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PubMed1979

Effects of valproate and ethosuximide on thalamocortical excitability.

Sodium valproate and ethosuximide are anticonvulsants employed in the treatment of petit mal epilepsy; both drugs are considered to be thalamically active. Valproate and ethosuximide both decreased the average evoked response following the second of two stimuli delivered to the ventrolateral thalamus at stimulus frequencies in the region of 3 Hz. Ethosuximide, but not valproate, enhanced the average evoked response at high stimulus frequencies an action shared with several convulsant treatments having different modes of action. The clinical effects of valproate and ethosuximide can be related to this differential modulation of thalamocortical excitability.

Animals↗

PubMedDate not supplied

Factors influencing plasma concentrations of ethosuximide.

The relation between steady-state plasma ethosuximide level and drug dose was studied in 46 patients. In this population, plasma drug levels were proportional to drug dose, expressed on a body weight basis. Age did not alter this relationship, but plasma levels increased more rapidly, relative to dose, in females than in males. Intake of methylphenobarbitone, but not intake of certain other anticonvulsants (phenytoin, phenobarbitone, primidone and carbamazepine) altered the relationship between plasma ethosuximide level and ethosuximide dose. In individual patients, successive dose increments of equal size produced progressively greater increases in steady-state plasma ethosuximide levels. This phenomenon has obvious therapeutic implications.

Adolescent↗

PubMed1976

Effects of ethosuximide upon psychomotor responses and electromyographic parameters of healthy individuals.

The purpose of this paper was to investigate the effects of anticonvulsant ethosuximide upon physiological parameters, psychomotor reactions and electromyographic criteria. Ethosuximide increased the reaction times to flashes and the choice reaction time in most subjects, often provoked a greater amount of errors during choice reactions and decreased the average heart frequency. The functional activation during the tasks was diminished. The EEG showed no marked qualitative or quantitative changes. Ethosuximide reduced the maximum conduction velocity of the motor nerve and changed the action potential duration but not the action potential shape. There is no exact parallelism between the increase in reaction time and decrease of nerve conduction velocity. The drug effect upon psychomotor reactions seems to be caused by reduction of vigilance and an inhibitory effect upon the individual's motor responsiveness. Like other anticonvulsants, ethosuximide may alter the electrical properties of all excitable membranes and, by this ubiquitous site of action, exerts the described effects.

Action Potentials↗

PubMed1990

[The effect of ethosuximide on epileptic after-discharges induced by thalamic stimulation in young laboratory rats].

An influence of ethosuximide on thalamically induced epileptic afterdischarges was studied in 47 rats aged 12 and 18 days. An afterdischarge formed by spike-and-wave rhythm was induced only in 18-day-old rats. It exhibited a tendency to progressive prolongation with repeated stimulations (with 15 min intervals). Ethosuximide in a dose of 125 mg/kg i.p. immediately after the first afterdischarge did not change the duration of subsequent afterdischarges. The second type of epileptic afterdischarge formed by spikes and/or serrated waves could be induced in both age groups studied. Ethosuximide even worsened the tendency to progression of epileptic afterdischarges in 12- as well as 18-day-old animals. Ethosuximide did not exhibit an anticonvulsant action against the spike-and-wave afterdischarge in 18-day-old rats. On the contrary, it aggravated the course of progressive changes with repeated stimulations in both age groups.

Aging↗

PubMed1977

Comparison of enzyme immunoassay and gas chromatography for determination of carbamazepine and ethosuximide in human serum.

Patients' sera were analyzed for carbamazepine and ethosuximide by enzyme immunoassay (x) and gas chromatography (y), and the results were compared. The correlation coefficients were: for carbamazepine, x vs. y 0.94 (n = 93); for ethosuximide, x vs. y 0.99 (n = 30). These results suggest that the two methods could be used interchangeably. Ten serum samples supplemented with carbamazepine (2.5 to 12.5 mg/liter) and ethosuximide (20.0 to 130.0 mg/liter) were analyzed by both methods. The correlation coefficients were: x vs. y 0.99 (n = 10) for carbamazepine and x vs. y 0.99 (n =10) for ethosuximide.

Carbamazepine↗

PubMed1986

Fluorescence polarization immunoassay for ethosuximide evaluated and compared with two other immunoassay techniques.

