Omar R F, Harvie P, Gourde P, Désormeaux A, Tremblay M, Beauchamp D, Bergeron M G
Centre de Recherche en Infectiologie, Faculté de Médecìne, Unìversìté Laval, Québec, Canada.
Toxicol Appl Pharmacol. 1997 Mar;143(1):140-51. doi: 10.1006/taap.1996.8080.
The antiviral efficacy and toxicity of ribavirin, foscarnet (PFA), and combinations of both drugs at two different doses have been evaluated in the murine AIDS (MAIDS) model. Our results clearly demonstrated that infected mice treated with ribavirin at 100 mg/ kg/day were protected against splenomegaly, lymphadenopathy, and hypergammaglobulinemia whereas PFA alone at 180 or 360 mg/kg/day did not afford any protection. Treatment with drug combinations showed protective effects similar to those observed with ribavirin alone. Hyperplasia and deorganization of the lymphoid architecture were noted in spleen and lymph nodes of infected mice compared to those of the uninfected group. However, treatment with ribavirin restored the lymphoid tissue architecture and reduced the emergence of germinal centers. Electron microscopic examination of renal cortex of animals treated with PFA at 360 mg/kg/day revealed clear mitochondrial necrosis (bursting of mitochondria) of the distal tubules and vacuolization of the proximal tubules which was more striking with combination therapy. Regarding hematotoxicity, PFA did not cause significant hematotoxicity at both doses, whereas ribavirin was hematotoxic at both doses (50 and 100 mg/kg/day), this toxicity being more evident at the higher dose. In conclusion, treatment with ribavirin showed clear efficacy against MAIDS whereas PFA had no efficacy. Furthermore, ribavirin treatment caused hematoxicity and PFA treatment resulted in nephrotoxicity.
在小鼠获得性免疫缺陷综合征（MAIDS）模型中，已对利巴韦林、膦甲酸钠（PFA）以及两种药物不同剂量组合的抗病毒疗效和毒性进行了评估。我们的结果清楚地表明，以100 mg/kg/天的剂量用利巴韦林治疗的感染小鼠可预防脾肿大、淋巴结病和高球蛋白血症，而单独使用180或360 mg/kg/天的PFA则没有任何保护作用。药物组合治疗显示出与单独使用利巴韦林观察到的保护作用相似。与未感染组相比，感染小鼠的脾脏和淋巴结出现了淋巴组织结构的增生和紊乱。然而，利巴韦林治疗可恢复淋巴组织结构并减少生发中心的出现。对以360 mg/kg/天的剂量用PFA治疗的动物的肾皮质进行电子显微镜检查发现，远端小管出现明显的线粒体坏死（线粒体破裂），近端小管出现空泡化，联合治疗时更为明显。关于血液毒性，两种剂量的PFA均未引起明显的血液毒性，而两种剂量（50和100 mg/kg/天）的利巴韦林均具有血液毒性，这种毒性在较高剂量时更为明显。总之，利巴韦林治疗对MAIDS显示出明显疗效，而PFA无效。此外，利巴韦林治疗导致血液毒性，PFA治疗导致肾毒性。
