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PubMed2003

Development of a liquid chromatography-mass spectrometric method for measuring the binding of memantine to different melanins.

A sensitive and selective liquid chromatography-mass spectrometric method was validated for the determination of free memantine in melanin binding studies. The sources of melanin studied were sepia, synthetic and bovine melanin. Memantine was chromatographed on a reversed-phase column (Prodigy 5 microm, ODS(3), 100 A, 100 x 4.6 mm) using gradient elution with mobile phases of 0.1% formic acid in deionised water and 0.1% formic acid in methanol at a flow-rate of 0.8 ml/min. The mode of ionisation was atmospheric pressure-electrospray and detection by single ion monitoring of the memantine ion m/z 180. Validation of the method showed that the assay was linear from 0.1 to 1200 nM and 0.5 to 1200 nM memantine in deionised water and phosphate-buffered saline (PBS), respectively. Accuracy for sample preparations in deionised water was between 80 and 108% and between 80 and 123% for PBS. For both media, intra- and inter-day precision was below 1% for retention time and below 5% for analyte peak area. At the LLOQ, the variation of peak area was less than 17%. Binding of memantine to melanin was measured indirectly by determining the unbound fraction of memantine. After incubation of melanin with memantine, the sample was centrifuged and filtered to separate the memantine-melanin complex effectively from suspension. The filtrate was then assayed for free memantine from which the extent of binding was then calculated.

Chromatography, High Pressure Liquid↗

PubMed2006

Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement.

Glutamate is accumulated in abundance during the early period of experimental hematoma, and the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate can result in an influx of calcium and neuronal death in cases of intracerebral hemorrhage (ICH). Memantine, which is known to be a moderate-affinity, uncompetitive, NMDA receptor antagonist, was investigated with regard to its ability to block the glutamate overstimulation and tissue plasminogen activator (tPA)/urokinase plasminogen activator (uPA)/matrix metalloproteinase (MMP)-9 modulation in experimental ICH. Intracerebral hemorrhage was induced via the infusion of collagenase into the left basal ganglia of adult rats. Either memantine (20 mg/kg/day) or PBS was intraperitoneally administered 30 min after the induction of ICH, and, at daily intervals afterwards, for either 3 or 14 days. Hemorrhage volume decreased by 47% in the memantine group, as compared with the ICH-only group. In the memantine group, the numbers of TUNEL+, myeloperoxidase (MPO)+, and OX42+ cells decreased in the periphery of the hematoma. Memantine resulted in an upregulation of bcl-2 expression and an inhibition of caspase-3 activation. Memantine also exerted a profound inhibitory effect on the upregulation of tPA/uPA mRNA, and finally decreased the MMP-9 level in the hemorrhagic brain. In modified limb-placing test, the memantine-treated rats exhibited lower scores initially, and recovered more quickly and thoroughly throughout the 35 days of the study. Here, we show that memantine causes a reduction of hematoma expansion, coupled with an inhibitory effect on the tPA/uPA and MMP-9 level. Subsequently, memantine was found to reduce inflammatory infiltration and apoptosis, and was also determined to induce functional recovery after ICH.

Animals↗

PubMed1996

Effects of memantine and MK-801 on NMDA-induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices.

The effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, memantine (1-amino-3,5-dimethyladamantane) and MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclo-hepten-5,10-imin e maleate) were compared on synaptic transmission and long-term potentiation (LTP) in hippocampal slices and on NMDA-induced currents in cultured superior collicular neurones. 2. Memantine (10-100 microM) reversibly reduced, but did not abolish, NMDA receptor-mediated secondary population spikes recorded in area CA1 of hippocampal slices bathed in Mg(2+)-free artificial cerebrospinal fluid. 3. Memantine (100 microM) antagonized NMDA receptor-mediated excitatory postsynaptic currents recorded in area CA1 in a strongly voltage-dependent manner i.e. depressed to 11 +/- 4% of control at -35 mV and 95 +/- 5% of control at +40 mV (n = 9), with no apparent effect on response kinetics. 4. The effects of MK-801 and memantine on the induction of LTP were assessed after prolonged pre-incubations with these antagonists. When present for 6.6 +/- 0.4 h prior to tetanic stimulation, memantine blocked the induction of LTP with an IC50 of 11.6 +/- 0.53 microM. By comparison, similar long pre-incubations with MK-801 (6.4 +/- 0.4 h) blocked the induction of LTP with an IC50 of 0.13 +/- 0.02 microM. 5. Memantine and MK-801 reduced NMDA-induced currents in cultured superior colliculus neurones recorded at -70 mV with IC50s of 2.2 +/- 0.2 microM and 0.14 +/- 0.04 microM respectively. The effects of memantine were highly voltage-dependent and behaved as though the affinity decreased epsilon fold per 50 mV of depolarization (apparent delta = 0.71). In contrast, under the conditions used, MK-801 appeared to be much less voltage-dependent i.e. affinity decreased epsilon fold per 329 mV of depolarization (apparent delta = 0.15). 6. Depolarizing steps from -70 mV to +50 mV in the continuous presence of memantine (10 microM) caused a rapid relief of blockade of NMDA-induced currents from 83.7 +/- 1.9% to 21.8 +/- 1.8% (n = 5). This relief was best fitted by a double exponential function (17.2 +/- 11.7 and 698 +/- 204 ms), the faster component of which was most pronounced. 7. In conclusion, whereas MK-801 is equipotent in blocking NMDA-induced currents (at - 70 mV) and the induction of LTP, memantine is relatively less potent in blocking the induction of LTP. This is due to its rapid relief of blockade upon depolarization; a property which might explain its promising clinical profile in the treatment of chronic neurodegenerative diseases.

Action Potentials↗

PubMed2004

Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons.

The N-methyl-d-aspartate (NMDA) receptor antagonist memantine is an approved drug for treatment of Alzheimer's disease (AD). Other such treatments are cholinesterase inhibitors and nicotinic acetylcholine receptor (nAChR)-sensitizing agents such as galantamine. The present study was designed to test whether memantine exerts any effect on the cholinergic system, in particular the Ca(2+)-conducting alpha7(*) nAChR, in cultured hippocampal neurons. Memantine caused a concentration-dependent reduction of the amplitudes of whole-cell currents evoked by the alpha7(*) nAChR-selective agonist choline (10 mM) or by N-methyl-d-aspartate (NMDA) (50 muM) plus glycine (10 muM). It also inhibited tonically activated NMDA receptors. Memantine was more potent in inhibiting alpha7(*) nAChRs than NMDA receptors; at -60 mV, the IC(50) values for memantine were 0.34 and 5.1 muM, respectively. Consistent with an open-channel blocking mechanism, memantine-induced NMDA receptor inhibition was voltage and use-dependent; the Hill coefficient (n(H)) was approximately 1. Memantine-induced alpha7(*) nAChR inhibition had an n(H) < 1 and showed a variable voltage dependence; the effect was voltage-independent at 0.1 muM, becoming voltage-dependent at >/=1 muM. Thus, memantine interacts with more than one class of sites on the alpha7(*) nAChRs. One is voltage-sensitive and therefore likely to be within the receptor channel. The other is voltage-insensitive and therefore likely to be in the extracellular domain of the receptor. It is suggested that blockade of alpha7(*) nAChRs by memantine could decrease its effectiveness for treatment of AD, particularly at early stages when the degrees of nAChR dysfunction and of cognitive decline correlate well.

Animals↗

PubMed2005

The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism.

In western countries, Alzheimer's disease (AD) is the most common form of dementia. In fact, if left uncurbed, the economic cost of caring for AD patients could consume the entire gross national product of the USA by the middle of this century. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of both mild and moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.

Alzheimer Disease↗

PubMed2004

Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer's disease and other neurologic disorders.

Alzheimer's disease (AD) is the most common form of dementia, as least in western countries. It has been estimated that the cost to society for caring for AD patients will consume the entire gross national product of the U.S.A. by the middle of this century if left unabated. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca(2+) influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.

