Abstracts

Clomethiazole has been used since 1938 for treatment of states of agitation and ethanol withdrawal syndrome. Because of its anticonvulsant effect it is additionally indicated for intractable status epilepticus.
As demonstrated in in vitro and in vivo studies in rat the mechanism of action is a potentiating effect of the inhibitory action of GABA and glycine. The effect on the excitability of human motor cortex has not been sufficiently investigated yet.
Transcranial magnetic stimulation is a well-established method to investigate the excitability of the human motor cortex. Different TMS-measures using single and paired pulse paradigms reflect different actions of synaptic receptors (GABA-A/B-agonism, glutamate antagonism) and ion channels.
The aim of our study was to verify the acute effects of clomethiazole on human motor cortex excitability by single and paired pulse TMS. In a double-blind, placebo-controlled, crossover study, the effect of single oral doses of 192 and 384 mg clomethiazole on resting motor tresholds (RMT), MEP recruitment curves (REC), cortical induced silent period (CSP) and on intracortical inhibition (ICI) and facilitation (ICF) was investigated in 15 healthy subjects. Peripheral excitability was monitored by means of F-Wave and M-latency. For statistical analysis the nonparametric Wilcoxon signed rank test with Bonferroni correction for the comparison placebo versus 384 mg clomethiazole was used. For the confirmatory analysis level of significance was set to 0.01 after Bonferroni correction applying five tests (RMT, REC, CSP, ICI, ICF). Other data were evaluated by explanatory analysis. 90 minutes after a single oral 384 mg dose clomethiazole a significant increase of ICI at short interstimulus intervals (ISI 2ms, p=0,008) was noticed. Furthermore a dose-independent trend of CSP prolongation was noticed (192 mg: p= 0,005; 384 mg: p= 0,033). RMT, REC and ICF were not influenced. A peripheral impact of clomethiazole could be excluded. Serum concentrations of clomethiazole were below the therapeutic range in all subjects after 192 mg and in 8 subjects after 384 mg dose. All subjects developed dose-dependent moderate adverse effects, which were mainly flu like symptoms or CNS-related (somnolence, vertigo, ataxia). The results of this study confirm the potentiating effect of GABA, possibly by affecting GABAA receptors, in human motor cortex as expressed by an increase of ICI. The dose-independent prolongation of the CSP suggests an effect on GABAB-ergic transmission.
This may explain the anticonvulsive efficacy of clomethiazole in intractable status epilepticus. The lack of dose dependence could be due to a low and variable oral bioavailibility. (Supported by ULRAN Professorship for Neurology/Epileptology.)