Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine
Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine
复制标题
DOI：
10.1093/brain/awz199
复制
发表时间：
2019-09-01
期刊：
影响因子：
14.5
通讯作者：
Ashina, Messoud
中科院分区：
文献类型：
--
作者：
Al-Karagholi, Mohammad Al-Mahdi;Hansen, Jakob Moller;Ashina, Messoud
偏头痛是所有疾病中最致残和最普遍的一种。为了提高对偏头痛机制的理解并提出新的治疗靶点，我们研究了ATP敏感性钾通道（K-ATP）的开放是否会引起偏头痛发作。在这项随机、双盲、安慰剂对照、交叉研究中，16名年龄在18-49岁、每月偏头痛发作1 - 5次的患者被随机分配接受0.05 mg/min K-ATP通道开放剂左克罗卡林和安慰剂输注，输注时间为两个不同的日期（ClinicalTrials.gov编号，NCT 03228355）。主要终点是左克罗卡林和安慰剂之间偏头痛发作、头痛发生率的差异以及头痛强度评分（0-12 h）和大脑中动脉血流速度（0-2 h）曲线下面积（AUC）的差异。2017年5月24日至2017年11月23日期间，16例患者在不同的两天随机接受左克罗卡林和安慰剂治疗。16名患者（100%）在左克罗卡林治疗后发生偏头痛发作，与安慰剂治疗后的1名患者（6%）相比（P = 0.0001）;发生率差异为94% [95%置信区间（CI）78-100%]。在12小时观察期内，左克罗卡林组（n = 16）的头痛发生率高于安慰剂组（n = 7），但不显著（P = 0.016）（95% CI 16-71%）。与安慰剂相比，左克罗卡林治疗后头痛强度的AUC显著更大（AUC（0- 12 h），P50.0001）。与安慰剂相比，左克罗卡林给药后的平均大脑中动脉血流速度无变化（AUC（0- 2 h）P = 0.46）。K-ATP通道开放导致所有患者偏头痛发作。这表明这些通道在偏头痛病理生理学中起着至关重要的作用，并且K-ATP通道阻断剂可能是偏头痛新药的潜在靶点。
Migraine is one of the most disabling and prevalent of all disorders. To improve understanding of migraine mechanisms and to suggest a new therapeutic target, we investigated whether opening of ATP-sensitive potassium channels (K-ATP) would cause migraine attacks. In this randomized, double-blind, placebo-controlled, crossover study, 16 patients aged 18-49 years with one to five migraine attacks a month were randomly allocated to receive an infusion of 0.05 mg/min K-ATP channel opener levcromakalim and placebo on two different days (ClinicalTrials.gov number, NCT03228355). The primary endpoints were the difference in incidence of migraine attacks, headaches and the difference in area under the curve (AUC) for headache intensity scores (0-12 h) and for middle cerebral artery blood flow velocity (0-2 h) between levcromakalim and placebo. Between 24 May 2017 and 23 November 2017, 16 patients randomly received levcromakalim and placebo on two different days. Sixteen patients (100%) developed migraine attacks after levcromakalim compared with one patient (6%) after placebo (P = 0.0001); the difference of incidence is 94% [95% confidence interval (CI) 78-100%]. The incidence of headache over the 12 h observation period was higher but not significant after levcromakalim (n = 16) than after placebo (n = 7) (P = 0.016) (95% CI 16-71%). The AUC for headache intensity was significantly larger after levcromakalim compared to placebo (AUC(0-12h), P50.0001). There was no change in mean middle cerebral artery blood flow velocity after levcromakalim compared to placebo (AUC(0-2h) P = 0.46). Opening of K-ATP channels caused migraine attacks in all patients. This suggests a crucial role of these channels in migraine pathophysiology and that K-ATP channel blockers could be potential targets for novel drugs for migraine.