Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Ethosuximide”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1992

In vivo evidence that ethosuximide is a substrate for cytochrome P450IIIA.

The role of various subfamilies of rat hepatic cytochrome P450 in the oxidation of ethosuximide was evaluated by comparing ethosuximide clearance in control rats and those pretreated with relatively selective P450 inducers and/or inhibitors. Clotrimazole pretreatment increased ethosuximide clearance threefold (p less than 0.005). Dexamethasone increased ethosuximide clearance twofold (p less than 0.001), and the dexamethasone effect was completely abolished by a single dose of triacetyloleandomycin. These results suggest a prominent role for cytochrome P450IIIA in ethosuximide metabolism in the rat. Isoniazid increased ethosuximide clearance twofold (p less than 0.001), and this effect was abolished by a single dose of diallylsulfide, suggesting that ethosuximide is also processed by cytochrome P450IIE1 in rats. Phenobarbital pretreatment increased ethosuximide clearance 2-2.7 fold (p less than 0.001); an effect that was only partially reversed by orphenadrine, an inhibitor of cytochrome P450IIB/IIC enzymes. This suggests a quantitatively less important role for the IIB/IIC subfamilies in processing ethosuximide, since phenobarbital is an inducer of P450 subfamilies IIB, IIC, IIE, and IIIA. Neither the cytochrome P450IA inducer, beta-naphthoflavone, nor the inhibitor, alpha-naphthoflavone altered ethosuximide clearance. Ajmaline, an inhibitor of cytochrome P450IID, had no effect on ethosuximide clearance. Together, these findings suggest that ethosuximide is principally oxidized by cytochrome P450IIIA, and that cytochrome P450IIE may play an important role. Cytochromes P450IIB/C play less prominent roles in ethosuximide oxidation, and neither cytochrome P450IA nor cytochrome P450IID is involved.

Animals↗
PubMed1981

Hemodialysis clearance of ethosuximide in patients with chronic renal disease.

Clearance of ethosuximide by hemodialysis was studied. Four patients with chronic renal disease supported by hemodialysis were given ethosuximide 500 mg four hours before dialysis. Samples of arterial and venous blood and dialysate were collected before and during the four-hour dialysis procedure. Ethosuximide concentration was measured by gas-liquid chromatography. The extraction efficiency for the dialysis systems used in this study ranged from 61.1 to 100%, and dialysis clearance was from 122.3 to 156.3 ml/min. Recovery of ethosuximide from the dialysate was 38.8 to 52.4% of the administered dose. Hemodialysis reduced the elimination half-life of ethosuximide from a presumable value of 55 hours to an average of 3.5 hours. The authors concluded that ethosuximide is dialyzable. Hemodialysis patients concurrently receiving ethosuximide may require a supplemental dose or an altered ethosuximide dosing schedule. Because hemodialysis quickly clears ethosuximide, it may be useful in treating ethosuximide overdosage.

Adult↗
PubMed1995

Chiral aspects of the 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 urinary metabolites of ethosuximide (following i.p. administration of the racemate or individual enantiomers to rats) have been studied using chiral gas chromatography (GC) and gas chromatography-mass spectroscopy (GCMS). The metabolites identified were unchanged ethosuximide enantiomers, all four stereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide, and a single stereoisomer of 2-ethyl-3-hydroxy-2-methylsuccinimide [derived from (R)-ethosuximide]. Preliminary quantitative studies indicate a degree of stereoselectivity in the fate of ethosuximide since the ratio of (R)- to (S)-ethosuximide in the urine was found to be 0.77:1 (0-24 h sample), 0.64:1 (24-48 h sample), and 0.83:1 (48-72 h sample). This would suggest that the (R)-isomer is preferentially metabolised. Results obtained following the administration of individual enantiomers of ethosuximide indicate that the 2-(1-hydroxyethyl)-2-methylsuccinimide diastereoisomers derived from (R)-ethosuximide are produced in approximately equal proportions [ratio 1.05:1 (0-24 h sample), 1.10:1 (24-48 h sample)], whilst those from (S)-ethosuximide are produced in unequal proportions [ratio 1.65:1 (0-24 h sample), 1.74:1 (24-48 h sample)].

