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PubMed1999

Ethosuximide is effective in the treatment of epileptic negative myoclonus in childhood partial epilepsy.

The aim of our study was to evaluate the effectiveness of ethosuximide in the treatment of epileptic negative myoclonus, a motor disorder that can occur in childhood partial epilepsy. We introduced ethosuximide in nine patients with partial epilepsy of varying etiology (idiopathic, cryptogenic, symptomatic) who presented with epileptic negative myoclonus. The drug was added to the patients' preexisting antiepileptic drugs, which were maintained unchanged for the following 6 months. Epileptic negative myoclonus disappeared in all patients 15 to 30 days after ethosuximide was started. Plasma ethosuximide levels ranged from 55 to 89 micrograms/mL. The clinical response was not influenced by the patients' preexisting treatment or by the etiology of the epilepsy. No side effects were observed, and none of the patients presented a recurrence of epileptic negative myoclonus during follow-up. Furthermore, in five patients we observed the disappearance of partial seizures; in the remaining patients seizures were reduced by more than 75%. Electroencephalograms showed a decrement or disappearance of focal paroxysmal abnormalities. Our results suggest that ethosuximide is effective in the treatment of epileptic negative myoclonus and that it should be considered as a first-choice drug in the treatment of this motor disorder.

Adolescent↗

PubMed1988

Ethosuximide disposition kinetics in rats.

1. Single and multiple dose disposition kinetics of ethosuximide were studied in male Sprague-Dawley rats following intravenous administration. 2. The plasma disappearance of a single 35 mg/kg dose followed for 75 h was not linear. A dose-ranging study suggested that the apparent non-linearity of ethosuximide's plasma disappearance might be due to enzyme induction over time with the drug exhibiting a faster elimination from 24 h onward. 3. Ethosuximide, after only two daily doses of 35 mg/kg/day, shortened pentobarbital-induced sleep in rats. The clearance of ethosuximide was also significantly faster after four daily 35 mg/kg doses than after a single 35 mg/kg dose. 4. Single sample clearance estimates calculated from ethosuximide concentrations prior to enzyme induction, viz. up to 24 h post-dose, were practically identical to multiple sample clearance values. Both single and multiple sample clearances were calculated assuming linear rather than non-linear elimination.

Animals↗

PubMed1998

Ethosuximide inducted changes in the gastro-intestinal tract.

Ethosuximide is an alternative medicament that is used for coupling of petit mal, especially in childhood. Some clinical observations show that it has secondary effects on the gastro intestinal tract (GIT). The present research tries to define the characteristics of Ethosuximide--the inducted secondary effects on the GIT, and to explain some of the possible mechanisms that cause them. The changes that occur in the GIT of patients cured with Ethosuximide are registered roentgenologically. The main change is the atony of the stomach and intestines and the reduced peristaltic activity. The influence of Ethosuximide is examined on smooth muscular samples of human stomach, taken in vitro using stomach resection. The medicament authoritatively reduce the spontaneous bioelectrical activity of the smooth muscular tissue, influences mainly it's components that have Ca+ nature. Together with that is indicated relaxation of the smooth muscular samples. In that research is expressed the thesis that this Ethosuximide reduction of the Ca(+)-influx in the smooth muscular cells and the related relaxation probably are one of the main reasons of the secondary effects on the GIT.

Adolescent↗

PubMed1986

Single sample estimate of ethosuximide clearance.

Ethosuximide was administered in single oral doses (ca. 15 mg/kg) to each of 12 healthy, male subjects. Serial blood and salivary ethosuximide concentrations were measured by a polarization immunofluorescence technique. The following parameters were estimated: CL/F, V/F, and plasma disappearance t1/2. Mean (+/- SD) values were 0.0091 (+/- 0.0023) l X h-1 X kg-1, 0.063 (+/- 0.12) l X kg-1, and 48.8 (+/- 9.3) h, respectively. Estimates of CL/F (CL/F) were calculated from single plasma or single salivary measurements. When V/F was set at 0.63 l X kg-1 and the 120-h plasma concentration was used, CL/F was 0.0091 (+/- .0018) l X h-1 X kg-1. CL/F was 0.0089 (+/- .0020) when the 120-h salivary concentration was used. These data demonstrate that under specified conditions ethosuximide clearance (CL/F) can be estimated from a single measurement of ethosuximide in either plasma or saliva, thereby permitting ethosuximide to be used safely and noninvasively as a probe of hepatic mixed function oxidase activity in humans.

