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PubMed1988

Treatment of impaired cerebral function in psychogeriatric patients with memantine--results of a phase II double-blind study.

Memantine was investigated in a phase II double-blind trial on 30 elderly patients by comparison with a placebo with the aid of several psychometric tests. It was found that vigilance, short-term memory, and concentration improve significantly under Memantine. It was also found that Memantine exerted a beneficial effect on psychiatric and neurological symptoms despite the presence of an organic psychosyndrome of many years' duration and multiple morbidity. The tolerance of the preparation was good in virtually all cases and a gradually increasing dosage is recommended. On the basis of these findings the authors assume that the therapeutic efficiency can be confirmed in a phase III trial.

Aged↗
PubMed1984

[Effects of oral memantine administration on Parkinson symptoms. Results of a placebo-controlled multicenter study].

The effectiveness of memantine on the symptoms of Parkinson's disease was investigated in 67 patients (39 males, 28 females) mostly between 55 and 75 years. The study was multi-center placebo-controlled with four treatment groups, i. e. patients with and without pre- and after-treatment with other anti-Parkinson medication receiving either placebo or memantine as sole or additional medication. The analysis of 61 evaluable cases showed a positive statistically significant influence on the single symptom tremor as well as on the neurological overall symptomatology (Webster-scale total score). Despite the inadequately ascertained mode of action memantine promises success particularly in milder and initial forms of the Parkinson syndrome either used as monotherapy or as an adjuvant.

Administration, Oral↗
PubMed1989

Prevention and antagonism of acute carbofuran intoxication by memantine and atropine.

Male Sprague-Dawley rats administered with a sublethal acute dose of carbofuran (1.5 mg/kg, sc) developed the observable toxic signs of anticholinesterase nature within 5-7 min. The toxic signs with increasing propensity to maximal severity including tremors, generalized muscle fasciculations, and convulsions were evident during 15 min to 1 h and lasted for 2 h. Thereafter, signs were seen up to 3 h with reduced intensity. By the end of 3.5 h toxic signs were completely subsided. Maximal acetylcholinesterase (AChE) inactivation occurred at 1 h in discrete brain regions (cortex, stem, striatum, and hippocampus) and hemidiaphragm muscle when most severe signs of toxicity were also evident. A single sc dose of memantine HCl (MEM, 18 mg/kg) and atropine sulfate (ATS, 16 mg/kg) 60 and 15 min, respectively, prior to carbofuran administration completely prevented the expected gross toxic signs and significantly (p less than .01) attenuated the carbofuran-induced inhibition of AChE activity. When given therapeutically, this combined treatment completely reversed the clinical evidence of carbofuran toxicity within 15 min and also markedly reduced AChE inactivation. Memantine or atropine when given alone was less effective compared to their combined administration. The results of this study suggested that, in addition to cholinolytic effects of atropine, memantine may prevent and antagonize the acute toxicity of carbofuran by (a) protection of AChE activity and its rapid reactivation from inhibition and (b) rapid elimination of carbofuran.

Acetylcholinesterase↗
PubMed2006

A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders.

BACKGROUND: This pilot study examined the effectiveness of memantine hydrochloride in improving cognitive functioning and behavioral symptoms in children with pervasive developmental disorders (PDDs). METHOD: Subjects aged 3-12 years inclusive were enrolled in this 8-week, open-label study. Expressive and receptive language, nonverbal IQ, and nonverbal memory measures were administered at baseline and after 8 weeks of treatment with 0.4 mg/kg of memantine hydrochloride. Throughout the study, the Aberrant Behavior Checklist (ABC) was sent in weekly by parents as a measure of behavioral change. RESULTS: Twelve of 14 subjects completed the study. Significant improvement from baseline was noted on the memory test (Children's Memory Scale Dot Learning Subtest). There were no significant differences from baseline on measures of expressive or receptive language or nonverbal IQ. There were significant improvements on a number of ABC subscales, including hyperactivity, lethargy, and irritability. There were no overall significant statistical differences from baseline on the Clinical Global Improvement-Severity (CGI-S) scale. On the Clinical Global Improvement-Improvement (CGI-I), 4 of 14 subjects showed minimal improvement, and none was deemed "much-improved" or "very much improved." CONCLUSIONS: This small, prospective, open-label study suggests that memantine may be useful in the treatment of memory functioning and some behavioral symptoms in PDDs. The investigators did not see the same degree of change as endorsed by caretakers. Controlled studies are needed to substantiate and clarify these preliminary findings.

