Wang Hua, Larriviere Kylyana S, Keller Kristen E, Ware Kathleen A, Burns Ted M, Conaway Mark A, Lacomis David, Pattee Gary L, Phillips Lawrence H, Solenski Nina J, Zivkovic Sasa A, Bennett James P
Department of Neurology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Amyotroph Lateral Scler. 2008 Feb;9(1):50-8. doi: 10.1080/17482960701791234.
R+ pramipexole (PPX) is a lipophilic cation that concentrates into brain and mitochondria and efficiently scavenges reactive oxygen and nitrogen species (RONS). Under the auspices of a Physician-Sponsor IND, R+PPX was dosed to small numbers of ALS patients for tolerability and safety while efficacy measures were also collected. The purpose of this paper is to describe the outcomes of these initial clinical studies. In a futility design study, 30 patients with early SALS were evaluated monthly for ALSFRS-R scores and FVC measurements for three months during lead-in, followed by open-label dosing at 30 mg/day of R+PPX for the next six months. In the dose escalation study, 10 subjects with early ALS received daily doses of R+PPX from 10 mg t.i.d. to 100 mg t.i.d. over seven weeks. In the open-label extension analysis, subjects from the initial studies were treated with 30 mg/day for at least six months, then switched to 60 mg/day. R+PPX was tolerated well in all studies. In the futility study, slopes of decline in ALSFRS-R scores and neurophysiological index (NI) values yielded non-significant reductions during treatment. In the dose-escalation study, all subjects increased daily R+PPX intake safely to 100 mg t.i.d. Markers of ALS did not change (ALSFRS-R) or improved (FVC). Trough and peak plasma (PPX) increased linearly with dosing, and several subjects achieved plasma (PPX) >1 microM. In the open-label extension protocol, changing from 30 to 60 mg/day caused a non-significant 17% reduction in slope of decline of ALSFRS-R. It was concluded that R+PPX was tolerated well in long-term dosing at 30 and 60 mg/day. Encouraging but non-significant effects of R+PPX on ALS decline were observed. High doses of R+PPX were tolerated well and yielded neuroprotective plasma levels. These findings support longer-term testing of higher R+PPX doses as a potential disease-altering therapy for SALS.
R+普拉克索（PPX）是一种亲脂性阳离子，可浓缩进入大脑和线粒体，并有效清除活性氧和氮物种（RONS）。在医师发起的研究性新药（IND）支持下，R+PPX被给予少数肌萎缩侧索硬化症（ALS）患者以评估耐受性和安全性，同时也收集疗效指标。本文旨在描述这些初始临床研究的结果。在一项无效性设计研究中，30例早期散发性ALS（SALS）患者在导入期的三个月内每月评估ALS功能评定量表修订版（ALSFRS-R）评分和用力肺活量（FVC）测量值，随后在接下来的六个月内以30毫克/天的剂量进行R+PPX开放标签给药。在剂量递增研究中，10例早期ALS受试者在七周内每日接受的R+PPX剂量从10毫克每日三次递增至100毫克每日三次。在开放标签扩展分析中，初始研究的受试者先以30毫克/天治疗至少六个月，然后改为60毫克/天。在所有研究中，R+PPX的耐受性良好。在无效性研究中，治疗期间ALSFRS-R评分和神经生理指标（NI）值的下降斜率有非显著性降低。在剂量递增研究中，所有受试者均安全地将每日R+PPX摄入量增加至100毫克每日三次。ALS指标未改变（ALSFRS-R）或有所改善（FVC）。血浆普拉克索（PPX）的谷值和峰值随给药剂量呈线性增加，部分受试者的血浆（PPX）>1微摩尔/升。在开放标签扩展方案中，从30毫克/天改为60毫克/天导致ALSFRS-R下降斜率非显著性降低17%。得出的结论是，R+PPX在30毫克/天和60毫克/天的长期给药中耐受性良好。观察到R+PPX对ALS病情进展有令人鼓舞但不显著的影响。高剂量的R+PPX耐受性良好，并产生神经保护作用的血浆水平。这些发现支持对更高剂量的R+PPX进行长期测试，作为SALS的一种潜在疾病改变疗法。
