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United States: American Society for Pharmacology and Experimental Therapeutics
Erscheinungsjahr
2008
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
We hypothesized that lacosamide modulates voltage-gated sodium channels (VGSCs) at clinical concentrations (32-100 μM). Lacosamide
reduced spiking evoked in cultured rat cortical neurons by 30-s depolarizing ramps but not by 1-s ramps. Carbamazepine and
phenytoin reduced spike-firing induced by both ramps. Lacosamide inhibited sustained repetitive firing during a 10-s burst
but not within the first second. Tetrodotoxin-sensitive VGSC currents in N1E-115 cells were reduced by 100 μM lacosamide,
carbamazepine, lamotrigine, and phenytoin from V h of -60 mV. Hyperpolarization (500 ms) to -100 mV removed the block by carbamazepine, lamotrigine, and phenytoin but not by
lacosamide. The voltage-dependence of activation was not changed by lacosamide. The inactive S -stereoisomer did not inhibit VGSCs. Steady-state fast inactivation curves were shifted in the hyperpolarizing direction by
carbamazepine, lamotrigine, and phenytoin but not at all by lacosamide. Lacosamide did not retard recovery from fast inactivation
in contrast to carbamazepine. Carbamazepine, lamotrigine, and phenytoin but not lacosamide all produced frequency-dependent
facilitation of block of a 3-s, 10-Hz pulse train. Lacosamide shifted the slow inactivation voltage curve in the hyperpolarizing
direction and significantly promoted the entry of channels into the slow inactivated state (carbamazepine weakly impaired
entry into the slow inactivated state) without altering the rate of recovery. Lacosamide is the only analgesic/anticonvulsant
drug that reduces VGSC availability by selective enhancement of slow inactivation but without apparent interaction with fast
inactivation gating. The implications of this unique profile are being explored in phase III clinical trials for epilepsy
and neuropathic pain.