Stiripentol, a Putative Antiepileptic Drug, Enhances the Duration of Opening of GABAA‐Receptor Channels

@article{Quilichini2006StiripentolAP,
  title={Stiripentol, a Putative Antiepileptic Drug, Enhances the Duration of Opening of GABAA‐Receptor Channels},
  author={Pascale P. Quilichini and Catherine Chiron and Yehezkel Ben-Ari and Henri Gozlan},
  journal={Epilepsia},
  year={2006},
  volume={47}
}
Summary:  Purpose: Stiripentol (STP) is currently an efficient drug for add‐on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown. 
Stiripentol in the Management of Epilepsy
Stiripentol is a structurally unique antiepileptic drug that has several possible mechanisms of action, including diverse effects on the gamma-aminobutyric acid (GABA)-A receptor and novel inhibition
The effects of stiripentol on GABAA receptors
TLDR
Positive modulation by stiripentol was most effective at GABAA receptors containing an α3 subunit, which is developmentally regulated, with highest levels in the immature brain, and may explain the greater clinical efficacy of stiripENTol in childhood‐onset epilepsies, including Dravet syndrome.
The anti-convulsant stiripentol acts directly on the GABAA receptor as a positive allosteric modulator
  • J. Fisher
  • Chemistry, Medicine
    Neuropharmacology
  • 2009
TLDR
Findings suggest that STP acts as a direct allosteric modulator of the GABAR at a site distinct from many commonly used anti-convulsant, sedative and anxiolytic drugs.
Characterization of the Anticonvulsant, Behavioral and Pharmacokinetic Interaction Profiles of Stiripentol in Combination with Clonazepam, Ethosuximide, Phenobarbital, and Valproate Using Isobolographic Analysis
TLDR
Isobolographic analysis was used to characterize the interactions between stiripentol and clonazepam, ethosuximide, EMT, phenobarbital, and valproate in suppressing pentylenetetrazole‐induced clonic seizures in mice.
Interactions between modulators of the GABA(A) receptor: Stiripentol and benzodiazepines.
  • J. Fisher
  • Medicine
    European journal of pharmacology
  • 2011
TLDR
It is suggested that stiripentol and the benzodiazepines act independently at GABA(A) receptors and that polytherapy could be expected to increase the maximum effect beyond either drug alone, even without consideration of changes in metabolism.
Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus
TLDR
Compared the ability of STP and diazepam (DZP), a commonly used BZD, to terminate behavioral convulsions in a rodent model of pharmacoresistant SE, STP was anticonvulsant in this model and remained effective during prolonged SE, unlike DZP which exhibited a 14 fold increase in its ED(50).
Stiripentol – characteristic of a new antiepileptic drug
TLDR
Stiripentol represents a group of drugs indirectly enhancing GABA-ergic neurotransmission and it exerts a protective activity in some experimental seizure models, including maximal electroshock (MES)-, pentylenetetrazol-, bicuculline-, strychnine-, and cocaine-induced convulsions.
Mechanisms of action of antiepileptic drugs
TLDR
The proposed mechanisms of action of marketed AEDs in the US are reviewed, the future of Aeds in development is discussed and the proposed targets of action at more than one molecular target are discussed.
Mechanisms of action of currently used antiseizure drugs
TLDR
Attempts are being made to engineer specific small molecule, antisense and gene therapies that functionally reverse or structurally correct pathogenic defects in epilepsy syndromes, but targeted therapies will remain elusive for the vast majority of epilepsies until their causes are identified.
Stiripentol exhibits higher anticonvulsant properties in the immature than in the mature rat brain
TLDR
After the first positive experimental data in rodents in the early 1970s demonstrating the anticonvulsant effect of stiripentol (STP), in vitro studies showed that STP acts directly on γ‐aminobutyric acid A (GABAA) receptors, leading to the hypothesis thatSTP might exhibit higher efficacy in the immature brain.
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References

SHOWING 1-10 OF 77 REFERENCES
Effects of Clobazam and Its Active Metabolite on GABA‐Activated Currents in Rat Cerebral Neurons in Culture
TLDR
The purpose of this study was to learn how clobazam and its active metabolite modulate γ‐aminobutyric acid (GABA)‐activated currents in rat cerebral neurons in culture.
Stiripentol: Efficacy and Tolerability in Children with Epilepsy
TLDR
Stiripentol (STP) is a new antiepileptic drug (AED) that inhibits cytochrome P450′ resulting in increased plasma concentrations of concomitant AEDs.
A new type of anticonvulsant, stiripentol. Pharmacological profile and neurochemical study.
TLDR
Findings suggest that the anticonvulsant activity of stiripentol involves two aspects of the GABAergic mechanism in which the metabolic transamination and synaptosomal uptake of this neurotransmitter are inhibited.
Clinically significant pharmacokinetic drug interactions between antiepileptic drugs
  • E. Tanaka
  • Chemistry, Medicine
    Journal of clinical pharmacy and therapeutics
  • 1999
TLDR
This review discusses pharmacokinetic drug interactions of clinical significance involving antiepileptics and cytochrome P450 (CYP), which represents a major potential complication of epilepsy treatment.
Neurosteroids and GABAA receptor function.
TLDR
Recent advances in this field are reviewed and the therapeutic potential of this novel, non-genomic effect of steroids is discussed and whether they may influence behaviour under physiological, or pathophysiological, conditions is investigated.
Neurosteroids: endogenous regulators of the GABAA receptor
GABAA (γ-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring
A Mechanistic Approach to Antiepileptic Drug Interactions
  • G. Anderson
  • Chemistry, Medicine
    The Annals of pharmacotherapy
  • 1998
TLDR
By understanding the mechanisms of drug interactions, the pharmacist can play a key role in patient care by anticipating and preventing AED drug interactions.
Preclinical evaluation of newly approved and potential antiepileptic drugs against cocaine-induced seizures.
TLDR
This study provides the first description of the effectiveness of new antiepileptic drugs against experimentally induced cocaine seizures and points to several drugs that deserve clinical scrutiny for this indication.
Neurosteroids and GABA, receptor function
Jeremy J. lambett, Delia Belelli, Claire Hill-Venning and John A. Peters In 1994, a potent and selective interaction of the steroidal anaesthetic alphaxalone with the GABA, receptor was demonstrated.
Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1.
TLDR
Data suggest that the anticonvulsant activity of these compounds is mediated via inhibition of uptake by GAT-1, which may be useful in the treatment of various neuropsychiatric disorders.
...
1
2
3
4
5
...