TOPS-Ester: Pharmacokinetics and Imaging in Human Skin

TOPS-酯：人体皮肤的药代动力学和成像

• 批准号: 6692850
• 负责人: Carleton Hsia
• 金额: $ 10万
• 依托单位: SYNZYME TECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2004-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6692850
• 关键词: anions; chemical synthesis; clinical research; electron spin resonance spectroscopy; esterase; esters; hairless mouse; high performance liquid chromatography; human subject; hydrolysis; hydropathy; imaging /visualization /scanning; oxidation reduction reaction; pharmacokinetics; skin; skin pharmacology; succinates; technology /technique development

DESCRIPTION (provided by applicant): TOPS-ester is a topical drug selected for development for it's unique ability to compartmentalize within skin cells and express antioxidant activity that limits oxidant mediated pathologies including psoriasis, sunburn, skin aging and skin cancer. The objective of this proposal is to use a non-invasive electron paramagnetic resonance (EPR) spectroscopy and imaging technique to monitor TOPS-ester (i.e. diethyl 2,2,6,6-tetramethyl-1-oxyl-4-piperidene succinate, or DETOPS) in human skin for the purpose of guiding the prophylactic and therapeutic treatment of skin disease. The DETOPS ester is a paramagnetic molecule and hence can be conveniently studied using EPR spectroscopy. Based on our preliminary data, we propose that after DETOPS penetrates cells of the epidermis and dermis, the succinate-ester moiety of the molecule is hydrolyzed by intracellular esterases to succinate anions; thereby facilitating intracellular retention of negatively charged carboxylate derivatives of DETOPS in the skin. The specific aims are to demonstrate the feasibility of distinguishing the difference between DETOPS and Tempol in their temporal distribution in human skin. The EPR measurements will be performed using the newly developed topical EPR imaging instrumentation for humans at the Johns Hopkins University. The skin penetration, compartmentalization and metabolism of the DETOPS in the forearm skin of human volunteers will be investigated using spatially resolved pharmacokinetic imaging data. It is expected that this preliminary study will lead to the evaluation of the therapeutic potential of the DETOPS formulation for the prevention and treatment of a variety of skin pathophysiological disorders.

描述(申请人提供)：TOPS-ESTER是一种选择开发的外用药物，因为它具有独特的能力，可以在皮肤细胞内分隔，并表达抗氧化剂活性，限制氧化介导的病理，包括牛皮癣、晒伤、皮肤老化和皮肤癌。该方案的目的是利用非侵入性电子顺磁共振(EPR)波谱和成像技术监测人体皮肤中的TOPS-酯(即2，2，6，6-四甲基-1-氧基-4-哌啶琥珀酸二乙酯，简称DETOPS)，以指导皮肤病的预防和治疗。DETOPS酯是一种顺磁性分子，因此可以方便地用EPR光谱进行研究。根据我们的初步数据，我们认为DETOPS渗透到表皮和真皮细胞后，分子中的琥珀酸酯部分被细胞内酯酶水解为琥珀酸阴离子，从而促进DETOPS的带负电荷的羧酸盐衍生物在皮肤中滞留。具体目的是为了证明区分DETOPS和Tempols在人体皮肤中的时间分布差异的可行性。EPR测量将使用约翰·霍普金斯大学新开发的人体局部EPR成像仪器进行。将利用空间分辨药动学成像数据研究DETOPS在人体前臂皮肤中的渗透、分区和代谢。预计这项初步研究将导致对DETOPS制剂预防和治疗各种皮肤病理生理疾病的治疗潜力进行评估。