Dose Of Valproate Research Articles

Risk of excessive weight gain in epileptic children treated with valproate.

We sought to identify factors associated with excessive weight gain in children treated with valproate, excluding patients fed by gastrostomy or treated with medications known to affect appetite (eg, stimulants). Weight and height were recorded before treatment and at the time of follow-up; a measure of adiposity, body mass index, was computed and expressed in kg/m2, and weight and height for age were converted to Z-score. Putative risk factors included sex, age at start of treatment, monotherapy at start of treatment, duration of follow-up, mental retardation, seizure type (generalized or partial), etiology (idiopathic or cryptogenic versus remote symptomatic), and dose of valproate. Fifty-five children (30 girls, 25 boys), ranging in age at the start of therapy from 1.8 to 16.9 years were followed for 8.6 to 33.8 months. Forty-three patients had primarily generalized seizures, 34 had idiopathic or cryptogenic epilepsy (including 30 with generalized idiopathic epilepsy), and 18 had mental retardation. Valproate was the first antiepileptic drug for 21 patients, and 43 were on monotherapy at the time of follow-up. Height Z-score decreased significantly in girls but was stable in boys. There was a significant increase in body mass index and in weight Z-score. Body mass index was greater than the 90th percentile for age in 14 patients at the start of treatment and in 20 patients at follow-up. Decrease in height Z-score was significantly correlated with female sex and duration of follow-up. Changes in weight Z-score and body mass index were significantly correlated with initial weight Z-score and initial body mass index, respectively, but not with age at start of therapy, duration of follow-up, sex, seizure type, etiology, dose of valproate, or monotherapy.

Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.

1. Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for the conversion of glutamate to glutamine, and for the detoxification of ammonia. 2. We have investigated the effects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on GS activity in mouse brain. 3. Four hours after the final dose, animals were sacrificed and the brains removed for analysis of GS activity. 4. Both single and repeated doses of phenytoin and carbamazepine were found to reduce enzyme activity (P<0.05). 5. Single doses of phenobarbitone, felbamate and topiramate were without effect, however repeated administration of these drugs dose-dependently reduced GS activity (P<0.05). 6. Single and repeated doses of sodium valproate, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam and desglycinyl-remacemide were found to have no effect on GS activity. 7. The reduction in enzyme activity demonstrated is unlikely to be related to the anti-epileptic actions of these drugs, but may contribute to their toxicity.

Valproate reduces intake of alcoholic beverage among rats.

A series of experiments was carried out to assess the effects of valproate (VAL) on the intake of ethanol by rats. In Experiment 1, the effects of VAL (150 and 200 mg/kg, i.p.) were assessed across 10 days. Compared with controls, the 200 mg/kg dose reliably reduced intake of ethanol while also reliably increasing intake of water. The 150 mg/kg dose did not reliably reduce the intake of ethanol across the initial days, but it did across later days. Neither dose affected the total intake of fluids. Similarly, 5 days of oral dosing with VAL (400 and 600 mg/kg) reliably reduced the intake of ethanol without affecting the intake of water. However, body weights were reduced by the oral doses across the procedure. In another procedure, VAL (200 mg/kg, i.p.) produced a mild conditioned taste aversion to a saccharin solution, suggesting that VAL may reduce intake of ethanol because it produces a general malaise. However, this dose of VAL enhanced the intoxicating effects of ethanol (2.0 g/kg). Overall, the results are equivocal with respect to VAL as a potential medicine for treating alcohol misuse and alcoholism.

Safety of high intravenous valproate loading doses in epilepsy patients

Parenteral antiepileptic drugs (AEDs) are required in patients needing emergent treatment or unable to take oral medication. In the two United States trials of IV valproate, only low therapeutic serum levels were achieved. This study evaluated the safety of high loading doses to achieve therapeutic levels rapidly. Twenty-five epilepsy patients without active seizures received a single loading dose of IV valproate (Depacon) based on body weight and infused over 1 hour. Ages were 4–39 years (mean: 13.1 ± 8.6 years). Electrocardiogram (ECG) and electroencephalogram (EEG) were monitored throughout infusion; blood pressure was measured before and after. Serum valproate was measured 10 minutes postinfusion. The IV valproate dose range was 15–44 mg/kg (mean: 28.3 ± 7.4 mg/kg); infusion rates were 0.25–0.73 mg/ kg/minute (mean: 0.47 ± 0.1 mg/kg/minute). Postinfusion serum valproate concentrations were 71–277 μg/ml (mean: 135.3 ± 59.5 μg/ml). There were no significant changes in blood pressure, no redness or tenderness at the IV site, and no ECG abnormalities. One patient with serum valproate ⩾ 200 μg/ml had mild sedation (resolving in 24 hours). We concluded that serum valproate concentrations of ⩾ 100 μg/ml can be achieved rapidly and safely parenterally, a finding with important implications for the treatment of status epilepticus.

