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肺结核患者的动态成像揭示肺部病变药物暴露的异质性
作者:小柯机器人 发布时间:2020/2/19 9:07:25

美国约翰·霍普金斯大学医学院Sanjay K. Jain研究团队通过肺结核患者的动态成像揭示出肺部病变药物暴露的异质性。这一研究成果2020年2月17日在线发表在国际学术期刊《自然—医学》上。

研究人员应用了一种新工具对人体中的抗菌素浓度-时间曲线进行了无偏差、无创和多区室测量。使用动态[11C]利福平(微剂量给药)正电子发射断层扫描(PET)和计算机断层扫描(CT),对首次确定的具有利福平敏感性肺结核的患者进行了一项首次人体研究。[11C]利福平PET-CT是安全的,并且在同一患者内病理学上不同的结核病灶中显示了空间分隔的利福平暴露。重复的PET-CT测量揭示了,同一患者不同病灶中利福平暴露轨迹的独立时间演变。PET-CT在实验感染的兔中也重现了类似的发现,并使用尸检质谱法进行了证实。细菌杀灭曲线实验中PET捕获的浓度-时间曲线集成模型提供了在4个月内达到治愈所需利福平的大致剂量。这些数据捕获了病灶内药代动力学(PK)的时空异质性,对抗菌药物的开发具有重要意义。
 
据悉,结核病(TB)能够导致死亡,需要至少6个月的多药物治疗才能治愈。但是,感染部位抗微生物药代动力学(PK)数据的缺乏阻碍了对抗微生物药剂量的优化和结核病治疗周期的缩短。
 
附:英文原文
 
Title: Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions

Author: Alvaro A. Ordonez, Hechuan Wang, Gesham Magombedze, Camilo A. Ruiz-Bedoya, Shashikant Srivastava, Allen Chen, Elizabeth W. Tucker, Michael E. Urbanowski, Lisa Pieterse, E. Fabian Cardozo, Martin A. Lodge, Maunank R. Shah, Daniel P. Holt, William B. Mathews, Robert F. Dannals, Jogarao V. S. Gobburu, Charles A. Peloquin, Steven P. Rowe, Tawanda Gumbo, Vijay D. Ivaturi, Sanjay K. Jain

Issue&Volume: 2020-02-17

Abstract: Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure1. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments2. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration–time profiles in humans3. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study4 using dynamic [11C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [11C]rifampin PET–CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET–CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET–CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration–time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.

DOI: 10.1038/s41591-020-0770-2

Source: https://www.nature.com/articles/s41591-020-0770-2

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex