van der Meer C, Versluijs-Broers J A
Exp Parasitol. 1986 Aug;62(1):98-113. doi: 10.1016/0014-4894(86)90013-5.
In rats infected with monomorphic Trypanosoma brucei brucei, the efficacy of the therapy with salicylhydroxamic acid plus glycerol, i.e., combined therapy, decreased with increasing time after infection. It failed completely after the infection was made chronic by suboptimal treatment for 6 weeks. When this chronic infection had been established and "optimal" treatment was given, viable trypanosomes could still be detected 1 day later in brain and muscle but not in blood. In most organs, the concentrations of salicylhydroxamic acid and glycerol were lower than in the blood plasma; the maximum concentration of glycerol in the brain was only 20% of that in plasma. The most likely explanation for the failure of the combined therapy is that, in certain tissues, the concentration of the drugs remains too low to kill extravascular trypanosomes. Other explanations, such as the selection of a resistant strain or the survival of (extravascular) forms with a more active mitochondrion, could be excluded with a high degree of probability. Suramin was very effective, even after combined therapy had failed repeatedly, while melarsoprol was less effective. As in combined therapy, the dose of melarsoprol that could cure an acute infection was insufficient to cure a chronic infection. Combined therapy failed after a spontaneous chronic infection with T. b. rhodesiense had existed for 5-7 weeks, but it was effective in T. vivax infected rats even when parasitemia had been present for at least 4 days. Effective alternative schedules for combined therapy were not found.
在感染布氏锥虫单一型的大鼠中，水杨羟肟酸加甘油疗法（即联合疗法）的疗效随感染后时间的增加而降低。在经6周次优治疗使感染转为慢性后，该疗法完全失效。当这种慢性感染确立并给予“最佳”治疗后，1天后仍可在脑和肌肉中检测到活的锥虫，但在血液中未检测到。在大多数器官中，水杨羟肟酸和甘油的浓度低于血浆中的浓度；脑中甘油的最大浓度仅为血浆中的20%。联合疗法失败的最可能解释是，在某些组织中，药物浓度仍然过低，无法杀死血管外的锥虫。其他解释，如选择了耐药菌株或具有更活跃线粒体的（血管外）形式存活下来，极有可能被排除。苏拉明非常有效，即使在联合疗法多次失败后也是如此，而美拉胂醇的效果较差。与联合疗法一样，能治愈急性感染的美拉胂醇剂量不足以治愈慢性感染。在罗得西亚锥虫自发慢性感染存在5至7周后，联合疗法失败，但在感染了活泼锥虫的大鼠中，即使已经出现至少4天的寄生虫血症，联合疗法仍然有效。未找到联合疗法的有效替代方案。
