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Nerve Agent–Induced Seizures and Status Epilepticus: Neuroprotective Strategies
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Frederic Doreu, Karine Thibault, Nina Dupuis
Significant elevations in hippocampal calcium levels after OP (paraoxon) SE have been observed, which were sustained for weeks (Deshpande et al., 2010, 2014, 2016b), and these elevations could be reduced by drugs inhibiting intracellular calcium-induced calcium release, such as dantrolene, levetiracetam, and carisbamate. This may be a way to enhance neuroprotection (Deshpande et al., 2016a). Earlier work had also stressed the potential interest of this approach: drugs blocking delayed calcium overload, such as HU-211, a nonpsychotropic derivative of tetrahydrocannabinol (Filbert et al., 1999), or dantrolene, a ryanodine receptor antagonist that augmented the protection afforded by the administration of diazepam 40 min after soman injection, proved to be neuroprotectant without being anticonvulsant (Newmark et al., 2003). Further work is needed with other OPs.
Current and future pharmacotherapy options for drug-resistant epilepsy
Published in Expert Opinion on Pharmacotherapy, 2022
Carisbamate is an alkyl-carbamate whose precise mechanism of action is unknown, but it is thought to inhibit voltage-gated sodium channels [62]. It is currently under Phase III development for drug-resistant focal epilepsy and LGS. A recent Cochrane systematic review of carisbamate as adjunctive therapy for drug-refractory focal epilepsy analyzed data from four double-blind RCTs (NCT00228969, NCT00740623, NCT00425282, NCT00433667) totaling 2211 participants and showed slightly higher responder rates with carisbamate as compared to placebo (RR 1.36) but also dizziness (RR 2.06) and somnolence (RR 1.82) [86]. The Cochrane review concluded that whilst carisbamate might display efficacy and tolerability as an adjunctive therapy, evidence for all outcomes (other than responder rate) was of low-very low certainty and limited by risk of attrition bias. For LGS, carisbamate has received orphan drug designation from the FDA and III trials for use of carisbamate in LGS are underway. An open-label phase I study to assess pharmacokinetics and adverse effects of carisbamate in 24 adult and pediatric patients with LGS has been completed and results are awaited (NCT03731715). A phase III randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of two doses of carisbamate in 250 patients with LGS-related seizures is planned (NCT05219617).
Novel and emerging therapeutics for genetic epilepsies
Published in Expert Review of Neurotherapeutics, 2021
Ana Pejčić, Slobodan M. Janković, Miralem Đešević, Refet Gojak, Snežana Lukić, Nenad Marković, Miloš Milosavljević
Several investigational compounds with anticonvulsant effect are currently being tested in phase I studies on patients with genetic epilepsies. Carisbamate ((S)-2-O-carbamoyl-1-O-chlorophenyl-ethanol), also known as YKP509, is an antiepileptic structurally similar to felbamate, with an insufficiently known mechanism of action [113,141]. It showed a broad anticonvulsant effect, both elevating seizure threshold and preventing seizure spread, in preclinical studies conducted on animal models for primary generalized, complex partial, and absence-type of epilepsy [142–144]. However, in phase II and phase III placebo-controlled clinical studies, carisbamate did not show significant seizure reduction potential compared to placebo in patients with drug-resistant focal epilepsy [113]. A phase I open-label multicenter study for single and multiple-dose pharmacokinetics assessment in adult and pediatric patients with Lennox-Gastaut syndrome is ongoing (NCT03731715) [145]. The most common adverse effects of carisbamate are dizziness, headache, somnolence, and nausea [146]. Carisbamate did not show significant potential for drug-drug interactions with most commonly used antiepileptic drugs [146].
Stereoselective pharmacokinetic and pharmacodynamic analysis of a CNS-active sulphamoylphenyl carbamate derivative
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
David Bibi, Bella Shusterman, Alessio Nocentini, Claudiu T. Supuran, Meir Bialer
Among our current antiepileptic armamentarium as well as among the AEDs in development there are drugs containing carbamate or sulphonamide moieties in their chemical structure. Felbamate is a carbamate that exhibits a broad anticonvulsant activity and has been on the market since 1993. However, currently, it is seldom used due to the fatal aplastic anaemia and hepatotoxicity that is associated with its therapy16,17. Two additional carbamates, carisbamate, and cenobamate completed phase III clinical trials and their new drug application (NDA) were submitted to the Food and Drug Administration (FDA). Carisbamate regulatory application was withdrawn in 2010, due to lack of consistent efficacy across a clinically-relevant dose range18–19. Two cenobamate well-controlled studies demonstrated statistically significant reduction in seizure frequency as well as high responder rates, including seizure freedom, in patients with uncontrolled partial seizures treated with cenobamate for up to 18 weeks18–22. Due to three reported cases of drug reaction with eosinophilia and systemic symptoms (DRESS) in patients exposed to cenobamate, a large Phase III open-label study took place to evaluate the long-term safety of cenobamate when using a lower starting dose (<100 mg) and slower titration rate in order to mitigate the serious coetaneous reactions (e.g. DRESS)22. Subsequently, cenobamate-NDA submission was accepted by the FDA on 4/2/2019 and its Prescription Drug User Fee Act (PDUFA) date is set for 21/11/201923.