van Rijckevorsel Antiepileptic drugs in development Carisbamate (RWJ-333369) Carisbamate is an investigational drug (Kulig and Malawska 2007) with broad anticonvulsant activity in preclinical studies, elevating seizure threshold and preventing seizure spread. In animal models, it is effective in focal and generalized seizures, and may prevent the development of spontaneous recurrent epileptiform discharges and damage related to SE. The safety proﬁle seems encouraging as do results from initial studies in epileptic patients. In view of these properties, this AED could become a drug of choice for LGS. Fluoro-felbamate Fluorofelbamate, a dicarbamate, is a drug candidate in development, designed to retain the broad spectrum activity of FBM, but with a modiﬁed metabolism that avoids the production of the reactive metabolite, aldehyde, believed to be the cause of the idiosyncratic life-threatening toxicity (Roecklein et al 2007; Bialer et al 2007). Results in vitro are promising and research is ongoing. If the better safety proﬁle of this AED is conﬁrmed, it could become a useful treatment in LGS. Ganaxolone (GNX) GNX belongs to a novel class of neurosteroids called epalons, which speciﬁcally modulate the GABA-A receptor in the CNS, acting through binding sites which are distinct from the BZD binding site. Chemically related to progesterone but devoid of any hormonal activity, the epalons have potent antiepileptic activities in animals. (Monghan et al 1997). In view of its potential efﬁcacy and after preliminary encouraging results in patients (Laxer et al 2000; Pieribone et al 2007), clinical trials are planned in several epilepsy syndromes, including LGS (Perucca et al 2007). Derivatives of LEV: brivaracetam and seletracetam Brivaracetam (BRI) possesses a binding afﬁnity for the synaptic vesicle protein 2A (SV2A) that is ten-fold more powerful than LEV and also shows an ability to inhibit Na+ channels. Acute toxicity is low and the safety proﬁle in humans is favorable. BRI is primarily metabolized via hydrolysis of the acetamide group and by CYP2C8. Clearance of BRI is reduced in patients with hepatic insufﬁciency and there is a potential for some drug-drug interactions (Bialer et al 2007, von Rosenstiel 2007). However, this drug could be promising in LGS because of its potential broad spectrum of action, in spite of probable drug-drug interactions. 1010 Seletracetam (SEL) is another new pyrrolidone derivative structurally related to LEV (Bennet et al 2007; Bialer et al 2007), discovered because of its high binding afﬁnity to the synaptic vesicle 2A (SV2A) protein. Pharmacokinetic studies in animals suggest a linear pharmacokinetics with no or mild metabolic interactions and a low plasma protein binding ( 10%). This suggests a low potential for drug-drug interactions. SEL shows very potent seizure suppression in different models of acquired or genetic epilepsy, suggesting a broad spectrum of activity and may be useful in LGS. Remacemide (RMC) RMC is a low-afﬁnity NMDA receptor blocker as well as Na+ channel blocker. The drug exerts anticonvulsant activity in various animal seizure models and in clinical studies (Malek et al 2003). In addition, the drug seems to provide some neuroprotection. In view of its potential broad spectrum of action, RMC could be useful in LGS. Stiripentol (STP) STP was ﬁrst identiﬁed in 1978 with clinical trials starting in the 1980s in all forms of epileptic syndromes, including LGS in which it was used in combination with CBZ (Tran et al 1996). The LGS study BC-274, a single blind triphasic study showed a decrease in ﬁts in 72% of the 24 participants aged 1–22 years. (http://www.emea.europa.eu/humandocs/ PDFs/EPAR/diacomit/H-664-en6.pdf). STP was recently shown to increase GABA-ergic transmission (Quilichini et al 2006) in vitro in an experi- mental immature rat model and to act as a direct allosteric modulator of the GABA receptor. Clinical studies were based on the fact that STP also acts as a powerful inhibitor of CYP3A4, CYP1A2, and CYP2C19, but gave disappointing results in adult patients. STP has been shown to be effective in atypical absences (Farwell et al 1993) and in myoclonic epilepsies, if combined with VPA and CLB (Chiron 2007). At the present time, STP is mainly used in Dravet and related syndromes added to CLB and VPA. However, the interactions of STP with a large number of drugs or toxic endogenous products need to be carefully considered from a long term safety perspective. Other AEDs in development Among the other numerous AEDs in the pipeline, VPA-like agents, such as diisopropyl acetamide (PID) and valrocemide are the most promising drugs in LGS because they have a similar broad spectrum of activity to VPA but fewer adverse events in terms of somnolence, weight problems and teratogenicity (Rogawski 2006). Neuropsychiatric Disease and Treatment 2008:4(6)