Animals↗
PubMed1993

Ethosuximide suppresses seizures and lethality induced by picrotoxin in developing rats.

The action of ethosuximide (125 or 250 mg/kg, IP) against picrotoxin-induced seizures (3-6 mg/kg, IP) was assessed in rats 12, 18, 25, and 90 days old. In 18-day-old and older controls, picrotoxin regularly elicited clonic seizures; tonic-clonic seizures were induced in all age categories with high consequent mortality. Only the higher dose of ethosuximide (250 mg/kg) increased the latency of clonic seizures in 18- and 25-day-old pups. Tonic-clonic seizures were delayed by ethosuximide in 12-, 18-, and 90-day-old rats. Picrotoxin-induced lethality was suppressed only in 18- and 90-day-old rats by the 250-mg/kg dose of ethosuximide. In contrast, ethosuximide pretreatment increased the incidence of clonic seizures in 12-day-old rats. The results suggest that only high doses of ethosuximide can suppress clonic seizures, and this action is not consistent. Tonic-clonic seizures probably have model-specific sensitivity to ethosuximide because in previous studies ethosuximide completely suppressed pentylenetetrazol-induced tonic-clonic seizures but had no effect on kainic acid-induced tonic-clonic seizures. The suppression of mortality rates is probably due to nonspecific effects of high doses of ethosuximide.

Animals↗
PubMed1986

Effect of ethosuximide alone and in combination with gamma-aminobutyric acid receptor agonists on brain gamma-aminobutyric acid concentration, anticonvulsant activity and neurotoxicity in mice.

The acute administration of an anticonvulsant dose of ethosuximide (150 mg/kg) had no effect on brain gamma-aminobutyric acid (GABA) concentration, whereas a toxic dose (400 mg/kg) increased significantly the concentration of brain GABA (1.23 +/- 0.05 vs. 1.92 +/- 0.14 mumol/g of wet tissue). The administration of 500 mg/kg/day of ethosuximide for 1, 2, 4, 6, 8 and 11 days induced neurotoxicity in 100, 100, 67, 0, 0 and 0% of animals, respectively, and increased brain GABA concentration 46, 38, 25, 14, 9 and 0%, respectively. These results imply that the tolerance that develops in response to the chronic administration of toxic doses of ethosuximide correlates well with the concentration of brain GABA. 4,5,6,7-Tetrahydroisoxazolo [5,4-c]pyridin-3-ol even in toxic doses had no effect on the anticonvulsant activity of ethosuximide. Combination studies with ethosuximide and progabide demonstrated that the antipentylenetetrazol activity of the individual components interacts additively. Likewise, combinations of either ethosuximide and 4,5,6-tetrahydroisoxazolo [5,4-c]pyridin-3-ol or ethosuximide and progabide showed an additive effect by the rotorod test. These results indicate that the antipentylenetetrazol activity of ethosuximide is unrelated to GABA function and that the increase in brain GABA concentration induced by toxic doses of ethosuximide contributes to its neurotoxicity.

Animals↗
PubMed1975

Pharmacokinetic properties of ethosuximide in monkeys. I. Single-dose intravenous and oral administration.

