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再利用阿莫地喹作为宿主靶向治疗炭疽的活性。

Activity of Repurposed Amodiaquine as a Host-Targeting Therapy for the Treatment of Anthrax.

机构信息

Henry E. Riggs School of Applied Life Sciences, Keck Graduate Institute (KGI), 535 Watson Drive, Claremont, California 91711, United States.

Shield Pharma LLC, 1420 North Claremont Boulevard, Suite 102A, Claremont, California 91711, United States.

出版信息

ACS Infect Dis. 2021 Aug 13;7(8):2176-2191. doi: 10.1021/acsinfecdis.1c00190. Epub 2021 Jul 4.

DOI:10.1021/acsinfecdis.1c00190
PMID:34218660
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8369491/
Abstract

Anthrax is caused by and can result in nearly 100% mortality due in part to anthrax toxin. Antimalarial amodiaquine (AQ) acts as a host-oriented inhibitor of anthrax toxin endocytosis. Here, we determined the pharmacokinetics and safety of AQ in mice, rabbits, and humans as well as the efficacy in the fly, mouse, and rabbit models of anthrax infection. In the therapeutic-intervention studies, AQ nearly doubled the survival of mice infected subcutaneously with a dose lethal to 60% of the animals (LD). In rabbits challenged with 200 LD of aerosolized , AQ as a monotherapy delayed death, doubled the survival rate of infected animals that received a suboptimal amount of antibacterial levofloxacin, and reduced bacteremia and toxemia in tissues. Surprisingly, the anthrax efficacy of AQ relies on an additional host macrophage-directed antibacterial mechanism, which was validated in the toxin-independent model of infection. Lastly, a systematic literature review of the safety and pharmacokinetics of AQ in humans from over 2 000 published articles revealed that AQ is likely safe when taken as prescribed, and its pharmacokinetics predicts anthrax efficacy in humans. Our results support the future examination of AQ as adjunctive therapy for the prophylactic anthrax treatment.

摘要

炭疽是由 引起的，由于炭疽毒素的作用，几乎 100%会导致死亡。抗疟药阿莫地喹 (AQ) 是一种宿主定向的炭疽毒素内吞作用抑制剂。在这里，我们确定了 AQ 在小鼠、兔子和人类中的药代动力学和安全性，以及在炭疽感染的蝇、鼠和兔模型中的疗效。在治疗干预研究中，AQ 使经皮下感染 剂量（LD）的 60%动物致死的小鼠的存活率几乎增加了一倍。在经气溶胶化 200LD 挑战的兔子中，AQ 作为单一疗法可延迟死亡，使接受了亚最佳剂量抗菌左氧氟沙星的感染动物的存活率增加一倍，并降低组织中的菌血症和毒血症。令人惊讶的是，AQ 的炭疽疗效依赖于另一种宿主巨噬细胞定向的抗菌机制，该机制在 感染的毒素非依赖性 模型中得到了验证。最后，对来自 2000 多篇已发表文章的关于 AQ 在人类中的安全性和药代动力学的系统文献综述表明，AQ 按规定服用时可能是安全的，其药代动力学可预测人类的炭疽疗效。我们的研究结果支持未来将 AQ 作为预防炭疽治疗的辅助疗法进行检查。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/33cf8c83e185/id1c00190_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/a02b1d5b4292/id1c00190_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/775423ab7455/id1c00190_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/5d2fdeaf5925/id1c00190_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/44a794d98174/id1c00190_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/33cf8c83e185/id1c00190_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/a02b1d5b4292/id1c00190_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/775423ab7455/id1c00190_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/5d2fdeaf5925/id1c00190_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/44a794d98174/id1c00190_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8277/8369491/33cf8c83e185/id1c00190_0005.jpg

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