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: M Grundman, E Capparelli, H T Kim, J C Morris, M Farlow, E H Rubin, J Heidebrink, A Hake, G Ho, A N Schultz, K Schafer, W Houston, R Thomas, L J Thal, Alzheimer's Disease Cooperative Study
• Journal: Life sciences (Life Sci) Vol. 73 Issue 5 Pg. 539-53 (Jun 20 2003) ISSN: 0024-3205 [Print] Netherlands
• PMID: 12770610 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Nootropic Agents

Topics

• Administration, Oral
• Aged
• Alzheimer Disease (drug therapy, psychology)
• Area Under Curve
• Cognition (drug effects)
• Female
• Humans
• Male
• Neuropsychological Tests
• Nootropic Agents (administration & dosage, adverse effects, blood)
• Severity of Illness Index
• United States