Preclinical Testing of Tetrandrine against Noise-Induce Hearing Loss

 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）是感音神经性听力障碍的第二种最常见形式，仅次于年龄相关性听力损失，这并不奇怪。虽然靶向自由基途径的治疗方法已显示出减少NIHL的前景，但美国食品和药物管理局尚未批准用于NIHL的药物。NIHL中涉及的复杂的细胞和分子途径阻碍了有效治疗的发展。因此，需要一种新的方法来对抗这些多种信号通路，以便使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物可以预防NIHL。汉防己甲素（泰特）是一种从中草药中提取的双苄基异喹啉类生物碱，具有抗氧化、抗炎和阻断钙离子通道的作用，有望成为NIHL的治疗药物。此外，临床上使用泰特显示出长期安全性。基于我们的初步发现，即泰特可以预防NIHL，在本I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（目的1）和治疗（目的2）NIHL的半数有效剂量（ED 50）。我们使用泰特方法的创新方面是：（1）泰特已经具有良好的药理学特性和长期的临床应用历史;（2）已知泰特干预NIHL中涉及的多种信号通路。我们将使用这些研究的数据来完成一个研究性新药（IND）的数据包，用于我们的SBIR II期临床研究。该计划的目标是将泰特推向市场，用于预防和治疗NIHL。

 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.