Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Memantine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 325 records · Page 18Linked to original sources
PubMed2005

A new anti-obesity drug treatment: first clinical evidence that, antagonising glutamate-gated Ca2+ ion channels with memantine normalises binge-eating disorders.

The regulation of appetite relies on complex hypothalamic neurocircuitry of which the arcuate nucleus, and the hormone leptin play important roles. Arcuate nucleus neurones are essential for the regulation of eating behaviour, but they can be intoxicated by elevated serum levels of the amino acid glutamate (GLU). Neurotoxic effects of GLU are mediated by the N-methyl-D-aspartate receptor (NMDA-R). But the neurotoxic effects of GLU can be prevented. Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent non-competitive NMDA-R antagonist, antagonises GLU-gated Ca2+ ion channels and completely prevents the adverse effects of GLU. Also the non-competitive NMDA-R antagonist memantine displays neuroprotective properties. In view of a previously published hypothesis that human obesity results from chronic over-consumption of GLU, we performed a therapeutic trial in five obese, but otherwise healthy women. Memantine treatment markedly decreased appetite within few hours and complete suppressed the binge-eating disorder within 24 h. Body weight decreased markedly within a few days. The findings strongly support the hypothesis that elevated levels of nutritional GLU play an important role in the pathomechanism of human obesity. We suggest to treat human obesity by protecting the hypothalamic signalling cascade of leptin action with low to moderate affinity, non-competitive NMDA-R antagonists that selectively block the GLU-gated Ca2+ ion channels.

Adult↗
PubMed2006

Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by Memantine.

The activity of protein phosphatase (PP)-2A, which regulates tau phosphorylation, is compromised in Alzheimer disease brain. Here we show that the transient transfection of PC12 cells with inhibitor-2 (I2PP2A) of PP2A causes abnormal hyperphosphorylation of tau at Ser396/Ser404 and Ser262/Ser356. This hyperphosphorylation of tau is observed only when a sub-cellular shift of I2PP2A takes place from the nucleus to the cytoplasm and is accompanied by cleavage of I2PP2A into a 20 kDa fragment. Memantine, an un-competitive inhibitor of N-methyl-D-aspartate receptors, inhibits this abnormal phosphorylation of tau and cell death and prevents the I2PP2A-induced inhibition of PP2A activity in vitro. These findings demonstrate novel mechanisms by which I2PP2A regulates the intracellular activity of PP2A and phosphorylation of tau, and by which Memantine modulates PP2A signaling and inhibits neurofibrillary degeneration.

Animals↗
PubMed2006

Determination of memantine in human plasma by liquid chromatography-electrospray tandem mass spectrometry: application to a bioequivalence study.

A simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of memantine (I) in human plasma is presented. Sample preparation consisted of the addition of amantadine (II) as internal standard (IS), liquid-liquid extraction in basic conditions using a mixture of diethyl ether-chloroform (7:3, v/v) as extracting solvent, followed by centrifugation, solvent evaporation and sample reconstitution in methanol. Both I and II (internal standard) were analyzed using a C18 column and a mobile phase composed of methanol-water-formic acid (80:20:0.1, v/v/v). Eluted compounds were monitored using positive mode electrospray (ES) tandem mass spectrometry. The analyses were carried out by selected reaction monitoring (SRM) using the parent to daughter combinations of m/z 180>163 (memantine) and m/z 152>135 (amantadine). The peak areas from the analyte and IS were used for quantification of I. The achieved limit of quantification (LOQ) was 0.1 ng/mL; the assay exhibited a linear dynamic range of 0.1-50.0 ng/mL with a determination coefficient (r2) of at least 0.98. Validation results on linearity, specificity, accuracy, precision and stability, as well as on application to the analysis of samples taken up to 320 h after oral administration of 20mg (two 10mg capsules) of I in healthy volunteers demonstrated the applicability to bioequivalence studies.

Antiparkinson Agents↗
PubMed2005

Amantadine and memantine induce the expression of the glial cell line-derived neurotrophic factor in C6 glioma cells.

