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Results for “VALERIC ACID”

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PubMed2001

Characterization of plasma acylcarnitines in patients under valproate monotherapy using ESI-MS/MS.

OBJECTIVES: The effect of administration of the antiepileptic drug valproate (VPA), on the composition of the plasma acylcarnitine profile (including free carnitine) was investigated. DESIGN AND METHODS: Plasma samples were obtained from 18 individuals (13 males:5 females; 15-65 y) on long-term treatment with VPA (resulting in plasma levels of 14.6-135.0 mg/L; therapeutic conc.: 40-100 mg/L). Acylcarnitines (AC) in plasma were quantified by electrospray tandem mass spectrometry (ESI-MS/MS). RESULTS: VPA was found to increase the levels (mean +/- SD, microM) of 3-hydroxy-isovalerylcarnitine (0.10 +/- 0.04; controls: 0.02-0.06), C14:2 acylcarnitine (0.11 +/- 0.05; controls: 0.02-0.08), propylglutarylcarnitine (0.06 +/- 0.05; controls: 0.00-0.04), and C18-0H-acylcarnitine (0.09 +/- 0.05; controls: 0.00-0.04). The free carnitine (C) (42.2 +/- 9.0; controls: 22.3-54.9) and the total carnitine (52.3 +/- 10.1; controls: 26.5-73.6) were not significantly altered by VPA. Other AC (C2-C18, monounsaturated and hydroxylated) were all within the control range and especially no increase of C8 (valproyl) carnitine was observed. A positive correlation was found between the ratios [AC] / [C] (p < 0.05) or [long-chain AC (C10-C18)] / [C] (p < 0.09) with the plasma VPA concentration. CONCLUSIONS: The unequivocal increase in 3-hydroxy-isovalerylcarnitine is consistent with the increase of 3-hydroxy-isovaleric acid observed in urine of VPA treated patients. This finding suggests an interaction mechanism of VPA with specific enzymes, namely involved in leucine metabolism. Adult patients under VPA monotherapy do not suffer from carnitine deficiency; the effect of the accumulating acylcarnitines is ill-defined.

Adolescent↗

PubMed1978

Sodium valproate in Huntington's disease.

The authors assessed the effect of sodium valproate, which is thought to elevate brain gamma-aminobutyric acid (GABA) levels, in the treatment of Huntington's disease by an objective ultrasound method in three patients with Huntington's disease. Despite plasma levels ranging from 47.0 to 140.8 microgram/ml (mean, 104.7), sodium valproate had no beneficial effect on involuntary movements. The authors stress the importance of activation to achieve a standard level of arousal in the assessment of involuntary movements.

Adult↗

PubMed1977

Gamma-aminobutyric acid (GABA) and sleep. The influence of di-n-propylacetic acid on sleep in man.

The effects of di-n-propylacetic acid (DPA) on sleep, for some years used as an anticonvulsive drug, has been investigated in 11 healthy volunteers using all-night sleep EEG recordings. DPA acts by an enhancement of the gamma-aminobutyric acid (GABA) level of the brain. Its influence on sleep seemed to be of interest on account of the metabolic relationship of GABA to other short chain fatty acids. After short-term application only a shortening of the time to fall asleep and of the waking time could be found, whereas under long-term administration a decrease in deep synchronous sleep could be observed. In contrast to the results known from animal studies no marked influence on REM sleep was observed. The action of DPA on sleep is similar to that of diphenylhydantoin. No so-called matitudinal 'hangover' could be revelaed in either drug;

Adult↗

PubMed1977

Interlaboratory variability of valproic acid determinations.

19 pooled plasma specimens were sent as unknowns to 13 participating research laboratories. The interlaboratory variability between the results was very high. Only 4 out of 13 laboratories had 6--12% of their results within the 95% confidence limit for each sample. The precision of repeated determinations was fairly good. 6 out of 10 participating laboratories had a coefficient of variation of less then 5%. The reproducibility and the agreement between the different procedures for quantitative analysis of dipropylacetate is similar to that reported for other major antiepileptic drugs.

Laboratories↗

PubMed1977

A study of the action of valproic acid on the kindling effect.