Adult↗

PubMed1980

Valproic acid and ethosuximide interaction.

The addition of valproic acid to ethosuximide in treatment to prevent seizures caused increased serum concentration of ethosuximide in four of five patients observed. Ethosuximide levels increased from 73 to 112 microgram/ml (53% higher), with concomitant toxicity. Both were reversed by reduction of the ethosuximide dose from 27.4 to 20.4 mg/kg. Serum concentrations of these two drugs should be monitored closely when they are given together.

Adolescent↗

PubMed2005

Chiral aspects of the human metabolism of ethosuximide.

Ethosuximide is a chiral drug substance primarily indicated for the treatment of absence seizures. This drug is used clinically as the racemate. The human urinary metabolites of ethosuximide (I) have been studied using chiral gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). The metabolites identified were the previously reported unchanged ethosuximide (I) enantiomers, all four stereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide (II), and the four stereoisomers of 2-ethyl-3-hydroxy-2-methylsuccinimide (III). Through chemical derivatization methodology and GC/MS (using electron impact ionization [EI] and chemical ionization [CI] techniques) two enantiomers of a previously unreported metabolite of ethosuximide, 2-ethyl-2-hydroxymethylsuccinimide (VI), have been identified.

Anticonvulsants↗

PubMed1975

The effect of phenytoin and ethosuximide on primidone metabolism in patients with epilepsy.

Little is known about the influence of phenytoin and ethosuximide on primidone. Therefore we studied three groups of patients: 28 receiving primidone alone, 16 on comedication of primidone with phenytoin and 9 on primidone plus ethosuximide. Antiepileptic drug determinations were done with Kupferberg's gas chromatographic method. The results show that the addition of phenytoin--but not ethosuximide--does increase the plasma concentration of phenobarbital derived from primidone but not of primidone itself. The phenobarbital/primidone plasma concentration ratio is with 4.2 +/- 0.7 (+/- S.E.) significantly (P less than 0.001) higher in patients receiving primidone and phenytoin as compared to those on primidone alone (1.6 +/- 0.2) or together with ethosuximide (1.4 +/- 0.7). The effect of phenytoin occurs and persists for several days after the steady state plasma concentration of phenytoin has been reached. This effect is probably not due to induction of enzymes hydroxylating primidone but rather to inhibition of the metabolism and/or excretion of phenobarbital. A case of phenobarbital intoxication due to addition of phenytoin to primidone medication is described in detail.

Drug Interactions↗

PubMed1985

Effects of valproic acid and ethosuximide on the responding of pigeons maintained under a multiple fixed-ratio fixed-interval schedule of food delivery.

The effects of valproic acid and ethosuximide were examined in pigeons responding under a multiple Fixed-Ratio 50 Fixed-Interval 90-sec schedule of food delivery. When given acutely 30 min prior to behavioral testing, both valproic acid (40, 60, 80, 100, and 120 mg/kg) and ethosuximide (40, 60, 80, 100, and 120 mg/kg) produced generally dose-dependent decreases in responding under both the Fixed-Ratio and Fixed-Interval components. Detailed analysis of drug effects on the temporal distribution of responding under the Fixed-Interval failed to reveal rate-dependent effects for either drug. Varying the presession injection interval from 15 to 120 min indicated that both valproic acid and ethosuximide reduced responding to the greatest extent when given 30 or 60 min before behavioral testing. These results indicate that the anticonvulsants valproic acid and ethosuximide similarly affect schedule-controlled responding, although previous studies have revealed the drugs to have different effects under other procedures.

