Piwoni Katarzyna, Jaeckel Gilta, Rasa Agnija, Alberts Pēteris
Charles River Laboratories Edinburgh Ltd., Elphinstone Research Centre Tranent, East Lothian, EH33 2NE, UK.
Rigvir, Riga, Latvia.
Toxicol Rep. 2021 Jan 19;8:230-238. doi: 10.1016/j.toxrep.2021.01.009. eCollection 2021.
The oncolytic ECHO-7 virus Rigvir was registered in Latvia in 2004 and later in Georgia, Armenia and Uzbekistan. No severe adverse events have been observed. During drug development good laboratory practice (GLP) pre-clinical toxicology studies are generally required by regulatory agencies. Since such studies had previously not been performed, the aim of this 4-week repeated dose GLP toxicity study was to determine the potential toxicity, and reversibility of any findings after a 4-week treatment-free period. Han-Wistar rats were randomly assigned to control, Rigvir (210, 110 and 210 TCID) groups. Intramuscular administration was on days 1-3, 8-10, 15-17, and 22-24. Clinical signs, average food-intake, body weights, ophthalmology, clinical pathology parameters, bioanalysis, gross necropsy, organ weights, biodistribution and histopathology were evaluated. There were no unscheduled deaths, adverse clinical signs, no changes in body weight, body weight gain, food intake, ophthalmoscopy, clinical pathology, urine volume or composition, or organ weights. Slightly higher numbers of eosinophils in Rigvir treated animals returned to normal after recovery. Rigvir biodistributed to the spleen. Low incidence of inflammatory cell infiltration at administration sites and increased lymphoid cellularity at the regional (inguinal and popliteal) lymph nodes were observed; after recovery, only those in popliteal lymph nodes remained. Therefore, 4-week Rigvir at 210 TCID administration was well tolerated in rats. The no-observed-adverse-effect level (NOAEL) was the highest dose tested, 210 TCID.
The objectives of this study were to determine the potential toxicity of Rigvir, an ECHO-7 oncolytic virus, when administered intramuscularly for 4 weeks to rats, with a 4-week recovery period, and to evaluate the reversibility of any potential findings. In addition, the biodistribution of Rigvir in selected tissues was determined.
溶瘤性ECHO - 7病毒Rigvir于2004年在拉脱维亚注册，随后在格鲁吉亚、亚美尼亚和乌兹别克斯坦注册。未观察到严重不良事件。在药物研发过程中，监管机构通常要求进行符合良好实验室规范（GLP）的临床前毒理学研究。由于此前未进行此类研究，这项为期4周的重复给药GLP毒性研究的目的是确定潜在毒性，以及在4周无治疗期后任何发现的可逆性。将Han - Wistar大鼠随机分为对照组、Rigvir（210、110和210 TCID）组。于第1 - 3天、8 - 10天、15 - 17天和22 - 24天进行肌肉注射。评估临床体征、平均食物摄入量、体重、眼科检查、临床病理参数、生物分析、大体尸检、器官重量、生物分布和组织病理学。未出现非预期死亡、不良临床体征，体重、体重增加、食物摄入量、检眼镜检查、临床病理学、尿量或成分以及器官重量均无变化。接受Rigvir治疗的动物中嗜酸性粒细胞数量略有增加，恢复后恢复正常。Rigvir在脾脏中进行生物分布。观察到给药部位炎症细胞浸润发生率较低，区域（腹股沟和腘窝）淋巴结淋巴细胞增多；恢复后，仅腘窝淋巴结的情况仍然存在。因此，大鼠对210 TCID的4周Rigvir给药耐受性良好。未观察到不良反应水平（NOAEL）为测试的最高剂量，即210 TCID。
本研究的目的是确定溶瘤性ECHO - 7病毒Rigvir肌肉注射4周并恢复4周后对大鼠的潜在毒性，并评估任何潜在发现的可逆性。此外，还确定了Rigvir在选定组织中的生物分布。
