Pharmacology Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., 14 Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042, Japan.
Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., 301 Gensuke, Fujieda-shi, Shizuoka 426-8646, Japan.
J Mycol Med. 2022 Aug;32(3):101259. doi: 10.1016/j.mycmed.2022.101259. Epub 2022 Feb 25.
To be effective against onychomycosis, topically applied drugs have to reach the infection site at an effective concentration to exert antifungal activity against the parasitic form of dermatophytes. We established a novel in vitro method for predicting drug efficacy at the infection site and verified the method by comparing the efficacy of two azole class topical anti-onychomycosis drugs. To predict drug efficacy in the nail plate, a human nail permeability test was conducted and the activities of the free-drugs in the upper, middle, and lowest layers of the nail plate were determined by measuring the growth inhibitory zone. Efinaconazole permeated the nail more efficiently than luliconazole, and the amount of efinaconazole in the middle and lowest layers was higher compared with that of luliconazole. Efinaconazole demonstrated antifungal activities at the concentrations in all of the nail layers, whereas luliconazole was only active at the concentrations in the upper and middle layers. The results could be explained by differences in their affinity for keratin and nail permeability. The established method enables the evaluation of nail permeability and anti-arthrospore activity of free-drugs in the nail plate to predict drug efficacy. This method will be useful for new topical drug development.
为了有效治疗甲真菌病，局部应用药物必须达到有效浓度，以发挥抗真菌活性，对抗寄生形式的皮肤癣菌。我们建立了一种新的体外方法来预测感染部位的药物疗效，并通过比较两种唑类局部抗甲真菌病药物的疗效来验证该方法。为了预测指甲板中的药物疗效，进行了人体指甲通透性试验，并通过测量生长抑制区来确定指甲板上层、中层和最下层中游离药物的活性。依氟康唑比卢立康唑更有效地渗透指甲，并且依氟康唑在中层和最下层的量比卢立康唑高。依氟康唑在所有指甲层的浓度下均表现出抗真菌活性，而卢立康唑仅在指甲上层和中层的浓度下具有活性。这些结果可以用它们对角蛋白的亲和力和指甲通透性的差异来解释。所建立的方法能够评估游离药物在指甲板中的指甲通透性和抗孢子活性，以预测药物疗效。该方法将有助于新的局部药物开发。