Alzheimer Disease↗

PubMed2006

The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease.

OBJECTIVES: To provide an update review of the best quality evidence for the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine for mild to moderately severe Alzheimer's disease (AD) and of memantine for moderately severe to severe AD. DATA SOURCES: Electronic databases, experts in the field and manufacturer submissions to the National Institute for Health and Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. The quality of included randomised controlled trials (RCTs) was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. An outline assessment of economic evaluations was undertaken using a standard checklist. The clinical and cost-effectiveness data were synthesised through a narrative review with full tabulation of the results of included studies. Where appropriate, meta-analysis of data was undertaken. RESULTS: For mild to moderately severe AD, the results of the study suggested that all three treatments were beneficial when assessed using cognitive outcome measures. Global outcome measures were positive for donepezil and rivastigmine, but mixed for galantamine. Results for measures of function were mixed for donepezil and rivastigmine, but positive for galantamine. Behaviour and mood measures were mixed for donepezil and galantamine, but showed no benefit for rivastigmine. For memantine, two published RCTs were included; in one of these trials the participants were already being treated with donepezil. The results suggest that memantine is beneficial when assessed using functional and global measurements. The effect of memantine on cognitive and behaviour and mood outcomes is, however, less clear. Literature on the cost-effectiveness of donepezil, rivastigmine and galantamine was dominated by industry-sponsored studies, and studies varied in methods and results. Of the three UK studies, two report donepezil as not cost-effective, whereas a third study reports an additional cost (1996 pounds sterling) of between 1200 pounds sterling and 7000 pounds sterling per year in a non-severe AD health state (concerns over these estimates are raised, suggesting that they may underestimate the true cost-effectiveness of donepezil). Cost-effectiveness analysis undertaken in this review suggests that donepezil treatment has a cost per quality-adjusted life-year (QALY) in excess of 80,000 pounds sterling, with donepezil treatment reducing the mean time spent in full-time care (delays progression of AD) by 1.42-1.59 months (over a 5-year period). From four published cost-effectiveness studies, two UK studies report additional costs associated with rivastigmine treatment. Cost-effectiveness analysis undertaken in the current review suggests that rivastigmine treatment has a cost per QALY in excess of 57,000 pounds sterling, with rivastigmine treatment reducing the mean time spent in full-time care (delays progression) by 1.43-1.63 months (over a 5-year period). From five published cost-effectiveness studies, one UK study reports a cost per QALY of 8693 pounds sterling for 16-mg galantamine treatment and 10,051 pounds sterling for 24-mg galantamine treatment (concerns raised suggest that this may underestimate the true cost-effectiveness of galantamine). Cost-effectiveness analysis undertaken in the present review suggests that galantamine treatment has a cost per QALY in excess of 68,000 pounds sterling, with galantamine reducing the time spent in full-time care (delays progression) by 1.42-1.73 months (over a 5-year period). From two published cost-effectiveness studies, one reports analysis for the UK, finding that memantine treatment results in cost savings and benefits in terms of delaying disease progression (concerns raised suggest that this may underestimate the true cost-effectiveness of memantine). In the current review, the cost-effectiveness of memantine has not been modelled separately, but where alternative parameter inputs on the cost structure and utility values have been used in a reanalysis using the industry model, the cost-effectiveness is reported at between 37,000 pounds sterling and 52,000 pounds sterling per QALY, with this alternative analysis still based on what is regarded as an optimistic or favourable effectiveness profile for memantine. CONCLUSIONS: Although results from the clinical effectiveness review suggest that these treatments may be beneficial, a number of issues need to be considered when assessing the results of the present review, such as the characteristics of the participants included in the individual trials, the outcome measures used, the length of study duration, the effects of attrition and the relationship between statistical significance and clinical significance. Many included trials were sponsored by industry. For donepezil, rivastigmine and galantamine, the cost savings associated with reducing the mean time spent in full-time care do not offset the cost of treatment sufficiently to bring estimated cost-effectiveness to levels generally considered acceptable by NHS policy makers. It is difficult to draw conclusions on the cost-effectiveness of memantine; it is suggested that further amendments to the potentially optimistic industry model (measure of effect) would offer higher cost per QALY estimates. Future research should include: information on the quality of the outcome measures used; development of quality of life instruments for patients and carers; studies assessing the effects of these interventions of durations longer than 12 months; comparisons of benefits between interventions; and research on the prediction of disease progression.

