Developing D-methionine as an Aminoglycoside Otoprotectant

描述（由申请方提供）：氨基糖苷类诱导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），我们的专利，许可，现在正在使用其他FDA批准的临床试验，防止阿米卡星和庆大霉素诱导的听力损失，而没有抗菌素干扰的动物研究。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验证数据，以确定D-met是否也能防止妥布霉素诱导的耳毒性，并确保D-met不会干扰这些氨基糖苷类或临床护理中通常伴随使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进行安全有效的FDA批准的D-met作为氨基糖苷类诱导的耳毒性的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这一目的的药物。具体目标是：1）通过比较庆大霉素豚鼠模型中相同日剂量的每日一次与每日两次给药，确定D-met每日分次给药是否改善了对氨基糖苷类耳毒性的保护; 3）通过首先改进妥布霉素耳毒性的豚鼠模型，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，确定D-met是否可以保护免受妥布霉素诱导的耳毒性;和4）确保D-met不干扰庆大霉素、阿米卡星或妥布霉素单独或与临床护理中使用的其它伴随抗生素联合的抗微生物作用。前三个具体目标的结果测量将是听觉脑干反应阈值偏移和内外毛细胞计数。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药物引起的听力损失，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，从而改善公共健康。

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.