The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Hansjorg Mobius - One of the best experts on this subject based on the ideXlab platform.
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Memantine in moderate to severe alzheimer s disease a meta analysis of randomised clinical trials
Dementia and Geriatric Cognitive Disorders, 2007Co-Authors: Bengt Winblad, Yvonne Wirth, Albrecht Stoffler, Roy W Jones, Hansjorg MobiusAbstract:The efficacy of Memantine in Alzheimer's disease (AD) has been investigated in multiple randomised, placebo-controlled phase III trials. Recently, the indication label for Memantine in Europe was extended to cover patients with moderate to severe AD, i.e. Mini-Mental State Exam total scores below 20. The efficacy data for Memantine in this patient subgroup has been summarised by a meta-analysis of 1,826 patients in six trials. Efficacy was assessed using measures of global status (Clinician's Interview-Based Impression of Change Plus Caregiver Input), cognition (Alzheimer's Disease Assessment Scale - Cognitive Subscale, or Severe Impairment Battery), function (Alzheimer's Disease Cooperative Study Activities of Daily Living 19- or 23-item scale), and behaviour (Neuropsychiatric Inventory). Results (without replacement of missing values) showed statistically significant effects for Memantine (vs. placebo) in each domain. Memantine was well tolerated, and the overall incidence rates of adverse events were comparable to placebo. This meta-analysis supports Memantine's clinically relevant efficacy in patients with moderate to severe AD.
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a 24 week open label extension study of Memantine in moderate to severe alzheimer disease
JAMA Neurology, 2006Co-Authors: Barry Reisberg, Albrecht Stoffler, Rachelle S Doody, Frederick A Schmitt, Steven H Ferris, Hansjorg MobiusAbstract:Background This study is an extension of a 28-week, randomized, double-blind, placebo-controlled study of Memantine in 252 patients with moderate to severe Alzheimer disease. Objective To evaluate long-term Memantine treatment in moderate to severe Alzheimer disease. Design, Setting, and Patients Open-label, 24-week extension trial. Raters remained blind to the patients' initial study treatment. Patients (n = 175) were enrolled from the previous double-blind study in an outpatient setting. Intervention Twenty mg of Memantine was given daily. Main Outcome Measures Efficacy assessments from the double-blind study were continued and safety parameters were monitored. Results Patients who switched to Memantine treatment from their previous placebo therapy experienced a significant benefit in all main efficacy assessments (functional, global, and cognitive) relative to their mean rate of decline with placebo treatment during the double-blind period ( P Conclusion These results extend previous findings that demonstrated the efficacy and safety of Memantine in the treatment of patients with moderate to severe Alzheimer disease.
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resource utilisation and cost analysis of Memantine in patients with moderate to severe alzheimer s disease
PharmacoEconomics, 2003Co-Authors: Anders Wimo, Yvonne Wirth, Bengt Winblad, Albrecht Stoffler, Hansjorg MobiusAbstract: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 $US1089.74/month [non-overlapping 95% CI for treatment difference −1954.90, −224.58]; p = 0.01). The main differences between the groups were total caregiver costs ($US-823.77/month; p = 0.03) and direct nonmedical costs ($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.
Albrecht Stoffler - One of the best experts on this subject based on the ideXlab platform.
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Memantine in moderate to severe alzheimer s disease a meta analysis of randomised clinical trials
Dementia and Geriatric Cognitive Disorders, 2007Co-Authors: Bengt Winblad, Yvonne Wirth, Albrecht Stoffler, Roy W Jones, Hansjorg MobiusAbstract:The efficacy of Memantine in Alzheimer's disease (AD) has been investigated in multiple randomised, placebo-controlled phase III trials. Recently, the indication label for Memantine in Europe was extended to cover patients with moderate to severe AD, i.e. Mini-Mental State Exam total scores below 20. The efficacy data for Memantine in this patient subgroup has been summarised by a meta-analysis of 1,826 patients in six trials. Efficacy was assessed using measures of global status (Clinician's Interview-Based Impression of Change Plus Caregiver Input), cognition (Alzheimer's Disease Assessment Scale - Cognitive Subscale, or Severe Impairment Battery), function (Alzheimer's Disease Cooperative Study Activities of Daily Living 19- or 23-item scale), and behaviour (Neuropsychiatric Inventory). Results (without replacement of missing values) showed statistically significant effects for Memantine (vs. placebo) in each domain. Memantine was well tolerated, and the overall incidence rates of adverse events were comparable to placebo. This meta-analysis supports Memantine's clinically relevant efficacy in patients with moderate to severe AD.
