Romand S, Pudney M, Derouin F
Laboratoire de Parasitologie-Mycologie, Hôpital Saint-Louis, Paris, France.
Antimicrob Agents Chemother. 1993 Nov;37(11):2371-8. doi: 10.1128/AAC.37.11.2371.
The efficacy of atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, and minocycline was examined in vitro and in a murine model of acute toxoplasmosis. In vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of Toxoplasma growth by an enzyme-linked immunosorbent assay. For in vivo studies, mice were acutely infected intraperitoneally with 10(4) tachyzoites of the virulent RH strain and then treated perorally for 10 days from day 1 postinfection. The following drug regimens were investigated: atovaquone at 100 and 50 mg/kg of body weight per day and the combinations of atovaquone at 50 mg/kg with sulfadiazine at 200 mg/kg, pyrimethamine at 12.5 mg/kg, clarithromycin at 200 mg/kg, or minocycline at 50 mg/kg. Efficacy was assessed by determination of survival rates and sequential determination of parasite burdens in blood, brain, and lungs. In vitro, atovaquone inhibited Toxoplasma growth at a concentration of > or = 0.02 mg/liter; the 50% inhibitory concentration was estimated to be 0.023 mg/liter. No synergistic effect was observed when it was combined with sulfadiazine, clarithromycin, or minocycline, whereas a significant antagonistic effect was noted for the combination of atovaquone with pyrimethamine. In vivo, administration of atovaquone at 100 or 50 mg/kg/day for 10 days resulted in prolonged survival compared with that in untreated mice; this survival was associated with a reduction of parasite burdens in blood and tissues during the course of treatment. The combinations of atovaquone with pyrimethamine, clarithromycin, or sulfadiazine were more efficient than each drug administered alone, in terms of survival, but parasite burdens in blood and organs were not reduced compared with those in mice treated with any of the agents alone. These experimental results confirmed the activity of atovaquone against Toxoplasma gondii, but no marked improvement in efficacy was observed in vitro and in vivo when this drug was combined with pyrimethamine, sulfadiazine, minocycline, or clarithromycin.
在体外以及急性弓形虫病小鼠模型中检测了阿托伐醌单独使用或与乙胺嘧啶、磺胺嘧啶、克拉霉素及米诺环素联合使用的疗效。体外研究采用MRC5成纤维细胞组织培养，并通过酶联免疫吸附测定法对弓形虫生长进行定量分析。体内研究中，小鼠经腹腔急性感染10⁴个强毒株RH株速殖子，然后在感染后第1天开始口服给药10天。研究了以下药物方案：每天100和50mg/kg体重的阿托伐醌，以及50mg/kg的阿托伐醌与200mg/kg的磺胺嘧啶、12.5mg/kg的乙胺嘧啶、200mg/kg的克拉霉素或50mg/kg的米诺环素的组合。通过测定生存率以及连续测定血液、脑和肺中的寄生虫负荷来评估疗效。体外实验中，阿托伐醌在浓度≥0.02mg/L时可抑制弓形虫生长；50%抑制浓度估计为0.023mg/L。当它与磺胺嘧啶、克拉霉素或米诺环素联合使用时未观察到协同作用，而阿托伐醌与乙胺嘧啶联合使用时则观察到显著的拮抗作用。在体内，每天给予100或50mg/kg的阿托伐醌，持续10天，与未治疗的小鼠相比，生存期延长；这种生存期的延长与治疗过程中血液和组织中寄生虫负荷的减少有关。就生存率而言，阿托伐醌与乙胺嘧啶、克拉霉素或磺胺嘧啶联合使用比单独使用每种药物更有效，但与单独使用任何一种药物治疗的小鼠相比，血液和器官中的寄生虫负荷并未降低。这些实验结果证实了阿托伐醌对刚地弓形虫的活性，但当该药物与乙胺嘧啶、磺胺嘧啶、米诺环素或克拉霉素联合使用时，在体外和体内均未观察到疗效的显著改善。
