Sohaskey Charles
Tuberculosis Research Laboratory 151, Department of Veterans Affairs Medical Center, 5901 East Seventh Street, Long Beach, CA 90822, USA.
Recent Pat Antiinfect Drug Discov. 2011 May;6(2):139-46. doi: 10.2174/157489111796064551.
Approximately 1/3 of the world's population is infected with Mycobacterium tuberculosis. In the vast majority of cases this results in latent not active disease. Latent disease is defined as a positive reaction to tuberculin antigens but without any further clinical symptoms. Models have been developed to study latent tuberculosis with the two most prominent being the in vivo murine model and the in vitro Wayne model. In both cases M. tuberculosis undergoes a change in its respiratory profile as it shifts down to a nonreplicating state. However in both the mouse and the Wayne model, dormant M. tuberculosis is sensitive to the phenothiazine thioridazine. This antibiotic has several targets, and the main one is respiration. There is a growing burden of multidrug resistant and extensively drug resistant tuberculosis. Treatment of these cases is expensive with high mortality. We propose that thioridazine alone, or with other antibiotics, be used to treat drug resistant latent tuberculosis. The advantages are that thioridazine is inexpensive, effective against drug resistant tuberculosis, well characterized and unlikely to induce drug resistance. The disadvantages include possible side effects, although these should be rare at the doses and length of time of treatment. Recent patents involving analogs of thioridazine suggest this class of drugs may hold great promise for the future treatment of the most drug resistant strains.
世界上约三分之一的人口感染了结核分枝杆菌。在绝大多数情况下，这会导致潜伏性而非活动性疾病。潜伏性疾病被定义为对结核菌素抗原呈阳性反应但无任何进一步临床症状。已经开发出模型来研究潜伏性结核病，其中最突出的两种是体内小鼠模型和体外韦恩模型。在这两种情况下，结核分枝杆菌在转变为非复制状态时其呼吸特征都会发生变化。然而，在小鼠模型和韦恩模型中，休眠的结核分枝杆菌对吩噻嗪类药物硫利达嗪敏感。这种抗生素有多个靶点，主要靶点是呼吸作用。耐多药和广泛耐药结核病的负担日益加重。这些病例的治疗费用高昂且死亡率高。我们建议单独使用硫利达嗪或与其他抗生素联合使用来治疗耐药潜伏性结核病。其优点是硫利达嗪价格低廉、对耐药结核病有效、特性明确且不太可能诱导耐药性。缺点包括可能有副作用，不过在治疗剂量和疗程下这些副作用应该很少见。最近涉及硫利达嗪类似物的专利表明这类药物可能对未来治疗最耐药菌株有很大前景。
