Grossman P L, Remington J S
Am J Trop Med Hyg. 1979 May;28(3):445-55. doi: 10.4269/ajtmh.1979.28.445.
Trimethoprim (TMP) and sulfamethoxazole (SMZ) were studied alone and in combination to determine their effect in vitro on intracellular Toxoplasma gondii and in vivo against murine toxoplasmosis. In the in vitro experiments, whereas 1 and 2 microgram/ml TMP had no demonstrable effect on intracellular T. gondii, 10-20 microgram/ml TMP resulted in death of the intracellular organisms; concentrations as high as 100 microgram/ml SMZ had no demonstrable effect against the intracellular organisms. When used in combination, a significant synergistic effect was noted with 2 microgram/ml TMP-50 microgram/ml SMZ. Studies on the kinetics of inhibition and/or killing of Toxoplasma revealed that 18 hours of treatment with 2 microgram/ml TMP-50 microgram/ml SMZ resulted in irreversible inhibition of the intracellular organisms. When used in vivo against a 50,000 LD100 dose of Toxoplasma, TMP fed by gavage or mixed in the diet had no effect in murine toxoplasmosis at doses as high as 200 mg/kg a day. SMZ administered by gavage had no effect at doses up to 200 mg/kg a day; but at 300 and 400 mg/kg SMZ, protection was 47% and 83%, respectively. Treatment of infected mice was continued for 14 consecutive days, whether the drugs were administered alone or in combination. The combination 200 mg/kg TMP-200 mg/kg SMZ, when administered by gavage, protected 87% of mice. Survival after 14 days of SMZ mixed in the diet was 0% at 100 mg/kg, 47% at 200 mg/kg, and 100% at 300 mg/kg. Survival with the combination was 40% for 200 mg/kg TMP-100 mg/kg SMZ and 100% for 100 mg/kg TMP-200 mg/kg SMZ. The half-life of TMP in serum of Swiss Webster mice was calculated to be 24 min. The results obtained in vivo were inferior to those obtainable with the combination of pyrimethamine plus sulfadiazine. The problems of interpretation of results obtained in the murine model using TMP-SMZ and in their extrapolation to the treatment of the infection in man are discussed.
对甲氧苄啶（TMP）和磺胺甲恶唑（SMZ）分别及联合用药进行了研究，以确定它们在体外对细胞内弓形虫的作用以及在体内对鼠弓形虫病的疗效。在体外实验中，1微克/毫升和2微克/毫升的TMP对细胞内弓形虫没有明显作用，而10 - 20微克/毫升的TMP可导致细胞内病原体死亡；高达100微克/毫升的SMZ对细胞内病原体没有明显作用。联合使用时，2微克/毫升TMP - 50微克/毫升SMZ具有显著的协同作用。对弓形虫抑制和/或杀灭动力学的研究表明，用2微克/毫升TMP - 50微克/毫升SMZ处理18小时可导致细胞内病原体不可逆抑制。在体内用于对抗50,000个半数致死剂量（LD100）的弓形虫时，经口灌胃或混入饲料中的TMP，剂量高达每天200毫克/千克时，对鼠弓形虫病无效。经口灌胃给予的SMZ，剂量高达每天200毫克/千克时无效；但在300毫克/千克和400毫克/千克时，保护率分别为47%和83%。无论药物单独使用还是联合使用，对感染小鼠的治疗均持续14天。经口灌胃给予200毫克/千克TMP - 200毫克/千克SMZ的联合用药可保护87%的小鼠。混入饲料中的SMZ，100毫克/千克时14天后存活率为0%，200毫克/千克时为47%，300毫克/千克时为100%。200毫克/千克TMP - 100毫克/千克SMZ联合用药的存活率为40%，100毫克/千克TMP - 200毫克/千克SMZ联合用药的存活率为100%。经计算，TMP在瑞士韦伯斯特小鼠血清中的半衰期为24分钟。体内实验结果不如乙胺嘧啶加磺胺嘧啶联合用药的效果。讨论了在小鼠模型中使用TMP - SMZ获得的结果的解释问题以及将其外推至人类感染治疗的问题。
