Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model
Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model
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DOI：
10.1128/aac.01164-06
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发表时间：
2007-08-01
影响因子：
4.9
通讯作者：
Edwards, D.
中科院分区：
文献类型：
--
作者：
Garcia-Contreras, L.;Fiegel, J.;Edwards, D.
卷曲霉素用于治疗耐多药结核病（MDR-TB），但其严重的副作用在治疗上受到限制。本研究的目的是（i）设计用于有效肺部递送的低密度多孔硫酸卷曲霉素颗粒，以改善局部和全身药物生物利用度和以与肌内注射所实现的方式类似的方式降低肺部中的细菌负荷的能力;（ii）确定肺部施用这些卷曲霉素颗粒后的药代动力学参数;和（iii）评价这些颗粒在TB的小气雾剂接种豚鼠模型中治疗动物的功效。卷曲霉素颗粒通过喷雾干燥制备，并在尺寸和药物含量方面进行表征。健康豚鼠吹入卷曲霉素颗粒后，采用非房室方法测定药代动力学参数。通过组织病理学分析以及TB感染动物的湿器官重量和细菌负荷来评价颗粒的功效。接受14.5 mg/kg剂量卷曲霉素颗粒的动物的肺显示出比接受任何其他治疗的动物显著更低的湿重和更小的细菌负荷。这些结果得到了组织病理学分析的支持。豚鼠的药代动力学和药效学研究证明了吸入卷曲霉素新粉末形式的可行性，其最终目的是治疗耐多药结核病。如果应用于耐多药结核病患者，这种治疗方法可能会通过消除注射来简化药物输送，并可能通过降低剂量来减少不良反应。
Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.