Johns Hopkins University School of Nursing, 525 North Wolfe Street, Baltimore, MD, 21205, USA.
Johns Hopkins University School of Nursing, The REACH Initiative, 855 N. Wolfe Street, 21205, Baltimore, MD, USA.
Arch Toxicol. 2019 May;93(5):1385-1399. doi: 10.1007/s00204-019-02407-8. Epub 2019 Apr 8.
Individuals treated for multidrug-resistant tuberculosis (MDR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss. However, AG ototoxicity has never been conceptually integrated or causally linked to MDR-TB patients' pre-treatment health condition. We sought to develop a framework that examines the relationships between pre-treatment conditions and AG-induced hearing loss among MDR-TB-infected individuals in sub-Saharan Africa. The adverse outcome pathway (AOP) approach was used to develop a framework linking key events (KEs) within a biological pathway that results in adverse outcomes (AO), which are associated with chemical perturbation of a molecular initiating event (MIE). This AOP describes pathways initiating from AG accumulation in hair cells, sound transducers of the inner ear immediately after AG administration. After administration, the drug catalyzes cellular oxidative stress due to overproduction of reactive oxygen species. Since oxidative stress inhibits mitochondrial protein synthesis, hair cells undergo apoptotic cell death, resulting in irreversible hearing loss (AO). We identified the following pre-treatment conditions that worsen the causal linkage between MIE and AO: HIV, malnutrition, aging, noise, smoking, and alcohol use. The KEs are: (1) nephrotoxicity, pre-existing hearing loss, and hypoalbuminemia that catalyzes AG accumulation; (2) immunodeficiency and antioxidant deficiency that trigger oxidative stress pathways; and (3) co-administration of mitochondrial toxic drugs that hinder mitochondrial protein synthesis, causing apoptosis. This AOP clearly warrants the development of personalized interventions for patients undergoing MDR-TB treatment. Such interventions (i.e., choosing less ototoxic drugs, scheduling frequent monitoring, modifying nutritional status, avoiding poly-pharmacy) will be required to limit the burden of AG ototoxicity.
在资源有限的环境中，接受氨基糖苷类药物（AGs）治疗的耐多药结核病（MDR-TB）患者常经历永久性听力损失。然而，AG 耳毒性从未在概念上被整合或因果关系与 MDR-TB 患者的治疗前健康状况联系起来。我们试图开发一个框架，以检查撒哈拉以南非洲地区 MDR-TB 感染个体的治疗前条件与 AG 诱导的听力损失之间的关系。采用不良结局途径（AOP）方法来开发一个框架，将生物途径内的关键事件（KEs）与导致不良结局（AO）的途径联系起来，这些结局与化学干扰分子起始事件（MIE）有关。该 AOP 描述了从 AG 在毛细胞中的积累开始的途径，AG 给药后立即成为内耳的声音传感器。给药后，药物由于活性氧（ROS）的过度产生而催化细胞氧化应激。由于氧化应激抑制线粒体蛋白合成，毛细胞经历凋亡性细胞死亡，导致不可逆的听力损失（AO）。我们确定了以下治疗前条件，这些条件会加剧 MIE 和 AO 之间的因果联系：HIV、营养不良、衰老、噪音、吸烟和饮酒。KEs 是：（1）肾毒性、先前存在的听力损失和低白蛋白血症，这些会促进 AG 积累；（2）免疫缺陷和抗氧化剂缺乏，这些会触发氧化应激途径；（3）线粒体毒性药物的共同给药，这些药物会阻碍线粒体蛋白合成，导致细胞凋亡。该 AOP 清楚地表明需要为接受 MDR-TB 治疗的患者开发个性化干预措施。这些干预措施（即选择毒性较小的药物、定期监测、改善营养状况、避免多种药物联合使用）将是限制 AG 耳毒性负担所必需的。
