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: 7736460
• 负责人: JOHN N GALGIANI
• 金额: $ 35.06万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736460
• 关键词: Acquired Immunodeficiency Syndrome; Adrenal Cortex Hormones; Affect; African American; Animal Model; Antifungal Agents; Area; Arizona; Biological; Biological Availability; Businesses; California; Cardiac; Chemicals; Chemistry; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Coccidioides; Coccidioidomycosis; Complement; Development; Development Plans; Disease; Dosage Forms; Dose; Drug Formulations; Drug Interactions; Drug Kinetics; Economics; Ensure; Fever; Filipino; Funding; Future; Genes; Genetic Engineering; Goals; Grant; 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; 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; Reporting; Research; Safety; Screening procedure; Streptomyces; Symptoms; Syndrome; TNF gene; Testing; Therapeutic Agents; Travel; United States National Institutes of Health; Universities; Work; analytical method; assay development; base; cost; disorder control; drug metabolism; fungus; 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（由申请人提供）：球孢子菌病是美国西南部沙漠地区的一种区域性真菌病，对亚利桑那州和加利福尼亚州尤为重要。由于人们广泛前往流行地区，这种疾病的重要性超出了流行地区的范围。球孢子菌感染。可能导致从轻微的自限性肺部综合症到严重或危及生命的疾病。后者更有可能发生在器官移植、癌症化疗或艾滋病后免疫力受损的患者中。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药物（皮质类固醇、TNF 拮抗剂）的患者也可能出现并发症。 Nikkomycin Z 已被 FDA 宣布为孤儿药，并有资格进行快速审评。在动物模型中，尼可霉素 Z 显示出根除肺部病变中真菌的潜力，这是现有抗真菌药物所未见的。 NikZ 口服后被吸收，根据在人体中完成的单剂量研究，其耐受性良好且安全。该提案的目标是支持 NikZ 的进一步开发，并补充针对球虫肺炎患者的 I/II 期研究计划。该提案的目的包括：在患有实验性球孢子菌病的小鼠中进行 PK/PD 研究，建立符合 GLP 要求的分析实验室并开发优化的分析方法，以及进行支持持续临床研究所需的额外临床前研究。同时，下一个临床研究（I/II 期）的规划将在 NIH R34 规划拨款的支持下进行。需要进行 PK/PD 研究来确定最有效的剂量策略。结果可以外推到人类，并以与人类药代动力学和现有单剂量安全性结果相关的小鼠暴露目标为指导。 NikZ 在生物液体中存在稳定性问题，在进行未来的人体研究之前需要进一步开发测定方法，以定义处理程序并确保考虑到临床环境的局限性的可靠性。此外，还需要一个 GLP 设施，并将其作为 NikZ 正在进行的所有研究的核心实验室。 FDA 要求在开始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。计划中的研究将为持续发展铺平道路。 项目叙述：球孢子菌病（谷热）是一种发生在美国西南部的真菌感染，影响居民和游客。尽管大多数受影响的人仅出现轻微症状，无需治疗即可缓解，但有些人会出现长期疾病，有时甚至是严重疾病。目前可用的疗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，它代表了一种有前途的谷热新疗法。