Ceska Slov Farm. 2020 Winter;69(5-6):203-210.
The prevalence of multidrug-resistant tuberculosis (MDR--TB) and extensively drug-resistant tuberculosis (XDR--TB) has been increasing at an alarming rate worldwide. Todays “Fight against Tuberculosis“ programmes in the Russian Federation are subsidized by state and regional governments as well as health authorities. Each region has its own specific characteristics and needs specific interventions. Although some novel anti-tuberculosis (anti-TB) drugs (bedaquiline, delamanid) were approved by relevant authorities, and some promising compounds, especially those of oxazolidinones, are in various phases of clinical trials worldwide, the finding of effective, safe, pharmacokinetically favo-rable, economically and logistically accessible anti-TB agents still remains a serious challenge for medical and pharmaceutical sciences. Perchlozone, a compound containing a thiosemicarbazone scaffold, was approved in the Russian Federation in 2012 for the treatment (alone or as the active component of complex treatment regimens) of HIV-1 negative as well as HIV-1 positive patients suffering from MDR-TB or XDR-TB. Mechanism of anti-TB action of perchlozone might be similar to that of thiacetazone, which belongs into the same chemical class. Perchlozone has to be probably activated into reactive species by a mycobacterially encoded monoxygenase (EthA). The activated forms might act in multiple ways, including inhibition of mycobacterial cell wall synthesis due to interfence with a dehydration step of the type II fatty acid synthase pathway or sensitization of the Mycobacterium tuberculosis cell to oxidative stress. Favorable toxicological properties of perchlozone and its tolerability by the human organism were confirmed within revevant preclinical and clinical studies. However, recent preliminary investigations in vivo (animal models) could indicate genotoxicity after subacute inhalation of the drug. Regarding this issue, further development of more convenient nano- or microparticle-based formulations of perchlozone potentially improving targeted delivering and efficiency as well as decreasing (eliminating) its eventual toxicity might be taken into strong consideration.
全球范围内，耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）的患病率正以惊人的速度增长。如今，俄罗斯联邦的“抗击结核病”计划得到了州和地区政府以及卫生当局的资助。每个地区都有其自身的特点和特定的干预需求。虽然一些新型抗结核（抗 TB）药物（贝达喹啉、德拉马尼）已获得相关部门的批准，并且一些有前途的化合物，特别是那些恶唑烷酮类化合物，正在全球范围内处于不同的临床试验阶段，但寻找有效、安全、药代动力学有利、经济实惠且便于获取的抗 TB 药物仍然是医学和制药科学面临的严峻挑战。过氧氯唑，一种含有硫代半卡巴腙支架的化合物，于 2012 年在俄罗斯联邦获得批准，用于治疗（单独使用或作为复杂治疗方案的活性成分）HIV-1 阴性和 HIV-1 阳性的耐多药结核病或广泛耐药结核病患者。过氧氯唑的抗结核作用机制可能与噻唑酰胺相似，噻唑酰胺属于同一类化学物质。过氧氯唑可能需要被分枝杆菌编码的单加氧酶（EthA）激活成反应性物质。激活的形式可能通过多种方式发挥作用，包括通过干扰 II 型脂肪酸合酶途径的脱水步骤来抑制分枝杆菌细胞壁的合成，或者使结核分枝杆菌细胞对氧化应激敏感。在相关的临床前和临床研究中证实了过氧氯唑良好的毒理学特性及其在人体中的耐受性。然而，最近在体内（动物模型）的初步研究可能表明，该药物亚急性吸入后具有遗传毒性。关于这个问题，进一步开发更方便的过氧氯唑纳米或微颗粒制剂，具有提高靶向性和效率以及降低（消除）其潜在毒性的潜力，可能会受到强烈关注。
