Intervenable Host Leishmania (Viannia) Interactions

可干预宿主利什曼原虫（Viannia）相互作用

• 批准号: 6964088
• 负责人: Diane McMahon Pratt
• 金额: $ 87.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-16 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6964088
• 关键词: Colombia; Leishmania; clinical research; cooperative study; host organism interaction; leishmaniasis; skin infection

DESCRIPTION (provided by applicant): Dermal leishmaniasis is widely distributed throughout Latin America, where Leishmania of the Viannia subgenus predominate. In Colombia, reported cases have almost doubled from 5,000 annually to close to 10,000 in 2003 excluding cases in military personnel. Dermal leishmaniasis in the New World is generally considered a zoonosis. However, changing demographic patterns have led to the "domestication" of transmission in and around households of settlements in previously undeveloped areas and the periphery of urban centers. This phenomenon has contributed to both a large increase, and a shift in the age distribution of reported cases. Children now constitute a large proportion of cases. The trend of domestication of transmission has been recognized in several areas, among them, the Departments of Huila, Boyaca, Tolima and Narino. Children constitute a high proportion of cases and have been shown to have a poor response to treatment with pentavalent antimonial drugs. In new and especially in old areas of transmission, recurrent disease among previously infected inhabitants is an important cause of new incident disease. Therefore control measures must address the human host response and more effective treatment, as well as vector targeted interventions. The projects in this research program will address three current problems of human dermal leishmaniasis in Colombia and the region: 1) The lack of an effective treatment in children; 2) The domestication of transmission and the need for effective intervention measures; 3) Persistent infection, chronic and recurrent disease, and the limited understanding of the role of host response in these manifestations. To achieve these goals, the program will draw together the strengths in public health, epidemiology, leishmaniasis, vector biology, and immunology of individuals from the State Health Service of Tolima, the Institute Nacional de Salud (Bogata), Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM) and Yale University School of Medicine. PROJECT 1: Miltefosine in Pediatric Cutaneous Leishmaniasis (McMahon-Pratt, D.) PROJECT 1 DESCRIPTION (provided by applicant): This multicenter clinical trial will be conducted in Colombia, under the Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM) coordination in collaboration with Lyda Osorio, MD, PhD, as Project 1 of the ICIDR program. This study will compare the efficacy and tolerability of the new oral drug, miltefosine with the standard drug therapy, Glucantime in children with cutaneous leishmaniasis (CL) caused by Leishmania of the Viannia subgenus. Pentavalent antimonials have been the standard treatment for CL for more than 50 years in spite of its parenteral use, high toxicity, and relative high costs. On the other hand, children constitute a highly vulnerable population since more than 23% of the cases in the major Colombian endemic regions are patients under 12 years of age. Children also have a lower response to antimonial treatment explained by the different pharmacokinetic behaviour in these ages, where approximately half of the exposure to the drug is observed as a result of having twice the clearance rate as compared to adults. These data, along with the different immune response, make children below 12 years a population at high risk of treatment failure, increased morbidity, aesthetically deleterious scars or mucosal involvement. One hundred and twenty children below 12 years will be enrolled. Half of the randomized patients will receive Glucantime 20 mg/kg/day for 20 days (standard treatment), and the other half will receive miltefosine 2.5 mg/kg/day for 28 days. A 60% efficacy of antimonials and 90% efficacy of miltefosine is expected. Clinical response will be assessed at the end of the treatment, and at 13 and 26 weeks. Also the presence of adverse events will be identified by clinical and laboratory examination. Ethical approval from the Institutional Review Boards at CIDEIM and other participating institutions will be obtained. The availability of an efficacious, tolerable, orally administrable treatment for dermal leishmaniasis would revolutionize the treatment and perhaps even the prevention of this disease.

描述（由申请人提供）：皮肤利什曼病广泛分布于拉丁美洲，其中Viannia亚属的利什曼原虫占优势。在哥伦比亚，报告的病例几乎翻了一番，从每年5，000例增加到2003年的近10，000例，其中不包括军事人员的病例。新大陆的皮肤利什曼病通常被认为是一种人畜共患病。然而，不断变化的人口模式已导致在以前不发达地区和城市中心周边的定居点家庭内部和周围传播的“驯化”。这一现象造成了报告病例的大量增加和年龄分布的变化。儿童现在占病例的很大比例。在一些地区，如乌伊拉省、博亚卡省、托利马省和纳里尼奧省，已经认识到了家庭化传播的趋势。儿童在病例中所占比例很高，而且已证明对五价锑药物的治疗反应不佳。在新的传播地区，特别是在旧的传播地区，以前受感染的居民中的复发性疾病是新的发病率的重要原因。因此，控制措施必须针对人类宿主的反应和更有效的治疗，以及针对病媒的干预措施。该研究计划中的项目将解决哥伦比亚和该地区目前人类皮肤利什曼病的三个问题：1）儿童缺乏有效治疗; 2）传播的驯化和有效干预措施的必要性; 3）持续感染，慢性和复发性疾病，以及对宿主反应在这些表现中的作用的有限理解。为了实现这些目标，该计划将汇集公共卫生，流行病学，利什曼病，病媒生物学和托利马州卫生服务处，国家健康研究所（博加塔），国际药物研究中心（CIDEIM）和耶鲁大学医学院的个人免疫学的优势。 项目1：米替福新治疗儿童皮肤利什曼病（McMahon-Pratt，D.） 项目1描述（由申请人提供）：本多中心临床试验将在哥伦比亚进行，由国际医学研究中心（CIDEIM）与Lyda Osorio，MD，PhD合作，作为ICIDR项目的项目1。本研究将比较新型口服药物米替福新与标准药物治疗Glucantime在由Viannia亚属利什曼原虫引起的皮肤利什曼病（CL）儿童中的疗效和耐受性。五价锑剂是CL的标准治疗方法已有50多年，尽管其胃肠外使用、高毒性和相对高的成本。另一方面，儿童是一个非常脆弱的群体，因为在哥伦比亚主要流行地区，23%以上的病例是12岁以下的病人。儿童对锑的反应也较低 这些年龄段的药代动力学行为不同解释了这种治疗，在这些年龄段，由于清除率是成人的两倍，观察到约一半的药物暴露。这些数据，沿着不同的免疫应答，使得12岁以下的儿童成为治疗失败、发病率增加、美学上有害的疤痕或粘膜受累的高风险人群。将招收120名12岁以下的儿童。一半的随机化患者将接受Glucantime 20 mg/kg/天，持续20天（标准治疗），另一半将接受米替福新2.5 mg/kg/天，持续28天。预期锑剂的疗效为60%，米替福新的疗效为90%。将在治疗结束时以及第13周和第26周评估临床应答。此外，将通过临床和实验室检查确定是否存在不良事件。将获得CIDEIM机构审查委员会和其他参与机构的伦理批准。皮肤利什曼病的有效、可耐受、可口服治疗的可用性将彻底改变这种疾病的治疗甚至预防。