Primaquine metabolism and treatment of P. vivax in Madagascar

马达加斯加间日疟原虫的伯氨喹代谢和治疗

• 批准号: 10078592
• 负责人: Scott Matthew Williams
• 金额: $ 81.73万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078592
• 关键词: Address; Adherence; Admixture; Alleles; Aminoquinolines; Antimalarials; Area; Awareness; Beds; Blood; Blood Transfusion; Body Weight; CYP2D6 gene; Clinical; Complex; Country; Coupled; Culicidae; Cytochrome P450; Dangerousness; Defect; Dextromethorphan; Disease Reservoirs; Dose; Drug Targeting; Effectiveness; Enzymes; Erythrocytes; FDA approved; Failure; G6PD gene; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Goals; Half-Life; Health; Hematuria; Hemolysis; Hemolytic Anemia; High Prevalence; Hospitalization; Hour; Human; Human Genetics; Individual; Infection; Isoenzymes; Knowledge; Letters; Life; Liver; Madagascar; Malaria; Measures; Metabolic; Metabolism; N-methylchlorphentermine; Oral cavity; Parasites; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physicians; Plasmodium vivax; Population; Populations at Risk; Predisposition; Preparation; Price; Primaquine; Public Health; Recurrence; Relapse; Reporting; Research; Research Personnel; Resistance; Risk; Safety; Severities; Supervision; Testing; Time; United States; Variant; Vivax Malaria; World Health Organization; design; drug metabolism; enzyme deficiency; expectation; genome-wide; genomic data; genomic variation; improved; insight; medical attention; member; metabolic abnormality assessment; population based; recruit; screening; study population; transmission process

Project Summary – Plasmodium vivax presents unique challenges to malaria elimination because it produces hypnozoites, dormant liver-stages that cause relapse infections from weeks to years without mosquito transmission. If untreated, hypnozoites represent a disease reservoir whose extent is unknown. Our studies in Madagascar provide evidence that P. vivax is now able to infect red blood cells of Duffy- negative people, demonstrating the capacity to evolve beyond a significant previously recognized barrier. At this time, there is also greater recognition of the clinical severity of vivax malaria and the capacity of this parasite to persist despite availability of bed nets and drugs that target blood stage parasites. To address this substantial public health challenge and threat to malaria elimination, efforts must focus on reducing the hypnozoite reservoir. Primaquine (PQ) is the only WHO-recommended drug that is able to kill hypnozoites and achieve radical cure of P. vivax. However, a number of factors must be considered regarding optimal use of this important antimalarial drug. Genetic variation in the gene encoding the human cytochrome P450 isoenzyme 2D6 (CYP2D6) has been associated with PQ failure through P. vivax relapses in people who have received standard PQ treatment (0.25-0.50 mg/kg body weight by mouth daily for 14 days). PQ may also cause life-threatening hemolytic anemia in G6PD deficient (G6PDd) people if drug treatment is not curtailed after signs of hemolysis become evident (usually hematuria). These observations emphasize the importance of developing effective strategies to use PQ and other 8-aminoquinoline drugs (tafenoquine; TQ). TQ delivered as a single-dose treatment (recently FDA-approved; not yet WHO-recommended) would improve adherence, but its much longer half-life (PQ ≈5 hours; TQ ≈15 days) makes it particularly dangerous in people with the most severe form of this enzymopathy. Here, we focus on the need to optimize PQ treatment. Our preliminary results reveal complex polymorphism in the CYP2D6 gene, significant variation in activity scores associated with the probe drug dextromethorphan (DM), and increasing variation in PQ effectiveness against P. vivax. We will address these challenges through the following Specific Aims. Aim 1: Evaluate CYP2D6 diplotypes and genome variation to identify individuals to be studied for identifying modifiers of PQ metabolism and develop a global framework to estimate PQ effectiveness. Aim 2: Evaluate PQ metabolism phenotype and CYP2D6 diplotype association in uninfected Malagasies. Aim 3: Assess PQ radical cure of P. vivax vs. recurrence in association with CYP2D6 and genomic variation in Malagasy study participants. Nearly 2.5 billion people are at risk of P. vivax malaria. Human genetic variation complicates population-based treatment using PQ in P. vivax-endemic areas. The proposed studies will investigate CYP2D6 genetic variation that confounds optimal use of PQ to develop population-based strategies to eliminate P. vivax.

项目摘要 - 疟原虫为消除疟疾带来了独特的挑战，因为它 产生催眠者，休眠的肝脏，导致几周到几年的缓解感染 蚊子传播。如果未经治疗，催眠症代表疾病储层，其程度尚不清楚。 我们在马达加斯加的研究提供了证据，证明Vivax现在能够感染达菲的红细胞 负面的人，表明发展能力超出了以前认可的障碍。 目前，人们对Vivax疟疾的临床严重程度也有更高的认识和能力 这种寄生虫可以持续到目的地的床网和靶向血液寄生虫的药物。到 应对消除疟疾的实质性公共卫生挑战和威胁，努力必须关注 减少催眠症储层。 Primaquine（PQ）是唯一可以推荐的药物 杀死催眠症并实现天疟原虫的根本治疗。但是，必须考虑许多因素 关于这种重要的抗疟药的最佳使用。编码基因的遗传变异 人细胞色素P450同工酶2D6（CYP2D6）与PQ通过P衰竭有关。 接受标准PQ治疗的人（0.25-0.50 mg/kg体重） 每天嘴14天）。 PQ也可能引起G6PD特异性的威胁生命的溶血性​​贫血 （g6pdd）人们如果在溶血迹象后不限制药物治疗，通常会成为证据（通常 血尿）。这些观察结果强调了制定使用PQ的有效策略的重要性 和其他8种氨基喹啉药物（Tafenoquine; TQ）。 TQ作为单剂量治疗（最近 FDA批准；尚未推荐谁）会提高依从性，但其半衰期更长（PQ ≈5小时； TQ≈15天）使其在最严重的人中特别危险 酶病。在这里，我们专注于优化PQ治疗的需求。我们的初步结果揭示了 CYP2D6基因中的复杂多态性，与该活性评分的显着差异 探针药物右美甲苯酚（DM），以及对疟原虫的PQ有效性的变化增加。我们 将通过以下特定目标解决这些挑战。目标1：评估CYP2D6外交类型 和基因组变异，以识别个体是研究的，以识别PQ代谢和 开发一个全球框架来估计PQ有效性。目标2：评估PQ代谢表型 和CYP2D6外交型协会未感染的魔术。 AIM 3：评估Vivax的PQ根部治疗 与CYP2D6相关的复发与马达加斯加研究参与者的基因组变异相关。几乎 25亿人有疟原虫疟疾的风险。人遗传变异使基于人群的复杂 使用PQ在疟原虫 - 末端区域中进行处理。拟议的研究将研究CYP2D6通用 将PQ的最佳用途混淆以开发基于人群的策略以消除息肉假单胞菌的变化。