Aminoadamantanes are commonly used in the treatment of Parkinson's and Alzheimer's diseases. While these drugs are shown to antagonise ionotropic glutamate receptors on neuronal cells, additional mechanisms could contribute to their neuroprotective properties. The aim of the present study was to investigate the effect of aminoadamantanes on the production of the glial cell line-derived neurotrophic factor (GDNF) in glial cells. For this purpose, we measured the modulation of GDNF release in C6 glioma cell cultures treated for 24 h with amantadine and memantine. Both drugs dose-dependently increased GDNF level in the culture medium with similar potency (submicromolar range) and efficacy (three to four-fold induction). RT-PCR studies revealed that both compounds also increased GDNF mRNA levels and their influence on the GDNF gene transcription was further evidenced using a rat GDNF promoter luciferase reporter assay. Together, these results demonstrate that the neuroprotective effect of amantadine and memantine could involve the regulation of GDNF production by glial cells.

5' Untranslated Regions↗
PubMed2006

Memantine augmentation for refractory obsessive-compulsive disorder.

Glutamatergic hyperactivity hypothesis in obsessive-compulsive disorder (OCD) has been proposed but not tested. Memantine is an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. We report two cases of refractory obsessive-compulsive disorder treated with an augmentation of memantine at 15 mg/day. The first case did not benefit from such treatment, while the second showed immediate and substantial improvement. Contrasting results, reflecting different subtypes of OCD, are discussed. We hypothesized that in certain OCD subtypes an agent that enhances memory for actions may promote a reduction in orbitofrontal activation.

Adult↗
PubMed2006

Neuronal oxidative injury and dendritic damage induced by carbofuran: protection by memantine.

Carbamate insecticides mediate their neurotoxicity by acetylcholinesterase (AChE) inactivation. Male Sprague-Dawley rats acutely intoxicated with the carbamate insecticide carbofuran (1.5 mg/kg, sc) developed hypercholinergic signs within 5-7 min of exposure, with maximal severity characterized by seizures within 30-60 min, lasting for about 2 h. At the time of peak severity, compared with controls, AChE was maximally inhibited (by 82-90%), radical oxygen species (ROS) markers (F(2)-isoprostanes, F(2)-IsoPs; and F(4)-neuroprostanes, F(4)-NeuroPs) were elevated 2- to 3-fold, and the radical nitrogen species (RNS) marker citrulline was elevated 4- to 8-fold in discrete brain regions (cortex, amygdala, and hippocampus). In addition, levels of high-energy phosphates (HEPs) were significantly reduced (ATP, by 43-56%; and phosphocreatine, by 37-48%). Values of total adenine nucleotides and total creatine compounds declined markedly (by 41-56% and 35-45%, respectively), while energy charge potential remained unchanged. Quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant decreases in dendritic lengths (by 64%) and spine density (by 60%). Pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (18 mg/kg, sc), in combination with atropine sulfate (16 mg/kg, sc), significantly attenuated carbofuran-induced changes in AChE activity and levels of F(2)-IsoPs and F(4)-NeuroPs, declines in HEPs, as well as the alterations in morphology of hippocampal neurons. MEM and ATS pretreatment also protected rats from carbofuran-induced hypercholinergic behavioral activity, including seizures. These findings support the involvement of ROS and RNS in seizure-induced neuronal injury and suggest that memantine by preventing carbofuran-induced neuronal hyperactivity blocks pathways associated with oxidative damage in neurons.

Acetylcholinesterase↗
PubMed1997

The antiseizure efficacies of MK-801, phencyclidine, ketamine, and memantine are altered selectively by stress.

