N,N-Dimethylacetamide Vaginal Self-nanoemulsifying Drug Delivery System for the Prevention or Preterm Birth

N,N-二甲基乙酰胺阴道自纳米乳化给药系统用于预防或早产

基本信息

批准号：
10620777
负责人：
Sandra Eve Reznik
金额：
$ 16.4万
依托单位：
ST. JOHN'S UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-11 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620777
关键词：
37 weeks gestation Acute Address Affect Atopobium vaginae Attenuated Birth Caproates Cells Cervix Uteri Clinical Clinical Trials Clinics and Hospitals Cognitive Collagen Communities Connective Tissue Country Creativeness Cytoplasm Data Dose Drug Delivery Systems Drug Formulations Excipients Extracellular Matrix FDA approved Family Fetus Formulation Funding Genetic Transcription Goals Health Personnel Health Professional Human Hydroxyprogesterone I Kappa B-Alpha Immune Impaired cognition Inflammation Inflammatory Inflammatory Response Investigation Knowledge Laboratories Leukocytes Life Longevity Macrophage Matrix Metalloproteinases Mediating Microscopic Modeling Molecular Morbidity - disease rate Mus N-Dimethylacetamide N NF-kappa B Neonatal Mortality Nuclear Translocation Pathologist Patients Perinatal Perinatal mortality demographics Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phenotype Placebos Population Population Heterogeneity Pre-Clinical Model Premature Birth Preparation Prevention Process Public Health Research Personnel Resources Risk Safety Signaling Molecule Societies Solvents Spontaneous abortion Structure Students Talents Teratogenic effects Teratogens Testing Tissues Toxic effect Training Translational Research Underserved Population United States Food and Drug Administration Uterus Vagina Work World Health Organization biomedical scientist care costs collagenase crosslink cytokine design drug development experience extracellular intraperitoneal mortality mouse model multicatalytic endopeptidase complex multidisciplinary nanoformulation neurobehavioral test nonhuman primate novel novel strategies p65 pre-clinical premature prevent pup research and development risk minimization skills small molecule systemic toxicity transcription factor trophoblast ubiquitin ligase

项目摘要

ABSTRACT Based on World Health Organization estimates, the annual rate of preterm birth (PTB) is greater than 10% in the majority of countries. Premature birth before 37 completed weeks of gestation is the leading cause of mortality in the first year of life and is associated with morbidity that has life-long cognitive consequences. Acute and lifespan care costs associated with preterm births have broad and sustained effects on families and are enormously expensive for society. Causes of PTB are multifactorial, but the single most common cause of PTB is inflammation. Sadly, there is currently no United States Food and Drug Administration approved drug for the prevention of PTB. One of the hurdles in translational research and drug development in this field is the risk of drug related toxicity affecting the fetus. Several years ago, we made the fortuitous discovery that the safe pharmaceutical solvent, N,N-dimethylacetamide (DMA), prevents PTB and rescues pups from spontaneous abortion in our mouse model. Further studies in our laboratory revealed that DMA suppresses nuclear translocation and activation of nuclear factor kappa B (NF-kB), a transcription factor that regulates immune cell-mediated inflammation. In addition, we have shown that DMA attenuates cytokine secretion from cultured human trophoblasts and from human placental explants. Recently, our laboratory has teamed up with our collaborator’s to develop a vaginal (pv) self-nanoemulsifying drug delivery system (SNEDDS), which takes advantage of the first uterine/cervix pass effect to deliver drugs introduced into the vaginal cavity directly to the cervix and uterus, thereby minimizing risk of systemic toxicity and teratogenicity. The specific aims of the current project are to 1) test the effects of our pv DMA SNEDDS on histomorphology and inflammatory responses in the cervix in a murine model; 2) determine the molecular mechanism whereby DMA inhibits NF-kB transcriptional activity; and 3) compare toxic and teratogenic effects of a DMA SNEDDS to intraperitoneal administration of DMA. To accomplish these aims, we assembled a team of experts in PTB, cervix histomorphology and drug formulation. This multidisciplinary team will be working alongside our students, who come from a diverse and underserved population. Although PTB is a global public health problem, rates of PTB are significantly higher among underserved populations. The novelty of re-purposing a readily available and inexpensive common drug excipient to prevent PTB, together with designing a vaginal formulation that can be administered by patients remote from clinics or hospitals, addresses a critical gap in the field of drug development for PTB.

抽象的根据世界卫生组织的估计，每年的早产率（PTB）更高大多数国家在妊娠 37 周之前早产的比例超过 10%。是生命第一年死亡的主要原因，并且与以下疾病的发病率相关：与早产相关的终身认知后果。对家庭产生广泛而持久的影响，对社会来说代价高昂。 PTB 的发生是多因素的，但遗憾的是，最常见的 PTB 原因是炎症。目前尚无美国食品和药物管理局批准的药物预防 PTB 是转化研究和药物开发的障碍之一。几年前，我们提出了与药物相关的毒性影响胎儿的风险。偶然发现安全的药物溶剂 N,N-二甲基乙酰胺 (DMA) 可防止在我们的小鼠模型中，PTB 可以挽救自然流产的幼崽。实验室揭示DMA抑制核转位和核因子激活 kappa B (NF-kB)，一种调节免疫细胞介导的炎症的转录因子。此外，我们还发现 DMA 会减弱培养人细胞因子的分泌最近，我们的实验室与我们合作。合作者开发阴道（pv）自纳米乳化药物输送系统（SNEDDS），它利用第一次子宫/子宫颈通过效应将药物输送到子宫内阴道腔直接到达子宫颈和子宫，从而最大限度地减少全身毒性的风险当前项目的具体目标是 1) 测试我们的光伏 DMA 的效果。 SNEDDS 对小鼠模型宫颈组织形态学和炎症反应的影响 2) 确定 DMA 抑制 NF-kB 转录活性的分子机制；3) 比较 DMA SNEDDS 与腹膜内给药的毒性和致畸作用为了实现这些目标，我们组建了一个 PTB、宫颈组织形态学专家团队。这个多学科团队将与我们的学生一起工作，他们尽管 PTB 是一个全球性公共卫生问题，在服务不足的人群中，PTB 发生率明显更高。一种现成且廉价的预防 PTB 的常用药物辅料，以及设计一种阴道制剂，可供患者在远程诊所或医院，填补了 PTB 药物开发领域的一个关键空白。