activity in rats which were administrated to valproic acid.

Valproic acid (VPA) is an antiepileptic drug widely used and well-tolerated by most of patients. Its non-dose-dependent side effects seen mostly are the temporary gastrointestinal disturbances including anorexia and nausea, and hepatoxicity. As to its dose-dependent side effects are the weight loss, tremor, skin eruption and the alopecia. In this study we aimed to put forward the biotinidase deficiency considered as a possible cause of alopecia in the rats administered with valproic acid, and the correlation between liver and serum biotinidase enzyme activities (BEA) and transaminases, albumin and serum valproic acid levels. In our study, 4 groups of which one of them was a control group, each consisting of 15 male Wistar rats was organized. 200, 400, and 600 mg/kg/day of VPA, and distilled water, two divided doses per day, were administered per orally to VPA-1, VPA-2, VPA-3, and control group, respectively, in 60 days. Their serum and liver biotinidase enzyme activities, serum AST, ALT, albumin, and valproic acid levels were measured. Alopecia was seen in the subjects of 6.6% of VPA-1, 13.3% of VPA-2, and 26.6% of VPA-3. Significant difference in the liver tissues BEA was noted only between VPA-3 and the control group. Reductions were observed both in the liver tissues BEA and the serum BEA levels, which are inversely proportional to the VPA doses. A positive correlation between the liver biotinidase enzyme activities and the serum valproic acid levels, and the negative correlation between the liver tissues biotinidase activities and the serum valproic acid levels were noted, respectively. As a conclusion, the partial alopecia which is an initial symptom of reduced biotinidase activity may also be created depending on the reduction of biotinidase activity during valproic acid therapy. The alopecia which may further be observed in the patients receiving valproic acid therapy may be prevented by means of administration of biotin in a dose of 10 mg/day.

Alopecia↗
PubMed2002

Insulin resistance in epileptic girls who gain weight after therapy with valproic acid.

Valproic acid is effective for treatment of many types of epilepsy, but its use in epileptic patients can be associated with an increase in body weight that could interfere with treatment compliance. The weight gain may result from different mechanisms, but the exact pathogenesis is still unknown. To evaluate insulin sensitivity in adolescents who gained weight during treatment with valproic acid, we studied 20 girls with different types of epilepsy: 15 patients had primary generalized seizures, including absence seizures (3 cases), and 5 patients had partial seizures. After 1 year of valproic acid treatment, the obese patients had serum insulin levels significantly higher than patients who did not gain weight (51.4 +/- 25.3 versus 28.2 +/- 12.9). Moreover, we observed that epileptic patients who gained weight were also insulin resistant in comparison with nonobese epileptic subjects. At the end of treatment, all patients showed normal levels of serum testosterone, androstenedione, dehydroepiandrosterone sulfate, follicle-stimulating hormone (FSH), and luteinizing hormone. We found no significant correlation between insulinemia and serum valproic acid concentrations in obese and nonobese patients treated with valproic acid. Our study demonstrates that basal hyperinsulinemia and insulin resistance can be present in patients who develop obesity during valproic acid treatment. Therefore, these obese patients could be exposed to the risks related to these metabolic abnormalities; if these data are confirmed in longer studies, these side effects may raise some concerns about the safety of valproic acid.

Androgens↗
PubMedDate not supplied

Teratogenic potential of valproic acid.

Valproic acid administration in pregnancy may be a potential teratogen to the developing fetus. Numerous animal studies have linked valproic acid to vertebral anomalies and renal agenesis. Recent European data have suggested valproic acid as a causal agent of neural tube defects in human offspring. Research relative to teratogenicity of valproic acid administration for petit mal epilepsy is reviewed. Conclusions indicate that the benefits of valproic acid administration outweigh the hazards of teratogenicity.

Animals↗
PubMed2003

Permeation across hydrated DPPC lipid bilayers: simulation of the titrable amphiphilic drug valproic acid.

