HJO Hans Journal of Ophthalmology 2167-6542 Scientific Research Publishing 10.12677/HJO.2022.111010 HJO-49147 HJO20220100000_36829546.pdf 医药卫生 前列腺素类滴眼液副作用的研究进展 Advances of the Side Effects of Prostaglandin Eye Drops 陆 叶 2 1 曹 阳 2 1 华中科技大学同济医学院附属协和医院眼科，湖北 武汉 null 24 01 2022 11 01 55 69 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

前列腺素类滴眼液由于其降眼压效果显著、副作用少、一天一次的使用频率成为治疗青光眼的一线药物。但随着人们对前列腺素类药物运用和研究的进一步深入，其在眼部及眼外的副作用及其机制被逐步报道。与此同时，一些副作用更少、降眼压效果良好的新型前列腺素类药物的出现，为饱受传统前列腺素类药物副作用折磨的青光眼患者带来了福音。本文将对目前主要的前列腺素类药物的副作用及其机制作一综述，旨在为眼科医生合理选择前列腺素类药物，防治其副作用提供参考。 Prostaglandin eye drops have become first-line drugs for the treatment of glaucoma due to their significant efficacy of lowering intraocular pressure, few side effects, and the frequency of once a day. However, as the application and the study of it develops in depth, the intraocular and extraocular side effects of prostaglandin eye drops have gradually been reported. Simultaneously, the emergence of some new prostaglandin drugs with fewer side effects and comparable effects of lowering intraocular pressure has also brought the gospel to glaucoma patients who suffer from the side effects of traditional prostaglandin drugs. This article will review the side effects of the main prostaglandin drugs and the mechanisms of their side effects, aiming to provide a reference for ophthalmologists to rationally select prostaglandin drugs and prevent their side effects.

 前列腺素类药物，青光眼，副作用, Prostaglandin Glaucoma Side Effect 摘要

前列腺素类滴眼液由于其降眼压效果显著、副作用少、一天一次的使用频率成为治疗青光眼的一线药物。但随着人们对前列腺素类药物运用和研究的进一步深入，其在眼部及眼外的副作用及其机制被逐步报道。与此同时，一些副作用更少、降眼压效果良好的新型前列腺素类药物的出现，为饱受传统前列腺素类药物副作用折磨的青光眼患者带来了福音。本文将对目前主要的前列腺素类药物的副作用及其机制作一综述，旨在为眼科医生合理选择前列腺素类药物，防治其副作用提供参考。

 关键词

前列腺素类药物，青光眼，副作用

 Advances of the Side Effects of Prostaglandin Eye Drops<sup> </sup>

Ye Lu, Yang Cao*

Department of Ophthalmology, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei

Received: Feb. 6th, 2022; accepted: Feb. 19th, 2022; published: Mar. 7th, 2022

 ABSTRACT

Prostaglandin eye drops have become first-line drugs for the treatment of glaucoma due to their significant efficacy of lowering intraocular pressure, few side effects, and the frequency of once a day. However, as the application and the study of it develops in depth, the intraocular and extraocular side effects of prostaglandin eye drops have gradually been reported. Simultaneously, the emergence of some new prostaglandin drugs with fewer side effects and comparable effects of lowering intraocular pressure has also brought the gospel to glaucoma patients who suffer from the side effects of traditional prostaglandin drugs. This article will review the side effects of the main prostaglandin drugs and the mechanisms of their side effects, aiming to provide a reference for ophthalmologists to rationally select prostaglandin drugs and prevent their side effects.

Keywords:Prostaglandin, Glaucoma, Side Effect

Copyright © 2022 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 引言

青光眼是一种慢性进行性视神经退行性疾病，其主要特点是视乳头和神经纤维层的损害。这可导致周边视野缺损，甚至有时可影响中心视力 [ 1 ] 。青光眼亦是全球不可逆性失明的首要原因 [ 2 ] 。据估计，世界上有超过7600万人患有青光眼，预计到2040年，该数字将超过1亿 [ 3 ] 。而据Song等的估计，到2050年，我国青光眼患者人数也将达到1500万 [ 4 ] ，因而需要更加重视该病。升高的眼压(Intraocular pressure, IOP)是其主要危险因素，且是唯一已知的可改变的危险因素。因此，目前治疗青光眼的干预措施均是降IOP [ 1 ] 。青光眼的治疗主要包括手术干预和药物治疗 [ 5 ] 。但是，由于手术过程和术后恢复的风险对患者来说较复杂，且费用昂贵 [ 6 ] ，所以安全有效的药物治疗成为青光眼患者的首选 [ 7 ] 。抗青光眼药物的种类主要包括前列腺素类(Prostaglandins, PGs)、rho激酶抑制剂、α肾上腺素能激动剂、β肾上腺素能阻滞剂(β-Adrenergic blocker, BB)和碳酸酐酶抑制剂。其中，PGs由于其降IOP的能力、一天一次的频率和较少的副作用，成为青光眼的一线治疗药物 [ 8 ] 。虽然PGs副作用小，但青光眼患者需要长期使用它，因此了解其副作用对医生的决策和患者的依从性至关重要。目前还未见国内有关于PGs副作用的文献报道，遂本文将对目前主要的PGs副作用及其机制作一综述。

