Oatess Tai L, Chen Patty H, Daniels Anthony B, Himmel Lauren E
Department of Pathology, Microbiology, and Immunology, Division of Comparative Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
United States Army Laboratory Animal Medicine Residency Program, Animal Care and Use Review Office, Office of Research Protections, Medical Research and Development Command, Fort Detrick, Maryland.
Comp Med. 2020 Apr 1;70(2):176-182. doi: 10.30802/AALAS-CM-18-000146. Epub 2020 Mar 11.
Endovascular microcatheter-based intraarterial (ophthalmic artery) chemotherapy is becoming widely used for the clinical treatment of intraocular retinoblastoma due to its apparent increased efficacy compared with traditional intravenous chemotherapy; however local ocular complications are not uncommon. Carboplatin is a chemotherapeutic agent used in both intravenous and intraarterial chemotherapy. We used rabbits to assess pharmacokinetics and ocular and systemic toxicity after intraarterial carboplatin infusion. Subsequent to unilateral intraarterial administration of carboplatin, severe unilateral or bilateral periocular edema occurred in 6 adult male New Zealand white rabbits. Time to onset varied from less than 4 h after administration ( = 3, 50 mg) to approximately 24 h afterward ( = 3, 25 mg). After becoming symptomatic, 5 of the 6 animals were promptly euthanized, and the remaining animal (25 mg treatment) was medically managed for 4 d before being euthanized due to intractable edema-related lagophthalmos. Globes and orbits from all 6 euthanized rabbits were harvested en bloc; whole-mount sections were prepared for histologic evaluation, which revealed drug-induced vasogenic edema in confined spaces as the main underlying pathogenesis. Transient and self-limiting periocular edema is a common side effect of intraarterial chemotherapy but is thought to occur predominantly with melphalan monotherapy or combination therapy using melphalan, carboplatin, and topotecan. The severity of this adverse consequence in rabbits was unexpected, and its use in the study was subsequently discontinued. Although the definitive cause for this vasotoxicity and striking clinical presentation is unknown, we suspect species-specific anatomic features and sensitivity might have contributed to amplified complications after intraarterial carboplatin chemotherapy of the eye. Due to the adverse effects of intraarterial carboplatin chemotherapy that we observed in 2 experimental cohorts of rabbits, we recommend caution regarding its use in this species.
基于血管内微导管的眼动脉内化疗因其与传统静脉化疗相比疗效明显提高，正广泛应用于眼内视网膜母细胞瘤的临床治疗；然而，局部眼部并发症并不少见。卡铂是一种用于静脉和动脉内化疗的化疗药物。我们使用兔子评估动脉内输注卡铂后的药代动力学以及眼部和全身毒性。在对6只成年雄性新西兰白兔进行单侧动脉内给予卡铂后，出现了严重的单侧或双侧眼周水肿。出现水肿的时间从给药后不到4小时（3只，50毫克）到给药后约24小时（3只，25毫克）不等。出现症状后，6只动物中的5只被迅速安乐死，其余动物（接受25毫克治疗）因顽固性水肿相关的兔眼症接受了4天的药物治疗，之后也被安乐死。对所有6只安乐死兔子的眼球和眼眶进行了整块切除；制备了整装切片用于组织学评估，结果显示局限空间内药物诱导的血管源性水肿是主要的潜在发病机制。短暂且自限性的眼周水肿是动脉内化疗的常见副作用，但被认为主要发生在美法仑单药治疗或使用美法仑、卡铂和拓扑替康的联合治疗中。这种不良反应在兔子中的严重程度出乎意料，因此在后续研究中停止了使用。尽管这种血管毒性和显著临床表现的确切原因尚不清楚，但我们怀疑物种特异性的解剖特征和敏感性可能导致了眼动脉内卡铂化疗后并发症的加剧。由于我们在两个兔子实验队列中观察到了动脉内卡铂化疗的不良反应，我们建议在该物种中使用时要谨慎。
