Introduction Memantine, an NMDA receptor antagonist is currently being tested by Forest Laboratories for the treatment of dementia, including advanced Alzheimer's disease (AD) for which there are currently no FDA approved medications (current cholinesterase inhibitors are approved for mild and moderate dementia). Newly released data on memantine suggests it might have some neuroprotective effects against the disease that can lead to improvements in functioning even in more advanced levels of the disease process. At the American Psychiatric Association (APA) annual meeting back in May, data were released regarding the clinical potential and unique neuroprotective effects of using memantine in treating Alzheimer's disease. The outcome of this significant U.S. trial revealed possible benefits to patients with moderate to severe Alzheimer's disease, relative to those treated with placebo. Cognition, day-to-day functioning and overall performance showed positive effects, according to the trial results. Additionally, presented at the recent American Academy of Neurology (AAN) conference in Philadelphia, results of a second study exemplified memantine's neuroprotective potential during a transient ischemic episode. This second study found that in the event of continued cerebral ischemia due to restricted cerebral blood flow and the resulting oxygen reduction to the brain, memantine reduced neuronal damage.
What is Memantine? Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, differs from other agents currently used to treat Alzheimer's disease. Unlike an acetyl cholinesterase (AchE) inhibitor, this new investigational drug is an orally active NMDA antagonist that targets natural neurotransmitters -- i.e., excitatory amino acids, such as glutamate. Critical to learning and memory, glutamate is thought to affect electrical signals across approximately 70 percent of the central nervous system's excitatory synapses. An excess of glutamate causes overstimulation of NMDA receptors. In clinical trials, memantine's mechanism of action appears to correct an existing glutamate imbalance but does not interfere with glutamate's role as an integral neural pathway. According to Ivan Gergel, M.D., overseer for clinical development at Forest Laboratories, memantine's ability to modulate glutamate is leading researchers to speculate that it may ameliorate Alzheimer's disease. "Elevated levels of glutamate are associated with neuronal nerve cell death," he says. This overabundance of glutamate causes excitotoxicity (neuronal damage from overstimulation), which in turn leads to neuronal cell death found in neurodegenerative disorders, including Alzheimer's disease and peripheral neuropathy. "Memantine works to treat symptoms and prevent the deterioration of cognition, activities of daily living and global functioning," says Gergel. He reports that a considerable database of information that supports this hypothesis has been developed from several significant studies.
European Studies Show Promise In Sweden, researchers at the Karolinska Institutet at Huddinge University Hospital tested the clinical efficacy and safety of memantine in patients with moderately severe to severe primary dementia as defined by DSM-III-R criteria. The Global Deterioration Scale (stages 5-7) and the Mini-Mental State Examination (<10 points) were used to assess severity. Primary endpoints included the Clinical Global Impression of Change (CGI-C) rating by the physician and the Behavioral Rating Scale for Geriatric Patients (BGP), subscore 'care dependence,' evaluation by nursing staff, while the secondary endpoints included the modified D-Scale (Arnold/Ferm). In this study 166 patients comprised the ITT sample and 151 patients received protocol treatment. Forty-nine percent of the patients displayed Alzheimer type dementia and 51 percent had vascular type dementia (based on CT findings and Hachinski score). At the 12-week ITT endpoint analysis, 82 patients received 10 mg memantine and 84 received placebo. Results showed positive response in CGI-C at a rate of 73 percent versus 45 percent, in favor of memantine (stratified Wilcoxon p<0.001), regardless of etiology of dementia. A 3.1 point improvement on memantine versus 1.1 points under placebo (p+0.0016) was indicated in the BGP subscore 'care dependence.' Additionally, the two independent target variables showed a coincident response of 61.3 percent memantine versus 31.6 percent placebo. Secondary endpoint analysis of the D-Scale assessment of basic ADL functions concurs with the primary findings. No significant differences regarding safety were noted in either treatment group. These findings support the theory that memantine therapy initiates functional improvement. Another European study conducted at Georg-August University in Gottingen, Germany assessed the efficacy of memantine in the first large-scale systematic and prospective clinical trial of pharmacotherapeutic intervention in advanced stages of dementia. A group of 531 advanced dementia patients, separated by severity according to GDS stages, determined the drug's efficacy on two independent levels -- by assessing physicians' CGI-C rating at the end of the six-week observation period and by the elementary ADL function levels given by caregivers using the D-Scale-of-Change. Caregivers noted improvement in cognitive and motor functions as well as in elementary functions of daily life in patients at each GDS stage, including stage 7 (which is considered "very severe" and in which patients have lost verbal abilities and may lose ability to walk or carry out normal physical functions). Physicians recorded an overall clinical improvement in 75.5 percent of patients after six weeks. Thirty-five percent of patients classified tolerability as "well" and 59.5 percent as "very well." No serious adverse drug reactions were reported. Again, these findings correspond to favorable symptomatic effects of memantine as demonstrated in repeated randomized, double-blind, placebo- controlled studies in mild to moderate dementia.
