Memantine: a new approach to Alzheimer's disease.

You know, being a human is not about having a good jump shot. It is about having a good mind. Don't ever waste it. --Physician to one of the authors, more than 35 years ago on the night shift at a state hospital. Since the headline-making release of tacrine a little more than a decade ago and the disappointing aftertaste of news "too good to be true," families, professionals working with patients suffering from Alzheimer's disease (AD), and individuals worried about their own cognitive future have greeted the advent of each new AD product with hopeful restraint. Although research continues to explore several different fronts of this battle, the medications most often prescribed have been those with a very particular approach to restoring mental function--drugs that block the breakdown of acetylcholine. Each succeeding generation of these acetylcholine-enhancing agents has added something to the drug molecule to give it a unique mechanism of action, yet all, at the core, increased levels of intrasynaptic acetylcholine (e.g., tacrine [Cognex], donepezil [Aricept], rivastigmine [Exelon], and galantamine [Reminyl]). The newest drug for AD breaks out of the acetylcholine-enhancing mode and focuses on a different receptor complex. Memantine (Namenda), was approved for the U.S. market in October 2003 and has been used in Europe for more than 20 years. AD is the most common type of dementia and the fourth leading cause of death for those over the age of 65. It is thought that 4 million people in the United States suffer from AD, and that number is expected to grow both in real numbers and in percentage of the population. The estimated cost of caring for a single patient ranges from $18,000/year (mild form) to $36,000/year (severe form) (Alzheimer Research Forum, 2004). Memantine approaches the treatment of this cruel disease from a different perspective from the aforementioned acetylcholine-boosting drugs. Further, while those drugs are marketed for patients suffering from mild to moderate levels of AD, memantine is marketed for patients at the moderate to severe stages of the disease. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. Specifically, it blocks abnormal (i.e., sustained) signaling from glutamate neurotransmitters but does not affect the normal binding of this endogenous ligand. Glutamate, the most abundant neurotransmitter in the brain, is involved in learning and memory pathways; however, overstimulation by this neurotransmitter has been linked to cognitive decline and neuronal death via mechanism referred to as excitotoxicity (Doraiswamy, 2002). Abnormal glutamate activity is reduced by memantine, and it is thought that the drug may slow the deteriorating course of the illness. The manufacturer of Namenda, however, clearly states that there has not been confirmation that memantine prevents or slows the neurodegenerative process. It should be noted that the NMDA receptor has been a receptor of interest for years. For instance, significant antagonism by the street drug PCP causes psychotic (often violent) behavior similar to that of paranoid schizophrenia disorder, whereas significant agonist stimulation causes the aforementioned excitotoxicity. Chemotherapeutic targeting of this receptor, therefore, suffers from inherent risks in both directions. Pharmacokinetics Memantine is 100% absorbed after oral dosing, demonstrates 45% protein binding, undergoes only slight metabolism, is eliminated primarily unchanged (~75%), and has a half-life of 60 to 80 hours (Forest Laboratories, 2003). …