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：
10798724
负责人：
Sandra Eve Reznik
金额：
$ 6.71万
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/10798724
关键词：
Acute Affect Atopobium vaginae Attenuated Automobile Driving Birth Caproates Cell Culture Techniques Cells Cervical Cervix Uteri Clinical Clinical Trials Cognitive Collagen Communities Connective Tissue Country Development Disease Drug Delivery Systems Drug usage Excipients Family Formulation Genetic Transcription Goals Grant Health Personnel Health Professional Human Hydroxyprogesterone Immune Incubators Inflammation Inflammatory Intervention Knowledge Laboratories Leukocytes Life Link Long-Term Care Macrophage Matrix Metalloproteinases Mediating Morbidity - disease rate N-Dimethylacetamide N NF-kappa B Neonatal Mortality Nuclear Translocation Parents Pathogenesis Perinatal mortality demographics Phagocytes Phagocytosis Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phenotype Placebos Play Population Pre-Clinical Model Premature Birth Prevention Process Recommendation Research Personnel Resources Risk Role Safety Signaling Molecule Societies Solvents Spontaneous abortion Teratogenic effects Teratogens Testing Time Tissues Training Underserved Population United States United States Food and Drug Administration Uterus Vagina Work World Health Organization biomedical scientist care costs cell analyzer collagenase crosslink cytokine drug candidate drug development experimental study extracellular follow-up insight mortality mouse model parent grant premature prevent prophylactic pup risk minimization systemic toxicity transcription factor trophoblast

项目摘要

ABSTRACT The World Health Organization estimates that the annual rate of preterm birth (PTB) is greater than 10% in most countries. Premature birth is the leading cause of mortality in the first year of life and is associated with morbidity that includes life-long cognitive challenges. Acute and long-term care costs associated with preterm birth have far reaching effects on families and are enormously expensive for society. Although PTB is a multifactorial disorder, the single most common cause is inflammation. Sadly, there is currently no Food and Drug Administration approved drug for the prevention of PTB. Efforts to develop drug therapy to delay or prevent PTB have been hampered by the low efficacy and potential teratogenicity of candidate drugs. Several years ago, we made the fortuitous discovery that the widely used pharmaceutical excipient, 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-B), 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 major goal of the parent grant is to test the hypothesis that our vaginal (pv) DMA loaded SNEDDS will deliver efficacious concentrations of DMA directly to cervix target tissue to prevent PTB without causing teratogenic effects. The Cellcyte X live cell analyzer provided by this grant supplement will allow us to investigate how DMA loaded SNEDDS and neat DMA affect the function of cervical macrophages in the pathogenesis of inflammation driven preterm birth. The specific aims of this grant supplement are 1) to test the hypothesis that DMA promotes M1 to M2 macrophage phenotype switching and 2) to test the effect of DMA on macrophage phagocytic function. The Cellcyte X live cell analyzer will be housed in the PD/PI’s laboratory and fits into a standard cell culture incubator. Young investigators, who come from under-resourced parts of the world where rates of PTB are high, will use it routinely, as they develop into well-trained biomedical scientists. This proposal will provide important information that will sharpen our understanding of the effect of two different DMA formulations on cervical macrophages that play a key role in PTB and will help refine the development of the ideal DMA formulation for the prevention of PTB.

抽象的世界卫生组织估计，我国每年的早产率 (PTB) 超过 10% 在大多数国家，早产是婴儿出生后第一年死亡的主要原因。发病率，包括与早产相关的终身认知挑战。尽管 PTB 是一种生育行为，但出生对家庭有着深远的影响，并且对社会来说代价高昂。多因素疾病，最常见的原因是炎症，遗憾的是，目前没有食物和药物。药物管理局批准了用于预防 PTB 的药物，努力开发治疗方法以延迟或治疗。候选药物的低功效和潜在致畸性阻碍了预防 PTB 的发展。多年前，我们偶然发现广泛使用的药用辅料N,N- 在我们的小鼠模型中，二甲基乙酰胺 (DMA) 可预防 PTB 并挽救幼崽免于自然流产。我们实验室的进一步研究表明，DMA 抑制核转位和核激活 kappa B 因子 (NF-κB)，一种调节免疫细胞介导的炎症的转录因子。研究表明，DMA 可减弱培养的人滋养层细胞和人胎盘细胞的细胞因子分泌最近，我们的实验室与我们的合作者合作开发了一种阴道（pv）自体移植物。纳米乳化药物递送系统（SNEDDS），利用子宫/宫颈首过效应将引入阴道腔的药物直接输送到子宫颈和子宫，从而最大限度地减少风险全身毒性和致畸性家长资助的主要目标是检验我们的阴道的假设。 (pv) 加载 DMA 的 SNEDDS 将有效浓度的 DMA 直接输送至子宫颈目标组织，以本次资助提供的 Cellcyte X 活细胞分析仪可预防 PTB，且不会造成致畸作用。补充将使我们能够研究 DMA 加载的 SNEDDS 和整洁的 DMA 如何影响宫颈巨噬细胞在炎症驱动早产的发病机制中的具体目的。补助金补充是 1) 检验 DMA 促进 M1 到 M2 巨噬细胞表型转换的假设 2）使用Cellcyte X活细胞分析仪测试DMA对巨噬细胞吞噬功能的影响。安置在 PD/PI 的实验室中，适合前来的年轻研究人员。来自世界上 PTB 发病率高的资源贫乏地区的人，将常规使用它，因为他们发展成为训练有素的生物医学科学家将提供重要的信息来提高我们的能力。了解两种不同 DMA 制剂对宫颈巨噬细胞的影响，这些巨噬细胞在 PTB 并将有助于完善预防 PTB 的理想 DMA 配方的开发。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vaginal Nanoformulations for the Management of Preterm Birth.

用于治疗早产的阴道纳米制剂。

DOI：
发表时间：
2022-09-23
期刊：
影响因子：
5.4
作者：
Mir, Asad;Vartak, Richa V;Patel, Ketan;Yellon, Steven M;Reznik, Sandra E
通讯作者：
Reznik, Sandra E

The relationship between elastin cross linking and alveolar wall rupture in human pulmonary emphysema.

人肺气肿弹性蛋白交联与肺泡壁破裂的关系。

DOI：
发表时间：
2023-06-01
期刊：
影响因子：
0
作者：
Fagiola, Michael;Reznik, Sandra;Riaz, Muhammad;Qyang, Yibing;Lee, Seoyeon;Avella, Joseph;Turino, Gerard;Cantor, Jerome
通讯作者：
Cantor, Jerome

Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function.

棕榈酸通过增加 MRP1 表达和功能来阻碍绒毛外滋养层活性。