Developing D-methionine as an Aminoglycoside Otoprotectant

说明(申请人提供)：氨基糖苷类药物引起的耳毒性可导致接受这些抗生素治疗的患者中约三分之一的患者永久听力受损，有时会限制治疗剂量。D-蛋氨酸(D-MET)，我们申请了专利，获得了许可，现在正用于FDA批准的其他临床试验，到目前为止，在动物实验中没有抗菌药物干扰，它可以保护阿米卡星和庆大霉素引起的听力损失。这些拟议研究的目的是优化D-MET的给药方案，获得庆大霉素和阿米卡星耳保护的进一步概念数据，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上通常同时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FDA批准的D-MET作为氨基糖苷类耳毒性的耳保护剂的安全有效的临床试验，并获得FDA NDA的批准，从而改善患者的护理。D-MET将是第一个被批准用于这一目的的代理。其具体目的是：1)在庆大霉素豚鼠模型中，通过比较每天1次和2次相同剂量的D-MET每日给药是否能改善对氨基糖苷类耳毒性的保护作用；2)通过获得D-MET的剂量反应曲线，优化D-MET对庆大霉素和阿米卡星所致耳毒性的耳保护作用；3)通过首先对妥布霉素耳毒性豚鼠模型进行改进，然后在妥布霉素耳毒性豚鼠模型上获得D-MET的剂量反应曲线，以确定D-MET是否可以对抗妥布霉素所致的耳毒性；以及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治疗中使用的其他伴随抗生素一起使用的抗菌作用。前三个特定目标的结果衡量标准将是听觉脑干反应阈值漂移和内外毛细胞计数。对于第四个特定目标，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和细菌计数。这些研究可以通过开发一种新药来改善公众健康，这种新药可以在不降低抗生素有效性的情况下减少氨基糖苷类药物引起的听力损失，并可能允许更高的剂量来更好地控制传染病。

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.