McLoon L K, Wirtschafter J
Department of Ophthalmology, University of Minnesota, Minneapolis 55455, USA.
Invest Ophthalmol Vis Sci. 1997 Apr;38(5):834-41.
Doxorubicin chemomyectomy is an effective alternative treatment option for patients with blepharospasm and hemifacial spasm. One side effect of the use of doxorubicin in localized injections is the development of acute inflammation and skin injury at the injection site. Corticotropin releasing factor (CRF) was reported to reduce inflammation after acute inflammatory injuries due to other causes and at other sites. This study was performed to assess the potential of CRF to prevent the development of skin injury and eyelid soreness after local doxorubicin injection.
Rabbits received lower eyelid injections of either 75 or 150 micrograms CRF followed by injection of either 0.5, 1, or 2 mg doxorubicin or doxorubicin alone. Eyelids were assessed for changes in acute inflammation by immunohistochemical localization of macrophages and monocytes using anti-CD11, an antibody specific for these cell types. Short-term alterations in vascular permeability were assessed using an Evans blue assay. Additional eyelids were followed daily for changes in the skin over the injection site to determine day of onset of skin injury and the total duration of skin injury. After 1 month, the eyelids were processed histologically for morphometric analysis of muscle fiber loss. Monkey eyelids also were examined for the effect of CRF and doxorubicin injections.
Doxorubicin alone produced an acute inflammatory reaction in the treated eyelids, with a large influx of macrophages and monocytes throughout the connective tissue at 1 and 2 days. Corticotropin releasing factor pretreatment significantly reduced this influx of inflammatory cells into the connective tissue. Doxorubicin produced a large increase in vascular permeability in the treated eyelids, with resultant edema. Corticotropin releasing factor did not alter this change in vascular permeability, indicating that CRF appears to have a specific effect on migration of inflammatory cells rather than just a generalized effect on vascular permeability. Corticotropin releasing factor and doxorubicin cotreatments delayed the onset of skin injury and decreased the total duration of injury to the skin compared to doxorubicin alone. The effectiveness of doxorubicin chemomyectomy was maintained; muscle loss was significant at all doses of CRF combined with doxorubicin.
Corticotropin releasing factor dramatically decreased the acute inflammatory reaction that results in the eyelid from local doxorubicin injections. Not only did CRF reduce the acute influx of monocytes and macrophages, but it protected the skin overlying the injection site, substantially reducing the extent of skin injury. The efficacy of doxorubicin-induced muscle toxicity was maintained. A treatment protocol that combines myotoxicity with antiinflammatory activity in the treated eyelids may lead to a more effective patient treatment by increasing patient acceptance. The potential should be explored that CRF may be of clinical use in limiting tissue injury when administered immediately after extravasation during cancer chemotherapy.
阿霉素化学性眼肌切除术是治疗眼睑痉挛和半面痉挛患者的一种有效替代治疗选择。局部注射阿霉素的一个副作用是注射部位出现急性炎症和皮肤损伤。据报道，促肾上腺皮质激素释放因子（CRF）可减轻因其他原因和在其他部位导致的急性炎症损伤后的炎症反应。本研究旨在评估CRF预防局部注射阿霉素后皮肤损伤和眼睑酸痛发生的潜力。
给兔子下眼睑注射75微克或150微克CRF，随后注射0.5毫克、1毫克或2毫克阿霉素或仅注射阿霉素。通过使用抗CD11（一种针对这些细胞类型的特异性抗体）对巨噬细胞和单核细胞进行免疫组织化学定位来评估眼睑急性炎症的变化。使用伊文思蓝试验评估血管通透性的短期改变。每天观察额外的眼睑注射部位皮肤的变化，以确定皮肤损伤的起始日期和皮肤损伤的总持续时间。1个月后，对眼睑进行组织学处理，以对肌肉纤维损失进行形态计量分析。还检查了猴子眼睑注射CRF和阿霉素的效果。
单独使用阿霉素在治疗的眼睑中产生急性炎症反应，在第1天和第2天整个结缔组织中有大量巨噬细胞和单核细胞涌入。促肾上腺皮质激素释放因子预处理显著减少了炎症细胞向结缔组织的这种涌入。阿霉素使治疗的眼睑中的血管通透性大幅增加，导致水肿。促肾上腺皮质激素释放因子并未改变这种血管通透性的变化，表明CRF似乎对炎症细胞的迁移有特异性作用，而不仅仅是对血管通透性有普遍作用。与单独使用阿霉素相比，促肾上腺皮质激素释放因子和阿霉素联合治疗延迟了皮肤损伤的发生，并减少了皮肤损伤的总持续时间。阿霉素化学性眼肌切除术的有效性得以维持；在所有与阿霉素联合使用的CRF剂量下，肌肉损失都很显著。
促肾上腺皮质激素释放因子显著减轻了局部注射阿霉素导致的眼睑急性炎症反应。CRF不仅减少了单核细胞和巨噬细胞的急性涌入，还保护了注射部位上方的皮肤，大幅减少了皮肤损伤的程度。阿霉素诱导的肌肉毒性疗效得以维持。一种在治疗的眼睑中将肌毒性与抗炎活性相结合的治疗方案可能会通过提高患者的接受度而导致更有效的患者治疗。应探索CRF在癌症化疗期间外渗后立即给药时在限制组织损伤方面可能具有临床应用价值的潜力。
