Intervenable Host Leishmania (Viannia) Interactions

描述(申请人提供)：皮肤利什曼病广泛分布在拉丁美洲，在那里利什曼亚属的文氏菌占主导地位。在哥伦比亚，报告的病例几乎翻了一番，从每年5000例增加到2003年的近10000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，不断变化的人口结构导致以前不发达地区和城市中心外围地区的居民点及其周围家庭内部和周围的传播被“驯化”。这一现象导致了报告病例的大幅增加和年龄分布的转变。儿童现在占病例的很大比例。在几个地区已经认识到传播的驯化趋势，其中包括惠拉省、博亚卡省、托利马省和纳里诺省。儿童在病例中所占比例很高，而且已被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，以前感染的居民中的复发性疾病是新发疾病的重要原因。因此，控制措施必须针对人类宿主的反应和更有效的治疗，以及媒介靶向干预。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)儿童缺乏有效的治疗；2)传播的驯化和有效干预措施的必要性；3)持续感染、慢性病和复发性疾病，以及对宿主反应在这些表现中所起作用的有限了解。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、媒介生物学和免疫学方面的优势，这些个人来自托利马国家卫生服务、国家医学研究所(Bogata)、国际医学研究中心(CIDEIM)和耶鲁大学医学院。 项目1：米替福辛治疗儿童皮肤利什曼病(McMahon-Pratt，D.) 项目1描述(申请人提供)：这项多中心临床试验将在哥伦比亚进行，在国际医学研究中心(CIDEIM)的协调下，与Lyda Osorio医学博士合作，作为ICIDR计划的项目1。这项研究将比较新的口服药物米替福辛和标准药物格华泰治疗由万古氏亚属利什曼引起的皮肤利什曼病(CL)的疗效和耐受性。50多年来，五价锑一直是CL的标准治疗方法，尽管它具有非肠道使用、高毒性和相对较高的成本。另一方面，儿童是一个高度脆弱的人群，因为哥伦比亚主要流行地区23%以上的病例是12岁以下的患者。儿童对锑的反应也较低。 治疗解释为这些年龄段的不同药代动力学行为，大约一半的药物暴露是由于与成年人相比清除率的两倍而观察到的。这些数据，加上不同的免疫反应，使12岁以下的儿童成为治疗失败、发病率增加、美观有害的疤痕或黏膜受累的高风险人群。120名12岁以下的儿童将被录取。随机分组的患者中，一半将接受格卢西汀20毫克/公斤/天，为期20天(标准治疗)，另一半将接受米替福辛2.5毫克/公斤/天，为期28天。锑类药物的有效率为60%，米替福辛的有效率为90%。临床反应将在治疗结束时、13周和26周时进行评估。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和其他参与机构的机构审查委员会的道德批准。一种有效的、可耐受的、可口服的皮肤利什曼病治疗方法的可获得性将彻底改变治疗方法，甚至可能是预防这种疾病的方法。

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.