Tennant B C, Baldwin B H, Graham L A, Ascenzi M A, Hornbuckle W E, Rowland P H, Tochkov I A, Yeager A E, Erb H N, Colacino J M, Lopez C, Engelhardt J A, Bowsher R R, Richardson F C, Lewis W, Cote P J, Korba B E, Gerin J L
College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Hepatology. 1998 Jul;28(1):179-91. doi: 10.1002/hep.510280124.
Woodchucks were used to study the antiviral activity and toxicity of fialuridine (FIAU; 1,-2'deoxy-2'fluoro-1-beta-D-arabinofuranosyl-5-iodo-uracil). In an initial experiment, groups of six chronic woodchuck hepatitis virus (WHV) carrier woodchucks received daily doses of FIAU by intraperitoneal injection for 4 weeks. At 0.3 mg/kg/d, the antiviral effect was equivocal, but at 1.5 mg/kg/d, FIAU had significant antiviral activity. No evidence of drug toxicity was observed during the 4-week period of treatment or during posttreatment follow-up. In a second experiment, groups of nine WHV carriers or uninfected woodchucks were given 1.5 mg/kg/d of FIAU orally for 12 weeks, and the results compared with placebo-treated controls. After 4 weeks, the serum WHV-DNA concentration in the FIAU-treated carrier group was two to three logs lower than that in the placebo-treated group. After 12 weeks of FIAU treatment, serum WHV DNA was not detectable by conventional dot-blot analysis, hepatic WHV-DNA replicative intermediates (RI) had decreased 100-fold, and hepatic expression of WHV core antigen was remarkably decreased. No evidence of toxicity was observed after 4 weeks, but, after 6 to 7 weeks, food intake decreased and, after 8 weeks, the mean body weights of woodchucks treated with FIAU were significantly lower than controls. Anorexia, weight loss, muscle wasting, and lethargy became progressively severe, and all FIAU-treated woodchucks died or were euthanized 78 to 111 days after treatment began. Hepatic insufficiency (hyperbilirubinemia, decreased serum fibrinogen, elevated prothrombin time), lactic acidosis, and hepatic steatosis were characteristic findings in the final stages of FIAU toxicity in woodchucks. The syndrome of delayed toxicity in woodchucks was similar to that observed previously in humans treated with FIAU, suggesting that the woodchuck should be valuable in future investigations of the molecular mechanisms of FIAU toxicity in vivo and for preclinical toxicological evaluation of other nucleoside analogs before use in patients.
土拨鼠被用于研究非阿尿苷（FIAU；1，-2'-脱氧-2'-氟-1-β-D-阿拉伯呋喃糖基-5-碘尿嘧啶）的抗病毒活性和毒性。在最初的实验中，每组6只慢性土拨鼠肝炎病毒（WHV）携带土拨鼠通过腹腔注射接受每日剂量的FIAU，持续4周。在0.3毫克/千克/天的剂量下，抗病毒效果不明确，但在1.5毫克/千克/天的剂量下，FIAU具有显著的抗病毒活性。在4周的治疗期或治疗后随访期间未观察到药物毒性的证据。在第二个实验中，每组9只WHV携带者或未感染的土拨鼠口服1.5毫克/千克/天的FIAU，持续12周，并将结果与安慰剂治疗的对照组进行比较。4周后，FIAU治疗的携带者组的血清WHV-DNA浓度比安慰剂治疗组低两到三个对数。FIAU治疗12周后，通过传统的斑点印迹分析无法检测到血清WHV DNA，肝脏WHV-DNA复制中间体（RI）减少了100倍，并且肝脏中WHV核心抗原的表达显著降低。4周后未观察到毒性证据，但6至7周后，食物摄入量减少，8周后，接受FIAU治疗的土拨鼠的平均体重显著低于对照组。厌食、体重减轻、肌肉消瘦和嗜睡逐渐加重，所有接受FIAU治疗的土拨鼠在治疗开始后78至111天死亡或被安乐死。肝功能不全（高胆红素血症、血清纤维蛋白原降低、凝血酶原时间升高）、乳酸性酸中毒和肝脂肪变性是土拨鼠FIAU毒性终末期的特征性表现。土拨鼠延迟毒性综合征与先前接受FIAU治疗的人类中观察到的综合征相似，这表明土拨鼠在未来对FIAU体内毒性分子机制的研究以及其他核苷类似物在患者中使用前的临床前毒理学评估中将具有重要价值。
