Buckheit Karen W, Furlan-Freguia Christian, Ham Anthony S, Buckheit Robert W
ImQuest BioSciences, Inc. 7340 Executive Way, Suite R, Frederick, Maryland USA.
Curr Top Med Chem. 2016;16(10):1118-34. doi: 10.2174/1568026615666150901113939.
In the absence of an approved and effective vaccine, topical microbicides have become the strategy of choice to provide women with the ability to prevent the sexual transmission of HIV. Topical microbicides are chemical and physical agents specifically developed and formulated for use in either the vaginal or rectal environment to prevent the sexual transmission of infectious organisms. Although a microbicide product will have many of the same properties as other anti-infective therapeutic agents, the microbicide development pathway has significant differences which reflect the complex biological environment in which the products must act. These challenges to the development of an effective microbicide are reflected in the recently released FDA Guidance document which defines the microbicide development algorithm and includes the evaluation of preclinical efficacy and toxicity, and safety and toxicology, and indicates the necessity of testing of the active pharmaceutical product as well as an optimal formulation for delivery of the microbicide product. The microbicide development algorithm requires evaluation of the potential microbicidal agent and final formulated product in assays which mimic the microenvironment of the vagina and rectum during the sexual transmission of HIV, including the evaluation of activity and cytotoxicity in the appropriate biological matrices, toxicity testing against normal vaginal flora and at standard vaginal pH, testing in ectocervical and colorectal explant tissue, and irritation studies to vaginal, rectal and penile tissue. Herein, we discuss currently accepted practices required for the development of a successful microbicide product which will prevent virus transmission in the vaginal and rectal vaults.
在缺乏经批准的有效疫苗的情况下，局部用杀微生物剂已成为使女性具备预防艾滋病毒性传播能力的首选策略。局部用杀微生物剂是专门开发和配制用于阴道或直肠环境以预防性传播感染性生物体的化学和物理制剂。尽管一种杀微生物剂产品会具有许多与其他抗感染治疗剂相同的特性，但杀微生物剂的研发途径存在显著差异，这反映了产品必须发挥作用的复杂生物环境。这些有效杀微生物剂研发面临的挑战在最近发布的美国食品药品监督管理局（FDA）指南文件中有所体现，该文件定义了杀微生物剂研发流程，包括临床前疗效和毒性评估、安全性和毒理学评估，并指出了测试活性药物产品以及杀微生物剂产品最佳给药制剂的必要性。杀微生物剂研发流程要求在模拟艾滋病毒性传播过程中阴道和直肠微环境的试验中评估潜在的杀微生物剂和最终配制产品，包括在适当生物基质中评估活性和细胞毒性、针对正常阴道菌群和标准阴道pH值进行毒性测试、在外宫颈和结肠直肠外植体组织中进行测试以及对阴道、直肠和阴茎组织进行刺激性研究。在此，我们讨论成功研发一种能预防阴道和直肠穹窿部病毒传播的杀微生物剂产品所需的当前公认做法。
