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: 6608543
• 负责人: A ROBERT ROBERT NEURATH
• 金额: $ 111.48万
• 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/6608543
• 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.

描述（由申请人提供）：邻苯二甲酸纤维素（CAP）具有 被用作肠膜涂料材料或矩阵粘合剂 平板电脑和胶囊。它被广泛用于口服药品和 通常被视为无毒的材料，没有不利影响。这是 包括在FDA非活动成分指南中，并在Pharmacoeias中列出 国际。帽子大量可用，价格便宜。它 被证明CAP：1）对HIV-1具有抗病毒活性和几个 疱疹病毒（HSV）； 2）当以微粉化形式配制时a） 失活的体外HIV-1，HSV-1。 HSV-2，巨细胞病毒，奈瑟氏菌 Gonorrhoeae，Trichomonas Vaginalis，Heamophilus Ducreyi和衣原体 气管体； b）与细菌性阴道病有关的灭活细菌； c） 通过HSV-2保护小鼠免受阴道感染； d）受保护的4/6恒河 来自阴道感染的猴子感染了猿猴免疫缺陷病毒（SIVMAC251）。 这些结果已经确立了CAP作为杀菌剂的承诺 预防HIV-1的性传播。其他临床前研究是 需要进一步支持这一诺言。这包括：（项目I）：预防 原代HIV-1分离株和细胞中不同的HIV-1进化株感染 体外和人类宫颈和直肠组织模型的培养； （项目 ii）：a）通过阴道镜检查评估猴子模型中帽的安全性 促炎性趋化因子和细胞因子的测量； b）评估 阴道在猴子中使用化学标记的帽子分布 CAP和阴道镜检查以及磁共振成像（MRI）；和c）评估 CAP对病原X4和R5特异性感染感染的功效 邻氨酸/人类嵌合HIV病毒（SHIV）； （项目III）： 暴露后测量促炎性趋化因子和细胞因子 培养中的宫颈和阴道上皮细胞； （项目IV）：研究 关于帽帽的精子相互作用，以评估精子/避孕药 CAP及其配方的潜力。从提议中获得的信息 研究，由统一和质量控制的协调和提供 核心A，B的配方分别有望促进设计 第一阶段，II和III人类临床试验。帽子符合提议的标准 理想的菌心：精液和血液存在的活性；活动 反对HIV-1以外的性传播感染；避孕套 兼容性，可以忽略不计的全身吸收（由于其大的分子 质量和微粉状态）；缺乏颜色和不愉快的味道；和低成本。 拟议的研究有望帮助将这一理想转变为现实。