Center for Parasitology and Mycology, Instituto Adolfo Lutz, Sao Paulo, Brazil.
Center for Parasitology and Mycology, Instituto Adolfo Lutz, Sao Paulo, Brazil.
Acta Trop. 2019 Jul;195:6-14. doi: 10.1016/j.actatropica.2019.04.017. Epub 2019 Apr 16.
Leishmaniases are infectious diseases caused by protozoan parasites Leishmania and transmitted by sand flies. Drug repurposing is a therapeutic approach that has shown satisfactory results in their treatment. Analyses of antihistaminic drugs have revealed their in vitro and in vivo activity against trypanosomatids. In this way, this study evaluated the antileishmanial activity of H1-antihistamines and identified the cellular alterations in Leishmania (L.) infantum. Cinnarizine, cyproheptadine, and meclizine showed activity against promastigotes with 50% inhibitory concentration (IC) values between 10-29 μM. These drugs also demonstrated activity and selectivity against intracellular amastigotes, with IC values between 20-35 μM. Fexofenadine and cetirizine lacked antileishmanial activity against both forms. Mammalian cytotoxicity studies revealed 50% cytotoxic concentration values between 52 - >200 μM. These drugs depolarized the mitochondria membrane of parasites and caused morphological alterations, including mitochondrial damage, disorganization of the intracellular content, and nuclear membrane detachment. In conclusion, the L. infantum death may be ascribed by the subcellular alterations followed by a pronounced decrease in the mitochondrial membrane potential, indicating dysfunction in the respiratory chain upon H1-antihistamine treatment. These H1-antihistamines could be used to explore new routes of cellular death in the parasite and the determination of the targets at a molecular level, would contribute to understanding the potential of these drugs as antileishmanial.
利什曼病是由原生动物寄生虫利什曼原虫引起的传染病，通过沙蝇传播。药物再利用是一种治疗方法，在治疗中已显示出满意的效果。对抗组胺药物的分析显示了它们在体外和体内对锥虫的活性。通过这种方式，本研究评估了 H1 抗组胺药的抗利什曼原虫活性，并确定了利什曼（L.）婴儿体内的细胞变化。桂利嗪、赛庚啶和甲氯噻嗪对前鞭毛体具有活性，50%抑制浓度（IC）值在 10-29 μM 之间。这些药物还对细胞内无鞭毛体表现出活性和选择性，IC 值在 20-35 μM 之间。非索非那定和西替利嗪对这两种形式均无抗利什曼原虫活性。哺乳动物细胞毒性研究显示 50%细胞毒性浓度值在 52- >200 μM 之间。这些药物使寄生虫的线粒体膜去极化并引起形态改变，包括线粒体损伤、细胞内内容物的紊乱和核膜分离。总之，L. 婴儿的死亡可能归因于亚细胞变化，随后线粒体膜电位明显下降，表明 H1 抗组胺治疗后呼吸链功能障碍。这些 H1 抗组胺药可用于探索寄生虫中新的细胞死亡途径，并在分子水平上确定靶标，有助于了解这些药物作为抗利什曼原虫的潜力。
