High-potency nitro antimicrobials for topical treatment of trichomoniasis
用于局部治疗滴虫病的高效硝基抗菌剂
基本信息
- 批准号:9049219
- 负责人:
- 金额:$ 35.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-02-04 至 2018-01-31
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAmericanAnimalsBackBiological TestingCase StudyChromatographyClinicalDataDevelopmentDisease OutcomeDoseDrug resistanceEvaluationFDA approvedFormulationGenitourinary systemHIVHeterocyclic CompoundsIn VitroIncidenceInfectionLeadLibrariesMalignant neoplasm of cervix uteriMalignant neoplasm of prostateMammalian CellMetronidazoleMetronidazole resistanceModificationNitro CompoundsOralOral AdministrationParasitesPatientsPharmaceutical PreparationsPhasePopulationPrevalencePropertyRefractoryReportingResistanceResistance developmentRiskRouteSamplingSeveritiesSexually Transmitted DiseasesStructure-Activity RelationshipSystemic TherapyTestingTinidazoleTopical AntibioticTopical applicationToxic effectTreatment FailureTrichomonas InfectionsTrichomonas vaginalisVaginaWorkabsorptionadverse pregnancy outcomeantimicrobialbasecombatcytotoxicitydensitydesigngenotoxicityin vitro activityin vitro testingin vivoinsightmouse modelnext generationnovelnovel therapeuticspathogenpre-clinicalpublic health relevanceresistant strainsuccesstherapy resistanttransmission process
项目摘要
DESCRIPTION (provided by applicant): Trichomonas vaginalis is the causative agent of the most common, non-viral sexually-transmitted infection with ~250 million new cases reported annually in the world and 5-7 million cases in the U.S. In addition to infections of the urogenital
tract, trichomoniasis increases the risk of adverse pregnancy outcomes and HIV transmission, and increases the incidence and severity of cervical and prostate cancers. Only two drugs are FDA-approved for the treatment of trichomoniasis, the nitro-heterocyclic compounds metronidazole (Mz) and tinidazole. Oral dosing leads to clinical and microbiological cure in the majority of cases, but treatment failures occur in a significant fraction of patients (up to 17%), with reports of increasing resistance in the U.S. High oral Mz or tinidazole doses in combination with topical treatment of the same drug(s) have been used with success for Mz-refractory vaginal trichomoniasis, whereas topical Mz treatment alone is only modestly effective and so is not recommended. While topical treatment is possible in principle, as shown in murine models, and would be attractive because low systemic absorption is likely to reduce systemic adverse effects compared to oral formulations, current drugs are not sufficiently potent for this preferred
administration route. Given the prevalence of trichomoniasis, its association with multiple disease outcomes, and the increase in drug-resistant strains (as well as the potential for more resistance), development of new antimicrobials against trichomoniasis is an urgent need. Our preliminary studies of >1,100 newly synthesized nitro compounds provide compelling evidence that novel nitro drugs can be developed with marked improvements in potency and the ability to completely overcome existing drug resistance. Such "next-generation" nitro drugs have the distinct advantage that this antimicrobial class, contrary to any other compound class, is already established to be effective and safe against trichomoniasis. The increased potency of our novel compounds should allow development of a topical treatment. Therefore, the project has the overall objective to develop a new lead nitro compound for the topical treatment of Mz-sensitive and Mz-resistant trichomoniasis. Based on our prior data, we have selected several of the most promising structural domains, and will now perform focused structural explorations within these domains. The new derivatives will be tested for activity and potency against Mz-sensitive and Mz- resistant T. vaginalis in vitro, for cytotoxicity and genotoxicity in mammalian cells in vitro,
and for efficacy in a murine model of vaginal trichomoniasis in vivo. The comprehensive bioactivity and toxicity data to be generated in this project will be used to select two non-toxic compounds with the best combination of high potency and ability to overcome resistance in vitro, and good efficacy in vivo as lead and back-up for subsequent preclinical development of a novel high-potency compound for the topical treatment of trichomoniasis in phase II of the project.
描述(由申请人提供):阴道毛滴虫是最常见的非病毒性传播感染的病原体,世界上每年报告约2.5亿例新病例,美国有5-7百万例。
阴道毛滴虫病增加了不良妊娠结局和艾滋病毒传播的风险,并增加了宫颈癌和前列腺癌的发病率和严重程度。只有两种药物被FDA批准用于治疗滴虫病,硝基杂环化合物甲硝唑(Mz)和替硝唑。口服给药在大多数情况下导致临床和微生物学治愈,但在相当一部分患者中发生治疗失败(高达17%),在美国报告耐药性增加。高口服Mz或替硝唑剂量联合相同药物的局部治疗已成功用于Mz难治性阴道滴虫病,而单独的局部Mz治疗仅适度有效,因此不推荐。虽然局部治疗原则上是可能的,如在鼠模型中所示,并且由于与口服制剂相比,低全身吸收可能减少全身不良反应,因此是有吸引力的,但是目前的药物对于这种优选的治疗并不足够有效。
给药途径。考虑到滴虫病的流行,其与多种疾病结局的相关性,以及耐药菌株的增加(以及更多耐药性的可能性),迫切需要开发新的抗滴虫病抗生素。我们对> 1,100种新合成的硝基化合物进行的初步研究提供了令人信服的证据,表明可以开发出具有显着改善效力和完全克服现有耐药性的能力的新型硝基药物。这种“下一代”硝基药物具有明显的优势,即与任何其他化合物类别相反,这种抗微生物类别已经被确定为对滴虫病有效和安全。我们的新化合物的增加的效力应该允许开发局部治疗。因此,该项目的总体目标是开发一种新的硝基先导化合物,用于局部治疗Mz敏感和Mz耐药的滴虫病。根据我们以前的数据,我们选择了几个最有前途的结构域,现在将在这些域中进行重点结构探索。将测试新衍生物对Mz敏感和Mz抗性T的活性和效力。体外迷走神经毒性,体外哺乳动物细胞的细胞毒性和遗传毒性,
以及在阴道毛滴虫病小鼠模型中的体内功效。本项目中产生的全面生物活性和毒性数据将用于选择两种无毒化合物,其具有高效力和体外克服耐药性能力的最佳组合,以及良好的体内疗效,作为后续临床前开发的先导和后备,用于项目II期局部治疗滴虫病的新型高效化合物。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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