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PubMed2003

Memantine for dementia.

BACKGROUND: Alzheimer's disease, vascular and mixed dementia are the commonest forms of dementia in older people. There is evidence that the excitatory activity of L-glutamate plays a role in the pathogenesis of Alzheimer's disease and in the damage from an ischaemic stroke. A low affinity antagonist to N-Methyl-D-aspartate (NMDA) type receptors, such as memantine, may prevent excitatory amino acid neurotoxicity without interfering with the physiological actions of glutamate required for memory and learning. OBJECTIVES: To determine the clinical efficacy and safety of memantine for people with Alzheimer's disease, vascular, or mixed dementia. SEARCH STRATEGY: Trials were identified from a search of the Trial-based Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 9 October 2002 using the terms: memantin*, D-145, DMAA, DRG-0267. All major health care databases and trial databases within the scope of the group are searched regularly to keep this Register up to date. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomized and unconfounded trials in which memantine was administered to people with dementia. DATA COLLECTION AND ANALYSIS: Data were extracted, pooled where possible, and weighted mean differences, standardized mean differences or odds ratios were estimated. Intention-to-treat (ITT) and observed cases (OC) analyses are reported, where data were available. MAIN RESULTS: There were a total of seven trials that met inclusion criteria, of which five had sufficient data for analysis. The analysis of change from baseline for cognition gave statistically significant results in favour of memantine (20 mg/day) (MD: -2,83 95% CI -4.37 to -1.29, P=0.0003) at 28 weeks and for memantine (30mg/day) at 6 weeks (MD: -3.04. 95% CI -5.68 to -0.40, P=0.02). Effects on Activities of Daily living (ADL) were difficult to interpret. One study provided data using a non-validated scale for measuring five simple instrumental tasks under the guidance of an investigator. When pooled with another study the analysis gave statistically significant results in favour of memantine for 30 mg/day at 6 weeks (SMD: -1.36 95% CI -1.77 to -0.96, P=0.0003). Mood and behaviour: One trial provided data on memantine 30 mg/day at 6 weeks using the NOSIE scale. The OC analysis found statistically significant differences in favour of treatment (MD: 23.30 95% CI 17.83 to 28.77, P<0.00001). Global scales: The analysis revealed a statistically significant difference in favour of memantine (20mg/day ) at 6 weeks (MD: -12.30 95% CI -16.90 to -7.70, P<0.00001). Similar results were found for larger doses (memantine 30 mg/day) at 6 weeks in a pooled meta-analysis of two other studies (WMD: -10.77 95% CI -13.46 to -8.09, P<0.00001). With regard to the Global Impression of Change three studies found statistically significant results in favour of 10, 20 and 30 mg/day of memantine compared with placebo at 6 or 12 weeks. There was a benefit in favour of memantine (20 mg/day) compared with placebo at 6 weeks, for the numbers improved ( 24/41 compared with 11/41)(OR, 3.85, 95% CI 1.52 to 9.75, P=0.004), in favour of memantine (30 mg/day) compared with placebo at 6 weeks, for the numbers improved ( 20/30 compared with 8/29)(OR, 5.25, 95% CI 1.72 to 15.98, P=0.004) and in favour of memantine (10 mg/day) compared with placebo at 12 weeks, for the numbers improved ( 60/82 compared with 38/84)(OR, 3.30, 95% CI 1.72 to 6.33, P=0.0003). In general memantine seemed to be well tolerated. There was no statistically significant difference between memantine and placebo for the three studies that reported adverse events. There were some data on specific adverse events. In one study the incidence of restlessness by the end of the treatment at 6 weeks was statistically significantly lower in the placebo group than in the group taking memantine 30 mg/day (15/30 compared with 2/29) (OR 13.50, 95% CI 2.71 to 67.19, P=0.001). The number of dropouts was similar in treatment and placebo groups at 6 or 28 weeks time for memantine 20 mg/day and at 6 weeks for memantine 30 mg/day. REVIEWER'S CONCLUSIONS: Memantine is a safe drug and may be useful for treating Alzheimer's, vascular,and mixed dementia of all severities. Most of the trials so far reported have been small and not long enough to detect clinically important benefits. However there is a possible benefit on cognition and global measures, and an early improvement in behaviour in people with dementia. More studies are needed.