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a 24 week open label extension study of Memantine in moderate to severe alzheimer disease
JAMA Neurology, 2006Co-Authors: Barry Reisberg, Albrecht Stoffler, Rachelle S Doody, Frederick A Schmitt, Steven H Ferris, Hansjorg MobiusAbstract:Background This study is an extension of a 28-week, randomized, double-blind, placebo-controlled study of Memantine in 252 patients with moderate to severe Alzheimer disease. Objective To evaluate long-term Memantine treatment in moderate to severe Alzheimer disease. Design, Setting, and Patients Open-label, 24-week extension trial. Raters remained blind to the patients' initial study treatment. Patients (n = 175) were enrolled from the previous double-blind study in an outpatient setting. Intervention Twenty mg of Memantine was given daily. Main Outcome Measures Efficacy assessments from the double-blind study were continued and safety parameters were monitored. Results Patients who switched to Memantine treatment from their previous placebo therapy experienced a significant benefit in all main efficacy assessments (functional, global, and cognitive) relative to their mean rate of decline with placebo treatment during the double-blind period ( P Conclusion These results extend previous findings that demonstrated the efficacy and safety of Memantine in the treatment of patients with moderate to severe Alzheimer disease.
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resource utilisation and cost analysis of Memantine in patients with moderate to severe alzheimer s disease
PharmacoEconomics, 2003Co-Authors: Anders Wimo, Yvonne Wirth, Bengt Winblad, Albrecht Stoffler, Hansjorg MobiusAbstract: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 $US1089.74/month [non-overlapping 95% CI for treatment difference −1954.90, −224.58]; p = 0.01). The main differences between the groups were total caregiver costs ($US-823.77/month; p = 0.03) and direct nonmedical costs ($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.
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efficacy and safety of Memantine in patients with mild to moderate vascular dementia a randomized placebo controlled trial mmm 300
Stroke, 2002Co-Authors: Jeanmarc Orgogozo, Albrecht Stoffler, Annesophie Rigaud, Hansjorgen Mobius, F ForetteAbstract:Background and Purpose — Based on the hypothesis of glutamate-induced neurotoxicity (excitotoxicity) in cerebral ischemia, this study examined the efficacy and tolerability of Memantine, an uncompetitive N -methyl-d-aspartate antagonist, in the treatment of mild to moderate vascular dementia. Methods — In this multicenter, 28-week trial carried out in France, 321 patients received 10 mg/d Memantine or placebo twice a day; 288 patients were valid for intent-to-treat analysis. Patients had to meet the criteria for probable vascular dementia and have a Mini-Mental State (MMSE) score between 12 and 20 at inclusion. The 2 primary end points were the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog) and the global Clinician’s Interview Based Impression of Change (CIBIC-plus). Results — After 28 weeks, the mean ADAS-cog scores were significantly improved relative to placebo. In the intention-to-treat population, the Memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score had declined by 1.6 points, ie, a difference of 2.0 points (95% confidence interval, 0.49 to 3.60). The response rate for CIBIC-plus, defined as improved or stable, was 60% with Memantine compared with 52% with placebo ( P =0.227, intention to treat). Among the secondary efficacy parameters, which were analyzed in the per-protocol subset, MMSE was significantly improved with Memantine compared with deterioration with placebo ( P =0.003). The Gottfries-Brane-Steen Scale intellectual function subscore and the Nurses’ Observation Scale for Geriatric Patients disturbing behavior dimension also showed differences in favor of Memantine ( P =0.04 and P =0.07, respectively). Memantine was well tolerated with a frequency of adverse events comparable to placebo. Conclusions — In patients with mild to moderate vascular dementia, Memantine 20 mg/d improved cognition consistently across different cognitive scales, with at least no deterioration in global functioning and behavior. It was devoid of concerning side effects.
Wojciech Danysz - One of the best experts on this subject based on the ideXlab platform.
