Anti-HIV Microbicide: Cellulose Acetate Phthalate (CAP)

抗 HIV 杀菌剂：邻苯二甲酸醋酸纤维素 (CAP)

• 批准号: 6443010
• 负责人: A ROBERT ROBERT NEURATH
• 金额: $ 98.89万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-26 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6443010
• 关键词: HIV infections; acetates; antiviral agents; cellulose; chemical structure function; drug screening /evaluation; phthalates; topical drug application

DESCRIPTION (provided by applicant): Cellulose acetate phthalate (CAP) has been used as an enteric film coating material or as a matrix binder for tablets and capsules. It is widely used in oral pharmaceutical products and is generally regarded as a nontoxic material free of adverse effects. It is included in the FDA Inactive Ingredients Guide and is listed in pharmacopoeias internationally. CAP is available in large quantities and is inexpensive. It was demonstrated that CAP: 1) has antiviral activity against HIV-1 and several herpesviruses (HSV); and 2) when formulated in a micronized form a) inactivated in vitro HIV-1, HSV-1. HSV-2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi and Chlamydia trachomatis; b) inactivated bacteria associated with bacterial vaginosis; c) protected mice against vaginal infection by HSV-2; and d) protected 4/6 rhesus monkeys from vaginal infection with simian immunodeficiency virus (SIVmac251). These results have established the promise of CAP as a microbicide for prevention of sexual transmission of HIV-1. Additional preclinical studies are needed to further support this promise. This includes: (Project I): Prevention of infection by primary HIV-1 isolates and distinct HIV-1 clades in cell cultures in vitro and in human cervical and rectal tissue models; (Project II): a) Assess the safety of CAP in a monkey model by colposcopic examinations and measurement of pro-inflammatory chemokines and cytokines; b) Assessment of CAP distribution after vaginal application in monkeys using chemically tagged CAP and colposcopy, and magnetic resonance imaging (MRI); and c) Evaluate the efficacy of CAP against infection with pathogenic X4- and R5-specific simian/human chimeric HIV viruses (SHIV), respectively; (Project III): Measurement of pro-inflammatory chemokines and cytokines after exposure of cervical and vaginal epithelial cells in culture to CAP; (Project IV): Studies on CAP-human sperm interactions to assess the spermicidal/contraceptive potential of CAP and its formulations. Information gained from the proposed studies, coordinated and supplied by uniform and quality controlled formulations by Cores A, B, respectively, is expected to facilitate the design of Phase I, II and III human clinical trials. CAP meets criteria proposed for an ideal microbicide: activity in presence of semen and blood; activity against sexually transmitted infections other than HIV-1; condom compatibility, negligible systemic absorption (due to its large, molecular mass and micronized state); lack of color and unpleasant taste; and low cost. The proposed research is expected to help transform this ideal into a reality.

说明(申请人提供)：邻苯二甲酸纤维素(CAP) 用作肠溶膜包衣材料或作为基质粘合剂 片剂和胶囊。它广泛应用于口腔医药产品和 通常被认为是一种无毒、无不良影响的物质。它是 包括在FDA非活性成分指南中，并列在药典中 在国际上。帽子有大量供应，而且价格不贵。它 证明CAP：1)具有抗HIV-1和几种 疱疹病毒(HSV)；和2)以微粉化形式配制时) 体外灭活HIV-1、HSV-1。单纯疱疹病毒2型、巨细胞病毒、奈瑟氏菌 淋病、阴道毛滴虫、杜热氏嗜血杆菌和衣原体 沙眼衣原体；b)与细菌性阴道病有关的灭活细菌；c) 保护小鼠免受HSV-2的阴道感染；和d)保护4/6的恒河猴 猴子阴道感染猴免疫缺陷病毒(SIVmac251)。 这些结果为CAP作为一种杀菌剂的前景奠定了基础 预防艾滋病毒-1的性传播。其他临床前研究包括 需要进一步支持这一承诺。这包括：(项目一)：预防 由HIV-1初级分离株和细胞内不同的HIV-1分支感染 体外培养和人类宫颈和直肠组织模型；(项目 二)：a)通过镜检查评估CAP在猴子模型中的安全性 以及促炎趋化因子和细胞因子的测定；b)评估 化学标记法在猴阴道给药后的帽子分布 帽和阴道镜检查以及核磁共振成像(MRI)；以及c)评估 CAP对致病性X4和R5特异性感染的疗效 猴/人嵌合艾滋病毒病毒(SIV)；(项目三)： 暴露后致炎趋化因子和细胞因子的检测 宫颈和阴道上皮细胞对CAP的培养；(项目IV)：研究 CAP与人精子相互作用评价杀精/避孕效果的研究 CAP及其制剂的潜力。从建议的 学习，统一协调，统一供应，质量控制 由岩芯A、B分别配制的配方有望促进设计 一期、二期和三期人体临床试验。上限符合建议的标准 一种理想的杀微生物剂：在精液和血液存在下的活性 预防艾滋病毒-1以外的性传播感染；避孕套 兼容性，可忽略的系统吸收(由于其大的分子 大批量和微粉化)；缺乏颜色和难吃的味道；以及低成本。 这项拟议的研究有望帮助将这一理想转变为现实。