Child↗
PubMed2004

The NMDA receptor channel blocker memantine and opioid receptor antagonist naltrexone inhibit the saccharin deprivation effect in rats.

Several drugs, such as N-methyl-D-aspartate (NMDA) receptor channel blockers (memantine), naltrexone (but not naloxone) and acamprosate, have previously been reported to attenuate the expression of the alcohol deprivation effect, a phenomenon seen as an increase in post-deprivation alcohol consumption. The present study aimed to evaluate the effects of these drugs on the development and expression of the saccharin deprivation effect in adult male Wistar rats. Memantine (13 mg/kg per day) and naltrexone (5 mg/kg, twice daily), but not naloxone (24 mg/kg per day) or acamprosate (200 mg/kg, twice daily), prevented the increase in the consumption of saccharin after a 1-week deprivation from free-choice, unlimited access to saccharin (0.1%, w/v). Taken together with the results of previous studies, these results suggest that naltrexone and memantine attenuate the expression of both the alcohol and saccharin deprivation effects.

Acamprosate↗
PubMed2002

New approaches to clinical trials in vascular dementia: memantine in small vessel disease.

Although criteria for the diagnosis of vascular dementia (VaD) are established, the diagnostic concept is still controversial and there is no regulatory guidance for clinical drug development. Clinical trials in VaD present a number of pitfalls and challenges and, so far, no compound has received regulatory approval for this indication. The methodological issues of clinical VaD trials are discussed using the development of memantine for this indication as an example. In a pooled analysis of two placebo-controlled trials with the NMDA-antagonist memantine in VaD, the cognitive benefit by memantine treatment was more pronounced for patients with 'small vessel disease' than for those with other neuroradiological findings at baseline. In a subgroup of patients with 'large vessel disease' or macrolesions, there was less cognitive decline among the placebo patients. It may therefore be helpful to use predefined diagnostic subcategories in clinical studies in this indication. The findings further suggest that stroke or multiple infarctions may not be the primary reason for cognitive decline in VaD patients.

Aged↗
PubMed2002

Different action of memantine and caroverine on glutamatergic transmission in the mammalian cochlea.

Glutamate is the major transmitter candidate between inner hair cells and the afferent neurons of the mammalian cochlea. We investigated the action of memantine (1-amino-3,5-dimethyl-adamantane) and the quinoxaline derivative caroverine [1-diethylaminoethyl-3,8-(p-methoxybenzyl)-1,2-dihydro-quinoxaline-dione] on the glutamatergic transmission in the guinea pig cochlea utilizing extracellular recording techniques and microiontophoretic ejection of substances. While memantine was able to inhibit the NMDA (N-methyl-D-aspartate)-induced firing, the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)-stimulated activity was unaffected. In contrast, caroverine could block both NMDA- as well as AMPA-induced firing. As memantine and caroverine are currently in clinical use, these substances could be introduced to the treatment of several cochlear disorders.

Animals↗
PubMed1987

Radioelectroencephalographic comparison of memantine with receptor-specific drugs acting on dopaminergic transmission in freely moving rats.

