Population biology of malaria drug resistance in Yunnan

云南省疟疾耐药性的人群生物学

• 批准号: 7668547
• 负责人: Zhaoqing Yang
• 金额: $ 8.15万
• 依托单位: KUNMING MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7668547
• 关键词: Advocate; Antimalarials; Area; Artemisinins; Back; Biological Assay; China; Chloroquine; Chloroquine resistance; Clinical; Combined Modality Therapy; Country; County; Detection; Development; Dihydrofolate Reductase; Dihydropteroate Synthase; Drug Delivery Systems; Drug resistance; Drug usage; Evaluation; Evolution; Falciparum Malaria; Family; Frequencies; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genotype; Glutamine; Goals; Hypoxanthines; In Vitro; Infection; Knowledge; Label; Laboratories; Malaria; Merozoite Surface Protein 1; Methods; Modeling; Molecular; Molecular Analysis; Multi-Drug Resistance; P-Glycoprotein; Parasite resistance; Parasites; Pattern; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Policies; Policy Maker; Polymerase Chain Reaction; Population; Population Biology; Predisposition; Proteins; Province; Pyrimethamine; Pyrimethamine-Sulfadoxine; Quinine; Recording of previous events; Recrudescences; Reporting; Research Personnel; Resistance; Resistance development; Site; Snow; Sodium-Hydrogen Antiporter; Source; Southeastern Asia; Staging; Sulfadoxine; Therapeutic; Time; Treatment Failure; Treatment Protocols; Work; Yang; artemisinine; artesunate; authority; base; benflumetol; chemotherapy; drug sensitivity; genome wide association study; in vitro Assay; mefloquine-sulfadoxine-pyrimethamine; molecular marker; non-compliance; pressure; prevent; programs; resistance mechanism; response; theories

DESCRIPTION (provided by applicant): Multidrug resistance of the malaria parasite Plasmodium falciparum is a major contributor to the resurgence of malaria in the world. With the failing of many antimalarial drugs, the use of artemisinin and its derivatives has been endorsed by many malaria-endemic countries. Although these are the only class of antimalarial drugs to which there are no confirmed clinical resistance, the reports of artemisinin treatment failures in many regions of the world are of great concern. To prevent or delay the development of artemisinin resistance, artemisinin-based combination therapy (ACT) has been advocated and applied. Yet, the partner drugs vary geographically, depending on the drug history of the regions. To choose the best partner drug for artemisinins for a specific region, it is essential to have a comprehensive knowledge of drug resistance in the parasite populations. In addition, close surveillance for reduced sensitivity of parasites to artemisinins as the early stage of resistance development and better understanding the resistance mechanism are critical for taking adequate countermeasures to prevent and slow down resistance development. In the subtropical Yunnan province of China, malaria is perennial with -300,000 cases per year. In contrast to the recent introduction of artemisinin for malaria therapy elsewhere, artemisinin monotherapy has been the mainstay of malaria chemotherapy in Yunnan for almost three decades. Malaria treatment is mostly family-based and there is a high degree of non-compliance to the drug regimens, which favors resistance development. Our past surveillance has detected a significant proportion of parasite field isolates with more than three-fold decrease in susceptibility to artemisinins and their derivatives. Based on the unique malaria drug history in Yunnan and the lack of a comprehensive picture of drug resistance in the parasite populations, we propose to (1) systematically evaluate parasite's sensitivity to a wide range of antimalarials; and (2) determine the polymorphisms in known and putative molecular markers of drug targets and evaluate their associations with in vitro drug resistance. Clinical parasite isolates before and after artesunate monotherapy will be assayed for responses to antimalarials and genotyped for polymorphisms in known and putative resistant markers. The integration of accurate drug assays and molecular analysis will provide essential information for elucidating the mechanism of artemisinin resistance, understanding how drug resistance evolves, and helping local policy makers select the most appropriate ACTs. Malaria resurgence is partially due to the emergence and spread of multidrug resistant parasites. Resistance surveillance and elucidation of resistance mechanisms for antimalarial drugs, especially for artemisinin family drugs, are important for malaria control.

描述（由申请人提供）： 疟原虫恶性疟原虫的多重耐药性是世界上疟疾死灰复燃的主要原因。随着许多抗疟药物的失败，青蒿素及其衍生物的使用已得到许多疟疾流行国家的认可。尽管这些是唯一一类尚无证实的临床耐药性的抗疟药物，但世界许多地区青蒿素治疗失败的报道仍令人高度关注。为了预防或延缓青蒿素耐药性的发展，以青蒿素为基础的联合治疗（ACT）已被提倡和应用。然而，合作药物因地理位置而异，具体取决于各地区的药物历史。要为特定地区选择青蒿素的最佳搭档药物，必须全面了解寄生虫群体的耐药性。此外，在耐药性发展的早期阶段，密切监测寄生虫对青蒿素的敏感性降低，并更好地了解耐药性机制，对于采取适当的对策来预防和减缓耐药性的发展至关重要。在中国亚热带云南省，疟疾常年流行，每年有-30万例病例。与其他地方最近引入青蒿素治疗疟疾不同，近三十年来，青蒿素单药疗法一直是云南疟疾化疗的支柱。疟疾治疗大多以家庭为基础，对药物治疗的不依从性很高，这有利于耐药性的发展。我们过去的监测发现，很大一部分寄生虫野外分离株对青蒿素及其衍生物的敏感性降低了三倍以上。基于云南独特的疟疾药物史以及缺乏对疟原虫种群耐药性的全面了解，我们建议：（1）系统评估疟原虫对多种抗疟药物的敏感性； (2)确定已知和推定的药物靶点分子标记的多态性，并评估它们与体外耐药性的关联。将检测青蒿琥酯单一疗法之前和之后的临床寄生虫分离株对抗疟药的反应，并对已知和推定的耐药标记物的多态性进行基因分型。准确的药物测定和分子分析的结合将为阐明青蒿素耐药机制、了解耐药性如何演变以及帮助当地政策制定者选择最合适的 ACT 提供重要信息。疟疾死灰复燃的部分原因是多重耐药寄生虫的出现和传播。抗疟药物特别是青蒿素家族药物的耐药性监测和耐药机制的阐明对于疟疾控制具有重要意义。