Experimental Pharmacology and Chemical Studies of Nikkomycin Z

尼可霉素 Z 的实验药理学和化学研究

• 批准号: 7406159
• 负责人: JOHN N GALGIANI
• 金额: $ 10.26万
• 依托单位: VALLEY FEVER THERAPIES LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406159
• 关键词: Acquired Immunodeficiency Syndrome; Adrenal Cortex Hormones; Affect; African American; American Type Culture Collection; Animal Model; Antifungal Agents; Area; Arizona; Biological; Biological Availability; Businesses; California; Cardiac; Chemicals; Chemistry; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Coccidioides; Coccidioidomycosis; Complement; Condition; Development; Development Plans; Disease; Dosage Forms; Dose; Drug Formulations; Drug Interactions; Drug Kinetics; Economics; Ensure; Fever; Filipino; Funding; Future; Genes; Genetic Engineering; Goals; Grant; Guanosine Monophosphate; Human; Human Volunteers; Immunity; Induced Hyperthermia; Infection; Ion Channel; Knock-out; Laboratories; Lesion; Life; Liquid substance; Location; Lung; Medical; Metabolism; Mus; Mycoses; Oral Administration; Organ Transplantation; Orphan; Orphan Drugs; Ownership; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Phase I/II Trial; Pneumonia; Powder dose form; Pregnancy; Procedures; Process; Production; Program Development; Published Comment; Qualifying; Race; Range; Rate; Reporting; Research; Safety; Score; Screening procedure; Streptomyces; Symptoms; Syndrome; TNF gene; Testing; Therapeutic Agents; Travel; United States Food and Drug Administration; United States National Institutes of Health; Universities; Work; analytical method; assay development; base; cost; day; disorder control; drug metabolism; fungus; human study; immune function; improved; man; mouse model; nikkomycin; nikkomycin X; novel therapeutics; pre-clinical; preclinical study; validation studies

DESCRIPTION (provided by applicant): Coccidioidomycosis is a regional fungal disease in desert areas of the Southwestern U.S. and is of particular importance to Arizona and California. The importance of this disease extends beyond the endemic areas due to extensive travel to these locations. Infection with Coccidioides spp. may cause illness ranging from a mild, self-limiting, pulmonary syndrome to serious or life-threatening disease. The later is more likely in patients with compromised immunity as seen following organ transplant, cancer chemotherapy, or AIDS. Complications are also seen in certain racial groups (African American and Filipino), pregnancy, and in patients receiving drugs that suppress immune function (corticosteroids, TNF antagonists). Nikkomycin Z has been declared an orphan drug by the FDA and is eligible for fast track review. In animal models, nikkomycin Z has shown potential to eradicate the fungus from lung lesions which is not seen with existing antifungal drugs. NikZ is absorbed after oral administration and was well tolerated and safe based on a single dose study completed in man. The goal of this proposal is to support further development of NikZ and complement plans for a Phase I/II study in patients with coccidioidal pneumonia. The aims of this proposal include: conduct of PK/PD studies in mice with experimental coccidioidomycosis, establishment of a GLP complient analytical laboratory and development of optimized analytical methods, and conduct of additional preclinical studies needed to support continued clinical studies. Simultaneous, planning for the next clincial study (Phase I/II) will be ongoing with support from an NIH R34 planning grant. The PK/PD studies are needed to determine the most effective dose strategy. The results can be extrapolated to humans and guided by exposure targets in mice in relation to human pharmacokinetics and existing single dose safety results. NikZ has stability problems in biological fluids and further assay development is needed before future human studies are performed to define handling procedures and ensure reliability given limitations in clinical settings. Moreover, a GLP facility will be needed and will serve as a core laboratory for all studies ongoing with NikZ. The FDA is requiring drug metabolism/drug interaction screening before any treatment studies are initiated, and screening for cardiac ion channel effects is also needed. The planned studies will pave the way for continued development. Project Narrative: Coccidioidomycosis (Valley Fever) is a fungal infection occurring in the southwestern U.S. and affecting residents as well as visitors. Although most affected people develop only mild symptoms that resolve without treatment, some will develop prolonged and sometimes serious illness. Currently available therapies do not fully control this disease, thus our goal is to further study a new drug that represents a promising new therapy for Valley Fever.

描述(申请人提供)：球孢子菌病是美国西南部沙漠地区的一种地区性真菌病，对亚利桑那州和加利福尼亚州特别重要。由于对流行地区的广泛旅行，这种疾病的重要性超出了这些地区。球孢子虫感染。可能会导致从轻微的自限性肺部综合征到严重或危及生命的疾病。后者更有可能出现在器官移植、癌症化疗或艾滋病后免疫力低下的患者身上。并发症也见于某些种族群体(非裔美国人和菲律宾人)、怀孕以及接受抑制免疫功能的药物(皮质类固醇、肿瘤坏死因子拮抗剂)的患者。尼克霉素Z已被FDA宣布为孤儿药物，并有资格接受快速通道审查。在动物模型中，尼可霉素Z显示出了从肺部病变中根除真菌的潜力，这是现有抗真菌药物所未见的。尼可地平在口服后被吸收，耐受性和安全性良好，在人体内完成了单剂量研究。这项建议的目标是支持NikZ的进一步发展，并补充球虫肺炎患者的I/II期研究计划。这项建议的目的包括：在实验性球孢子菌病小鼠身上进行PK/PD研究，建立符合GLP要求的分析实验室，开发优化的分析方法，以及进行支持继续临床研究所需的额外临床前研究。同时，下一项临床研究(I/II阶段)的规划将在NIH R34规划拨款的支持下进行。需要进行PK/PD研究以确定最有效的剂量策略。根据人体药代动力学和现有的单次剂量安全性结果，这些结果可以外推到人类，并以小鼠的暴露靶标为指导。NikZ在生物液中存在稳定性问题，考虑到临床环境的限制，在进行未来的人体研究以确定处理程序和确保可靠性之前，需要进一步的分析开发。此外，将需要一个普洛斯设施，作为与日兴正在进行的所有研究的核心实验室。FDA要求在启动任何治疗研究之前进行药物代谢/药物相互作用筛查，还需要筛查心脏离子通道效应。计划中的研究将为继续发展铺平道路。 项目简介：球孢子菌病(山谷热)是一种真菌感染，发生在美国西南部，影响居民和游客。虽然大多数受影响的人只出现轻微的症状，不需要治疗就能缓解，但有些人会发展成长期的、有时是严重的疾病。目前可用的治疗方法不能完全控制这种疾病，因此我们的目标是进一步研究一种新药，代表着一种有希望的治疗山谷热的新方法。