Chronic implantation of four bipolar concentric electrodes into frontal cortex, hippocampus, striatum and reticular formation allows repetitive recordings of field potentials from freely moving rats. After radiotransmission the EEG signals are submitted to a quantitative spectral power analysis. Drug-induced changes in single frequency bands as obtained from the power spectra from different brain areas lead to a drug-specific pattern which can be compared with those of various standard compounds known to influence dopaminergic transmission in the central nervous system. With regard to receptor specificity the research compounds SK & F 38393 (D-1 agonist), SCH 23390 (D-1 antagonist), quinpirole (D-2 agonist) as well as haloperidol (D-2 antagonist, less specific) are tested under identical conditions. Memantine (1-6 mg/kg, i.p.) induces power decreases in a dose-dependent manner in nearly all frequency bands thus resembling the action of apomorphine. Less similar but still comparable is the action of amphetamine, whereas among the receptor-specific dopaminergic drugs only SK & F 38393 can be regarded as similar in as much as mainly delta, alpha-2 and beta-1 frequencies decrease at the same time. Thus memantine develops its own specific pattern of changes in the EEG which can be used to discriminate it from other drugs. The results are in accordance with the drug's proposed action of enhancing the dopaminergic transmission, which probably implies an indirect mechanism of action as biochemically no direct interaction with any of the dopaminergic receptors has been described for memantine so far.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

A double-blind, placebo-controlled study of memantine in the treatment of major depression.

OBJECTIVE: This study was designed to assess possible antidepressant effects of memantine, a selective N-methyl-D-aspartate (NMDA) receptor antagonist in humans. METHOD: In a double-blind, placebo-controlled study, 32 subjects with major depression were randomly assigned to receive memantine (5-20 mg/day) (N=16) or placebo (N=16) for 8 weeks. Primary efficacy was assessed by performance on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: The linear mixed models for total MADRS scores showed no treatment effect. CONCLUSIONS: In an 8-week trial, the low-to-moderate-affinity NMDA antagonist memantine in doses of 5-20 mg/day was not effective in the treatment of major depressive disorder.

Major Depressive Disorder↗
PubMed2005

Effect of donepezil in patients with Alzheimer's disease previously untreated or treated with memantine or nootropic agents in Germany: an observational study.

OBJECTIVE: This open-label, prospective, observational, Post-Marketing Surveillance (PMS) study assessed the efficacy and safety of donepezil in patients who had been switched from therapies currently used in Germany to treat Alzheimer's disease (AD), such as memantine and nootropics, due to insufficient efficacy or poor tolerability. A treatment-naive population was included as a comparator. RESEARCH DESIGN AND METHODS: Patients with AD were treated with donepezil and observed for a period of approximately 3 months. A cognitive assessment was made using the Mini-Mental State Examination (MMSE). Quality of life (QoL) was assessed by the investigators who answered the question 'How did therapy with donepezil influence the QoL of the patient and/or his family over the observation period?' and was graded using three ratings: improved/unchanged/worsened. Adverse events (AEs) were also monitored. RESULTS: A total of 913 patients entered the study (mean +/- SD MMSE score 18.03 +/- 5.34). Efficacy assessments were analyzed for three groups: an overall group of patients who had received any form of prior AD drug therapy (N+ group; n = 709); a subgroup of patients from the N+ group who had received prior memantine therapy only (M+ group; n = 111) and patients who were drug treatment naive (N- group; n = 204). In the evaluable population donepezil improved MMSE scores by 2.21 +/- 3.47 points on average, with similar improvements observed in all three groups. QoL was judged to be improved in at least 70% of patients, again with similar results obtained for all three groups. Donepezil was well tolerated, with 85 of 913 (9.3%) patients reporting AEs. The most common AEs were those typically seen with cholinergic therapies (i.e., diarrhoea, vomiting and nausea). CONCLUSIONS: In this observational PMS study, donepezil was shown to be efficacious and well tolerated in patients who were being insufficiently treated with memantine or nootropic therapy. The magnitude of response was similar to that observed in patients who were previously treatment naive, suggesting prior medication does not effect donepezil's efficacy.

Adult↗
PubMed1992

Memantine prevents HIV coat protein-induced neuronal injury in vitro.

