Topical Drug Treatment of Cutaneous Leishmaniasis

皮肤利什曼病的局部药物治疗

• 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
• 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

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的病原体， 其特征在于一系列临床表现，从溃疡性皮肤损伤到致命的 内脏感染利什曼病是一种与贫困有关的疾病，与营养不良有关， 流离失所、住房条件差、文盲、性别歧视、免疫系统薄弱和缺乏 资源利什曼病因与人类共同感染的出现而进一步受到影响。 免疫缺陷病毒（艾滋病毒）在流行地区。在全球范围内，估计有150万至200万新病例 每年有8万人死于利什曼病，3.5亿人面临感染和患病的风险。在 缺乏疫苗接种、化疗以及病媒控制， 控制利什曼病的要素。然而，这种策略受到了高毒性的严重威胁 临床药物的滥用和该领域耐药性的猖獗增加。由于利什曼病是一种 由于贫困，制药公司寻找新型抗利什曼病药物的动力有限 因为他们的投资回报率很低。 该SBIR应用的目标是开发一种负担得起且有效的抗利什曼病软膏， 在世界发达地区和发展中地区治疗皮肤利什曼病（CL）。我们的团队 最近发现锌（II）-吡啶二甲基胺（ZnDPA）配合物具有很强的抗利什曼原虫活性 主要利什曼原虫的致病因子之一的CL。分子靶向技术公司将 开发ZnDPA的软膏配方，圣母大学的研究小组将对这些配方进行测试。 软膏剂在CL的体内模型中，其利用遗传修饰的L.主要菌株， 稳定表达红色荧光mCherry蛋白。此外，拟议的皮肤毒性研究和 ZnDPA的生物分布对于成功的临床转化将是重要的。