Activities of Daily Living↗

PubMed1993

Evidence for lysosomotropism of memantine in cultured human cells: cellular kinetics and effects of memantine on phospholipid content and composition, membrane fluidity and beta-adrenergic transmission.

Memantine, an amantadine derivative, is therapeutically used for the treatment of various neurological and psychiatric disorders such as Parkinson's disease, spasticity, and dementia. Pharmacokinetics of memantine and its effects on phospholipid content and composition, on membrane properties and functions such as fluidity and beta-adrenergic transmission were studied in cultured human fibroblasts and macrophages. The kinetic behaviour of memantine was characteristic for a lysosomotropic drug. Fibroblasts exposed to 14C-memantine in the microM range accumulated the drug up to 200 fold above initial medium concentrations. Lysosomal drug storage was proven by indirect evidence and by analyses of subcellular fractions. Repetitive exposure to memantine resulted in a cumulative uptake. While memantine uptake after single exposure was fully reversible, the rate and extent of release of chronically accumulated drug was reduced but could be enhanced by the addition of unlabelled memantine or ammonium chloride to the medium. Chronic, but not single, exposure to memantine above 10 microM resulted in a concentration dependent phospholipid accumulation and in a shift in the phospholipid composition. There was an overproportionate increase in phosphatidylinositol at the expense of phosphatidylserine and sphingomyelin. Chronic exposure of cultured cells to memantine increased fluidity in the superficial layers of the plasma membrane and reduced the isoproterenol-stimulated cAMP-response without affecting beta-adrenoceptor density. All these findings were compatible with the kinetic behaviour and the effectiveness expected of a weak lysosomotropic drug.

Anisotropy↗

PubMed1999

Dopamine release in the prefrontal cortex in response to memantine following sub-chronic NMDA receptor blockade with memantine: a microdialysis study in rats.

Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist which blocks the NMDA receptor with moderate-affinity in a use- and voltage dependent manner. In clinical practice it is used chronically in the treatment of dementia and does not induce psychotomimetic effects as, high affinity, uncompetitive antagonists. Thus, it was of interest to determine dopamine (DA) and metabolite (DOPAC - dihydroxyphenylacetic acid and HVA - homovanillic acid) concentrations in the prefrontal cortex (PFC) in response to 14 days administration of memantine (20 mg/kg/day). It was previously determined that in rats this treatment induces sensitization to the locomotor effect and tolerance to the learning impairing properties of high doses of memantine. Acute administration of memantine (20 mg/kg, i.p.) did not affect dopamine levels in the PFC. It did however increase DA metabolite (DOPAC and HVA) concentrations. Administration of memantine (20 mg/kg/day) for 14 days before the acute challenge only slightly changed memantine's effect on PFC neurochemistry even though pharmacokinetic tolerance was observed. When memantine was administered to the sham group, which had been repeatedly treated with Hypnorm (including neuroleptic), an increase in PFC dopamine and metabolite content was seen. In accordance with the fact that memantine does not possess psychotomimetic activity at therapeutically relevant doses, these experiments showed that it does not affect the prefrontal cortex dopamine levels.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine).

OBJECTIVES: To assess clinical efficacy and safety of memantine--an uncompetitive N-methyl-D-aspartate (NMDA) antagonist--in moderately severe to severe primary dementia. MATERIALS AND METHODS: Dementia was defined by DSM-III-R criteria and severity was assessed by the Global Deterioration Scale (stages 5-7) and the Mini-Mental State Examination (< 10 points). Primary endpoints were the Clinical Global Impression of Change (CGI-C) rated by the physician, and the Behavioural Rating Scale for Geriatric Patients (BGP), subscore 'care dependence', rated by the nursing staff. Secondary endpoints included the modified D-Scale (Arnold/Ferm). RESULTS: The ITT sample comprised 166 patients and 151 patients were treated per protocol. At 12-week ITT endpoint analysis, 82 received memantine 10 mg per day, 84 placebo. Dementia was in 49% of the Alzheimer type and in 51% of the vascular type (CT, Hachinski score). A positive response in the CGI-C was seen in 73% versus 45% in favour of memantine (stratified Wilcoxon p < 0.001), independent of the etiology of dementia. The results in the BGP subscore 'care dependence' were 3.1 points improvement under memantine and 1.1 points under placebo (p = 0.016). A coincident response of the two independent target variables was observed in 61.3% (memantine) versus 31.6% (placebo). Secondary endpoint analysis of the D-Scale assessing basic ADL functions support the primary results. Regarding the safety profile, no significant differences between treatment groups were observed. CONCLUSIONS: The results of this trial support the hypothesis that memantine treatment leads to functional improvement and reduces care dependence in severely demented patients.

