Felix Christian M, Lee Sujin, Levin Marc H, Verkman Alan S
Departments of Medicine and Physiology, University of California, San Francisco, California, United States.
Department of Ophthalmology, Palo Alto Medical Foundation, Palo Alto, California, United States.
Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4506-4513. doi: 10.1167/iovs.17-22525.
Pharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro-secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTRact-K267), fully activated human wildtype CFTR with EC50 ∼ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-K267 were done in adult New Zealand white rabbits.
CFTR chloride conductance was measured in vivo by ocular surface potential differences and in ex vivo conjunctiva by short-circuit current. Tear volume was measured by the Schirmer tear test II and CFTRact-K267 pharmacokinetics and tissue distribution by liquid chromatography/mass spectrometry. Toxicity profile was studied for 28 days with twice-daily topical administration.
Electrophysiological measurements in vivo and in ex vivo conjunctiva demonstrated CFTR activation by CFTRact-K267. A single topical dose of 3 nmol CFTRact-K267 increased tear production by >5 mm for 9 hours by the Schirmer tear test, with predicted therapeutic concentrations maintained in tear fluid. No tachyphylaxis was seen following 28-day twice-daily administration, and changes were not observed in corneal surface integrity or thickness, intraocular pressure, or ocular histology. At day 28, CFTRact-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs.
These studies support the development of CFTRact-K267 as a pro-secretory therapy for dry eye disorders.
眼表囊性纤维化跨膜传导调节因子（CFTR）氯离子通道的药理学激活是一种治疗干眼疾病的潜在促分泌方法。我们之前报道了氨基苯基-1,3,5-三嗪的发现，其中一种，N-甲基-N-苯基-6-(2,2,3,3-四氟丙氧基)-1,3,5-三嗪-2,4-二胺（以下称为CFTRact-K267），能完全激活人类野生型CFTR，其半数有效浓度（EC50）约为30 nM，并能使小鼠泪液量增加8小时。在此，我们对成年新西兰白兔进行了CFTRact-K267的功能和药理学研究。
通过眼表电位差在体内测量CFTR氯离子传导率，通过短路电流在体外结膜中测量。通过Schirmer泪液试验II测量泪液量，通过液相色谱/质谱法测量CFTRact-K267的药代动力学和组织分布。通过每日两次局部给药进行28天的毒性研究。
体内和体外结膜的电生理测量表明CFTRact-K267可激活CFTR。单次局部给予3 nmol CFTRact-K267，通过Schirmer泪液试验可使泪液分泌在9小时内增加超过5 mm，泪液中维持了预测的治疗浓度。每日两次给药28天后未观察到快速耐受现象，角膜表面完整性、厚度、眼压或眼部组织学也未观察到变化。在第28天，CFTRact-K267集中在角膜和结膜中，在血液或外周器官中未检测到。
这些研究支持将CFTRact-K267开发为一种治疗干眼疾病的促分泌疗法。
