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PubMedDate not supplied

Memantine: an antiglutamatergic option for dementia.

Alzheimer's disease (AD) is the most common form of dementia in occidental countries. Currently approved treatments for AD provide mainly symptomatic benefits without clear evidence of neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in several central nervous system disorders, including neuroprotective treatment in chronic neurodegenerative diseases, and symptomatic treatment in other neurologic diseases. Memantine, an NMDA antagonist, has been recently approved for the treatment of advanced AD. Due to its mechanism of action, memantine is considered a neuroprotective drug, whose utility has been demonstrated in preclinical studies. In addition, memantine is a useful symptomatic treatment for AD and vascular dementia. This paper reviews both aspects of memantine as well as some basic mechanisms mediating cognition and glutamatergic neurodegeneration.

Clinical Trials as Topic↗
PubMed2004

A placebo-controlled randomized crossover trial of the N-methyl-D-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain.

UNLABELLED: In the present study we investigated the effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine (30 mg/d) on the intensity of chronic phantom limb pain (PLP) and cortical reorganization. In 8 patients with chronic PLP, memantine was tested in a placebo-controlled double-blinded crossover trial of 4 wk duration per trial. The intensity of PLP was rated hourly by the patients on a visual analog scale during baseline and both treatment periods. At the same time points, the functional organization of the primary somatosensory cortex (SI) was determined by neuromagnetic source imaging. In comparison to baseline and placebo, the NMDA receptor antagonist had no effect on the intensity of chronic PLP. In none of the periods were significant changes in the functional organization of SI observed. Although the conclusions regarding the clinical effect are limited because of the small sample size, the data indicate that in the studied dosage the NMDA receptor antagonist memantine is ineffective in the treatment of chronic PLP and is also ineffective for the reduction of associated neural plasticity in the primary SI. IMPLICATIONS: NMDA receptors play a substantial role in central nervous system changes underlying neuropathic pain. In a placebo-controlled double-blinded study we tested the effect of 30 mg memantine on chronic phantom limb pain and pain-associated cortical reorganization.

Adult↗
PubMed2004

Intraarticular pretreatment with ketamine and memantine could prevent arthritic pain: relevance to the decrease of spinal c-fos expression in rats.

To determine whether intraarticular pretreatment with N-methyl-D-aspartic (NMDA) receptor antagonist ketamine or memantine currently used in humans has prophylactic analgesia in arthritic pain, we examined the effects of their intraarticular injection before carrageenan injection into the knee joint on pain-related behavior and spinal c-Fos expression in rats. Injection of ketamine (0.2 mg and 1 mg) or memantine (0.1 mg, 0.2 mg, and 1 mg) into the knee joint, but not the abdominal cavity, immediately before carrageenan injection (2%, 40 microL) significantly prevented pain-related behavior. The intraarticular injection of ketamine (1 mg) or memantine (0.2 mg) also suppressed c-Fos expression in the laminae I-II and laminae V-VI at the L3-4 spinal level. Subsequent statistical analyses revealed that the degree of the spinal c-Fos expression was correlated with the extent of the pain-related behavior. These results suggest that peripheral administration of NMDA receptor antagonists has prophylactic analgesic effects in arthritic pain, which might be associated with the decrease of central nociceptive signaling. Because ketamine and memantine are currently used in humans and considered clinically safe, they may have therapeutic value in the treatment of joint pain.

Animals↗
PubMed2003

Is memantine a breakthrough in the treatment of moderate-to-severe Alzheimer's disease?

Over stimulation of the NMDA receptor by glutamate has long been considered to have a role in Alzheimer's disease (AD). Memantine, a non-competitive antagonist of NMDA receptors, has recently been tested in moderate-to-severe AD. At 28 weeks, there was a small significant mean difference of 0.3 in favour of memantine, showing benefit in the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) global score. The other primary efficacy variable was the Alzheimer's disease Cooperative Study Activities of Daily Living Inventory, modified for more severe dementia (ADCS-ADL-sev) and there was significantly less deterioration in the ADCSADL-sev score in the memantine group than in the placebo group (2.1 versus 3.4, respectively). As there are no drugs commonly used for their effectiveness in moderate-to-severe AD, any drug that causes a benefit, however small, as memantine has been shown to do in this trial, represents a breakthrough.

