Robinson Kelsey, Platt Simon, Bibi Katherine, Banovic Frane, Barber Renee, Howerth Elizabeth W, Madsen Gary
Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, United States.
Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA, United States.
Front Vet Sci. 2020 Jul 30;7:447. doi: 10.3389/fvets.2020.00447. eCollection 2020.
Acute spinal cord injury consists of a primary, traumatic event followed by a cascade of secondary events resulting in ongoing cell damage and death. There is great interest in prevention of these secondary effects to reduce permanent long-term neurologic deficits. One such target includes reactive oxygen species released following injury, which can be enzymatically converted into less harmful molecules by superoxide dismutase and catalase. Canine intervertebral disc herniation has been suggested as a naturally occurring model for acute spinal cord injury and its secondary effects in people. The aims of this study were to test the safety of a novel antioxidant delivery system in four healthy dogs and to indirectly test effect of delivery via cytokine measurement. All dogs experienced adverse events to some degree, with two experiencing adverse events considered to be severe. The clinical signs, including combinations of bradycardia, hypotension, hypersalivation, pale gums, and involuntary urination, were consistent with complement activation-related pseudoallergy (CARPA). CARPA is a well-known phenomenon that has been reported to occur with nanoparticle-based drug delivery, among other documented causes. Two dogs also had mild to moderate changes in their blood cell count and chemistry, including elevated alanine transferase, and thrombocytopenia, which both returned to normal by day 7 post-administration. Cytokine levels trended downwards over the first 3 days, but many were elevated at measurement on day 7. Intradermal testing suggested catalase as a potential cause for reactions. No long-term clinical signs were observed, and necropsy results revealed no concerning pathology. Additional evaluation of this product, including further characterization of reactions to catalase containing components, dose-escalation, and desensitization should be performed before evaluation in clinically affected dogs.
急性脊髓损伤包括一次原发性创伤事件，随后是一系列继发性事件，导致持续的细胞损伤和死亡。人们对预防这些继发性影响以减少永久性长期神经功能缺损非常感兴趣。其中一个目标包括损伤后释放的活性氧，超氧化物歧化酶和过氧化氢酶可将其酶促转化为危害较小的分子。犬椎间盘突出症被认为是人类急性脊髓损伤及其继发性影响的一种自然发生模型。本研究的目的是在四只健康犬中测试一种新型抗氧化剂递送系统的安全性，并通过细胞因子测量间接测试递送效果。所有犬都在一定程度上经历了不良事件，其中两只经历了被认为是严重的不良事件。临床症状包括心动过缓、低血压、流涎过多、牙龈苍白和不自主排尿等组合，与补体激活相关的假过敏（CARPA）一致。CARPA是一种众所周知的现象，据报道在基于纳米颗粒的药物递送中会发生，还有其他一些已记录的原因。两只犬的血细胞计数和血液化学也有轻度至中度变化，包括丙氨酸转氨酶升高和血小板减少，给药后第7天均恢复正常。细胞因子水平在最初3天呈下降趋势，但在第7天测量时许多细胞因子水平升高。皮内试验表明过氧化氢酶可能是反应的原因。未观察到长期临床症状，尸检结果未发现相关病理学异常。在对临床患病犬进行评估之前，应对该产品进行进一步评估，包括对含过氧化氢酶成分的反应进行进一步表征、剂量递增和脱敏。
