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LASSBio-1491 的临床前评估：从体外药代动力学研究到体内抗利什曼原虫活性。

Pre-clinical evaluation of LASSBio-1491: From in vitro pharmacokinetic study to in vivo leishmanicidal activity.

机构信息

National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio®, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil.

Laboratory of Pharmacology and Immunity (LaFI), Sector of Physiology and Pharmacology, ICBS, UFAL, Maceió, Alagoas, Brazil.

出版信息

PLoS One. 2022 Jun 6;17(6):e0269447. doi: 10.1371/journal.pone.0269447. eCollection 2022.

DOI:10.1371/journal.pone.0269447
PMID:35666748
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9170106/
Abstract

Leishmaniasis is a public health issue. It is among the top five parasitic illnesses worldwide and is one of the most neglected diseases. The current treatment disease includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. LASSBio-1736 was described as antileishmanial drug-candidate to cutaneous leishmaniasis, displaying plasma stability and with no preliminary signals of hepatic or renal toxicity. In this paper, we described the in vitro pharmacokinetic study of LASSBio-1491 (a less lipophilic isostere of LASSBio-1736) and it is in vitro and in vivo leishmanicidal activities. Our results demonstrated that LASSBio-1491 has high permeability, satisfactory aqueous solubility, long plasma and microsomal half-lives and low in vitro systemic clearance, suggesting a pharmacokinetic profile suitable for its use in a single daily dose. The antileishmanial effect of LASSBio-1491 was confirmed in vitro and in vivo. It exhibited no cytotoxic effect to mammalian cells and displayed good in -vivo effect against BALB/c mice infected with Leishmania major LV39 substrain, being 3 times more efficient than glucantime.

摘要

利什曼病是一个公共卫生问题。它是全球前五种寄生虫病之一，也是最被忽视的疾病之一。目前的治疗方法包括毒性限制、疗效不稳定、成本高、剂量和治疗方案不方便等。LASSBio-1736 被描述为一种针对皮肤利什曼病的抗利什曼病候选药物，具有血浆稳定性，没有肝毒性或肾毒性的初步信号。在本文中，我们描述了 LASSBio-1491（LASSBio-1736 的一种疏水性较低的等排体）的体外药代动力学研究及其体外和体内杀利什曼原虫活性。我们的结果表明，LASSBio-1491 具有高通透性、令人满意的水溶解度、长血浆和微粒体半衰期以及低体外全身清除率，表明其药代动力学特征适合每日单剂量使用。LASSBio-1491 的抗利什曼原虫作用在体外和体内得到了证实。它对哺乳动物细胞没有细胞毒性作用，并对感染利什曼原虫 LV39 亚株的 BALB/c 小鼠表现出良好的体内效果，比葡萄糖酸锑钠有效 3 倍。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/69929a104731/pone.0269447.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/5b9e7947f7c0/pone.0269447.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/2179629327e7/pone.0269447.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/bb3bb612c97d/pone.0269447.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/69929a104731/pone.0269447.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/5b9e7947f7c0/pone.0269447.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/2179629327e7/pone.0269447.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/bb3bb612c97d/pone.0269447.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9855/9170106/69929a104731/pone.0269447.g004.jpg

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