Radial astrocytes: Toxic effects induced by antiepileptic drug in the developing rat hippocampus in vitro

Neuron-glia relationships are crucial for differentiation of both glial and neuronal cells. Interference with these intricate cell interactions could affect regular neuroembryogenesis. In order to analyse potential developmental neurotoxic effects of therapeutically administered antiepileptics such as valproate, we employed organotypic cultures of the rat hippocampus. In these cultures thin tissue slices were continuously rotated between the gas and medium phases, which greatly improved oxygen and nutrient accessibility. This resulted in long-term preservation of the native cytoarchitecture. Exposure of organotypically cultured hippocampi to valproate hampered, in a dose-dependent manner, regular formation of the pyramidal cell layer. Most interestingly, radial astrocytes, which comprise a transient cell population during distinct developmental periods, were selectively affected even by low doses of valproate, but not by structurally related non-teratogenic isomer 2-ethyl-4-methyl-pentanoic acid. The xenobiotic effect did not represent a general gliotoxic insult, since neither the glutathione quotient as determined by HPLC, nor the DNA content, nor the total amount of glial fibrillary acidic protein evaluated by ELISA were significantly altered. Instead, the morphology of astrocytes proved to be the most sensitive index of intoxication with the orientation of radial astrocytes being most affected as revealed by immunofluorescence. In contrast to radial astrocytes, other astrocytic populations proved to be fairly resistent. The data indicate that developmentally regulated cell polarity of astrocytes is a target of therapeutically relevant xenobiotics. This could in turn disturb neuronal differentiation and normal histogenesis.

A potential anti-asthmatic drug, CR 2039, enhances the anticonvulsive activity of some antiepileptic drugs against pentetrazol in mice

CR 2039 (4-(1H-tetrazol-5-yl)- N-[4-(1H-tetrazol-5-yl]phenylbenzamide), in doses of 10, 20, and 100 mg/kg i.p., did not modify the seizure pattern observed after subcutaneous pentetrazol, administered at its CD 97 of 90 mg/kg for the clonic phase. However, when combined with antiepileptic drugs, this phenylbenzamide derivative (20 mg/kg) converted the subprotective doses of ethosuximide (100 mg/kg) or valproate (100 mg/kg) against the clonic phase into anticonvulsive ones. The protection observed was comparable to that noted after doubling the doses of these antiepileptics. Also, a combination of valproate (100 mg/kg) with CR 2039 (10 mg/kg) resulted in a clear-cut protection against clonic seizures induced by pentetrazol. The protective efficacy of clonazepam was not affected by the phenylbenzamide derivative up to 40 mg/kg. The potentiation of the anticonvulsive activity of ethosuximide or valproate was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (20 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied, which speaks against a pharmacokinetic mechanism in the observed results. In conclusion, CR 2039 seems devoid of a hazardous influence of the anti-asthmatic drug, aminophylline, on the anticonvulsive effects of conventional antiepileptics.

