Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial.
BACKGROUND
Alzheimer disease (AD) may be caused by the toxic accumulation of beta-amyloid (Abeta).


OBJECTIVE
To test this theory, we developed a clinical intervention using clioquinol, a metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to Abeta, thereby promoting Abeta dissolution and diminishing its toxic properties.


METHODS
A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease.


RESULTS
Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, >/=25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma Abeta42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group. The drug was well tolerated.


CONCLUSIONS
Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein-attenuating compound.
Ritchie
Craig W
CW
Departments of Pathology, The University of Melbourne, The Mental Health Research Institute of Victoria, Parkville, Victoria, Australia.
Bush
Ashley I
AI
Mackinnon
Andrew
A
Macfarlane
Steve
S
Mastwyk
Maree
M
MacGregor
Lachlan
L
Kiers
Lyn
L
Cherny
Robert
R
Li
Qiao-Xin
QX
Tammer
Amanda
A
Carrington
Darryl
D
Mavros
Christine
C
Volitakis
Irene
I
Xilinas
Michel
M
Ames
David
D
Davis
Stephen
S
Beyreuther
Konrad
K
Tanzi
Rudolph E
RE
Masters
Colin L
CL
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000097:blood; D002614:Chelating Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007464:Clioquinol / Q000009:adverse effects / Q000627:therapeutic use*; D003071:Cognition; D003300:Copper / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood; D010865:Pilot Projects; D012720:Severity of Illness Index; D015032:Zinc / Q000037:antagonists & inhibitors* / Q000097:blood
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003300:Copper; D007464:Clioquinol; D015032:Zinc