Activities of Daily Living↗

PubMed1997

Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism.

1. N-methyl-D-aspartic acid (NMDA)-activated currents were recorded from dissociated rat retinal ganglion cells using whole-cell recording. The NMDA open-channel blocking drug memantine was evaluated for non-competitive and/or uncompetitive components of antagonism. A rapid superfusion system was used to apply various drugs for kinetic analysis. 2. Dose-response data revealed that memantine blocked 200 microM NMDA-evoked responses with a 50% inhibition constant (IC50) of approximately 1 microM at -60 mV and an empirical Hill coefficient of approximately 1. The antagonism followed a bimolecular reaction process. This 1:1 stoichiometry is supported by the fact that the macroscopic blocking rate of memantine (kon) increased linearly with memantine concentration and the macroscopic unblocking rate (koff) was independent of it. The estimated pseudo-first order rate constant for macroscopic blockade was 4 x 10(5) M-1 S-1 and the rate constant for unblocking was 0.44 s-1. Both the blocking and unblocking actions of memantine were well fitted by a single exponential process. 3. The kon for 2 microM memantine decreased with decreasing concentrations of NMDA. By analysing kon behaviour, we estimate that memantine has minimal interaction with the closed-unliganded state of the channel. As channel open probability (Po) approached zero, a small residual action of memantine may be explained by the presence of endogenous glutamate and glycine. 4. Memantine could be trapped within the NMDA-gated channel if it was suddenly closed by fast washout of agonist. The measured gating process of channel activation and deactivation appeared at least 10-20-fold faster than the kinetics of memantine action. By combining the agonist and voltage dependence of antagonism, a trapping scheme was established for further kinetic analysis. 5. With low agonist concentrations, NMDA-gated channels recovered slowly from memantine blockade. By analysing the probability of a channel remaining blocked, we found that memantine binding appeared to stabilize the open conformation of the blocked channel and did not affect ligand affinity. Validity of the "trapping model' and stabilization of the open conformation were further suggested by agreement between the predicted dose-response curve for NMDA in the presence of 2 microM memantine and the empirically derived dose-response relationship. 6. Based on simple molecular schemes, the degree of blockade at various concentrations of agonist for "pure' non-competitive vs. uncompetitive inhibition was computer simulated. The measured degree of blockade by 6 microM memantine was close to ideal for pure uncompetitive antagonism. Taken together, we conclude that the predominant mechanism of open-channel blockade by memantine is uncompetitive. In general, the relative magnitude of the dissociation rate of an open-channel blocker from the open but blocked channel (the apparent off-rate) compared with the rate of leaving the closed and blocker-trapped state (the leak rate) will determine the contribution of uncompetitive vs. non-competitive actions, respectively. 7. Millimolar internal Cs+ competed with memantine for binding in the NMDA-gated channel, and reduced the association rate of memantine, but had no effect on the voltage dependence of the dissociation rate. After removal of Cs+, the calculated Ki for memantine remained voltage dependent. These observations would be difficult to reconcile with models in which memantine binds to a site outside the channel pore and instead strongly support the supposition that the blocking site for memantine is within the permeation pathway.

Animals↗

PubMed1995

Modulation of NMDA effects on agonist-stimulated phosphoinositide turnover by memantine in neonatal rat cerebral cortex.

