Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
Antimicrob Agents Chemother. 2012 Apr;56(4):1762-8. doi: 10.1128/AAC.05183-11. Epub 2012 Jan 23.
Toxoplasma gondii is a parasite that generates latent cysts in the brain; reactivation of these cysts may lead to fatal toxoplasmic encephalitis, for which treatment remains unsuccessful. We assessed spiramycin pharmacokinetics coadministered with metronidazole, the eradication of brain cysts and the in vitro reactivation. Male BALB/c mice were fed 1,000 tachyzoites orally to develop chronic toxoplasmosis. Four weeks later, infected mice underwent different treatments: (i) infected untreated mice (n = 9), which received vehicle only; (ii) a spiramycin-only group (n = 9), 400 mg/kg daily for 7 days; (iii) a metronidazole-only group (n = 9), 500 mg/kg daily for 7 days; and (iv) a combination group (n = 9), which received both spiramycin (400 mg/kg) and metronidazole (500 mg/kg) daily for 7 days. An uninfected control group (n = 10) was administered vehicle only. After treatment, the brain cysts were counted, brain homogenates were cultured in confluent Vero cells, and cysts and tachyzoites were counted after 1 week. Separately, pharmacokinetic profiles (plasma and brain) were assessed after a single dose of spiramycin (400 mg/kg), metronidazole (500 mg/kg), or both. Metronidazole treatment increased the brain spiramycin area under the concentration-time curve from 0 h to ∞ (AUC(0-∞)) by 67% without affecting its plasma disposition. Metronidazole plasma and brain AUC(0-∞) values were reduced 9 and 62%, respectively, after spiramycin coadministration. Enhanced spiramycin brain exposure after coadministration reduced brain cysts 15-fold (79 ± 23 for the combination treatment versus 1,198 ± 153 for the untreated control group [P < 0.05]) and 10-fold versus the spiramycin-only group (768 ± 125). Metronidazole alone showed no effect (1,028 ± 149). Tachyzoites were absent in the brain. Spiramycin reduced in vitro reactivation. Metronidazole increased spiramycin brain penetration, causing a significant reduction of T. gondii brain cysts, with potential clinical translatability for chronic toxoplasmosis treatment.
刚地弓形虫是一种寄生虫，它会在大脑中产生潜伏的囊肿；这些囊肿的重新激活可能导致致命的弓形体脑炎，目前这种病的治疗仍然不成功。我们评估了螺旋霉素与甲硝唑联合应用的药代动力学、脑囊肿的消除以及体外再激活。雄性 BALB/c 小鼠经口喂食 1000 个速殖子以发展慢性弓形体病。四周后，感染的小鼠接受不同的治疗：（i）感染未治疗的小鼠（n = 9），仅接受载体；（ii）螺旋霉素单一组（n = 9），每天 400 mg/kg ，持续 7 天；（iii）甲硝唑单一组（n = 9），每天 500 mg/kg ，持续 7 天；（iv）联合组（n = 9），每天接受螺旋霉素（400 mg/kg）和甲硝唑（500 mg/kg）联合治疗 7 天。一组未感染的对照组（n = 10）仅接受载体。治疗后，计算脑囊肿数量，脑匀浆在汇合的 Vero 细胞中培养，1 周后计算囊肿和速殖子数量。另外，在单次给予螺旋霉素（400 mg/kg）、甲硝唑（500 mg/kg）或两者后，评估药代动力学（血浆和大脑）。甲硝唑治疗使螺旋霉素的血浆浓度-时间曲线下面积（0 小时至无穷大，AUC（0-无穷大））增加了 67%，而不影响其血浆分布。甲硝唑联合治疗后，其血浆和脑 AUC（0-无穷大）值分别减少了 9%和 62%。联合用药后，螺旋霉素在大脑中的暴露增加了 15 倍（联合治疗组为 79 ± 23，未治疗对照组为 1198 ± 153 [P < 0.05]），与螺旋霉素单一组相比降低了 10 倍（768 ± 125）。甲硝唑单独使用没有效果（1028 ± 149）。大脑中没有速殖子。螺旋霉素减少体外再激活。甲硝唑增加了螺旋霉素在大脑中的穿透性，导致弓形虫脑囊肿显著减少，这为慢性弓形体病的治疗提供了潜在的临床转化前景。
