Bezprozvanny Ilya
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Drug News Perspect. 2010 Oct;23(8):518-23. doi: 10.1358/dnp.2010.23.8.1500435.
Dimebon (latrepirdine) was developed and used in Russia as an over-the-counter oral antihistamine for allergy treatment. In the early 1990s, Dimebon was characterized as a low-affinity NMDA receptor antagonist by Dr. Sergey Bachurin and his colleagues. An initial small-scale, open-label trial of Dimebon in 14 Alzheimer's disease (AD) patients demonstrated potential efficacy. Dimebon was then patented for the treatment of neurodegenerative disorders and licensed by Medivation. Extremely promising results were obtained in a double-blind, placebo-controlled, phase II AD trial in 183 patients; however, a phase II trial of Dimebon in 91 Huntington's disease patients was much less successful. Recently, a phase III AD trial of Dimebon in 598 patients failed to result in any significant improvement in primary or secondary outcomes. The failure of Dimebon may be in large part due to insufficient understanding of its mechanism of action. The NMDA receptor blocking activity of Dimebon is too weak to be physiologically relevant, while the proposed "novel mitochondrial mechanism of action" lacks credible scientific evidence or a molecular target. Independent studies indicate that the clinical effects of Dimebon most likely result from inhibition of histamine H₁ and serotonin 5-HT₆ receptors. Careful preclinical studies of novel potential therapies are needed to minimize chances of making similar costly mistakes in the future.
二甲金刚胺(latrepirdine)在俄罗斯被开发并用作非处方口服抗组胺药用于过敏治疗。在20世纪90年代初,谢尔盖·巴丘林博士及其同事将二甲金刚胺鉴定为低亲和力N-甲基-D-天冬氨酸(NMDA)受体拮抗剂。最初对14名阿尔茨海默病(AD)患者进行的小规模开放标签二甲金刚胺试验显示出潜在疗效。随后,二甲金刚胺获得了治疗神经退行性疾病的专利,并由Medivation公司授权。在一项针对183名患者的双盲、安慰剂对照的AD II期试验中取得了非常有前景的结果;然而,在91名亨廷顿病患者中进行的二甲金刚胺II期试验则不太成功。最近,在598名患者中进行的二甲金刚胺AD III期试验未能使主要或次要结局有任何显著改善。二甲金刚胺的失败可能在很大程度上归因于对其作用机制的理解不足。二甲金刚胺的NMDA受体阻断活性太弱,在生理上不相关,而所提出的“新的线粒体作用机制”缺乏可靠的科学证据或分子靶点。独立研究表明,二甲金刚胺的临床效果很可能源于对组胺H₁和5-羟色胺5-HT₆受体的抑制。需要对新的潜在疗法进行仔细的临床前研究,以尽量减少未来犯类似代价高昂错误的可能性。