Preclinical Testing of Tetrandrine against Noise-Induce Hearing Loss

 说明书(申请人提供)：噪声是最常见的职业危害和环境危害，因此，噪声性听力损失(NIHL)是仅次于年龄相关性听力损失的第二种最常见的感觉神经性听力损失也就不足为奇了。尽管针对自由基途径的疗法已经显示出减少NIHL的希望，但美国食品和药物管理局(FDA)还没有批准治疗NIHL的药物。NIHL涉及的一系列复杂的细胞和分子通路阻碍了有效治疗方法的发展。因此，需要一种新的方法来对抗这些多个信号通路，以使治疗方法在预防和治疗NIHL方面取得成功。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。粉防己碱(Tet)是一种从中草药中提纯的双苄基异喹啉生物碱，由于其抗氧化和抗炎特性以及阻断钙通道的能力，在治疗NIHL方面显示出很好的前景。此外，TET在临床上的使用已显示出长期的安全性。基于我们的初步发现，Tet可以预防NIHL，在这一阶段的STTR应用中，我们将确定该药物在两个不同动物模型中预防(Aim 1)和治疗(Aim 2)NIHL的半数有效剂量(ED50)。我们使用Tet的方法的创新方面是：(1)Tet已经具有良好的药理特性和长期的临床应用历史；以及(2)Tet已知可以干预涉及NIHL的多个信号通路。我们将使用这些研究的数据来完成该药物的SBIR第二阶段临床研究的研究新药(IND)数据包。该计划的目标是将Tet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.