Developing D-methionine as an Aminoglycoside Otoprotectant

开发 D-蛋氨酸作为氨基糖苷类耳保护剂

• 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
• 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

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）：氨基糖苷类药物引起的耳毒性可导致约三分之一接受这些抗生素的患者出现永久性听力损伤，有时会限制治疗剂量。 D-蛋氨酸 (D-met) 已获得专利、获得许可，目前正在 FDA 批准的其他临床试验中使用，可预防阿米卡星和庆大霉素引起的听力损失，迄今为止在动物研究中没有抗菌素干扰。这些拟议研究的目的是优化 D-met 给药方案并获得庆大霉素和阿米卡星耳保护的进一步概念数据，以确定 D-met 是否也能预防妥布霉素引起的耳毒性，并确保 D-met 不会干扰这些氨基糖苷类药物或临床护理中常用的其他抗生素的抗菌作用。这些研究的长期目标是使我们能够安全有效地进行 FDA 批准的 D-met 作为氨基糖苷类耳毒性耳保护剂的临床试验，并获得 FDA NDA 批准，从而改善患者护理。 D-met 将是第一个被批准用于此目的的药物。具体目标是：1) 通过在庆大霉素豚鼠模型中比较相同每日剂量的每日一次和两次给药，确定每日分次给药 D-met 是否可以改善对氨基糖苷类耳毒性的保护； 2) 通过获得 D-met 剂量反应曲线，优化 D-met 耳保护作用的剂量，以对抗庆大霉素和阿米卡星诱导的耳毒性； 3)首先完善妥布霉素耳毒性豚鼠模型，然后获得妥布霉素耳毒性豚鼠模型中的D-met剂量反应曲线，以确定D-met是否可以预防妥布霉素诱导的耳毒性； 4) 确保 D-met 不会干扰庆大霉素、阿米卡星或妥布霉素的抗菌作用，单独使用或与临床护理中使用的其他抗生素联合使用。前三个具体目标的结果测量将是听觉脑干反应阈值变化以及内毛细胞和外毛细胞计数。对于第四个具体目标，体外结果包括最低抑菌浓度、最低杀菌浓度和抗生素后效应，体内研究结果包括存活率和细菌计数。这些研究可以通过开发一种新药来减少氨基糖苷类引起的听力损失，而不降低抗生素的有效性，并可能允许更高的剂量来更好地控制传染病，从而改善公众健康。