The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond

Abstract

Epilepsy is one of the most common and disabling chronic neurological disorders. Antiseizure medications (ASMs), previously referred to as anticonvulsant or antiepileptic drugs, are the mainstay of symptomatic epilepsy treatment. Epilepsy is a multifaceted complex disease and so is its treatment. Currently, about 30 ASMs are available for epilepsy therapy. Furthermore, several ASMs are approved therapies in nonepileptic conditions, including neuropathic pain, migraine, bipolar disorder, and generalized anxiety disorder. Because of this wide spectrum of therapeutic activity, ASMs are among the most often prescribed centrally active agents. Most ASMs act by modulation of voltage-gated ion channels; by enhancement of gamma aminobutyric acid-mediated inhibition; through interactions with elements of the synaptic release machinery; by blockade of ionotropic glutamate receptors; or by combinations of these mechanisms. Because of differences in their mechanisms of action, most ASMs do not suppress all types of seizures, so appropriate treatment choices are important. The goal of epilepsy therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients. Both in vivo and in vitro models of seizures and epilepsy are used to discover ASMs that are more effective in patients with continued drug-resistant seizures. Furthermore, therapies that are specific to epilepsy etiology are being developed. Currently, ~ 30 new compounds with diverse antiseizure mechanisms are in the preclinical or clinical drug development pipeline. Moreover, therapies with potential antiepileptogenic or disease-modifying effects are in preclinical and clinical development. Overall, the world of epilepsy therapy development is changing and evolving in many exciting and important ways. However, while new epilepsy therapies are developed, knowledge of the pharmacokinetics, antiseizure efficacy and spectrum, and adverse effect profiles of currently used ASMs is an essential component of treating epilepsy successfully and maintaining a high quality of life for every patient, particularly those receiving polypharmacy for drug-resistant seizures.

Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients’ Perspectives

“…Although a lively debate is ongoing regarding how long EVE treatment should be continued before an effect on seizures can be expected, our data show that treatment success can be achieved within an interval of 1-3 years [59]. The responder rate is comparable to other modern ASDs, such as brivaracetam, perampanel, eslicarbazepine acetate or cenobamate, which highlights the potential of EVE treatment for TSC-related DRE [60][61][62][63][64][65][66][67][68][69][70]. In SEGA, size reductions under EVE therapy have frequently been used as therapeutic success markers.…”

Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy

“…no data available (or found by literature review using Pubmed). For detailed data and references see Löscher (2020) and Löscher and Klein (2021a) effective treatments, but the process of target validation is complex, long-lasting, and associated with high attrition rates (Sams-Dodd, 2005;Swinney and Anthony, 2011).…”

“…ASMs can be grouped into three categories: 1) ASMs with a narrow spectrum of preclinical efficacy such as ethosuximide (only active against absence and myoclonic seizures); 2) ASMs which mainly act in MES and focal-onset seizure models (the vast majority of compounds shown in Tables 1 and 2 ) ASMs with a broad spectrum of efficacies such as brivaracetam, valproate, and alkyl-carbamates, such as cenobamate. At least in part, the preclinical profile of antiseizure efficacy resembles the clinical spectrum ( Löscher and Klein, 2021a ). For instance, ethosuximide is almost exclusively used for the treatment of absence seizures in humans; phenytoin and carbamazepine act mainly against focal-onset and primary or secondary generalized tonic-clonic seizures in animal models and patients, and valproate exhibits a broad spectrum of preclinical and clinical efficacy.…”

“…There are more than a dozen types of epilepsy and numerous types of epileptic seizures, underlining the complexity of the disease ( Savage, 2014 ). The first-line treatment for epilepsy is antiseizure medications (ASMs; also termed antiepileptic drugs), which symptomatically suppress SRS ( Löscher and Klein, 2021a ). However, despite the availability of >30 ASMs, about one-third of epilepsy patients are resistant to treatment and this figure has not changed over recent decades ( Chen et al, 2018 ; Janmohamed et al, 2020 ).…”

“…Following the discovery and preclinical characterization of a novel ASM and clinical phase I trial for evaluation of the drug's tolerability and pharmacokinetics, randomized, double-blind, placebo-controlled adjunctive-therapy trials in patients with drug-resistant focal seizures continue to be the primary tool to obtain regulatory approval of novel ASMs (Perucca, 2019;Boada et al, 2020). However, because the ASM market is crowded and costs of drug development are constantly increasing, the interest of industry has increased in developing novel molecules for Rogawski and Löscher (2004), Rogawski et al (2016), Rogawski (2020), andKlein (2021a).…”