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pharmacodynamics of Memantine an update
Current Neuropharmacology, 2008Co-Authors: Gerhard Rammes, Wojciech Danysz, C. G. ParsonsAbstract:Memantine received marketing authorization from the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of moderately severe to severe Alzheimer´s disease (AD) in Europe on 17th May 2002 and shortly thereafter was also approved by the FDA for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage-dependency and fast kinetics. Due to this mechanism of action (MOA), there is a wealth of other possible therapeutic indications for Memantine and numerous preclinical data in animal models support this assumption. This review is intended to provide an update on preclinical studies on the pharmacodynamics of Memantine, with an additional focus on animal models of diseases aside from the approved indication. For most studies prior to 1999, the reader is referred to a previous review [196]. In general, since 1999, considerable additional preclinical evidence has accumulated supporting the use of Memantine in AD (both symptomatic and neuroprotective). In addition, there has been further confirmation of the MOA of Memantine as an uncompetitive NMDA receptor antagonist and essentially no data contradicting our understanding of the benign side effect profile of Memantine.
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inhibition of reinforcing effects of morphine and motivational aspects of naloxone precipitated opioid withdrawal by n methyl d aspartate receptor antagonist Memantine
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Piotr Popik, Wojciech DanyszAbstract:The present study focused on the effects of 1-amino-3,5-dimethyladamantane (Memantine), a clinically used, low-affinity Nmethyl-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 morphineinduced 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. The treatment of drug abuse focuses on prevention of the development of addiction, elimination of existing addiction and suppression of symptoms associated with drug withdrawal (Jaffe, 1987). Current pharmacotherapies usually target specific neurotransmitter systems, which are presumed to mediate the effects of a given class of abused substances. These “targeted,” specific pharmacotherapies are used in spite of striking similarities concerning the long-term consequences produced by all of known drugs of abuse such as drug addiction. Moreover, opioid antagonists and agonists are used in the treatment of opioid abuse despite the fact that some therapies (e.g., naltrexone) are not only ineffective, but, in addition, are consistently refused by addicted individuals. In opioid substitution therapy (e.g., with methadone), Ball and Ross (1991) reported a recidivism rate after discontinuation of treatment of ;80%. Dopaminergic pathways, particularly of the mesolimbic system, have been associated with
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Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents - Preclinical studies
Neuroscience and Biobehavioral Reviews, 1997Co-Authors: Wojciech Danysz, C. G. Parsons, W J Schmidt, Johannes Kornhuber, Günter QuackAbstract:Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino- 3,5-dimethyladamantane (Memantine) are N-methyl-D-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinson's patients. The issue of whether NMDA antagonism plays a role in the symptomatological antiparkinsonian activity of amantadine and Memantine is addressed by comparing: behaviourally effective doses, serum/brain levels, and their potency as NMDA receptor antagonists. In the case of Memantine, blockade of NMDA receptors is probably the only mechanism responsible for antiparkinsonian activity, whereas for amantadine the situation is clearly far more complex. There are a number of differences between Memantine and amantadine both in vitro and in vivo, and although NMDA receptor antagonism certainly participates in the antiparkinsonian activity of amantadine, other effects, some of which are elusive, also play a role. Moreover, it has been suggested that the pathomechanism of Parkinson's disease involves excitotoxic processes and that treatment with NMDA receptor antagonists might also slow the progression of neurodegeneration. If this claim is true, such an effect could be achieved with amantadine and Memantine which show neuroprotective activity in animals at therapeutically relevant doses.
Stuart A Lipton - One of the best experts on this subject based on the ideXlab platform.
