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，早产率（PTB）大于10％大多数国家。早产是生命第一年死亡的主要原因，并且与发病率包括终身认知挑战。与早产相关的急性和长期护理费用生日对家庭产生了巨大影响，对社会的影响非常昂贵。虽然PTB是一个多因素障碍，最常见的原因是炎症。可悲的是，目前没有食物，药物管理局批准了预防PTB的药物。努力开发药物疗法以延迟或预防PTB受到候选药物的低效率和潜在致致致造性的阻碍。一些几年前，我们做出了一个偶然的发现，即广泛使用的药物赋形剂N，N- 二甲基乙酰氨酰胺（DMA）可防止PTB并在我们的小鼠模型中拯救幼崽自发流产。我们实验室的进一步研究表明，DMA抑制了核易位和核的激活因子Kappa B（NF-B），一种调节免疫细胞介导的注射的转录因子。另外，我们已经表明，DMA减弱了培养的人滋养细胞和人类斑点的细胞因子分泌 epplants。最近，我们的实验室与我们的合作者合作开发阴道（PV）自我纳米乳化药物输送系统（SNEDDS），它利用第一个子宫/子宫颈通行效果将引入阴道腔引入子宫颈和子宫的药物将全身毒性和致畸性。父母赠款的主要目标是检验我们阴道的假设（PV）DMA负载的SNEDD会将有效浓度的DMA直接传递到子宫颈目标组织到防止PTB而不会引起致畸作用。该赠款提供的Cellcyte X Live Cell分析仪补充剂将使我们能够研究DMA负载的SNEDD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理中。这个特定的目的授予补充剂是1）测试DMA将M1促进M2巨噬细胞表型切换的假设 2）测试DMA对巨噬细胞吞噬功能的影响。 Cellcyte X Live Cell分析仪将是安装在PD/PI的实验室中，适合标准的细胞培养孵化器。年轻的调查员来从资源不足的PTB率很高的世界各地，随着它们发展成常规的使用训练有素的生物医学科学家。该提案将提供重要的信息，以使我们提升了解两个不同的DMA公式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公式的发展。

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）

Therapeutic Intervention of Neuroinflammatory Alzheimer Disease Model by Inhibition of Classical Complement Pathway with the Use of Anti-C1r Loaded Exosomes.

使用负载抗 C1r 的外泌体抑制经典补体途径对神经炎症性阿尔茨海默病模型进行治疗干预。

DOI：
10.21203/rs.3.rs-3399248/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Richards,Terjahna;Perron,JeanetteC;Patel,Ketan;Wurpel,John;Reznik,SandraE;Schanne,Francis
通讯作者：
Schanne,Francis

FDA-Approved Excipient N, N-Dimethylacetamide Attenuates Inflammatory Bowel Disease in In Vitro and In Vivo Models.

FDA 批准的赋形剂 N,N-二甲基乙酰胺可减轻体外和体内模型中的炎症性肠病。

DOI：
10.26502/fjhs.076
发表时间：
2022
期刊：
Fortune journal of health sciences
影响因子：
0
作者：
Koya,JagadishB;Shen,Tong;Lu,Geming;Gauthier,Alex;Mantell,Lin;AshbyJr,CharlesR;Reznik,SandraE
通讯作者：
Reznik,SandraE

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