Novel carrageenan-based microbicides

描述(由申请人提供)：项目总监(同时也是 项目负责人[项目I])之前已经开发出卡拉胶 杀菌剂CarraGuardTM(PC-515)。卡拉胶属于硫酸盐类 多糖类化合物，其中许多已知具有抗病毒作用 属性。卡拉胶有着悠久的安全历史，它既是 活性成分和CalTaguard中的车辆目前正在FDA 批准的安全试验涉及400名使用该产品的女性，为期一年。在……里面 为提高卡拉胶对艾滋病毒的疗效，联合国艾滋病规划署 Director已经开发出两种改进的卡拉胶配方，已经显示出 提高体外抗HIV和抗单纯疱疹病毒2(HSV)活性 -2)在小鼠体内。一种修饰涉及将锌与卡拉胶结合，并 另一种是添加硫酸多糖和分散剂， 木素磺酸(LSA)。本计划项目的目标是 锌-卡拉胶和/或LSA-卡拉胶作为生物活性物质的研究 外用杀微生物剂(S)。项目主管建议分析 两种制剂对不同毒株及分支HIV的体外阻断作用 通过利用PBMC检测，以及他之前开发的一种检测 它使用的是来自人类宫颈的上皮细胞。方剂 也将在老鼠身上评估它们在预防阴道感染方面的有效性 以及单纯疱疹病毒2型的直肠感染，它们阻止艾滋病毒传播的能力， 以及从阴道穹隆运来的单核血细胞。请告诉我 在该计划的其他项目中提出以下建议：Howett博士将分析 阻断人阴道HIV感染的有效方剂 小鼠系统中的异种移植。波普博士将评估配方如何 树突状细胞在介导HIV传播中的作用以及 预防SIV在恒河猴阴道传播效果的检测 猕猴。阿纳佐多博士将检查其稳定性、毒性和 锌和LSA-卡拉胶的药代动力学。最后，卡茨博士将检查 该制剂的体外展开性和保留性。 人类。此外，将对配方进行评估(在提到的化验中 上图)，用于在存储期间保持活动。在第一次会议结束时 两年内，所有调查人员的调查结果将用于 优化最终配方的评估(S)。申请人 相信拟议的研究将导致临床前 一种安全、高效的新型杀微生物剂的研制 爱滋病毒。

DESCRIPTION (provided by applicant): The Program Director (who is also the Project Leader [PL] of Project I) has previously developed the carrageenan microbicide, CarraguardTM (PC-515). Carrageenan belongs to the sulfated polysaccharide class of compounds, many of which are known to have anti-viral properties. Carrageenan, which has a long history of safety, is both the active ingredient and the vehicle in CalTaguard that is currently in FDA approved safety trials involving 400 women with product use for one year. In an effort to increase the efficacy of carrageenan against HIV, the Program Director has developed two modified carrageenan formulations that have shown improved activity against HIV in vitro and against herpes simplex virus-2 (HSV -2) in mice. One modification involves binding zinc to carrageenan and the other is the addition of the sulfated polysaccharide and dispersing agent, lignosulfonic acid (LSA). This Program Project is directed toward investigating the potential of Zn-carrageenan and/or LSA-carrageenan as topical microbicide(s). The Program Director proposes to assay the activity of the two formulations in blocking different strains and clades of HIV in vitro by utilizing a PBMC assay, as well as an assay that he previously developed which employs epithelial cells derived from the human cervix. The formulations will also be evaluated in mice for their effectiveness in preventing vaginal and rectal infection by HSV -2, their ability to block the transport of HIV, and the trafficking of mononuclear blood cells from the vaginal vault. The PLs of other projects in this Program propose the following: Dr. Howett will assay the formulations for efficacy in blocking HIV infection of human vaginal xenografts in a mouse system. Dr. Pope will evaluate how formulations influence dendritic cell function in mediating transmission of HIV, as well as assaying for efficacy in preventing vaginal transmission of SIV in rhesus macaques. Dr. Anazodo will examine the stability, toxicity and pharmacokinetics of Zn-, and LSA-carrageenan. Lastly, Dr. Katz will examine the spreading and retention properties of the formulations in vitro and in humans. Additionally, formulations will be evaluated (in the assays mentioned above) for retaining activity during storage. At the conclusion of the first two years, the findings of all PLs Investigators will be used for the optimization of an evaluation for a final formulation(s). The applicant believes that the proposed research will result in the pre-clinical development of a safe, novel microbicide that is superior in efficacy against HIV.