We evaluated a new fluorescence polarization immunoassay (FPIA) for ethosuximide in the Abbott TDx and compared results with those by two other ethosuximide immunoassays, EMIT (Syva Co.) and aca (DuPont). The FPIA assay produced within- and between-day CVs of less than 5% at the low, medium, and high ranges of the standard curve. For the ethosuximide FPIA assay the standard curve was stable during the 47 days of the study. By all three methods, we analyzed 100 serum and plasma samples from patients who were receiving ethosuximide. The coefficient of determination (r2) for TDx versus EMIT was 0.973 (slope, 0.96; intercept, -0.80); for TDx vs aca it was 0.985 (slope, 1.00; intercept, -2.44); both relationships were statistically significant (p less than 0.05). Values for patient's specimens were significantly lower by the TDx than by the aca or EMIT methods (p less than 0.05).

Ethosuximide↗

PubMed1979

Electron-capture gas-liquid chromatographic determination of ethosuximide and desmethylmethsuximide in plasma or serum.

We describe the determination of ethosuximide and desmethylmethsuximide, simultaneously or separately, in 50 to 100 microliter of plasma or serum. Derivatives of ethosuximide and desmethylmethsuximide formed by reaction with pentafluorobenzoyl chloride are extremely sensitive to the electron-capture detector of a gas-liquid chromatograph. The sample, with added internal standard and ammonium sulfate as a pH-adjusting and salting-out agent, is extracted with ethyl acetate/benzene (20/80 by vol). The extract is evaporated and the derivatives are formed. Analytical recoveries of ethosuximide and desmethylmethsuximide exceed 99%, and the relative standard deviation (CV) between analyses is usually less than 4.0%. alpha-Methyl-alpha-propylsuccinimide is used as the internal standard for ethosuximide, 2-phenylsuccinimide as the internal standard for desmethylmethsuximide.

Chromatography, Gas↗

PubMed1980

Differential effects of the anticonvulsants phenobarbital, ethosuximide and carbamazepine on neuromuscular transmission.

The actions of the anticonvulsants phenobarbital, ethosuximide and carbamazepine were examined electrophysiologically at the frog neuromuscular junction. Phenobarbital reduced miniature end-plate potential (MEPP) amplitude, did not significantly affect end-plate potential amplitude and increased quantal content. Ethosuximide decreased MEPP and end-plate potential amplitudes proportionally; quantal content was unchanged. Carbamazepine decreased end-plate potential amplitude more than MEPP amplitude; quantal content was decreased. In a solution containing elevated (7.5 mM) K+, phenobarbital and carbamazepine increased MEPP frequency, whereas ethosuximide had no effect. Carbamazepine had to be dissolved in a solvent, propylene glycol, which was shown to produce small, but sometimes statistically significant, alterations in the measured parameters of neuromuscular transmission. The results show that all three of these anticonvulsants depress postjunctional sensitivity to released acetylcholine producing parallel dose-response curves for MEPP amplitude inhibition. These experiments also show that these drugs exhibit different mechanisms of action with respect to nerve-stimulated neurotransmitter release from nerve terminals at the neuromuscular junction: phenobarbital enhances acetylcholine release, ethosuximide has no effect and carbamazepine decreases transmitter release.

Acetylcholine↗

PubMed1978

Exacerbation generalized nonconvulsive seizures with ethosuximide therapy.

We describe a patient whose absence seizures increased greatly in number after the addition of ethosuximide to ongoing phenobarbital therapy. This unusual response and review of other cases in the literature suggested the possibility of some as yet underfined interaction between ethosuximide and other anticonvulsant drugs. That a particular subytpe of epilepsy may be worsened by ethosuximide therapy is also considered.

Child↗

PubMed1986

Effects of clonazepam and ethosuximide on the responding of pigeons under a fixed-consecutive-number schedule with and without an external discriminative stimulus.

