MECHANISMS OF CHOLESTEROL GALLSTONE DISSOLUTION

我们提出的研究旨在提供一种系统的方法 以及对相关动力学因素的机械理解 与胆固醇结石溶解在胆汁中的物理 化学观点 特别值得注意的问题是 胆固醇-卵磷脂（C-L）中间相的重要性 胆固醇一水合物（ChM）的形成和分散 解散 C-L中间相形成/分散和胶束 胆固醇增溶被认为在 熊去氧胆酸治疗和熊去氧胆酸 酸/鹅去氧胆酸治疗，以及相对重要性 这两个过程将在一个范围内确定， 在我们的胆固醇治疗意义的条件 一水合物（“模型胆结石”）溶解研究。 我们实验室新开发的技术和概念将在 用于测定与胆固醇相关的平衡 分布在胶束和C-L中间相中，并确定 这些平衡与ChM动力学之间的关系 解散 ChM颗粒溶解速率和简单胶束混合 胶束共存的数据将获得和分析广泛的 胆盐和L浓度范围。 同时胶束 ChM溶解和C-L中间相（囊泡）形成将是 在这些胆汁盐-L系统中进行定量研究。 CHM 中间相开始后的溶解速率模式 形成将建立从长期溶解 实验 开发并验证了硅胶聚合物方法 最近在我们的实验室将被用来确定 胆固醇在胆盐-L溶液中的热力学活性 不饱和和相对于ChM过饱和。 胆固醇 将在各种固定胆汁中进行增溶实验 盐活性（即，通过透析确定的恒定NMBS 我们实验室开发的方法）和各种固定卵磷脂 系统中的浓度。 这些数据将用于 实际上，构建胶束溶液- C-L中间相 各种胆固醇活性和胆盐的图表 活动，其结果将用于分析 胶束溶解和C-L中间相形成的同时进行 动力学

Our proposed research is aimed at providing a systematic approach and a mechanistic understanding of the kinetic factors associated with cholesterol gallstone dissolution in bile from the physical chemical standpoint. The question receiving special attention is that of the importance of cholesterol-lecithin (C-L) mesophase formation and dispersion during cholesterol monohydrate (ChM) dissolution. C-L mesophase formation/dispersion and micellar cholesterol solubilization are both believed to be important during ursodeoxycholic acid therapy and in the combination ursodeoxycholic acid/chenodeoxycholic acid therapy, and the relative importances of these two processes will be determined over a range of conditions of therapeutic significance in our cholesterol monohydrate ("model gallstone") dissolution studies. Techniques and concepts newly developed in our laboratory will be utilized to determine the equilibria associated with cholesterol distributed in micelles and in the C-L mesophase and to determine the relationship between these equilibria and the kinetics of ChM dissolution. ChM pellet dissolution rates and simple micelle-mixed micelle coexistence data will be obtained and analyzed for wide ranges of bile salt and L concentrations. Simultaneous micellar ChM dissolution and C-L mesophase (vesicle) formation will be quantitatively studied in these bile salts-L systems. ChM dissolution rate patterns beyond the onset of the mesophase formation will be established form long term dissolution experiments. The silicone polymer method developed and validated recently in our laboratory will be employed to determine the cholesterol thermodynamic activity in the bile salt-L solutions unsaturated and supersaturated with respect to ChM. Cholesterol solubilization experiments will be conduced at various fixed bile salt activities (i.e., constant NMBS determined by the dialysis method developed in our laboratory) and various fixed lecithin concentrations in the system. These data will be used to construct, in effect, micellar solution - C-L mesophase phase diagrams at various cholesterol activities and bile salt activities, and the results will be employed in the analysis of the simultaneous micellar dissolution and C-L mesophase formation kinetics.