Alzheimer Disease↗
PubMed2005

Exacerbation of Lewy bodies dementia due to memantine.

INTRODUCTION: Lewy body dementia (DLB) is common but frequently misdiagnosed as Alzheimer's disease plus delirium or parkinsonism. DRUGS USED IN THIS DISORDER CAN CAUSE EXACERBATIONS: neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, antiparkinsonian medication has the potential to exacerbate psychotic symptoms, and even cholinesterase inhibitors, while relatively safe, have provoked adverse responses in some DLB patients. There are few data available about the use of memantine in DLB. CASE PRESENTATION: A 74-year-old man was diagnosed with Alzheimer disease and parkinsonism. After memantine was started he developed severe fluctuations in awareness, visual hallucinations, agitation, and worsened parkinsonism. When he was evaluated thoroughly, the diagnosis was revised to Lewy body dementia, leading to changes in treatment that were associated with dramatic improvement in the patient's mental status. CONCLUSIONS: In our patient, motor and cognitive symptoms worsened with memantine treatment; these resolved after memantine was discontinued.

Aged↗
PubMedDate not supplied

Clinically available NMDA antagonist, memantine, attenuates tolerance to analgesic effects of morphine in a mouse tail flick test.

Converging lines of evidence indicate that N-methyl-D-aspartate (NMDA) receptor antagonists attenuate the development of morphine tolerance tested in antinociception assays in rodents. The present study extends these findings to the effects of clinically available NMDA receptor antagonist, memantine. Male Albino Swiss mice were tested for analgesia using the tail-flick apparatus. Preliminary experiment was designed to find out the optimal dose of morphine and the number of injections that would produce tolerance to its analgesic effects. In the main experiment, during the development of tolerance period (6 days), mice received 10 mg/kg sc b.i.d. morphine injections in the animal room (non-associative tolerance). This treatment resulted in 5.8 fold rightward shift of morphine cumulative dose-response effect from 3.39 mg/kg on day 1 to 16.19 mg/kg on day 8 of the experiment. Memantine pretreatment (5 and 10 mg/kg, but not 2.5 mg/kg), given 30 min prior to each morphine dose during the development of tolerance period, inhibited the rightward shift of morphine cumulative dose-response curve. Thus, pretreatment with memantine at doses of 2.5, 5 and 10 mg/kg resulted in ED50 values of 12.13, 4.74 and 1.95 mg/kg, respectively, corresponding to 3.35, 1.02 and 0.94 fold changes. These data indicate that low affinity, clinically available NMDA receptor antagonist, memantine, may be used to inhibit the development of morphine tolerance.

Analgesics, Opioid↗
PubMedDate not supplied

[The clinical relevance of memantine use].

Memantine is an NMDA receptor antagonist with moderate affinity, which results in neuroprotective potential due to reducing overstimulation caused by glutamate (excitotoxicity) and simultaneous lack of adverse events (especially psychosis) typical for an antagonist with higher affinity like phencyclidine. In randomized, controlled studies it has been shown that memantine is beneficial in the treatment of moderate to severe dementia of Alzheimer's type and it became the very first compound to be registered for this purpose both in Europe (including Poland) and in the United States. Further investigation require usefulness of memantine in less advanced stages of Alzheimer's disease as well as other types of dementia especially vascular; promising results are shown in dual therapy: memantine + cholinesterase inhibitor.

Alzheimer Disease↗
PubMed2004

Memantine: pharmacological properties and clinical uses.

