Nitric Oxide and Malaria

一氧化氮和疟疾

• 批准号: 8331804
• 负责人: Joe Brice Weinberg
• 金额: $ 19.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331804
• 关键词: Adult; Adult Respiratory Distress Syndrome; Angiopoietin-2; Antibiotics; Antimalarials; Applications Grants; Arginine; Biological Availability; Blood Platelets; Borneo; Breathing; Budgets; Cell Adhesion Molecules; Cessation of life; Child; Citrulline; Clinical; Clinical Protocols; Clinical Trials; Coma; Consent Forms; Data; Data Analyses; Development; Disease; Disodium Salt Nitroprusside; Drug Kinetics; Endothelial Cells; Enzymes; Functional disorder; Gases; Gene-Modified; Genes; Genetic Polymorphism; Grant; Hemeproteins; Hospitals; Human; Hypotension; Infection; Inflammatory; Intravenous; Investigational Drugs; Isosorbide Dinitrate; Isosorbide Mononitrate; Lead; Malaria; Malaria Vaccines; Malaysia; Malaysian; Manuals; Measures; Methemoglobinemia; Monitor; Morbidity - disease rate; Muscle relaxation phase; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Nitroglycerin; Ornithine; Outcome Measure; Pamphlets; Parasitemia; Patients; Performance; Pharmacodynamics; Plasmodium falciparum; Preparation; Production; Pulmonary Hypertension; Recovery; Relative (related person); Reporting; Research; Research Design; Research Infrastructure; Research Personnel; Respiratory Failure; Sabah; Safety; Severities; Sickle Cell Anemia; Site; Smooth Muscle; Special Equipment; Tanzania; Therapeutic; Time; Toxic effect; Training; United States Food and Drug Administration; United States National Institutes of Health; Universities; Urea; Vaccines; Xanthine Dehydrogenase; arginase; base; clinical care; cytokine; data sharing; improved; in vivo; intravenous administration; mortality; neonate; operation; patient safety

DESCRIPTION (provided by applicant): There were more than 225 million cases of malaria in 2009, with approximately 781,000 people dying that year. There is a great need for a malaria vaccine, and for new treatments-9-15% of those with malaria die despite our best therapies. Over the past 17 years, we have methodically and clearly demonstrated that nitric oxide (NO) is protective against the development of severe malaria and death in humans with malaria. We have shown: (i) patients with clinical malaria have reduced NO production, (ii) polymorphisms in the NO synthase 2 (NOS2) gene that modify NO production and protect against clinical malaria, (iii) markedly low levels of the NOS substrate arginine that correlate with low level NO production, (iv) and endothelial dysfunction that correlates closely with malaria severity and low arginine and low NO levels. We have also established that (v) administration of intravenous arginine to adults with moderately severe malaria is safe and that it corrects hypoargininemia, low NO levels, and endothelial dysfunction. Based on results of our studies, we have proposed that improving NO levels and NO bioavailability will be a safe and effective adjunctive treatment for humans with malaria. This is a grant in which we will carefully plan for an application for a U01 grant to perform the following aims: Determine the safety, pharmacokinetics, and pharmacodynamics of intravenous arginine in (1A) children with moderately severe malaria and (1B) children with severe malaria; and Determine the safety, pharmacokinetics, and pharmacodynamics of intravenous nitrite in (A) adults with moderately severe malaria and (B) adults with severe malaria. The arginine and nitrite will be given in addition to standard antibiotc and supportive treatment of the malaria. Measured outcomes will be patient safety, arginine and nitrite pharmacokinetics, NO production, parasitemia, angiopoietin 2 levels, and endothelial function. In severe malaria patients, we will also measure lactate clearance, coma recovery time, and survival. Aim 1 studies will be done with children at the Hubert Kairuki Memorial University (HKMU) in Dar es Salaam, Tanzania; Aim 2 studies will be done with adults at the Queen Elizabeth Hospital in Sabah, Malaysian Borneo. Our Research team is already in place with excellent established site infrastructure and staff in both Tanzania and Malaysia. During this one year planning grant, we will (a) identify the research team/sites; (b) design the study; develop (c) the clinical protocol; (d) the data analysis and (e) statistical management & analysis plans; (f) the informed consent forms; (g) the investigator's brochure; (h) a manual of operations; (i) a data sharing plan; (j) milestones; (k) plans for acquisition and administration of study agents; (l) plans for acquisition of a US Food and Drug Administration (FDA) investigational new drug (IND) certificate for nitrite; (m) a data and safety monitoring plan; (n) a detailed budget fo design of the study; (o) a detailed budget for performance of the clinical trial, including a budge for preparation of a final study report; and (p) training materials for study staff. PUBLIC HEALTH RELEVANCE: There were more than 225 million malaria cases in 2009, with approximately 781,000 malaria deaths. There is no effective vaccine for this disease, and despite recent improvements in treatment, 9 to 15% of malaria patients die. Adjunctive treatments have not been beneficial. There is a great need for new treatments. Our studies indicate that increasing arginine may be a useful adjunctive therapy. The studies for which we plan here will answer important questions relative to the pathophysiology of severe malaria regarding arginine, nitrite, and nitric oxide, and they may lead to use of an adjunctive therapy such as arginine or nitrite that would reduce morbidity and mortality caused by malaria infection.