Aged↗

PubMedDate not supplied

Studies on the mechanism of action of the antiparkinsonian drugs memantine and amantadine: no evidence for direct dopaminomimetic or antimuscarinic properties.

The effects of the antiparkinsonian drugs amantadine and memantine and of the noncompetitive NMDA receptor antagonist MK-801 were studied in the model of the electrically evoked release of [3H]dopamine and [3H]acetylcholine in slices of the rabbit caudate nucleus in vitro. In the [3H]dopamine release model, high concentrations (> 10 microM) of the drugs investigated showed a marked increase in spontaneous 3H-efflux, with the following order of potency: memantine > MK-801 > amantadine. The spontaneous 3H-efflux induced by 50 microM memantine was diminished by pargyline (10 microM), but was insensitive to the presence of tetrodotoxin (0.3 microM), or nomifensine (1 microM), or to the omission of Ca2+ in the superfusion medium; in the absence of nomifensine it consisted mainly of 3H-metabolites of dopamine. The latter findings indicate that the memantine-induced spontaneous 3H-efflux is unrelated to the firing of striatal interneurons but point to a direct releasing effect of memantine on dopaminergic storage granules. On the other hand, the electrically evoked release of [3H]dopamine seemed to be unaffected by memantine, was only slightly reduced by amantadine but significantly inhibited by MK-801. In the model of the electrically evoked release of [3H]acetylcholine, only MK-801 (> 50 microM) showed significant inhibitory effects, both on spontaneous and evoked overflow of [3H]acetylcholine; the effects of memantine and amantadine were negligible. Since only high concentrations of amantadine and memantine (exceeding those which, according to the literature, may be reached in vivo) showed effects in the present in vitro dopamine and acetylcholine release models, it is concluded that the clinical efficacy of these antiparkinsonian drugs is most probably unrelated to an enhancement of dopaminergic transmission as suggested from earlier in vitro and in vivo findings. The higher activity of MK-801 in the present model and the recent observation that both memantine and amantadine bind--although with lower affinity--to an MK-801 binding site in the NMDA receptor-linked ion channel, suggest a possible involvement of striatal NMDA receptors in the antiparkinsonian effects of these drugs.

Acetylcholine↗

PubMed2004

Memantine hydrochloride: pharmacological and clinical profile.

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.

Alzheimer Disease↗

PubMed1997

Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine.

The present study focused on the effects of 1-amino-3,5-dimethyladamantane (memantine), a clinically used, low-affinity N-methyl-D-aspartate channel blocker, on the motivational impact of morphine and morphine withdrawal syndrome. Memantine (7.5 mg/kg) inhibited the acquisition as well as the expression of morphine-induced conditioned place preference. However, memantine did not affect significantly the acquisition or expression of conditioned place preference induced by food presentation. In addition, at the dose that blocked morphine-induced conditioned place preference, memantine by itself produced neither conditioned place preference nor conditioned place aversion. Memantine attenuated the negative motivational aspects of morphine withdrawal as assessed by conditioned place aversion produced by a low dose (0.1 mg/kg) of naloxone in morphine-dependent rats. Drug discrimination studies revealed that the inhibitory effects of memantine on morphine-induced conditioned place preference could not be attributed to the attenuation by memantine of the interoceptive cue produced by morphine. In addition, the inhibitory effects of memantine on the expression of morphine-induced conditioned place preference seemed not to be related to effects on memory retrieval, as revealed in the Morris water maze spatial task. These data suggest that memantine at a low, pharmacologically relevant dose of 7.5 mg/kg blocks the reinforcing effects of morphine and aversive effects of morphine withdrawal in rats, which suggests a new potential clinical indication for this agent in the treatment of opioid abuse.

