Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease
Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease
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DOI：
10.1124/jpet.104.071886
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发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Boucher, RC
中科院分区：
文献类型：
--
作者：
Hirsh, AJ;Sabater, JR;Boucher, RC
上皮钠通道（ENaC）阻断剂已被提议作为恢复囊性纤维化（CF）气道中的粘液清除（MC）的疗法。然而，第一代ENaC阻滞剂阿米洛利在CF患者中的治疗效果是最小的。由于阿米洛利的失败反映了其对气道表面的低效力和短持续时间的作用，我们研究了苯扎明和非那明的效力增加是否会产生更有利的药效学特性。在体外效力，最大疗效，恢复率从最大块的ENaC，药物吸收率进行了比较阿米洛利，苯扎明，和非那明在培养的人和绵羊支气管上皮细胞。在人和绵羊支气管上皮细胞中，其作用顺序为苯扎米尔>非那米尔>阿米洛利，最大作用顺序为苯扎米尔=非那米尔=阿米洛利，钠转运恢复至基线水平顺序为非那米尔< benzamil benzamil >>阿米洛利。基于更大的效力，在绵羊体内药效学研究中比较了苯扎明和阿米洛利，包括气管粘液流速（TMV）和MC。苯扎明增强MC和TMV，但急性效力或作用时间没有超过阿米洛利。总之，我们的数据支持ENaC阻滞剂气雾剂治疗增加MC的假设。然而，苯扎明从粘膜表面的快速吸收抵消了其更大的效力，使其在体内与阿米洛利等效。有效的雾化CF药物治疗需要更强效、更难吸收的第三代ENaC阻滞剂。
Epithelial sodium channel (ENaC) blockers have been proposed as a therapy to restore mucus clearance ( MC) in cystic fibrosis (CF) airways. The therapeutic effects of the first generation ENaC blocker, amiloride, in CF patients, however, were minimal. Because the failure of amiloride reflected both its low potency and short duration of action on airway surfaces, we investigated whether the increased potency of benzamil and phenamil would produce more favorable pharmacodynamic properties. In vitro potency, maximal efficacy, rate of recovery from maximal block of ENaC, and rate of drug absorption were compared for amiloride, benzamil, and phenamil in cultured human and ovine bronchial epithelial cells. In both human and ovine bronchial epithelia, the rank order of potency was benzamil > phenamil >> amiloride, the maximal efficacy was benzamil = phenamil = amiloride, the recovery to baseline sodium transport was phenamil < benzamil benzamil >> amiloride. Based on greater potency, benzamil was compared with amiloride in in vivo pharmacodynamic studies in sheep, including tracheal mucus velocity (TMV) and MC. Benzamil enhanced MC and TMV, but acute potency or duration of effect did not exceed that of amiloride. In conclusion, our data support the hypothesis that ENaC blocker aerosol therapy increases MC. However, rapid absorption of benzamil from the mucosal surface offset its greater potency, making it equieffective with amiloride in vivo. More potent, less absorbable, third generation ENaC blockers will be required for an effective aerosol CF pharmacotherapy.