Citrulline adjunctive therapy for cerebral malaria

瓜氨酸辅助治疗脑型疟疾

• 批准号: 8089237
• 负责人: HENRI C VAN DER HEYDE
• 金额: $ 29.25万
• 依托单位: LA JOLLA INFECTIOUS DISEASE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089237
• 关键词: Affect; Amino Acids; Animals; Area; Arginine; Biological Availability; Biological Markers; Blood - brain barrier anatomy; Brain; Cardiovascular system; Catheters; Cell physiology; Cerebral Malaria; Cessation of life; Chloroquine; Citrulline; Clinic; Clinical; Clinical Trials; Complex; Critiques; Data; Development; Disease; Dose; Drug Kinetics; Endothelial Cells; Evaluation; Event; Exhibits; Falciparum Malaria; Flow Cytometry; Goals; Guidelines; Healthcare; Histology; Human; Hyperemia; Immune response; Individual; Injection of therapeutic agent; Investigational Drugs; Investigational New Drug Application; Investigational Therapies; Kidney; Life; Liver; Malaria; Measures; Mediating; Medicine; Myocardial Infarction; NIH Program Announcements; National Institute of Neurological Disorders and Stroke; Nature; Nitric Oxide; Nitric Oxide Donors; Nitrites; Parasitemia; Parasites; Pathogenesis; Patients; Plasma; Platelet Activation; Platelet aggregation; Positron-Emission Tomography; Process; Production; Publishing; Quinine; Regimen; Regulation; Reporting; Research; Research Infrastructure; Resources; Role; Saline; Sickle Cell Anemia; Signal Transduction; Study Section; Syndrome; Testing; Time; Toxic effect; Translating; Translational Research; Update; Work; Writing; arginase; base; chemotherapy; comparative efficacy; design; human NOS3 protein; immune activation; improved; inhaled nitric oxide; killings; meetings; mortality; nervous system disorder; novel; novel therapeutics; prevent; public health relevance; research study; response; restoration; vascular endothelial dysfunction; vascular inflammation

DESCRIPTION (provided by applicant): We recently published in Nature Medicine that low nitric oxide (NO) bioavailability contributes to cerebral malaria (CM), the neurological disorder that kills over 2 million people annually; thus, improving NO bioavailability represents a potential adjunctive therapy for this deadly disease. Adjunctive therapy is important because about 30% of CM patients succumb despite appropriate anti-parasite chemotherapy. Low NO bioavailability in experimental cerebral malaria contributes to inflammation and vascular leak during experimental cerebral malaria (ECM). In other diseases, low NO bioavailability contributes to platelet activation and aggregation, endothelial dysfunction, vascular leak, and immune activation and regulation; these events also contribute to the complex malaria syndrome. NO therapy may therefore be effective against this complex disease because of its pleiotropic inhibitory effects of the above processes. Indeed, inhaled NO and i.v. injection of a NO donor significantly (P<0.05) protected against ECM mortality, providing the rationale for being a potential adjunctive therapy for CM. Unfortunately, neither of the above NO therapies are suitable for implementation in resource poor clinics in malaria endemic areas. There are, however, alternate approaches to restore NO bioavailability during ECM that will work in these clinics. Because the low NO bioavailability during CM is caused in part by severe hypoargininemia, which leads to decreased endothelial nitric oxide synthase-derived NO production, one approach is to restore arginine levels by parenteral administration of the amino acid. This is the basis for Anstey and colleagues ongoing trials that have shown marked restoration of NO-dependent endothelial cell function during human falciparum malaria. We posit that citrulline will be a more effective approach to restore arginine levels and hence NO bioavailability because (i) citrulline inhibits arginases released from RBCs during malaria, (ii) citrulline is not metabolized by the liver, (iii) citrulline is less toxic than arginine, and (iv) citrulline ameliorates hypoargininemia better than arginine itself. Citrulline is converted by the kidneys into arginine. Indeed, our preliminary indicate that citrulline completely protects all recipients against ECM mortality whereas the same dose of arginine caused toxicity and early death. To provide the initial proof of concept required to move toward an IND, we propose in aim 1 to measure the pharmacokinetics of arginine and citrulline therapy. In aim 2, we compare the efficacy of equimolar arginine and citrulline in protecting against mortality during ECM. Because mortality by citrulline and arginine therapy can only be improved by decreasing ECM pathogenesis and restoring NO production, we will confirm the differences in mortality with pathogenesis and NO bioavailability studies. Aim 3 determines whether the adjunctive therapy affects anti-parasite chemotherapy. Based on the complete protection against ECM by citrulline and the studies in the cardiovascular and sickle cell disease fields, we anticipate that citrulline represents a novel IND for cerebral malaria, a life threatening neurological disorder. As such, the proposed therapy meets the guidelines for the R21 Exploratory/developmental Projects in Translation Research, which is designed to test new therapeutics with mechanisms not as yet supported by substantial data and precedent. Public Health Relevance: We have reported the low nitric oxide bioavailability contributes to the pathogenesis of experimental cerebral malaria. This research finding is translated into a potential adjunctive therapy for cerebral malaria that rescues patients from their neurological disease. The proposed research generates proof-of-principle data needed to move the proposed adjunctive therapy toward an Investigational New Drug application. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.