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Memantine preferentially blocks extrasynaptic over synaptic nmda receptor currents in hippocampal autapses
The Journal of Neuroscience, 2010Co-Authors: Peng Xia, Hueisheng Vincent Chen, Dongxian Zhang, Stuart A LiptonAbstract:Glutamate is the major excitatory neurotransmitter in the brain. The NMDA subtype of glutamate receptors (NMDAR) is known to mediate many physiological neural functions. However, excessive activation of NMDARs contributes to neuronal damage in various acute and chronic neurological disorders. To avoid unwanted adverse side effects, blockade of excessive NMDAR activity must therefore be achieved without affecting its physiological function. Memantine, an adamantane derivative, has been used for the treatment of Alzheimer9s disease with an excellent clinical safety profile. We previously showed that Memantine preferentially blocked neurotoxicity mediated by excessive NMDAR activity while relatively sparing normal neurotransmission, in part because of its uncompetitive antagonism with a fast off-rate. Here, using rat autaptic hippocampal microcultures, we show that Memantine at therapeutic concentrations (1–10 μm) preferentially blocks extrasynaptic rather than synaptic currents mediated by NMDARs in the same neuron. We found that Memantine blocks extrasynaptic NMDAR-mediated currents induced by bath application of 100 μm NMDA/10 μm glycine with a twofold higher potency than its blockade of the NMDAR component of evoked EPSCs (EPSCs NMDAR ); this effect persists under conditions of pathological depolarization in the presence of 1 mm extracellular Mg 2+ . Thus, our findings provide the first unequivocal evidence to explain the tolerability of Memantine based on differential extrasynaptic/synaptic receptor blockade. At therapeutic concentrations, Memantine effectively blocks excessive extrasynaptic NMDAR-mediated currents, while relatively sparing normal synaptic activity.
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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
Neuroscience, 1998Co-Authors: Hueisheng Vincent Chen, Stuart A Lipton, Y F Wang, P V Rayudu, P Edgecomb, J C Neill, Michael M Segal, Frances E JensenAbstract:The potential of most N-methyl-d-aspartate antagonists as neuroprotectants is limited by side eVects. We previously reported that Memantine is an open-channel N-methyl-d-aspartate blocker with a faster oV-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 eYcacy, 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 eVects. Compared to dizocilpine maleate, Memantine displayed virtually no eVects on Morris water maze performance or on neuronal vacuolation. At concentrations similar to those in brain following clinical administration, Memantine (6-10 µM) 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 µM) or d-2-amino-5- phosphovalerate (50 µM) 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. ? 1998 IBRO. Published by Elsevier Science Ltd.
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chronic low dose glutamate is toxic to retinal ganglion cells toxicity blocked by Memantine
Investigative Ophthalmology & Visual Science, 1996Co-Authors: C K Vorwerk, Stuart A Lipton, David Zurakowski, B T Hyman, Bernhard A Sabel, Evan B DreyerAbstract:PURPOSE It is well known that acute exposure to high concentrations of glutamate is toxic to central mammalian neurons. However, the effect of a chronic, minor elevation over endogenous glutamate levels has not been explored. The authors have suggested that such chronic exposure may play a role in glaucomatous neuronal loss. In the current study, they sought to explore whether a chronic, low-dose elevation in vitreal glutamate was toxic to retinal ganglion cells and whether this toxicity could be prevented with Memantine, a glutamate antagonist. METHODS Rats were injected serially and intravitreally with glutamate to induce chronic elevations in glutamate concentration. A second group of rats was treated with intraperitoneal Memantine and glutamate. Control groups received vehicle injection with or without concurrent Memantine therapy. After 3 months, the animals were killed, and ganglion cell survival was evaluated. RESULTS Intravitreal injections raised the intravitreal glutamate levels from an endogenous range of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate elevation killed 42% of the retinal ganglion cells after 3 months. Memantine treatment alone had no effect on ganglion cell survival. However, when Memantine was given concurrently with low-dose glutamate, Memantine was partially protective against glutamate toxicity. CONCLUSIONS These data suggest that minor elevations in glutamate concentration can be toxic to ganglion cells if this elevation is maintained for 3 months. Furthermore, Memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity.
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open channel block of n methyl d aspartate nmda responses by Memantine therapeutic advantage against nmda receptor mediated neurotoxicity
The Journal of Neuroscience, 1992Co-Authors: Hueisheng Vincent Chen, J W Pellegrini, S K Aggarwal, S Z Lei, Steven Warach, Frances E Jensen, Stuart A LiptonAbstract: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.
Roy W Jones - One of the best experts on this subject based on the ideXlab platform.
