Pharmacokinetics of Ethosuximide in the Dog

Sayed, El; Löscher, Wolfgang; Hh, Frey

doi:10.1007/978-3-662-39532-5_225

Cited by 15 publications

(15 citation statements)

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“…We evaluated whether SWDs returned in the ethanol-exposed mice treated with ETX, due to the rapid metabolism of ETX in mice (el Sayed, Löscher, & Frey, 1978), with anticipation that ETX effects would be transient. In a subset of animals, we prolonged the fourth withdrawal EEG recording to evaluate the number of events from 5:00–8:00 PM (“washout” period).…”

Section: Resultsmentioning

confidence: 99%

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Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

Riegle

Masicampo

Caulder

et al. 2014

Alcohol

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Chronic alcohol abuse depresses the nervous system and, upon cessation, rebound hyperexcitability can result in withdrawal seizure. Withdrawal symptoms, including seizures, may drive individuals to relapse, thus representing a significant barrier to recovery. Our lab previously identified an upregulation of the thalamic T-type calcium (T channel) isoform CaV3.2 as a potential contributor to the generation and propagation of seizures in a model of withdrawal. In the present study, we examined whether ethosuximide (ETX), a T-channel antagonist, could decrease the severity of ethanol withdrawal seizures by evaluating electrographical and behavioral correlates of seizure activity. DBA/2J mice were exposed to an intermittent ethanol exposure paradigm. Mice were treated with saline or ETX in each withdrawal period, and cortical EEG activity was recorded to determine seizure severity. We observed a progression in seizure activity with each successive withdrawal period. Treatment with ETX reduced ethanol withdrawal-induced spike and wave discharges (SWDs), in terms of absolute number, duration of events, and contribution to EEG power reduction in the 6–10 Hz frequency range. We also evaluated the effects of ETX on handling-induced convulsions. Overall, we observed a decrease in handling-induced convulsion severity in mice treated with ETX. Our findings suggest that ETX may be a useful pharmacological agent for studies of alcohol withdrawal and treatment of resulting seizures.

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Section: Resultsmentioning

confidence: 99%

“…ETX is metabolized in mice very quickly with a biological half-life of approximately one hour (el Sayed et al, 1978). In a subset of mice within the ETX-treated ethanol-exposed group, we extended the fourth withdrawal period for an additional 3 h from 5:00–8:00 PM to determine if the SWDs would return as ETX was metabolized.…”

Section: Discussionmentioning

confidence: 99%

Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

Riegle

Masicampo

Caulder

et al. 2014

Alcohol

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“…A literature search was conducted to obtain values for the pharmacokinetic parameters (Cl, V c , and t 1/2 ) for ethosuximide [15], cyclosporin [16 -18] and ciprofloxacin [19 -22]. Ethosuximide and cyclosporine are mainly eliminated by metabolism ( = 75%) whereas ciprofloxacin is excreted mainly by renal route.…”

Section: Methodsmentioning

confidence: 99%

“…Ethosuximide kinetics can be best described by one compartment model, whereas cyclosporine and ciprofloxacin follow a two compartment model following IV administration. The plasma concentrations versus time data for ethosuximide in mice, rat and dog were generated by simulation (STELLA II, High Performance Systems, Inc., Hanover, NH) using pharmacokinetic parameters as described by Syed et al [15]. Cyclosporine and ciprofloxacin plasma concentrations versus time data in rat, rabbit and dog were obtained from the plots published in the literature [16 -22].…”

Section: Methodsmentioning

confidence: 99%

A comparative study of allometric scaling with plasma concentrations predicted by species-invariant time methods

Mahmood

Yuan

1999

Biopharm. Drug Dispos.

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“…In order to obtain the parameters necessary for the calculation of the priming doses and maintenance infusion rates, the pharmacokinetics of the respective antiepileptic drugs were determined some days before the final experiment. Details have been described in previous papers (El Sayed et al, 1978;Frey and Loscher, 1978;Loscher and Esenwein, 1978;Frey et al, 1979;Frey and Loscher, 1980u,b;Loscher and Frey, 1981;Al-Tahan et al, 1984).…”

Section: Methodsmentioning

confidence: 99%

Kinetics of Penetration of Common Antiepileptic Drugs into Cerebrospinal Fluid

Löscher

Frey

1984

Epilepsia

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The rate of entry of common antiepileptic drugs and some active metabolites into cerebrospinal fluid (CSF) was studied in anesthetized dogs from which blood and CSF samples were withdrawn at short intervals. Diazepam, its active metabolites desmethyldiazepam and oxazepam, clonazepam, and ethosuximide entered the CSF very rapidly with mean half-times to equilibrium between 3 and 7 min. Valproic acid, phenytoin, phenobarbital, and carbamazepine went in more slowly, but mean penetration half-times were still only 12-18 min. Primidone, its metabolite phenylethylmalondiamide , and the active metabolite of carbamazepine, i.e., carbamazepine-10,11-epoxide, passed into CSF considerably slower, with half-times of 40-50 min. In order to evaluate to what extent physicochemical properties determine the penetration rates of antiepileptic drugs into the CSF, three factors were examined: the degree of ionization of the respective drugs at physiologic pH, the plasma protein binding, and the lipid-solubility, measured by organic solvent/buffer distribution ratios. Ionization was not considered as a rate-limiting factor, because all compounds except valproic acid were highly non-ionized at pH 7.4. No correlation was found between penetration rates and plasma protein binding, but at equilibrium, the ratio between CSF and total plasma concentrations was almost equal to the free fraction of drug in plasma. A significant correlation was found between penetration rate and the benzene/buffer distribution ratio of antiepileptic drugs, which indicates that the lipid-solubility, rather than the protein binding or the degree of ionization, plays the major role in determining the differences in rate of entry of these drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

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Pharmacokinetics of Ethosuximide in the Dog

Cited by 15 publications

References 0 publications

Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

A comparative study of allometric scaling with plasma concentrations predicted by species-invariant time methods

Kinetics of Penetration of Common Antiepileptic Drugs into Cerebrospinal Fluid

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