描述(由申请人提供)：我们最近在《自然医学》上发表了一篇文章，指出一氧化氮(NO)生物利用度低会导致脑型疟疾(CM)，这是一种每年导致200多万人死亡的神经系统疾病；因此，提高NO的生物利用度是治疗这种致命疾病的潜在辅助疗法。辅助治疗很重要，因为大约30%的CM患者在适当的抗寄生虫化疗后死亡。实验性脑型疟疾的NO生物利用度低导致了实验性脑型疟疾(ECM)期间的炎症和血管泄漏。在其他疾病中，NO生物利用度低导致血小板激活和聚集、内皮功能障碍、血管渗漏和免疫激活和调节；这些事件也导致复杂的疟疾综合征。因此，由于其对上述过程的多效性抑制作用，任何治疗方法都可能对这种复杂的疾病有效。的确，吸入了NO和静脉注射。注射NO供体显著(P&lt；0.05)预防ECM死亡，为作为CM的潜在辅助治疗提供了理论基础。不幸的是，上述两种疗法都不适合在疟疾流行地区资源贫乏的诊所实施。然而，有其他方法可以在ECM期间恢复无生物利用度，这些方法将在这些诊所奏效。由于CM期间NO生物利用度低的部分原因是严重的低精氨酸血症，导致内皮型一氧化氮合酶衍生的NO产生减少，因此一种方法是通过静脉注射氨基酸来恢复精氨酸水平。这是Anstey和他的同事正在进行的试验的基础，这些试验表明，在人类恶性疟疾期间，一氧化氮依赖的内皮细胞功能显着恢复。我们假设瓜氨酸将是恢复精氨酸水平的更有效的方法，因此没有生物利用度，因为(I)瓜氨酸抑制疟疾期间红细胞释放的精氨酸酶，(Ii)瓜氨酸不被肝脏代谢，(Iii)瓜氨酸比精氨酸毒性小，(Iv)瓜氨酸比精氨酸本身更好地改善低精氨酸血症。瓜氨酸由肾脏转化为精氨酸。事实上，我们的初步研究表明，瓜氨酸完全保护所有受体免受ECM死亡的影响，而相同剂量的精氨酸会导致毒性和早期死亡。为了提供走向IND所需的初步概念证明，我们在目标1中建议测量精氨酸和瓜氨酸疗法的药代动力学。在目标2中，我们比较了等摩尔精氨酸和瓜氨酸在预防ECM期间死亡率方面的效果。由于瓜氨酸和精氨酸治疗的死亡率只有通过减少ECM的致病机制和恢复NO的产生才能改善，所以我们将证实有发病机制和无生物利用度研究的死亡率的差异。目的3确定辅助治疗是否影响抗寄生虫化疗。基于瓜氨酸对细胞外基质的完全保护作用，以及在心血管和镰状细胞疾病领域的研究，我们预计瓜氨酸将成为治疗脑型疟疾的新药物。因此，建议的疗法符合翻译研究R21探索性/发展项目的指导方针，该项目旨在测试新的疗法，其机制尚未得到大量数据和先例的支持。 公共卫生相关性：我们已经报道了一氧化氮生物利用度低导致实验性脑疟疾的发病机制。这项研究发现被转化为一种潜在的脑型疟疾辅助疗法，可以将患者从神经系统疾病中拯救出来。这项拟议的研究产生了将拟议的辅助疗法推向研究性新药应用所需的原则证明数据。 免责声明：请注意，以下批评是由评审员在研究小组会议之前准备的，基本上是以未经编辑的形式提供的。虽然审查员有机会根据小组的讨论更新或修订其书面评价，但不能保证在会议讨论之后更新了个别批评意见。因此，这些评论可能不能完全反映个别评审员在小组讨论结束时的最终意见或小组的最终多数意见。因此，讨论纪要和总结是审查员在会议上实际上认为至关重要的最后结论。