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Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Christopher Kobylecki, Ling K. Lee, Mark W. Kellett
The novel antiepileptic drug retigabine, an activator of KCNQ2/3 potassium channels, has been shown to cause urinary hesitancy and retention in a number of patients, leading to recommendations for its use with caution in patients at risk of urinary retention.189,190 This adverse effect seems consistent with the documented pharmacological effects of retigabine on smooth muscle in preclinical studies.191
Antiepileptic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
The action of drugs at synaptic cleft is shown in Figure 14.6. Sodium channel activation causes depolarization of neurons which leads to generation of seizures within the foci, drugs like phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, zonisamide, and sodium valproate inhibits these sodium channels, thereby decreasing the firing of neurons. Benzodiazepines like lorazepam, midazolam, clonazepam, and barbiturate like phenobarbital and thiopental act by increasing GABA chloride channel activity, thereby decreasing the generation of generalized tonic–clonic seizure as well as partial seizures. Tiagabine increase GABA concentration by inhibiting the GAT-1 transporters, thereby decreasing GABA reuptake while vigabatrin and valproate decrease the metabolism of GABA by inhibiting GABA aminotransferase. Gabapentin and pregabalin act by modulation of α2δ subunit of calcium channels, decreasing calcium entry through voltage-activated Ca2+ Levetiracetam and brivaracetam may also affect release by binding to synaptic vesicles protein SV2A. Retigabine act by increasing the K+ conductance along KCNQ/Kv7, thereby increasing the hyperpolarization and decreasing the generation of synchronous neural firing. Sodium valproate displays wide spectrum of activity by inhibiting sodium channels as well as T-type Ca2+ channels and increasing GABA brain levels. Topiramate mechanism includes decreasing sodium channel and calcium channel activity, inhibiting glutamate receptors and increasing GABA activity in brain. Perampanel has its effects on both inhibitory (GABA–orange dots) and excitatory (Glutamate pink dots) nerve transmission (Shih et al., 2013).
Activation of Kv7 channels with the anticonvulsant retigabine alleviates neuropathic pain behaviour in the streptozotocin rat model of diabetic neuropathy
Published in Journal of Drug Targeting, 2019
Laiche Djouhri, Mohammed Imad Malki, Asad Zeidan, Karim Nagi, Trevor Smith
To confirm that the analgesic effects of retigabine are mediated by activation of Kv7 channels, we used the Kv7 channel blocker XE991 to examine whether the effects of retigabine on STZ-induced mechanical and heat hypersensitivity could be reversed. As shown in Figure 4, the effects of retigabine (15 mg/kg) on PWT (Figure 4(A)) was antagonised by XE991 (3 mg/kg), compared with the vehicle, indicating that the effects of retigabine on mechanical hypersensitivity in the STZ rats can be reversed by this blocker. Interestingly, the antiallodynic effects of retigabine were similar to those of the positive control gabapentin (Figure 4(A)). As a control, we also tested both retigabine and XE991 for effect on PWT and PWL in naïve (normal) rats. The result showed that neither retigabine nor XE991 had any effect on the baseline PWT or PWL, compared with the vehicle group (Figure 5(A,B)) indicating that the effects of these drugs were mediated by Kv7 channels.
A resurging boom in new drugs for epilepsy and brain disorders
Published in Expert Review of Clinical Pharmacology, 2018
Iyan Younus, Doodipala Samba Reddy
1OP-2198 is a positive modulator of neuronal Kv7 (KCNQ) potassium channel. These channels are responsible for the slow activating and deactivating voltage-gated M-current. Studies demonstrate that opening of Kv7 channels may have valuable application in states of hyperexcitability such as epilepsy [71]. Earlier generation Kv7 channel modulators such as flupirtine and retigabine have shown valuable application as adjunctive treatment for partial epilepsies. However, retigabine (ezogabine) was withdrawn from clinical use in 2017 due to limited usage, decline in new patient initiation, and metabolite liabilities causing a host of adverse effects that included dizziness, tinnitus, vertigo, and slurred speech [18,72]. Therefore, highly selective, second-generation Kv7 potassium channel openers are needed to overcome metabolite restrictions for successful application of this novel antiepileptic mechanism.
Perampanel as monotherapy and adjunctive therapy for focal onset seizures, focal to bilateral tonic-clonic seizures and as adjunctive therapy of generalized onset tonic-clonic seizures
Published in Expert Review of Neurotherapeutics, 2019
Ivana Tyrlikova, Milan Brazdil, Ivan Rektor, Michal Tyrlik
Some interesting trends in perampanel adjunctive treatment showed the observational study by Rohracher et al. [32]. The usage of co-administrated enzyme-inducing ASD was weakly associated with lower chance of seizure freedom, but there was seen a trend toward increased retention rate in patients using Na-channel blockers (versus no Na-channel blockers). A weak association suggesting a higher chance of seizure freedom with the concomitant SV2A modulator (i.e. levetiracetam or brivaracetam) than in those with no SV2A modulator was seen. Retention rates did not differ between these two subgroups. Another trend toward increased retention rates was seen in patients using concomitant retigabine. None of these observations achieved statistical significance [32],