VANADOCENES AS A NEW CLASS OF SPERMICIDAL DRUGS

Vanadocenes 作为一类新的杀精药物

基本信息

批准号：
7224806
负责人：
OSMOND J D'CRUZ
金额：
$ 28.77万
依托单位：
PARADIGM PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7224806
关键词：
Acquired Immunodeficiency Syndrome Adult Adverse effects Anti-Retroviral Agents Artificial Insemination Barrier Contraception Benzalkonium Chloride Biological Biological Markers Biology Biopsy Cells Cervical Class Classification Clinical Colposcopy Complement Complex Contraceptive Agents Contraceptive methods Control Groups Daily Data Detergents Development Dose Drug Formulations Electrochemistry Electron Spin Resonance Spectroscopy Embryo End Point Enzymes Epithelial Cells Evaluation Failure Family suidae Feline Immunodeficiency Virus Felis catus Fertility Fetal Development Fetal Viability Fetal Weight Fetus Flow Cytometry Funding Gel Gene Expression Goals Gynol II HIV Histocompatibility Histopathology Human IL8 gene Immune Immune Targeting Implant In Vitro Inflammation Inflammatory Inflammatory Response Institutes Interleukin-10 Interleukin-18 Interleukin-4 Interleukin-6 Irrigation Irritants Lead Legal patent Lesion Licensing Life Liquid substance Litter Size Maternal Health Measurement Measures Mediator of activation protein Modeling Molecular Molecular Profiling Monoclonal Antibodies Mucositis Mucous Membrane Mus Nonoxynol 9 Numbers Organ Organogenesis Oryctolagus cuniculus Partner in relationship Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Phase II Clinical Trials Pre-Clinical Model Pregnancy Probability Range Reaction Reproduction Safety Score Seminal fluid Sex Ratio Sexual Transmission Sexually Transmitted Diseases Skeletal system Small Business Funding Mechanisms Small Business Innovation Research Grant Sperm Motility Spermatocidal Agents Standards of Weights and Measures Subgroup Sus scrofa Testing Time Tissues Toxic effect Vagina Vaginal Spermicides Vanadium Viral Physiology Visceral WHI 07 Water Week Woman Work X-Ray Crystallography Zidovudine base bis(cyclopentadienyl)-N,N-diethyldithiocarbamato triflate salt complex IV contraceptive efficacy corpus luteum cytokine cytotoxic day design digital video recording extracellular fetal implantation improved in vivo in vivo Model indexing inorganic phosphate irritation metallocene microbicide novel pre-clinical preclinical study prevent prophylactic reproductive research study technology development

项目摘要

DESCRIPTION (provided by applicant): There is an urgent need, worldwide, for improved contraceptives, especially prophylactic contraceptives. Barrier methods are the only class of contraceptives that protects users against sexually transmitted diseases. However, currently available spermicidal contraceptives suffer from poor efficacy and/or have undesirable toxicity. In a systematic effort to identify non-toxic spermicides potentially capable of performing better and without the drawbacks of detergent-type spermicides, we have rationally designed and synthesized several disubstituted metallocene derivatives. We discovered bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes to have rapid, potent, and selective spermicidal activity. Under Phase I funding, we demonstrated: (i) in vivo contraceptive activity of VDDTC via a gel-microemulsion in rabbits and porcine models; (ii) confirmed the lack of mucosal inflammatory potential of VDDTC in mice, rabbits, and pigs; (iii) developed a physiologically relevant and sensitive porcine model for vaginal irritation; and (iv) discovered that VDDTC significantly enhanced the microbicide efficacy of the antiretroviral spermicide WHI- 07 in the feline immunodeficiency virus/cat model of AIDS. Under SBIR Phase II support, we will expand the utility of the porcine and rabbit models to test the in vivo contraceptive efficacy, mucosal safety as well as developmental toxicity studies of VDDTC. We will perform these efficacy and safety studies of VDDTC in combination with WHI-07. We hypothesize that the combination of these two active agents with different mechanisms of action will potentially improve efficacy and duration of dual-protection when compared with VDDTC alone while maintaining an adequate safety profile. The goals of Phase II study are (i) to expand the utility of porcine model for the in vivo contraceptive efficacy of VDDTC versus VDDTC plus WHI-07 gel microemulsion; (ii) to expand the utility of porcine vaginal irritation model for the preclinical evaluation of VDDTC and VDDTC plus WHI-07 by characterizing the extracellular, cellular, molecular and histological endpoints; and (iii) to assess the developmental toxicity potential of VDDTC in rabbits. The proposed Phase II work will complement and enhance the discovery and preclinical development of safe and effective prophylactic contraceptives at Paradigm Pharmaceuticals that may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing fertility control for women.

描述（由申请人提供）：全世界迫切需要改进的避孕药具，尤其是预防性避孕药具。屏障避孕法是唯一一种可以保护使用者免受性传播疾病侵害的避孕方法。然而，目前可用的杀精避孕药功效较差和/或具有不期望的毒性。为了系统地识别无毒杀精剂，其性能可能更好，并且没有洗涤剂型杀精剂的缺点，我们合理地设计和合成了几种二取代茂金属衍生物。我们发现钒 (IV) 或二茂钒的双环戊二烯基络合物具有快速、有效和选择性的杀精子活性。在第一阶段的资助下，我们证明了：（i）通过凝胶微乳液在兔子和猪模型中实现 VDDTC 的体内避孕活性； (ii) 证实 VDDTC 在小鼠、兔子和猪中缺乏粘膜炎症潜力； (iii) 开发了一种生理相关且敏感的阴道刺激猪模型； (iv) 发现 VDDTC 显着增强了抗逆转录病毒杀精剂 WHI-07 在艾滋病猫免疫缺陷病毒/猫模型中的杀微生物功效。在 SBIR II 期支持下，我们将扩大猪和兔模型的效用，以测试 VDDTC 的体内避孕功效、粘膜安全性以及发育毒性研究。我们将结合 WHI-07 进行 VDDTC 的这些功效和安全性研究。我们假设，与单独使用 VDDTC 相比，这两种具有不同作用机制的活性药物的组合可能会提高双重保护的功效和持续时间，同时保持足够的安全性。 II 期研究的目标是 (i) 扩大猪模型的效用，以验证 VDDTC 与 VDDTC 加 WHI-07 凝胶微乳的体内避孕功效； (ii) 通过表征细胞外、细胞、分子和组织学终点，扩大猪阴道刺激模型在 VDDTC 和 VDDTC 加 WHI-07 临床前评估中的效用； (iii) 评估 VDDTC 对兔子的潜在发育毒性。拟议的第二阶段工作将补充和加强 Paradigm Pharmaceuticals 安全有效的预防性避孕药的发现和临床前开发，这可能为预防艾滋病毒性传播同时为女性提供生育控制的新策略奠定基础。