Ganjei J Kelly
RemeGenix, Inc., Rockville, MD 20850, USA.
Drug News Perspect. 2010 Nov;23(9):573-84. doi: 10.1358/dnp.2010.23.9.1507297.
This review evaluates past and present clinical trials, as well as the current preclinical drug candidates focused on treating Alzheimer's disease (AD), in order to better assess the trends in AD drug discovery in context with specific drug mechanisms. The author begins by presenting a summary of the results of over 160 clinical trials targeted at AD, of which 52% have either failed to meet clinical endpoints or stalled (defined for the purpose of this review as no clinical or publicly mentioned progress for at least 3 years). The author postulates that many of the current clinical approaches fail to sufficiently regulate the amyloid cascade that includes, but is not limited to, the production of soluble β-amyloid precursor protein, β-amyloid and/or amyloid precursor protein intracellular domain and including activation of the tau cascade, ultimately translating to no improvement in cognitive function. To support this argument, the author compares clinical results and peer-reviewed opinions to postulate that appropriately focused multifunctional or dual pathway drugs could make the optimal candidate(s) for further investigations.
本综述评估了过去和现在针对治疗阿尔茨海默病（AD）的临床试验以及当前临床前的候选药物，以便结合特定药物机制更好地评估AD药物研发的趋势。作者首先介绍了160多项针对AD的临床试验结果总结，其中52%要么未达到临床终点，要么停滞不前（为本综述目的定义为至少3年没有临床进展或未公开提及进展）。作者推测，当前许多临床方法未能充分调节淀粉样蛋白级联反应，该反应包括但不限于可溶性β-淀粉样前体蛋白、β-淀粉样蛋白和/或淀粉样前体蛋白细胞内结构域的产生，以及tau蛋白级联反应的激活，最终导致认知功能没有改善。为支持这一论点，作者比较了临床结果和同行评审意见，推测适当聚焦的多功能或双途径药物可能是进一步研究的最佳候选药物。
