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干眼又称作干燥性角结膜炎，其临床表现为眼部干涩，有搔痒感、灼烧感、视物模糊等症状，严重影响患者的生活质量。近年来干眼的发病率逐年升高，已成为眼科临床的常见疾病之一。目前治疗干眼的手段主要有药物治疗、手术治疗和临床护理等，其中药物治疗是治疗干眼最为常用的手段。本文对近年来临床上基于渗透通路和炎症通路的药物治疗干眼的应用及研究进展进行归纳总结，为后续干眼的治疗及药物研发提供一些思路。
干眼是临床上常见的眼科疾病，在全世界的发病率为5%~35%，随着人口老龄化逐渐加深，干眼带来的经济负担持续增加。在国际泪膜与眼表协会发表的最新版干眼专家共识（Dry Eye Workshop Ⅱ）中，认定干眼是一种多因素引发的眼表疾病，以泪膜不稳定为主要表现，同时伴有渗透压增加和眼表炎症[1]。目前临床主要应用人工泪液治疗干眼，但其对眼表炎症作用较小，只能起到缓解干眼症状的作用。在过去的一段时间内，针对不同病理途径引发干眼的治疗药物不断出现，如新型人工泪液、促泌剂、非甾体抗炎药（Nonsteroidal antiinflammatory drug，NSAIDs）、皮质类固醇等，同时中西医联合治疗干眼的研究逐渐深入，极大推动了药物治疗干眼的进程。因此本文从渗透通路和炎症通路两大干眼治疗药物领域，对近年来药物治疗干眼的临床应用进行归纳总结，以期为后续干眼药物的研发提供参考。
1 渗透通路
1.1 人工泪液
人工泪液与人体泪液功能相似，可以有效缓解搔痒、疼痛等干眼症状，临床上具有不可替代的作用。常用的人工泪液主要分为润滑保湿型、维生素型、细胞因子型和血清提取物型等，面对种类、功效各不相同的人工泪液，如何对症合理应用是考验临床医生的重要问题[2]，同时人工泪液也不宜频繁使用，过多使用会使正常的泪膜流失，进而加重干眼的症状。人工泪液的常见药物见表1。
润滑保湿型人工泪液如聚乙二醇滴眼液、玻璃酸钠滴眼液等，多应用于水液缺乏型干眼，在眼表形成保护层、润湿眼表，有着良好的安全性和生物相容性，对眼表无刺激性或刺激性较小，但存在给药频繁和对眼表炎症无明显疗效等问题；维生素型滴眼液如维生素A棕榈酸酯眼用凝胶，应用于黏蛋白异常型干眼，可促进黏蛋白和泪液分泌、角膜糖蛋白合成，改善角膜和结膜上皮细胞脱水症状，不含防腐剂，对眼表刺激性小，但使用后会出现视线模糊、有轻微灼烧感；细胞因子型和血清提取物型人工泪液如碱性成纤维细胞生长因子、重组人表皮生长因子和小牛血去蛋白提取物眼用凝胶等，多应用于混合型干眼，可促进角膜上皮细胞增值分化，加速角膜上皮层修复，缓解眼表炎症，治疗术后干眼，但生物制品不易保存，同时也存在需频繁给药的问题。综上所述，人工泪液大多通过润湿眼表、缓解炎症、保护眼表组织等方式达到缓解干眼症状的目的，但普遍在眼表留存时间短，需频繁给药，新剂型的研发有望解决此类问题。
目前有一种卡波姆的单剂量滴眼液正在开发，虽然给药频率更加频繁，但其不含防腐剂，且减少了视物模糊等不良反应。以N-三甲基壳聚糖为包衣材料，以泊洛沙姆407为基底，在热敏原位凝胶中制备了负载维生素A棕榈酸酯的阳离子脂质体原位凝胶，具有药物缓释、延长药物在眼表滞留时间、提高角膜透过性和生物安全性等优点[42]。Ohigashi等[26]发现含有热休克蛋白47（heat shock protein 47，HSP47）siRNA的维生素A偶联脂质体可以特异性将HSP47 siRNA传递给致病性成纤维细胞，显著改善泪腺纤维化。作用机制可能是siRNA能特异性抑制靶基因的转录，改善组织细胞的纤维化，但体内给药后，siRNA迅速降解，阻碍了其临床应用。维生素A偶联脂质体保护HSP47 siRNA不被降解，并优先将siRNA传递至纤维化的泪腺细胞中，有效增加了其生物利用度。
1.2 促泌剂
促泌剂是一类能增加眼表黏液分泌的药物，其能有效增加干眼患者泪液和黏蛋白的分泌量，具有良好的临床效果，目前上市的促泌剂主要有地夸磷索钠和瑞巴派特，具体见表2。
地夸磷索钠和瑞巴派特同时在日本上市，地夸磷索钠可以促进泪液、黏蛋白、脂质的分泌，增加泪膜水层、黏蛋白层、脂质层的厚度和稳定性 [43]。瑞巴派特最初用于治疗胃炎和胃溃疡，近年来发现其具有促进眼表黏蛋白分泌的作用，已成为临床治疗干眼的常规用药[49]。
