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地夸磷索钠治疗干眼的作用机制及其临床应用

Mechanism and clinical application of diquafosol tetrasodium in dry eye treatment

来源期刊： 眼科学报 | 2021年4月 第36卷 第4期： 288-292 发布时间： 收稿时间：2023/5/11 16:34:16 阅读量：7671
作者：
廖颖琳,
李晶,
梁凌毅,
关键词：
地夸磷索钠P2Y2受体激动剂黏蛋白干眼
diquafosol tetrasodium P2Y2 purinoceptor agonists mucins dry eye
DOI：
10.3978/j.issn.1000-4432.2021.03.012
收稿时间：
 
修订日期：
 
接收日期：
 
干眼是以泪膜稳态丢失及伴随眼部不适症状为特征的最常见眼表疾病，泪膜不稳定、泪液高渗透性、眼表炎症及感觉神经异常为其主要病因。地夸磷索钠是一种P2Y2受体激动剂，能刺激黏蛋白及泪液分泌，其独特的作用机制为干眼的治疗开辟了新的方向，本文就地夸磷索钠近年的临床及基础研究进展作一综述。
Dry eye is one of the most common ocular surface diseases. It is characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and tear hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities play major etiological roles. Diquafosol tetrasodium is a purinergic P2Y2 receptor agonist that promotes mucin and aqueous tear secretion. The unique pharmacological mechanism of diquafosol tetrasodium opens up a new direction for the medical therapies of dry eye. This article reviews the clinical therapeutic effect and research progress of diquafosol tetrasodium for the past few years.
干眼是以泪膜稳态失衡伴随眼部不适症状为特征的多因素眼表疾病，近年来发病率呈逐年上升趋势，达5%~50%[1]。眼干、眼红、异物感、畏光等眼部不适和/或视觉障碍(视力波动等)为常见症状。目前干眼的药物治疗以人工泪液为主，传统人工泪液主要通过润滑作用改善患者不适。不同于传统人工泪液，3%地夸磷索钠(diquafosol tetrasodium，DQS)可通过促进黏蛋白及泪液分泌从而稳定泪膜，是一种全新作用机制的人工泪液。随着2003年美国食品及药物管理局宣布接受地夸磷索钠用于干眼治疗的新药申请，地夸磷索钠滴眼液的相关研究及临床试验逐步开展，其安全性及疗效经临床实践和观察获得了肯定[2-3]。本文将对于DQS治疗干眼的作用机制及其临床应用作一综述。

1 地夸磷索钠的作用机制

地夸磷索钠是稳定的三磷酸尿苷衍生物，也是强效的嘌呤类P2Y2受体激动剂。P2Y2受体是由核苷酸激活的嘌呤受体家族P2受体的成员之一，广泛分布于人体各器官。已有研究[4]证实P2Y2受体在角结膜上皮细胞(包括杯状细胞)、睑板腺腺体及导管细胞等多种组织中分布。地夸磷索钠主要通过增加上述细胞内Ca2+浓度，促进与Cl-通道耦联的水通道蛋白开放，Cl-分泌增多，同时促进H2O从细胞内流至细胞外，起到促进黏蛋白、水液和脂质分泌的作用[5]。

1.1 促进黏蛋白分泌

早期研究[6]发现P2Y2受体激动剂在兔干眼模型中能促进杯状细胞释放黏蛋白MUC5AC。同样，3% DQS可显著改善空气炭黑颗粒造成的眼表损害，同时促进MUC5AC的分泌[7]。而Moon等[8]在小鼠干眼模型中发现3% DQS能同时上调分泌性黏蛋白MUC5AC及膜相关性黏蛋白MUC1与MUC4的表达，从而促进结膜杯状细胞修复。

1.2 促进泪液分泌

DQS通过激活结膜P2Y2受体促进Cl-从浆膜面分泌至黏膜面，从而促进水液分泌。Nagahara等[9]对佩戴角膜接触镜的兔眼进行研究，发现与Soft Santear®及0.1%玻璃酸钠滴眼液(hyaluronic acid，HA)相比，使用3% DQS后接触镜前、后泪膜均有显著液体积累，且面积显著增大(P<0.01)，提示3% DQS可能为角膜接触镜相关干眼的有效治疗方式。此外，3% DQS在糖尿病大鼠模型中能有效促进泪液分泌，改善角膜上皮病变[10]。