 2. 前列腺素类滴眼液的分类<sup> </sup>

前列腺素(Prostaglandins, PGs)与血栓烷A2(Thromboxane A2, TXA2)统称为前列腺素类化合物。它们是一组具有生理活性的脂质化合物，由细胞膜脂质合成，具有多种功能，并在其局部靶组织中立即降解。PGs可分为前列腺素F2α(Prostaglandin F2α, PGF2α)，前列腺素E2(Prostaglandin E2, PGE2)，前列腺素I2和前列腺素D2四类 [ 9 ] 。PGs和TXA2可与前列腺素受体结合并调节IOP。前列腺素受体由前列腺素假阳性(Prostanoid false positive，FP)受体，EP1-4受体，IP受体，DP1-2受体和TP受体组成。上述四种PGs分别与前四种受体结合，而TXA2则与TP受体结合 [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] 。全球市场上最常见的四种PGs有拉坦前列腺素(Latanoprost, LAT)、曲伏前列腺素(Travoprost, TRA)、比马前列腺素(Bimatoprost，BIM)和他氟前列腺素(Tafluprost, TAF)。它们均属于PGF2α，因其化学结构与天然的PGF2α，所以亦被称为前列腺素类似物(Prostaglandin analogues, PGAs) [ 14 ] 。

此外，新型PGs相继出现，详见表1。对此，Aihara建议：应当像AA和BB，将PGs按照其作用受体分类，如：PGAs属于FP受体激动剂(Prostanoid false positivereceptor agonist，FPRA)，OMDI属于EP2受体激动剂等 [ 9 ] 。该方法能体现其药理特点，因此本文也将按此法分类。

Classification of PG
药物名称 公司 开发阶段 作用机制 降眼压途径 副作用
LAT 辉瑞 我国上市 FPRA 葡萄膜巩膜途径 结膜充血，干眼症，角膜炎，前列腺素相关性眶周病变综合征(Prostaglandin-associated periorbi-topathy syndrome, PAPS)，前葡萄膜炎，黄斑水肿，脉络膜脱离等 [ 15 ] [ 16 ] [ 17 ] [ 18 ]
TRA 爱尔康 我国上市 FPRA 葡萄膜巩膜途径
BIM 眼力健 我国上市 FPRA 葡萄膜巩膜途径
TAF 参天 我国上市 FPRA 葡萄膜巩膜途径
赛佩前列腺素(DE-126/ONO-9056) 参天 IIb期临床试验 EP3和FPRA 葡萄膜巩膜途径 结膜充血 [ 19 ]
OMDI (DE-117) 参天 日本和韩国：上市 美国：III期临床试验 EP2受体激动剂 葡萄膜巩膜途径 结膜充血，角膜增厚，黄斑水肿，前葡萄膜炎等 [ 20 ]
拉坦前列醇布诺德 Valeant 美国上市 NO供体和FPRA 葡萄膜巩膜途径和小梁网途径 结膜充血，眼部刺激，眼痛等 [ 21 ]
NO供体型BIM (NCX-470) Nicox III期临床试验 NO供体和FPRA 葡萄膜巩膜途径和小梁网途径 结膜充血 [ 19 ]