Memantine is a relatively new drug specially developed for use in moderate-to-severe dementia. It is an uncompetitive N-methyl-D-aspartate receptor antagonist and reduces glutamatergic excitotoxicity. Though Alzheimer's disease (AD) is the commonest cause of dementia in the world, there is no "cure" available for the same. Cholinesterase inhibitors such as donepezil and rivastigmine have been shown to provide symptomatic relief in patients with AD but have no effect on disease progression or survival. Moreover, they are not helpful in more severe stages of dementia. Memantine has been shown to cause modest improvement in clinical symptoms in severe stages of AD and may retard the disease progression. Moreover, it has been shown to be useful in various forms of dementia including AD, vascular dementia and Wernicke-Korsakoff psychosis. It is also the first drug to cause complete disappearance of pendular nystagmus due to multiple sclerosis. The current review focuses on the pharmacological properties of memantine and examines the recent evidence in favor of memantine.

Alzheimer Disease↗
PubMed2005

Memantine for treatment of moderate to severe Alzheimer's disease.

Health Canada has issued a Notice of Compliance with conditions (NOC/c) for memantine in the treatment of moderate to severe Alzheimer's disease (AD). The evidence of relative benefit and harm from memantine in this population derives from two randomized controlled trials (RCT) of 24 to 28 weeks duration, in a total of 656 patients; and a post hoc subgroup analysis of 79 patients with severe AD from a third trial of 12 weeks. Memantine alone or in combination with donepezil demonstrates improvements in primary outcome scores of activities of daily living and cognition, but not of global performance. Memantine's rate of diffusion may be rapid, as it is the only drug available for severe AD and it has a potential for use in unapproved indications.

Aged↗
PubMedDate not supplied

[The action of memantine on the cognitive disorders of patients with dementia: reflections following two years' experience in Spain].

AIMS: To review the literature on the effectiveness of memantine in cognitive disorders, and to discuss data from our own personal experience. DEVELOPMENT: In moderately advanced or advanced stages of Alzheimer's disease (AD), use of memantine for cognitive disorders and functional independence is significantly effective, regardless of whether anticholinesterases are taken or not. Effectiveness lasts at least 1 year (open trial). The NNT (number needed to treat) of 7 means it has a value that is similar to that of anticholinesterases for the treatment of the early or moderate phases and the magnitude effect of 0.47 can be graded as intermediate. In incipient or moderate AD its effectiveness on the cognitive functions is lower. In early or moderate vascular dementia, memantine has favourable effects with regard to cognition, especially in dementia due to 'small-vessel' disease, although this is not reflected in functional independence, probably because it is also affected by other neurological and systemic factors. A retrospective analysis of 43 of our own cases (AD at GDS 6-7) showed a percentage of 'not worse' between successive visits (mean interval of 6 months) of 40-70%, the best result being obtained by those who take anticholinesterase. CONCLUSIONS: The effectiveness of memantine on cognitive impairment is significant in moderately advanced and advanced stages of AD, although we need to know physicians' impressions in order to determine the extent to which the first expectations from clinical trials are confirmed. This effect is less pronounced in the early and intermediate stages and in vascular dementia.

Alzheimer Disease↗
PubMed1977

[The effect of memantine (dimethylamino-adamantane) on membranes of sensory nerve fibres (author's transl)].

The effect of memantine (dimethylaminoadamantane), a new amantadinederivate with antiparknison-properties was investigated by the help of the sucrose gap method on sensory nerve fibres of the rat In normal Locke-solution memantine 10(-4) M reduced the amplitude of the compound action potential without change of the resting potential, increased the membrane resistance and depressed the repetitive activity elicited by depolarizing rectangular currents. The results of the experiments with changed concentrations of sodium, potassium and chloride ions in the suspensionmedium indicate that the membrane conductance of all three ions was reduced by memantine. Beside the antiparkinson properties these effects as well as those reported by others might be interpreted as a central muscle relaxing action of memantine. The possible implication of the demonstrated membrane effects of the drug is discussed in relation to its action on the dopaminergic transmission in the nigro-striatal system.

Action Potentials↗
PubMed1982

[Valve of symptomatic therapy with memantine in cerebral coma. I. Correlation with coma stages and EEG spectral patterns].

