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: 6797384
• 负责人: A ROBERT ROBERT NEURATH
• 金额: $ 99.75万
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797384
• 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）：邻苯二甲酸醋酸纤维素（CAP）具有 用作肠溶膜包衣材料或基质粘合剂 片剂和胶囊。广泛应用于口服药品和 通常被认为是无毒材料，没有不良影响。这是 包含在 FDA 非活性成分指南中并被列入药典 国际上。 CAP 大量供应且价格低廉。它 已证明 CAP：1) 对 HIV-1 和多种病毒具有抗病毒活性 疱疹病毒（HSV）； 2) 当以微粉化形式配制时 a) 体外灭活HIV-1、HSV-1。 HSV-2、巨细胞病毒、奈瑟菌 淋病、阴道毛滴虫、杜克雷嗜血杆菌和衣原体 沙眼衣原体; b) 与细菌性阴道病相关的灭活细菌； c) 保护小鼠免受 HSV-2 阴道感染； d) 受保护的 4/6 恒河猴 猴子阴道感染猿猴免疫缺陷病毒（SIVmac251）。 这些结果证实了 CAP 作为杀微生物剂的前景 预防 HIV-1 的性传播。其他临床前研究是 需要进一步支持这一承诺。这包括：（项目一）：预防 原代 HIV-1 分离株和细胞中不同 HIV-1 进化枝的感染率 体外培养以及人类宫颈和直肠组织模型中的培养； （项目 II): a) 通过阴道镜检查评估 CAP 在猴模型中的安全性 促炎趋化因子和细胞因子的测量； b) 评估 使用化学标记的猴子阴道施用后 CAP 分布 CAP 和阴道镜检查以及磁共振成像 (MRI)； c) 评估 CAP 对致病性 X4 和 R5 特异性感染的功效 分别是猿猴/人类嵌合HIV病毒（SHIV）； （项目三）： 暴露后促炎趋化因子和细胞因子的测量 宫颈和阴道上皮细胞培养至 CAP； （项目四）：研究 CAP 与人类精子相互作用以评估杀精/避孕效果 CAP 及其配方的潜力。从提议中获得的信息 由统一和质量控制协调和提供的研究 核心 A、B 的配方预计将有助于设计 I、II 和 III 期人体临床试验。 CAP 符合建议的标准 理想的杀菌剂：在精液和血液存在下具有活性；活动 预防 HIV-1 以外的性传播感染；避孕套 相容性，可忽略不计的全身吸收（由于其大分子 质量和微粉化状态）；缺乏颜色和难闻的味道；且成本低。 拟议的研究预计将有助于将这一理想变为现实。

项目成果

Guiding the vaginal microbicide trials with biomarkers of inflammation

• DOI: 10.1097/00126334-200410013-00010
• 发表时间: 2004-10-01
• 期刊: JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
• 影响因子: 3.6
• 作者: Fichorova, RN

Anti-HIV-1 activity of poly(mandelic acid) derivatives.

• DOI: 10.1021/bm070221y
• 发表时间: 2007-10
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: Marty Ward;Bing Yu;V. Wyatt;Jelani Griffith;Tara L. Craft;A. Neurath;N. Strick;Yun-yao Li;D. Wertz;J. Pojman;A. Lowe

Safety and distribution of cellulose acetate 1,2-benzenedicarboxylate (CAP), a candidate anti-HIV microbicide in rhesus macaques.

醋酸纤维素 1,2-苯二甲酸 (CAP) 的安全性和分布，它是一种候选抗 HIV 杀菌剂，在恒河猴中使用。

• DOI: 10.1097/01.aids.0000185990.16477.47
• 发表时间: 2005
• 期刊: AIDS (London, England)
• 作者: Ratterree,Marion;Gettie,Agegnehu;Williams,Victoria;Malenbaum,Susan;Neurath,ARobert;Cheng-Mayer,Cecilia;Blanchard,James
• 通讯作者: Blanchard,James