表1. PG类药物的分类

 3. 前列腺素类滴眼液的副作用 3.1. 眼表副作用 3.1.1. 角膜改变

1) 角膜上皮改变

为防止变质，FPRA常含有防腐剂，如苯扎氯氨(Benzalkonium chloride, BAK)和多季铵盐(Polyquad, PQ)。在研究含防腐剂(Preserved, P-)和不含防腐剂的(Preserved free, PF-)FPRA对人角膜上皮细胞的影响中，Tong等的体外实验发现适利达®(含0.02% BAK的0.05% LAT)、0.01%卢美根®(含0.02% BAK的0.01% BIM)和0.03%卢美根®(含0.005% BAK的0.03% BIM)会减少细胞活性并引起细胞形态改变，其中适利达®和0.01%卢美根®还诱导了细胞坏死。此外，适利达®、0.01%卢美根®、0.03%卢美根®和泰普罗斯®(含0.001% BAK的0.0015% TAF)刺激了ROS (活性氧)的产生。苏为坦®(含PQ的0.004% TRA)和0.03%卢美根®提高了培养基白细胞介素6和白细胞介素8的产生。该结果提示适利达®和0.01%卢美根®比0.03%卢美根®、苏为坦®、泰普罗斯®和PF-泰普罗斯®有更强的细胞毒性，而这种细胞毒性与BAK有关 [ 22 ] 。在体内实验中，Lee等在显微镜下发现，含0.015%BAK的TRA组的兔角膜上皮细胞比其他组(含0.001% BAK的TAF组，含0.001% PQ的TRA组和PF-人工泪液组)有更多的空泡形成。他们还在电镜下观察到含0.015% BAK的TRA组和含0.001% BAK的TAF组的细胞表面微绒毛的减少和破坏 [ 23 ] 。这表明含更高浓度BAK的FPRA对角膜上皮有更强的毒性作用。此外，FPRA还能减少角膜上皮的厚度 [ 24 ] 。分子机制上，Takada等结果显示，在细胞培养基中，TRA的加入会上调表皮生长因子(Epidermal growth factor, EGF)的mRNA表达和细胞增殖，同时，其细胞与细胞之间接触区域的E-钙粘蛋白减少。添加PD168393 (表皮生长因子受体抑制剂)可逆转该过程。在小鼠眼球培养基中也出现了类似的结果。这提示TRA可上调EGF相关信号以激活上皮细胞增殖，同时抑制细胞之间接触区域的E-钙粘蛋白定位。这可能与TRA对角膜屏障功能的破坏有关，并部分揭示TRA对角膜上皮损害的分子机制。此外，调节EGF信号可能是逆转TRA的角膜上皮损害的策略 [ 25 ] 。

2) 角膜基质的改变

Bergonzi等的病例对照研究对129只眼进行了激光共聚焦显微镜扫描，并将角膜基质分为前、中、后基质3个亚层。结果显示FPRA组的全角膜基质细胞密度比对照组大(P < 0.001)，前基质(P = 0.001)和后基质(P = 0.016)也是如此。此外，FPRA组的全角膜基质细胞密度比BB组大(P < 0.001)，且各层的基质细胞密度也比BB组大。而对照组和BB组之间无统计学差异。这表明FPRA能提高角膜基质各层的细胞密度，尤其是前角膜基质层。这可能和基质金属蛋白酶的激活和金属蛋白酶组织抑制因子的抑制有关 [ 26 ] 。

3) 角膜神经和内皮的改变

Rossi等的前瞻性队列研究将成年参与者被分为3组：1组(对照组)：16名健康参与者；2组(新患者组)：20名新诊断的开角型青光眼或高眼压患者；3组(已治疗组)：39名已经使用过一种P-眼药水的开角型青光眼或高眼压患者。其中，2组和3组接受PF-TAF治疗。结果显示，基线时，3组的角膜上皮细胞和角膜神经数量明显少于另外两组，而角膜细胞活化、珠样结构和神经弯曲则比另外两组多；在第12个月时，3组的角膜上皮细胞和角膜神经数量增加，而角膜细胞活化、珠样结构和神经弯曲减少，并且角膜内皮没有明显改变。与此对应的，2组的激光共聚焦显微镜的结果没有显著改变。此外，2组和3组的眼压均明显下降，而他们的中央角膜厚度(Cornea central thickness, CCT)没有明显改变。该研究证明了PFTAF不仅具有良好的降IOP效果，并且也有更好的角膜安全性 [ 27 ] 。Ranno等人观察了使用FPRA或BB至少2年的患者的角膜神经纤维和内皮细胞。他们发现，已治疗组的神经纤维数、弯曲、反应性和内皮细胞密度与对照组和新患者组有明显差异。与Rossi等的研究不同，这项研究还第一次记录了使用FPRA患者的内皮细胞减少 [ 28 ] 。此外，其他几项关于使用抗青光眼药物患者的角膜亚基底神经丛(Sub-basalnerve plexus, SNP)特点的研究也揭示了其密度、数量和长度的减少，以及神经纤维反应性和弯曲的增加 [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ] 。Agnifili等还发现，青光眼患者的药物治疗方案越复杂，SNP改变越明显。这提示SNP的改变可能是青光眼治疗相关眼表疾病的一个特点，并且对患者的生活质量有着消极影响 [ 34 ] 。

