PRODRUG BASED METHODS FOR TOPICAL DELIVERY OF ARA-A

这项研究的目的是发展一种系统的方法 涉及基于前药的局部治疗的设计和优化。 前药 抗病毒剂，9-β-D-阿拉伯呋喃糖基腺嘌呤（阿糖腺苷， ara-A），通过基于以下的新方法进行研究： 物理化学的概念和技术， 各种物理和生物化学过程影响交付的 将药物的活性形式转移到靶位点。 转运和代谢 旨在确定和/或预测靶部位的研究 阿糖腺苷种类的浓度对于各种最近的 将进行合成阿糖腺苷前药。 这些研究将 包括无毛老鼠皮肤和阴道膜的实验 的豚鼠。 数据分析将涉及使用最近的 开发了物理化学方法来处理相对复杂的 同时扩散和酶促反应的问题 生物膜和组织中的多组分系统。 此外，本发明还 将用无毛小鼠和 豚鼠测定稳态靶组织物质浓度 不同阿糖胞苷种类的谱和血液水平 当施用阿糖腺苷及其前药时的前药递送速率 局部给药和全身给药。 上述数据将与以下结果进行比较： 关于阿糖胞苷-A前体药物在肿瘤中的功效的通量/响应研究 单纯疱疹病毒（HSV）1型皮肤感染的局部治疗 在无毛小鼠和HSV 2型生殖器局部治疗中 感染豚鼠。 这些研究的结果如下： 预期：（1）类似物效应（前药）之间的差异 本身具有内在效应）和前药效应（前药起作用 作为活性物质的前体）;（2）来自感染动物研究 对于局部和全身给药， 活性部分必须被递送至其以实现其 （3）根据上述（1）和（2）， 前体药物/递送系统组合具有最佳治疗活性。

The objective of this research is the development of a systematic approach to the design and optimization of prodrug based topical therapy. Prodrugs of the antiviral agent, 9-Beta-D-arabinofuranosyladenine (vidarabine, ara-A), with be investigated by means of a novel approach based upon concepts and techniques of physical chemistry which permit factoring out the various physical and biochemical processes influencing the delivery of the active form of the drug to the target sites. Transport and metabolism studies aimed at determining and/or predicting the target site concentrations of the vidarabine species for a variety of recently synthesized vidarabine prodrugs will be conducted. The studies will include experiments with the hairless mouse skin and the vaginal membrane of the guinea pig. The data analysis will involve the use of the recently developed methods of physical chemistry for handling the relatively complex problem of simultaneous diffusion and enzymatic reactions for a multi-component system in biological membranes and tissues. Additionally, flux dependence studies will be conducted with hairless mice and with guinea pigs to determine steady-state target tissue species concentration profiles and blood levels of the various vidarabine species for different prodrug delivery rates when vidarabine and its prodrugs are administered topically and when they are administered systemically. The data provided from the above will be compared to the results of flux/response studies on the efficacy of the prodrugs of ara-A in the topical treatment of herpes simplex virus (HSV) type 1 cutaneous infections in hairless mice and in the topical treatment of HSV type 2 genital infections in guinea pigs. The following outcomes from these studies are expected: (1) the differentiation between analog effects (the prodrug itself having an intrinsic effect) and prodrug effects (the prodrug serving as a precursor to the active species); (2) from infected animal studies with both topical and systemic administration, the determination of the locale to which the active moiety must be delivered to achieve its activity; and (3) based on (1) and (2), above, the determination of prodrug/delivery system combinations with optimal therapeutic activity.