XEN1101 at 1 μM restored peak contractile force to 70%-100% of baseline in murine models of hypokalemic periodic paralysis after 2 mM K+ induced weakness.
Does XEN1101 prevent and abort low-K+ induced loss of force in mouse models of hypokalemic periodic paralysis?
XEN1101 effectively prevents and reverses low-potassium induced weakness in murine models of hypokalemic periodic paralysis, providing a rationale for future clinical trials.
Absolute Event Rate: 0% vs 0%
ABSTRACT Introduction/Aims Effective management remains lacking for recurrent episodes of acute weakness in hypokalemic periodic paralysis (HypoPP). We assessed the efficacy of a second‐generation potassium channel agonist, XEN1101, to prevent and abort the low‐K + induced loss of force in mouse models of HypoPP. Methods An ex vivo contractility assay was used to interrogate the efficacy of XEN1101 for preserving contractile force and for enhancing recovery of force in the setting of a low‐K + challenge for HypoPP mice carrying the sodium channel Na V 1.4‐R669H or the calcium channel Ca V 1.1‐R528H mutations. Results The acute loss of force for HypoPP muscle, triggered by a 2 mM K + challenge, was prevented by low micromolar XEN1101, with an effective concentration of 0.30 μM for 50% protection. Application of 1 μM XEN1101, after the onset of 2 mM K + induced weakness, restored the peak contractile force (70%–100% of baseline). Discussion The K V 7 potassium channel agonist XEN1101 is effective as both a prophylactic agent and as abortive therapy for management of low‐K + induced weakness in murine models of HypoPP. XEN1101 is more potent than the first‐generation Kv7 agonist, retigabine, in our murine models of HypoPP and is also better tolerated in patients. These improvements provide a rationale for future clinical trials of XEN1101 in HypoPP patients.
Chanchykov et al. (Wed,) reported a other. XEN1101 at 1 μM restored peak contractile force to 70%-100% of baseline in murine models of hypokalemic periodic paralysis after 2 mM K+ induced weakness.