4) 角膜厚度的改变

较薄的角膜是原发性开角型青光眼发生和进展的独立危险因素 [ 35 ] 。目前测量眼压的金标准是Goldmann眼压计，而CCT会影响其测量的准确性。所以，了解PGs对CCT的影响很重要，但关于PGs对CCT的影响的结果有很大的不一致性。Bafa等人发现在使用拉坦前列腺素1年后CCT明显变薄，但在随后的第二年里CCT没有明显改变 [ 36 ] 。Uzunel的长达5年的回顾性研究中也发现了FPRA有减少青光眼患者CCT的作用，且在1~3年减少不明显，在4~5年出现明显改变。此外，作者还通过亚组分析发现BIM和TRA减少CCT的作用更显著 [ 37 ] 。Jang等人回顾性研究中也发现，在FPRA使用了3年后，正常眼压性青光眼患者的CCT明显减少。并且，这种CCT改变在LAT组、TAF组和TRA组之间没有显著区别 [ 38 ] 。但也有人认为FPRA对角膜厚度无影响 [ 39 ] [ 40 ] 。目前关于FPRA对CCT影响的研究的参与者人数都较少且均未收集视野、神经纤维层厚度等视神经相关数据，因此，尚不能从现有研究中推断出PGs相关的角膜变薄对青光眼的发生和进展的作用，需要更大的样本、更长时间的随访以探究该作用。

5) 角膜缘的改变

角膜缘是角膜到巩膜的移行区域，角膜上皮干细胞就位于此处。Schwarts和Holland首次报道了抗青光眼药物毒性能引起接受眼部手术的青光眼患者的角膜缘干细胞的缺乏 [ 41 ] 。Liang等证明了接受BAK或P-LAT处理的兔眼角膜缘有炎症细胞浸润，而PF-TAF组的角膜缘无明显改变 [ 42 ] 。该结果也被Pauly等 [ 43 ] 支持。他们发现BAK组和P-LAT组兔的角膜缘和周边角膜有炎症细胞浸润，而PF-LAT组无该变化。关于抗青光眼药物对人角膜缘的影响的研究很少，Mastropasqua等发现与使用PF-抗青光眼药物的患者相比，使用P-抗青光眼药物(FPRA或BB)患者的角膜边缘过渡细胞、基底内皮细胞和更深层的Vogt栅中出现了代表炎症征兆的点状反射元素，且其角膜缘树突细胞(骨髓来源的抗原提呈细胞)密度更高 [ 44 ] [ 45 ] 。但该结果不能明确P-FPRA和BB之间的差别以及PF-FPRA和BB的差别，因而不能确定是防腐剂还是药物本身对树突细胞产生影响。此外，Mastropasqua等的结果与其之前报道的干眼症(Dry eye disease, DED)患者和多药物治疗的青光眼患者的相关结果一致，提示树突细胞在青光眼相关眼表疾病(Ocular surface disease, OSD)中起到重要作用，但其具体机制还需进一步研究 [ 45 ] 。

 3.1.2. 结膜副作用

1) 结膜充血

结膜充血是公认的FPRA的副作用。为明确不同FPRA发生结膜充血的差异，Honrubia等的荟萃分析显示，LAT的结膜充血发生率比TRA和BIM低 [ 15 ] 。此后，PR-FPRA越来越受重视。Ameen等的横断面研究结果显示患者从P-LAT换成PF-药物后，其眼部症状和结膜充血明显改善，且其IOP控制良好 [ 46 ] 。Hedengran等的荟萃分析与该结果不同。该研究显示，结膜充血或眼部充血、眼部不良事件和泪膜破裂时间(Tear broke up time, TBUT)在使用含BAK的眼药水(FPRA或BB)、含其他非BAK防腐剂的眼药水和PF-眼药水的患者之间无明显差异。但因纳入的研究对副作用的测量方法和评级方式的差异，故应谨慎看待该结果 [ 47 ] 。此外，赛佩前列腺素、OMDI、LBN和NCX-470等新型PGs的主要副作用亦是结膜充血(表1)。结膜充血会影响青光眼患者的外观，从而降低患者依从性，因此医生应在患者使用前向其强调结膜充血的副作用。

