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

基本信息

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
项目类别：
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

项目摘要

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——间日疟原虫对消除疟疾提出了独特的挑战，因为它产生休眠子，即休眠的肝脏阶段，可导致数周至数年的复发感染，而无需如果不加以治疗，休眠子就是一种疾病储存库，其程度未知。我们在马达加斯加的研究提供了证据，表明间日疟原虫现在能够感染达菲的红细胞- 消极的人，表现出超越先前认识到的重大障碍的能力。此时，人们也更加认识到间日疟疾的临床严重性和治疗疟疾的能力。尽管有针对血液阶段寄生虫的蚊帐和药物，但这种寄生虫仍会持续存在。应对这一重大公共卫生挑战和对消除疟疾的威胁，努力必须集中于伯氨喹 (PQ) 是世界卫生组织推荐的唯一能够减少催眠体储存的药物。杀死休眠子并实现间日疟原虫的根治然而，必须考虑许多因素。关于这种重要的抗疟药物的最佳使用，编码基因的遗传变异。人细胞色素 P450 同工酶 2D6 (CYP2D6) 通过 P. 接受标准 PQ 治疗（0.25-0.50 毫克/公斤体重每天口服 14 天，PQ 也可能导致 G6PD 缺乏症患者出现危及生命的溶血性贫血。 (G6PDd) 如果在溶血迹象变得明显后不减少药物治疗的人（通常这些观察结果强调了制定有效策略来使用 PQ 的重要性。和其他 8-氨基喹啉药物（他非诺喹；TQ）作为单剂量治疗（最近）。 FDA 批准；尚未 WHO 推荐）将提高依从性，但其半衰期更长（PQ）约 5 小时；TQ 约 15 天）对于患有最严重形式的人来说尤其危险在此，我们重点关注优化 PQ 治疗的必要性。我们的初步结果表明。 CYP2D6 基因中存在复杂的多态性，与探索药物右美沙芬 (DM)，并且 PQ 对间日疟原虫的有效性变化不断增加。将通过以下具体目标 1 来应对这些挑战：评估 CYP2D6 双倍型。和基因组变异来识别要研究的个体，以识别 PQ 代谢的修饰剂和开发一个评估 PQ 有效性的全球框架目标 2：评估 PQ 代谢表型。目标 3：评估 PQ 间日疟原虫的根治性。与马达加斯加研究参与者中 CYP2D6 和基因组变异相关的复发。 25 亿人面临间日疟原虫疟疾的风险，人类遗传变异使人群的情况变得更加复杂。在间日疟原虫流行地区使用 PQ 进行治疗拟议的研究将调查 CYP2D6 遗传。混淆 PQ 的最佳使用以制定基于群体的策略来消除间日疟原虫的变异。