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PubMed1994

Is the site of action of ethosuximide in the hindbrain?

The action of ethosuximide, valproate and clonazepam against pentylenetetrazol-induced epileptic EEG phenomena was studied in acute experiments in rats with intercollicular brainstem transection. Ethosuximide lost its action against both rhythmic metrazol activity (model of human absences) and EEG seizures. On the contrary, the action of valproate and clonazepam in cerveau isolé rats was the same as in intact animals. The site of anticonvulsant action of ethosuximide may be localized in hindbrain structures, whereas the actions of both valproate and clonazepam may be demonstrated even if hindbrain structures had been eliminated.

Animals↗

PubMed1977

Ethosuximide and bicuculline inhibition in petit mal epilepsy.

The mechanisms of petit mal epilepsy remain a mystery despite successful therapy. Previous workers have proposed that paroxysmal activity of cortical inhibitory systems plays a role in absence seizures. In this study, we have compared the effects of bicuculline, a potent convulsive agent and GABA antagonist, with ethosuximide, a drug used to treat petit mal epilepsy, on the thalamocortical motor system of the cat. Under chloralose anesthesia, sequential pairs of pulses were delivered to ventrolateral thalamus (VL) varying either pulse amplitude or interval. The evoked responses were recorded from sensorimotor cortex, analyzed on-line by computer, and plotted as an excitability curve (mean response amplitude as a function of pulse interval), or a family of threshold curves (mean response amplitude as a function of stimulus amplitude at various fixed intervals). Administration of each drug resulted in increased thalamocortical excitability and decreased threshold to stimulation for short pulse-pair intervals, with diminished duration of the excitability curve. Increased alertness was produced by both drugs. Studies with grand mal anticonvulsants demonstrated entirely different effects. Because GABA is thought to be the primary inhibitory transmitter in VL and cerebral cortex, bicuculline would be expected to result in disinhibition. The similarity of the data for ethosuximide suggests that ethosuximide also suppresses inhibition in the thalamocortical motor system and adds further to the accumulating evidence of the role of inhibitory system in petit mal epilepsy.

Animals↗

PubMed1976

Anticonvulsant drug mechanisms. Phenytoin, phenobarbital, and ethosuximide and calcium flux in isolated presynaptic endings.

Phenytoin, phenobarbital, ethosuximide, and procaine hydrochloride were evaluated for their ability to inhibit Ca2+ flux into isolated presynaptic endings (synaptosomes) prepared from rabbit neocortex. Calcium influx produced by depolarizing concentrations (69 mM) of K+ was inhibited 7% to 63% by phenytoin, phenobarbital, or procaine, whereas ethosuximide was ineffective. Decreased Ca2+ influx was observed with as little as 0.08 mM phenytoin and 0.04 mM phenobarbital. In contrast, 4 mM procaine was needed to produce an effect. These results lead to the conclusion that ability to produce membrane stabilization is not a property of all anticonvulsant drugs; however, this property may be essential for the action of drugs effective in the treatment of major seizures.

Animals↗

PubMed1983

Valproate-ethosuximide combination therapy for refractory absence seizures.

Five patients had absence seizures refractory to treatment with either ethosuximide or valproate sodium. To determine their response to combination therapy with the two drugs, four of the five had serial 24-hour intensive monitoring studies that included cable telemetric EEG recording, closed-circuit television observation, and frequent antiepileptic drug (AED) serum level determinations. The resultant data confirmed the clinical and EEG effects of serial alterations in AED programs. All five became seizure free with combination therapy. Combination therapy with ethosuximide and valproate should be considered in patients whose absence seizures do not respond to standard therapeutic measures.

Adolescent↗

PubMed1978

Urinary metabolites of 2-ethyl-2-methylsuccinimide (ethosuximide) studied by combined gas chromatography mass spectrometry.

