Schmidt L H, Harrison J, Rossan R N, Vaughan D, Crosby R
Am J Trop Med Hyg. 1977 Sep;26(5 Pt 1):837-49. doi: 10.4269/ajtmh.1977.26.837.
The experiments described in this report have dealt with the dimensions of therapeutic potentiation achieved when combinations of pyrimethamine and sulfadiazine were administered to rhesus monkeys infected with a drug-susceptible strain of Plasmodium cynomolgi or its pyrimethamine-resistant variant and to owl monkeys infected with strains of P. falciparum and P. vivax of varying degrees of resistance to this pyrimidine. These evaluations showed: 1) that when delivered in combination, the activities of both pyrimethamine and sulfadiazine against infections with any of the above strains were enhanced significantly; 2) that in infections with the Ro and Ro/PM strains of P. cynomolgi and the Vietnam Palo Alto strain of P. vivax, concomitant delivery of the two agents resulted in a 32-fold increase in the activity of pyrimethamine and a 50- to 100-fold increase in the activity of sulfadizine; 3) that as a result of this synergism, infections with the pyrimethamine resistant Ro/PM and Palo Alto strains could be cured with a fraction of the maximum tolerated dose of this drug; 4) that in marked contrast to the above result, infections with the Malayan Camp and Vietnam Smith strains of P. falciparum could not be cured regularly by combination regimens which included the maximally tolerated dose of pyrimethamine. This poor response has been attributed to the high levels of pyrimethamine-resistance possessed by these strains. It is believed that the comparatively small but not insignificant incidences of treatment failures associated with delivery of pyrimethamine-sulfonamide combinations to both patients and human volunteers infected with multidrug-resistant strains of P. falciparum rest on a similar basis.
本报告中描述的实验涉及将乙胺嘧啶和磺胺嘧啶联合应用于感染对药物敏感的食蟹猴疟原虫菌株或其乙胺嘧啶抗性变体的恒河猴，以及感染对该嘧啶具有不同程度抗性的恶性疟原虫和间日疟原虫菌株的夜猴时所实现的治疗增效幅度。这些评估表明：1）联合给药时，乙胺嘧啶和磺胺嘧啶对上述任何菌株感染的活性均显著增强；2）在感染食蟹猴疟原虫的Ro和Ro/PM菌株以及间日疟原虫的越南帕洛阿尔托菌株时，两种药物同时给药导致乙胺嘧啶活性增加32倍，磺胺嘧啶活性增加50至100倍；3）由于这种协同作用，用该药物最大耐受剂量的一小部分就能治愈对乙胺嘧啶耐药的Ro/PM和帕洛阿尔托菌株感染；4）与上述结果形成鲜明对比的是，包含最大耐受剂量乙胺嘧啶的联合用药方案不能定期治愈感染恶性疟原虫的马来亚营地和越南史密斯菌株。这种不良反应归因于这些菌株对乙胺嘧啶的高抗性水平。据信，在感染多重耐药恶性疟原虫菌株的患者和人类志愿者中，与乙胺嘧啶 - 磺胺类药物联合给药相关的治疗失败发生率相对较小但并非微不足道，其原因也基于类似情况。
