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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.

Sodium valproate has a broad spectrum of anticonvulsant activity, but is structurally unrelated to conventional antiepileptic drugs. Its proposed mode of action is mediated through effects on the function of brain gamma-aminobutyric acid (GABA). However, the elevations in brain and cerebellar GABA, and the concomitant reductions in levels of cyclic guanosine monophosphate, occur in animals at dose levels which are unlikely to be achieved during treatment of epileptic patients.

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.

Eight fasting normal subjects were given a single dose of sodium valproate, 400 mg, phenobarbital, 60 mg, or the two drugs in combination, in a double-blind placebo-controlled study. The effects were assessed behaviorally and by a standard 30-min EEG, begun 1 hr after the treatments had been given. The recording was rated for the amount of drowsiness and sleep, independent of which drug had been given. The scores obtained indicated that valproate intself has hypnotic action, and there is a tendency for this to be increased by the simultaneous administration of phenobarbital.

Regional brain GABA distribution studies show that after administration of sodium n dipropylacetate, a competitive inhibitor of GABA transaminase, the concentration of GABA increases in some regions i.e. Olfactory Bulbs, Hypothalamus, Cortex, Cerebellum. The GABA level remains unchanged in Caudate Nucleus, Pons Medulla, Hippocampus in our experimental conditions. These variations do not correlate with the initial GABA level.

When effects of di-n-propylacetate (nDPA) on various patterns of behaviour in mice in "novel environment" tests are compared with the effects of oxazepam, it appears that the stimulating action of nDPA is more evident than its antianxiety effects. Learning seems to be facilitated by this stimulating action.

n-di-propylacetate (nDPA) reduced the heart rate level of Mice. Heart rate is often related to animal's emotionality. The nDPA would reduce the emotional behaviour.

n-Dipropylacetate (nDPA), at a dose of 100 mg/kg, has a facilitating action on the acquisition of conditioned reactions with negative reinforcement in mice. On the other hand, nDPA reduces the number of conditioned reactions with a dose of 200 mg/kg. These effects of nDPA on conditioned behaviour are correlated with the increase of the level of brain gamma-aminobutyric acid, following administration of nDPA.

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.

The influence of Dipropyl-Acetate (DPA, Ergenyl) on hemostasis parameters was examined in 12 patients. In 8 cases there was a prolongation of bleeding time, in 2 cases thrombocytopenia, in 6 out of 10 cases the platelet adhesiveness was pathologically reduced. We therefore recommend hemostasis-examinations--with emphasis on the thrombocytic system--in patients taking DPA.

The anticonvulsant effect of di-n-propylacetic acid (n-DPA) was studied in mice and compared to those of phenobarbital, trimethadione and ethosuximide. n-DPA was only weakly active in the maximal electroshock test, but had an ED50 of 420 mg/kg orally in the pentetrazole seizure threshold test, which corresponds rather well to the activity of trimethadione and ethosuximide. The duration of action was only short, and the first signs of neurotoxicity--inability to perform in the chimney test--appeared well below the anticonvulsant ED50 against pentetrazole. n-DPA proved to be most active against convulsions induced by picrotoxin (ED50 200 mg/kg orally), which might indicate a role of the elevation of the central levels of gamma-aminobutyric acid in the anticonvulsant effect of the drug.

In vivo and in vitro experimental data are presented in support of the hypothesis that sodium valproate displaces diphenylhydantoin (DPH) from plasma protein binding sites. This interaction could have important practical implications in the management of patients on combined therapy with these two drugs. Acute neurological features of DPH intoxication may be precipitated as a result of an increased free (pharmacologically active) fraction, which would not be detected by routine plasma DPH estimations since these reflects largely the bound fraction.

Sodium valproate is an anticonvulsant which, unlike phenobarbitone, does not produce an increase in rat hepatic P450 when given in large nontherapeutic doses.

The influence of dipropylacetate (D.P.A.) on behaviour was studied in 20 patients using a double blind cross over trial. 5 patients were rated as improved on D.P.A., 6 on placebo, 3 as deteriorated on D.P.A., 3 on placebo, 12 as unchanged on D.P.A. and 11 on placebo. This study gives us no reason to believe that D.P.A. exerts a psychotropic action within 3 weeks which is better than a placebo effect.

The effect of di-n-propylacetate (DPA) on the 'binding' of gamma-aminobutyric acid (GABA) to a synaptosome-enriched fraction of rat cerebral cortex has been examined using differential centrifugation and double-isotope liquid scintillation spectrometry. DPA at 10(-4) M caused a slight decrease in GABA binding. This effect could explain in part the in vivo anticonvulsant and behavioral effects of this drug when administered to animals in high systemic doses.

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;

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.

The effects of dipropylacetic acid (DPA) on primary, secondary and afterdischarge waves of the photically evoked potential were examined. It was observed that DPA selectively attenuated late wave components and afterdischarge. A thalamic locus of action for these effects is postulated.

It was shown that oxygen at high pressure (OHP) induced epileptic seizures and pulmonary damages on mice. Dipropylacetate protected mice against nervous syndrome better than did dipropylacetamide. No significant pulmonary protection was observed with both drugs.

Rats were trained to run treadmill fashion along a moving belt to avoid electric shock. After stabilization of performance, the effects of the anticonvulsant di-n-propylacetate (DPA; 100, 200 and 400 mg/kg) on treadmill locomotion were measured. Disturbances in gait and balance were reflected by an increased time off belt in a dose-related manner. In addition, animals showed a progressive improvement over the 3 two-min trials. A second experiment which measured the effects of 300 mg/kg DPA either 5 or 20 min postinjection revealed that the progressive improvement noted in the first experiment was not due to a diminished drug concentration or to an increased exposure to the drug. Thus, acute functional tolerance to the performance decrement produced by DPA appears to depend upon behavioural processes which enable an animal to overcome the drug-induced functional deficit by practicing the task while in the drug state.

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.

Slices from guinea pig brain containing the lateral olfactory tract (LOT) and the prepiriform cortex were studied in vitro. Field potentials, evoked by stimulation of the LOT, were recorded extracellularly. This field potential comprises a compound action potential, a surface negative wave (identified as EPSP), and superimposed positive peaks ("population spikes" or PSs) reflecting postsynaptic activity. In a previous article the penicillin-induced increase of EPSP and of both amplitude and number of PSs was described. Now we are reporting the slight depression of EPSP and PSs and the prevention of the appearance of penicillin-induced PSs by an antiepileptic drug sodium dipropylacetate (Depakine). The effect was dose-dependent. Models explaining the effects of penicillin and dipropylacetate are discussed.

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.