The effect of an antiepileptic drug, valproic acid (VPA), on an experimental form of epilepsy, the kindling phenomenon, is described. In cat, 50 mg/kg i.p. per day is sufficient to block the progressive establishment of generalized seizures produced normally by repetitive electrical stimulation of the amygdala. However, a focal afterdischarge persists during the entire treatment. Higher doses (75-150 mg/kg) are necessary to protect the animal against the generalized tonic-clonic seizure when the kindling phenomenon is established. These effects and the action of barbiturates, which was also tested, seem to attribute to VPA a complex role in the mechanism of this action.

Amygdala↗

PubMed1977

Monoamine and GABA metabolism and the anticonvulsant action of di-n-propylacetate and ethanolamine-O-sulphate.

The time course of changes in behaviour, seizure response and cerebral monoamine and gamma-aminobutyric acid (GABA) metabolism has been studied in relation to the anticonvulsant actions of di-n-propylacetic acid (DPA) and ethanolamine-O-sulphate (EOS) on sound-induced seizures in DBA/2 mice. Changes in cerebral monoamine metabolism after EOS (75 or 150 mug, intracerebroventricularly) were not related to its anticonvulsant action. The primary effect was GABA-transaminase inhibition (by 50-70%) leading to a 2-4 fold increase in cerebral GABA concentration. Increases in brain GABA concentration (maximally 36%), 5-hydroxyindoleacetic acid (5HIAA, maximally 134%) and homovanillic acid (HVA, maximally 183%) were seen after DPA (400-600 mg/kg, i.p.). The time course of the increases in HVA and 5HIAA did not correlate with the anticonvulsant effect. Elimination of these increases by the use of inhibitors of monoamine synthesis (alpha-methyl-p-tyrosine and p-chlorophenyl-alanine) did not alter the anticonvulsant effect of DPA. Experiments using probenecid suggested that the increases in 5HIAA and HVA after DPA result from inhibition of their active transport out of the brain.

Acoustic Stimulation↗

PubMed1976

Huntington's disease: treatment with dipropylacetic acid and gamma-aminobutyric acid.

Dipropylacetic acid (DPA), and anticonvulsant known to raise brain gamma-aminobutyric acid (GABA), was administered orally to eight patients with Huntington's disease. Both alone and in combination with high oral doses of GAGA, DPA failed to ameliorate and motor signs of this disorder. At maximum dose levels, combined DPA and GABA treatment led to an apparent increase in the central turnover of both dopamine and serotonin, as estimated by the oral probenecid-loading test. These latter observations may indicate a close functional interrelation between monoaminergic and GABAnergic neural pathways in the central nervous system of man.

Adult↗

PubMed2000

Chloride-dependent inhibition of vesicular glutamate uptake by alpha-keto acids accumulated in maple syrup urine disease.

Maple syrup urine disease is a metabolic disorder caused by mutations of the branched chain keto acid dehydrogenase complex, leading to accumulation of alpha-keto acids and their amino acid precursors in the brain. We now report that alpha-ketoisovaleric, alpha-keto-beta-methyl-n-valeric and alpha-ketoisocaproic acids accumulated in the disease inhibit glutamate uptake into rat brain synaptic vesicles. The alpha-keto acids did not affect the electrochemical proton gradient across the membrane, suggesting that they interact directly with the vesicular glutamate carrier. Chloride anions have a biphasic effect on glutamate uptake. Low concentrations activate the uptake (0.2 to 8 mM), while higher concentrations are inhibitory. The alpha-keto acids inhibited glutamate uptake by a new mechanism, involving a change in the chloride dependence for the activation of glutamate uptake. The activation of glutamate uptake by low chloride concentrations was shifted toward higher concentrations of the anion in the presence of alpha-keto acids. Inhibition by alpha-keto acids was abolished at high chloride concentrations (20 to 80 mM), indicating that alpha-keto acids specifically change the stimulatory effect of low chloride concentrations. High glutamate concentrations also reduced the inhibition by alpha-keto acids, an effect observed both in the absence and in the presence of low chloride concentrations. The results suggest that in addition to their possible pathophysiological role in maple syrup urine disease, alpha-keto acids are valuable tools to study the mechanism of vesicular transport of glutamate.

ATP-Binding Cassette Transporters↗

PubMed1977

[1-glutamine and dipropylacetic acid as subsidiary psychotropic agents in the treatment of psychiatric in-patients. Effect on the neuroleptic consumption].