1. The ability of memantine (1-amino-3,5-dimethyladamantane) to antagonize the modulatory effects of N-methyl-D-aspartate (NMDA) on phosphoinositide turnover stimulated by muscarinic cholinoceptor- and metabotropic glutamate receptor-agonists has been examined in neonatal rat cerebral cortex slices. 2. Memantine antagonized the inhibitory effect of NMDA (100 microM) on both total [3H]-inositol phosphate ([3H]-InsPx) and inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) mass accumulations stimulated by carbachol (1 mM) with EC50 values of 21 and 16 microM respectively. 3. Memantine concentration-dependently antagonized (IC50 24 microM) the ability of NMDA (10 microM) to potentiate [3H]-InsPx accumulation in response to a sub-maximal concentration of the metabotropic glutamate receptor agonist, 1S,3R-ACPD (10 microM). 4. The small (approx. 3 fold), concentration-dependent increase in [3H]-InsPx accumulation stimulated by NMDA was completely antagonized by the prototypic NDMA receptor-channel blocker, MK-801 (1 microM) at all concentrations of NDMA studied (1-1000 microM). In contrast, antagonism by memantine (100 microM) was observed only at low concentrations of NMDA (1-10 microM), whilst [3H]-InsPx accumulation stimulated by high concentrations of NMDA (300-1000 microM) was markedly enhanced by memantine. 5. Assessment of the incorporation of [3H]-inositol into inositol phospholipids revealed that memantine (100 microM) caused an approximate 2 fold increase in the labelling of phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. 6H.p.l.c. separation of [3H]-inositol (poly)phosphates demonstrated that whilst memantine (100 microM)alone had no significant effect on the accumulation of any isomer, it substantially altered the profile of accumulation stimulated by NMDA (1 mM), greatly facilitating accumulation of Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4).7.These data provide evidence that memantine can antagonize the actions of NMDA in neonatal rat cerebral cortex slices in a manner consistent with this agent acting as a NMDA receptor-channel blocker. In addition, at least two further actions of memantine can be proposed. Memantine increases the rate of [3H]-inositol incorporation into the cellular inositol phospholipid fraction, without significantly stimulating phosphoinositide turnover. Furthermore, memantine can substantially alter patterns of inositol (poly)phosphates stimulated by NMDA, promoting the accumulation of the established and putative second messengers Ins(1,4,5)P3 and Ins(1,3,4,5)P4 which are not increased by NMDA in the absence of memantine. It is unknown whether these latter loci of memantine action contribute to known therapeutic actions of this agent.

Animals↗

PubMed1997

Trapping channel block of NMDA-activated responses by amantadine and memantine.

We investigated the mechanisms by which the antiparkinsonian and neuroprotective agents amantadine and memantine inhibit responses to N-methyl-D-aspartic acid (NMDA). Whole cell recordings were performed using cultured rat cortical neurons or Chinese hamster ovary (CHO) cells expressing NMDA receptors. Both amantadine and memantine blocked NMDA-activated channels by binding to a site at which they could be trapped after channel closure and agonist unbinding. For neuronal receptors, the IC50s of amantadine and memantine at -67 mV were 39 and 1.4 microM, respectively. When memantine and agonists were washed off after steady-state block, one-sixth of the blocked channels released rather than trapped the blocker; memantine exhibited "partial trapping." Thus memantine appears to have a lesser tendency to be trapped than do phencyclidine or (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[1,d]cyclihepten-5,1 0-imine (MK-801). We next investigated mechanisms that might underlie partial trapping. Memantine blocked and could be trapped by recombinant NMDA receptors composed of NR1 and either NR2A or NR2B subunits. In these receptors, as in the native receptors, the drug was released from one-sixth of blocked channels rather than being trapped in all of them. The partial trapping we observed therefore was not due to variability in the action of memantine on a heterogeneous population of NMDA receptors in cultured cortical neurons. Amantadine and memantine each noncompetitively inhibited NMDA-activated responses by binding at a second site with roughly 100-fold lower affinity, but this form of inhibition had little effect on the extent to which memantine was trapped. A simple kinetic model of blocker action was used to demonstrate that partial trapping can result if the presence of memantine in the channel affects the gating transitions or agonist affinity of the NMDA receptor. Partial trapping guarantees that during synaptic communication in the presence of blocker, some channels will release the blocker between synaptic responses. The extent to which amantadine and memantine become trapped after channel block thus may influence their therapeutic effects and their modulation of NMDA-receptor-mediated excitatory postsynaptic potentials.

