Study on antimalarial efficacy and genetic diversities of human, parasites and mosquitoes

人类、寄生虫和蚊子的抗疟功效和遗传多样性研究

• 批准号: 11694318
• 负责人: KANEKO Akira
• 金额: $ 3.97万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694318/
• 关键词: malaria; Plasmodium falciparum; CYP2C19; dihydrofolate reductase; cycloguanil; proguanil; mass drug administration; Vanuatu; Chytochrome P450; poor metabolizer; 太平洋島嶼; 集団投薬; マラリア根絶; 三日熱マラリア; dihydrofolate reductace; サクログアニール; プログアニール

The genetic diversities displayed by human and malaria parasites at different frequencies in different geographical areas represent a major obstacle for the development of malaria control strategies including malaria chemotherapy and malaria vaccine. We investigated some genetic diversities on Vanuatu islands with various malaria endemicities. Malaria in Vanuatu is unstable, mainly hypo-to mesoendemic and seasonal with occasional epidemics.The frequencies of the cytochrome P450 (CYP) 2C19 mutant alleles were uniformly greater in Vanuatu. However there were differences between populations from different islands. Comparisons of genetic, linguistic and geographic patterns suggested that short range gene flow is largely responsible for the current distribution of CYP2C19alleles in Vanuatu. Our data in malaria patients demonstrated an association between CYP2C19 mutations and poor metabolism of proguanil to cycloguanil, a strong dihydrofolate reductase (DHFR) inhibitor, and an apparent gene … More dose effect relationship.Restricted diversity in the dhfr gene was shown in a total of 140 P.falciparunm cases on isolated islands of Vanuatu. All isolates had the same Asn- 108 mutation, and all, except in Gaua, also had Arg-59 mutation, normally associated with moderate resistance to DHFR-inhibiting drugs. The 3 remaining isolates in Gaua had His-51, a change not previously reported in the literature. Despite these partly resistant variants, pyrimethamine and sulfadoxine treatment was still highly effective. The restricted diversity of the dhfr gene in unstable malaria endemicity on Vanuatu islands may be at least partly explained by a loss in heterozygosity of the parasite populations derived from periodically interrupted transmission and isolation with limited gene flows between islands.Mutations in human CYP2C19 and parasite dhfr genes, related to poor metabolism of proguanil and resistance to cycloguanil respectively, have both been assumed to be associated with poor antimalarial effect by proguanil. We however observed high antimalarial efficacy of proguanil also in patients with CYP2C19 related poor metabolize genotype and the common dhfr genotype (Arg-59 and Asn-108). This suggested that the parent compound proguanil has an intrinsic efficacy independent of the metabolite cycloguanil and the dhfr mutation.The frequencies of the cytochrome P450 (CYP) 2C19 mutant alleles were uniformly greater in Vanuatu. However there were differences between populations from different islands. Comparisons of genetic, linguistic and geographic patterns suggested that short range gene flow is largely responsible for the current distribution of CYP2C19alleles in Vanuatu. Our data in malaria patients demonstrated an association between CYP2C19 mutations and poor metabolism of proguanil to cycloguanil, a strong dihydrofolate reductase (DHFR) inhibitor, and an apparent gene dose effect relationship. Less