Self‐Induced Pattern‐Sensitive Epilepsy

Case Report: A 6‐year‐old girl developed self‐induced pattern‐sensitive epilepsy. Her elder sister is normal, and there is no family history of epilepsy. She was born after a 39–week gestation at a birth weight of 3,120 g. Her early psychomotor development was normal. She spoke her first meaningful words at 12 months and walked along at 18 months. At 6 years, she developed repetitive myoclonic jerks of the shoulder and arms, mainly on voluntary viewing of vertically striped patterns such as her mother's clothes, gates, and escalator steps. Neither spontaneous nor photosensitive seizures occurred. At 7 years, she first experienced a generalized tonic‐clonic seizure after seeing the mesh of a screen window. Physical and neurologic examinations were unremarkable. The interictal EEGs showed diffuse polyspike‐and‐wave complexes but no photosensitivity, and computed tomography on the head revealed no abnormalities. She was treated with valproate (VPA), which partially suppressed her seizures. After age 10 years, the seizures increased in frequency and occurred exclusively by self‐induction. She displayed an irresistible urge to approach the mesh of screen windows at home every morning and developed myoclonic jerks after staring at the pattern. Even when her parents scolded her not to approach the window and drew a curtain over it, she deliberately opened the curtain and glanced at the mesh, inducing the jerks. She did not seem to relieve any tension through having the seizures. At that age, EEGs showed an ictal generalized polyspike‐and‐wave complex with myoclonic jerks a few seconds after viewing the same mesh pattern as that from her house. Interictal recordings had normal background activities. The EEGs after viewing other patterns were not obtained. Visual evoked responses to flashes were normal. At age 11 years, she developed another generalized tonic‐clonic seizure after viewing a vertically striped pattern in a gate. After an increasing in the dose of VPA, her self‐induced seizures were controlled by the end of her 12th year. However, she had an obsessive interest in patterns until age 12 years. She demanded to view the vertical strips of a notebook, even if her mother prohibited viewing it and concealed the notebook. She did not have other behavioral problems, but her intelligence quotient was 71 on the Kyoto Scale of Psychological Development. Her visual memory was especially poor in the test. She is now 13 years old and still taking VPA. She is seizure free and shows no more obsessive behavior toward patterns. Conclusions: In this patient, only pattern‐sensitive seizures occurred, and only self‐induced seizures after age 10 years. The seizures were primarily myoclonic with rare generalized tonic‐clonic seizures. She also displayed obsessive behavior toward patterns. She did not have photosensitive seizures, and her EEGs showed no photosensitivity. This is not in accordance with the previous reports on the close relation between pattern‐sensitive and photosensitive epilepsy. Her low intelligence quotient was mostly caused by her poor visual memory. This suggests that pattern‐sensitive epilepsy is linked to focal dysfunction involving the occipital lobe.

Clinical correlates of response to valproate in geriatric inpatients.

The efficacy of valproate for the management of adults with bipolar disorder has been repeatedly demonstrated in several studies. Patients with mixed states, rapid cycling, and EEG abnormalities have been shown to respond favorably to valproate. Valproate is also being increasingly used in disorders with aggressive or agitated features, such as the behavioral disorders of dementia; yet, few studies have documented the utility of valproate in geriatric patients. The need to document safe and effective pharmacologic agents to treat geriatric mood and behavioral disorders continues to increase with the growing elderly population. We conducted a retrospective study of the use of valproate in patients consecutively hospitalized over a 5-year period on a psychiatric unit. Thirty-nine patients over age 60 were identified and then categorized into non-, partial, and full responders based on Clinical Global Impression ratings. Information on diagnosis, age, valproate dose and serum concentration, psychiatric symptoms, medical comorbidity, concurrent psychotropic medications, and side effects was collected. Results suggest that responders to valproate (full or partial) over the age of 60 years were more likely to be female, younger, carry a diagnosis of bipolar disorder, and achieve higher serum valproate concentrations. Full responders had fewer psychotic symptoms but usually displayed manic symptoms. The date of this study suggests the need for controlled clinical trials to clarify the utility and clinical predictors of response to valproate in the geriatric population.

Effect of Valproate on the Pharmacokinetics of Free and Total Plasma Bilirubin in Experimental Hyperbilirubinemia in Guinea Pigs

□ The effects of valproate (VPA) on free and total bilirubin concentrations in plasma were studied in guinea pigs. Steady-state hyperbilirubinemia (around 2.5–3.0mg/100mL) was induced by constant intravenous (iv) infusion of bilirubin followed by an iv bolus dose of sodium valproate (VPA-Na) of 50 (n=4) or 200 (n=5) mg/kg. Steady-state plasma total bilirubin concentration was lowered by 40% and 55% and the unbound fraction (fu) increased by 1.9- and 4.9-fold at the respective doses of 50mg/kg and 200mg/kg VPA-Na. Free bilirubin was not significantly changed by 50mg/kg VPA-Na, but did show a significant transient elevation with the 200mg/kg dose. In another experiment, guinea pigs (n=3) were given a constant iv infusion of VPA-Na to maintain a steady-state plasma concentration (58μg/mL), followed by an iv bolus dose of bilirubin (2mg/kg). A control study (n=3) was performed simultaneously using normal saline instead of VPA. Free bilirubin was detectable only following induction of hyperbilirubinemia in either group. A higher volume of distribution and lower elimination rate constant of bilirubin were observed in the VPA-treated than in the control animals. The displacement effect of VPA on bilirubin-plasma binding in vitro was studied by adding serial concentrations of VPA-Na to bilirubin–plasma solution. VPA displaced bilirubin from the high-affinity plasma protein binding site, with a binding constant (KD) of 5.7 × 10–2/μΜ. Similar displacement of bilirubin plasma protein binding was observed in vivo. These results suggest that VPA reduces plasma protein binding and slows the elimination rate of bilirubin. The principal mechanism for decreased plasma concentrations of total bilirubin by administration of VPA is caused by decreased plasma binding, as opposed to metabolic induction.

