Topical Drug Treatment of Cutaneous Leishmaniasis

皮肤利什曼病的局部药物治疗

基本信息

批准号：
9383791
负责人：
Brian David Gray
金额：
$ 21.42万
依托单位：
MOLECULAR TARGETING TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9383791
关键词：
Acetates Address Adverse effects Aftercare Animal Model Anions Area Biodistribution Biological Assay Blood Circulation Cessation of life Chemicals Clinical Complex Cutaneous Cutaneous Leishmaniasis Data Dermal Development Disease Drug Industry Economics Elements Ethanol Excipients Exhibits FDA approved Female Fluorescence Formulation Gel Goals HIV Harvest Housing Human Image Immune system In Vitro Inbred BALB C Mice Incentives Infection International Health Problems Investments Irritants Leishmania Leishmania major Leishmaniasis Lesion Malnutrition Measures Methods Molecular Target Monitor Morbidity - disease rate Mus Necrosis Nitrates Octanols Ointments Organ Parasites Permeability Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Polyethylene Glycols Poverty Property Propylene Glycols Proteins Protozoa Reporting Resistance Resources Risk Sampling Sex Discrimination Skin Skin Ulcer Slice Small Business Innovation Research Grant Stains Structure Technology Testing Tissue Viability Tissues Topical application Toxic effect Toxicology Universities Vaccination Visceral World Health Organization Zinc chemotherapy clinical translation clinically relevant co-infection cohort drug development drug discovery expectation experimental study histological stains illiteracy in vivo Model mortality mouse model new technology novel skin irritation skin lesion standard measure standard of care vector control

项目摘要

Protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis, a disease that is characterized by a spectrum of clinical manifestations ranging from ulcerative skin lesions to fatal visceral infections. Leishmaniasis is a poverty-related disease and is associated with malnutrition, displacement, poor housing, illiteracy, gender discrimination, weakness of the immune system and lack of resources. Leishmaniasis is further compromised by the emergence of co-infection with human immunodeficiency virus (HIV) in endemic areas. Globally, there are an estimated 1.5–2 million new cases of leishmaniasis and 80,000 deaths each year, and 350 million people are at risk of infection and disease. In the absence of vaccination, chemotherapy, together with vector control, remains one of the most important elements in the control of leishmaniasis. However, this strategy is seriously threatened by the high toxicity of clinical drugs and the rampant increase of resistance in the field. As leishmaniasis is a disease of poverty, pharmaceutical companies have had limited incentive for the search of novel anti-leishmanial drugs because there would be low economic return on their investment. The goal of this SBIR application is to develop an affordable and effective antileishmanial ointment for treating cutaneous leishmaniasis (CL) in both developed and developing areas of the world. Our team recently discovered that zinc(II)-dipicolylamine (ZnDPA) complexes have strong antileishmanial activity against Leishmania major one of the causative agents of CL. Molecular Targeting Technologies Inc. will develop ointment formulations of ZnDPA and the team at the University of Notre Dame will test these ointments in an in vivo model of CL that takes advantage of a genetically modified L. major strain which stably express a red fluorescent mCherry protein. Furthermore, the proposed studies on skin toxicity and biodistribution of ZnDPA will be significant for a successful clinical translation.

利什曼原虫属的原生动物寄生虫是利什曼病（一种疾病）的病原体其特征是一系列临床表现，从溃疡性皮肤损伤到致命内脏感染是一种与贫困有关的疾病，并与营养不良有关，流离失所、住房条件恶劣、文盲、性别歧视、免疫系统薄弱和缺乏利什曼病因与人类共同感染的出现而进一步受到损害。全球范围内，艾滋病毒流行地区估计有 150 万至 200 万例新病例。利什曼病每年导致 8 万人死亡，3.5 亿人面临感染和疾病的风险。缺乏疫苗接种、化疗以及病媒控制仍然是最重要的措施之一然而，这种策略受到高毒性的严重威胁。由于利什曼病是一种疾病，因此临床药物的使用和耐药性的急剧增加。由于贫困，制药公司寻找新型抗利什曼病药物的动力有限因为他们的投资的经济回报率很低。该 SBIR 申请的目标是开发一种经济实惠且有效的抗利什曼药膏，用于我们的团队在世界发达地区和发展中地区治疗皮肤利什曼病 (CL)。最近发现锌(II)-二吡啶胺(ZnDPA)络合物具有很强的抗利什曼胺活性 CL 的主要病原体之一是针对利什曼原虫。开发 ZnDPA 软膏配方，圣母大学团队将测试这些配方 CL 体内模型中的软膏，利用基因改造的大型乳杆菌菌株，稳定表达红色荧光 mCherry 蛋白此外，还提出了对皮肤毒性和毒性的研究。 ZnDPA 的生物分布对于成功的临床转化具有重要意义。