Animals↗

PubMed2006

Memantine protects neurons from shrinkage in the lateral geniculate nucleus in experimental glaucoma.

OBJECTIVE: To determine whether memantine as a treatment for glaucoma prevents neuron shrinkage in the lateral geniculate nucleus, the major target for retinal ganglion cells. METHODS: Sixteen monkeys with right-eye unilateral experimental glaucoma for 14 months were studied and treated with memantine (n = 9) or vehicle only (n = 7). Left lateral geniculate nucleus relay neurons (layers 1, 4, and 6) were examined following parvalbumin immunolabeling. Cell body cross-sectional areas and neuron numbers were assessed using unbiased methods. Memantine- and vehicle-treated glaucoma groups were compared using t tests and analysis of covariance. RESULTS: Compared with vehicle-treated animals, memantine-treated animals showed significantly less mean +/- SD neuron shrinkage in layers 1 (-4.0% +/- 13.9% vs 28.2% +/- 17.4%; P = .001) and 4 (24.9% +/- 10.0% vs 37.2% +/- 12.3%; P = .04). For layer 6, the difference was not statistically significant (34.2% +/- 10.1% vs 45.3% +/- 14.5%; P = .10). Analysis of covariance results showed significantly less neuron shrinkage in the memantine-treated group for layers 1, 4, and 6 (P < .001; P < .02; and P < .04, respectively). This difference was greatest in layer 1. In each of these layers, neuron numbers did not differ significantly between groups. CONCLUSION: Monkeys with glaucoma that were treated with memantine showed significantly less neuron shrinkage in the lateral geniculate nucleus than the vehicle-treated glaucoma group. CLINICAL RELEVANCE: The finding that memantine protects adult visual neurons from transsynaptic atrophy in experimental glaucoma could have therapeutic value. Currently, memantine is being tested in an ongoing clinical trial as a treatment for glaucoma.

Animals↗

PubMed2004

The place of memantine in the treatment of Alzheimer's disease: a number needed to treat analysis.

INTRODUCTION: Memantine is currently the only treatment approved for moderately severe to severe Alzheimer's disease (AD). There is still some discussion as to its place in clinical practice and many UK clinicians are discouraged for economic reasons from prescribing it. We adopt a 'number needed to treat' (NNT) approach to assess the benefits reported in memantine trials. METHOD: We searched Medline and the Cochrane Dementia and Cognitive Improvement Specialised Register for double-blind, randomised and controlled trials of memantine in AD. If efficacy was only reported in terms of mean change, rather than as number of individuals who responded or were harmed by an intervention, we contacted the drug companies (Merz and Lundbeck) to ask for more data. We also calculated effect size. RESULTS: We found two trials of memantine in AD that met our criteria. We found that NNTs for global outcome were 3 and 6, for cognitive outcome 7 and for activities of daily living 4 and 8. The effect size for memantine varied between 0.32 and 0.62. For NNH memantine was no more harmful than placebo and significantly less so for the outcome of agitation. CONCLUSION: The small NNTs and the lack of harm shown by the NNHs strongly suggest that memantine, as with cholinesterase inhibitors, has a valuable place in the current clinical management of AD. The effect sizes are mainly in the 'medium' range for clinical effect, which also suggests that memantine has a clinical place in terms of cognition and dependency. There remains a need for more studies that examine carer burden, behavioural and psychological effects, and quality of life for both the person with dementia and the caregiver.

Activities of Daily Living↗

PubMed2005

Effects of memantine on behavioural symptoms in Alzheimer's disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies.