1.3 促进角膜上皮损伤修复

目前认为P2Y2受体与角膜上皮细胞增殖密切相关。P2Y2受体可能通过四磷酸二腺苷促进角膜损伤修复。在角膜缘上皮细胞下调P2Y2受体表达，Ca2+的释放显著下降，酪氨酸激酶及细胞外调节蛋白激酶的磷酸化显著减少，细胞增殖、创伤修复受抑制。在大鼠角膜上皮损伤模型及猿猴病毒40-转染人类角膜上皮细胞体外实验发现：3% DQS可能通过P2Y2受体介导细胞内Ca2+升高，刺激诱导表皮生长因子受体/细胞外调节蛋白激酶(epidermal growth factor receptor/extracellular-signal-regulated kinase，EGFR/ERK)磷酸化，通过EGFR/ERK通路诱导细胞增殖及迁移，促进角膜损伤修复[11]。同时，有研究[12]发现3% DQS还可通过上调细胞角蛋白4和细胞角蛋白13表达及下调谷氨酰胺转移酶-1表达，促进眼表上皮细胞正常分化。

1.4 抑制细胞炎症反应

近年来研究[13-14]发现：3% DQS能抑制白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α、细胞间黏附分子-1、血管细胞黏附分子-1、NF-кB-p65及基质金属蛋白酶2等炎症介质的表达。其中Park等[14]发现：DQS通过上调磷酸化Erk1/2、磷酸化p90RSK、磷酸化Akt及IкB - α水平，降低角膜上皮细胞内活性氧浓度，从而抑制细胞凋亡。3% DQS在人体角膜上皮细胞(human corneal epithelial cells，HCECs)可通过抑制NF-κB通路减轻高渗因素诱导的炎症反应[15]。

1.5 其他

在铜/锌-超氧化物歧化酶-1(superoxide dismutase 1，Sod1)敲除鼠睑板腺功能障碍(meibomian gland dysfunction，MGD)模型中，3% DQS促进眼表上皮修复同时促进睑板腺脂质小滴数量增加，提示3% DQS可能是治疗MGD的有效手段[12]。此外，在Sod1敲除鼠模型中，DQS能缓解抗青光眼药的眼表毒性[16]。

2 临床研究进展

正常人眼表应用3% DQS后可短时间内改善泪河(P<0.05)，促进黏蛋白分泌，延长泪膜破裂时间(tear film break-up time，TBUT)，增加脂质层厚度(lipid layer thickness，LLT)[17]。此外，Koh等[18]发现：相较于0.3% HA及2%瑞巴派特(rebamipide，RBM)，滴用3% DQS后短期视觉效果更佳。以上结论提示3% DQS可能在临床治疗上具有良好的应用前景。
干眼患者应用3% DQS短时间内能有效增加泪液体积及LLT，长期应用可有效改善干眼症状及体征(TBUT、眼表染色、Schirmer试验等)[19]。部分研究发现结膜杯状细胞密度增高，泪液中的N-乙酰-神经氨酸显著升高，表明3% DQS能有效促进干眼患者分泌性黏蛋白分泌[20]。近年来，DQS对不同原因引起的干眼的缓解作用也得到证实。

2.1 水液缺乏型干眼

水液缺乏型干眼(aqueous-deficient dry eye，ADDE)患者长期应用3% DQS可有效改善干眼症状及TBUT、眼表染色、泪河高度(tear meniscus height，TMH)[21]。同时，连续治疗4周后能通过降低高阶像差(higher-order aberrations，HOAs)改善患者视觉质量，但初次应用3% DQS后15 min HOAs无明显改变。此外，相比单一用药，3% DQS联合应用0.1%HA对ADDE患者的改善效果更佳[22]。
上述部分研究[21]中包括干燥综合征(Sj?gren’s syndrome，SS)患者，提示3% DQS可能对难治性干眼有一定疗效。Yokoi等[23]发现SS患者应用3% DQS短时间内可不依赖泪腺分泌功能改善泪液体积。对原有治疗效果不佳的SS患者改为3% DQS持续治疗12个月，干眼症状及TBUT、角膜荧光素染色、TMH等客观体征均显著改善。然而，Jeon等[24]研究发现：3% DQS对SS患者的痛觉及干眼症状无明显改善。此外，有研究[25]报道慢性眼部移植物抗宿主病(ocular graft-versus-host disease，oGVHD)及眼部瘢痕形类天疱疮患者长期局部应用RBM及DQS能有效改善相关症状与体征，其中DQS能有效缓解oGVHD的眼部疼痛。

