scholarly journals The efficacy of lacosamide as monotherapy and adjunctive therapy in focal epilepsy and its use in status epilepticus: clinical trial evidence and experience

2016 ◽  
Vol 10 (2) ◽  
pp. 103-126 ◽  
Author(s):  
Sebastian Bauer ◽  
Laurent M. Willems ◽  
Esther Paule ◽  
Christine Petschow ◽  
Johann Philipp Zöllner ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Sodium Channels ◽  
Focal Epilepsy ◽  
Comparable Efficacy ◽  
Slow Inactivation ◽  
Seizure Reduction ◽  
Voltage Gated Sodium Channels ◽  
Clinical Trial Evidence ◽  
Post Marketing ◽  
Trial Evidence

Lacosamide (LCM) is approved for anticonvulsive treatment in focal epilepsy and exhibits its function through the slow inactivation of voltage-gated sodium channels (VGSCs). LCM shows comparable efficacy with other antiepileptic drugs (AEDs) licensed in the last decade: in three randomized placebo-controlled trials, significant median seizure reduction rates of 35.2% for 200 mg/day, 36.4–39% for 400 mg/day and 37.8–40% for 600 mg/day were reported. Likewise, 50% responder rates were 38.3–41.1% for 400 mg/day and 38.1–41.2% for 600 mg/day. Similar rates were reported in post-marketing studies. The main adverse events (AEs) are dizziness, abnormal vision, diplopia and ataxia. Overall, LCM is well tolerated and has no clinically-relevant drug–drug interactions. Due to the drug’s intravenous availability, its use in status epilepticus (SE) is increasing, and the available data are promising.

scholarly journals A gating charge interaction required for late slow inactivation of the bacterial sodium channel NavAb

2013 ◽  
Vol 142 (3) ◽  
pp. 181-190 ◽  
Author(s):  
Tamer M. Gamal El-Din ◽  
Gilbert Q. Martinez ◽  
Jian Payandeh ◽  
Todd Scheuer ◽  
William A. Catterall
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
Late Phase ◽  
Membrane Potentials ◽  
Charge Movement ◽  
Slow Inactivation ◽  
Functional Studies ◽  
Voltage Gated Sodium Channels ◽  
Gating Charge ◽  
Charge Interaction

Voltage-gated sodium channels undergo slow inactivation during repetitive depolarizations, which controls the frequency and duration of bursts of action potentials and prevents excitotoxic cell death. Although homotetrameric bacterial sodium channels lack the intracellular linker-connecting homologous domains III and IV that causes fast inactivation of eukaryotic sodium channels, they retain the molecular mechanism for slow inactivation. Here, we examine the functional properties and slow inactivation of the bacterial sodium channel NavAb expressed in insect cells under conditions used for structural studies. NavAb activates at very negative membrane potentials (V1/2 of approximately −98 mV), and it has both an early phase of slow inactivation that arises during single depolarizations and reverses rapidly, and a late use-dependent phase of slow inactivation that reverses very slowly. Mutation of Asn49 to Lys in the S2 segment in the extracellular negative cluster of the voltage sensor shifts the activation curve ∼75 mV to more positive potentials and abolishes the late phase of slow inactivation. The gating charge R3 interacts with Asn49 in the crystal structure of NavAb, and mutation of this residue to Cys causes a similar positive shift in the voltage dependence of activation and block of the late phase of slow inactivation as mutation N49K. Prolonged depolarizations that induce slow inactivation also cause hysteresis of gating charge movement, which results in a requirement for very negative membrane potentials to return gating charges to their resting state. Unexpectedly, the mutation N49K does not alter hysteresis of gating charge movement, even though it prevents the late phase of slow inactivation. Our results reveal an important molecular interaction between R3 in S4 and Asn49 in S2 that is crucial for voltage-dependent activation and for late slow inactivation of NavAb, and they introduce a NavAb mutant that enables detailed functional studies in parallel with structural analysis.

scholarly journals Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels II: A periodic paralysis mutation in NaV1.4 (L689I)

2013 ◽  
Vol 141 (3) ◽  
pp. 323-334 ◽  
Author(s):  
Jonathan R. Silva ◽  
Steve A.N. Goldstein
Keyword(s):  
Sodium Channels ◽  
Time Course ◽  
Slow Component ◽  
Companion Paper ◽  
Causal Link ◽  
Periodic Paralysis ◽  
Slow Inactivation ◽  
Hyperkalemic Periodic Paralysis ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

In skeletal muscle, slow inactivation (SI) of NaV1.4 voltage-gated sodium channels prevents spontaneous depolarization and fatigue. Inherited mutations in NaV1.4 that impair SI disrupt activity-induced regulation of channel availability and predispose patients to hyperkalemic periodic paralysis. In our companion paper in this issue (Silva and Goldstein. 2013. J. Gen. Physiol. http://dx.doi.org/10.1085/jgp.201210909), the four voltage sensors in NaV1.4 responsible for activation of channels over microseconds are shown to slowly immobilize over 1–160 s as SI develops and to regain mobility on recovery from SI. Individual sensor movements assessed via attached fluorescent probes are nonidentical in their voltage dependence, time course, and magnitude: DI and DII track SI onset, and DIII appears to reflect SI recovery. A causal link was inferred by tetrodotoxin (TTX) suppression of both SI onset and immobilization of DI and DII sensors. Here, the association of slow sensor immobilization and SI is verified by study of NaV1.4 channels with a hyperkalemic periodic paralysis mutation; L689I produces complex changes in SI, and these are found to manifest directly in altered sensor movements. L689I removes a component of SI with an intermediate time constant (∼10 s); the mutation also impedes immobilization of the DI and DII sensors over the same time domain in support of direct mechanistic linkage. A model that recapitulates SI attributes responsibility for intermediate SI to DI and DII (10 s) and a slow component to DIII (100 s), which accounts for residual SI, not impeded by L689I or TTX.

Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: A comparison with carbamazepine, oxcarbazepine and lacosamide

2015 ◽  
Vol 89 ◽  
pp. 122-135 ◽  
Author(s):  
Simon Hebeisen ◽  
Nuno Pires ◽  
Ana I. Loureiro ◽  
Maria João Bonifácio ◽  
Nuno Palma ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Slow Inactivation ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels
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