The pharmacokinetic profile of ethosuximide was studied in 6 chronically catheterized male rhesus monkeys at three dose levels (30, 60, and 90 mg/kg), intravenously and orally. Plasma and urine levels were assayed by GLC. The intravenous and oral kinetics of ethosuximide were described in terms of a one-compartment open model with first-order elimination (and first-order absorption for oral kinetics). Volume of distribution (overall mean +/- SD=0.80 +/- 0.09 liters/kg), total body clearance (overall mean +/- SD= 19.2 +/- 2.70 ml/hr/kg) and elimination half-life (overall mean +/- SD=28.98+/-3.35 hr and 28.10+/-3.17 hr following intravenous and oral administration, respectively) remained constant over the dosage range Appendix) was selected to describe the disposition of ethosuximide in monkeys. Accordingly, plasma concentrations of individual animals and the average concentrations of Fig. 1 were fitted to a monoexponential equation [Eq. (A1)]. A close agreement between experimental datum points and least-squares fit lines was observed at all three dose levels. Plots of C0 and area under the plasma concentration-time curve [AUC, measured by trapezoidal rule, Eq. (A3)] vs dose (Fig. 4) were linear as predicted by Model I. It may be concluded, therefore, that a one-compartment open model with first-order elimination is appropriate to describe the intravenous kinetic behavior of ethosuximide in monkeys. The volume of distribution (overall mean +/- SD = 0.80 +/- 0.09 liters/kg) observed in the present study is higher than total body water and therefore suggests accumulation of ethosuximide in body tissues. Tissue distribution studies have not been performed in monkeys. However, data on tissue/plasma ratios in rats (Dill et al., 1965; Chang et al., 1972) indicate that ethosuximide can partition outside the total body water compartment. This behavior is compatible with the high pKa value and negligible protein-binding characteristics of ethosuximide (Chang et al., 1972). As discussed by several workers (Levy, 1968; DiSanto and Wagner, 1972; Lockard et al., 1974), the establishment of dose independency in elimination processes (kinetic linearity) requires that single-dose studies be performed at several dose levels. In the dose range examined in the present study (30 to 90 mg/kg), there was no evidence of dose-dependent elimination kinetics after intravenous or oral administration. The overall mean (+/- SD) elimination half-life (28.5 +/- 3.24 hr) obtained in the present study is somewhat longer than the value (22.0 hr) observed by Chang et al. (1972) following a single-dose (100 mg/kg) oral administration of ethosuximide in 4 rhesus monkeys. In view of the agreement between the predictions of Model I and experimental intravenous data, a one-compartment open model with first-order absorption and elimination processes (Model II, Appendix) was studied. The bioavailability of the syrup formulation used in the oral studies was essentially complete (overall mean +/- SD=96% +/- 12.0) and dose-independent...

Administration, Oral↗
PubMed1980

Kinetics of a carbamazepine-ethosuximide interaction.

Carbamazepine and ethosuximide are used together to treat epileptic mixed-seizure patterns. Since carbamazepine has been shown to induce drug-metabolizing enzyme(s) in the liver, it follows that carbamazepine may alter ethosuximide disposition. Six normal subjects took one 250-mg ethosuximide capsule twice each day for 55 consecutive doses (study days 1 to 28) and one 200-mg carbamazepine tablet each evening from study days 11 to 27. Plasma samples were collected on study days 10, 17, 21, and 28. Mean steady-state concentrations of ethosuximide declined by 17% from a preinduction (study day 10) level of 32.2 +/- 5.6 micrograms/ml to a postinduction level of 26.8 +/- 5.2 micrograms/ml on study day 28. Ethosuximide clearance increased (alpha = 0.05) between study days 10 and 28 from 0.664 +/- 0.120 to 0.800 +/- 0.0154 l/hr. The time course of induction was analyzed using a kinetic induction theory. Ethosuximide half-life was lowered from mean - 53.7 +/- 11.5 hr (before induction) to mean = 44.6 +/- 10.7 hr (after induction); the difference between some subjects was large. These data show that ethosuximide disposition is altered by carbamazepine.

Adult↗
PubMed1996

Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients.

1. To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine. 2. Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0 +/- 7.8 vs 53.7 +/- 14.3 h, means +/- s.d., P < 0.001) and higher apparent oral clearance (CL/F) values (15.3 +/- 3.8 vs 9.2 +/- 1.9 ml kg-1 h-1, P < 0.001). The apparent volume of distribution (V/F) of ethosuximide was slightly lower in the patients than in controls (0.6 +/- 0.1 vs 0.7 +/- 0.1 l kg-1, P < 0.05). 3. These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity. 4. The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.

Adult↗
PubMed1989

Ethosuximide affects both pentylenetetrazole- and kainate-induced clonic seizures but differentiates between tonic-clonic seizures.

