Kaminsky R, Schmid C, Grether Y, Holý A, DeClercq E, Naesens L, Brun R
Swiss Tropical Institute, Basel, Switzerland.
Trop Med Int Health. 1996 Apr;1(2):255-63. doi: 10.1111/j.1365-3156.1996.tb00036.x.
The unique features of purine salvage systems of pathogenic haemoflagellates render them selectively susceptible to the cytotoxic effects of purine analogues. A series of acyclic nucleoside phosphonates were evaluated for activity against pathogenic haemoflagellates in vitro. One of the phosphonylmethoxyalkylpurines, namely (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], was active in vitro against bloodstream forms of Trypanosoma brucei rhodesiense, T. b. gambiense, multidrug-resistant T. b. brucei, T. congolense and T. evansi, but not against intracellular T. cruzi or Leishmania donovani. Cytotoxic effects against mammalian cells were observed at 4900-27 300-fold higher concentrations than those necessary to inhibit T. b. rhodesiense. (S)-HPMPA was able to eliminate T. b. rhodesiense and multidrug-resistant T. b. brucei in an acute rodent model with two administrations of 10 mg/kg each.
致病性血鞭毛虫嘌呤补救系统的独特特性使其对嘌呤类似物的细胞毒性作用具有选择性敏感性。评估了一系列无环核苷膦酸酯对致病性血鞭毛虫的体外活性。其中一种膦酰甲氧基烷基嘌呤，即（S）-9-（3-羟基-2-膦酰甲氧基丙基）腺嘌呤[（S）-HPMPA]，在体外对罗德西亚布氏锥虫、冈比亚布氏锥虫、多药耐药的布氏锥虫、刚果锥虫和伊氏锥虫的血流形式有活性，但对细胞内的克氏锥虫或杜氏利什曼原虫无活性。对哺乳动物细胞的细胞毒性作用在比抑制罗德西亚布氏锥虫所需浓度高4900-27300倍的浓度下观察到。在急性啮齿动物模型中，（S）-HPMPA以每次10mg/kg的剂量给药两次，能够清除罗德西亚布氏锥虫和多药耐药的布氏锥虫。