Doses of carbamazepine and valproate in bipolar affective disorder

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The tolerability and safety of valproate sodium injection given as an intravenous infusion

Patients with epilepsy may sometimes require antiepileptic drugs (AEDs) parenterally. This study assessed the safety and tolerability of valproate sodium injection (IV valproate) (Depacon, Abbott Laboratories, Abbott Park, IL), given by intravenous infusion, as replacement therapy for oral valproate in a placebo-controlled trial involving stable epilepsy inpatients on steady doses of divalproex sodium (DVPX). Thirty-four patients received IV valproate and oral placebo, and 17 received IV placebo and oral DVPX (Depakote, Abbott Laboratories) every 6 hours for 4 days. The dose of IV valproate was the same (milligram for milligram) as that of previous oral DVPX. Concomitant AEDs were continued as usual. No serious adverse events were observed with IV valproate, nor were any clinically significant differences found between study groups for changes in average, minimum, or maximum systolic or diastolic blood pressure or heart rate. Positional changes caused no significant group differences in these variables, and no evidence of either acute or cumulative cardiotoxicity was found. The only changes found in laboratory values were increased SGOT and SGPT levels in the IV valproate group, compared with decreases in the control group ( P = 0.014 and 0.001, respectively). In conclusion, intravenous sodium valproate appears to be a well-tolerated substitute for an equivalent dose of oral valproate.

Doses of carbamazepine and valproate in bipolar affective disorder

Carbamazepine and valproate are now well established treatments for bipolar affective disorder (BAD). Both drugs are used in the acute treatment of mania and, more frequently, as longer-term mood stabilisers. The British National Formulary (BNF, Vol. 32, 1996) provides information on the use of carbamazepine in the ‘prophylaxis of manic depressive illness' and suggests that the ‘usual range’ of doses is between 400 mg and 600 mg daily. No guidance on the use of valproate in BAD is given in the BNF because the drug is not licensed for this indication in the UK.

Reduction in blood free carnitine levels in association with changes in sodium valproate (VPA) disposition in epileptic patients treated with VPA and other anti-epileptic drugs.

Reduction in the blood free carnitine (FC) level as a side effect of sodium valproate (VPA) given epileptic patients was pharmacokinetically studied in connection with changes in the VPA disposition. The serum FC level in patients taking at least one of phenobarbital (PB), phenytoin (PHT) and/or carbamazepine (CBZ) in addition to VPA was significantly lower than that in the controls given only these other anti-epileptic drugs (AEDs). Patients medicated only with VPA also tended to have a lower serum FC level than the controls, although the difference was not significant. Among all the patients taking VPA with or without other AED(s), a significantly positive correlation was observed between the serum FC level and the value of dose and level ratio (L/D) of VPA, indicating that both the serum FC concentration and the L/D value of VPA were remarkably reduced in those patients receiving both medications. These results suggested that reduction in the blood FC level as a side effect of VPA reflected FC deficiency associated with the accelerated degradation of VPA in liver; such a condition appears to result from medication with VPA and other AED(s) which induce(s) enzyme(s) for the VPA metabolism.

Effect of valproate and felbamate on carbamazepine and its metabolites in epileptic children

The metabolism of carbamazepine (CBZ) has been reported to be influenced by comedication with both valproate (VPA) and felbamate (FBM). We replaced VPA with FBM in a group of four patients receiving VPA and CBZ who failed to achieve satisfactory seizure control and/or experienced side effects. In the process of tapering VPA and initiating FBM, we conducted serial therapeutic drug monitoring to investigate the drug interactions. As compared with baseline levels, CBZ and its metabolite concentrations were all decreased. The levels of CBZ were decreased by 25–31%, whereas carbmazepine-10,11-epoxide (CBZ-E) concentrations were lower by more than 55%. The trans -10,11-dihydroxy-10,11-dihydro-CBZ (CBZ-H) concentrations were slightly decreased. Both CBZ-H/CBZ-E and CBZ-H/CBZ concentration ratios were increased, while CBZ-E/CBZ concentration ratios were decreased. These results suggest that the biotransformation of CBZ-E to CBZ-H is increased during the process of tapering VPA, presumably due to the release of the inhibitory effect on liver epoxide-hydrolase by the reduction of VPA doses. The most likely mechanism for the decreased CBZ levels appears to be the induction of CBZ metabolism produced by introducing FBM. These drug interactions and the potential clinical consequence should be monitored and correctly interpreted, since both CBZ and CBZ-E are active in the treatment of seizures.

