Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation
Autor: | Robert Freedman, Josette G. Harris, William R. Kem, Uwe Christians, Robert W. Buchanan, Ann Olincy, Lynn Johnson, Brandie D. Wagner |
---|---|
Rok vydání: | 2017 |
Předmět: |
Agonist
Adult Male Adolescent alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Pyridines Archaeal Proteins Pharmacology behavioral disciplines and activities complex mixtures Benzylidene Compounds law.invention 03 medical and health sciences Young Adult 0302 clinical medicine Cognition Pharmacokinetics Randomized controlled trial Double-Blind Method law mental disorders Medicine Humans Nicotinic Agonists Receptor business.industry Middle Aged medicine.disease 030227 psychiatry Psychiatry and Mental health Nicotinic Receptor Agonist nervous system Schizophrenia Delayed-Action Preparations Female Schizophrenic Psychology Original Article Extended release business Cognition Disorders psychological phenomena and processes 030217 neurology & neurosurgery Antipsychotic Agents |
Zdroj: | Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 43(3) |
ISSN: | 1740-634X |
Popis: | The aim of the trial was to assess whether extending plasma levels of the alpha7-nicotinic acetylcholine receptor (nAChR) agonist 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) over time enhances its cognitive effects in schizophrenia. Both smoking and non-smoking patients were studied, to determine whether effects differ between these two groups. Forty-three smokers and thirty-seven non-smokers who met DSM-IV criteria for schizophrenia were enrolled in a double-blind, randomized, placebo-controlled 1 month trial. DMXB-A 150 mg was formulated with hypromellose to produce extended release over 4 h and administered four times daily. The primary outcome (the Neurocognitive Composite of the MATRICS Consensus Cognitive Battery) and secondary outcomes (the MATRICS Attention-Vigilance Domain and P50 gating), showed no significant effect. Plasma levels were obtained 2.5 h post administration. In non-smokers, levels were similar to those reached transiently with 75–150 mg DMXB-A immediate-release formulations twice daily, which were earlier shown to be effective doses. However, the extended-release formulation produced no cognitive or clinical effect either in non-smokers or smokers. The 10-fold lower DMXB-A plasma levels in smokers suggest that chronic smoking enhances DMXB-A metabolism. Pro-cognitive effects of DMXB-A may result from transient increases in cell signaling that are limited by receptor tachyphylaxis. Future efforts to improve cognition in schizophrenia by enhancing alpha7 nAChR function may require consideration of these pharmacokinetic limitations. |
Databáze: | OpenAIRE |
Externí odkaz: |