title: Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease.
abstract: 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 (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 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.
authors.affiliation: Virginia Commonwealth University Parkinson's Center, Richmond, VA, USA.|Neurodegeneration Therapeutics, Inc., Charlottesville, VA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bennett
authors.affiliation: University of Kansas School of Medicine Alzheimer's Disease Center, Kansas City, KS, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burns
authors.affiliation: University of Kansas School of Medicine Alzheimer's Disease Center, Kansas City, KS, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Welch
authors.affiliation: University of Kansas School of Medicine Alzheimer's Disease Center, Kansas City, KS, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bothwell
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D052160:Benzothiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D049268:Positron-Emission Tomography; D000077487:Pramipexole; D012720:Severity of Illness Index; D016896:Treatment Outcome; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D015415:Biomarkers; C054369:MAPT protein, human; D018697:Nootropic Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D000077487:Pramipexole; D005947:Glucose
keywords: Alzheimer’s disease; PET scan; biomarkers; cognitive disorder; investigational treatment; oxidative stress