The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: Implications for clinical use

Abstract

SUMMARYRetigabine [RTG (international nonproprietary name); ezogabine (EZG; U.S. adopted name)] is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (K v 7) potassium (K + ) channels. RTG/EZG has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. In this review we discuss the activity that RTG/EZG has demonstrated across a broad spectrum of in vitro/in vivo animal models of seizures, including generalized tonic-clonic, primary generalized (absence), and partial seizures, in addition to the compound's ability to resist and block the occurrence of seizures induced by a range of stimuli across different regions of the brain. The potency of RTG/EZG in models refractory to several conventional AEDs and the work done to assess antiepileptogenesis and neuroprotection are discussed. Studies that have evaluated the central nervous system side effects of RTG/EZG in animals are reviewed in order to compare these effects with adverse events observed in patients with epilepsy. Based on its demonstrated effect in a number of animal epilepsy models, the synergistic and additive activity of RTG/EZG with other AEDs supports its potential use in therapeutic combinations for different seizure types. The distinct mechanism of action of RTG/EZG from those of currently available AEDs, along with its broad preclinical activity, underscores the key role of KCNQ (K v 7) K + channels in neuronal excitability, and further supports the potential efficacy of this unique molecule in the treatment of epilepsy.

Protective Role of Kv7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

“…These effects occurred at a retigabine concentration (1 μmol/L) close to the EC 50 for activation of K v 7.2/K v 7.3 heteromers underlying M current, 8 and to the plasma concentrations achieved in vivo in humans. 22 Because these aberrant dopamine concentrations have been shown to be neurotoxic, reductions in the peak dopamine efflux or the rate of dopamine efflux can be considered neuroprotective, as also suggested by TTC staining experiments. This view was corroborated by the results of FCV and TTC experiments using ICA27243, a compound with higher selectivity at K v 7.2/K v 7.3 heterotetramers.…”

Antiepileptic Drugs 2012: Recent Advances and Trends

“…6,8,22 Efficacy Ezogabine has been evaluated for efficacy as adjunctive therapy in partial-onset seizures in 3 multicenter, randomized, double-blind, placebo-controlled trials in 1239 adult patients. 7,[22][23][24] The primary end point was percent change in seizure frequency from baseline. Enrolled patients experienced a minimum of 4 partial seizures per month despite use of up to 3 AEDs or vagus nerve stimulation.…”

“…Compared with placebo, ezogabine reduced seizure frequency at 600 mg/d by 27%, 900 mg/d by 25%, and 1200 mg/d by 24%. 7,[22][23][24] …”

“…1,3 Novel in the recently approved group of medications is the first AED to act by potassium channel modulation (ezogabine). [4][5][6][7][8] Although most AEDs introduced in the past 2 decades were indicated for adjunctive therapy of partial epilepsy, 3 of the 5 newest AEDs have indications only for seizures associated with specific severe epilepsy syndromes (Table 1), particularly infantile spasms and Lennox-Gastaut syndrome (LGS). Infantile spasms are brief myoclonic or tonic seizures and a common manifestation of epileptic encephalopathies, such as West syndrome, consisting of a triad of spasms, hypsarrhythmic electroencephalography, and developmental failure or regression.…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…(20) represents a unique mechanism of action among AEDs which is enhancing of the activity of K V 7 channels in central nervous system resulting in reduction of neuronal excitability. The other mechanism constitutes enhancing of -aminobutyric acid transmission but only at supra-therapeutic concentration (while tested in vitro) [100]. The compound showed broad anticonvulsant activity in several animal seizure models: MES, scMet, 6-Hz test, hippocampal-kindled rats, amygdala-kindled rats ,and many more, including some genetic animal models of epilepsy [100].…”