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: 6526238
• 负责人: A ROBERT ROBERT NEURATH
• 金额: $ 109.6万
• 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/6526238
• 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）：邻苯二甲酸乙酸纤维素（CAP）具有 用作肠溶薄膜包衣材料或用作基质粘合剂， 片剂和胶囊。它广泛用于口服药物产品， 通常被认为是无副作用的无毒材料。是 包括在FDA非活性成分指南中，并列入药典 化国际大CAP可大量获得，并且价格低廉。它 已证明CAP：1）具有抗HIV-1的抗病毒活性， 疱疹病毒（HSV）;和2）当配制成微粒化形式时a） 体外灭活HIV-1、HSV-1。HSV-2、巨细胞病毒、奈瑟氏球菌 淋病、阴道毛滴虫、杜克雷嗜血杆菌和衣原体 沙眼; B）与细菌性阴道病相关的灭活细菌; c） 保护小鼠免受HSV-2的阴道感染;和d）保护4/6的恒河猴 猴阴道感染猴免疫缺陷病毒（SIVmac 251）。 这些结果确立了CAP作为杀微生物剂的前景， 预防HIV-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 感染的主要HIV-1分离株和细胞中不同的HIV-1进化枝 体外培养和人类宫颈和直肠组织模型;（项目 II）：a）通过阴道镜检查评估CAP在猴模型中的安全性 以及促炎趋化因子和细胞因子的测量; B）评估 使用化学标记的猴阴道应用后的CAP分布 CAP和阴道镜检查，以及磁共振成像（MRI）;以及c）评估 CAP抗致病性X4和R5特异性感染有效性 猴/人嵌合HIV病毒（SHIV）;（项目III）： 暴露后促炎趋化因子和细胞因子的测量 培养宫颈和阴道上皮细胞以进行CAP;（项目IV）：研究 CAP-人类精子相互作用，以评估杀精子/避孕 CAP及其制剂的潜力。从拟议的 研究，由统一和质量控制协调和提供 由核心A，B，分别配方，预计将促进设计 I、II和III期人体临床试验的结果。履约协助方案符合 理想的杀微生物剂：在精液和血液中的活性;活性 预防HIV-1以外的性传播感染;避孕套 相容性，可忽略的全身吸收（由于其大的，分子 质量和微粉化状态）;没有颜色和令人不快的味道;和低成本。 拟议的研究预计将有助于将这一理想转变为现实。