Pharmacological insights into antimalarial exposure, clinical outcomes, and drug resistance in Africa

项目概要 疟疾仍然是一个巨大的问题，药物对于治疗疟疾发作至关重要， 预防高危人群患病，限制传播。基于青蒿素的联合疗法（ACT）， 主要是蒿甲醚-本芴醇或青蒿琥酯-阿莫地喹，是抗疟治疗的基石 非洲。标准化学预防方法是使用磺胺多辛进行间歇性预防治疗 乙胺嘧啶（SP）在孕妇中的应用以及阿莫地喹 SP 的季节性疟疾化学预防 萨赫勒次区域的儿童，正在研究改进的方法。在此背景下，抗疟药 抵抗力值得高度关注。对 ACT 的耐药性，包括青蒿素和伙伴药物，已经 兴起于东南亚。对阿莫地喹和 SP 的耐药性由来已久，但敏感性各不相同， 对化学预防的影响不确定。对高危人群进行的确定性研究表明， 需要接触抗疟药物、治疗和预防功效以及耐药性的选择。 该项目将建立在我们第一个资助周期中对乌干达的研究的基础上，其中我们描述了 最有前途的ACT双氢青蒿素哌喹的药代动力学（PK）和药效学 非洲化学预防的新剂。我们的目标将扩大，以深入了解协会 药物暴露、疟疾结果、出生结果和耐药性选择之间的关系 非洲抗疟药物的 3 个主要适应症：治疗疟疾、妊娠期化学预防、 对接触季节性疟疾的儿童进行化学预防。一个指导原则是，最好的方法是 防止选择耐药性就是有效治疗和预防疟疾，因为接触不足 抗疟药物会增加药物敏感型和耐药型疟疾的风险。我们的研究将建立在 我们的药理学专业知识以及加州大学旧金山分校和疟疾研究小组之间的长期合作 乌干达和布基纳法索。我们将使用严格的 PK 评估来测试儿童中的相关假设 乌干达和布基纳法索以及乌干达孕妇接触 ACT 与以下风险相关： 疟疾和耐药寄生虫的选择。更好地表征药物之间的关联 暴露以及临床和耐药性结果将帮助我们优化药物的治疗和使用 预防疟疾。具体目标是：1）描述关键 ACT 暴露之间的关联性 治疗疟疾的乌干达儿童的合作药物、临床结果和耐药性选择，2) 评估接触 DP 和 SP 与预防疟疾和不良分娩之间的关联 乌干达孕妇的结果，以及 3) 描述季节性暴露之间的关联 布基纳法索儿童的疟疾化学预防药物和疟疾结果。这些研究将有助于 确定能够以最少的选择提供针对疟疾的最佳治疗和预防功效的方案 抗疟药物耐药性。

Project Summary Malaria remains an enormous problem, and drugs are of critical importance to treat episodes of malaria, prevent disease in high risk groups, and limit transmission. Artemisinin-based combination therapies (ACTs), mostly artemether-lumefantrine or artesunate-amodiaquine, are the cornerstones of antimalarial therapy in Africa. Standard chemoprevention approaches are intermittent preventive therapy with sulfadoxine- pyrimethamine (SP) in pregnant women and seasonal malaria chemoprevention with amodiaquine+SP in children in the Sahel sub-region, and improved approaches are under study. In this context, antimalarial drug resistance is of great concern. Resistance to ACTs, including both artemisinins and partner drugs, has emerged in southeast Asia. Resistance to amodiaquine and SP is longstanding, but sensitivities vary, with uncertain impacts on chemoprevention. Definitive studies in at risk populations of associations between exposure to antimalarial drugs, treatment and preventive efficacy, and selection of drug resistance are needed. This project will build on studies in Uganda during our first cycle of funding in which we characterized the pharmacokinetics (PK) and pharmacodynamics of the ACT dihydroartemisinin-piperaquine, the most promising new agent for chemoprevention in Africa. Our goals will be broadened to gain insights into associations between drug exposure, malaria outcomes, birth outcomes, and selection of drug resistance in the context of the 3 primary indications for antimalarial drugs in Africa: treatment of malaria, chemoprevention in pregnancy, and chemoprevention in children exposed to seasonal malaria. A guiding principal is that the best means of preventing selection of drug resistance is to effectively treat and prevent malaria, as inadequate exposure to antimalarial drugs increases risks for both drug sensitive and drug resistant malaria. Our studies will build on our pharmacology expertise and longstanding collaborations between UCSF and malaria research groups in Uganda and Burkina Faso. We will use rigorous PK assessments to test related hypotheses in children in Uganda and Burkina Faso and pregnant women in Uganda that exposure to ACTs is associated with risks of malaria and the selection of drug-resistant parasites. Better characterization of associations between drug exposure and clinical and drug resistance outcomes will help us to optimize use of drugs for the treatment and prevention of malaria. Specific aims will be: 1) to characterize associations between exposure to key ACT partner drugs, clinical outcomes, and selection of drug resistance in Ugandan children treated for malaria, 2) to evaluate associations between exposure to DP and SP and protection against malaria and adverse birth outcomes in pregnant Ugandan women, and 3) to characterize associations between exposure to seasonal malaria chemoprevention drugs and malaria outcomes in children in Burkina Faso. These studies will help to identify regimens that offer optimal treatment and preventive efficacy against malaria with minimal selection of antimalarial drug resistance.