2) 结膜上皮的改变

FPRA可影响结膜上皮细胞和杯状细胞(Goblet cells, GC)。Moreno等对使用LAT的患者进行了6个月的观察。印记细胞学结果显示在不同的治疗时间后非GC上皮细胞密度无明显改变，但其大小在1个月后有减少并在后期恢复到初始的形态。相应的，GC密度则在1个月后增加，而在后来的治疗后又减少，并且其大小没有改变。该研究表明P-LAT能使结膜上皮发生大小和密度的变化 [ 48 ] 。Ammar等研究了含不同防腐剂的FPRA对人角结膜上皮细胞的毒性作用。其结果显示含BAK的FPRA (LAT，TAF和TRA)的毒性与其各自浓度的BAK相似。含sofZia的TRA (0.004%)比含BAK的TRA具有更高的角膜和结膜细胞存活率。含PQ的TRA (0.004%)的毒性在统计学上也优于其含BAK的制剂。该研究表明，与sofZia和PQ相比，BAK对人的角膜和结膜上皮细胞具有更显著的毒性 [ 49 ] 。Yang等发现0.005% LAT能通过促进鼠眼表的炎症来减少泪液产生，诱导GC减少，破坏角膜上皮屏障和促进眼表细胞的凋亡，这形成了鼠的干眼样眼表损害 [ 50 ] 。Hedengran等发现LAT (0.02% BAK)、酒石酸溴莫尼定(0.005% BAK)和多佐胺(0.0075% BAK)以一种时间依赖的方式减少人GC的存活率，而噻吗洛尔(0.01% BAK)则没有改变细胞的存活率。在这些药物中，还发现LAT组的细胞存活率最低。该研究提示GC的存活率可能与BAK浓度有关，且浓度越小其存活率越高。但由于药物活性成分不同，BAK浓度反应关系不能在该研究中明确 [ 51 ] 。为此，Mullertz等最近研究了P-LAT和PF-LAT对GC的活性和对黏蛋白分泌的影响。粘蛋白由GC产生，是泪膜的组成部分，在稳定泪膜和保护眼表等方面有重要作用。GC的损失导致粘蛋白产生减少，增加泪膜的不稳定性，最终导致DED [ 52 ] 。他们发现经过30分钟的孵育后，与名牌P-LAT和普通P-LAT相比，PF-LAT更能维持人GC活性，且不会刺激黏蛋白的分泌，这表明PF-LAT对人GC的毒性更小。该结果还需在活体实验中得到进一步验证 [ 53 ] 。

3) 结膜上皮微囊(Conjunctival Epithelial Microcysts, CEM)的改变

CEM首先在功能性小梁切除术的滤过疱上皮中被发现，是房水跨结膜运输的指标 [ 54 ] [ 55 ] [ 56 ] 。其3D重建结构显示CEM为椭圆形、透明的微囊肿，位于上皮下 [ 57 ] 。CEM不仅存在于滤过性手术眼中，它还存在于未经治疗的高眼压症、药物治疗的开角型青光眼和无滤过疱的手术眼中 [ 58 ] - [ 64 ] 。Ciancaglini等首次研究了抗青光眼药物对CEM的影响。他们发现使用BB和FPRA联合治疗的患者的球结膜中的ECM平均密度(Microcyst mean density, MMD)和平均面积(Microcyst mean area, MMA)比仅使用一种FP受体激动剂或BB治疗的患者大，这表明联合治疗比单药治疗更能加强房水跨结膜运输。但作者不能排除BAK对MMD和MMA的影响 [ 65 ] 。为此，Mastropasqua等做了进一步的研究并发现：经过3个月的时间，与P-BB组、PF-BB组和对照组相比，P-LAT组和PF-LAT组的MMA明显增加，且二者中P-LAT组MMA值更高。但所有组的MMD无明显改变。这表明FPRA可通过已存在的结膜通路来加强跨结膜房水引流，而BB无该作用 [ 63 ] 。

4) 结膜相关淋巴组织(Conjunctiva-associated lymphoidtissue, CALT)改变

CALT是眼相关淋巴组织的结膜部分，在睑结膜和球结膜中发育，形成了眼表和外部环境之间的免疫界面 [ 66 ] [ 67 ] 。Mastropasqua报道了LAT引起的CALT改变。在新诊断的患者使用P-LAT后，出现了炎症细胞浸润的滤泡和滤泡间间隙，而在使用PF-TAF患者中却未发现此炎症表现。此外，被治疗眼也出现了由于胶原蛋白的积累而发生的结构改变。但由于该结果是基于共聚焦显微镜观察到的，所以不能完全将其观察到的结构与CALT相对应，因而还需免疫组织学研究证明该结果 [ 62 ] [ 68 ] 。