Adaptive changes in the NMDA receptor complex occur in response to exposure to stress. We have previously shown that the ability of MK-801, an uncompetitive NMDA receptor antagonist, to antagonize electrically precipitated tonic hind-limb extension is reduced 24 h after mice are forced to swim for up to 10 min in cold water. The stress-induced reduction of the antiseizure efficacy of MK-801 stimulated the proposal that mice exposed to swim stress may serve as "an intact animal model" of altered or diminished NMDA-mediated neural transmission. In the current investigation, the dose-dependent abilities for the antagonism of electrically precipitated seizures in mice were determined for MK-801, phencyclidine, ketamine, and memantine. Interestingly, a single session of cold water swim stress reduced the antiseizure efficacies of MK-801 and memantine without affecting phencyclidine and ketamine when tested 24 h later. The data do not suggest that stress results in a simple reduction in the number of activated or open channels, but rather alters their size or charge characteristics.

Animals↗
PubMed2001

The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner.

The type 3 serotonin (5-HT(3)) receptor is a ligand-gated ion channel. In concentration-clamp experiments, we investigated the effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists memantine, amantadine and MRZ 2/579 on 5-HT receptors stabley expressed in HEK-293 cells and on native 5-HT(3) receptors in the N1E-115 cell line. All agents antagonized serotonin (10 microM)-induced inward currents with similar potency to that reported for NMDA receptors. This effect was characterized by inducing a pronounced receptor desensitization, and was probably non-competitive and voltage-independent. In contrast, (S)-ketamine was much weaker as an antagonist of 5-HT(3) receptors than NMDA receptors. Similar effects on 5-HT(3) receptors have been reported previously for a variety of anti-depressants and it is possible that the clinical anti-depressant effects reported for both memantine and amantadine are mediated, at least in part, by antagonistic effects at 5-HT(3) receptors.

Animals↗
PubMed2001

Memantine, but not dizocilpine, ameliorates cognitive deficits in adult rats withdrawn from chronic ingestion of alcohol.

Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months and then withdrawn from alcohol. During the first 4 weeks of the withdrawal period, animals were intraperitoneally injected with either memantine (20 mg/kg bolus followed by 1 mg/kg every 12 h) or dizocilpine (MK-801; 0.1 mg/kg every 12 h), both of which are antagonists of N-methyl-D-aspartate receptors. Ten weeks after initiation of the withdrawal procedure, cognitive status of animals was assessed using the Morris water maze. Withdrawal from alcohol produced robust deficits in the performance of rats on the acquisition task and on the probe trial. Treatment with memantine resulted in a complete reversal of these behavioral impairments. In contrast, treatment with MK-801 was found to be ineffective in preventing cognitive alterations associated with chronic alcohol consumption and withdrawal.

Alcohol-Induced Disorders, Nervous System↗
PubMed1998

The non-competitive N-methyl-D-aspartate-antagonist memantine does not affect segmental mono- and polysynaptic reflexes in man.

Studies in rats have shown that the polysynaptic flexor reflex (FR) but not the monosynaptic reflexes are affected by N-methyl-D-aspartate (NMDA) receptor antagonists. Theoretically, the suppression of FR might be caused by an alteration of the spinal nociceptive neurons. To investigate, whether the non-competitive NMDA receptor antagonist memantine interferes with nociception in man, we studied both its effect on pain perception and on FR. In a double-blind study 14 male subjects were randomly assigned to either placebo or memantine (30 mg p.o.) treatment. H-reflex (HR) and FR as well as pain and tolerance threshold were determined prior to and 6 h after drug intake. Contrary to expectations, there were no differential treatment effects either on FR threshold and magnitude or on pain and tolerance thresholds or the HR amplitude.

Adult↗
PubMed2006

Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond.

Neuroprotective drugs tested in clinical trials, particularly those that block N-methyl-D-aspartate-sensitive glutamate receptors (NMDARs), have failed miserably in large part because of intolerable side effects. However, one such drug, memantine, was recently approved by the European Union and the US FDA for the treatment of dementia following our group's discovery of its clinically tolerated mechanism of action. Here, we review the molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca(2+) influx through the receptor's associated ion channel and consequent free-radical formation.

Animals↗
PubMed2000

A prospective PMS study to validate the sensitivity for change of the D-scale in advanced stages of dementia using the NMDA-antagonist memantine.

