IMPACT OF TS PROPHYLAXIS ON ANTIFOLATE RESISTANT MALARIA

TS 预防对抗叶酸抗药性疟疾的影响

• 批准号: 6358641
• 负责人: James G. Kublin
• 金额: $ 2.7万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2001-11-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6358641
• 关键词: AIDS therapy; Africa; HIV infections; Plasmodium falciparum; antimalarial agents; clinical research; clinical trials; cooperative study; dihydrofolate reductase; drug resistance; drug screening /evaluation; folate antagonist; gene mutation; human morbidity; human mortality; human subject; human therapy evaluation; longitudinal human study; malaria; opportunistic infections; parasitic disease chemotherapy; placebos; polymerase chain reaction; sulfamethoxazole; trimethoprim

DESCRIPTION (applicant's abstract): An international research scientist development award will support James G. Kublin, MD, MPH to become an independent investigator in international health. Dr. Kublin is a research fellow at the University of Maryland, and is currently conducting field and laboratory research on drug resistant malaria in Malawi, Central Africa. Two recent studies found that trimethoprim-sulfamethoxazole (TS) prophylaxis benefited HlV-infected persons in Cote d'lvoire. TS shares its mechanism of action with pyrimethamine-sulfadoxine (PS) and other antifolate drugs used to treat malaria. Resistance to the antifolates in Plasmodium falciparum is caused by point mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). In vitro studies suggest that TS will select resistance-conferring DHFR and DHPS mutations in P. falciparum. Such selection could accelerate the development of Plasmodium falciparum resistance to antifolate antimalarials in areas where HIV infection and malaria are both highly prevalent. HlV-infected persons receiving TS prophylaxis who are or become infected with P. falciparum may be more likely to fail PS treatment and to progress to severe disease and death. Antifolate-resistant P. falciparum malaria is increasing in the same African countries where HIV infection rates are highest, including Malawi. Bacterial pathogens prevented by TS prophylaxis appear to be less susceptible to TS in Malawi than in the Cote D'lvoire studies. The potential impact of TS prophylaxis on antifolate-resistant malaria needs to be assessed quickly and definitively, and the benefit of TS prophylaxis demonstrated thus far in a single setting needs to be confirmed in settings with high malaria endemicity and different bacterial resistance profiles. The overall research aims of this project are to determine whether the benefits of TS prophylaxis seen in Cote d'lvoire can be confirmed in Malawi, and to test the hypothesis that TS prophylaxis selects for antifolate- resistant P. falciparum and is associated with higher rates of PS treatment failure. This will be accomplished in a prospective, double-blinded, placebo-controlled trial in an area of Malawi with high rates of both HIV and malaria. Dr. Kublin will continue his training at the Center for Vaccine Development in Baltimore, Maryland and at the Malaria Project in Blantyre, Malawi. Dr. Christopher V. Plowe and Pr. Malcolm E. Molyneux, noted specialists in malaria research, will be his mentors throughout the training period. At the end of the training period Dr. Kublin will be well-positioned to develop an independent research program in international health.

描述（申请人的摘要）：国际研究科学家 开发奖将支持MD的James G. Kublin，MPH成为 国际健康的独立研究者。库布林博士是一项研究 马里兰大学的研究员，目前正在进行领域和 中非马拉维的耐药性疟疾实验室研究。 最近的两项研究发现，甲氧苄啶 - 磺胺甲氧唑（TS）预防 受益于Cote d'lvoire的HLV感染者。 TS分享其机制 用乙胺胺 - 硫糖苷（PS）和其他用于 治疗疟疾。 恶性疟原虫中对抗染料的抗性为 由二氢叶酸还原酶（DHFR）的点突变和 二氢蛋白酶合酶（DHP）。体外研究表明TS会选择 恶性疟原虫中的抗性限制DHFR和DHPS突变。这样的选择 可能加速恶性疟原虫对 HIV感染和疟疾的区域中 非常普遍。 受到HLV感染者接受TS预防的人或 被恶性疟原虫感染可能更可能失败PS治疗和 发展为严重的疾病和死亡。 在同一非洲 包括马拉维在内的艾滋病毒感染率最高的国家。细菌 预防TS预防的病原体似乎不太容易受到TS的影响 马拉维比在cote d'lvoire研究中。 TS的潜在影响 需要迅速评估对抗卵酸抗性疟疾的预防 迄今为止，一定的TS预防益处在A中得到了证明 需要在高疟疾中流性的设置中确认单个设置 和不同的细菌抗性谱。 该项目的总体研究目的是确定 可以在马拉维确认Cote d'lvoire中预防的好处 并检验以下假设：TS预防选择抗叶酸 - 恶性疟原虫抗性，与较高的PS治疗率有关 失败。 这将在一个潜在的，双盲的， 马拉维地区的安慰剂对照试验，艾滋病毒率高和 疟疾。 库布林博士将继续在疫苗中心接受培训 巴尔的摩，马里兰州和布兰特尔的疟疾项目的发展 马拉维。 Christopher V. Plowe博士和PR。 Malcolm E. Molyneux，指出 疟疾研究专家将在整个培训中成为他的导师 时期。在培训期结束时 制定国际健康方面的独立研究计划。