 3.1.3. 睑板腺(Meibomian gland, MG)副作用

睑板腺功能障碍(Meibomian gland dysfunction, MGD)常发生在使用FPRA的患者中，其特点是终末导管阻塞和腺体定性或定量的改变 [ 69 ] 。MGD与泪膜改变、刺痛、炎症和OSD有关。Cunniffe等发现，43名接受过霰粒肿手术的患者中，8名患者(19%)有FPRA滴眼液的用药史，于是推测FPRA可能通过直接刺激或改变MG的分泌来促进睑板腺囊肿的形成 [ 70 ] 。Mocan等也发现使用FPRA的患者的MGD患病率为92%，明显高于使用非FPRA药物的患者(58.3%)，且其MGD类型主要为阻塞型(95.7%) [ 71 ] 。此外，Cho等的结果显示，使用FPRA的患者的睑板腺缺失率比使用其他抗青光眼药物的患者更高，且TBUT更短 [ 72 ] 。Arita等的横断面研究也证明了类似的结果 [ 73 ] 。但上述结果没有明确防腐剂和药物本身对睑板腺的影响。Ha等解决了该问题，其研究结果显示：P-FPRA组比PF-FPRA组和对照组拥有更高的眼表疾病指数(Ocular surface disease index, OSDI)，更短的TBUT，更严重的眼表染色(Ocular surface staining, OSS)和更差的MG相关参数。此外，PF-FPRA组比对照组也显示了更差的睑板评分，睑脂评分和OSS分数。该结果表明，防腐剂和FPRA本身都会对MG造成损害，但PF-FPRA对MG的损害要比P-FPRA轻。因此患有OSD或MGD的患者应使用PF-FPRA。另外，更长时间的前瞻性研究和停用FPRA是否能逆转MGD是未来需要研究的课题 [ 74 ] 。

 3.1.4. 泪膜的改变

评价泪膜的客观指标有：TBUT，泪膜渗透压，Schirmer’s 试验和泪河高度。其中，前两者体现泪膜的稳定性，而后两者体现泪腺的分泌量。Wong等的研究结果显示，与对侧眼相比，使用抗青光眼药物眼的TBUT、泪膜渗透压、Schirmer’s 试验(麻醉后)和泪河高度的表现更差。但该研究没有直接指出FPRA对泪膜的影响 [ 75 ] 。Su等为研究单独的FPRA对眼表的影响进行前瞻性研究。其结果显示，使用P-LAT的4个月后，青光眼患者的泪膜不稳定(TBUT < 10 s)的百分比从6.21%增加到9.11%，Schirmer’s试验从9.42下降到6.84 mm。这表明P-LAT可通过减少基础泪液分泌和泪膜稳定性来引起青光眼患者的眼表改变。且在这些患者中，一部人因眼部干涩使用人工泪眼后，其TBUT和Schirmer’s试验有了轻微的改善。这提示对泪液分泌少和泪膜稳定性差较敏感的使用FPRA的患者，可选择人工泪液来缓解症状 [ 76 ] 。对于该过程的分子机制，Sedlak等的横断面研究评估了使用不同类型的FPRA的患者泪膜中的氧化应激标志(如：高级氧化蛋白产物含量，总巯基基团含量，超氧化物歧化酶活性等)。其结果提示FPRA的使用与泪膜中的氧化应激反应的增加有关，且防腐剂的存在能加重该反应。由此推测，氧化应激参数的变化是产生影响的第一个迹象，并且进一步长期使用FPRA将导致该药物的局部副作用(例如炎症和/或DED)的氧化应激表现的恶化。但目前关于氧化应激系统对泪膜影响的研究很少，还需更多的研究证明氧化应激与抗青光眼药物之间的关系 [ 77 ] 。

 3.2. 其他眼部副作用 3.2.1. 前葡萄膜炎和眼底改变

自FPRA上市后，关于使用该药物后发生前葡萄膜炎和黄斑囊样水肿(Cystoid macular edema, CME)的罕见不良反应时有报道。Hu等对此类报道做一系统综述并发现：前葡萄膜炎和CME在使用FPRA的患者中的发生率分别为0.22%和0.09%。此外，与BIM相比，LAT使用者的葡萄膜炎和CME的发生率更高。需要注意的是，该项研究没有排除眼部手术、无晶体眼和人工晶状体半脱位等混杂因素，且关于FPRA相关的前葡萄膜炎和CME的前瞻性研究过少，所以应谨慎看待FPRA的这一副作用 [ 78 ] 。最近报道了一例FPRA相关的双眼前葡萄膜炎的女患者。她的双眼是人工晶状体眼，其中左眼做过小梁切除术。在使用BIM后，她发生了双眼前葡萄膜炎和左眼的脉络膜脱离。在停用BIM并局部使用类固醇激素后，其视力提升，且局部症状缓解。该报道再一次揭示了FPRA相关葡萄膜炎的病理生理学机制 [ 79 ] 。此外，一项关于OMDI的2期和3期临床试验的汇总分析显示，CME在所有被治疗的患者中的发生率为5.2%。且这些患有CME的患者均有人工晶状体植入的手术史 [ 20 ] 。因此，根据缺乏有晶状体眼患者发生PG相关CME的报道，可以推断PG相关CME可能只特定的发生在人工晶状体眼中 [ 80 ] 。

