Becquet F, Goldschild M, Moldovan M S, Ettaiche M, Gastaud P, Baudouin C
Department of Ophthalmology, ERCA INSERM, Ambroise Paré Hospital, University of Paris V, Boulogne, France.
Curr Eye Res. 1998 Apr;17(4):419-25. doi: 10.1080/02713689808951223.
Long term use of topical drugs has clearly been shown to induce toxic immunopathological changes in the ocular surface. However, little is known concerning the respective roles of active compounds and preservatives. Benzalkonium chloride (BAC) is the most used preservative and its cytotoxicity is well known, but other preservatives have not yet been clearly evaluated. We thus performed a comparative study to investigate toxic side effects induced in the rat ocular surface by applications of various preservatives, with special attention to inflammatory infiltrates.
A total of 35 brown Norway rats were divided into seven groups of five each. They received, for one month, in both eyes, either 0.01% cetrimonium chloride, 0.01% benzalkonium chloride, 0.01% benzododecinium bromide, 0.004% thiomersal, 0.05% methyl parahydroxybenzoate or phosphate-buffered saline (PBS), the last group remaining untreated. Then, animals were sacrificed and eyes were processed for histological and immunological procedures with monoclonal antibodies to rat immunocompetent cells.
When compared to controls, all preservative-treated eyes consistently showed corneal and conjunctival damage, including epithelial alterations, various degrees of keratinization and inflammatory infiltrates at the limbus and within the conjunctival stroma and epithelium. No difference was found between the five tested drugs.
This study confirms that most preservatives used in ophthalmic eyedrops may similarly induce strong histopathological and inflammatory changes in the ocular surface after short term use. Although obtained in animal model, these results confirm strong toxic side effects in patients with preexisting ocular surface disorders and/or receiving topical drugs for long periods.
长期使用局部用药已明确显示会在眼表诱发毒性免疫病理变化。然而，关于活性成分和防腐剂各自的作用却知之甚少。苯扎氯铵（BAC）是最常用的防腐剂，其细胞毒性众所周知，但其他防腐剂尚未得到明确评估。因此，我们进行了一项比较研究，以调查各种防腐剂应用于大鼠眼表所诱发的毒副作用，特别关注炎症浸润情况。
总共35只棕色挪威大鼠被分为七组，每组五只。它们双眼接受为期一个月的以下处理：0.01%西曲溴铵、0.01%苯扎氯铵、0.01%苯度氯铵、0.004%硫柳汞、0.05%对羟基苯甲酸甲酯或磷酸盐缓冲盐水（PBS），最后一组不做处理。然后，处死动物，取出眼睛进行组织学和免疫学检测，使用针对大鼠免疫活性细胞的单克隆抗体。
与对照组相比，所有使用防腐剂处理的眼睛均持续出现角膜和结膜损伤，包括上皮改变、不同程度的角化以及角膜缘、结膜基质和上皮内的炎症浸润。在五种受试药物之间未发现差异。
本研究证实，大多数眼科滴眼液中使用的防腐剂在短期使用后可能同样会在眼表诱发强烈的组织病理学和炎症变化。尽管这些结果是在动物模型中获得的，但它们证实了对于已有眼表疾病和/或长期接受局部用药的患者存在强烈的毒副作用。
