Preclinical Testing of Tetrandrine against Noise-Induce Hearing Loss

粉防己碱抗噪声性听力损失的临床前测试

• 批准号: 9140718
• 负责人: Jianxin Bao
• 金额: $ 22.47万
• 依托单位: GATEWAY BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140718
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Aftercare; Alkaloids; American; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiepileptic Agents; Antioxidants; Auditory Brainstem Responses; Benzylisoquinolines; CBA/CaJ Mouse; Calcium Channel; Calcium Channel Blockers; Chinchilla (genus); Chinese Herbs; Chinese People; Clinical; Clinical Research; Clinical Trials; Complex; Consult; Data; Development; Dose; Drug Kinetics; Environmental Hazards; Free Radicals; Future; Goals; Hearing; Hearing problem; Hour; Immunodeficiency and Cancer; Intervention; Intraperitoneal Injections; Investigational Drugs; Investigational New Drug Application; Magic; Marketing; Measures; Medicinal Herbs; Modeling; Molecular; Molecular Target; Noise; Noise-Induced Hearing Loss; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Pre-Clinical Model; Preclinical Testing; Presbycusis; Prevention; Process; Property; Publishing; Recording of previous events; Safety; Signal Pathway; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Suggestion; T-Type Calcium Channels; Testing; Therapeutic; Toxic effect; United States Food and Drug Administration; Work; base; cellular targeting; clinical application; combat; dosage; drug development; hearing impairment; innovation; novel strategies; novel therapeutics; occupational hazard; phase 2 study; preclinical study; pressure; prevent; programs; prophylactic; public health relevance; research study; sound; therapeutic target

 DESCRIPTION (provided by applicant): Noise is the most common occupational and environmental hazard, thus it is not surprising that noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, second only to age-related hearing loss. Although therapeutics that target the free radical pathway have shown promise for reducing NIHL, there are no medications approved by the U.S. Food and Drug Administration for NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. Therefore, a new approach is necessary to combat these multiple signaling pathways in order for therapeutics to be successful at preventing and treating NIHL. Recent preclinical studies have demonstrated that calcium channel blockers and anti-inflammatory drugs can prevent NIHL. Tetrandrine (TET), a bis-benzylisoquinoline alkaloid originally purified from a Chinese medicinal herb, shows strong promise as a NIHL therapeutic due to its antioxidant and anti-inflammatory properties, as well as its ability to block calcium channels. Moreover, the use of TET clinically has shown a long-term safety profile. Based on our preliminary findings that TET could protect against NIHL, in this Phase I STTR application, we will determine the median effective dose (ED50) for this drug to prevent (Aim 1) and treat (Aim 2) NIHL in two different animal models. The innovative aspects in our approach for using TET are: (1) TET already has well-characterized pharmacological properties and a long history of clinical applications; and (2) TET is known to intervene in multiple signaling pathways involved in NIHL. We will use the data from these studies to complete an Investigational New Drug (IND)-enabling data package for our SBIR phase II clinical studies of this agent. The goal of this program is to bring TET to market for use in prevention and treatment of NIHL.

 描述（由申请人提供）：噪声是最常见的职业和环境危害，因此噪声性听力损失（NIHL）成为第二常见的感音神经性听力缺陷形式，仅次于年龄相关性听力损失，这一点并不奇怪。尽管针对自由基途径的疗法已显示出减少 NIHL 的希望，但美国食品和药物管理局尚未批准用于治疗 NIHL 的药物。 NIHL 涉及的一系列复杂的细胞和分子途径阻碍了有效治疗的发展。因此，需要一种新方法来对抗这些多重信号通路，以便治疗方法能够成功预防和治疗 NIHL。最近的临床前研究表明，钙通道阻滞剂和抗炎药可以预防 NIHL。粉防己碱 (TET) 是一种双苄基异喹啉生物碱，最初从中草药中纯化出来，由于其抗氧化和抗炎特性以及阻断钙通道的能力，显示出作为 NIHL 治疗剂的强大前景。此外，TET 的临床使用已显示出长期的安全性。基于我们初步发现 TET 可以预防 NIHL，在这一期 STTR 申请中，我们将确定该药物在两种不同动物模型中预防（目标 1）和治疗（目标 2）NIHL 的中位有效剂量（ED50）。我们使用TET的方法的创新之处在于：（1）TET已经具有良好的药理特性和悠久的临床应用历史； (2) TET 已知可干预与 NIHL 相关的多种信号通路。我们将使用这些研究的数据来完成该药物 SBIR II 期临床研究的研究性新药 (IND) 支持数据包。该计划的目标是将 TET 推向市场，用于预防和治疗 NIHL。