Optimizing D-methionine (D-met) Pre-loading and Rescue Dosing Through Functional and Biomarker Measures

通过功能和生物标志物测量优化 D-蛋氨酸 (D-met) 预加载和救援剂量

• 批准号: 8877767
• 负责人: KATHLEEN CAMPBELL
• 金额: $ 57.34万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877767
• 关键词: Acute; Address; Air Bags; Americas; Aminoglycosides; Animals; Antioxidants; Auditory Brainstem Responses; Biological Assay; Biological Markers; Blood; Chinchilla (genus); Chronic; Cisplatin; Clinical; Clinical Trials; Cochlea; Control Groups; Cysteine Synthase; D-Amino Acid Dehydrogenase; Data; Data Collection; Department of Defense; Diet; Dose; Emergency Situation; Enzymes; Funding; Future; Glutathione Reductase; Goals; Health; Hour; Human Resources; Injection of therapeutic agent; Intraperitoneal Injections; Investigational Drugs; Legal patent; Lipid Peroxidation; Malondialdehyde; Measures; Methionine; Noise; Noise-Induced Hearing Loss; Patients; Phase III Clinical Trials; Prophylactic treatment; Regimen; Relative (related person); Saline; Schedule; Serum; Signal Transduction; Smoke; Soldier; Stress; Superoxide Dismutase; Synthase D; Testing; Time; Tinnitus; Training; United States Food and Drug Administration; antioxidant enzyme; catalase; clinically relevant; enzyme activity; glutaredoxin 2; glutathione peroxidase; hearing impairment; instructor; intraperitoneal; meetings; non-smoker; operation; prevent; public health relevance; response; round window; treatment strategy; weapons

 DESCRIPTION (provided by applicant): The purpose of these studies is fourfold: 1) to determine the maximum time before noise exposure that the otoprotective agent D-methionine (D-met) can first be effectively administered and then stopped prior to noise exposure, an administration strategy termed "pre-loading", and still prevent or reduce subsequent permanent noise induced hearing loss (NIHL) with no further D-met administration 2) to determine optimal D- met dosing levels for various "preloading" time periods, 3) to determine optimal D-met dosing levels at the various "rescue" time periods, meaning that the otoprotective agent D-met is first administered up to 36 hours after noise cessation and still provides NIHL protection and 4) to investigate a variety of possible serum and cochlear biomarkers that could be used to indicate optimal or non-optimal dosing in a given patient given probable intersubject variability in the patients oxidative status prior to and during D-met treatment. These biomarkers could then be used to guide D-met dosing and dose adjustment for a given patient for optimal otoprotection for either systemic or round window D-met administration. These studies will be conducted for both steady state and impulse noise exposures because we have found that optimal dosing may vary by noise exposure type. Permanent NIHL is the most common hearing loss world-wide and the third leading chronic health condition in America. D-met, patented in my lab, is the first otoprotective agent approved for Phase 3 clinical trials under a Food and Drug Administration (FDA) Investigational New Drug (IND) filing to prevent NIHL and tinnitus, administering D-met before, during and after the 2 week noise exposure. We are currently collecting data for this Department of Defense (DoD) funded clinical trial in soldiers during M-16 weapons training. However optimal dosing for pre-loading or rescue dosing may be different than for this clinical trial dosing regimen. As we move closer to possible FDA approval for the first otoprotective agent, we need to prepare for possible clinical guidance's for optimal patient treatment strategies to accommodate clinical variability in noise exposures, the practicalities of when the patient can actually be treated relative to the noise exposure and the probable endogenous intrasubject variability in oxidative state and possibly response to treatment. Biomarkers may be helpful in signaling optimal and non-optimal dosing levels in a given patient allowing for dose adjustment .The proposed studies will correlate optimal protective D-met dose and affiliated cochlear and serum biomarkers for each D-met administration time and dose level before or after a single steady state or impulse noise exposure. Our overall goal is to optimize and provide clinical guidance for a safe and effective pharmacologic agent to prevent NIHL worldwide in a variety of settings. These studies are critical to achieve that goal.

 描述（适用提供）：这些研究的目的是四重：1）确定噪声暴露前的最大时间，即可以先有效地进行噪声剂D-Methionine（D-MET）（D-MET），然后在噪声暴露之前停止，然后在噪声曝光之前停止，在噪声策略中，一种被称为“预加载”的管理策略，并仍然可以防止或降低随后的噪声损失（nih dihl dihl dihl dihl dihl dihl dihl dihl dihl dihl dihl dihl） “预加载”时间段，3），以确定各种“救援”时间段的最佳D-MET剂量水平，这意味着首先要在噪声戒断后最多使用otoprotapertaptaptim d-met进行NIHL保护和4），以调查可能会在各种可能的患者中给出了a niHl保护和不适合的生物标志物，以使A的相互作用具有最佳性或不合格性，以使A的相互作用具有最佳的变化。患者在D-MET治疗之前和期间氧化状态。然后，这些生物标志物可用于指导给定患者的D-MET剂量和调整剂量调整，以实现全身或圆形窗户D-MET给药的最佳局限性。这些研究将针对稳态和冲动噪声暴露进行，因为我们发现最佳剂量可能因噪声暴露类型而有所不同。 永久性NIHL是全球最常见的听力损失，也是美国第三领先的慢性健康状况。 D-MET是在我的实验室获得专利的D-MET，是第3阶段临床试验（FDA）研究新药物（IND）提交的第3阶段临床试验的Otosation剂，以防止NIHL和TINNINUS，在2周噪声暴露之前，之中和之后对D-MET进行了D-MET。我们目前正在M-16武器培训期间为士兵的该国国防部（DOD）基本临床试验收集数据。但是，预载或救援给药的最佳剂量可能与该临床试验剂量方案不同。随着我们越来越接近可能对第一种眼药物的FDA批准，我们需要为最佳患者治疗策略的可能临床指导做准备，以适应噪声暴露的临床可变性，相对于噪声暴露的何时可以治疗患者的实践，并且相对于噪声暴露以及有问题的内生内源性内源性内源性内源性内源性内源性内源性内源性可变性，并且对治疗的氧化和可能的治疗方法。生物标志物可能有助于给定患者的最佳和非最佳剂量水平发出允许剂量调整的最佳剂量水平。拟议的研究将在单个稳态或脉冲噪声暴露之前或之后，将最佳保护的D-MET剂量和会员耳蜗和血清生物标志物与分支机构耳蜗和血清生物标志物相关联。 我们的总体目标是为安全有效的药物剂优化和提供临床指导，以防止在各种环境中全球NIHL。这些研究对于实现这一目标至关重要。