A novel therapeutic approach for pressure ulcers

压疮的新治疗方法

基本信息

批准号：
8368259
负责人：
Edward Paul Monaghan
金额：
$ 14.83万
依托单位：
THESAN PHARMACEUTICALS INC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8368259
关键词：
Acids Acute Agonist Amidohydrolases Analgesics Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Area Atrophic Beds Biochemical Biological Biology Blood Circulation CD31 Antigens California Carrageenan Cells Chronic Connective Tissue Cysteine Data Decubitus ulcer Degenerative polyarthritis Dependence Development Drug Formulations Drug Kinetics Elderly Enzymes Epidermal Growth Factor Epithelial Epithelium Event FDA approved Fibrosis Funding Goals Granulation Tissue Growth Factor Healed Human Hydrolysis Immobilization Immune In Vitro Infection Inflammation Inflammatory Inflammatory Response Ischemia Knowledge Laboratories Lipids Lipopolysaccharides Measures Medical Medicine Modeling Morbidity - disease rate Mus Muscle relaxants Nuclear Receptors PECAM1 gene Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase Plasma Platelet-Derived Growth Factor Play Positioning Attribute Pre-Clinical Model Process Production Rattus Reaction Regulation Reperfusion Therapy Research Rheumatoid Arthritis Role Route Safety Signal Transduction Skin Skin Ulcer Small Business Innovation Research Grant Stimulus Surface Testing Tissues Tongue Topical application Translating Ulcer Universities Vascular Endothelial Growth Factors Work Wound Healing amidase cytokine drug efficacy effective therapy efficacy testing fighting healing in vivo inflammatory pain inhibitor/antagonist innovation irritation liquid chromatography mass spectrometry macrophage mast cell member migration mortality mouse model neutrophil novel novel therapeutic intervention open wound palliative palmidrol pre-clinical pressure prototype repaired research study wound

项目摘要

DESCRIPTION (provided by applicant): The management of chronic wounds, including bed sores in the elderly, remains a huge unmet medical need. Palmitoylethanolamide (PEA) is an endogenous lipid-derived agonist of the nuclear receptor, PPAR-¿ (peroxisome-proliferator-activate receptor-¿), which is thought to play important roles in the regulation of inflammation and skin repair. Tissue PEA levels are substantially decreased in patients suffering from rheumatoid arthritis or osteoarthritis. Moreover, pro-inflammatory stimuli suppress PEA production in innate immune cells from rats and mice, suggesting that endogenous PEA might serve as a stop signal for inflammation. The biological actions of PEA are terminated by the enzyme N-acylethanolamine-hydrolyzing acid amidase (NAAA), which is highly expressed in macrophages. To explore the role of PEA in the regulation of inflammatory pain, the lab of Daniele Piomelli at the University of California, Irvine, has developed the first class of potent NAAA inhibitors and showed that these compounds increase PEA levels and reduce inflammatory responses in vitro and in vivo. A new member of this class, called ARN077, was recently shown to suppress inflammatory responses in the skin and accelerate wound healing in mice. These results support the hypothesis that NAAA inhibitors such as ARN077 might offer an innovative target to treat bed sores and other chronic wounds. Our application has two primary goals aimed at testing this hypothesis: (1) Characterize the effects of ARN077 in preclinical models of wound healing. We will characterize, both at histological and biochemical level, the effects of ARN077 in a mouse model of open wound healing and a rat model of pressure-induced skin ulcers. (2) Evaluate the pharmacokinetic and safety profile of ARN077. Preliminary experiments have shown that ARN077 is chemically stable in FDA-approved topical formulations and highly effective when administered as a topical drug, but is rapidly hydrolyzed in plasma. We will use liquid chromatography/mass spectrometry to determine the pharmacokinetic profile of ARN077 following acute or prolonged topical administration in mice. In addition, we will test whether prolonged treatment with ARN077 might cause irritation or other pathological alterations of the skin (e.g., atrophy). If the results of the studies outlined above support our hypothesis, we will apply for SBIR Phase 2 funding to continue the preclinical development of ARN077. PUBLIC HEALTH RELEVANCE: Current medicines do not adequately treat pressure ulcers (also called 'bed sores'), a common ailment associated with prolonged confinement to a bed. We recently discovered a new class of compounds that alleviate inflammation and accelerate wound healing in animals by targeting a newly identified enzyme called N-Acylethanolamide-hydrolyzing Acid Amidase (NAAA). Here, we propose to lay the groundwork needed to translate this research finding into a clinically useful treatment for bed sores in the elderly.

描述（由申请人提供）：慢性伤口（包括老年人的褥疮）的治疗仍然是一个巨大的未满足的医疗需求，棕榈酰乙醇酰胺（PEA）是核受体 PPAR-¿ 的内源性脂质衍生激动剂。（过氧化物酶体增殖物激活受体-¿），被认为在炎症调节和皮肤修复中发挥重要作用，患有类风湿性关节炎或骨关节炎的患者组织中的 PEA 水平显着降低，而且促炎刺激会抑制 PEA。大鼠和小鼠先天免疫细胞中的产生，表明内源性 PEA 可能作为炎症的停止信号，PEA 的生物作用被 N-酰基乙醇胺水解酸酰胺酶终止。 (NAAA) 在巨噬细胞中高度表达，为了探索 PEA 在调节炎症疼痛中的作用，加州大学欧文分校的 Daniele Piomelli 实验室开发了第一类有效的 NAAA 抑制剂，并表明这些抑制剂可以抑制炎症性疼痛。此类化合物的一种新成员，称为 ARN077，最近被证明可以抑制小鼠皮肤的炎症反应并加速伤口愈合。这些结果支持了 NAAA 的假设。 ARN077 等抑制剂可能提供治疗褥疮和其他慢性伤口的创新靶标，我们的应用有两个主要目标旨在检验这一假设：（1）表征 ARN077 在伤口愈合的临床前模型中的作用。在组织学和生化水平上，ARN077 对开放性伤口愈合小鼠模型和压力性皮肤溃疡大鼠模型的影响 (2) 评估 ARN077 的药代动力学和安全性。 ARN077。初步实验表明，ARN077 在 FDA 批准的外用制剂中化学稳定，作为外用药物给药时非常有效，但在血浆中会迅速水解，接下来我们将使用液相色谱/质谱法来确定 ARN077 的药代动力学特征。此外，我们将测试 ARN077 的长期治疗是否会引起皮肤刺激或其他病理改变。（例如，萎缩）。如果上述研究结果支持我们的假设，我们将申请 SBIR 第 2 期资助，以继续 ARN077 的临床前开发。公共健康相关性：目前的药物不能充分治疗压疮（也称为“褥疮”），这是一种与长期卧床有关的常见疾病。我们最近发现了一类新的化合物，可以通过以下方式减轻动物炎症并加速伤口愈合。在此，我们建议为将这一研究发现转化为临床上有用的卧床治疗方法奠定基础。老年人的疮口。