Memantine hydrochloride: Pharmacological and clinical profile

Abstract

Memantine (Axura, Merz Pharmaceuticals GmbH; Ebixa, H. Lundbeck A/S, Namenda, Forest Laboratories, Inc.) is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with low to moderate affinity for the (+)MK-801 binding site. It is characterized as a voltage-sensitive open-channel NMDA receptor blocker that antagonizes NMDA receptor-mediated inward currents in vitro with an IC50 of 1-3 microM. In animal models, memantine displays both neuroprotective (antiexcitotoxic) and cognition-enhancing properties at therapeutically relevant concentrations. The strong voltage dependency and rapid blocking/unblocking kinetics of memantine are thought to be the basis for its excellent clinical tolerability. Recently completed clinical studies demonstrate positive effects of memantine in Alzheimer's disease both as a monotherapy and in patients receiving continuous donepezil treatment. Memantine treatment also has demonstrated significant improvement of cognitive performance in patients suffering from vascular dementia. Furthermore, the safety and tolerability of memantine in clinical trials has been excellent, with the incidence of premature withdrawals due to adverse events no greater than placebo and overall low frequencies of total adverse events. In 2002, memantine was approved by the European Medicines Agency (EMEA) for the treatment of moderately severe to severe Alzheimer's disease. More recently, memantine was approved in the US for the treatment of moderate to severe Alzheimer's disease (October 2003). Here, we review the most recent pharmacological and clinical data in dementia patients that has emerged from the systematic evaluation of memantine.