Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials

Pong, Amanda W.; Ross, Jonathan; Tyrlíková, Ivana; Giermek, Alexander J.; Kohli, Maya P; Khan, Yousef A; Salgado, Roger D; Klein, Pavel

doi:10.1080/14728214.2022.2059464

Cited by 17 publications

(8 citation statements)

References 77 publications

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“…GABA is ultimately catabolic to succinic acid semialdehyde mediated by GABA aminotransferase (GABA-AT). Clinical studies have demonstrated that drugs enhancing GABA-mediated inhibitory synaptic transmission are effective in treating epilepsy. , GABA receptors (GABAR), GABA-AT, and GATs have become important targets for the development of ASDs recently. − …”

Section: The Pathogenesis Of Epilepsymentioning

confidence: 99%

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

Zhang

Wang

et al. 2023

J. Med. Chem.

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Epilepsy is a common disease of the nervous system characterized by transient brain dysfunction caused by an abnormal electrical discharge from the brain neurons. The pathogenesis of epilepsy is complex and remains elusive. Nowadays, drug therapy is the mainstay method for the treatment of epilepsy. More than 30 antiseizure drugs (ASDs) were approved for clinical use. Unfortunately, about 30% of patients still display pharmacoresistance against ASDs. The long-term use of ASDs may cause adverse effects, raise tolerability concerns, bring unexpected drug interactions, generate withdrawal symptoms, and increase the economic burden. Thus, the research uncovering more effective ASDs that are safe is still a difficult and urgent task. In this Perspective, we describe the pathogenesis, clinical trials, and drug therapy progress of epilepsy, focusing on summarizing the current situation of small-molecule drug candidates progressing in epilepsy therapy, which provides future directions for the development of more promising ASDs.

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Section: The Pathogenesis Of Epilepsymentioning

confidence: 99%

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

Zhang

Wang

et al. 2023

J. Med. Chem.

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“…The bioavailability of Valtoco relative to intravenous diazepam is 97%. Time to maximum plasma concentration ( C max ) is 1.5 h. [47,48 ▪ ]. The half-life after a 10 mg dose is 49.2 h. Plasma concentration is less variable than with rectal diazepam.…”

Section: Rescue Therapymentioning

confidence: 99%

Recent advances in pharmacotherapy for epilepsy

Pong

Klein

2023

Current Opinion in Neurology

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Purpose of reviewEpilepsy affects 70 million people worldwide and is a significant cause of morbidity and early mortality. The mainstay of therapy is oral medications. Epilepsy drug development is escalating, driven by continued drug resistance in up to a third of epilepsy patients. Treatment development now focuses on discovery of novel mechanisms of action and syndrome-specific therapiesRecent findingsDifficult-to-treat epilepsy related to conditions including tuberous sclerosis complex (TSC), Lennox Gastaut syndrome (LGS) and Dravet syndrome (DS) have been the target of recent developments. Disease-modifying therapy for epilepsy related to TSC with vigabatrin at onset of first electroencephalographic epileptiform changes, rather than after first clinical seizure, has demonstrated strongly positive seizure and developmental outcomes. Fenfluramine, approved for DS and, more recently, LGS, has robust data supporting efficacy, safety/tolerability, as well as mortality, quality of life and cognitive function. Rescue therapy has expanded to include better tolerated benzodiazepines in the form of nasal midazolam and valium. Cenobamate, a first-in-class inactivator of the persistent voltage-gated sodium channel and approved for adult partial onset epilepsy, has exceptional efficacy and tolerability and will be expanded to children and to generalized onset epilepsy in adults.SummaryThe repertoire of available and developmental therapies for epilepsy is rapidly expanding, and now includes disease-modifying vigabatrin in TSC and agents with extraordinary efficacy, fenfluramine and cenobamate.

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“…At present, antiepileptic drugs are still the mainly clinical treatment for epilepsy [ 85 , 86 ]. Among children receiving long-term treatment with VPA, carbamazepine (CBZ) and lamotrigine (LTG), the serum leptin level remarkably increases in the VPA group [ 87 ].…”

Section: The Effects Of Leptin On Epilepsymentioning

confidence: 99%

Regulatory Basis of Adipokines Leptin and Adiponectin in Epilepsy: from Signaling Pathways to Glucose Metabolism

Shan

Chen

et al. 2023

Neurochem Res

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Epilepsy is a common and severe neurological disorder in which impaired glucose metabolism leads to changes in neuronal excitability that slow or promote the development of epilepsy. Leptin and adiponectin are important mediators regulating glucose metabolism in the peripheral and central nervous systems. Many studies have reported a strong association between epilepsy and these two adipokines involved in multiple signaling cascades and glucose metabolism. Due to the complex regulatory mechanisms between them and various signal activation networks, their role in epilepsy involves many aspects, including the release of inflammatory mediators, oxidative damage, and neuronal apoptosis. This paper aims to summarize the signaling pathways involved in leptin and adiponectin and the regulation of glucose metabolism from the perspective of the pathogenesis of epilepsy. In particular, we discuss the dual effects of leptin in epilepsy and the relationship between antiepileptic drugs and changes in the levels of these two adipokines. Clinical practitioners may need to consider these factors in evaluating clinical drugs. Through this review, we can better understand the specific involvement of leptin and adiponectin in the pathogenesis of epilepsy, provide ideas for further exploration, and bring about practical significance for the treatment of epilepsy, especially for the development of personalized treatment according to individual metabolic characteristics.

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Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials

Cited by 17 publications

References 77 publications

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

Recent advances in pharmacotherapy for epilepsy

Regulatory Basis of Adipokines Leptin and Adiponectin in Epilepsy: from Signaling Pathways to Glucose Metabolism

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