INTRODUCTION: Behavioural symptoms are common in moderate to severe Alzheimer's disease (AD). We have analysed the databases of two randomised studies with regard to the effects of memantine treatment on behavioural symptoms, measured using the 12-item version of the Neuropsychiatric Inventory (NPI). SUBJECTS: The monotherapy study (memantine only) reported by Reisberg et al. (2003) involved 252 patients with baseline MMSE total score of between 3 and 14, whereas the combination study (memantine and donepezil) reported by Tariot et al. (2004) comprised 404 patients with MMSE scores of between 5 and 14. In both studies, patients received 10 mg memantine b.i.d. or matching placebo, and lived in the community. METHODS: For both studies NPI total and individual domains scores were analysed in the ITT population. For the monotherapy study a dichotomised analysis was performed separately for patients who had behavioural symptoms at baseline and for those without pre-existing symptoms. Furthermore, a factor analysis was used to identify any behavioural clusters within the patient population. RESULTS: In both studies, the change in NPI total scores at endpoint was consistently in favour of memantine treatment, reaching statistical significance in the combination study (p = 0.002). Memantine treatment showed a significant beneficial effect in comparison to placebo treatment in the NPI agitation/aggression domain in both studies (p = 0.008; p = 0.001). The dichotomised analysis of the monotherapy study showed that there was significantly less agitation/aggression emerging in the memantine-treated group compared to placebo (p = 0.003). Factor analysis showed that hyperactivity accounted for 27% of the data variance. CONCLUSIONS: Memantine has a beneficial effect on the behavioural symptoms of patients with moderate to severe AD, with the most pronounced effect on agitation/aggression.

Aged↗

PubMed1999

Ethanol discrimination in the rat: lack of modulation by restraint stress and memantine.

There is a large body of experimental evidence that both stress and N-methyl-D-aspartate (NMDA) receptor antagonists may alter acute behavioural effects of ethanol. Notably, an uncompetitive, low-affinity NMDA receptor antagonist, memantine, has been recently claimed to possess anti-craving properties in rats with a long-term history of ethanol consumption. The aim of the present study was to assess the effects of restraint stress and memantine on the dose-response curve of ethanol discrimination. Rats were trained to discriminate 1 g/kg ethanol from saline in the two-lever drug discrimination procedure. When ethanol discrimination was acquired, the subjects were exposed to 30-min sessions of acute restraint stress, and different doses of ethanol (0.25, 0.5 or 1 g/kg) or saline were administered. In subsequent experiments the effects of memantine (2.25 or 4.5 mg/kg) on the cueing effects of ethanol were tested. Neither the stress sessions nor memantine influenced the ethanol discrimination dose-response curve. Moreover, the stress did not alter the rate of responding. However, both doses of memantine tended to increase the rate of responding when given in combination with lower doses of ethanol (0.25-0.5 g/kg). In contrast, 4.5 mg/kg memantine decreased the response rate when combined with 1 g/kg ethanol. These results suggest that: (1) pre-exposure to acute restraint stress or memantine does not affect the dose-response curve of ethanol discrimination; (2) memantine given in combination with low doses of ethanol may stimulate operant behaviour in the food-reinforced drug discrimination procedure.

Analysis of Variance↗

PubMed2006

Cost-effectiveness of memantine in community-based Alzheimer's disease patients: An adaptation in Spain.

Several clinical trials have demonstrated the efficacy and safety of the NMDA antagonist memantine in moderately severe to severe Alzheimer's disease (AD) patients. A 28-week pharmacoeconomic study conducted in the US also showed a reduction of total healthcare costs and informal care compared to placebo. Long-term implications of memantine treatment were modelled in the UK and Finland and revealed reductions in dependency, institutionalization and costs. However, these conclusions were not directly applicable to the Spanish setting where patients are mainly treated within the community. The objective of this study was to estimate the long-term implications in terms of costs and health benefits of memantine therapy compared to standard care using a Spanish adaptation of previous models over a 2-year time horizon. As in previous adaptations, Markov health states were defined as a combination of severity (mild-moderate, moderately severe, severe) and dependency plus death as the absorbing state. Spain-specific data (costs, mortality and epidemiological data) were obtained from local and recently published cohorts of AD patients. Data on the effectiveness of memantine were derived from a randomized double-blind placebo-controlled clinical trial of 252 moderately severe to severe AD patients. Effectiveness was measured as the time spent in a non-dependent health state. The evaluation was conducted over 2 years, while the efficacy of memantine was applied for 1 year only in order to ensure a conservative approach. The robustness of the model was tested by conducting stochastic analyses and various sensitivity analyses on the key assumptions. Patients receiving standard care were estimated to spend 6 months in a non-dependent state and to incur average total costs of Euro 24,700 over 2 years. The memantine strategy was associated with an additional 2.5 months in a non-dependent state and a Euro 700 cost reduction. Monte-Carlo simulations and sensitivity analyses supported these findings. Memantine appears to be cost-effective compared with standard care in moderately severe to severe AD patients in a Spanish setting. The prolonged independence provided by memantine treatment translated into cost reductions which offset drug costs and resulted in overall cost-savings.