描述(申请人提供)：2009年有超过2.25亿疟疾病例，当年约有781,000人死亡。人们非常需要疟疾疫苗，也需要新的治疗方法--尽管我们采用了最好的治疗方法，但仍有9%-15%的疟疾患者死亡。在过去的17年里，我们有条不紊地清楚地证明了一氧化氮(NO)对严重疟疾的发展和疟疾患者的死亡具有保护作用。我们发现：(I)临床疟疾患者NO生成减少，(Ii)NO合成酶2(NOS2)基因多态性改变NO生成并预防临床疟疾，(Iii)与低水平NO产生相关的一氧化氮合酶底物精氨酸水平显著降低，(Iv)与疟疾严重程度及低精氨酸和低NO水平密切相关的内皮功能障碍。我们还证实，(V)对患有中度疟疾的成年人静脉注射精氨酸是安全的，它可以纠正低精氨酸血症、低NO水平和内皮功能障碍。根据我们的研究结果，我们提出，提高NO水平和NO生物利用度将是治疗人类疟疾的安全和有效的辅助治疗。在这笔赠款中，我们将仔细计划U01拨款的申请，以实现以下目标：测定静脉注射精氨酸对(1A)中度疟疾儿童和(1B)重度疟疾儿童的安全性、药代动力学和药效学；以及(A)中度疟疾成人和(B)重度疟疾成人静脉注射亚硝酸盐的安全性、药代动力学和药效学。精氨酸和亚硝酸盐将在标准抗菌药和疟疾支持性治疗的基础上给予。测量结果将包括患者安全性、精氨酸和亚硝酸盐药代动力学、一氧化氮产生、寄生虫血症、血管生成素2水平和内皮功能。在严重疟疾患者中，我们还将测量乳酸清除、昏迷恢复时间和存活率。Aim 1研究将在坦桑尼亚达累斯萨拉姆的Hubert Kairuki纪念大学(HKMU)的儿童中进行；Aim 2将在马来西亚婆罗洲沙巴州的伊丽莎白女王医院进行成人研究。我们的研究团队已经到位，在坦桑尼亚和马来西亚都有出色的基础设施和员工。在这一年的规划赠款期间，我们将(A)确定研究团队/地点；(B)设计研究；(C)临床方案；(D)数据分析和(E)统计管理和分析计划；(F)知情同意书；(G)研究人员手册；(H)操作手册； (I)数据共享计划；(J)里程碑；(K)研究试剂的采购和管理计划；(L)获取美国食品和药物管理局(FDA)亚硝酸盐新药(IND)证书的计划；(M)数据和安全监测计划；(N)研究设计的详细预算；(O)临床试验绩效的详细预算，包括编写最终研究报告的预算；以及(P)研究工作人员的培训材料。 与公共卫生有关：2009年有超过2.25亿疟疾病例，约有781,000人死于疟疾。目前还没有针对这种疾病的有效疫苗，尽管最近在治疗方面有所改进，但仍有9%至15%的疟疾患者死亡。辅助性治疗并没有带来好处。非常需要新的治疗方法。我们的研究表明，增加精氨酸可能是一种有用的辅助治疗。我们在这里计划的研究将回答与严重疟疾的病理生理学有关的重要问题，涉及精氨酸、亚硝酸盐和一氧化氮，它们可能导致使用诸如精氨酸或亚硝酸盐的辅助治疗，以减少疟疾感染造成的发病率和死亡率。