Purpose

To test long-term ocular toxicity and analgesic/anti-inflammatory efficacy of two novel ocular formulations of neurokinin 1 receptor (NK1R) antagonist Aprepitant.

Methods

for toxicity studies, two Aprepitant formulations (X and Y) were tested on C57BL/6 N mice. Gold standards were 0.4% Oxybuprocaine, 0.1% Diclofenac, or saline. For efficacy studies, C57BL/6 N mice underwent corneal alkali burn, and then received Aprepitant formulation X, Dexamethasone or saline. Eye-drops were applied 3 times/day for 90 days (toxicity) and 14 days (efficacy). Stromal opacity, corneal epithelial damage, nociception and sensitivity were assessed in vivo. The eye-wiping test and corneal sensitivity were assessed to evaluate analgesic efficacy and nerve function. At the end of the experiments mice were euthanized, and corneas were dissected for immunohistochemistry and RT-PCR analyses.

Results

In normal mice, formulation X was not toxic when topically administered for 90 days. Formulation Y was associated with increased leukocyte infiltration in the cornea (p < 0.001). X1 and X2 formulations significantly reduced corneal pain, as Diclofenac and Oxybuprocaine, but did not reduce corneal sensitivity. Formulation Y, instead, was not analgesic at any time point. In the alkali burn model, X1 and X2 formulation enhanced epithelial damage recovery, and reduced inflammation both at day 7 and 14. Moreover, formulation X showed a stronger analgesic effect when compared to the saline and Dexamethasone groups (p < 0.01). Finally, formulation X1 and X2 restored corneal sensitivity by promoting corneal nerve regeneration.

Conclusions

Aprepitant X formulation is a promising candidate for the treatment of pain associated with inflammation of the ocular surface.

中文翻译：

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阿瑞吡坦的外用制剂可安全有效地缓解疼痛和炎症，并促进神经再生

目的

测试神经激肽 1 受体 (NK1R) 拮抗剂阿瑞匹坦的两种新型眼部制剂的长期眼部毒性和镇痛/抗炎功效。

方法

对于毒性研究，在 C57BL/6 N 小鼠上测试了两种阿瑞吡坦制剂（X 和 Y）。金标准是 0.4% 奥布卡因、0.1% 双氯芬酸或盐水。为了进行功效研究，C57BL/6 N 小鼠接受角膜碱烧伤，然后接受阿瑞匹坦制剂 X、地塞米松或盐水。每天滴眼3次，持续90天（毒性）和14天（功效）。在体内评估基质混浊、角膜上皮损伤、伤害感受和敏感性。通过擦眼试验和角膜敏感性评估镇痛效果和神经功能。实验结束时，对小鼠实施安乐死，并解剖角膜进行免疫组织化学和 RT-PCR 分析。

结果

在正常小鼠中，局部给药 90 天时，制剂 X 没有毒性。制剂Y与角膜中白细胞浸润增加相关(p<0.001)。X1和X2制剂与双氯芬酸和奥布卡因一样显着减轻角膜疼痛，但不降低角膜敏感性。相反，制剂Y在任何时间点都没有镇痛作用。在碱烧伤模型中，X1和X2配方在第7天和第14天均增强了上皮损伤的恢复，并减少了炎症。此外，与盐水组和地塞米松组相比，配方X显示出更强的镇痛效果（p < 0.01）。最后，制剂X1和X2通过促进角膜神经再生来恢复角膜敏感性。

结论

阿瑞吡坦 X 制剂是治疗与眼表炎症相关的疼痛的有前途的候选药物。