Evaluation of the antiinflammatory activity of sodium valproate in rats and mice

1. 1. Treatment of rats with sodium valproate (100, 200 and 400 mg/kg IP) reduced the paw oedema induced by carrageenan by 36, 15 and 48%, respectively, within 3 h. 2. 2. The effect produced by the higher dose (400 mg/kg) was equivalent to that produced by indomethacin (100 mg/kg). At 100 and 400 mg/kg, sodium valproate decreased the granuloma formation by a significant level. Similar doses of sodium valproate did not affect the rectal temperature in yeast-fevered mice, except with a dose of 200 mg/kg, which showed a significant decrease at 180 and 240 min posttreatment. 3. 3. In comparison, sodium salicylate reduced the hyperthermia very significantly throughout the study period. 4. 4. In normothermic mice, the rectal temperature changed only with a 400 mg/kg dose, but did not respond to lower SV doses. 5. 5. The results indicate that sodium valproate, useful clinically as an epileptic drug, may have a potential therapeutic use as a mild antiinflammatory agent.

Metabolite profiles in patients on high-dose valproate monotherapy.

To investigate the mechanism of valproate (VPA)-induced hepatotoxicity, we measured the serum and urine metabolites of VPA in high-dose VPA monotherapy by GC/MS/SIM and discussed the relationship between liver function and beta-oxidation, omega-, (omega-1)-oxidation metabolites and 4-en-VPA. In high-dose VPA monotherapy, the concentrations of beta-oxidation metabolites were not increased except for 2-en-VPA, but the concentrations of {omega + (omega-1)}-oxidation metabolites and of 4-en-VPA were increased about 4-5 times compared to those of standard dose VPA monotherapy. Serum GOT was not significantly correlated to 4-en-VPA and the ratio of beta-oxidation/{omega + (omega-1)} oxidation metabolites of VPA in serum. In high-dose VPA monotherapy, it is speculated that the beta-oxidation of VPA in the mitochondria reached the saturation point. However, instead of the beta-oxidation, the {omega + (omega-1)}-oxidation in microsomes was increased. We could not find significant relationship between the formation of toxic metabolites of VPA and liver dysfunction. Our data in VPA monotherapy suggest that the mechanisms of VPA-induced fatal hepatotoxicity cannot be explained by decreased beta-oxidation, increased omega-oxidation and increased 4-en-VPA level.

Effect of sodium valproate on luteinizing hormone secretion in pre- and postmenopausal women and its modulation by naloxone infusion.

The synchronized activity of the GnRH neurons can be modulated through both excitatory and inhibitory circuits: one such inhibitory modulator is gamma-aminobutyric acid (GABA), but this has been little studied in humans. The aim of this study was to examine whether acute or chronic modulation of the GABA-ergic system with the drug sodium valproate (VPA) affects gonadotropin secretory frequency and/or amplitude in a steroid-dependent manner, and whether any such modulation might interact with endogenous opioids. Sixty postmenopausal women (age range 50-60 yr, group I), 50 postmenopausal women who had been on estrogen replacement therapy (group II), and 30 women in the luteal phase of their regular menstrual cycle (age range 25-40 yr, group III) were studied. VPA was administered acutely using doses of 300, 600, and 1200 mg orally. Samples for serum gonadotropins were taken at intervals over 24 h. Each dose of VPA caused significant LH suppression in group I. The maximum degree of suppressibility was the same with the three doses of VPA (14-20%). However, no dose had any effect on gonadotropin levels in group II. In group III, the single high dose of 1200 mg VPA significantly suppressed serum LH levels. The efficacy of chronic VPA administration in the three groups studied was assessed by measuring LH pulsatility (10-min samples) over 6 h, before and after 1 month's treatment with VPA. No change in either mean basal LH or in the LH pulsatility parameters was found. Naloxone infusion (1.6 mg/h for 6 h) had no effect on LH pulsatility in group I. When 1200 mg of VPA was administered before naloxone infusion, the level of LH suppression was 18% and was associated with a significant decrease in LH pulse frequency (P < 0.01). Naloxone infusion alone significantly increased mean serum LH and LH pulse frequency in group II patients (P < 0.01), and this elevation was antagonized by VPA pretreatment. Naloxone infusion alone significantly increased mean LH levels and LH pulse frequency in patients in group III, and this was also blocked by VPA pretreatment. These results suggest that an acute increase in GABA-ergic tone may inhibit gonadotropin secretion in the estrogen-deprived state, or when endogenous opioid inhibition is blocked in postmenopausal women on estrogens, as well as during the luteal phase of the menstrual cycle. It is possible that GABA-ergic pathways interact with opioids in the inhibitory modulation of gonadotropins in the human female.