Valproic acid is a short branched fatty acid used as an anticonvulsant drug whose therapeutic action has been proposed to arise from membrane-disordering properties. Static and kinetic properties of valproic acid interacting with fully hydrated dipalmitoyl phosphatidylcholine lipid bilayers are studied using molecular-dynamics simulations. We calculate spatially resolved free energy profiles and local diffusion coefficients using the distance between the bilayer and valproic acid respective centers-of-mass along the bilayer normal as reaction coordinate. To investigate the pH dependence, we calculate profiles for the neutral valproic acid as well as its water-soluble anionic conjugate base valproate. The local diffusion constants for valproate/valproic acid along the bilayer normal are found to be approximately 10(-6) to 10(-5) cm2 s(-1). Assuming protonation of valproic acid upon association with--or insertion into--the lipid bilayer, we calculate the permeation coefficient to be approximately 2.0 10(-3) cm s(-1), consistent with recent experimental estimates of fast fatty acid transport. The ability of the lipid bilayer to sustain local defects such as water intrusions stresses the importance of going beyond mean field and taking into account correlation effects in theoretical descriptions of bilayer translocation processes.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2002

Coagulation abnormalities and acquired von Willebrand's disease type 1 in children receiving valproic acid.

Valproic acid is commonly used in the management of childhood epilepsy. The known hematologic side effects of the drug are hemorrhagic diatheses, thrombocytopenia, and hypofibrinogenemia. We studied coagulation parameters in 29 epileptic children receiving valproic acid for at least 6 months. Their ages ranged between 2 and 18 years (10.2 +/- 4.9 years). The total valproic acid dose was 250 to 1000 mg/day equivalent to 20 to 30 mg/kg/day. Treatment duration ranged from 6 to 57 months. These children had not previously had a hemostatic defect and had no family history of bleeding disorders. Platelet count, prothrombin time, activated partial thromboplastin time, bleeding time, fibrinogen, platelet aggregation assays, and ristocetin cofactor activity levels were determined in all of the patients, but von Willebrand's factor antigen levels could be determined in only 14 patients. The values of von Willebrand's factor antigen ranged from 53 to 218% (104.1 +/- 42.3), and ristocetin cofactor activity levels ranged from 11.5 to 218% (94.5 +/- 43.1). Six of the 29 children (20.7%) had decreased values of ristocetin and cofactor activity and were considered to have acquired von Willebrand's disease. The decreases in coagulation parameters were not dependent on either valproic acid dose or treatment duration. Two patients with low ristocetin cofactor activity values had mild epistaxis, which did not require discontinuation of therapy. In patients receiving valproic acid therapy, this side effect must be considered, especially before surgical intervention and serious traumatic conditions.

Adolescent↗
PubMed1987

Teratogen update: valproic acid.

Valproic acid use during pregnancy results in an absolute risk for spina bifida of 1-2%. This increased risk is comparable to the recurrence risk for neural tube defects and warrants informed counselling and access to prenatal diagnosis. There is no substantial evidence that valproic acid use increases the risk for other specific major malformations above the increased risk due to maternal epilepsy. Valproic acid may cause a characteristic pattern of minor facial malformations. Further definition and confirmation are required, and the magnitude of the risk needs to be determined. There are inadequate data to assess the magnitude, if any, of the risks for postnatal growth abnormalities and developmental disabilities associated with the use of valproic acid during pregnancy. Birth-defect monitoring programs and international collaboration among the staffs of monitoring programs played a major role in determining that valproic acid is a human teratogen.

Abnormalities, Drug-Induced↗
PubMed1994

Synthesis and evaluation of amino analogues of valproic acid.

Valproic acid, an antiepileptic drug, is extensively metabolized in humans. Two putative metabolites, 2-n-propyl-3-aminopentanoic acid (3-aminovalproic acid, 3-amino-VPA; 2a) and 2-n-propyl-4-aminopentanoic acid (4-amino-valproic acid, 4-amino-VPA; 4a), which may result from the transamination of the respective keto acids 1a and 3a may explain the unusual extended seizure protection elicited by valproic acid. The title compounds were synthesized as their diasteriomeric ethyl esters 2b and 4b and submitted for anticonvulsant evaluation by the Antiepileptic Drug Development Program of the National Institute of Neurological and Communicative Disorders and Stroke. The results verified our hypothesis, as 4b was active in the subcutaneous pentylenetetrazol (scMet) evaluation at 30 mg/kg. Both compounds were highly toxic at 300 mg/kg.

Animals↗
PubMed1991

Developmental toxicity of valproic acid.

Valproic acid is a very effective anticonvulsant agent widely used in the management of various forms of epilepsy. Administration of the drug during pregnancy results in increased incidence of congenital abnormalities in both humans and experimental animals. In recent years, a significant number of research efforts have attempted to define the contributory role of valproic acid to the impairment of normal prenatal growth and development. The present report summarizes current knowledge that has emerged from clinical and research studies. The specific topics include: the placental transfer of valproic acid; the teratogenic potential; structure-teratogenicity and dose-response relationships; species and strain differences; biochemical changes evoked by the drug in the fetus.