2.2 蒸发过强型干眼

MGD是蒸发过强型干眼的重要病因之一。研究[26]发现：MGD患者长期使用3% DQS能有效改善睑缘毛细血管扩张、睑板腺开口阻塞、睑脂性状等。此外，合并MGD的干眼患者应用3% DQS短时间内能有效提高LLT[27]。在长期应用前列腺素类抗青光眼药物的患者中，3% DQS能有效减少睑板腺缺失[28]。以上研究均提示3% DQS对MGD可能存在一定疗效，然而样本量均较小，未来仍需随机对照研究进一步观察3% DQS对MGD特别是睑板腺严重萎缩者的疗效。
视频终端(visual display terminal，VDT)综合征早期可能会造成泪液蒸发增强。有研究[29]发现：3% DQS能有效改善VDT相关干眼患者TBUT、眼表染色及TMH等客观体征，同时能有效缓解异物感及阅读、使用VDT时的不适症状。此外，3% DQS明显改善视力、客观散射指数及HOAs，有效提高患者的视觉效果[30]。Kaido等[31]发现3% DQS能缓解角膜知觉的痛觉过敏现象，且与干眼症状改善程度成正比。

2.3 眼科手术后相关干眼

眼科手术是医源性干眼发生的重要因素之一。已有研究报道3% DQS对准分子激光手术(laser-assisted in situ keratomileusis，LASIK)、穿透性角膜移植术(penetrating keratoplasty，PK)、白内障手术等术后相关干眼疗效。
干眼是LASIK术后常见并发症之一，目前术后多用人工泪液缓解患者眼部干涩等不适症状。研究[32]发现：联合应用3% DQS与0.3%HA能更好促进术后早期视觉质量稳定，同时能显著改善干眼症状及体征。对LASIK术后干眼持续超过12个月且人工泪液治疗效果不佳的患者，加用3% DQS治疗能有效缓解干眼症状，并对角膜上皮修复有一定的促进作用。Kobashi等[33]在PK术后随访超过6个月的干眼患者应用3% DQS治疗4周可有效改善TBUT及眼表染色。
3%DQS能有效改善白内障术后干眼患者TBUT、角膜荧光素染色、HOAs及主观不适症状[34]。有研究[35]发现DQS能有效改善结膜鳞状上皮化生及杯状细胞密度，且相比HA更能有效改善睑缘异常及睑脂性状。但3% DQS对白内障术后干眼患者泪液分泌及泪液体积改善不明显[36]。与0.05%环孢素A滴眼液(cyclosporin A，CsA)相比，3% DQS对TBUT改善更佳。有趣的是，白内障术前4周应用3% DQS可改善术中角膜湿润性[37]。同时，围手术期应用3% DQS能有效预防干眼相关眼表改变(TBUT、眼表染色)[38]。

2.4 角膜接触镜相关干眼

软性角膜接触镜(contact lenses，CLs)会导致TMH降低，且高含水量CL佩戴者更为显著。而3% DQS能短时间使高含水量CL佩戴者TMH有效升高，且在低含水量CL佩戴者中有改善趋势[39]。对于伴有干眼症状的软性CL佩戴者，3% DQS能显著改善主观症状及客观体征(TBUT与角结膜染色)，促进膜结合性黏蛋白标记物浓度升高，但唾液酸(分泌性黏蛋白标记物)与泪液总蛋白浓度无明显改变[40]。

3 药物毒性及不良反应

早在2001年，Mundasad等[41]通过双盲随机对照研究评估不同浓度DQS滴眼液应用于正常人眼的安全性，仅5%浓度滴眼液出现了2个轻度不良事件(无痛性眼痉挛及流泪)，表明DQS在正常人眼部应用耐受性良好。而Lee等[42]发现：3% DQS可显著刺激HCECs上皮化，但对损伤的HCECs有显著的随时间增加的抑制增殖作用及细胞毒性。因此，应注意长期及过量应用DQS对存在角膜上皮点状病变患者的细胞毒性。
为减少药物眼部毒性且达到最佳疗效，目前3% DQS治疗干眼推荐眼部用药频率为1 d 6次，多数患者需连续治疗4周才能达到显著疗效[43]。据研究[44]报道：3% DQS药物不良反应发生率约为10.7%，约一半发生于用药第1个月，多数在用药2个月后消失。常见不良反应包括黏性分泌物、刺激感、瘙痒感、刺痛感、异物感等症状，以及结膜炎、睑缘炎等。没有严重药物不良反应报道。用药时应注意充分与患者交代用药注意事项及存在的不良反应，注意用药时长，在发挥药物作用的基础上提高患者的用药依从性。

4 结语

促黏蛋白分泌类药物的诞生，为干眼药物治疗提供新的手段，并获得了较好的治疗效果。DQS已在国外被广泛用于眼科临床，同时也在中国上市。但是，基于其特殊的机制，DQS的使用指针，对难治性干眼如oGVHD、SS等具体频率、疗程，远期治疗效果以及联合用药等，还有待进一步研究和探讨。

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