Effect of valproate on cerebral metabolism and blood flow: an 18F-2-deoxyglucose and 15O water positron emission tomography study.

We compared the effect of valproate (VPA) on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF), measured with 18F-2-deoxyglucose (18FDG) and 15O water positron emission tomography (PET), in 10 normal volunteers. Mean VPA dose was 17.7 mg/kg, and mean VPA level was 82.1 mg/L (+/-16.5) for 4 weeks. VPA reduced global CMRGlc by 9.4% (9.60 +/- 0.76 vs. 8.59 +/- 1.02 mg Glc/min/100 g, p < 0.05) and regionally in all anatomic areas (p < 0.05 for 11 of 26 areas). VPA diminished global CBF by 14.9% (56.55 +/- 6.70 vs. 47.48 +/- 4.42 ml/min/100 g, p < 0.002) and regionally in all anatomic areas (p < 0.05 for 12 of 26 areas). No significant correlation was noted between VPA level and either global CMRGlc or CBF. The effect of VPA on global CMRGlc is similar to that of carbamazepine (CBZ) and phenytoin but less than that of phenobarbital, valium, or combination therapy with VPA and CBZ. VPA reduced regional CBF (rCBF) but not CMRGlc in the thalamus, an effect that may be associated with VPA's mechanism of action against generalized seizures.

Pharmacology of cortical epileptic afterdischarges in rats.

Afterdischarges (ADs) elicited by electrical stimulation of the sensorimotor cortical area are characterized by rhythmic spikes and spike-wave complexes in the EEG and by clonic face and forelimb seizures. We studied the sensitivity of such ADs to phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), primidone (PRM), and valproate (VPA) in 78 adult male Wistar rats with implanted electrodes. Neither PHT (30 and 60 mg/kg intraperitoneally, i.p.) nor CBZ (25 and 50 mg/kg i.p.) suppressed cortical ADs. Indeed, ADs were prolonged by higher doses of both drugs. PRM had a similar effect: A dose of 40 mg/kg transiently shortened ADs, but a dose of 80 mg/kg prolonged ADs. PB (20 and 40 mg/kg) and VPA (200 and 400 mg/kg) were effective in suppressing ADs. Higher doses of VPA and PB reduced the intensity of motor phenomena related to the stimuli but had no effect on the motor correlates of ADs. These findings suggest that cortically induced ADs are not a good model of secondarily generalized seizures. The response to VPA and PB suggests that cortical ADs may represent a model of myoclonic seizures.

Effects of valproate on amino acid and monoamine concentrations in striatum of audiogenic seizure-prone Balb/c mice.

The effects of valproate on CNS concentrations of gamma-aminobutyric acid (GABA), glulamate (GLU), glutamine (GLN); dopamine (DA), serotonin (5-HT), and metabolites were examined in tissue extracts of caudate nucleus of genetic substrains of Balb/c mice susceptible (EP) or resistant (ER) to audiogenic seizures. Generalized tonic-clonic seizures observed in EP mice were inhibited by valproate, administered 1 h prior to testing, in a dose-response fashion. Concentrations of GABA, GLU, and GLN, which were lower in EP mice than in ER mice, were significantly increased by valproate at doses of 180 and 360 mg/kg. Concentrations of homovanillic acid (HVA) and hydroxyindoleacetic acid (5-HIAA), metabolites of DA and 5-HT, were substantially increased by valproate at these doses. The in situ activity of tyrosine hydroxylase (TH) was not significantly influenced by valproate, whereas a valproate-induced increase in tryptophan hydroxylase (TPH) activity was observed in both striatum and in midbrain tegmentum. The data are consistent with the interpretation that anti-convulsive doses of valproate influences the intraneuronal metabolism of monoamines, GABA, and glutamate concurrently. Valproate's influence on the metabolism of both major inhibitory (GABA) and excitatory (GLY amino acids in striatum could contribute to its anti-convulsive effects in genetically seizure prone mice, as well as to the accumulation of DA and 5-HT metabolites.