Animals↗
PubMed1985

Blood-brain barrier transport of valproic acid.

Valproic acid distribution in brain is less than that of other anticonvulsants such as phenytoin or phenobarbital. Possible mechanisms for this decreased distribution space in brain include (a) increased plasma protein binding of valproate relative to the other anticonvulsants and (b) asymmetric blood-brain barrier (BBB) transport of valproate such that the brain-to-blood flux exceeds the blood-to-brain flux. These mechanisms are investigated in the present studies using the intracarotid injection technique in rats and rabbits. In the rat, the brain uptake index (BUI) of [14C]valproate relative to [3H]water is 51 +/- 6%, indicating the blood-to-brain transport of water is twofold greater than that of valproate. However, the BUI of [14C]valproate relative to [3H]water decreased with time after carotid injection during a 4-min washout period, which indicates that brain-to-blood transport of valproate is greater than that of water. This suggests that the permeability of the BBB to valproate is polarized, with antiluminal permeability being much greater than luminal permeability. In rabbits, the BUI of [14C]valproate is 47 +/- 7% in newborns and 17 +/- 6% in adult animals. However, the high drug extraction in newborns may be attributed to decreased cerebral blood flow in the neonate as the BBB permeability-surface area (PS) products are unchanged (e.g., PS = 0.13 and 0.11 ml min-1 X g-1 in the newborn and adult rabbit, respectively). With regard to plasma protein binding effects on valproate transport, brain valproate uptake was also measured in the presence of human, lamb, pig, rat, horse, goat, hamster, dog, and mouse sera. Higher brain uptakes were observed when the unbound fraction of drug increased. However, our data indicate that a fraction of the valproic acid entering the capillaries bound to plasma proteins had the capacity to equilibrate with brain because of enhanced drug dissociation from albumin in the brain microcirculation. Since plasma protein-bound valproate is available for uptake by brain, the major factor underlying the diminished distribution of the drug in brain appears to be the asymmetric transport properties of the BBB to valproic acid.

Animals↗
PubMed1994

Can we develop improved derivatives of valproic acid?

Valproic acid is one of the major antiepileptic drugs. In animal models, valproate showed less anticonvulsant potency than the other three established antiepileptic drugs: phenobarbital, phenytoin and carbamazepine. In addition, two major side-effects, teratogenicity and hepatotoxicity, have been associated with valproate therapy. Due to the above and the shortage of new antiepileptic drugs there is a substantial need to develop improved derivatives of valproate. This paper analyses three kinds of valproate derivatives: valpromide, the primary amide of valproate, and its analogues; monoester prodrugs of valproate and an active metabolite of valproate, 2-n-propyl-2-pentenoate. The comparative evaluation was carried out by pharmacokinetic and pharmacodynamic analyses in animals. From the data accumulated so far, we can conclude that 2-n-propyl-2-pentenoate and/or a valpromide isomer, which does not undergo amide-acid biotransformation and preferably is not an epoxide hydrolase inhibitor, may prove to be improved derivatives of the parent compound valproic acid.

Animals↗
PubMed1979

Treatment of postanoxic intention myoclonus with valproic acid.

Valproic acid in therapeutic doses was used in the treatment of postanoxic intention myoclonus. Disappearance of the myoclonus occurred with marked improvement in the electroencephalogram. No significant side effects were noted. Hepatic function tests were monitored. Determination of valproic acid plasma levels was used to guide therapy. Levels above 55 micrograms were generally required. The patient remains free of myoclonus after four and one half months.

Humans↗
PubMed1980

Therapeutic monitoring of valproic acid.

Valproic acid, a new type of antiepileptic drug, has developed into one of the drugs of first choice in all types of epilepsy with the exception of infantile spasms and partial seizures. Due to its short biological half-life, a steady-state plasma concentration will be reached rapidly after initiation of therapy. However, no direct relationship between this plasma concentration and the clinical effect can be found. In autoradiography experiments, brain distribution appears to change with time, suggesting a gradual accumulation of the drug or its metabolites in certain brain areas. Two metabolites are detected in monkey and human blood plasma. Valprolactone is also found in brain tissue, but the substance is rapidly eliminated. beta, gamma-Unsaturated valproic acid has the longest half-life and is found in concentrations that can be quantitated by routine gas chromatographic analysis. The therapeutic effect appears to correlate better with dosage per kilogram body weight than with the actual plasma concentrations. Routine monitoring of valproate plasma concentrations in epileptic patients seems to be of limited value.

Aging↗