Amantadine↗

PubMed2003

Memantine for the treatment of dementia.

BACKGROUND: The use of cholinesterase inhibitors to correct the cholinergic deficit in patients with mild to moderate Alzheimer's disease (AD) is well established. However, the treatment is only effective in about half of the patients for whom it is prescribed. Vascular dementia may respond, at least to some extent, to these drugs (T Erkinjuntti and colleagues, Lancet 2002; 359: 1283-90). In 2002, the Committee of Proprietary Medicinal Products recommended that memantine-a drug that acts on the glutamatergic system rather than the cholinergic system-be approved by the European Commission for the treatment of moderately severe to severe AD. Clinical trials have shown some effectiveness of memantine in the treatment of vascular dementia, although it has not been approved for use in this disorder. RECENT DEVELOPMENTS: The results of a study of the effects of memantine on moderate to severe AD have recently been published (B Reisberg and colleagues, N Engl J Med 2003; 348: 1333-41). Reisberg and colleagues treated their patients for 28 weeks, assessed several outcome variables, and found that memantine reduced clinical deterioration without significant adverse effects. This study is important as memantine is the only treatment licensed for patients with more advanced AD. WHERE NEXT? Several questions about the use of memantine as a treatment for AD remain to be answered. How beneficial is memantine treatment in routine clinical practice compared with clinical trials? What is the best way to assess treatment effects? How long do the beneficial effects last? Does memantine have neuroprotective, rather than just symptomatic, effects? In addition, we need to know when to switch from cholinesterase inhibitors to memantine or when to co-prescribe memantine with cholinesterase inhibitors. The efficacy of memantine in vascular dementia also requires further investigation.

Animals↗

PubMed2003

Resource utilisation and cost analysis of memantine in patients with moderate to severe Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a devastating illness that causes enormous emotional stress to affected families and is associated with substantial medical and nonmedical costs. OBJECTIVE: To determine the effects of 28 weeks of memantine treatment for patients with AD on resource utilisation and costs. STUDY DESIGN AND METHODS: Multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial performed in the US. The Wilcoxon-Mann-Whitney test was used to examine the resource utilisation variables and logistic regression models were used for multivariate resource utilisation analyses. Analysis of covariance (ANCOVA) models (log and non-log) were computed to examine costs from a societal perspective. All costs were calculated in 1999 US dollars. STUDY POPULATION: Outpatients with moderate to severe AD. Overall, 252 patients received randomised treatment, and 166 patients (placebo n = 76, memantine n = 90) formed the treated-per-protocol (TPP) subset for the health economic analyses, on which the main cost analysis was based. MAIN OUTCOME MEASURE: Resource Utilisation in Dementia (RUD) scale, measuring patient and caregiver resource utilisation, and various sources for cost calculations. RESULTS: Controlling for baseline differences between the groups, significantly less caregiver time was needed for patients receiving memantine than for those receiving placebo (difference 51.5 hours per month; 95% CI -95.27, -7.17; p = 0.02). Analysis of residential status also favoured memantine: time to institutionalisation (p = 0.052) and institutionalisation at week 28 (p = 0.04 with the chi-square test). Total costs from a societal perspective were lower in the memantine group (difference dollars US 1089.74/month [non-overlapping 95% CI for treatment difference -1954.90, -224.58]; p = 0.01). The main differences between the groups were total caregiver costs (dollars US-823.77/month; p = 0.03) and direct nonmedical costs (dollars US-430.84/month; p = 0.07) favouring memantine treatment. Patient direct medical costs were higher in the memantine group (p < 0.01), mainly due to the cost of memantine. CONCLUSION: Resource utilisation and total health costs were lower in the memantine group than the placebo group. The results suggest that memantine treatment of patients with moderate to severe AD is cost saving from a societal perspective.

