期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 49, 期 4, 页码 1179-1187出版社
IOS PRESS
DOI: 10.3233/JAD-150788
关键词
Alzheimer's disease; biomarkers; cognitive disorder; investigational treatment; oxidative stress; PET scan
资金
- Alzheimer's Drug Discovery Foundation (ADDF)
- MCV Foundation for the VCU Parkinson's Center
- NIH
- NATIONAL INSTITUTE ON AGING [P30AG035982] Funding Source: NIH RePORTER
Alzheimer's disease (AD) is an aging-related, degenerative brain disease of adults. Most (similar to 95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) 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 F-18-2DG 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 [A beta (42)], [Tau], or [P-Tau]. Regional F-18-2DG 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.
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