Wyde P R, Six H R, Wilson S Z, Gilbert B E, Knight V
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030.
Antimicrob Agents Chemother. 1988 Jun;32(6):890-5. doi: 10.1128/AAC.32.6.890.
Enviroxime has been shown to inhibit the replication of rhinoviruses and other enteroviruses in concentrations as low as nanograms per milliliter in in vitro assays but is markedly less effective in clinical trials. The marked hydrophobicity and water insolubility of this compound may be a factor for this disparity. To overcome this handicap, we incorporated enviroxime into liposomes and then tested the antirhinovirus activity and toxicity of the liposome-incorporated enviroxime (LE) in cell culture and studied its administration by small-particle aerosol. Free enviroxime and LE were found to have equivalent efficacies against rhinovirus strains 1A and 13 in in vitro assays; however, preparations of LE were 10- to greater than or equal to 50-fold less toxic to tissue culture cells than was free enviroxime. In contrast to free enviroxime, which could not be delivered by small-particle aerosol because of its water insolubility, LE (4 mg/ml) was readily and successfully delivered by small-particle aerosol to the upper and lower respiratory tracts of mice; after just 20 min, significant levels of enviroxime were detected in the lungs and noses of exposed mice. Moreover, mice exposed to aerosols of liposomes containing both enviroxime and fluorescein isothiophosphatidylethanolamine showed accumulations of the fluorescent marker in the lungs, particularly in or around the tall columnar epithelial cells lining the bronchi and bronchioles.
在体外试验中，已证明恩韦肟在低至每毫升纳克的浓度下就能抑制鼻病毒和其他肠道病毒的复制，但在临床试验中其效果明显较差。该化合物显著的疏水性和水不溶性可能是造成这种差异的一个因素。为克服这一障碍，我们将恩韦肟包封于脂质体中，然后在细胞培养中测试了包封恩韦肟的脂质体（LE）的抗鼻病毒活性和毒性，并研究了其通过小颗粒气雾剂给药的情况。在体外试验中发现，游离恩韦肟和LE对鼻病毒1A和13株具有同等效力；然而，LE制剂对组织培养细胞的毒性比游离恩韦肟低10至大于或等于50倍。与因水不溶性而无法通过小颗粒气雾剂给药的游离恩韦肟不同，LE（4毫克/毫升）很容易且成功地通过小颗粒气雾剂递送至小鼠的上、下呼吸道；仅20分钟后，在暴露小鼠的肺部和鼻腔中就检测到了显著水平的恩韦肟。此外，暴露于含有恩韦肟和异硫氰酸荧光素磷脂酰乙醇胺的脂质体气雾剂的小鼠，其肺部尤其是支气管和细支气管内衬的高柱状上皮细胞内或其周围出现了荧光标记物的积聚。
