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

项目摘要 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， 预防高危人群的疾病，限制传播。基于青蒿素的联合疗法， 主要是蒿甲醚-苯芴醇或青蒿琥酯-阿莫地喹，是抗疟治疗的基石， 非洲标准的化学预防方法是用磺胺嘧啶进行间歇性预防治疗- 乙胺嘧啶（SP）在孕妇和季节性疟疾化学预防阿莫地喹+SP在 萨赫勒次区域的儿童，并正在研究改进办法。在这种情况下，抗疟疾药物 阻力是非常令人关注的。对青蒿素综合疗法，包括青蒿素和伙伴药物的耐药性， 出现在东南亚。对阿莫地喹和SP的耐药性是长期存在的，但敏感性不同， 对化学预防的不确定影响。在高危人群中进行的连续性研究， 需要接触抗疟药物、治疗和预防效力以及选择耐药性。 该项目将建立在我们第一个供资周期在乌干达进行的研究的基础上， ACT双氢青蒿素-哌喹的药代动力学（PK）和药效学， 非洲的化学预防新药物。我们的目标将扩大到深入了解协会 药物暴露、疟疾结局、出生结局和在以下背景下选择耐药性之间的关系： 非洲抗疟疾药物的3个主要适应症：疟疾治疗，妊娠期化学预防， 和化学预防。一个指导原则是， 预防选择性耐药性的关键是有效治疗和预防疟疾，因为接触疟疾的机会不足， 抗疟药物增加了对药物敏感和抗药性疟疾的风险。我们的研究将建立在 我们的药理学专业知识和UCSF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评估来检验儿童中的相关假设， 乌干达和布基纳法索以及乌干达孕妇接触青蒿素综合疗法与下列风险有关： 疟疾和抗药性寄生虫的选择。更好地描述药物之间的关联 暴露以及临床和耐药性结果将有助于我们优化治疗药物的使用， 预防疟疾。具体目标将是：1）描述暴露于关键ACT之间的关联 治疗疟疾的乌干达儿童的伙伴药物、临床结果和耐药性选择，2） 评估DP和SP暴露与预防疟疾和不良出生之间的关系 乌干达孕妇的结果，以及3）描述暴露于季节性 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 确定对疟疾具有最佳治疗和预防效果的疗法， 抗疟药耐药性。

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.