Validation of a Human In Vitro Vaginal Irritation Test

人体体外阴道刺激试验的验证

• 批准号: 7937022
• 负责人: Seyoum Ayehunie
• 金额: $ 49.19万
• 依托单位: MATTEK CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-16 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937022
• 关键词: Acquired Immunodeficiency Syndrome; Adolescent; Animal Experimentation; Animal Model; Animals; Biological Assay; Biological Markers; Blinded; C 31G; Caring; Cells; Cervix Uteri; Chemicals; Chlamydia trachomatis; Chronic; Contracts; Cyanovirin-N; Data; Dendritic Cells; Development; District of Columbia; Dose; Drug Formulations; Economics; Enhancers; Epidemic; Epithelial; Epithelium; Evaluation; Excipients; Exposure to; Family suidae; Gel; Gender; HIV; HIV-1; Human; In Vitro; Industry; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Irritants; Laboratories; Laboratory Animals; Local Microbicides; Macaca; Macaca mulatta; Materials Testing; Measures; Methodology; Methods; Modeling; Monitor; Mucositis; Mus; NF-kappa B; National Research Council; Nonoxynol 9; Oryctolagus cuniculus; Pathway interactions; Pattern; Pharmacologic Substance; Phase; Predisposition; Protocols documentation; Public Health; Reproducibility; Research; Retroviridae; Rivers; Running; SIV; Safety; Screening procedure; Sexuality; Sexually Transmitted Diseases; Site; Spermatocidal Agents; Structure; Surrogate Markers; System; Test Result; Testing; Therapeutic Agents; Time; Tissue Model; Tissue Viability; Tissues; Topical application; Toxicity Tests; Toxicology; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Vagina; Validation; Viral; Vision; Woman; Women' s Health; antimicrobial drug; base; chemokine; comparative; contraceptive microbicide; cost; cost effective; cytokine; cytotoxicity; genital herpes; hazard; high throughput screening; in vitro Assay; in vitro testing; in vivo; irritation; lymph nodes; meetings; microbicide; mouse model; novel; nucleoside analog; phase 1 study; phase 2 study; pre-clinical; prevent; public health relevance; rectal; sex; slug; transmission process; vaginal microbicide; vaginal transmission; validation studies

DESCRIPTION (provided by applicant): During Phase 1 research, the effects of 6 model test materials on a highly differentiated vaginal- ectocervical (VEC) tissue model were studied. Effects on tissue viability, structure, barrier function, and inflammatory cytokine release were monitored. Many of the assays gave results which supported one another and increased confidence in the in vitro results. For instance, histological damage and cytokine release paralleled losses in tissue viability. In addition, decreases in barrier function were measured when tissue viability decreased although the data indicated that barrier function was a more sensitive endpoint (i.e. decreases in barrier function occurred at lower concentrations that did not decrease tissue viability). Importantly, the one material which was mildly irritating in the rabbit vaginal irritation test induced significant decreases in tissue viability and barrier function and increased inflammatory mediator release. In addition, an economic analysis showed the in vitro method to be a cost-effective alternative to the currently used rabbit vaginal irritation test methodology. During Phase 2, the utility of the in vitro assay system will be further expanded to predict vaginal irritation following chronic, repeat exposure. Using the endpoints developed in Phase 1, a prediction model will be developed to accurately assess the in vivo vaginal irritation of test materials and formulations. The method will be transferred to outside contract testing labs and a multi-lab GLP validation study will be performed. In addition, the short and long term reproducibility of the assay will be assessed, and a high throughput version of the assay method will be developed. PUBLIC HEALTH RELEVANCE: A predictive test system for assessing the vaginal irritation potential of chemicals and formulations will have far reaching application in industries involved in women's care products, microbicide, contraceptives, excipient development, and topical pharmaceutical products. Evaluation of vaginal irritation is important to minimize chemical hazards to millions of women. The proposed human reconstructed tissue based system will provide a sensitive and validated assay method for screening of chemicals/formulations with vaginal irritation potential. Furthermore, the assay method will be cost effective and reduce the use of laboratory animals for experimentation.

描述（由申请人提供）：在第一阶段研究期间，研究了 6 种模型测试材料对高度分化的阴道-宫颈（VEC）组织模型的影响。监测对组织活力、结构、屏障功能和炎症细胞因子释放的影响。许多测定给出的结果相互支​​持并增加了体外结果的可信度。例如，组织学损伤和细胞因子释放与组织活力的丧失同时发生。此外，当组织活力下降时，测量到屏障功能的下降，尽管数据表明屏障功能是一个更敏感的终点（即，屏障功能的下降发生在较低浓度下，不会降低组织活力）。重要的是，在兔子阴道刺激试验中具有轻微刺激性的一种材料会导致组织活力和屏障功能显着降低，并增加炎症介质的释放。此外，经济分析表明，体外方法是目前使用的兔阴道刺激测试方法的一种经济有效的替代方法。在第二阶段，体外测定系统的用途将进一步扩大，以预测长期重复接触后的阴道刺激。使用第一阶段开发的终点，将开发一个预测模型，以准确评估测试材料和制剂的体内阴道刺激性。该方法将转移到外部合同测试实验室，并进行多实验室 GLP 验证研究。此外，还将评估该测定的短期和长期再现性，并将开发该测定方法的高通量版本。公共健康相关性：用于评估化学品和制剂潜在阴道刺激性的预测测试系统将在妇女护理产品、杀菌剂、避孕药具、赋形剂开发和外用药品等行业中产生深远的应用。评估阴道刺激对于最大程度地减少对数百万女性的化学危害非常重要。所提出的基于人体重建组织的系统将为筛选具有阴道刺激潜力的化学品/制剂提供灵敏且经过验证的测定方法。此外，该测定方法将具有成本效益，并减少实验动物的使用。