The present postmarketing surveillance (PMS) study is the first large scale systematic and prospective clinical trial of pharmacotherapeutic intervention in advanced stages of dementia. Within a validation program this study aimed at demonstrating the sensitivity of the D-Scale of change (DS-C) for measuring ADL-function. Efficacy of treatment with the NMDA-antagonist memantine was investigated in 531 patients with advanced dementia employing a parallel group design that stratified patient cohorts by severity according to GDS stages (Reisberg, 1992). Efficacy was determined on two independent levels: by the assessment of the physicians' Clinical Global Impression of Change (CGI-C) at the end of a 6-week observation period, and by the assessment of change in elementary ADL-functions by the caregivers using the D-Scale-of-Change. With the D-Scale-of-Change the caregivers can assess a change in broad functional items, i.e. cognitive and motor functions and also elementary functions of daily life. The effect size of this improvement increased constantly during the observation period. Even in patients of GDS stage 7 an improvement could be measured. These results were also seen by the physicians, who recorded an overall clinical improvement in 75.5% of the patients after 6 weeks. Tolerability evaluations resulted in the ratings "very well" by 59.5% or "well" by 35.0% of the patients. No serious adverse drug reactions occurred. A correlation analysis demonstrated a high congruency of both assessments. Furthermore, the observed time course of these improvements paralleled with the time course of symptomatic benefit by effects of memantine that had been repeatedly demonstrated in randomised, double-blind, placebo-controlled studies in mild to moderate dementia. Together with the evaluation of the scale-properties of the D-Scale for assessment of severity the D-Scale and the D-Scale-of-Change can be regarded as validated.

Activities of Daily Living↗
PubMed2003

Effects of memantine, an NMDA receptor antagonist, on place preference conditioned with drug and nondrug reinforcers in mice.

Antagonists of the N-methyl-D-aspartate (NMDA) receptor complex have been shown to inhibit the expression of place preferences conditioned with several drugs that are abused by humans, which suggests that this class of compounds may be beneficial in the treatment of substance dependence. Therefore it is important to assess the specificity of this effect, of whether inhibitory effects of NMDA receptor antagonists on conditioned drug stimuli generalize to behaviors produced by nondrug reinforcers. The present study was designed to compare the effects of the NMDA receptor channel blocker, memantine, on the expression of place preferences conditioned with: (1) consumption of regular laboratory food; (2) sexual encounters with females; and (3) injection of morphine (10 mg/kg) in adult male Swiss mice. For all three experiments reported here, unconditioned stimuli (food, receptive female or morphine) were presented before the exposures to the "to-be-conditioned" environments. Significant place preferences developed as a result of explicit pairings of the environmental context and food consumption, sexual encounter and morphine administration. Memantine (7.5 mg/kg, given prior to the post-conditioning test) inhibited the expression of place preferences conditioned with morphine and sexual encounter, but had no effects in food-conditioned mice. These findings suggest that the effects of NMDA receptor blockade may not be limited to drug-reinforced behaviors.

Animals↗
PubMed1998

Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine.

Recently, we cloned the human cation transporter hOCT2, a member of a new family of polyspecific transporters from kidney, and demonstrated electrogenic uptake of tetraethylammonium, choline, N1-methylnicotinamide, and 1-methyl-4-phenylpyridinium. Using polymerase chain reaction amplification, cDNA sequencing, in situ hybridization, and immunohistochemistry, we now show that hOCT2 message and protein are expressed in neurons of the cerebral cortex and in various subcortical nuclei. In Xenopus laevis oocytes expressing hOCT2, electrogenic transport of norepinephrine, histamine, dopamine, serotonin, and the antiparkinsonian drugs memantine and amantadine was demonstrated by tracer influx, tracer efflux, electrical measurements, or a combination. Apparent Km values of 1.9 +/- 0.6 mM (norepinephrine), 1.3 +/- 0.3 mM (histamine), 0.39 +/- 0.16 mM (dopamine), 80 +/- 20 microM (serotonin), 34 +/- 5 microM (memantine), and 27 +/- 3 microM (amantadine) were estimated. Measurement of trans-effects in depolarized oocytes and human embryonic kidney cells expressing hOCT2 suggests that there were different rates and specificities for cation influx and efflux. The hypothesis is raised that hOCT2 plays a physiological role in the central nervous system by regulating interstitial concentrations of monoamine neurotransmitters that have evaded high affinity uptake mechanisms. We show that amantadine does not interact with the expressed human Na+/Cl- dopamine cotransporter. However, concentrations of amantadine that are effective for the treatment of Parkinson's disease may increase the interstitial concentrations of dopamine and other aminergic neurotransmitters by competitive inhibition of hOCT2.

