Citrulline adjunctive therapy for cerebral malaria

瓜氨酸辅助治疗脑型疟疾

基本信息

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
项目类别：
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

项目摘要

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》上发表文章称，低一氧化氮 (NO) 生物利用度会导致脑型疟疾 (CM)，这种神经系统疾病每年导致超过 200 万人死亡；因此，提高一氧化氮的生物利用度代表了这种致命疾病的潜在辅助治疗。辅助治疗很重要，因为尽管进行了适当的抗寄生虫化疗，仍有约 30% 的 CM 患者死亡。实验性脑型疟疾中的低 NO 生物利用度会导致实验性脑型疟疾 (ECM) 期间的炎症和血管渗漏。在其他疾病中，低NO生物利用度会导致血小板活化和聚集、内皮功能障碍、血管渗漏以及免疫激活和调节；这些事件也导致了复杂的疟疾综合症。因此，NO 疗法可能对这种复杂的疾病有效，因为它对上述过程具有多效性抑制作用。事实上，吸入一氧化氮和静脉注射。注射 NO 供体可显着（P<0.05）预防 ECM 死亡率，为成为 CM 的潜在辅助治疗提供了理论基础。不幸的是，上述两种NO疗法都不适合在疟疾流行地区资源匮乏的诊所实施。然而，在 ECM 期间还有一些替代方法可以在这些诊所发挥作用来恢复 NO 生物利用度。由于 CM 期间的低 NO 生物利用度部分是由严重的低精氨酸血症引起的，这会导致内皮一氧化氮合酶衍生的 NO 产生减少，因此一种方法是通过肠胃外施用氨基酸来恢复精氨酸水平。这是 Anstey 及其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，NO 依赖性内皮细胞功能得到显着恢复。我们认为瓜氨酸将是恢复精氨酸水平并因此恢复一氧化氮生物利用度的更有效方法，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）瓜氨酸的毒性低于精氨酸，和（iv）瓜氨酸比精氨酸本身更好地改善低精氨酸血症。瓜氨酸通过肾脏转化为精氨酸。事实上，我们的初步表明，瓜氨酸完全保护所有接受者免受 ECM 死亡，而相同剂量的精氨酸会导致毒性和过早死亡。为了提供 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治疗的药代动力学。在目标 2 中，我们比较了等摩尔精氨酸和瓜氨酸在 ECM 期间预防死亡的功效。由于瓜氨酸和精氨酸治疗的死亡率只能通过减少 ECM 发病机制和恢复 NO 产生来改善，因此我们将通过发病机制和 NO 生物利用度研究来确认死亡率的差异。目标 3 确定辅助治疗是否影响抗寄生虫化疗。基于瓜氨酸对 ECM 的全面保护以及在心血管和镰状细胞疾病领域的研究，我们预计瓜氨酸代表了一种针对脑型疟疾（一种危及生命的神经系统疾病）的新型 IND。因此，拟议的疗法符合翻译研究中 R21 探索/发展项目的指南，该项目旨在测试尚未得到大量数据和先例支持的机制的新疗法。公共卫生相关性：我们已经报道，一氧化氮生物利用度低会导致实验性脑型疟疾的发病机制。这项研究结果被转化为一种潜在的脑型疟疾辅助疗法，可将患者从神经系统疾病中拯救出来。拟议的研究产生了将拟议的辅助疗法转向研究性新药应用所需的原理验证数据。免责声明：请注意，以下评论是由审稿人在研究部分会议之前准备的，并且以基本上未经编辑的形式提供。虽然审稿人有机会根据小组的讨论更新或修改他们的书面评估，但不能保证个人批评在会议讨论后得到更新。因此，评论可能无法完全反映小组讨论结束时个别审稿人的最终意见或小组的最终多数意见。因此，讨论的简历和摘要是审稿人在会议上实际认为关键的内容的最终决定。