Studies with in vitro model systems suggest that at least part of the neurologic deficits of human immunodeficiency virus (HIV)-1-associated cognitive/motor complex may stem from neuronal injury mediated by the HIV-1 coat protein gp120. Concurrent activation of N-methyl-D-aspartate (NMDA) receptors is also necessary for gp120 to induce neuronal damage. We studied memantine, a drug that blocks NMDA receptor-operated ion channels, for possible protective effects from gp120-induced neuronal injury. In identified rat retinal ganglion cells in culture, we found that 2 microM memantine completely prevented the injury engendered by 20 pM gp120. These data suggest that memantine has therapeutic potential as an NMDA antagonist capable of ameliorating neuronal damage associated with gp120.

Animals↗
PubMed2003

Evaluation of memantine for the treatment of Alzheimer's disease.

Increasing evidence suggests that disturbances in glutamatergic activity play an important role in Alzheimer's disease (AD). Excessive glutamate-mediated activation of NMDA receptors, for example, may contribute to the neuronal death that characterises AD. On the other hand, physiological activation of the NMDA receptor appears necessary for normal cognitive function. Therefore, compounds that finely modulate NMDA receptor activity hold promise as treatments for AD. Memantine (Namenda, Axura, Ebixa; Forest Laboratories, Inc., Merz Pharmaceuticals GmbH, H. Lundbeck A/S) is a low-moderate affinity, uncompetitive NMDA-receptor antagonist that appears to block pathological, but not physiological, activation of the NMDA receptor. Consequently, therapeutic doses of the drug are well-tolerated and do not seem to interfere with the acquisition or processing of cognitive information. Memantine has been shown to improve symptoms and reduce the rate of clinical deterioration among patients with moderate-to-severe AD and was approved in the US for this indication in October 2003. This review provides a brief rationale for the development of memantine as a therapy for AD, as well as an overview of the pharmacology, clinical efficacy, safety and tolerability of this novel therapeutic agent.

Alzheimer Disease↗
PubMed2004

Memantine protects hippocampal neuronal function in murine human immunodeficiency virus type 1 encephalitis.

Memantine, a low-to-moderate-affinity NMDA receptor antagonist, can be used to treat cognitive impairment associated with Alzheimer's disease. However, its potential neuroprotective effects for human immunodeficiency virus type 1-associated (HIV-1-associated) dementia are less well appreciated. To this end we studied hippocampal synaptic function in a severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE). Human monocyte-derived macrophages (MDMs) infected with HIV-1(ADA) were injected stereotactically into the caudate and putamen of SCID mice, generating HIVE. These brain subregions are among those most affected in humans. Impaired synaptic transmission and long-term potentiation (LTP) were detected in the CA1 region of hippocampal brain slices of HIVE mice. Memantine-treated HIVE mice showed significant improvements in synaptic function during frequency facilitation tests and LTP induced by high-frequency stimulation when compared with untreated animals. Immunocytochemical measures of neuronal antigens mirrored the neuronal physiological tests. These results demonstrate that memantine attenuates hippocampal synaptic impairment in murine HIVE and provide a rationale for its use in infected humans who experience cognitive decline.

AIDS Dementia Complex↗
PubMedDate not supplied

[Use of acetylcholinesterase inhibitors and memantine in Alzheimer-type dementia].

BACKGROUND: The therapeutic options to treat Alzheimer-type dementia (ATD) in recent years, have made it increasingly necessary to become familiar with the employment pattern of these new medicinal products. METHODS: A cross-sectional observational study of the population with ATD treated with acetylcholinesterase inhibitors and/or memantine in the Gallician Health Service. Databases were compiled with the demographic variables and use data during April 2005 of the medicinal products studied. RESULTS: Of the 5110 patients with ATD, 70.47% were women. The mean age of the women was 80.12 and of the men was 78.61 years old, with standard deviations of 6.66 and 7.03, respectively. The female sex was one of the factors associated with presenting ATD to pharmacological treatment (OR: 1.932 [CI 95%: 1.819-2.052]). The medication used most was donepezyl (44.46% of patients). Significant differences were found in that memantine was used to treat more patients in the group of patients < or =64 years (19.7% in < or =64 years vs. 14% in >64 years [p < 0.05]), and donepezyl was preferentially used in patients > or =95 years (75% in > or =95 years vs. 46.9% in <95 years [p < 0.03]). No significant differences were observed in the use of anti-dementia therapy, expressed in DDD/patient/day between the sexes, age groups, or in the age groups separated according to sex. CONCLUSIONS: The use of memantine (in monotherapy or in combination) is more frequent in patients under 64 years old. Female sex was found to be a factor associated with presenting ATD to pharmacological treatment.