Activities of Daily Living↗

PubMed1992

Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study.

The efficacy and the tolerability of memantine (1-amino-3,5-dimethyladamantane hydrochloride, Akatinol Memantine, CAS 41100-52-1) were investigated in patients with mild to moderate dementia syndrome in a randomized two-centre placebo-controlled clinical study. The test substance was administered at a dose of 10 mg/d from day 1 to day 3 and then at a dose of 2 x 10 mg/d from day 4 to the end of treatment after 42 days. Altogether, 88 patients were recruited to the study; their average age was 71.5 years. The efficacy of memantine was judged on the basis of the baseline/6 week differences in the total sum scores of the Clinical Assessment Geriatric Scale (SCAG), the Gottfries-Bräne-Steen Scale (GBS), the SCAG and GBS subscales and the global assessment of the change in the patient's condition. The effects of memantine on performance were studied with the aid of psychomotor tests and a behaviour investigation relating to activities of daily living (ADL). The tolerability of memantine was assessed on the basis of the doctor's global assessment and of entries on structured documentation forms (DOTES/TWIS). Further safety parameters--in the form of clinicochemical tests and measurements of blood pressure and heart rate--were also monitored during the study. On both the psychopathological measurement level (SCAG, global assessment of the change in the patient's condition) and the behavioural level (GBS), confirmatory statistical analysis brought to light significant differences between memantine and placebo (p less than or equal to 0.05), these differences showing a superiority of memantine. The tolerability of memantine was good in the main. The observed adverse reactions were not serious and, except in 3 patients, were rated as causing little or no impairment. The present clinical study demonstrates the efficacy of memantine in patients suffering from mostly moderate dementia syndrome. Clinical and statistically relevant improvements in the dementia-induced disturbances were found on the both the psychopathological level (SCAG, CGI) and the behavioural level (GBS). On the performance level also, the ADL behaviour investigation detected a highly significant improvement in the quality of performance of instrumented activities of daily living under memantine. Also the time taken to carry out these tasks was significantly reduced in comparison with placebo.

Aged↗

PubMed1992

Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity.

Excessive activation of NMDA receptors is thought to mediate the calcium-dependent neurotoxicity associated with hypoxic-ischemic brain injury, trauma, epilepsy, and several neurodegenerative diseases. For this reason, various NMDA antagonists have been investigated for their therapeutic potential in these diseases, but heretofore none have proven to be both effective and safe. In the present study, memantine, an adamantane derivative similar to the antiviral drug amantadine, is shown to block the channels activated by NMDA receptor stimulation. From whole-cell and single-channel recording experiments, the mechanism of action of memantine is deduced to be open-channel block, similar to MK-801; however, unlike MK-801, memantine is well tolerated clinically. Compared to MK-801, memantine's safety may be related to its faster kinetics of action with rapid blocking and unblocking rates at low micromolar concentrations. Furthermore, at these levels memantine is an uncompetitive antagonist and should theoretically allow near-normal physiological NMDA activity throughout the brain even in the face of pathologically high focal concentrations of glutamate. These pharmacological properties confer upon memantine a therapeutic advantage against NMDA receptor-mediated neurotoxicity with few side effects compared with other organic NMDA open-channel blockers. Moreover, memantine is increasingly effective against escalating levels of glutamate, such as those observed during a stroke. Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model. These results suggest that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMDA receptor-mediated neurotoxicity.

Animals↗

PubMed2001

The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans.

