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（由申请人提供）：这些研究的目的有四个：1) 确定在噪声暴露之前，可以首先有效施用耳保护剂 D-蛋氨酸 (D-met) 的最长时间，然后在噪声暴露之前停止，一种称为“预加载”的施用策略，并且在不进一步施用 D-met 的情况下仍然预防或减少随后的永久性噪声诱发的听力损失 (NIHL) 2) 确定各种情况下的最佳 D-met 剂量水平 “预加载”时间段，3) 确定在各个“救援”时间段的最佳 D-met 剂量水平，这意味着在噪声停止后 36 小时内首次施用耳保护剂 D-met，并且仍然提供 NIHL 保护，4) 研究各种可能的血清和耳蜗生物标志物，这些生物标志物可用于指示给定患者的最佳或非最佳剂量，考虑到可能的受试者间差异 D-met 治疗前和治疗期间患者的氧化状态。然后，这些生物标志物可用于指导特定患者的 D-met 给药和剂量调整，以实现全身或圆窗 D-met 给药的最佳耳保护。这些研究将针对稳态和脉冲噪声暴露进行，因为我们发现最佳剂量可能因噪声暴露类型而异。 永久性 NIHL 是全球最常见的听力损失，也是美国第三大慢性健康状况。 D-met 是我实验室的专利，是第一个根据食品和药物管理局 (FDA) 研究新药 (IND) 申请批准进行 3 期临床试验的耳保护剂，用于预防 NIHL 和耳鸣，在 2 周噪音暴露之前、期间和之后服用 D-met。我们目前正在收集国防部 (DoD) 资助的这项临床试验的数据，该试验对士兵进行 M-16 武器训练。然而，预负荷或救援剂量的最佳剂量可能与本临床试验的给药方案不同。随着第一种耳保护剂可能获得 FDA 批准，我们需要为最佳患者治疗策略提供可能的临床指导，以适应噪声暴露的临床变异性、相对于噪声暴露的患者实际治疗时间的实用性以及可能的内源性受试者体内氧化状态变异性以及可能对治疗的反应。生物标志物可能有助于在给定患者中发出最佳和非最佳剂量水平的信号，从而允许剂量调整。拟议的研究将在单次稳态或脉冲噪声暴露之前或之后，将最佳保护性 D-met 剂量与每个 D-met 给药时间和剂量水平的附属耳蜗和血清生物标志物相关联。 我们的总体目标是优化安全有效的药物并提供临床指导，以在全球范围内各种环境下预防 NIHL。这些研究对于实现这一目标至关重要。