聚乙二醇滴眼液对拉坦前列腺素眼表毒性的中和作用

Neutralization of polyethylene glycol on ocular surface toxicity induced by benzalkonium chloride-preservedlatanoprost

背景减少局部抗青光眼药物的眼表毒性、提高患者对药物治疗的依从性已经成为青光眼药物治疗过程中亟待解决的问题。聚乙二醇是一种新型的人工泪液，其是否可以减轻抗青光眼药物局部应用后的眼表毒性尚待研究。目的探讨聚乙二醇对拉坦前列腺素滴眼液中防腐剂苯扎氯胺所致眼表毒性的影响。方法采用随机数字表法将30只新西兰大白兔分为3个组，每组10只，正常对照组兔眼不给予任何干预，PBS处理组给予质量分数0．005％拉坦前列腺素联合PBS溶液连续点眼60d，聚乙二醇处理组给予0．005％拉坦前列腺素联合聚乙二醇滴眼液点眼60d。分别于用药前及用药后第31天和第61天行兔眼基础泪液分泌试验、角膜荧光素染色评分、角膜结膜虎红染色评分和结膜印迹细胞学检查，并于第61天获取角膜及球结膜组织标本行扫描电子显微镜和透射电子显微镜观察。结果对照组、PBS处理组及聚乙二醇处理组在实验第31天和第6l天的角膜荧光素染色评分差异均有统计学意义（H=25．265、29．426，P〈0．001）；3个组在实验第31天和第61天角膜球结膜虎红染色评分差异均有统计学意义（H=26．167、29．212，P〈0．001）；各组不同时间点基础泪液分泌量的差异有统计学意义（F女；镕目=4．746，P〈0．05），各组不同时间点球结膜杯状细胞密度的差异有统计学意义（F=18．055，P〈0．001）。与对照组比较，PBS处理组第6l天角膜荧光素染色评分[0（0，1．0）VS．3（2．0，3．0）]及虎红染色评分[0（0，1）VS．2（2，3）]均明显升高，差异均有统计学意义（P〈0．001）；PBS处理组第61天基础泪液分泌量和结膜上皮杯状细胞密度均明显低于对照组[（5．18＋0．46）mmVS．（9．43±O．57）mm；（53．04~2．98）个／高倍视野VS．（87．73±2．34）个／高倍视野]，差异均有统计学意义（P〈0．01）；扫描电子显微镜和透射电子显微镜下可见PBS处理组第61天角膜和结膜上皮细胞表面微绒毛及细胞器明显损伤。与PBS处理组比较，聚乙二醇处理组第61天角膜荧光素染色评分[3（2．0，3．0）VS．1（0．5，1．0）]及角膜结膜虎红染色评分[2（2，3）VS．1（0，1）]明显下降，差异均有统计学意义（P〈0．001）；聚乙二醇处理组第61天兔眼基础泪液分泌量明显多于PBS处理组[（7．00~0．71）mmVS．（5．18±O．46）mm]，差异有统计学意义（P〈0．05）；聚乙二醇处理组第61天结膜上皮杯状细胞密度值高于PBS处理组[（63．88±3．32）个／高倍视野VS．（53．04~2．98）个／高倍视野]，差异有统计学意义（P〈0．05）；球结膜印迹细胞学评分改善，角膜和结膜上皮细胞微绒毛及细胞器等超微结构完整。结论聚乙二醇可以减少含苯扎氯胺的拉坦前列腺素滴眼液所致的兔眼表毒性，改善青光眼局部用药所致的眼表损伤。

Background Reducing ocular surface toxicity induced by topical antiglaucoma medications,and thus improving the therapeutic compliance of glaueomatous patients to treating drug become an urgent issue in the long-term antiglaucomatous therapies. Whether polyethylene glycol, a new type of artificial tear, can play a protective role from ocular surface toxicity induced by topical antiglaucoma medications remains further study. ObjectiveThe present study was to investigate the protective effect of polyethylene glycol on ocular surface toxicity induced by prolonged use of benzalkonium chloride-preserved latanoprost eye drops. Methods Thirty adult female New Zealand rabbits were randomly divided into normal control group, phosphate buffer solution （PBS） group and polyethylene glycol eye drops group. PBS with 0. 005% latanoprost was topically administered for consequent 60 days in the PBS group, and 0. 005% latanoprost with polyethylene glycol eye drops was used at the same way in the polyethylene glycol group. Schirmer I test,fluorescein and rose bengal staining of cornea and conjunctiva,conjunctiva impression cytology specimens collecting were performed before experiment as well as 31 and 61 days after administration of drug. Histomorphological and uhrastructural changes of cornea and conjunctiva were observed under the light microscopy, scanning and transmission electron microscopy on day 61. Results The score of corneal fluorescine staining was significantly different among the control group,PBS group and polyethylene glycol group （H= 25. 265 ,P〈0. 001 ;H=29. 426,P〈0. 001 ） on day 31 and day 61. Significant difference also was found in the score of rose bengal staining of cornea and conjunctiva （ H= 26. 167, P〈0. 001 ;H= 29. 212 ,P〈O. 001 ） , Schirmer I test value （ F=4. 746 ,P〈0.05 ） and conjunctival goblet cell density （ F= 18. 055 ,P〈0. 001 ）. Compared with the control group, cornealfluorescein scores [0（0,1.0） vs. 3 （2.0,3.0）1 and rose bengal scores [0（0, 1） vs. 2（2,3）] were significantly increased （both P〈0. 001） ,and Schirmer [ test value scores and conjunctival goblet cell density were decreased （（5.18＋0.46/）mm vs. （9.43＋0.57）mm;（53.04_＋2.98）/HP vs. （87.73_＋2.34）/HP） （bothP〈0.01） on day 61. Impaired microvilli and organelles of the corneal and conjunctival epithelial cells were observed. Compared with PBS-treated group, PEG-treated group showed decrease in fluorescein [ 3 （2.0,3.0） vs. 1 （0.5,1.0） ] and rose bengal scores ~ 2 （ 2,3 ） vs. 1 （0,1） ] （ both P〈0. 001 ） ,increase in Schirmer I test value scores [ （7.00-＋0.71） mm vs. （5. 18-＋0.46）mm,P〈0.05] ,increase in goblet cell density （（63.88-＋3.32）/HP vs. （53.04＋2.98）/HP,P〈 0.05 ） and improvement of grading scores of conjunctival epithelium on day 61. In addition, complete mierovilli and cell organelles were found in the corneal and conjunetival epithelial cells in the polyethylene glycol group. Conclusions Topical application of polyethylene glycol can decrease the ocular surface toxicity induced by benzalkonium chloride-preserved latanoprost.