Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease.
Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease.
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DOI：
10.3233/jad-150788
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Bothwell R
中科院分区：
文献类型：
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作者：
Bennett J;Burns J;Welch P;Bothwell R
阿尔茨海默病（Alzheimer's disease，AD）是一种与年龄相关的成人退行性脑疾病。大多数（~95%）AD是偶发性的，并且与脑局部葡萄糖摄取的早期出现的缺陷、脑脊液AD相关蛋白的变化、局部脑萎缩和氧化应激损伤相关。我们用R（+）-盐酸普拉克索（R（+）PPX）治疗轻中度AD患者，R（+）-盐酸普拉克索是一种神经保护性、亲脂阳离子、自由基清除剂，可蓄积到脑和线粒体中。19例受试者在医生申办的IND（60，948，JPB）、IRB批准的方案和季度外部安全性委员会监测下接受R（+）PPX每日两次，每日剂量增加至300 mg/天。15人完成并提供了基线和治疗后血清、腰椎脊髓液、脑18F-2DG PET扫描和ADAS-Cog评分。在R（+）PPX治疗6个月期间，ADAS-Cog评分无变化（n=1）、改善（n=2）、下降1-3分（n= 5）或下降4- 1 - 3分（n=8）。血清PPX水平与ADAS-Cog评分变化无关。6个月时的空腹AM血清PPX水平在受试者之间变化很大，并且与CSF [PPX]强烈相关（r=0.97，p<0.0001）。CSF [PPX]与CSF [Aβ（42）]、[Tau]或[P-Tau]无关。脑葡萄糖摄取的局部18F-2DG测量显示R（+）PPX治疗期间下降3-6%。发生了56例轻中度不良事件，26例可能/肯定与R（+）PPX使用有关，4例退出。R（+）PPX通常耐受良好，线性进入脑细胞外间隙。在计划确定改变疾病进展的有效性所需的任何大型研究之前，R（+）PPX在AD中的进一步研究应包括受试者血清[PPX]峰谷值变化的详细药代动力学研究。
Alzheimer’s disease (AD) is an aging-related, degenerative brain disease of adults. Most (~95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid AD-related proteins, regional brain atrophy and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mitochondria. 19 subjects took R(+)PPX twice a day in increasing daily doses up to 300 mg/day under a physician-sponsor IND (60,948, JPB), IRB-approved protocol and quarterly external safety committee monitoring. 15 persons finished and contributed baseline and post-treatment serum, lumbar spinal fluid, brain 18F-2DG PET scans and ADAS-Cog scores. ADAS-Cog scores did not change (n=1), improved (n=2), declined 1–3 points (n= 5) or declined 4–13 points (n=8) over 6 months of R(+)PPX treatment. Serum PPX levels were not related to changes in ADAS-Cog scores. Fasting AM serum PPX levels at 6 months varied considerably across subjects and correlated strongly with CSF [PPX] (r=0.97, p<0.0001). CSF [PPX] was not related to CSF [Aβ(42)], [Tau], or [P-Tau]. Regional 18F-2DG measures of brain glucose uptake demonstrated a 3–6% decline during R(+)PPX treatment. 56 mild-moderate adverse events occurred, 26 probably/definitely related to R(+)PPX use, with 4 withdrawals. R(+)PPX was generally well-tolerated and entered brain extracellular space linearly. Further studies of R(+)PPX in AD should include a detailed pharmacokinetic study of peak and trough serum [PPX] variations among subjects prior to planning any larger studies that would be needed to determine efficacy in altering disease progression.