Metabolites of 2-ethyl-2-methylsuccinimide (ethosuximide) have been studied by combined gas chromatography mass spectrometry in a urine sample from a patient treated for petit mal epilepsy with ethosuximide. A new metabolite, 2-carboxymethyl-2-methylsuccinimide, was identified in the urine. It is presumably formed by omega 1-hydroxylation of the ethyl sidechain of the drug followed by a further oxidation of the primary alcohol to a carboxyl group. A previously identified metabolite, 2-ethyl-3-hydroxy-2-methylsuccinimide, was shown in the present study to yield two gas chromatographic peaks (as the N-methylated compound), indicating the existence of a diastereoisomeric pair. Thus, the enzyme responsible for the ring hydroxylation is probably not stereospecific, or alternatively two enzymes with different stereospecificity may exist.

Adolescent↗

PubMed1976

Ethosuximide dosage regimens.

A study was conducted in 9 children with petit mal epilepsy to compare the plasma levels of ethosuximide after divided daily administration with those after single daily administration. The children received their previously established dose in divided doses for 4 wk, single morning doses for 4 wk, and again in divided doses for 4 wk. None of the children suffered petit mal seizures during the study. Three had grand mal seizures but the frequency did not differ between the dosage regimens. Plasma levels during the single-dose period peaked more rapidly and fell more quickly than during the other periods, but mean levels remained in the therapeutic range. The mean half-life of the drug in these children was 29 hr. For reasons not understood, plasma levels generally were lower in the second divided dose period than in the other two periods. No adverse experiences were reported during the study. The data indicate that ethosuximide is clinically effective when given in a single daily dose. This regimen offers advantages in convenience and possibly in patient compliance.

Adolescent↗

PubMed1982

Rapid and simple GLC determination of valproic acid and ethosuximide in plasma of epileptic patients.

A GLC method for the determination of valproic acid and ethosuximide in plasma was developed. The procedure involved a single solvent extraction of drugs from acidified plasma samples, followed by a GLC injection of the unconcentrated organic phase. This rapid, sensitive, specific, and reproducible method has been used for 2 years for the routine determination of plasma levels of valproic acid and ethosuximide in epileptic patients who receive other antiepileptic drugs simultaneously.

Chromatography, Gas↗

PubMed1992

Ethosuximide and tremor in Parkinson's disease: a pilot study.

Following the demonstration of an anti-tremor effect of ethosuximide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model, we have tested the effect of this drug in 10 patients with typical parkinsonian tremor. Six patients suffered from Parkinson's disease with prominent, relatively drug-resistant rest tremor. The other four patients had a drug-induced parkinsonian tremor due to neuroleptic agents taken for a psychiatric condition. Five of the six parkinsonian patients and three of the four psychiatric patients reported within a few days a marked and intolerable exacerbation of their tremor. One patient in each group was improved, and this improvement was verified in repeated examinations. Thus, for unknown reasons, the effect of ethosuximide was not as predicted by the monkey model. Among possible explanations is the fact that we had chosen patients with drug-resistant tremor.

Adult↗

PubMed1992

Effect of ethosuximide on rest tremor in the MPTP monkey model.

Based on the hypothesis that low-threshold calcium conductance in the thalamus might be involved in the pathophysiology of parkinsonian tremor, ethosuximide was given chronically to a monkey previously treated with MPTP and displaying exceptionally a typical rest tremor. After 5 days of daily treatment, the tremor was reduced by 60%. Diltiazem and verapamil which act on different calcium channels had no such effect. Ethosuximide also potentiated the anti-tremor effect of the dopamine D2 agonist LY-171555.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Chronic effects of ethosuximide, phenytoin, clonazepam, and valproic acid on the delayed-matching-to-sample performance of pigeons.

Acute and chronic effects of ethosuximide (40, 80, and 120 mg/kg), phenytoin (2.5, 5, and 7.5 mg/kg), clonazepam (0.25, 0.5, and 0.75 mg/kg), and valproic acid (40, 80, and 120 mg/kg) were examined in pigeons performing under a delayed-matching-to-sample procedure. Acute administration of clonazepam or valproic acid produced generally dose-dependent decreases in accuracy; over 50 sessions of daily exposure, complete or nearly complete tolerance developed to the accuracy-reducing effects of these drugs. Whether administered acutely or chronically, ethosuximide and phenytoin failed to affect accuracy. When given acutely, all drugs typically reduced rate of responding to the sample stimulus. A degree of tolerance appeared to develop to the rate-decreasing effects of all of the drugs tested.