Treating Advanced AD A United States trial of memantine involved 32 sites across the country and 252 patients diagnosed with advanced Alzheimer's disease. It should be noted that, to date, no drug has been approved for treating this particular population. Researchers Barry Reisberg, M.D. and Steven Ferris, Ph.D., Professors of Psychiatry at the New York University School of Medicine, used a number of validated scales to measure changes in cognition, function and global performance, including the Severe Impairment Battery (SI, ADL Inventory and Clinician's Interview-Based Impression of Change. At the end of the study, researchers noted that patients receiving placebo scored more than 40 percent below patients taking memantine on standard assessment scales. A development program that includes more than ten years of clinical experience with memantine in Germany supports the results of these studies. Gergel notes that memantine is not the first NMDA receptor antagonist to be considered in the treatment of Alzheimer's disease. "The intriguing factor with this drug though is that it's a low affinity agent and not associated with severe side effects, " he says. "Other drugs were associated with psychosis in the past." Dr. Gergel indicates that common side effects such as dizziness and agitation did occur but with the same frequency or less than with placebo. "Memantine's tolerability profile was quite good," he says. In addition to reducing symptoms of dementia, memantine has also been found to relieve neuropathic pain associated with diabetes, according to Dr. Gergel. He notes that the drug's duality in treating disorders with common underlying factors enables it to effectively address various disorders. "If the drug has an effect on one pathology, it might work on the same pathology in another disease," he says. In Germany, memantine is prescribed more frequently than donepezil or any of the other available cholinesterase inhibitors and has already been approved in several European markets, according to Gergel. Merz and Company of Frankfurt, Germany has marketed memantine in that country since 1989 with labeling "dementia syndrome." Additionally, a scientific poster session presented at the National Disease Education Conference of the Alzheimer's Association in Chicago addressed memantine's unique in vitro ability to protect nerve cells from damage as well as to maintain cell-to-cell communication, which is critical in preserving memory and other cognitive functions.
Forest Seeking FDA Approval Gergel says that a New Drug Application (NDA) is scheduled for submission later this year or early next year. "We are hoping for approval in 2003 or earlier, depending on how rapidly the review process goes," he says. Additional ongoing studies are exploring memantine's efficacy in patients afflicted with moderate to severe dementia as well as for those suffering neuropathic pain. Merz, in collaboration with Neurobiological Technologies, noted in their recent U.S. study that memantine demonstrated help in relieving nighttime neuropathic pain in diabetic patients. Also, a clinical study in AIDS-related dementia is investigating the possibility of memantine as therapy for this disorder. According to Gergel, although further studies are necessary, memantine, of all existing agents, has a putative damage prevention factor that may prevent further deterioration or even onset of dementia.
References * Ruther E, et al.: A prospective PMS study to validate the sensitivity for change of the D-scale in advanced stages of dementia using the NMDA-antagonist memantine. Pharmacopsychiatry 2000; 33(3):103-8. * Winblad B, Poritis N: Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J. Geriatr Psychiatry 1999; 14:135-146.
Comentario
Son alentadores los resultados preliminares de la administración de memantina a pacientes demenciados.
Es importante hacer notar que en esta revisión, se indicó dicho medicamento a pacientes con demencia moderada a severa, con gradación de 10 o menos puntos, en el Mini Mental State Examination, habiendo mejorado la puntuación en alrededor de 40%.
Tambien llama la atención, la mejoría en el aspecto motor.
El mecanismo de acción de la memantina es diferente al de los inhibidores de colinesterasa, antagonizando los receptores de N-metil-D-aspartato, con accion básica inter e intrasináptica. Lo anterior nos lleva a la idea de que se pueda utilizar junto con los inhibidores de colinesterasa para reforzar respuesta.
Tambien cabe mencionar que se utilizó en pacientes con demencia de tipo vascular, con aceptables resultados en general con una p estratificada de Wilcoxon menor a 0.001, comparada con placebos).
Aún quedará pendiente demostrar nivel de evidencia fuerte (nivel 1) para su recomendación. También será necesario evaluar los efectos colaterales a largo plazo .
Atentamente Dr Hugo Navarrete Grupo de Estudio de Demencias Academia Mexicana de Neurología, A.C. Grupo Tijuana, B.C. hugon@telnor.net |