除CME外，FPRA相关的脉络膜脱离也时有报道。目前文献中报道的FPRA有关的脉络膜脱离主要发生在人工晶状体眼患者 [ 17 ] [ 81 ] - [ 86 ] 和Sturge-Weber综合征患者中 [ 87 ] [ 88 ] 。其主要机制是FPRA增加了葡萄膜巩膜途径的房水引流并出现了巩膜上静脉压增加，这导致了脉络膜上腔的房水的聚积，从而引起脉络膜脱离和炎症。因此，FPRA有引起白内障术后患者的脉络膜脱离的副作用。一旦发生此类情况，应当停用FPRA并使用口服或局部类固醇类药物以及睫状肌麻痹剂。而未发生脉络膜脱离的，需要使用降眼压的白内障术后患者应当在术后早期停用FPRA而改用其他类型的降IOP药物 [ 17 ] 。

 3.2.2. 老视

FPRA可作用于睫状肌来增加葡萄膜巩膜途径的房水引流，从而降低IOP，该过程是通过调节睫状肌来控制的。而睫状肌在调节晶状体曲率上起到主要作用。Romano和Lograno比较了BIM、LAT和TRA对人睫状肌收缩的作用。其结果显示BIM能显著收缩睫状肌，这提示FPRA可诱导老视 [ 89 ] 。Ayaki等回顾了23名使用LAT超过6个月的患者的临床资料。他们在对这些资料进行生存分析后发现，LAT组的屈光度比对照组更早到达+3.00 D。因此，加速老视是使用LAT的潜在副作用 [ 90 ] 。更早的研究结果也证明了这一点 [ 91 ] - [ 96 ] 。

 3.3. 眼附属器副作用 3.3.1. 睫毛增长

FPRA不仅能有效降IOP，也能促进睫毛增长，该副作用甚至被用来治疗毛发稀少症和斑秃 [ 97 ] 。Johnstone最先报道了LAT引起的睫毛增长和毛发色素沉着 [ 98 ] 。虽然FPRA的睫毛增长这一副作用对毛发稀少症患者是有益的，但其主要的降IOP作用也会成为这些患者的副作用。因此在使用FPRA用于治疗毛发稀少症时，应当注意其低IOP的风险并定期复查眼压，此外，其结膜充血、干眼、眼部刺痛、虹膜色素沉着以及上眼沟加深等副作用也应当监测 [ 99 ] 。而当青光眼患者想避免睫毛增长这一副作用时，EP2受体激动剂可能是更好的选择。Esaki等人的小鼠实验结果显示，OMDI组的睫毛数量(P = 0.795)、厚度(分为短、中、长睫毛3个亚组，每个亚组的P值均大于0.05)和球状乳突生长期的百分比(P > 0.05)与对照组(生理盐水)无差异，并且OMDI组的睫毛数量、睫毛厚度(短、中长度亚组)和睫毛球状乳突生长期百分比均显著低于BIM组(P < 0.05) [ 100 ] 。

 3.3.2. 眶周病变

Pelinski和Albiani首次报道了BIM引起的眼眶加深 [ 101 ] 。随后在LAT、TRA和TAF引起的眼眶加深被相继报道 [ 102 ] - [ 108 ] ，于是Sarnoff和Gotkind对PGs引起的眶周病变做了总结，提出了PAPS的概念。PAPS包括10种体征：上眼睑沟加深(deepening of the upper eyelid sulcus, DUES)、下眼袋变平(flattening of the lower eyelid bags, FLEB)、上睑下垂、皮肤松弛老化，眼眶脂肪萎缩，轻度眼球内陷、下巩膜暴露，眼眶狭窄，睫毛过多症以及虹膜和眶周皮肤色素沉着。这一概念能很好的概括FPRA引起的眶周外观改变 [ 109 ] 。