RATIONALE: Preclinical observations suggest that NMDA receptor-mediated glutamatergic neurotransmission is involved in the expression and maintenance of opioid dependence. OBJECTIVE: The present study evaluated whether memantine, the clinically available non-competitive NMDA receptor antagonist, decreases naloxone-precipitated withdrawal in morphine-dependent humans. METHODS: Eight heroin-dependent, non-treatment seeking, inpatient participants were stabilized on a fixed dose of morphine (30 mg PO qid). Subsequently, they received a series of challenges with naloxone (0.4 mg, IM) and the severity of opioid withdrawal was monitored. Either placebo or memantine (60 mg PO) was given 6 h before each naloxone challenge. A modified multiple baseline, across-participants design was used to evaluate the effects of memantine on the severity of naloxone-precipitated opioid withdrawal. RESULTS: Naloxone increased ratings and produced physical changes consistent with opioid withdrawal. Memantine attenuated the severity of opioid withdrawal as assessed with the Clinical Institute for Narcotic Withdrawal Scale scale. Withdrawal was significantly reduced when naloxone was administered at 6 and 52 h after memantine, but not when administered 126 h (5 days) after memantine. Medication effects, assessed 5 h after memantine administration and before naloxone administration, included significant increases in ratings of "strong" and "good" drug effect, and "I feel sedated", "mellow", and "high". CONCLUSIONS: Memantine attenuated the expression of opioid physical dependence in humans, indicating that glutamatergic neurotransmission at the NMDA receptor site contributes to the maintenance of opioid dependence. This finding suggests that memantine may be a useful adjunct in the treatment of opioid dependence.

Adult↗

PubMed1998

Ethanol-reinforced behaviour in the rat: effects of uncompetitive NMDA receptor antagonist, memantine.

Ethanol has been reported to alter NMDA receptor-mediated biochemical and electrophysiological responses in vitro. The aim of the present study was to evaluate the effects of an uncompetitive NMDA receptor antagonist memantine, in animal models of alcoholism. Male Wistar rats were trained to drink 8% ethanol in a free-choice, limited access procedure. A separate group of animals was trained to lever press for 8% ethanol in an operant procedure where ethanol was introduced in the presence of sucrose. The selectivity of memantine's actions was assessed by studying its effects on food or water consumption in separate control experiments. Memantine (4.5-24 mg/kg) significantly, but not dose dependently, affected ethanol drinking in the limited access procedure. However, only 6 mg/kg memantine selectively decreased ethanol drinking. Memantine did not alter ethanol intake in rats trained to lever press for ethanol in the operant procedure. Only 9 mg/kg memantine reduced operant responding in the extinction procedure in the rats trained to lever press for ethanol. The same dose of memantine significantly reduced the operant behaviour of rats trained to respond for water. These results indicate that: (i) single doses of memantine only moderately and not dose dependently reduce alcohol drinking in the limited access procedure; (ii) memantine produces non-selective effects on operant behaviour in rats trained to lever press for ethanol in an oral self-administration procedure.

Alcohol Drinking↗

PubMed1998

Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation.

The potential of most N-methyl-D-aspartate antagonists as neuroprotectants is limited by side effects. We previously reported that memantine is an open-channel N-methyl-D-aspartate blocker with a faster off-rate than many uncompetitive N-methyl-D-aspartate antagonists such as dizocilpine maleate. This parameter correlated with memantine's known clinical tolerability in humans with Parkinson's disease. Memantine is the only N-methyl-D-aspartate antagonist that has been used clinically for excitotoxic disorders at neuroprotective doses. Therefore, we wanted to investigate further the basis of its clinical efficacy, safety, and tolerability. Here we show for the first time for any clinically-tolerated N-methyl-D-aspartate antagonist that memantine significantly reduces infarct size when administered up to 2 h after induction of hypoxia/ischemia in immature and adult rats. We found that at neuroprotective concentrations memantine results in few adverse side effects. Compared to dizocilpine maleate, memantine displayed virtually no effects on Morris water maze performance or on neuronal vacuolation. At concentrations similar to those in brain following clinical administration, memantine (6-10 microM) did not attenuate long-term potentiation in hippocampal slices and substantially spared the N-methyl-D-aspartate component of excitatory postsynaptic currents, while dizocilpine maleate (6-10 microM) or D-2-amino-5-phosphovalerate (50 microM) completely blocked these phenomena. We suggest that the favorable kinetics of memantine interaction with N-methyl-D-aspartate channels may be partly responsible for its high index of therapeutic safety, and make memantine a candidate drug for use in many N-methyl-D-aspartate receptor-mediated human CNS disorders.

Animals↗

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↗

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↗

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↗

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↗