Animals↗

PubMed1990

Development of tolerance to the anticonvulsant effect of valproate but not to ethosuximide in a rat model of absence epilepsy.

Ethosuximide and valproic acid were tested for 4 and 2 weeks, respectively, in rats showing the spontaneous spike-wave syndrome. Ethosuximide suppressed the syndrome at plasma concentrations of 75-100 micrograms/ml. High doses of valproate (170 mg/kg i.p., t.i.d.), resulting in plasma concentrations of about 500 micrograms/ml, were necessary to suppress the syndrome, but signs of tolerance to the drug developed from day 5. Tolerance was confined to the number of spike-wave complexes, whereas the duration of the discharges was shortened to 60% of the control value, without there being signs of tolerance. It is assumed that increases in cerebral GABA, induced by the high concentration of valproate, counteracted the anti-absence effect of the drug in this model.

Animals↗

PubMed1990

Behavioral changes in juvenile rats after prenatal exposure to ethosuximide.

Juvenile rats 4-6 weeks old exposed prenatally at days 5-20 of gestation to ethosuximide at 10 mg/kg/dams' body weights per day were examined for behavioral abnormalities. Pinning behavior in the pups aged 4-5 weeks was significantly more frequent than that in age-matched controls. However, basal activity of open-field behavior and activity inhibited by diazepam administration in the pups aged 5-6 weeks showed no difference from the controls. The intensity of stereotyped behavior induced by apomorphine (1 mg/kg, SC) was significantly greater in the pups aged 5-6 weeks than in the controls. These results indicate that prenatal exposure to ethosuximide may cause changes in the dopaminergic neurons in the central nervous system.

Animals↗

PubMedDate not supplied

Effects of the combination of valproate and ethosuximide on spike wave discharges in WAG/Rij rats.

OBJECTIVE: We studied the interaction between valproate (VPA) and ethosuximide (ESM) in diminishing the incidence of absence-like spike-wave discharges (SWDs) in the EEG of WAG/Rij rats. METHODS: VPA, ESM, their combination and saline were evaluated in 16 rats. The doses of VPA ranged from 0 to 280 mg/kg and the doses of ESM ranged from 0 to 40 mg/kg. For the drug combination, a fixed weight ratio of 7/1 VPA/ESM was used. The incidence of SWDs in the EEG was determined for the period of 15-75 min after injection and compared to the incidence of SWDs prior to injection. The sigmoid-E(max) equation was fitted to the data. Isobolic analysis, on 50% effect, was used to assess the character of the drug interaction. RESULTS: The parameters for diminishing the incidence of the SWDs were: VPA: ED(50): 121mg/kg; ESM: ED(50): 21.5mg/kg; VPA/ESM: ED(50): 112/16 mg/kg. Isobolic analysis showed that a higher drug load was needed of the combination than of the individual drugs to achieve a 50% reduction of SWDs: factor 1.67; P = 0.012. CONCLUSION: The interaction between valproate and ethosuximide was shown to be infra-additive in diminishing the incidence of SWDs in WAG/Rij rats.

Action Potentials↗

PubMed2005

A systematic review of treatment of typical absence seizures in children and adolescents with ethosuximide, sodium valproate or lamotrigine.

PURPOSE: To evaluate the role of ethosuximide, sodium valproate and lamotrigine in children and adolescents with typical absence seizures (AS). METHODS: A systematic review of randomized controlled trials that included children or adolescents with typical absence seizures who received treatment with ethosuximide, sodium valproate or lamotrigine. RESULTS: Four RCTs fulfilled the inclusion criteria. Due to the heterogeneity of the studies the results could not be pooled in a meta-analysis. CONCLUSIONS: We found no reliable evidence to inform clinical practice. The design of further trials should be pragmatic and compare one drug with another.

Anticonvulsants↗

PubMed2001

Effects of ethosuximide, a T-type Ca(2+) channel blocker, on dorsal horn neuronal responses in rats.

