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（由申请人提供）：TOPS-ETER是一种用于发育的局部药物，用于其在皮肤细胞内分裂并表达抗氧化活性的独特能力，该活性限制了氧化剂介导的病理学，包括牛皮癣，晒伤，皮肤老化和皮肤癌。该提议的目的是使用非侵入性电子顺磁共振（EPR）光谱和成像技术来监测上层酯（即2,2,6,6,6-6,6-甲基-1-甲基-1-氧基-4-氧基-4-氧基-4-磷酸盐，或在人体皮肤中detops）在人类皮肤中的目的是诱导人类皮肤的治疗，以诱导性疾病和特定性治疗。 Detops酯是一种顺磁分子，因此可以使用EPR光谱进行方便研究。基于我们的初步数据，我们建议在渗透表皮和真皮细胞后，分子的琥珀酸酯部分被细胞内酯酶水解以琥珀酸盐。从而促进皮肤中的羧酸羧酸衍生物的细胞内保留。具体的目的是证明可行性是区分人类皮肤的时间分布中的抽吸与tempol之间的差异。 EPR测量将使用约翰霍普金斯大学的人类新开发的EPR成像仪器进行。将使用空间分辨的药代动力学成像数据研究，将研究人类志愿者前臂皮肤的皮肤渗透，隔室化和代谢。预计这项初步研究将导致对预防和治疗多种皮肤病理生理疾病的处理配方的治疗潜力的评估。