In a division of the neuropsychiatric hospital of Racconigi, with acute and chronic inpatients, the use of 1-glutamine and N-dipropylacetic acid as subsidiary psychodrugs, after one year follow-up, showed to have reduced the whole administration of neuroleptics, without diminishing the therapeutic efficacity. This administration, during the four sampler months (December, March, June and September), face with the sames of the preceding year, has been lesser than 29,04% (lesser than 38,21%, if we take into consideration the last two months). Such result has been confirmed by a corresponding diminution of orphenadrine, the drug used to counteract the neuroleptic syndrome, which during the last two months considered in this research, respectively subsided of 28,57% and 36,36%.

Clinical Trials as Topic↗

PubMed1977

Diurnal variation of valproic acid plasma levels and day-night reversal in monkey.

Four normal monkeys each equipped with an EEG plug and two indwelling catheters for drug infusion and sampling, respectively, were administered valproic acid (VPA) before and after a 12-hr light, 12-hr dark phase shift. Before day-night reversal, diurnal oscillations of VPA plasma levels under steady-state intravenous constant-rate infusions were 30-50%, with maximum concentrations during the dark phase of the cycle. After reversal, maximum VPA plasma concentrations tended to follow the dark phase shift. The correlation was not perfect, nor was the sleep cycle completely reversed since the animals slept less after the phase shift. Possible mechanisms of the diurnal plasma level fluctuations and the importance of oscillations of this magnitude to clinical drug regimens are discussed.

Animals↗

PubMed1977

Pharmacology of Huntington's chorea. Personal experience.

Dipropylacetic acid (DPA), gamma-aminobutyric acid (GABA), physostigmine, CB 154 and butyrophenones were administered to 26 patients affected by Huntington's chorea. The evaluation of the pharmacologic activity of the different drugs was determined by means of some clinical parameters and motor performance tests. Butyrophenones succeeded to ameliorate the hyperkinesias and the motor dexterity, CB 154 provoked a worsening of the motor signs of the disorder, while DPA, GABA and physostigmine did not modify the clinical pattern. The relationship between these results and the Hungtington's chorea physiopathology is discussed and a hypersensitivity of DA receptors is suggested.

Acetates↗

PubMed1977

[On the mechanism of action of valproid acid].

In mice, the influence of valproic acid (di-n-propylacetate, DPA) on central level of gamma-aminobutyric acid (GABA) as well as the activity of the enzymes regulating GABA metabolism, glutamate decarboxylase (GAD) and GABA-alpha-oxoglutarate aminotransferase (GABA-T) were studied. It was shown that the elevation of GABA by DPA was accompanied by an activation of GAD. GABA-T was inhibited only by toxic doses or high concentrations of DPA in vivo and in vitro, and so was GAD. DPA proved able to antagonize the biochemical alterations induced by convulsant doses of isoniazid, i.e., decreases in the level of GABA and the activity of GAD. These results point to a role of the transmitter pool of GABA regulated by GAD in the anticonvulsant effect of DPA.

4-Aminobutyrate Transaminase↗

PubMed1976

Valproic acid: reversibly acting drug?

Valproic acid [dipropylacetic acid (DPA)] was evaluated in an alumina-gel monkey model (N = 12) by constant-rate intravenous infusion. The data indicated: (a) a statistically significant decrease in seizure frequency the first 2 days of drug Step I (45-55 mug/ml) and drug Step II (90-110 mug/ml) which was temporary, lasting 2 days only; (b) a later, more permanent decrease in siezure frequency which was not apparent until drug Setp III (130-170 mug/ml); and a delayed return of the seizure frequency to predrug levels for 2 weeks after drug administration was discontinued, with no DPA detectable in plasma after the initial postdrug day. Whether DPA will behave as a reversibly acting drug was discussed.

Animals↗

PubMed1976

The modification of the ethanol withdrawal syndrome in rats by di-n-propylacetate.

Di-n-propylacetate (DPA), a drug known to increase brain gamma-aminobutyric acid (GABA) levels and to inhibit GABA-transamine (GABA-T) activity, was administered during the ethanol withdrawal period to rats made physically dependent upon ethanol. Under all conditions tested, 400 mg DPA/kg injected i.p. significantly reduced the withdrawal hyperexcitable state induced by acoustic stimulation. The effect was seen as early as 30 min after the administration of DPA and lasted for at least 2 hrs. Readministration of the same dose of DPA 6.5 hrs after its initial injection again mitigated withdrawal symptoms. A 200 mg/kg dose of DPA was significantly effective for only 1 hr after its administration. Neither dose led to mortality or observable tranquilization. The results suggest that DPA may be a useful agent in the control of the hyperexcitable state induced by ethanol withdrawal and that the GABA system may be involved in this state.