Amantadine↗
PubMed1996

The use of diurnal vigilance changes in the EEG to verify vigilance-enhancing effects of memantine in a clinical pharmacological study.

In elderly subjects there is a vigilance decrease from morning to noon which was used in a clinical pharmacological model as a state condition to verify vigilance-enhancing effects of an antidementia drug. In this model the effects of Memantine (20 mg, single-dose application) on the quantified EEG were investigated in 16 elderly (mean age: 65 +/- 5 years), healthy subjects (10 females, 6 males) in a randomised, twofold cross-over design vs. placebo under double-blind conditions. EEG was recorded before medication, and 2 and 4 h after medication under reaction time (RT) and resting (RS) conditions. EEG data were subjected to spectral analysis and the topographic distribution of the amplitude values was mapped. The results show that a time-dependent decrease (from morning to noon) in vigilance (indicated by an increase in average EEG amplitudes caused by increased synchronisation in the alpha and beta range and an increase in delta) occurred under placebo which was counteracted by Memantine. The diurnal variations of the EEG and their compensation by a pharmacological agent represent an effective model for investigating the vigilance-enhancing effects of antidementia drugs.

Aged↗
PubMed2006

Rationale for combination therapy with galantamine and memantine in Alzheimer's disease.

A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of Alzheimer's disease. Therefore, one hypothesis is that treatment strategies should address impairments in both systems. Galantamine is an acetylcholinesterase inhibitor that, unlike other acetylcholinesterase inhibitors, has a postulated dual mode of action as a nicotinic receptor modulator. Galantamine has demonstrated long-term efficacy in improving or maintaining cognition, functionality, and behavior in patients with mild to moderate Alzheimer's disease. Memantine, a noncompetitive N-methyl-D-aspartate-receptor antagonist, reduces deterioration in cognition and function in patients with moderate to severe Alzheimer's disease. Pharmacokinetic and pharmacodynamic as well as ongoing observation studies support the concept of adjunctive therapy with memantine in patients with advanced moderate Alzheimer's disease currently treated with an established galantamine regimen. The potential to modulate both acetylcholine and glutamate pathways in Alzheimer's disease presents a novel treatment strategy for the management of mild to moderately severe Alzheimer's disease.

Alzheimer Disease↗
PubMed2006

Added therapeutic value of memantine in the treatment of moderate to severe Alzheimer's disease.

When evaluating the added therapeutic value of a drug, evidence of greater overall benefit or at least an add-on benefit is increasingly being required. Therefore, cost-effectiveness in addition to clinical efficacy is an important consideration. The efficacy of a drug must be examined on the basis of clinical trials by measuring specific parameters that are affected by the drug (for example blood pressure with antihypertensive treatment). Today not only efficacy but also patient-relevant changes (patient benefits) must be demonstrated for a drug, often by measuring quality of life. In order to evaluate the benefit of monotherapy with the N-methyl-D-aspartate antagonist memantine in the management of moderate to severe Alzheimer's disease, a systematic literature review was conducted. The results showed a benefit for memantine in comparison with placebo in terms of a decrease in nursing care, a delay in care dependency and a delay in admission to nursing homes. In addition, an increase in quality of life has been observed.

Alzheimer Disease↗