Triple drug combination screening

三联药物筛选

• 批准号: 10691136
• 负责人: Alexey Zakharov
• 金额: $ 14.62万
• 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/10691136
• 关键词: Address; Antimalarials; Artemisinins; Beds; Biological Assay; Cambodia; Combination Drug Therapy; Combined Modality Therapy; Country; Diagnostic tests; Dose; Drug Combinations; Drug Interactions; Drug resistance; Effectiveness; Environment; Falciparum Malaria; Genetic; Genetic Determinism; Genetic Markers; Genotype; High Prevalence; In Vitro; Insecticides; Knowledge; Malaria; Measures; Mediating; Morbidity - disease rate; Parasite resistance; Parasites; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Plasmodium falciparum; Policies; Predisposition; Rapid diagnostics; Residual state; Resistance; Scientist; Treatment Efficacy; Treatment Failure; antagonist; base; clinical predictors; drug development; high throughput screening; mortality; next generation; novel; pressure; research clinical testing; response; screening; stem

The first line treatments for uncomplicated Plasmodium falciparum malaria are artemisinin-based combination therapies (ACT), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of P. falciparum isolates with decreased susceptibility to artemisinin and partner drugs presents a significant challenge to current malaria control efforts. To stem the spread of drug resistant parasites, novel chemotherapeutic strategies are being evaluated, including the implementation of triple artemisinin-based combination therapy (TACT). Currently, there is limited knowledge on the pharmacodynamics and pharmacogenetic interactions of proposed TACT drug combinations. As a means to evaluate these interactions, NCGC scientists have established an in vitro high-throughput assays measuring the drug dose-response to three distinct agents. Sixteen different TACT combinations were screened against fifteen parasite lines from Cambodia, with a focus on parasites with differential susceptibilities to piperaquine and artemisinins. Analysis revealed drug-drug interactions unique to specific genetic backgrounds. From this initial study, we were able to identify parasite genotypes with decreased susceptibility to specific TACTs as well as potential TACTs that display antagonism in a genotype dependent manner. Our assay and analysis platform can be further leveraged to inform drug policy decisions and evaluate next-generation TACTs.

治疗无并发症的恶性疟原虫疟疾的一线治疗方法是基于青蒿素的联合疗法（ACT），由青蒿素衍生物与长效伙伴药物联合组成。然而，对青蒿素和伙伴药物敏感性降低的恶性疟原虫分离株的传播对当前的疟疾控制工作提出了重大挑战。为了阻止耐药寄生虫的传播，正在评估新的化疗策略，包括实施基于三联青蒿素的联合疗法（TACT）。 目前，对所提出的 TACT 药物组合的药效学和药物遗传学相互作用的了解有限。作为评估这些相互作用的一种手段，NCGC 科学家建立了一种体外高通量测定法，测量三种不同药物的药物剂量反应。针对来自柬埔寨的 15 种寄生虫品系筛选了 16 种不同的 TACT 组合，重点关注对哌喹和青蒿素具有不同敏感性的寄生虫。分析揭示了特定遗传背景所特有的药物相互作用。从这项初步研究中，我们能够识别对特定 TACT 敏感性降低的寄生虫基因型，以及以基因型依赖性方式表现出拮抗作用的潜在 TACT。我们的检测和分析平台可进一步用于为药物政策决策提供信息并评估下一代 TACT。