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， 在高危人群中预防疾病，并限制传播。以青蒿素为基础的联合疗法(ACTs)， 主要是蒿甲醚-鲁米芬或青蒿琥酯-阿莫地喹，是#年抗疟疾治疗的基石。 非洲。标准的化学预防方法是使用磺胺多辛进行间歇预防治疗- 孕妇体内乙胺嘧啶与阿莫地喹季节性疟疾化学预防 目前正在研究萨赫勒次区域儿童的健康状况，以及改进的办法。在这方面，抗疟疾药物 抵抗是非常令人担忧的。对ACTs的耐药性，包括青蒿素和伙伴药物，已经 出现在东南亚。对阿莫地喹和SP的耐药性由来已久，但敏感性各不相同， 对化学预防的不确定影响。对高危人群之间关系的权威性研究 需要接触抗疟疾药物、治疗和预防效果以及选择抗药性。 这个项目将建立在我们第一个资助周期中在乌干达的研究基础上，我们在这个周期中描述了 最有前途的ACT双氢青蒿素-哌喹的药代动力学和药效学 非洲化学预防的新制剂。我们的目标将被拓宽，以获得对关联的洞察 在药物暴露、疟疾结果、出生结果和选择抗药性的背景下 非洲抗疟疾药物的3个主要适应症：疟疾的治疗，怀孕期间的化学预防， 以及对暴露于季节性疟疾的儿童进行化学预防。一个指导性的原则是， 预防选择耐药是有效治疗和预防疟疾的关键，因为暴露于 抗疟疾药物增加了药物敏感和耐药疟疾的风险。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在 乌干达和布基纳法索。我们将使用严格的PK评估来检验儿童的相关假设 乌干达和布基纳法索以及乌干达的孕妇暴露于ACT与罹患 疟疾和抗药性寄生虫的选择。更好地描述药物之间的联系 暴露以及临床和耐药性结果将有助于我们优化治疗和治疗药物的使用 预防疟疾。具体目标将是：1)描述暴露于关键行动之间的联系 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)至 评估接触DP和SP与预防疟疾和难产之间的关系 乌干达怀孕妇女的结局，以及3)表征季节性接触之间的联系 布基纳法索儿童疟疾化学预防药物和结果。这些研究将有助于 确定提供最佳治疗和预防疟疾效果的方案，选择最少的方案 抗疟疾药物耐药性。

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.