1.3-Dimethyl-5-aminoadamantane (DMAA, D-145, memantine, Memantine) was used in a group of 45 patients of both sexes in our intensive care ward for the purpose of symptomatic therapy. The patients included in the study had been suffering from obtuse craniocerebral trauma and post-traumatic cerebrovascular complications. We evaluated only those cases in which the initial duration of the coma had been not less than 3 days. The mean treatment period was 9.5 days and the observation was continued over an average of 25 days. The clinical course was recorded on the basis of Frowein's coma classification introduced by the European Association of Neurosurgical Societies. In addition, we observed the development of any cerebroorganic psychosyndrome or the emergence of an apallic syndrome. As expected, apart from individual exceptions, a regression of the coma stages 1 to 3 was observed in the course of the observation period. The significant improvement of coma stages 2 and 3 already during the treatment with memantine should be emphasized. There was a transient increase in the category-1 coma group and in the patients with cerebro-organic psychosyndromes. In correlation with the development of the clinical course, an increase significant at the 5% confidence level was found in the documentation of the EEG spectral patterns in the "normal findings/slight over-all change" evaluation, as opposed to a significant reduction of the "moderate/pronounced over-all change" EEG finding (same confidence limit). The tolerance of memantine was generally graded as very good to good. No side effects that would have led to discontinuation of the treatment were observed, and in particular there was no impairment of the blood coagulation or of the metabolic activity of the liver cells. In long-term cerebro-electric check-ups it was found that no spasm potentials are produced at the doses used here, nor was there any promotion of the propagation of epileptic attack patterns when these had been present.

Adolescent↗
PubMed1982

[Valve of symptomatic therapy with memantine in cerebral coma. II. Development of stretch synergisms in coma with brain stem symptoms].

1,3-Dimethyl-5-aminoadamantane (DMAA, D-145, memantine, Memantine) was used in a group of 25 patients of both sexes in coma and with brain stem symptoms for symptomatic therapy. Only adults in whom a severe obtuse craniocerebral trauma was present were included in the study. The mean treatment time was 9.5 days, and the mean observation period 25 days. The clinical courses were established in accordance with Frowein's classification of coma. As expected, coma forms 3-4 exhibited only insubstantial changes during the observation period. About 30% of the coma-3 patients underwent a development to the apallic syndrome. Contrary to our expectations, a development to coma 1 took place in just under half of the coma-3 patients under memantine therapy during the observation period. The efficacy of the memantine treatment was also checked electromyographically. Both a marked reduction of the spontaneous rhythmic discharges and a reduction of the stimulus-dependent stretch movements were found in the superficial EMG of quadriceps muscle. In the transition stages of coma 3-4 the effects of the aminoadamantane therapy were demonstrable only in the EMG. The results are interpreted in the sense of a suppressing action of the substance on the gamma system of positional and posture motor activity.

Amantadine↗
PubMed1982

[Memantine and neurogenic bladder disorders within the bounds of spastic conditions].

The action of 1,3-dimethyl-5-aminoadamantane (DMAA, D-145, memantine, Memantine) on neurogenic bladder dysfunction in spastic conditions was investigated. Under memantine treatment micturition was considerably facilitated, and spontaneous, involuntary voiding reduced. Additionally, memantine effected a decrease of residual urine and toned down the vesicular sphincter by simultaneously enhancing detrusor activity. At the same time the patients reported a considerable diminution of spastic hypertonicity and improved mobility of the limb muscles.

Adult↗
PubMed2000

Neuroprotective and symptomatological action of memantine relevant for Alzheimer's disease--a unified glutamatergic hypothesis on the mechanism of action.