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Memantine for patients with parkinson s disease dementia or dementia with lewy bodies a randomised double blind placebo controlled trial
Lancet Neurology, 2010Co-Authors: Murat Emre, Magda Tsolaki, Ubaldo Bonuccelli, A Destee, Eduardo Tolosa, Alexandra Kutzelnigg, Andres O Ceballosbaumann, Slobodan Zdravkovic, Bladstrom Anna, Roy W JonesAbstract:Summary Background Previous studies have suggested that patients with Lewy-body-related dementias might benefit from treatment with the N-methyl D-aspartate receptor antagonist Memantine, but further data are needed. Therefore, the efficacy and safety of Memantine were investigated in patients with mild to moderate Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB). Methods Patients (≥50 years of age) with mild to moderate PDD or DLB were recruited from 30 specialist centres in Austria, France, Germany, the UK, Greece, Italy, Spain, and Turkey. They were randomly assigned to placebo or Memantine (20 mg per day) according to a computer-generated list. Patients and all physicians who had contact with them were masked to treatment assignment. No primary endpoint was defined. Safety analyses were done for all patients who took at least one dose of Memantine or placebo, and efficacy analyses were done for all patients who had at least one valid postbaseline assessment. This trial is registered with ClinicalTrials.gov, number NCT00855686. Findings Of the 199 patients randomly assigned to treatment, 34 with DLB and 62 with PDD were given Memantine, and 41 with DLB and 58 with PDD were given placebo. 159 (80%) patients completed the study: 80 in the Memantine group and 79 in the placebo group. 93 patients treated with Memantine and 97 patients treated with placebo were included in the efficacy analysis. At week 24, patients with DLB who received Memantine showed greater improvement according to Alzheimer's disease cooperative study (ADCS)-clinical global impression of change scores than did those who received placebo (mean change from baseline 3·3 vs 3·9, respectively, difference −0·6 [95% CI −1·2 to −0·1]; p=0·023). No significant differences were noted between the two treatments in patients with PDD (3·6 with Memantine vs 3·8 with placebo, −0·1 [−0·6 to 0·3]; p=0·576) or in the total population (3·5 with Memantine vs 3·8 with placebo, −0·3 [−0·7 to 0·1]; p=0·120). Neuropsychiatric-inventory scores showed significantly greater improvement in the Memantine group than in the placebo group (−4·3 vs 1·7, respectively, −5·9 [−11·6 to −0·2]; p=0·041) in patients with DLB, but not in those with PDD (−1·6 vs −0·1, respectively, −1·4 [−5·9 to 3·0]; p=0·522) or in the total patient population (−2·6 vs 0·4, respectively, −2·9 [−6·3 to 0·5]; p=0·092). In most of the cognitive test scores, ADCS-activities of daily living, and Zarit caregiver burden scores, there were no significant differences between the two treatment groups in any of the study populations. The incidence of adverse events and number of discontinuations due to adverse events were similar in the two groups. The most common serious adverse events were stroke (n=3 in Memantine group), falls (n=2 in Memantine group; n=1 in placebo group), and worsening of dementia (n=2 in Memantine group). Interpretation Memantine seems to improve global clinical status and behavioural symptoms of patients with mild to moderate DLB, and might be an option for treatment of these patients. Funding Lundbeck.
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Memantine in moderate to severe alzheimer s disease a meta analysis of randomised clinical trials
Dementia and Geriatric Cognitive Disorders, 2007Co-Authors: Bengt Winblad, Yvonne Wirth, Albrecht Stoffler, Roy W Jones, Hansjorg MobiusAbstract:The efficacy of Memantine in Alzheimer's disease (AD) has been investigated in multiple randomised, placebo-controlled phase III trials. Recently, the indication label for Memantine in Europe was extended to cover patients with moderate to severe AD, i.e. Mini-Mental State Exam total scores below 20. The efficacy data for Memantine in this patient subgroup has been summarised by a meta-analysis of 1,826 patients in six trials. Efficacy was assessed using measures of global status (Clinician's Interview-Based Impression of Change Plus Caregiver Input), cognition (Alzheimer's Disease Assessment Scale - Cognitive Subscale, or Severe Impairment Battery), function (Alzheimer's Disease Cooperative Study Activities of Daily Living 19- or 23-item scale), and behaviour (Neuropsychiatric Inventory). Results (without replacement of missing values) showed statistically significant effects for Memantine (vs. placebo) in each domain. Memantine was well tolerated, and the overall incidence rates of adverse events were comparable to placebo. This meta-analysis supports Memantine's clinically relevant efficacy in patients with moderate to severe AD.