Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease.
BACKGROUND
This study evaluates the activity of SDZ ENA 713, a centrally-selective acetylcholinesterase (AChE) inhibitor, in the cerebral spinal fluid (CSF) of patients with Alzheimer's disease (AD), and its relationship to central and peripheral pharmacokinetic parameters.


METHODS
Eighteen AD patients were enrolled in this open-label, multiple-dose study. Patients were titrated in 1 mg bid/week increments to target doses of 1, 2, 3, 4, 5, or 6 mg bid SDZ ENA 713. After patients had been maintained at their target dose for at least 3 days, continuous CSF samples were obtained via a lumbar catheter for 12.5 h, beginning 0.5 h prior to the final dose of SDZ ENA 713.


RESULTS
Dose-dependent inhibition of CSF AChE was significantly correlated (P < 0.05) with plasma drug and metabolite concentrations. The 6 mg bid treatment group showed a maximum mean inhibition of 62% at 5.6 h post-dose.


CONCLUSIONS
Rapid, sustained, dose-dependent inhibition of CSF AChE suggests that SDZ ENA 713 has therapeutic potential in AD patients.
Cutler
N R
NR
California Clinical Trials, Beverly Hills 90211, USA.
Polinsky
R J
RJ
Sramek
J J
JJ
Enz
A
A
Jhee
S S
SS
Mancione
L
L
Hourani
J
J
Zolnouni
P
P
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D019540:Area Under Curve; D002219:Carbamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid; D002555:Cerebrospinal Fluid / Q000187:drug effects* / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D048448:Phenylcarbamates; D000068836:Rivastigmine
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D000068836:Rivastigmine