Intraocular properties of hexadecyloxypropyl-cyclic-cidofovir in Guinea pigs.
Intraocular properties of hexadecyloxypropyl-cyclic-cidofovir in Guinea pigs.
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十六烷氧基丙基环西多福韦在豚鼠中的眼内特性。
DOI：
10.1089/jop.2005.21.205
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Freeman,WR
中科院分区：
文献类型：
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作者：
Lu,Stephanie;Cheng,Lingyun;Hostetler,KarlY;Koh,HyoungJun;Beadle,JamesR;Davidson,MarieC;Freeman,WR
目的：我们先前报道了一种长效的结晶脂质环西多福韦前体药物，十六烷氧基丙基环西多福韦（HDP-cCDV），治疗兔眼实验性视网膜炎。HDP-cCDV的眼内治疗效果比西多福韦（CDV）更长，100 µg/眼无毒性。众所周知，CDV和相关类似物在局部使用后会降低眼内压（IOP），并且在人体临床试验之前，豚鼠是研究这种毒性的更好模型，这也是公认的。方法：将HDP-cCDV以20 μL/眼的4、9和18 μg剂量玻璃体内注射到10只豚鼠眼中。18 µg的剂量相当于家兔中100 µg/眼的剂量。每只动物只有一只眼睛接受药物，另一只眼睛作为对照。注射后，用眼压计、检眼镜、视网膜电图（ERG）和组织学进行监测。结果：在10周的观察期间，玻璃体内注射18 μg/眼或更低的剂量显示无毒性和高治疗指数（比人巨细胞病毒的50%有效浓度高132，000至3300倍）。晶体药物贮库在下玻璃体腔中眼底镜可见5-10周。除药物注射后第3天（P= 0.0338）外，在任何时间点，药物注射眼和对照眼之间的IOP均无差异（P> 0.05）。所有眼睛均显示正常的ERG波形，治疗眼和对照眼之间无差异（P= 0.85）。组织学显示正常的形态和结构的视网膜和睫状体在所有的眼睛（有或没有治疗）。结论：结晶HDP-cCDV可能是一个持久的和更安全的替代西多福韦治疗CMV视网膜炎没有视网膜或睫状体毒性观察CDV。
Objective:We previously reported a long-lasting crystalline lipid pro-drug of cyclic cidofovir, hexadecyloxypropyl–cyclic-cidofovir (HDP-cCDV), to treat experimental retinitis in rabbit eyes. With HDP-cCDV there was a longer intraocular therapeutic effect than with cidofovir (CDV) and no toxicity with 100 µg/eye. It has been known that CDV and related analogues lower intraocular pressure (IOP) after local use, and it is also accepted that the guinea pig is a better model to study this toxicity before human clinical trials.Methods:HDP-cCDV was intravitreally injected into 10 guinea pig eyes in doses of 4, 9, and 18 µg in 20 µL/eye. An 18-µg quantity is the dose equivalent to 100 µg/eye in the rabbit. Only one eye of each animal received drug and the fellow eye served as the control. After injection, the eyes were monitored with tonometry, ophthalmoscopy, electroretinography (ERG), and histology.Results:Intravitreal injections of doses of 18 µg/eye or lower revealed no toxicity and a high therapeutic index (132,000 to 3300 times higher than the 50% effective concentration for human cytomegalovirus) during 10 weeks of observation. The crystalline drug depot was ophthalmoscopically visible in the inferior vitreous cavity for 5–10 weeks. There was no difference in IOP between the drug-injected and control eyes at any time points (P> 0.05) except for day 3 after drug injection (P= 0.0338). All eyes demonstrated a normal ERG waveform with no differences between the treated and the fellow control eyes (P= 0.85). Histology revealed normal morphology and structures of the retina and ciliary body in all eyes (with or without treatment).Conclusion:Crystalline HDP-cCDV may be a long-lasting and safer alternative to cidofovir to treat CMV retinitis without the retinal or ciliary body toxicity observed with CDV.