Combination chemotherapy of Human African trypanosomiasis: the potential of drug synergism and the blood-brain barrier

我们的目标是更好地了解和改进对非洲人类锥虫病（又称昏睡病）的治疗。在整个撒哈拉以南非洲的36个国家，HAT是造成痛苦和死亡的一个主要原因，如果不加以治疗，总是致命的。这种疾病是由一种叫做锥虫的寄生虫引起的，这种寄生虫通过采采蝇的叮咬传播。东非形式的HAT是由布氏罗得西亚锥虫引起的，西非形式是由布氏冈比亚锥虫引起的。在疾病早期，寄生虫侵入血液和主要器官，在晚期，中枢神经系统（CNS）被侵入。为了让寄生虫进入中枢神经系统，它们必须穿过一个叫做“血脑屏障”（BBB）的结构。我们使用了一种与人类疾病密切相关的小鼠模型，其特征是大脑中出现了严重的炎症反应。美拉胂醇是最常用于治疗中枢神经系统感染的药物，由于脑部炎症，服用该药的患者中有5%死亡。因此，迫切需要新的治疗中枢神经系统疾病的方法。我们将使用减少剂量的美拉胂醇和其他药物联合治疗锥虫感染的小鼠。MRI是一种强大的血脑屏障可视化方法，将用于监测血脑屏障功能。该项目将突出哪些药物组合最有效。

Our goal is to gain a greater understanding and improve treatment of Human African Trypanosomiasis (HAT), also known as sleeping sickness. HAT is a major cause of suffering and death in 36 countries throughout sub-Saharan Africa and is always fatal if untreated. The disease is caused by parasites called trypanosomes that are spread by the bite of the tsetse fly. The East African form of HAT is caused by T.b.rhodesiense and the West African form by T.b.gambiense. In early-stage disease the parasites invade the bloodstream and major organs, and at the late-stage the central nervous system (CNS) is invaded. For the parasites to enter the CNS they must cross a structure called the ‘blood-brain barrier’ (BBB). We use a mouse model that closely mirrors the human disease, characterised by the development of a severe inflammatory reaction in the brain. Melarsoprol, the drug most frequently used for CNS infection, kills 5% of all patients who receive it due to brain inflammation. Because of this problem new methods of treating CNS disease are urgently needed. We will use reduced dosages of melarsoprol combined with other drugs to treat trypanosome-infected mice. MRI , a powerful method of visualising the BBB, will be used to monitor BBB function . This project will highlight which drug combinations are the most effective.