Ranjan Rajeev, Devireddy Venkata Siva Reddy
Faculty of Pharmacy, Gopal Narayan Singh University, Sasaram, Bihar, India.
Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.
J Aerosol Med Pulm Drug Deliv. 2024 Dec 9. doi: 10.1089/jamp.2024.0051.
Drug resistant tuberculosis is a major public health concern, since the causative agent Mycobacterium tuberculosis is resistant to the most effective drugs against tuberculosis treatment ie., rifampicin and isoniazid. Globally, it accounts 4.6 percent of the patients with tuberculosis, but in some low socioeconomic areas this proportion exceeds to 25 percent. The treatment of drug resistant tuberculosis is prolonged (9-12 months) and often have less favorable outcome with novel as well as recently repurposed drugs administered by conventional routes. Clinically, these repurposed drugs have shown several major concerns including low penetration of the drugs to the pulmonary region, emergence of resistant forms, first pass effects, drug-drug interactions, food effects, and serious side effects upon administration by conventional route of administration. Although, several antimicrobial agents have been either approved or are under investigation at different stages of clinical trials and in pre-clinical studies via inhalation route for the treatment of respiratory infections, inhalable formulation for the treatment of drug resistant tuberculosis is most untouched aspect of drug delivery to validate clinically. Only a single dry powder inhalation formulation of capreomycin is able to reach the milestone, ie., phase I for the treatment of drug resistant tuberculosis. Administering inhalable formulations of repurposed drugs as adjuvant in the treatment of drug resistant tuberculosis could mitigate several concerns by targeting drugs directly in the vicinity of bacilli. This review focuses on the limitations and major concerns observed during clinical trials of repurposed drugs (host directed or bactericidal drugs) administered conventionally for the treatment of drug resistant tuberculosis. The outcomes and the concerns of these clinical trials rationalized the need of repurposing formulation which could be administered by inhalation route as adjunctive treatment of drug resistant tuberculosis. [Figure: see text].
耐多药结核病是一个重大的公共卫生问题，因为致病因子结核分枝杆菌对治疗结核病最有效的药物即利福平和异烟肼具有耐药性。在全球范围内，耐多药结核病患者占结核病患者的4.6%，但在一些社会经济水平较低的地区，这一比例超过了25%。耐多药结核病的治疗疗程较长（9 - 12个月），而且使用传统给药途径的新型药物以及近期重新利用的药物治疗时，效果往往不太理想。临床上，这些重新利用的药物存在几个主要问题，包括药物在肺部区域的渗透率低、耐药形式的出现、首过效应、药物相互作用、食物影响以及传统给药途径给药时的严重副作用。尽管有几种抗菌药物已被批准或正处于临床试验的不同阶段以及临床前研究中，通过吸入途径用于治疗呼吸道感染，但用于治疗耐多药结核病的可吸入制剂是药物递送中最未被临床验证的方面。只有一种卷曲霉素的干粉吸入制剂能够达到里程碑，即进入治疗耐多药结核病的I期试验。将重新利用药物的可吸入制剂作为耐多药结核病治疗的辅助药物，可以通过将药物直接靶向到杆菌附近来减轻几个问题。本综述重点关注在耐多药结核病治疗中传统给药的重新利用药物（宿主导向或杀菌药物）临床试验期间观察到的局限性和主要问题。这些临床试验的结果和问题表明，需要重新开发可通过吸入途径给药的制剂，作为耐多药结核病的辅助治疗。[图：见正文]
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