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 (CDDP) 是临床常用的最有效的耳毒素。 CDDP 引起的听力损失可能很严重，并且几乎总是 永恒的。 由于 CDDP 用于治疗更广泛的癌症，并且 随着剂量的增加，CDDP 引起的耳毒性也随之增加 临床重要性。 此外，CDDP 引起的耳毒性是目前最严重的。 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 大鼠体内各类别 CDDP 保护剂的保护剂 模型。 耳毒性将通过听觉脑干反应进行评估 阈值，耳蜗毛细胞扫描电子显微镜 (SEM) 以及血管纹的透射电子显微镜（TEM）。 作为衡量总体健康状况的指标，体重减轻也将得到评估。 因为肾毒性是第二个最常见的剂量限制因素 用于 CDDP 化疗，并且因为许多保护剂 对耳毒性和肾毒性均有效，我们还将测量 每只动物的肌酐。 然而这笔赠款的主要目的 是开发耳保护剂并预防听力损失。 包括的试剂类别有：含硫化合物、抗- 氧化剂/自由基清除剂和类固醇。 各代理选定 符合以下标准： 有文件证明该代理人是 预防 CDDP 耳毒性和/或肾毒性，无 加剧其他 CDDP 毒性，并且不抑制 CDDP 抗- 肿瘤功效或无抑制抗肿瘤功效的机制。全部 药剂还必须适用于人类。 对照组，每组 11 只动物，将包括经过治疗的（16 mg/kg CDDP）和未处理的（等体积的盐水）对照组。 对于除 CDDP 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 每种药物的最佳剂量水平。 然后每个内的代理 将比较试剂类别（每组 11 只动物，最低 提供最佳保护的剂量水平。 实验安排如下： 第 1 年：含硫 化合物 第 2 年：抗氧化剂/自由基清除剂 第 3 年： 类固醇。 在资助的第四年和第五年，每个项目的最佳代理人 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和 肾保护的次要标准，因为目前耳毒性是 主要毒性和肾毒性 次要剂量限制毒性 CDDP。 希望这些实验能让我们更好的发展 接受 CDDP 化疗的患者的方案，以便他们可以 接受足够高的 CDDP 剂量以治愈癌症，无需接受侧面治疗 听力损失的影响。