Age Factors↗
PubMedDate not supplied

Effect of memantine (NMDA antagonist) on Parkinson's disease: a double-blind crossover randomized study.

Our aim was to evaluate the effect of Memantine (1-amino 3,5-dimethyl-adamantane hydrochloride) on cardinal symptoms of Parkinson's disease and on the latency, duration, and magnitude of the response to a single dose of L-Dopa and on drug-induced dyskinesias. Twelve Hoehn-Yahr III-IV patients with idiopathic Parkinson's disease with motor fluctuations and drug-induced dyskinesias were randomized to the NMDA antagonist memantine or placebo in a cross-over design. A single-dose L-Dopa challenge was performed after each medication arm. A significant drug effect on the Unified Parkinson's Disease Rating Scale motor score was observed in "off" and "on" states (F(1,11) = 13.5; p < 0.003). No significant effect on drug-induced dyskinesias was seen. The results suggest that memantine may improve parkinsonian symptoms independently of dopaminergic drugs and, in contrast to recent findings with amantadine, it has no effect on drug-induced dyskinesias.

Aged↗
PubMedDate not supplied

Memantine and ACPC affect conditioned place preference induced by cocaine in rats.

The influence of uncompetitive NMDA receptor antagonist, 1-amino-3,5--dimethyl-adamantane (memantine) and partial glycineB site agonist, 1-amino-cyclopropanecarboxylic acid (ACPC) on cocaine-induced conditioned place preference (CPP) were examined in male Wistar rats. After determination of initial preference, animals were conditioned with cocaine (5 mg/kg, ip) for 3 conditioning trials, alone or in combination with memantine (7.5 mg/kg, ip) or ACPC (50.0 mg/kg, ip). Memantine prevented acquisition and expression of the place preference produced by cocaine, while ACPC prevented only acquisition effect. Neither of the NMDA antagonists displayed any reinforcing properties by itself. Our current data suggest that the NMDA receptor complex may be involved in the rewarding effect of cocaine.

Amino Acids, Cyclic↗
PubMed2003

Memantine for dementia?

Memantine (Ebixa--Lundbeck Ltd), an oral medicine, is available in the UK for treating "patients with moderately severe to severe Alzheimer's disease". It differs from other licensed dementia medicines in that it is an N-methyl-D-aspartate (NMDA) receptor antagonist. The company has claimed that, with memantine therapy, "improvements in activities of daily living help patients to maintain a degree of independence and be easier to care for, potentially avoiding the need for nursing home care". We assess the efficacy of memantine for dementia and discuss its place in the management of patients with Alzheimer's disease.

Aged↗
PubMed2003

[Memantine for the treatment of dementia].

Problems in the Netherlands with respect to the reimbursement of memantine have led the patient organization 'Alzheimer Nederland' to establish an emergency fund. Several trials have documented the limited, but consistent beneficial effects of memantine in severely demented patients. It is not clear which subgroup of patients might benefit the most. The drug seems to have dopamimetic and antidepressant effects which might explain its overall effect. The publicity surrounding memantine contributes to an atmosphere in which patients and care providers have to explain why they are not yet using 'anti-dementia drugs'. This should be avoided. Patients can expect to gain more benefit from ongoing, thorough and independent investigations than from hastily established emergency funds to finance the use of a drug with a limited and poorly defined efficacy.

Dementia↗