Young (25-day-old) and adult (90-day-old) rats pretreated with ethosuximide (62.5 or 125 mg/kg i.p.) were injected with either s.c. pentylenetetrazole (100 mg/kg) or i.p. kainate (10 or 14 mg/kg). The incidences and latencies of minor (clonic) and major (tonic-clonic) seizures were registered. Ethosuximide (125 mg/kg) completely blocked clonic seizures induced by the lower dose of kainate, and slightly suppressed or delayed those induced by the higher dose of kainate or pentylenetetrazole in both age groups. The effect of ethosuximide on major kainate-induced seizures (elicited in young rats only) was insignificant (ethosuximide only partially decreased the incidence of major seizures), whereas ethosuximide abolished major pentylenetetrazole-induced seizures in both age groups. Ethosuximide also failed to affect the latencies of kainate-induced automatisms (e.g., scratching, wet dog shakes). Similarities between kainate- and pentylenetetrazole-induced clonic seizures, as well as a similar action of ethosuximide on both, suggest a common generator for the pattern of clonic seizures.

Animals↗
PubMedDate not supplied

Ethosuximide plasma concentrations: influence of age and associated concomitant therapy.

The relationship between oral dose and plasma concentration of ethosuximide was evaluated retrospectively in 198 epileptic patients aged 2.5 to 34 years. Age appears to be a major factor in determining the ethosuximide plasma level/dose (L/D) ratio. Children younger than 10 years had men L/D ratios significantly lower (p less than 0.0003) than adolescents (10 to 15 years of age) and adults (16 to 34 years of age). Associated antiepileptic therapy reduced the ethosuximide L/D ratio: mean ethosuximide L/D ratios were significantly lower in patients also taking primidone (p less than 0.0005) or valproic acid (p less than 0.02). The correlation between the dose of ethosuximide administered and the plasma concentration was significant in the 3 age groups considered (p less than 0.0004), but the wide scattering of individual plasma concentrations makes it impossible to predict what plasma concentration of ethosuximide will be obtained after a given dose. For this reason, routine monitoring of ethosuximide plasma concentrations still appears to be necessary, especially in children and patients on polytherapy.

Administration, Oral↗
PubMed1987

Discriminative stimulus properties of ethosuximide in the pigeon.

After initial exposure to 80 mg/kg, pigeons trained on a two-key drug discrimination procedure rapidly learned to discriminate 120 mg/kg ethosuximide from saline. When 40-160 mg/kg doses of ethosuximide were administered during generalization tests, the percentage of responses directed to the ethosuximide-appropriate key varied directly with dose. Time-effect determinations revealed that the discriminable properties of ethosuximide were evident as early as 15 min after, and as late as 2 h after, intramuscular injection. The discriminative stimulus properties of ethosuximide failed to generalize to the anticonvulsant compounds clonazepam (0.5-4 mg/kg), methsuximide (25-200 mg/kg), and phenytoin (5-15 mg/kg). Generalization was apparent with certain doses of primidone (250, 300 mg/kg) and mephenytoin (80, 160, 240 mg/kg). The concomitant administration of pentylenetetrazol (5, 10, 20 mg/kg) partially blocked the discriminable properties of the training dose of ethosuximide.

Animals↗
PubMed1975

Ethosuximide in the treatment of absence (peptit mal) seizures.

Thirty-seven patients with previously untreated absence seizures were treated with ethosuximide. Seizures were completely controlled in 7 patients (19 percent); 90 to 100 percent control was achieved in 18 patients (49 percent) and 50 to 100 percent control in 35 (95 percent). Plasma ethosuximide concentration increased with dose, but variability in the plasma concentration produced by a given ethosuximide dose made it impossible to predict a patient's plasma concentration from the dose. The therapeutic range of plasma ethosuximide concentration was 40 to 100 mug per milliliter. Patients with evidence of structural central nervous system abnormalities responded as well or better to the drug as patients without such evidence. Ethosuximide did not impair psychometric performance, but rather resulted in improved performance in 17 cases. The side effects of ethosuximide were minor, and rarely required withdrawal of the drug.

Adolescent↗
PubMedDate not supplied

[A pharmacological analysis of the mechanism of action of ethosuximide].

