基础胰岛素类似物的工程可预测性和延长性:地特米胰岛素的药理学。

P Kurtzhals
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引用次数: 123

摘要

皮下给药后人体胰岛素制剂的吸收特性不佳,这促使胰岛素类似物的开发更适合于治疗糖尿病。一个特别的挑战是设计长效药物,使其在每次注射时不会产生过度变化的反应。最近一种成功的方法是将胰岛素分子与脂肪酸酰基化,从而实现可逆的白蛋白结合。这种类型的第一种临床可用药物是地特米胰岛素。药理学研究已经证实,这一原理主要通过延缓吸收而有效地延长作用。地特胰岛素在瓶中和注射后的溶解度,以及血浆白蛋白结合影响的重要缓冲机制,解释了重复的异糖钳研究中观察到的地特胰岛素与其他基础胰岛素产品相比,药效学反应的受试者变异性显著降低的原因。由于在治疗浓度下,白蛋白结合位点与胰岛素分子的比例极高,没有确定与白蛋白结合有关的安全性考虑。detemir胰岛素分子保留了天然人胰岛素的分子药理学特性,包括代谢和有丝分裂潜能之间的生理平衡。因此,地特米胰岛素在临床环境中提供了改善耐受性:有效性比的希望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir.

The suboptimal nature of the absorption profiles of human insulin formulations following subcutaneous administration has prompted the development of insulin analogues better suited for therapeutic use in diabetes mellitus. A particular challenge has been to engineer long-acting agents that do not produce unduly variable responses from one injection to another. One recent approach that has met with success has been to acylate, the insulin molecule with a fatty acid, thereby enabling reversible albumin binding. The first clinically available agent of this type is insulin detemir. Pharmacological studies have established that this principle is effective in prolonging action, primarily by retarding absorption. The solubility of insulin detemir in the vial and after injection and an important buffering mechanism effected by plasma albumin binding explain a significant decrease in within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. Owing to the extremely high ratio of albumin-binding sites to insulin detemir molecules at therapeutic concentrations, no safety considerations have been identified pertaining to albumin binding. The insulin detemir molecule retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Thus, insulin detemir offers the promise of an improved tolerability:efficacy ratio in the clinical setting.

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