Nitric Oxide and Malaria

描述（由申请人提供）：2009年有超过2.25亿例疟疾病例，当年约有78.1万人死亡。我们非常需要疟疾疫苗和新的治疗方法——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，一氧化氮（NO）可以防止严重疟疾的发展和疟疾患者的死亡。我们已经证明：(1)临床疟疾患者一氧化氮产生减少，(2)一氧化氮合成酶2 （NOS2）基因多态性修饰一氧化氮产生并保护临床疟疾，(3)与低水平一氧化氮产生相关的一氧化氮底物精氨酸水平明显降低，(4)与疟疾严重程度、低精氨酸和低一氧化氮水平密切相关的内皮功能障碍。我们还确定(v)对患有中度严重疟疾的成人静脉注射精氨酸是安全的，它可以纠正低精氨酸血症、低一氧化氮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生物利用度将是一种安全有效的辅助治疗疟疾患者。这是一笔拨款，我们将仔细计划申请U01拨款，以实现以下目标：确定（1A）中度重度疟疾儿童和（1B）重度疟疾儿童静脉注射精氨酸的安全性、药代动力学和药效学；确定(A)中度重度疟疾成人和(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。除了标准的抗生素和疟疾的支持性治疗外，还将给予精氨酸和亚硝酸盐。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、NO生成、寄生虫血症、血管生成素2水平和内皮功能。在重症疟疾患者中，我们还将测量乳酸清除率、昏迷恢复时间和生存率。Aim 1研究将在坦桑尼亚达累斯萨拉姆的休伯特·凯鲁基纪念大学（HKMU）的儿童中进行；目标2研究将在马来西亚婆罗洲沙巴的伊丽莎白女王医院进行。我们的研究团队已经在坦桑尼亚和马来西亚建立了优秀的网站基础设施和工作人员。在为期一年的计划资助期内，我们会(a)确定研究团队/地点；(b)设计研究；制定(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)调查员手册；(h)操作手册；

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.