Ethosuximide is one of the means of treatment of minor epilepsy but hardly any data on its mechanism of action are available in the literature. Anticonvulsant agents are known to bring about changes in the functions and in the interaction between some of the mediator systems within the central nervous system. An assessment of the status of neuromediator systems can be made on the basis of the response of isolated smooth muscle strips to the action of agonists and antagonists of various receptors. It was found by the pharmacological analysis of isolated strips from the rat stomach (antrum and corpus strips), the seminal duct and the cervical vein that ethosuximide induces a reduction in the physical contractile activity and the tone of smooth muscle preparations. Smooth muscle relaxation caused by ethosuximide is not blocked by different receptor inhibitors such as dihydroergotamine, propranolol, atropine, chlorpromazine, haloperidod and indomethacin. Ethosuximide causes a significant reduction in the physical contraction of smooth muscles produced by potassium chloride depolarization, with a stronger impact on the subsequent tonic contraction caused by calcium ions. A reduction in the potassium content of the solution has no effect on the nature of the action of ethosutimide. It is thus assumed that the probable mechanism of action of ethosuximide consists in lowering calcium transport since the inhibitors of calcium transport sodium nitroprusside and verapamil intensify the blocking effect of ethosuximide on smooth muscle contractile activity.

Animals↗
PubMed1986

Behavioral toxicity of chronic ethosuximide and sodium valproate treatment in the epileptic baboon, Papio papio.

The purpose of this study was to assess the effects of chronic administration of gradually increasing doses of the anti-petit mal agents, ethosuximide (15-60 mg/kg/day) and valproic acid (7.5-240 mg/kg/day) on the performance of incremental repeated acquisition and incremental fixed-ratio tasks in the epileptic baboon, Papio papio. At approximately equipotent anticonvulsant doses, ethosuximide (45-60 mg/kg/day) was more behaviorally toxic than valproic acid (7.5-60 mg/kg/day), as determined by the ability of each drug to suppress the incremental repeated acquisition of behavioral chains. The behavioral deficits induced by ethosuximide (60 mg/kg/day) were still present 8 weeks after cessation of drug treatment in two of four animals. Evidence of enhanced acquisition of behavioral chains (decreases in errors) was noted in two of six animals during chronic treatment with valproic acid at a dose of 60 mg/kg/day but was never seen during chronic treatment with ethosuximide. Responding under an incremental fixed-ratio schedule of reinforcement was only affected minimally by either drug. These data suggest that 1) cognitive processes are more vulnerable to disruption by chronic ethosuximide administration than they are to chronic valproic acid administration, 2) performance under the more complex incremental repeated acquisition schedule is more sensitive to disruption than that under an incremental fixed-ratio schedule and 3) the effects of ethosuximide and valproic acid on performance under the incremental repeated acquisition schedule are not due to decreases in motivation or ability to manipulate the response levers.

Animals↗
PubMed1994

The ethosuximide-induced hyperpolarization of smooth muscle tissues--a cause of functional changes in the gastrointestinal tract of rats--is provoked by CA(2+)-dependent K(+)-efflux.

Ethosuximide is an antiepileptic drug successfully used in the treatment of petit mal especially in childhood. Clinical investigations reveal that ethosuximide has a number of adverse side effects on the gastrointestinal tract (GIT) of patients which may include heaviness, anorexia, pains in the region of the stomach, accompanied sometimes with nausea and vomiting. In the present study we attempt to explain the mechanisms of some of the drug's adverse side effects using an experimental animal model. White rats were employed in the experiments during which they were treated daily with ethosuximide (100 mg/kg) for 100 days. We made use of the following methods in the study: 1. Contrast X-rays study of the gastrointestinal tract. 2. Recording of the bioelectric activity of isolated smooth muscle strips using the sucrose-gap method. 3. Recording of the contractile activity of isolated smooth muscle. Characteristic changes occurring after treatment of rats with ethosuximide include atony of the stomach and the intestines, hypertonus in separate duodenal segments, diminished peristaltic activity, and delayed passage at the 24th hour. The drug inhibits the spontaneous contractile activity of isolated smooth muscle strips from rat gastrointestinal tract. In some duodenal preparations is minimised in the presence of apamin, an inhibitor of Ca2+(-dependent) K+ channels (Ka+(Ca)), while in duodenal preparations this effect may undergo a reversion. In the presence of coffeine the action of ethosuximide on the smooth musculature of rat gastrointestinal tract is reduced significantly. We hypothesis that the observed functional changes in the gastrointestinal tract occur as a result of the hyperpolarizing effect of ethosuximide on the gastrointestinal musculature caused by the outcoming K+(CA)-efflux.

Administration, Oral↗
PubMed1995

Effects of ethosuximide on the cerebral vasculature and hemodynamics of rats.