The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease is finding increasingly more acceptance in the scientific community. Central to this hypothesis is the assumption that in particular glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner. Such continuous mild activation leads under chronic conditions to neuronal damage. Moreover, one should consider that impairment of plasticity (learning) may result not only from neuronal damage per se but also from continuous activation of NMDA receptors. To investigate this possibility we tested whether overactivation of NMDA receptors using either non-toxic doses/concentrations of a direct NMDA agonist or through an indirect approach--decrease in magnesium concentration--produces deficits in plasticity. In fact NMDA both in vivo (passive avoidance test) and in vitro (LTP in CA1 region) impaired learning and synaptic plasticity. Under these conditions memantine which is an uncompetitive NMDA receptor antagonist with features of "improved magnesium" (voltage dependence, affinity) attenuated the deficit. The more direct proof that memantine can act as a surrogate for magnesium was obtained in LTP experiments under low magnesium conditions. In this case as well, impaired LTP was restored in the presence of therapeutically relevant concentrations of memantine (1 microM). In vivo, doses leading to similar brain/serum levels produce neuroprotection in animal models relevant for neurodegeneration in Alzheimer's disease such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. Hence, we postulate that if in Alzheimer's disease overactivation of NMDA receptors occurs indeed, memantine would be expected to improve both symptoms (cognition) and slow down disease progression because it takes over the physiological function of magnesium.

Journal Article↗
PubMed2003

The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence.

There is increasing evidence for the involvement of glutamate-mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD). We suggest that glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner in this disorder. This continuous mild activation may lead to neuronal damage and impairment of synaptic plasticity (learning). It is likely that under such conditions Mg(2+) ions, which block NMDA receptors under normal resting conditions, can no longer do so. We found that overactivation of NMDA receptors using a direct agonist or a decrease in Mg(2+) concentration produced deficits in synaptic plasticity (in vivo: passive avoidance test and/or in vitro: LTP in the CA1 region). In both cases, memantine-an uncompetitive NMDA receptor antagonists with features of an 'improved' Mg(2+) (voltage-dependency, kinetics, affinity)-attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1 microM). Moreover, doses leading to similar brain/serum levels provided neuroprotection in animal models relevant for neurodegeneration in AD such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. As such, if overactivation of NMDA receptors is present in AD, memantine would be expected to improve both symptoms (cognition) and to slow down disease progression because it takes over the physiological function of magnesium.

Aged↗
PubMed2002

Quantitative analysis of memantine in human plasma by gas chromatography/negative ion chemical ionization/mass spectrometry.

A sensitive and specific method for the determination of memantine in human plasma is presented. Memantine was extracted from plasma and derivatized to the pentafluorobenzoyl derivative in a one-step procedure avoiding any sample concentration steps. Amantadine was used as an internal standard. The compounds were measured by gas chromatography/negative ion chemical ionization mass spectrometry without any further processing. Using this detection mode, the fragment ions at m/z 353 and 325 were obtained at high relative abundance. Calibration graphs were linear over the range 0.117-30 ng ml(-1). At the limit of quantification (LOQ), the inter-assay precision was 2.00% and the intra-assay variability was 3.22%. The accuracy at the LOQ showed deviations of -1.42% (intra-assay) and -2.47% (inter-assay). The method is rugged, rapid and robust and was applied to the batch determination of memantine during pharmacokinetic profiling of the drug.

Amantadine↗
PubMed1992

Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson's disease.

Memantine is a 1-amino-adamantane derivative which has been proposed to be useful in the treatment of Parkinson's disease. Its beneficial effect has been related to its novel properties as an NMDA receptor blocker which can neutralize the effect of glutamate at striatal and subthalamic levels. In the present study, conducted in an open-fashion, 14 parkinsonian patients with motor fluctuations taking L-dopa, were given a supplement of memantine 30 mg/day. After one month, 10 patients completed the treatment (4 discontinued it due to abdominal pain, psychomotor agitation, confusion and dizziness). In 5 patients, the main parkinsonian features improved significantly (1 point or more on the Webster scale). In 6 patients, "off" episodes improved (from daily mean of 273 minutes, to 172 minutes). In summary, memantine addition to parkinsonian features, could form a basis for novel therapeutic strategies directed to neutralize the effects of glutamate at striatal and subthalamic levels.

Aged↗