地夸磷索钠和瑞巴派特能维持泪腺和睑板腺正常分泌，促进损伤角膜上皮层修复，调节黏蛋白、盐、水等泪液成分的平衡，综合改善眼表泪膜稳态。临床常用剂型为瑞巴派特水悬浮液和眼膏药，受泪液稀释等因素的影响，药物在眼表停留时间短，需要经常给药，存在患者接受度较差等问题。Nagai等[48]采用2-羟丙基-β-环糊精和甲基纤维素为添加剂制备瑞巴派特纳米颗粒制剂，可通过睑板腺持续释放药物到泪液，起到缓释的作用。
2 炎症通路
2.1 NSAIDs
NSAIDs是临床一线抗炎药，具有解热、镇痛、抗炎的作用。临床常应用于干眼治疗的NSAIDs主要有普拉洛芬滴眼液、双氯芬酸钠滴眼液等。不同NSAIDs之间的疗效存在差异，影响其治疗效果的主要因素是药物与环氧化酶（cyclooxygenase，COX）的选择性、CYP450酶基因多态性、手性对映体的差别[53]。然而患者个体之间的差异、环境差异等都会影响NSAIDs的效果。
NSAIDs的作用机制主要是通过抑制COX活性，减少PG合成从而达到抗炎的治疗效果。普拉洛芬的抗炎效果良好，但长时间使用后干眼症状无明显改善，可能与其防腐剂苯扎氯氨会降低眼表细胞活性有关。溴芬酸钠因其化学结构的独特性与COX能特异性结合，抑制其活性，抗炎效果约是双氯芬酸钠的4倍，且具有良好的亲脂性，能迅速透过角膜到达眼表炎症部位，持续作用24 h以上。双氯芬酸钠具有细胞毒性，会造成角膜上皮细胞损伤，有研究表明环糊精会降低双氯芬酸钠的细胞毒性，但需进一步研究证明环糊精的安全性和有效性[63]。
2.2 皮质类固醇
皮质类固醇由肾上腺皮质分泌，其中大部分为激素类，包括糖皮质激素和性激素等，但目前关于性激素治疗干眼的机制尚未明确，临床上尚未推广使用。目前临床上常用的皮质类固醇药物有氟米龙滴眼液、氯替泼诺滴眼剂等，具有良好的抗炎效果，能有效缓解干眼患者的眼表炎症。皮质固醇类常见药物的具体信息见表4。
3种糖皮质激素药物抗炎机制相似，通过抑制磷脂酶A2产生AA，从而减少PG和白三烯的产生。在抗炎效果良好的同时不良反应也较明显。妥布霉素/地塞米松会造成眼压升高，使用时需进行眼压监测，相比之下氟米龙滴眼液在进入眼表时会代谢生成20-二氢氟米龙，降低眼压升高和青光眼等不良反应的发生几率，氯替泼诺也因其化学结构的特殊性，在眼表能迅速水解成非活性代谢产物，药物耐受性良好。
剂型方面，氟米龙纳米晶体滴眼液具有良好的透过性和缓释性。对兔眼部给药后，能迅速透过眼表组织到达炎症部位，并且在4 h后仍检测到20-二氢氟米龙[68]。目前氯替泼诺混悬滴眼液常用浓度为0.2%和0.5%，0.2%氯替泼诺混悬滴眼液用于缓解过敏性结膜炎引发的干眼，而0.5%氯替泼诺混悬滴眼液较多用于缓解结膜和角膜部分炎症[70]。混悬滴眼液给药浓度稳定，含防腐剂苯扎溴铵浓度小，pH与泪液接近，对眼表刺激性小。KPI-121是氯替泼诺的纳米颗粒混悬液，采用黏液穿透粒子技术，降低氯替泼诺纳米颗粒的粒径和对黏蛋白的亲和性，使其能有效穿透黏液屏障到达眼表组织，提高生物利用度[73]。动物实验表明，KPI-121穿透角膜和结膜的能力是混悬液的3.6倍，临床研究表明其对轻症干眼有良好的治疗效果。对4项临床试验中2 871个干眼患者的安全性数据进行评估分析，证明KPI-121有良好的安全性和耐受性[74]。McCormick等[76]以黄原胶为载体制得TOBRADEX ST眼用混悬液，在兔泪液和眼表结构中浓度更高，有更好的抗炎和杀菌能力。
3 结语
电子产品使用率升高、环境污染加剧以及人们不健康的生活习惯等致使干眼发病率不断升高，严重影响患者的生活质量。已有研究普遍认为干眼是一种多因素引发的眼部疾病，泪液缺失、眼表炎症、免疫反应、眼表组织受损等均会引发干眼，因此干眼的治疗也较为复杂，这对新型干眼药物的研发提出极大挑战。传统治疗干眼的药物如人工泪液只能缓解患者的不适症状，不能彻底治愈，近年来国内外用于缓解干眼患者眼表炎症和抑制免疫反应的新药也在不断上市，但临床上疗效欠佳，大多数药物使用后仍有不同程度的不良反应，同时中西医联合治疗干眼的应用研究逐渐增多，结果表明其均有着较好的临床疗效，因此对于干眼药物的研发仍有很大的进步空间。
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