Traynor B J, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan S C, Cudkowicz M E
Neurology Clinical Trials Unit, Department of Neurology, Massachusetts General Hospital, Boston, USA.
Neurology. 2006 Jul 11;67(1):20-7. doi: 10.1212/01.wnl.0000223353.34006.54.
Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest.
To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug.
The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation.
Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1-viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered.
Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.
利鲁唑是目前唯一获得美国食品药品监督管理局批准用于治疗肌萎缩侧索硬化症（ALS）的药物，但其对生存期的影响有限。
确定可用于III期临床试验测试的潜在神经保护剂，并概述每种药物需要收集的数据。
作者通过邀请学术临床医生和研究人员提供意见并进行文献综述，以确定已在ALS动物模型和ALS患者中进行测试的药物，从而确定了113种化合物。根据对先前动物和人体研究中的科学依据、毒性和疗效的评估，该列表最初缩小至24种药物。对这24种药物进行了更详细的药理学评估。
20种药物被选为适合进一步开发用于治疗ALS患者的药物。他拉喷酯和他莫昔芬已完成II期早期试验，并显示出初步疗效。其他药物（头孢曲松、米诺环素、ONO-2506和IGF-1多肽）已进入涉及大量ALS患者的III期试验。其余药物（AEOL 10150、阿利克伦莫、雷公藤红素、辅酶Q10、考帕松、IGF-1病毒递送、美金刚、N-乙酰天门冬氨酸氨基水解酶抑制剂、尼美舒利、司立肽、苯丁酸钠、沙利度胺、海藻糖）在进行大规模III期人体试验之前，需要额外的临床前动物数据、人体毒性和药代动力学数据，包括中枢神经系统渗透性。应考虑利鲁唑类似物的进一步开发。
有几种潜在的神经保护化合物，其作用机制广泛，可用于ALS的研究，值得进一步探究。
