Development of Acoziborole for the Treatment of Human African Trypanosomiasis

用于治疗非洲人类锥虫病的 Acoziborole 的开发

• 批准号: 10470642
• 负责人: Sharie Haugabook
• 金额: $ 107.1万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470642
• 关键词: Africa; Africa South of the Sahara; African Trypanosomiasis; Aggressive behavior; Area; Bite; Blood; Blood - brain barrier anatomy; Blood Circulation; Body Fluids; Brain; Cerebrospinal Fluid; Cessation of life; Characteristics; Clinical; Coma; Development; Disease; Disorientation; Dose; Early Diagnosis; Early treatment; Eflornithine; Fatigue; Goals; Hallucinations; Headache; Health; Healthcare; Human; Infection; Infrastructure; Intermittent Pyrexia; Lead; Left; Life; Lymph; Medical; Neuraxis; Nifurtimox; Oral; Parasites; Parasitic Diseases; Pathogenicity; Patients; Pharmaceutical Preparations; Psychoses; Resources; Scientist; Seizures; Signs and Symptoms; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Symptoms; Therapeutics for Rare and Neglected Diseases; Toxicology; Training; Treatment Protocols; Trypanosoma; Trypanosoma brucei brucei; Tsetse Flies; abnormal reflex; authority; extracellular; fexinidazole; good laboratory practice; intravenous injection; neuropsychiatry; patient population; rural area; vector

HAT is transmitted by a vector, the tsetse fly, which introduces trypanosomes free-living extracellular parasites into the bloodstream, body fluids, lymph and cerebrospinal fluid. The Trypanosoma brucei species is pathogenic to humans and endemic to sub-Saharan Africa. T.b. gambiense accounts for over 98% of cases of HAT (gHAT) and T.b. rhodesiense accounts for about 2% of cases (rHAT). The disease progresses through two stages of infection, first in the blood and lymph and then into the central nervous system (CNS). While in the blood and lymph, clinical signs and symptoms are mild and non-specific, including headaches, fatigue, and intermittent fevers. By contrast, infection in the CNS is marked by pronounced neuropsychiatric signs, including disrupted sleep/wake cycles, hallucinations and aggression, abnormal reflexes, seizures, and coma. Once infection has progressed to the CNS, HAT is more difficult to treat, requiring drugs to cross the blood-brain barrier, making early diagnosis and treatment imperative. Until recently, first-line treatment for late-stage HAT relied on a combination of two drugs (nifurtimox and eflornithine), administered over a course of 10 days, requiring intravenous injection in a clinical setting. To reach wider patient populations in poorer, more remote areas with little healthcare infrastructure, the lead collaborators developed fexinidazole, an oral therapy taken once daily for 10 days that can treat both early and late stages of infection. To further simplify the treatment regimen, the lead collaborators have now developed acoziborole, which also treats both stages of infection, but requires only a single oral dose in lieu of a multi-day course. TRND scientists have completed Good Laboratory Practice (GLP)-compliant nonclinical toxicology studies necessary to support the registration of acoziborole with health regulatory authorities to treat HAT patients in Africa.

HAT由媒介传播，Tsetse Fly将锥虫自由生活的细胞外寄生虫引入血液，体液，淋巴和脑脊液。布鲁氏锥虫物种对人类是致病性的，对撒哈拉以南非洲是特有的。 T.B. Gambiense占HAT案件（GHAT）和T.B.的98％以上大约占病例（RHAT）的2％。该疾病通过感染的两个阶段发展，首先是血液和淋巴，然后进入中枢神经系统（CNS）。在血液和淋巴上，临床体征和症状是轻度和非特异性的，包括头痛，疲劳和间歇性发烧。相比之下，中枢神经系统中的感染以明显的神经精神症状为特征，包括睡眠/唤醒周期中断，幻觉和侵略性，反射异常，癫痫发作和昏迷。一旦感染发展到中枢神经系统，HAT就更难治疗，需要药物越过血脑屏障，从而使早期诊断和治疗势在必行。 直到最近，对后期帽子的一线治疗依赖于两种药物（Nifurtimox和eflornithine）的组合，在10天内进行了10天的治疗，需要在临床环境中进行静脉注射。为了到达更贫穷，更偏远地区的医疗保健基础设施的较偏远地区的更广泛的患者人群，首席合作者开发了fexinidazole，这是每天进行10天的口服疗法，可以治疗早期和晚期感染的阶段。为了进一步简化治疗方案，主要合作者现在已经开发了Acoziborole，这也可以治疗两个感染阶段，但仅需要一个口服剂量来代替多天的课程。 TRND科学家已经完成了良好的实验室实践（GLP） - 集合的非临床毒理学研究，以支持Acoziborole在卫生监管机构中注册以治疗非洲的HAT患者。