Melarsoprol Cyclodextrin Inclusion Complexes as Promising Oral Candidates for the Treatment of Human African Trypanosomiasis

Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites Trypanosoma brucei (T.b.) gambiense or T.b.rhodesiense and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage T.b.rhodesiense infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-β-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties in vitro and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy.

人类非洲锥虫病（Human African trypanosomiasis, HAT），又称昏睡病，由布氏锥虫（Trypanosoma brucei）冈比亚亚种（T.b. gambiense）或罗得西亚亚种（T.b. rhodesiense）原虫感染引发，若未接受治疗则必死无疑。整个撒哈拉以南非洲地区共有6000万人面临感染该疾病的风险。感染进程分为两个阶段：首先是血淋巴期，寄生虫会侵袭血液、淋巴系统与外周器官；随后进展至晚期脑炎期，此时寄生虫侵入中枢神经系统（Central Nervous System, CNS），引发严重的神经系统疾病。三价砷类药物美拉胂醇（melarsoprol，商品名Arsobal）是当前唯一可用于中枢神经系统期罗得西亚亚种锥虫感染的治疗手段，但由于其溶剂为丙二醇（propylene glycol），必须通过静脉给药，且会引发多种不良反应。约10%接受治疗的患者会出现严重的治疗后反应性脑病（post-treatment reactive encephalopathy），其中半数患者会死亡，因此美拉胂醇的致死率约为接受治疗患者的5%。环糊精（Cyclodextrins）已被用于提升多种药物的溶解度并降低其毒性。因此，本研究探究了两种美拉胂醇环糊精包合物：美拉胂醇羟丙基-β-环糊精（hydroxypropyl-β-cyclodextrin）与美拉胂醇随机甲基化-β-环糊精（randomly-methylated-β-cyclodextrin）。研究发现，这类化合物在体外（in vitro）仍保留锥虫杀伤活性，且以0.05 mmol/kg的剂量每日口服一次、连续给药7天时，可治愈中枢神经系统期的小鼠感染模型，且未观察到明显的毒性体征。给药后，脑内的寄生虫载量迅速降低；化疗结束时，磁共振成像（magnetic resonance imaging, MRI）结果显示血脑屏障（blood-brain barrier）的完整性已恢复至正常水平。上述研究结果充分表明，包合型美拉胂醇可作为中枢神经系统期人类非洲锥虫病的口服治疗方案，相较于当前的注射化疗（parenteral chemotherapy）手段，具有显著的临床改进价值。