An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates.
An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates.
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DOI：
10.1016/j.ejpb.2016.03.008
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Brown MB
中科院分区：
文献类型：
--
作者：
McAuley WJ;Jones SA;Traynor MJ;Guesné S;Murdan S;Brown MB
甲真菌病的治疗仍然存在问题，即使有几个有效的抗真菌药物可供患者使用。本研究的目的是了解当患者的指甲变成感染板时出现的结构改变是否会影响局部应用后药物渗透到指甲中。希望通过提高对疾病状态下甲屏障的理解，可以促进更有效的甲真菌病局部治疗的发展。在健康和甲真菌病感染的全层人指甲盖切片中评估了具有不同疏水性的三种化合物咖啡因、特比萘芬和阿莫罗芬（clog D在pH 7.4下分别为-0.55，3.72和4.49）的渗透。对健康和患病指甲进行的经甲失水（TOWL）测量支持了先前的观察结果，即指甲表现得像多孔屏障，因为TOWL值与较厚的患病指甲之间缺乏相关性。与健康指甲相比，更具亲水性的咖啡因在患病指甲中的通量是两倍，而疏水性分子特比萘芬和阿莫罗芬的指甲渗透率没有统计学显著变化。咖啡因通量通过指甲被发现与TOWL测量，虽然没有相关性存在的更疏水的药物。这些数据支持这样的观点，即感染打开的指甲孔促进了亲水性分子的通过，而疏水性分子的角蛋白结合意味着它们通过指甲板的运输没有改变。因此，为了利用由指甲真菌感染引起的结构变化，开发一种小分子量的亲水性抗真菌剂将是有益的，其表现出低水平的角蛋白结合。
The treatment of onychomycosis remains problematic even though there are several potent antifungal agents available for patient use. The aim of this investigation was to understand whether the structural modifications that arise when a patient’s nail become infected plates influences the permeation of drugs into the nail following topical application. It was hoped that through improving understanding of the nail barrier in the diseased state, the development of more effective topical treatments for onychomycosis could be facilitated. The permeation of three compounds with differing hydrophobicities, caffeine, terbinafine and amorolfine (clog D at pH 7.4 of −0.55, 3.72 and 4.49 respectively), was assessed across both healthy and onychomycosis infected, full thickness, human nail plate sections. Transonychial water loss (TOWL) measurements performed on the healthy and diseased nails supported previous observations that the nail behaves like a porous barrier given the lack of correlation between TOWL values with the thicker, diseased nails. The flux of the more hydrophilic caffeine was twofold greater across diseased in comparison with the healthy nails, whilst the hydrophobic molecules terbinafine and amorolfine showed no statistically significant change in their nail penetration rates. Caffeine flux across the nail was found to correlate with the TOWL measurements, though no correlation existed for the more hydrophobic drugs. These data supported the notion that the nail pores, opened up by the infection, facilitated the passage of hydrophilic molecules, whilst the keratin binding of hydrophobic molecules meant that their transport through the nail plate was unchanged. Therefore, in order to exploit the structural changes induced by nail fungal infection it would be beneficial to develop a small molecular weight, hydrophilic antifungal agent, which exhibits low levels of keratin binding.