Düzgüneş N, Perumal V K, Kesavalu L, Goldstein J A, Debs R J, Gangadharam P R
Cancer Research Institute, University of California, San Francisco 94143-0128, USA.
Antimicrob Agents Chemother. 1988 Sep;32(9):1404-11. doi: 10.1128/AAC.32.9.1404.
We examined the therapeutic effects of free and liposome-encapsulated amikacin on Mycobacterium avium-M. intracellulare complex infection by using the beige-mouse model of the disease. In the first series of studies, intravenous administration of four weekly doses of 5 mg of amikacin per kg encapsulated in large (approximately 0.4-micron diameter), unilamellar liposomes arrested the growth of M. avium-M. intracellulare complex organisms in the liver, as measured by CFU counts. M. avium-M. intracellulare complex levels in untreated animals and in those treated with the same dose of free amikacin increased by several orders of magnitude over 8 weeks. Liposome-encapsulated amikacin was also effective against M. avium-M. intracellulare complex organisms in the spleen and kidneys, reducing the CFU counts by about 1,000-fold compared with those of both untreated controls and free-drug-treated mice. In the lungs, a slight reduction in CFU was observed in the liposome-encapsulated-amikacin-treated group, but only at the 8-week point. Neither free nor liposome-encapsulated amikacin reduced the colony counts in the lymph nodes compared with those of control animals. Reductions in CFU in all organs greater than those caused by the liposome preparation could be achieved by intramuscular administration of free amikacin, but only at a 10-fold-higher dose given 6 days a week for 8 weeks. In the second series of studies, we investigated the effects of (i) doubling the dose of liposome-encapsulated amikacin and (ii) increasing the size of the liposomes and prolonging the treatment to five injections. Administration of 10 mg of amikacin per kg in liposomes 2 to 3 micrometer in diameter was more effective in the liver than 5 or 10 mg of amikacin per kg in liposomes 0.2 micrometer in diameter. A slight reduction in the CFU levels in the lungs was observed with the higher dose, irrespective of liposome size. Our results indicate that liposome-based delivery of amikacin enhances its anti-M. intracellulare complex activity, particularly in the liver, spleen, and kidney, and may therefore improve the therapy of this disease.
我们使用米色小鼠疾病模型，研究了游离阿米卡星和脂质体包裹的阿米卡星对鸟分枝杆菌-胞内分枝杆菌复合菌感染的治疗效果。在第一系列研究中，通过CFU计数测量，静脉注射每周4次、每次每千克5毫克包裹在大的（直径约0.4微米）单层脂质体中的阿米卡星，可抑制肝脏中鸟分枝杆菌-胞内分枝杆菌复合菌的生长。未治疗动物以及用相同剂量游离阿米卡星治疗的动物体内，鸟分枝杆菌-胞内分枝杆菌复合菌水平在8周内增加了几个数量级。脂质体包裹的阿米卡星对脾脏和肾脏中的鸟分枝杆菌-胞内分枝杆菌复合菌也有效，与未治疗对照组和游离药物治疗小鼠相比，CFU计数减少了约1000倍。在肺部，脂质体包裹阿米卡星治疗组在8周时观察到CFU略有下降。与对照动物相比，游离和脂质体包裹的阿米卡星均未降低淋巴结中的菌落计数。通过肌肉注射游离阿米卡星，所有器官中的CFU减少量均大于脂质体制剂，但仅在每周给药6天、持续8周的情况下，剂量要高10倍。在第二系列研究中，我们研究了（i）将脂质体包裹的阿米卡星剂量加倍以及（ii）增大脂质体尺寸并将治疗延长至5次注射的效果。每千克10毫克阿米卡星包裹在直径2至3微米的脂质体中，在肝脏中的效果比每千克5或10毫克阿米卡星包裹在直径0.2微米的脂质体中更有效。无论脂质体大小如何，较高剂量时肺部的CFU水平均略有下降。我们的结果表明，基于脂质体的阿米卡星递送增强了其抗胞内分枝杆菌复合菌活性，特别是在肝脏、脾脏和肾脏中，因此可能改善该疾病的治疗。
