title: A multicenter, randomized, placebo controlled, multiple-dose, safety and pharmacokinetic study of AIT-082 (Neotrofin) in mild Alzheimer's disease patients.
abstract: A phase 1, randomized, double-blind, placebo-controlled, dose escalation study of the purine derivative, AIT-082 (Neotrofin, NeoTherapeutics) was conducted in mild Alzheimer's disease (AD) patients to evaluate multiple-dose safety, tolerability, and pharmacokinetics. Possible short-term effects of AIT-082 on cognition and memory were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimer's disease and other neurological disorders. Pre-clinical studies indicate that AIT-082 has memory enhancing properties, stimulates neuritogenesis and the production of neurotrophic factors. Patients received an oral dose of AIT-082 or placebo daily for one week. Thirty-six AD patients were divided into three dose cohorts; each dose cohort consisted of twelve patients with 8 patients randomized to AIT-082 and 4 to placebo. The 3 doses of AIT-082 evaluated in this study were 100 mg/day, 500 mg/day, and 2,000 mg/day. There were no serious adverse events at any dose and the drug was well tolerated without significant side effects. AIT-082 was orally and rapidly absorbed, resulting in peak serum concentrations within 2 hours with an elimination half-life of approximately 20 hours. Higher doses resulted in corresponding increases in peak concentrations and areas under the curve (AUC). There was an approximate 2-fold accumulation in AIT-082 with daily dosing (as reflected by the AUC) at steady state. There were no significant differences by treatment arm on the clinical or neuropsychological evaluations. AIT-082 was rapidly absorbed by the oral route with a half-life suitable for dosing once or twice daily. No problems with tolerability or safety were found. AIT-082 appears suitable for testing in larger clinical trials for the treatment of AD and other neurologic disorders.
authors.affiliation: Department of Neurosciences, University of California-San Diego, 9500 Gilman, La Jolla, CA 92093, USA. mgrundman@ucsd.edu
authors.forename: M
authors.initials: M
authors.lastname: Grundman
authors.forename: E
authors.initials: E
authors.lastname: Capparelli
authors.forename: H T
authors.initials: HT
authors.lastname: Kim
authors.forename: J C
authors.initials: JC
authors.lastname: Morris
authors.forename: M
authors.initials: M
authors.lastname: Farlow
authors.forename: E H
authors.initials: EH
authors.lastname: Rubin
authors.forename: J
authors.initials: J
authors.lastname: Heidebrink
authors.forename: A
authors.initials: A
authors.lastname: Hake
authors.forename: G
authors.initials: G
authors.lastname: Ho
authors.forename: A N
authors.initials: AN
authors.lastname: Schultz
authors.forename: K
authors.initials: K
authors.lastname: Schafer
authors.forename: W
authors.initials: W
authors.lastname: Houston
authors.forename: R
authors.initials: R
authors.lastname: Thomas
authors.forename: L J
authors.initials: LJ
authors.lastname: Thal
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology; D019540:Area Under Curve; D003071:Cognition / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D012720:Severity of Illness Index; D014481:United States
chemical_list: D018697:Nootropic Agents