已有体外实验证明FPRA通过作用FP受体来抑制脂肪合成 [ 16 ] ，并引起眼部周围的一系列改变 [ 110 ] ，这提示FPRA可通过抑制脂肪合成引起DUES。FPRA引起的前列腺素相关性眶周病变(Prostaglandin-associated periorbitopathy, PAP)的程度还因药物种类的不同而不同。Kucukevcilioglu等的回顾性观察性病例系列的结果显示，在使用过FPRA一个月的105名患者中，BIM、TRA和LAT的PAP (包括上睑下垂、上眼睑眶加深、皮肤松弛老化、眶周脂肪垫消失和眼球内陷)发生率分别为93.3%，70%和41.4%。这表明BIM最易引起PAP [ 107 ] 。Hikage等使用3D细胞培养技术来模拟人的眼眶脂肪组织。他们的结果显示，OMD (Omidenepag，是OMDI渗透进眼内的活性成分)与BIM酸(BIM渗透进眼内的活性成分)对人眼眶成纤维细胞的脂肪合成的作用效果完全不同。这暗示着OMD可能没有参与DUES的发展过程 [ 111 ] 。此外，Oogi等的一项观察性研究也显示：12个使用FPRA的患者换成OMDI后，近一半的人的DUES有改善。但该研究未报道更换药物前后患者的IOP值 [ 112 ] 。一项最近的观察性研究也发现：在更换药物后，OMDI能改善70%的参与者的DUES，且这些患者在换药后的IOP也与之前使用FPRA时无明显差别 [ 110 ] 。该结果提示OMDI不仅能有效降IOP，且其在DUES方面的副作用也比FPRA小。

 3.4. 其他副作用 3.4.1. 头痛

Wang等报道了3个LAT相关的头痛病例。患者们在使用LAT后出现了头痛，且其头痛能在阻塞泪小点或改用TRA后缓解。这三个病例有以下共同点：相同的头痛部位，不伴随其他神经症状，随时间自我缓解和没有预兆 [ 113 ] 。这些特点与典型的偏头痛不同，且更像继发性头痛 [ 114 ] 。虽然Weston曾用“偏头痛”来描述其报道的3个LAT相关的头痛病例，但该病例不符合偏头痛的标准 [ 113 ] [ 115 ] 。目前关于LAT引起的头痛的机制尚不清楚，三叉神经血管系统可能在该过程起主要作用。前列腺素激活了三叉神经血管系统中的伤害性感受器并诱发了头痛 [ 113 ] [ 116 ] 。因此，当患者在使用FPRA后出现头痛，应当考虑药物引起的继发性头痛，从而减少患者不必要的痛苦和检查。

 3.4.2. 心血管不良事件

众所周知，心血管不良事件是BB的副作用之一，但FPRA也与该不良事件有关。美国药品和保健品监管机构曾收到49例与LAT有关的心血管疾病的报告，包括心悸、心肌病、心力衰竭、缺血性心脏病、多种心律失常以及两例心脏停搏的死亡病例 [ 117 ] 。De等也第一次报道了与LAT有关的2度房室传导阻滞。一名54岁开角型青光眼女性患者，从开始使用的BB改为LAT一周后，出现了轻微劳累性呼吸急促、嗜睡和心悸，于是被诊断为3:1房室传导。随后，该患者停用LAT2天后，心电图转为2:1房室传导，但其症状没有缓解。最后，该患者被植入了永久性心脏起搏器并康复 [ 118 ] 。既往FPRA的心血管不良事件报告不足可能是因为FPRA有良好的心脏安全性，但不能排除未及时报道和其他非药物因素。因此，即使FPRA常被作为有BB的心肺禁忌症的患者的首选，FPRA的心血管不良事件也不能被忽略。对于医生，在采集心脏病患者病史时不能忽略眼部用药史。未来需要更加深入和系统的研究来明确FPRA与心血管系统的关系 [ 118 ] 。

 4. 问题与展望

随着前列腺素类药物临床应用和研究的逐步深入，存在于这些药物中的眼及其附属器和全身的副作用也逐渐被揭示，可能大大降低青光眼患者用药的依从性，严重影响治疗效果。彻底弄清这些副作用的具体发生机制以及预防和治疗的方法成为亟待解决的问题。虽然新型的前列腺素药物也表现出良好的治疗效果，但这些新药物目前还处在试验或刚上市的阶段，对新药物的疗效和副作用的了解还不够透彻，还需要更长的时间来研究来加以明确。

 致谢

感谢学校及导师的培养，感谢家人默默的支持。

 文章引用

陆 叶,曹 阳. 前列腺素类滴眼液副作用的研究进展Advances of the Side Effects of Prostaglandin Eye Drops[J]. 眼科学, 2022, 11(01): 55-69. https://doi.org/10.12677/HJO.2022.111010

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