Developing D-methionine as an Aminoglycoside Otoprotectant

开发 D-蛋氨酸作为氨基糖苷类耳保护剂

基本信息

批准号：
7268234
负责人：
KATHLEEN CAMPBELL
金额：
$ 43.75万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268234
关键词：
Address Adverse effects Advisory Committees Amikacin Aminoglycoside Antibiotics Aminoglycosides Animal Model Animals Antibiotics Audiology Auditory Brainstem Responses Bacteria Bacterial Counts Biological Assay Blood Urea Nitrogen Caring Cavia Cell Count Cisplatin Clinical Clinical Trials Communicable Diseases Count Creatinine Daily Data Doctor of Philosophy Dose Drug Formulations Effectiveness End Point Ensure Future Gentamicins Goals Growth Hair Cells Hearing Hour Immunology In Vitro India Investigational New Drug Application Laboratories Legal patent Length Licensing Measures Medical Microbiology Methionine Minimum Inhibitory Concentration measurement Modeling Molecular Monitor Noise Oral Otolaryngology Outcome Outcome Measure Outcome Study Outer Hair Cells Patient Care Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Predisposition Protocols documentation Public Health Purpose Quality of life Radiation Research Personnel Science Serum Standards of Weights and Measures Testing Therapeutic Time Tobramycin Translational Research Treatment Efficacy United States Food and Drug Administration aminoglycoside-induced ototoxicity antimicrobial bactericide base concept drug development hearing impairment improved in vivo killings medical schools nephrotoxicity oral mucositis ototoxicity programs research study response

项目摘要

DESCRIPTION (provided by applicant): Aminoglycoside-induced ototoxicity can cause permanent hearing impairment in approximately one third of patients receiving these antibiotics, sometimes limiting therapeutic dosing. D-methionine (D-met), which we patented, licensed, and are now using in other FDA approved clinical trials, protects against amikacin- and gentamicin-induced hearing loss without antimicrobial interference in animal studies thus far. The purpose of these proposed studies is to optimize D-met dosing protocols and obtain further proof of concept data for gentamicin and amikacin otoprotection, to determine if D-met also protects against tobramycin-induced ototoxicity, and to ensure that D-met does not interfere with the antimicrobial action of these aminoglycosides or other antibiotics commonly administered concomitantly in clinical care. The long-term goal of the studies is to enable us to conduct safe and effective FDA approved clinical trials of D-met as an otoprotective agent for aminoglycoside-induced ototoxicity and obtain FDA NDA approval, thus improving patient care. D-met would be the first agent approved for that purpose. The specific aims are: 1) to determine if fractionating D-met daily dosing improves protection against aminoglycoside ototoxicity by comparing once versus twice daily dosing for the same daily dose in the gentamicin guinea pig model; 2) to optimize dosing for D-met's otoprotection against gentamicin- and amikacin-induced ototoxicity by obtaining D-met dose response curves; 3) to determine if D-met can protect against tobramycin-induced ototoxicity by first refining a guinea pig model for tobramycin ototoxicity and then obtaining D-met dose response curves in tobramycin-ototoxicity guinea pig models; and 4) to ensure that D-met does not interfere with the antimicrobial action of gentamicin, amikacin, or tobramycin, in isolation or in conjunction with other concomitant antibiotics used in clinical care. The outcome measures for the first three specific aims will be auditory brainstem response threshold shifts and inner and outer hair cell counts. For the fourth specific aim, in vitro outcomes include the Minimum Inhibitory Concentration, Minimum Bactericidal Concentration, and post-antibiotic effect, and in vivo study outcomes include survival and bacterial counts. These studies could improve public health by developing a new drug to reduce aminoglycoside-induced hearing loss without reducing the antibiotics' effectiveness and possibly allowing higher dosing to better control infectious diseases.

描述（由申请人提供）：氨基糖苷诱导的耳毒性可能会导致大约三分之一接受这些抗生素的患者的永久性听力障碍，有时会限制治疗剂量。 D-Methionine（D-MET），我们已获得专利，许可并正在其他FDA批准的临床试验中使用，可防止迄今为止动物研究中的动物研究中没有抗菌干扰的amikacin-和gentamicin诱导的听力损失。这些拟议的研究的目的是优化D-MET给药方案，并获得进一步的庆大霉素和氨基氨基蛋白局的概念证明，以确定D-MET是否也可以防止毒素诱导的耳毒性，并确保D-MET不会干扰这些抗药性的抗小体或其他抗小体或其他抗小体或其他抗小体。研究的长期目标是使我们能够对D-Met进行安全有效的FDA批准的临床试验，以作为氨基糖苷诱导的耳毒性的耳毒剂，并获得FDA NDA批准，从而改善患者护理。 D-MET将是为此目的批准的第一个代理商。具体目的是：1）确定分级D-Met每日给药是否可以通过比较一次与每天两次给药的氨基糖苷耳毒性的保护，以庆大霉素豚鼠模型中的同一每日剂量进行两次剂量； 2）通过获得D-Met诱导的庆大霉素和阿米卡打蛋白诱导的耳毒性的剂量通过获得D-MET剂量响应曲线，以优化D-MET的剂量。 3）确定D-MET是否可以通过首先精炼毒素的豚鼠模型来防止毒素诱导的毒素诱导的耳毒性，然后在毒素 - 毒素 - 毒素毒性豚鼠模型中获得D-MET剂量反应曲线； 4）为了确保D-MET不干扰庆大霉素，amikacin或dobramycin的抗菌作用，或与其他在临床护理中使用的其他伴随抗生素进行分离或结合。前三个特定目标的结果度量将是听觉脑干响应阈值移位以及内部和外毛细胞计数。对于第四个特定目的，体外结果包括最小抑制浓度，最低杀菌浓度和抗生素后效应，并且体内研究结果包括生存和细菌计数。这些研究可以通过开发一种新药来减少氨基糖苷引起的听力损失而不降低抗生素的有效性，并可能允许更高的剂量以更好地控制传染病，从而改善公共卫生。