Acoustic Stimulation↗

PubMed1978

Disposition of sodium valproate in epileptic patients.

1 Serum levels of valproic acid have been determined at fixed intervals after the administration of single oral and intravenous doses (800 mg) to six epileptic patients receiving chronic treatment with other antiepileptic drugs. 2 Serum levels declined monoexponentially shortly after the intravenous administration. Biological half-lives averaged 9.0 +/- 1.4 h (s.d.). Volumes of distribution were 0.175 +/- 0.025 l/kg. There was a statistically significant negative correlation between volumes of distribution and serum half-lives (P less than 0.005). 3 After oral doses serum levels rose rapidly to peak values within 0.5--2 h. Biological availability was 96 +/- 9%. 4 Comparison with a previous study performed according to the same protocol in healthy volunteers showed significantly increased volumes of distribution and rates of elimination in the patients. Total serum clearance was 85% higher in the patients as compared to the healthy subjects (P less than 0.001). Possible explanations for these findings are discussed.

Adult↗

PubMed1975

Sodium di-N-propylacetate (DPA) in the treatment of epilepsy. A review.

The literature on clinical and experimental studies of sodium dipropylacetate (DPA), a branched chain carboxylic acid with a unique antiepileptic structure, is critically reviewed. The clinical antiepileptic properties are evaluated by seizure type. DPA appears to be most efficacious in the treatment of absence seizures. The literature also provides evidence for efficacy in the treatment of generalized tonic-clonic seizures and partial seizures with elementary symptomatology. The clinical pharmacology of DPA has not been thoroughly investigated. Simple, accurate, and reproducible gas-liquid chromatographic methods are available for determining the concentration of DPA in body tissues and fluids. The plasma half-life in humans is 8 to 15 hr. The most frequently observed adverse effects are gastrointestinal disturbances. In patients receiving additional antiepileptic drugs, potentially serious sedative effects have also been noted, which may be due to an interaction between DPA and concurrently administered medications.

Adolescent↗

PubMed1977

Pharmacokinetic studies with valproic acid in man.

A specific gaschromatographic assay for the simultaneous determination of valproic acid (dipropylacetate, DPA) and ethosuximide was developed. In 13 epileptic patients only treated with DPA a significant correlation(r = 0.88; p less than 0.01) between the minimal steady state plasma level of DPA and its dose (mg/kg body weight) was found. Plasma protein binding experiments in 3 healthy volunteers revealed a relatively strong binding of approximately 95%. The pharmacokinetics of DPA was evaluated after a single oral solution of 600 mg in 2 healthy subjects. Absorption was rapid with maximum plasma levels of approximately 70 microng/ml within 1--3 h. DPA was eliminated with a half-life of 7.9 and 10 h. Assuming 100% absorption a total plasma clearance of 10--13 ml/min and an apparent distribution volume of 0.13--0.16 l/kg were calculated. The urinary excretion of unchanged DPA is neglegible (1% of dose). It is suggested that the great fluctuations of the plasma concentrations within a dosing interval may be minimized by special galenic formulations.

Adult↗

PubMed1977

Preliminary observations on valproic acid kinetics in patients with epilepsy.

A rapid gas chromatographic method for determination of sodium valproic acid (di-n-propylacetate, DPA) is described. A new sample can be injected every third min, and the reproducibility, in terms of the coefficient of variation, is better than 3%. The method has been used to study clinical pharmacokinetics of DPA in patients with epilepsy during long-term treatment. A poor correlation between daily dose (mg/kg) of DPA and steady state serum levels, attained within few days, was observed. A fixed sampling time in the individual patient, preferably before ingestion of the morning dose, is of great importance for DPA due to extended fluctuations of the serum levels during the day. Most patients had DPA serum levels in the order of 50 microng/ml. No constant relationship was found between increase of the dose and the corresponding increase of the serum levels. Interactions of clinical importance was observed between DPA and other antiepileptic drugs, as addition of DPA resulted in elevated serum levels of diphenylhydantoin and phenobarbital. Carbamazepine levels were unaltered. After withdrawal of DPA the half-life was about 14 h in adult patients. DPA levels in CSF were in the order of 10% of the corresponding serum levels.

Adult↗