A translational approach to evaluate the efficacy and safety of the novel AMPA receptor positive allosteric modulator org 26576 in adult attention-deficit/hyperactivity disorder.

Abstract

BACKGROUND:

It has been posited that glutamate dysregulation contributes to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Modulation of glutamate neurotransmission may provide alternative therapeutic options. The novel 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor positive allosteric modulator Org 26576 was investigated with a translational approach including preclinical and clinical testing.

METHODS:

Neonatal rat 6-hydroxydopamine lesion-induced hyperactivity was used as preclinical model. Seventy-eight ADHD adults entered a multicenter, double-blind, placebo-controlled, two-period crossover trial. After 1 week placebo lead-in, 67 subjects were randomized into one of four treatment sequences: sequence A (n = 15) Org 26576 (100 mg b.i.d.) for 3 weeks, followed by a 2-week placebo crossover and 3 weeks placebo; sequence B (n = 16) 5 weeks placebo followed by 3 weeks Org 26576 (100 mg b.i.d.); sequence C (n = 18) Org 26576 flexible dose (100-300 mg b.i.d.) for 3 weeks, then 5 weeks placebo; sequence D (n = 18) 5 weeks placebo followed by 3 weeks Org 26576 (100-300 mg b.i.d.). The Adult ADHD Investigator Symptom Rating Scale was used to assess changes in ADHD symptomatology.

RESULTS:

Org 26576 (1, 3, 10 mg/kg intraperitoneal) produced dose-dependent inhibition of locomotor hyperactivity in 6-hydroxydopamine-lesioned rats. Org 26576 (100 mg b.i.d.) was superior to placebo in treating symptoms of adult ADHD subjects. The primary Adult ADHD Investigator Symptom Rating Scale results were supported by some secondary analyses. However, Org 26576 (100-300 mg b.i.d.) did not confirm these results. Most frequently reported adverse events were nausea, dizziness, and headache.

CONCLUSIONS:

These preclinical and clinical findings suggest that Org 25676 may have utility in the treatment of ADHD.

• Authors: Lenard A Adler, René A Kroon, Mark Stein, Mohammed Shahid, Frank I Tarazi, Armin Szegedi, Jacques Schipper, Pilar Cazorla
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 72 Issue 11 Pg. 971-7 (Dec 01 2012) ISSN: 1873-2402 [Electronic] United States
• PMID: 22771238 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Org 26576
• Receptors, AMPA
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

Topics

• Adult
• Animals
• Attention (drug effects)
• Attention Deficit Disorder with Hyperactivity (drug therapy)
• Cross-Over Studies
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Male
• Rats
• Rats, Sprague-Dawley
• Receptors, AMPA (metabolism)
• Treatment Outcome
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)