Loiseau P M, Dreyfuss G, Daulouède S, Lachâtre G, Vincendeau P, Craciunescu D G
Laboratoire de Biologie et Contrôle des Organismes Parasites, Université de Paris-Sud, Châtenay-Malabry, France.
Trop Med Int Health. 1997 Jan;2(1):19-27. doi: 10.1046/j.1365-3156.1997.d01-128.x.
Pentamidine di-(iridium cyclo-octadiene)tetraphenylborate, called Ir-(COD)-pentamidine tetraphenylborate, was selected from a primary screening as a promising trypanocidal compound. The compound was evaluated against three isolates: Trypanosoma brucei brucei CMP, T.b. brucei GVR 35 and T.b. gambiense Feo. On the T.b. brucei GVR 35 murine CNS model, no mouse was cured when the treatment was commenced 21 days post-infection whatever the treatment regimen. Nevertheless, in vitro the compound killed the trypomastigote forms of T. b. gambiense Feo at 0.6 microM. In vivo, the compound cured all mice infected 1 hour previously with T. b. gambiense Feo after a 10 mg/kg (6.3 mumol/kg) treatment subcutaneously administered in a single dose. Moreover, the compound was active at 1 mg/kg (0.6 mumol/kg) in a single dose against the early stage of the T. b. brucei Antat 1-9 sheep model. Serum kinetics data showed that pentamidine di-(iridium cyclo-octadiene) tetraphenylborate was distributed within deep compartment according to a monocompartmental model. The maximum iridium serum concentration was 198 micrograms/l corresponding to 1 mumol/kg of iridium derivative and this value remained stable for 30-50 hours post-treatment. Iridium was completely eliminated from the serum 700 hours post-treatment. all data obtained from these models are in favour of an activity in the early stage of the disease but indicate that the compound could not cross the blood-brain barrier despite its lipophilicity. Although iterative treatments with the compound rapidly induced the selection of iridium derivative refractory populations, the compound could be studied on pentamidine refractory strains.
双（铱环辛二烯）四苯基硼酸喷他脒，即Ir-（COD）-喷他脒四苯基硼酸，在初步筛选中被选为一种有前景的杀锥虫化合物。该化合物针对三种分离株进行了评估：布氏布氏锥虫CMP、布氏布氏锥虫GVR 35和布氏冈比亚锥虫Feo。在布氏布氏锥虫GVR 35小鼠中枢神经系统模型中，无论采用何种治疗方案，感染后21天开始治疗时，没有小鼠被治愈。然而，在体外，该化合物在0.6微摩尔浓度时可杀死布氏冈比亚锥虫Feo的锥鞭毛体形式。在体内，经10毫克/千克（6.3微摩尔/千克）单剂量皮下给药后，该化合物可治愈所有1小时前感染布氏冈比亚锥虫Feo的小鼠。此外，该化合物在1毫克/千克（0.6微摩尔/千克）单剂量时对布氏布氏锥虫Antat 1-9绵羊模型的早期阶段具有活性。血清动力学数据表明，双（铱环辛二烯）四苯基硼酸喷他脒根据单室模型分布于深部隔室。铱血清最大浓度为198微克/升，相当于1微摩尔/千克的铱衍生物，该值在治疗后30至50小时保持稳定。治疗后700小时铱从血清中完全清除。从这些模型获得的所有数据都支持该化合物在疾病早期具有活性，但表明该化合物尽管具有亲脂性，但无法穿过血脑屏障。尽管用该化合物进行反复治疗会迅速诱导出对铱衍生物耐药的群体，但该化合物可用于对喷他脒耐药菌株的研究。