The effects of the anticonvulsant drugs clonazepam and ethosuximide were examined in pigeons performing under a fixed-consecutive-number schedule with and without an added external discriminative stimulus. Under these schedules, food was delivered whenever subjects responded between and 8 and 12 times on one response key (work key), and then responded once on a second response key (reinforcement key). For one group, an external discriminative stimulus signalled completion of the response requirement on the work key, while no stimulus change was programmed for the other group. Clonazepam (0.06-0.75 mg/kg) produced dose-dependent decreases in percentage of reinforced runs and rate of responding for both groups. The magnitude of the accuracy-decreasing effect was generally greater in the group without the external discriminative stimulus. For this group, the higher doses of clonazepam produced pronounced increases in switching to the reinforcement key before completing the minimum requirement of eight consecutive responses on the work key. No consistent patterns of errors were evident for the subjects with the added external discriminative stimulus. Although ethosuximide (20-160 mg/kg) produced dose-dependent decreases in rate of responding, it had little effect on the percentage of reinforced runs or the run length distributions. These findings are consistent with previous reports indicating that clonazepam, but not ethosuximide, substantially disrupts performance under operant tasks requiring conditional discriminations. These data also suggest that the addition of an external discrimination stimulus attenuates the disruptive behavioral effects of clonazepam.

Animals↗

PubMed1985

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

The effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin were examined in pigeons performing under a delayed matching-to-sample procedure. Clonazepam, valproic acid, ethosuximide, and phenytoin typically reduced the rate of responding to the sample stimulus, whereas phenobarbital usually increased response rates at high doses. Phenobarbital, clonazepam, and valproic acid produced generally dose-dependent decreases in accuracy; ethosuximide and phenytoin failed to do so. These results suggest that there are qualitative as well as quantitative differences in the effects of anticonvulsant drugs under the delayed matching-to-sample procedure.

Animals↗

PubMedDate not supplied

The metabolism of ethosuximide.

The metabolism of the antiepileptic drug ethosuximide (3-ethyl-3-methylpyrollidine-2,5-dione) (I) in animals and humans is reviewed. Chiral aspects of the metabolism of ethosuximide are discussed. Clarification of the precise nature of the hydroxymetabolites of ethosuximide is presented.

Animals↗

PubMed2002

Conventional anticonvulsant drugs in the guinea pig kindling model of partial seizures: effects of acute phenobarbital, valproate, and ethosuximide.

This study addressed the anticonvulsant effects of phenobarbital, valproate, and ethosuximide in the amygdala of kindled guinea pigs to further validate this model for the screening of anticonvulsant drugs. Behavioral toxic effects were assessed at 30 min following drug administration using quantitative locomotor tests, as well as scores on a sedation and muscle relaxation rating index. The anticonvulsant efficacy of the drugs were evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD), and behavioral seizure severity (SS) during early and late phases of kindling acquisition, and in kindled guinea pigs. ADD and SS were also measured in response to both threshold and suprathreshold kindling stimulation. All drugs exerted slight to moderate sedative effects in guinea pigs on both the behavioral tests and rating index. We found that phenobarbital exhibited effective anticonvulsant properties in guinea pigs by consistently reducing ADD and SS in response to both threshold and suprathreshold kindling stimulation. Valproate exhibited effective anticonvulsant properties at threshold stimulation and less effective properties at suprathreshold stimulation. Lastly, we found that ethosuximide lacked effective anticonvulsant action at either threshold or suprathreshold kindling stimulation. Our results indicate that the guinea pig kindling model correctly predicted the actions of phenobarbital, valproate, and ethosuximide in the treatment of partial seizures. Guinea pig amygdala kindling appears to serve as a useful and valid model for partial epilepsy.

Animals↗

PubMedDate not supplied

Once-daily ethosuximide in the treatment of absence epilepsy.

Once-daily ethosuximide was used to treat 10 consecutive children with typical absence seizures. Three patients had gastrointestinal side effects which resolved when the same total daily dose was divided into 2 doses. Two other patients continued to have seizures on ethosuximide, whether given once or twice daily. Five patients had complete seizure control without adverse effects on once-daily ethosuximide.

Adolescent↗

PubMed1991

The effect of carbamazepine and ethosuximide on hyperoxic seizures.