The development of epileptogenic activity has been proven to be closely related to changes in cerebral blood flow. This study was designed to examine the effects of ethosuximide, a widely used anticonvulsant drug, on cerebral hemodynamics. White Wistar rats were treated (p.o.) with 100 mg/kg b.w. ethosuximide. Three hours after administration, changes in cerebral blood flow due to vasodilation were recorded by means of angiography. Using the single sucrose gap method it was found that ethosuximide caused hyperpolarization of smooth muscle sample from rat internal carotid artery by 5.4 +/- 1.6 mV. The hyperpolarization was related to relaxation of smooth muscle tissue of vessels, which was recorded isometrically. Ethosuximide significantly depressed vascular reactions to the vasoconstrictive agents noradrenaline and serotonin. Ethosuximide-induced reaction was not significantly influenced by the Ca2+ antagonist verapamil, but was reduced by caffeine (10(-4) M) and apamine (5.10(-6) M), the latter being a blocker of Ca2+ -dependent K+ channels. The experimental data strongly suggest that changes in bioelectric and contractile activity of arterial smooth muscle samples are a result of Ca2+ -dependent K+ efflux, provoked by calcium which has been derived from intracellular Ca2+ store. These results show that ethosuximide-induced changes in cerebral blood flow are caused by reduced reactivity of smooth muscle tissue and vascular dilatation.

Animals↗
PubMed1998

Ethosuximide is primarily metabolized by CYP3A when incubated with isolated rat liver microsomes.

The cytochrome P450 (CYP) subfamily responsible for ethosuximide metabolism was investigated by HPLC assay of ethosuximide incubations with isolated rat liver microsomes from control rats and from rats treated with inducing agents to enrich hepatic microsomes in selected CYP isoforms. Inducing agents included beta-naphthoflavone (BNF, CYP1A inducer), phenobarbital (PB, CYP2B/2C/3A), isoniazid (INH, CYP2E1), clotrimazole (CTZ, CYP3A), clofibrate (CLO, CYP4A), and an imidazole CTZ-analog known as CDD3543 (CYP3A). Incubations with BNF, INH, CTZ, and control microsomes showed significantly (p<0.05) more metabolite produced by CTZ microsomes vs. BNF, INH, and control microsomes at 10, 30, 60, and 120 min incubation. Ethosuximide metabolite levels generated by CTZ microsomes at 120 min were 36.5 times those of control microsomes. Correspondingly, ethosuximide concentrations were significantly (p<0.05) lower for incubations with the CTZ microsomes compared with BNF, INH, and control microsomes at 60 and 120 min. Sixty-minute incubations with all microsome groups exhibited significantly (p<0.05) higher metabolite formation rates (nmol/nmol CYP/min) for CTZ (11.8x control) and PB (9.6x control) microsomes vs. all other groups. Antibody inhibition experiments demonstrated ethosuximide metabolite levels for PB microsomes were not affected by CYP2B1 antibodies, whereas CYP3A2 antibodies reduced metabolite levels for both PB and CTZ microsomes by over 80%. These results indicate CYP3A is primarily responsible for ethosuximide metabolism in rats.

Animals↗
PubMed1989

Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons.

The mechanism by which ethosuximide reduces thalamic low-threshold calcium current (LTCC) was analyzed using voltage-clamp techniques in acutely isolated ventrobasal complex neurons from rats and guinea pigs. The ethosuximide-induced reduction of LTCC was voltage dependent: it was most pronounced at more-hyperpolarized potentials and did not affect the time course of activation or inactivation of the current. Ethosuximide reduced LTCC without altering the voltage dependence of steady-state inactivation or the time course of recovery from inactivation. Dimethadione reduced LTCC by a similar mechanism, while valproic acid had no effect on LTCC. We conclude that ethosuximide reduction of LTCC in thalamic neurons is consistent with a reduction in the number of available LTCC channels or in the single LTCC channel conductance, perhaps indicating a direct channel-blocking action of this drug. Given the importance of LTCC in thalamic oscillatory behavior, a reduction in this current by ethosuximide would be a mechanism of action compatible with the known anticonvulsant effects of this drug in typical absence seizures.

Animals↗