Animals↗

PubMed1989

Pentylenetetrazol-induced seizures in pigeons and the effects of ethosuximide thereon.

Previous research has shown that ethosuximide in high enough doses disrupts operant responding in pigeons. Whether or not these same doses protect against seizure activity in this species has not been determined. In the present study a system for scoring pentylenetetrazol-induced seizures in pigeons was developed and the effects of ethosuximide on such seizures were evaluated. Pentylenetetrazol at 15, 27 and 47 mg/kg reliably induced seizures in Experiment 1. In Experiment 2 six doses of ethosuximide were tested for their seizure-controlling effectiveness. Doses of 20, 40, 80, 160 and 320 mg/kg ethosuximide had little effect on seizures induced by 27 mg/kg pentylenetetrazol; 640 mg/kg significantly reduced but did not completely eliminate seizures. This dose (640 mg/kg) is several times higher than the doses found to disrupt operant behavior in our previous studies.

Animals↗

PubMed1994

Valproic acid and ethosuximide slow the onset of maximal dentate activation in the rat hippocampus.

Valproic acid and ethosuximide are commonly used to treat absence seizures, but their mechanisms of action have not been clearly defined. This is partly due to testing in different experimental models and different species. We re-examined the effect of valproic acid and ethosuximide in an experimental model of reverberatory seizures in the hippocampus of the urethane-anesthetized rat, maximal dentate activation. Valproic acid, at 450 and 600 mg/kg i.p., caused an increase in the time to onset of seizure discharges, but only the changes with 600 mg/kg reached statistical significance. Both doses of valproic acid shortened the seizure duration. Serum levels of valproic acid were determined and it appears that in this system at least 200-400 micrograms/ml are needed to produce an effect on seizure onset and duration. Ethosuximide, at 600 mg/kg i.p., delayed the onset of the seizure discharge and blocked the increase in seizure duration. Both ethosuximide and valproic acid delayed the onset of the seizure discharge in this model suggesting that these drugs may help to determine the mechanisms behind seizure initiation in the hippocampal-parahippocampal circuits.

Animals↗

PubMed1996

Anticonvulsant drug effects on spontaneous thalamocortical rhythms in vitro: ethosuximide, trimethadione, and dimethadione.

Spontaneous generalized epileptiform discharges were elicited in rodent thalamocortical slices by perfusion with a medium containing no added Mg2+. In multiple-channel extracellular field potential recordings in thalamus and cortex, several distinct types of discharges were recorded, with two principal variants bearing marked similarity to spike-wave and generalized tonic-clonic seizure discharges recorded in patients with generalized seizure disorders. These discharges were termed sTBCs and cTBCs, respectively, for simple and complex thalamocortical burst complexes. The sensitivity of these discharges to the generalized absence anticonvulsants ethosuximide, trimethadione and dimethadione (the active metabolite of trimethadione) was studied. sTBCs were reduced or blocked by ethosuximide and dimethadione, when these drugs were applied in clinically relevant concentrations. The order of effectiveness of these agents was dimethadione > or = ethosuximide >> trimethadione. This paralleled the relative efficacy of these drugs in blocking T current in thalamic neurons. cTBCs were unaffected or exacerbated by these drugs. Structural control drugs including succinimide, the behaviorally inactive ring base of ethosuximide, and alpha, alpha-dimethyl-beta-methylsuccinimide, a convulsant succinimide, were inactive or exacerbated either sTBCs or cTBCs, respectively. These spontaneous generalized thalamocortical discharges in rodent thalamocortical slices may represent a potentially valuable in vitro model of generalized seizure discharges, with marked pharmacological and physiological similarities to various forms of clinical epileptic seizure activity.

Animals↗

PubMed2004

Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy.