Alzheimer Disease↗

PubMed1988

Memantine (1-amino-3,5-dimethyladamantane) blocks the serotonin-induced depolarization response in a neuronal cell line.

The influence of memantine on several properties of a neuronal cell line was tested. The aim was to get some insight into possible mechanisms of action of this drug which is therapeutically applicable in treatment of spasticity, Parkinson's disease, and cerebral coma. In neuroblastoma X glioma hybrid cells, memantine, at micromolar concentrations, blocked the depolarization induced by iontophoretically applied serotonin (5-hydroxytryptamine, 5-HT). In the hybrid cells, receptors of the 5-HT3 type mediated the depolarization, which was frequently accompanied by a series of action potentials. The inhibition by memantine of the serotonin response occurred fast and was completely reversible, irrespective of whether the cell showed a stable membrane potential or spontaneous action potentials. However, memantine did not alter spontaneous or electrically evoked action potential activity in the hybrid cells, and apparently did not block the underlying ionic conductances. Furthermore memantine did not affect either the cation permeability activated by substance P in the hybrid cells or the K+ channel triggered by bradykinin in a glioma cell line. Thus, memantine appears specifically to suppress the ion channel opened by serotonin in the hybrid cells. The interaction of memantine with serotonin receptors and the associated ion channels reported here, might give an important clue, as to a site of action of memantine in the nervous system.

Amantadine↗

PubMed1993

Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan).

Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-D-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg2+ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2-33 microM) concentration-dependently antagonized responses to NMDA 100 microM with an IC50 of 2.92 +/- 0.05 microM. In contrast, current responses to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (L-AMPA 50-100 microM) and gamma-amino butyric acid (GABA 10 microM) were unaffected by Memantine 8 microM. Memantine 8 microM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1-100 microM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1-100 microM) also selectively antagonized responses to NMDA (40 microM) in the cortical wedge preparation with IC50 of 12.9 +/- 1.5 microM.

Animals↗

PubMed1996

The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence.

The ability of memantine (1-amino-3,5-dimethyl-adamantane) to block the expression and maintenance of morphine dependence was examined in mice. When administered to morphine-dependent mice 45 min prior to naloxone challenge, memantine (7.5-30 mg/kg IP) in a dose-dependent manner reduced jumping behavior (a manifestation of the expression of dependence). The ability of memantine to attenuate naloxone-precipitated jumping was reversed by administration of glycine, an observation consistent with electrophysiological studies indicating that memantine is a use-dependent (uncompetitive) N-methyl-D-aspartate (NMDA) antagonist. In an independent series of experiments, the effect of memantine on a preestablished morphine dependence was investigated. A residual dependence to morphine was present 3 days after cessation of morphine administration. Repeated administration of memantine (10 mg/kg, IP) or the competitive NMDA antagonist NPC 17742 [2R, 4R, 5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid)] (6 mg/kg, IP) during this 3-day period abolished subsequent naloxone-precipitated jumping. In contrast, when administered concurrently with morphine after dependence had already been well established, memantine (10 and 20 mg/kg, IP) did not affect the maintenance of morphine dependence. Based on these finding, NMDA antagonists appear to inhibit the maintenance of opioid dependence, an action distinct from their acute inhibitory effects on the expression of dependence. Nonetheless, these regimen-dependent effects of memantine indicate that the most efficacious use of NMDA antagonists would be in detoxified subjects, rather than in individuals with an established dependence who are currently abusing opioids.

Amino Acids↗