人类和疟原虫在不同地理区域以不同频率显示的遗传多样性是疟疾控制策略（包括疟疾化疗和疟疾疫苗）发展的主要障碍。我们调查了瓦努阿图岛屿上的一些遗传差异，这些岛屿具有各种疟疾地方病。疟疾在瓦努阿图是不稳定的，主要是低到中度流行和季节性的，偶尔流行，细胞色素P450（P450）2C 19突变等位基因的频率在瓦努阿图一致较高。然而，不同岛屿的种群之间存在差异。遗传，语言和地理模式的比较表明，短程基因流是主要负责目前的分布CYP 2C 19等位基因在瓦努阿图。我们在疟疾患者中的数据表明，CYP 2C 19突变与氯胍代谢为环胍（一种强二氢叶酸还原酶（DHFR）抑制剂）的不良代谢之间存在关联， ...更多信息 剂量效应关系。在瓦努阿图孤岛上的总共140个恶性疟原虫病例中显示dhfr基因的有限多样性。所有分离株都有相同的Asn- 108突变，除Gaua外，所有分离株都有Arg-59突变，通常与对DHFR抑制药物的中度耐药性相关。Gaua中剩余的3个分离株具有His-51，这是文献中先前未报告的变化。尽管这些部分耐药的变种，乙胺嘧啶和磺胺嘧啶治疗仍然非常有效。在瓦努阿图群岛上的不稳定疟疾地方病中dhfr基因的有限多样性至少可以部分地解释为来自于周期性中断传播的寄生虫种群的杂合性缺失和岛屿之间有限基因流动的隔离。人CYP 2C 19和寄生虫dhfr基因的突变，分别与氯胍代谢不良和对环胍的抗性有关，都被认为与氯胍抗疟效果差有关。然而，我们在CYP 2C 19相关的低代谢基因型和常见的dhfr基因型（Arg-59和Asn-108）患者中也观察到了氯胍的高抗疟疗效。这表明母体化合物氯胍具有独立于代谢物环胍和dhfr突变的内在功效。瓦努阿图的细胞色素P450（P450）2C 19突变等位基因的频率一致较高。然而，不同岛屿的种群之间存在差异。遗传，语言和地理模式的比较表明，短程基因流是主要负责目前的分布CYP 2C 19等位基因在瓦努阿图。我们在疟疾患者中的数据表明，CYP 2C 19突变与氯胍代谢不良到环胍（一种强二氢叶酸还原酶（DHFR）抑制剂）之间存在关联，并且存在明显的基因剂量效应关系。少

项目成果

Kaneko A, Bergqvist Y, Taleo G, Kobayakawa T, Ishizaki T, Bjorkman A.: "Proguanil disposition and toxicity in malaria patient from Vanuatu with high frequencies of CYP2C19 mutations."Pharmacogenetics. 9. 317-326 (1999)

Kaneko A、Bergqvist Y、Taleo G、Kobayakawa T、Ishizaki T、Bjorkman A.：“具有高频率 CYP2C19 突变的瓦努阿图疟疾患者中氯胍的处置和毒性。”药物遗传学。

Shimamoto J., et al.: "Lack of differences in diclofenac (a substrate for CYP 2C9) pharmacokinetics in healthy volunteers with respect to the single CYP2C9*3 allele."Eur J Clin Pharmacol. 56. 65-68 (2000)

Shimamoto J. 等人：“就单个 CYP2C9*3 等位基因而言，健康志愿者中双氯芬酸（CYP2C9 的底物）药代动力学缺乏差异。”Eur J Clin Pharmacol。

Kaneko A, Bergqvist Y, Takechi M, Kalkoa M, Kaneko O, Kobayakawa T, Ishizaki T, Bjorkman A.: "Intrinsic efficacy of proguanil against falciparum and vivax malaria independent of the metabolite cycloguanil."J Infect Dis. 179. 974-979 (1999)

Kaneko A、Bergqvist Y、Takechi M、Kalkoa M、Kaneko O、Kobayakawa T、Ishizaki T、Bjorkman A.：“氯胍对抗恶性疟和间日疟的内在功效与代谢物环胍无关。”J Infect Dis。

Kaneko A., et al.: "A.Malaria eradication on islands"Lancet. 356. 1560-1567 (2000)

Kaneko A. 等人：“A. 岛屿上的疟疾根除”柳叶刀。

金子明 ら: "アネイチュウム島における脾腫率の推移"日本熱帯医学会雑誌. 増刊号28. 275 (2000)

Akira Kaneko 等：“Aneituum 岛脾肿大率的变化”日本热带医学会杂志特刊 28. 275 (2000)。