Kleinschnitz Christoph, Meuth Sven G, Wiendl Heinz
Department of Neurology, University of Wurzburg, Wurzburg, Germany.
Int MS J. 2008 Sep;15(3):79-90.
The development programme for novel therapies in multiple sclerosis (MS) has an impressive track record which is unique in the field of neurology, and has led to the approval of several drugs during the past decade. However, therapeutic prosperities face numerous trials that either failed to show efficacy or that had to be halted because of other reasons including adverse events. Moreover, certain treatment strategies are controversial, both for reasons of practicability and for their true clinical benefit. There are serious caveats that highly immunoselective approaches such as monoclonal antibodies can only be applied at the expense of an increased risk of acute or long-term adverse effects. This review focuses on the most important clinical trials on yet unlicensed compounds in relapsing-remitting and secondary-progressive MS which failed, were halted or are associated with significant adverse effects since 2002. Furthermore, we discuss the implications these experiences have for our current view of MS pathogenesis as well as future study design. Examples include agents that target leukocyte differentiation molecules, co-stimulatory molecules, adhesion molecules and chemotaxis, as well as novel immunomodulators and anti-infective therapies.
多发性硬化症（MS）新型疗法的研发项目成绩斐然，在神经学领域独树一帜，在过去十年间促成了数种药物获批。然而，治疗前景面临诸多考验，有些试验未能显示出疗效，有些则因包括不良事件在内的其他原因而不得不中止。此外，某些治疗策略在实用性及其真正的临床益处方面都存在争议。存在一些严重警告，诸如单克隆抗体等高度免疫选择性方法的应用，只能以增加急性或长期不良反应风险为代价。本综述聚焦于自2002年以来在复发缓解型和继发进展型MS中针对未获许可化合物开展的、失败、中止或伴有显著不良反应的最重要临床试验。此外，我们还讨论了这些经验对我们当前对MS发病机制的看法以及未来研究设计的影响。实例包括靶向白细胞分化分子、共刺激分子、黏附分子和趋化作用的药物，以及新型免疫调节剂和抗感染疗法。