Paclitaxel (Taxol) is one of the most effective and frequently used chemotherapeutics for the treatment of solid tumours. However, paclitaxel produces peripheral neurotoxicity with patients reporting sensory abnormalities and neuropathic pain during and often persisting after paclitaxel therapy. The mechanisms underlying this dose-limiting side effect are currently unknown and there are no validated drugs for its prevention or control. Male Sprague-Dawley rats received four intraperitoneal (i.p.) injections on alternate days of 2 mg/kg paclitaxel. Behavioural assessment using von Frey filaments and acetone showed that such paclitaxel treatment induced a pronounced mechanical and cold allodynia/hyperalgesia. Thus these studies aim to test potential analgesics on established paclitaxel-induced pain. Paclitaxel-induced pain appears to be relatively resistant to opioid therapy i.p. 4 mg/kg morphine was ineffective and i.p. 8 mg/kg morphine only elicited up to a 50% reversal of mechanical allodynia/hyperalgesia. Interestingly, a maximally tolerated dose (i.p. 0.2 mg/kg) of the potent NMDA receptor antagonist MK-801 produced no significant reversal of the mechanical allodynia/hyperalgesia suggesting that NMDA receptors have little role in paclitaxel-induced pain. Ethosuximide (i.p. 450 mg/kg) an anti-epileptic and relatively selective T-type calcium channel blocker elicited a near complete reversal of mechanical allodynia/hyperalgesia. Repetitive dosing with ethosuximide (i.p. 100 or 300 mg/kg daily for 3 days) showed a dose-related consistent reversal of mechanical allodynia/hyperalgesia with no evidence of tolerance. Ethosuximide (i.p. 300 mg/kg) also reversed paclitaxel-induced cold allodynia and vincristine-induced mechanical allodynia/hyperalgesia. These data suggest that T-type calcium channels may play a role in chemotherapy-induced neuropathy and moreover identify ethosuximide as a new potential treatment for chemotherapy-induced pain.

Animals↗

PubMed1999

N(G)-nitro-L-arginine impairs the anticonvulsive action of ethosuximide against pentylenetetrazol.

N(G)-nitro-L-arginine (NNA; an inhibitor of nitric oxide synthase) in a dose of 40 mg/kg impaired the protective activity of ethosuximide against the clonic phase of pentylenetetrazol-induced seizures in mice. The ED50 value of ethosuximide was significantly increased from 108 to 158 mg/kg. NNA (40 mg/kg) was ineffective against the protective effects of diazepam, phenobarbital and valproate against pentylenetetrazol-induced seizures. NNA (40 mg/kg) did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction is not probable. L-Arginine (500 mg/kg) prevented the NNA-induced reduction of the anticonvulsive activity of ethosuximide. It can be concluded that nitric oxide participates in the expression of the anticonvulsive action of ethosuximide, but not that of diazepam, phenobarbital and valproate, against pentylenetetrazol-induced seizures.

Animals↗

PubMed2003

Ethosuximide induced agranulocytosis.

Agranulocytosis caused by ethosuximide is extremely rare in children. Drug-induced agranulocytosis is an unexpected side effect of a drug, and delay in diagnosis of agranulocytosis can result in a fatal outcome. We experienced a case of a 16-month-old male infant with Down syndrome in whom fever appeared 16 days after the start of administration of ethosuximide and then severe pneumonia developed. Results of a blood test on admission showed a decreased leukocyte count of 1700/microl, and a hemogram showed that there were no granulocytes. The erythrocyte and thrombocyte counts were within normal ranges. The results of a bone marrow aspiration test showed that there was no production of any types of granulocytes. The patient required mechanical ventilation due to deterioration in his pneumonia and complication with disseminated intravascular coagulation, but the neutrophilic leukocytes began to increase from the 8th day after discontinuation of ethosuximide administration and start of treatment with granulocyte colony-stimulating factor, and the patient survived. The mechanism of onset in this case is thought to have been immunologic. Careful attention should be given to this type of agranulocytosis because of its sudden onset at 1-2 weeks after the start of administration of the causal drug. A drug-induced lymphocyte stimulation test was useful for diagnosis in this case, showing a positive reaction only for ethosuximide.

Agranulocytosis↗

PubMed2003

Thermal and rheological study of lipophilic ethosuximide suppositories.