Plasticity in transmission and modulatory systems are implicated in mechanisms of neuropathic pain. Studies demonstrate the importance of high voltage-activated Ca(2+) channels in pain transmission, but the role of low voltage-activated, T-type Ca(2+) channels in nociception has not been investigated. The Kim and Chung rodent model of neuropathy [Pain 50 (1992) 355] was used to induce mechanical and cold allodynia in the ipsilateral hindpaw. In vivo electrophysiological techniques were used to record the response of dorsal horn neurones to innocuous and noxious electrical and natural (mechanical and thermal) stimuli after spinal nerve ligation. Spinal ethosuximide (5-1055 microg) exerted dose-related inhibitions of both the electrically and low- and high-intensity mechanical and thermal evoked neuronal responses and its profile remained unaltered after neuropathy. Measures of spinal cord hyperexcitability were most susceptible to ethosuximide. This study, for the first time, indicates a possible role for low voltage-activated Ca(2+) channels in sensory transmission.

Action Potentials↗

PubMed2001

Repeated administration of CGP 46381, a gamma-aminobutyric acidB antagonist, and ethosuximide suppresses seizure-associated cyclic adenosine 3'5' monophosphate response element- and activator protein-1 DNA-binding activities in lethargic (lh/lh) mice.

To characterize seizure-associated increases in cerebral cortical and thalamic cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in lethargic (lh/lh) mice, a genetic model of absence seizures, we examined the effects of ethosuximide and CGP 46381 on these DNA-binding activities. Repeated administration (twice a day for 5 days) of ethosuximide (200 mg/kg) or CGP 46381 (60 mg/kg) attenuated both seizure behavior and the increased DNA-binding activities, and was more effective than a single administration of these drugs. These treatments did not affect either normal behavior or basal DNA-binding activities in non-epileptic control (+/+) mice. Gel supershift assays revealed that the increased CRE-binding activity was attributable to activation of the binding activity of CREB, and that the c-Fos-c-Jun complex was a component of the increased AP-1 DNA-binding activity.

Animals↗

PubMedDate not supplied

Differential neurochemical effects of chronic exposure of cerebral cortical cell culture to valproic acid, diazepam, or ethosuximide.

We have assessed the relative neurochemical effects of valproic acid, ethosuximide, and diazepam on dissociated cultures of mouse cerebral cortex. Cultures were exposed chronically (11 days) to each antiepileptic drug and assayed for number of neurons, total protein, tetanus toxin fixation, high-affinity uptake of gamma-aminobutyric acid and beta-alanine, choline acetyltransferase activity, and specific and clonazepam-displaceable benzodiazepine binding. Ethosuximide-exposed cultures did not evidence neuronal toxicity; exposure to valproic acid and diazepam resulted in modest neuronal toxicity. However, exposure to each of these drugs resulted in a marked reduction in benzodiazepine binding. This effect may relate to a common mechanism of action of drugs used to treat absence seizures.

Animals↗

PubMed2002

A sensitive gas chromatographic/mass spectrometric method for the resolution and quantification of ethosuximide enantiomers in biological fluids.

A modified specific, sensitive and reproducible chiral gas chromatographic (GC) method for the resolution and quantification of ethosuximide enantiomers in urine and plasma was developed. The samples were extracted by liquid-liquid extraction, using diethylether and the enantiomers were separated and quantified on a chiral gas chromatographic column (25QC2 / CYDEX- beta 0.25). The method involved the use of GC/MS instrumentation for the acquisition of data in the electron impact selective-ion monitoring mode, collecting ions characteristic of both ethosuximide and alpha, alpha - dimethyl - beta - methylsuccinimide, the internal standard and of mass-to-charge ratio (m/z) exactly equal to 55 and 70 units. The limit of quantitation of the method was 2.5 microg/ml for both urine and plasma with both enantiomers. The method proved to be linear, precise and reproducible in the 5-300 microg/ml concentration range for urine samples and in the 10-250 microg/ml concentration range for plasma samples. Future research work envisaged the application of this method in pharmacokinetic and pharmacodynamic studies.

Anticonvulsants↗