Intervenable Host Leishmania (Viannia) Interactions

描述（由申请人提供）：皮肤利什曼病广泛分布于整个拉丁美洲，在那里主要是Viannia亚属利什曼原虫。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1 000例，其中不包括军事人员的病例。皮肤利什曼病在新大陆通常被认为是一种人畜共患病。然而，不断变化的人口结构已导致以前不发达地区和城市中心外围住区家庭内部和周围传播的“驯化”。这一现象导致报告病例的年龄分布大幅增加和转变。儿童现在占病例的很大比例。在若干地区，包括韦拉省、博亚卡省、托利马省和纳里诺省，已经认识到病毒传播的归化趋势。儿童占病例的很大比例，并已证明对五价锑药物治疗反应不佳。在新的，特别是在旧的传播地区，以前感染的居民中的疾病复发是新发疾病的重要原因。因此，控制措施必须针对人类宿主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)缺乏有效的儿童治疗方法；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，该方案将汇集托利马州卫生局、国立卫生研究所（波加塔）、国际医学研究中心（CIDEIM）和耶鲁大学医学院在公共卫生、流行病学、利什曼病、媒介生物学和个人免疫学方面的优势。

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.