We have performed thermal (differential scanning calorimetry) and rheological studies in the preformulation phase of ethosuximide suppositories to determine the influence of the active ingredient and adjuvants on the melting characteristics and rheological performance of the suppositories. Both types of studies were performed on the fatty bases witepsol H-19 and suppocire AP, each mixed with 5% w/w polysorbate 80, 0.1% w/w docusate sodium and 3% w/w tetranyl AT-1/DP and on the suppository formulations obtained by the addition of 150 mg of ethosuximide to these excipients. Pure lipophilic excipients have two peaks in the DSC curve. The first one occurs at lower temperatures (27.35 degrees C for the suppocire AP and 34.3 degrees C for the witepsol H19) and the second peak at higher temperatures (36.27 and 35.95 degrees C for the suppocire AP and witepsol H19, respectively). Polysorbate 80, docusate sodium and tetranyl AT-1/DP cause the first melting peak to disappear and the second peak to occur at a lower temperature. The thermograms of the formulas show two melting peaks and the endothermic peak does not appear due to the melting of ethosuximide (47.8 degrees C). We attribute this behavior to the solubility of the drug in the melted excipient, thus originating a decrease of the melting temperature of the second peak in the DSC scan. The excipients and formulations behave as Newtonian fluids and the influence of ethosuximide and adjuvants can be noted in an increase in the viscosity of the suppository mass.

Calorimetry, Differential Scanning↗

PubMed1981

Ethosuximide in human milk and in plasma of a mother and her nursed infant.

1 The concentrations of ethosuximide were measured in the milk and in the plasma of a nursing mother and her infant during a period of 4.5 months after delivery. 2 The maternal and the infant's plasma concentrations rose after delivery. 3 The milk concentration ethosuximide was similar to that in maternal plasma on the third day after delivery. During the following 2 months the average milk/maternal plasma concentration ratio was 0.80. The rise in ethosuximide concentration in milk during the first month was steeper than that in infant's plasma, which may be due to an increase in the infant's clearance of the drug. 4 Even if the infant has subtherapeutic plasma concentrations it is recommended to control the levels in infants that are nursed by ethosuximide-treated mothers when nursing has been established.

Adult↗

PubMed2005

Neostigmine, but not metoclopramide, abolishes ethosuximide-induced functional gastrointestinal disturbances.

Ethosuximide is a drug used for the treatment of absence seizures. Its prolonged application leads to gastrointestinal (GI) disturbances. The purpose of the present study was to determine the severity and nature of the disturbances, as well as the influence exerted upon them by neostigmine methylsulfate and metoclopramide. The drug-induced alterations, occurring in the rat GI tract, were registered by X-ray contrast examination. In vitro experiments were carried out on isolated GI smooth muscle (SM) preparations. The latter revealed that the drug hyperpolarized the SM tissues and inhibited their contractile activity. X-rays of ethosuximide-treated rats showed GI hypotonia, disturbed peristalsis and decreased evacuation activity. The inhibition of the GI functions was associated with hyperpolarization of SM and a reduction in Ca(2+) influx, ensuring spontaneous contractile activity. The application of neostigmine methylsulfate significantly removed ethosuximide-induced functional GI disturbances in rats treated for 15 days with ethosuximide.

Animals↗

PubMed1975

Response of generalized penicillin epilepsy in the cat to ethosuximide and diphenylhydantoin.

The effects of ethosuximide and diphenylhydantoin sodium on feline generalized penicillin epilepsy, a model of human generalized corticoreticular (centreccephalic) epilepsy, were significantly reduced following administration of ethosuximide with plasma levels of 60 mug per milliliter, and there was a linear correlation between the plasma level and antiephilepileptic effect (p less than 0.01). Diphenylhydantoin produced a lesser reduction in epileptic activity, and there was no correlation between the plasma level and effect. Four cats that received both drugs successively responded well to ethosuximide, while only two responded to diphenylhdantoin. The good response to ethosuximide is in accord with clinical experience in human generalized corticoreticular epilepsy.

Animals↗