PREVENTION OF HEARING LOSS BY OTOPROTECTIVE AGENTS

使用耳保护剂预防听力损失

• 批准号: 2644088
• 负责人: KATHLEEN CAMPBELL
• 金额: $ 10万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2644088
• 关键词: antioxidants; auditory threshold; cis platinum compound; disease /disorder prevention /control; drug screening /evaluation; ear hair cell; free radical scavengers; hearing disorders; laboratory rat; neuroprotectants; ototoxin; scanning electron microscopy

Cisplatin (CDDP) is the most potent ototoxin in common clinical use. CDDP induced hearing loss can be severe and is almost always permanent. As CDDP is used for a wider variety of cancers and with increasingly higher dosing, CDDP induced ototoxicity is of increasing clinical importance. Further, CDDP induced ototoxicity is now the most common dose limiting factor for CDDP chemotherapy. The purpose of the proposed studies is to select the most effective protective agent from each class of CDDP protective agents in a rat model. Ototoxicity will be assessed by auditory brainstem response threshold, scanning electron microscopy of the cochlear hair cells (SEM) and transmission electron microscopy (TEM) of the stria vascularis. Weight loss, as a measure of general health, will also be assessed. Because nephrotoxicity is the second most common dose limiting factor for CDDP chemotherapy, and because many protective agents are effective for both ototoxicity and nephrotoxicity, we will also measure creatinine for each animal. However the primary purpose of this grant is to develop otoprotective agents and to prevent hearing loss. The classes of agents included are: sulfur containing compounds, anti- oxidants/free radical scavengers, and steroids. Each agent selected meets the following criteria: documented evidence that the agent is protective against CDDP ototoxicity and/or nephrotoxicity, no exacerbation of other CDDP toxicities, and no inhibition of CDDP anti- tumor efficacy or no mechanism for inhibition of anti-tumor efficacy. All agents must also be suitable for use in humans. Control groups, of 11 animals each, will include a treated (16 mg/kg CDDP), and an untreated (equivalent volume of saline) control group. For animals receiving protective agents in addition to the CDDP, first dose response curves (5 animals per level) will be obtained to determine the optimal dosing level for each agent. Then the agents within each class of agents will be compared (11 animals per group at the lowest dosing level that provides optimal protection. The schedule of experiments is as follows: Year 1: Sulfur containing compounds Year 2: Anti-oxidants/free radical scavengers Year 3: Steroids. In the fourth and five year of the grant, the best agent of each of the above experiments will be tested in various combinations. The "best" agent will be selected on the primary criterion of otoprotection and the secondary criterion of nephroprotection because currently ototoxicity is the primary and nephrotoxicity the secondary dose limiting toxicity for CDDP. It is hoped that these experiments will allow us to develop better protocols for patients receiving CDDP chemotherapy so that they may receive CDDP dosing high enough to cure their cancer without the side effect of hearing loss.

顺铂（Cisplatin，CDDP）是临床常用的最强耳毒性药物。 CDDP引起的听力损失可能很严重， 永久的 由于CDDP用于更广泛的癌症， 随着剂量的增加，CDDP诱导的耳毒性逐渐增加 临床重要性 此外，CDDP诱导的耳毒性现在是最 CDDP化疗的常见剂量限制因素。 拟议研究的目的是选择最有效的 在大鼠中的每类CDDP保护剂的保护剂 模型 将通过听性脑干反应评估耳毒性 阈值，耳蜗毛细胞的扫描电子显微镜（SEM） 血管纹透射电镜观察。 体重减轻，作为一般健康的衡量标准，也将进行评估。 因为肾毒性是第二个最常见的剂量限制因素 对于CDDP化疗，由于许多保护剂 对耳毒性和肾毒性有效，我们还将测量 每只动物的肌酐。 然而，这笔赠款的主要目的是 是开发耳保护剂和预防听力损失。 所包括的试剂的类别是：含硫化合物、抗- 氧化剂/自由基清除剂和类固醇。 每一个被选中的代理人 符合以下标准：有文件证明该代理人是 保护CDDP耳毒性和/或肾毒性，无 其他CDDP毒性加重，且CDDP抗- 肿瘤功效或无抑制抗肿瘤功效的机制。所有 试剂还必须适用于人类。 对照组，每组11只动物，将包括治疗组（16 mg/kg CDDP）和未处理（等体积盐水）对照组。 对于除了CDDP之外还接受保护剂的动物，首先 将获得剂量反应曲线（每个水平5只动物），以确定 每种药剂的最佳剂量水平。 然后每个内部的代理人 将比较药剂类别（最低每组11只动物 提供最佳保护的剂量水平。 实验时间表如下：第1年：含硫 第二年：抗氧化剂/自由基清除剂第三年： 类固醇. 在第四和第五年的赠款，最好的代理人的每一个 上述实验将以各种组合进行测试。 最好的 将根据耳保护的主要标准选择药物， 肾保护的次要标准，因为目前耳毒性是 原发性和肾毒性继发性剂量限制性毒性 CDDP。 希望这些实验能让我们发展得更好 接受CDDP化疗的患者的方案， 接受足够高剂量的CDDP治疗他们的癌症， 听力损失的影响。