The main manifestations of CNS oxygen toxicity are generalized tonic-clonic seizures. We tested the protective effect of 2 antiepileptic drugs, carbamazepine and ethosuximide, which are commonly used for the treatment of generalized seizures, on hyperbaric oxygen-induced convulsions. Rats implanted with chronic cortical electrodes for continuous EEG monitoring were injected i.p. with either carbamazepine (5 doses in the range of 1.5-50 mg/kg), ethosuximide (400 mg/kg), or their vehicles (40% propylene glycol and saline, respectively). The rats were exposed to 5 ATA (0.5 MPa) oxygen. The duration of the latency until the appearance of electrical discharges in the EEG was used as an index of toxicity. Ethosuximide did not protect against hyperoxic seizures. In contrast, rats pretreated (30 min) with carbamazepine exhibited a dose-related protective effect against hyperoxically induced seizures. The results of our study suggest that carbamazepine should be considered for prevention of oxygen-induced seizures during hyperbaric oxygen therapy.

Animals↗

PubMed1996

Ethosuximide specifically antagonizes the effect of pentylenetetrazol in the rat entorhinal cortex.

This study tested two related hypotheses. The first is that the entorhinal cortex has an important role in synchronization and spread of epileptiform activity into the dentate gyrus. The second is that ethosuximide acts by antagonizing the action of pentylenetetrazol (PTZ) in the entorhinal cortex. Experiments were carried out in urethane anesthetized rats. Recording electrodes were placed in the dentate gyrus and stimulating electrodes were placed in the angular bundle. Administration of PTZ reduced the time to onset of maximal dentate activation, which is a marker for synchronized reverberatory seizure activity in the hippocampal-parahippocampal circuits. Since PTZ facilitates the spread of epileptiform activity in, or through, the entorhinal cortex, these results support the hypothesis that the entorhinal cortex can influence the spread of seizure activity from the entorhinal cortex into the hippocampus. Ethosuximide specifically, and dose-dependently, reduced the polysynaptic response in the dentate gyrus that is initiated by PTZ, while having no effect on the response in the dentate gyrus to ipsilateral angular bundle stimulation. These results support the hypotheses that ethosuximide can antagonize this effect of PTZ.

Animals↗

PubMed2004

Ethosuximide and valproate display high efficacy against lindane-induced seizures in mice.

Both lindane (gamma-hexachlorocyclohexane), an organochlorine ectoparasiticide and pentylenetetrazol, used as a model of experimental epilepsy, produce convulsive seizures resulting from the blockade of the gamma-aminobutyric acid (GABAA) receptor. In the present study we established the protective effects of ethosuximide and valproate against seizures induced by lindane and compared them with the well-known protective effects of these drugs against pentylenetetrazol-induced seizures in mice. Both ethosuximide and valproate afforded complete and dose-dependent protection against seizures induced by lindane. However, the potencies of these drugs were lower than those obtained against pentylenetetrazol seizures. Nevertheless, the protective efficacy of ethosuximide and valproate against experimentally induced lindane seizures may suggest possible efficacy of these drugs against seizures in lindane-poisoned patients.

Animals↗

PubMed1998

Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide.

Based on small numbers of patients, it is possible to make the following suggestions rather than categorical statements. For myoclonic seizures and epilepsies which are not otherwise specified, valproate seems of proven efficacy. Ethosuximide may be a useful adjunct. The exact place of lamotrigine, which controls some myoclonia and makes them worse in other patients, requires further study. The findings are clearer when specific syndromes are considered. Valproate is the treatment of first choice for benign myoclonic epilepsy in infants, myoclonic astatic epilepsy, epilepsy with myoclonic absences, eyelid myoclonia with absences, juvenile myoclonic epilepsy and progressive myoclonus epilepsy. The addition of ethosuximide to valproate can be helpful to those with myoclonic absences, where this combination appears more beneficial than either valproate or ethosuximide alone and in eyelid myoclonia with absences. Lamotrigine can be effective therapy for juvenile myoclonic epilepsy and eyelid myoclonia with absences when used alone and, in conjunction with other antiepileptic drugs (AED) (usually valproate) for early myoclonic encephalopathy, myoclonic-astatic epilepsy and particularly, epilepsy with myoclonic absences. The myoclonia of infantile neuronal ceroid lipofuscinosis respond to lamotrigine. Severe myoclonic epilepsy of infants usually worsens with lamotrigine, but occasionally, children improve. Zonisamide added to clonazepam and valproate or a barbiturate, can reduce the cascade of myoclonia in progressive myoclonus epilepsies for at least 2 years, but relapse may occur thereafter.

Anticonvulsants↗