Tolerability Of Memantine Research Articles

Hero or Antagonist: A Case Series on the Tolerability of Memantine as Salvage Therapy for Catatonia from Anti-NMDA Receptor Encephalitis.

Hero or Antagonist: A Case Series on the Tolerability of Memantine as Salvage Therapy for Catatonia from Anti-NMDA Receptor Encephalitis.

Hero or Antagonist: A Case Series on the Tolerability of Memantine as Salvage Therapy for Catatonia From NMDA-Receptor Encephalitis

Hero or Antagonist: A Case Series on the Tolerability of Memantine as Salvage Therapy for Catatonia From NMDA-Receptor Encephalitis

Efficacy and safety profile of memantine in patients with cognitive impairment in multiple sclerosis: A randomized, placebo-controlled study

Memantine, an uncompetitive antagonist of N-methyl-d-aspartate (NMDA)-type glutamate receptors that was approved for the treatment of moderate to severe Alzheimer's disease, has been negatively evaluated for the treatment of cognitive disorders of multiple sclerosis, but these studies were conducted only during short-term administration and on a heterogeneous group of patients with different forms of the disease. In addition, many adverse reactions were observed in these patients. AimsThe purpose of the “EMERITE” (NCT01074619) study was to examine the efficacy and safety of the long-term administration of memantine as a symptomatic treatment for cognitive disorders in patients with relapsing-remitting multiple sclerosis (RR-MS). MethodsThe study was supported by the French Ministry of Health and received additional support from Lundbeck. In this double-blind, placebo-controlled, parallel group, randomized trial, the participants were assigned to receive memantine (20mg/day) or a placebo for 52weeks. The participants included males and females, 18–60years of age, with a diagnosis of RR-MS and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The data were collected in the Department of Neurology in 19 French centers. The primary outcome was the Paced Auditory Serial Addition Test (PASAT) score at week 52. Secondary measurements included additional neuropsychological tests and the annualized relapse rate. The scores were adjusted according to the baseline scores in the analysis. The safety was assessed by the number of adverse events. The random sequence was generated using the Excel software. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial. ResultsFifty patients were allocated to the memantine group, and 43 to the placebo group. The intent-to-treat (ITT) population included 31 patients in each group. After adjusting for the PASAT scores at baseline, the PASAT scores at the end point did not differ between the memantine and the placebo groups (p=0.88). Adjusted mean score difference (memantine minus placebo), was −0.40 (95% confidence interval: -5.5; +4.7). No significant differences were observed for the secondary outcomes (short term memory and attention scores, EDSS, and relapse rate). The findings remained unchanged after multiple imputation of the missing values. Neurological and psychiatric adverse events were significantly higher in the memantine group than in the placebo group, and these parameters were higher than those reported in the product literature of memantine. ConclusionsNo differences between the placebo and memantine groups were observed. Nevertheless, the tolerability of memantine was significantly worse than expected.

Memantine for the treatment of frontotemporal dementia: a meta-analysis.

BackgroundThere is no conclusive evidence supporting the efficacy of memantine in frontotemporal dementia (FTD). We conducted a comprehensive meta-analysis of memantine concerning the efficacy and tolerability of memantine in FTD.MethodsStudies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations up to April 10, 2015. Outcomes were Clinical Global Impression (primary), Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview scores as well as all-cause discontinuation. Standardized mean difference and risk ratio with 95% confidence interval were calculated.ResultsTwo randomized controlled trials (RCTs) (total n=130) met the inclusion criteria. Memantine was marginally superior to placebo as assessed by the Clinical Global Impression scores (standardized mean difference =−0.34, 95% confidence interval =−0.68–0.01, P=0.06). However, there were no significant differences in Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview scores as well as all-cause discontinuation between memantine and placebo.ConclusionOur results suggest that memantine may benefit FTD patients. However, because only two randomized controlled trials have addressed this issue, further studies using larger samples are needed.

Indistinguishable Synaptic Pharmacodynamics of the N-Methyl-d-Aspartate Receptor Channel Blockers Memantine and Ketamine

Memantine and ketamine, voltage- and activation-dependent channel blockers of N-methyl-d-aspartate (NMDA) receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these blockers have been reported, but it is unclear whether the compounds differentially affect dynamic physiologic signaling. In this study, we explored nonequilibrium conditions relevant to synaptic transmission in hippocampal networks in dissociated culture and hippocampal slices. Equimolar memantine and ketamine had indistinguishable effects on the following measures: steady-state NMDA currents, NMDAR excitatory postsynaptic current (EPSC) decay kinetics, progressive EPSC inhibition during repetitive stimulation, and extrasynaptic NMDAR inhibition. Therapeutic drug efficacy and tolerability of memantine have been attributed to fast kinetics and strong voltage dependence. However, pulse depolarization in drug presence revealed a surprisingly slow and similar time course of equilibration for the two compounds, although memantine produced a more prominent fast component (62% versus 48%) of re-equilibration. Simulations predicted that low gating efficacy underlies the slow voltage-dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations of gating efficacy. Excitatory postsynaptic potential-like voltage commands produced drug differences only with large, prolonged depolarizations unlikely to be attained physiologically. In fact, we found no difference between drugs on measures of spontaneous network activity or acute effects on plasticity in hippocampal slices. Despite indistinguishable synaptic pharmacodynamics, ketamine provided significantly greater neuroprotection from damage induced by oxygen glucose deprivation, consistent with the idea that under extreme depolarizing conditions, the biophysical difference between drugs becomes detectable. We conclude that despite subtle differences in voltage dependence, during physiologic activity, blocker pharmacodynamics are largely indistinguishable and largely voltage independent.

A pilot trial of memantine and riluzole in ALS: Correlation to CSF biomarkers

The objective of this trial was to determine the safety and tolerability of memantine in patients with sporadic ALS and to examine changes in CSF biomarkers during drug therapy. Twenty patients on stable doses of riluzole were enrolled. Patients received memantine, 10 mg b.i.d., for 18 months. Lumbar punctures were performed at baseline, six and twelve months. The ALSFRS was measured at six weeks, 3, 6, 9, 12 and 18 months. Results showed that patients treated with memantine and riluzole had an average rate of decline on the ALSFRS of -0.73 points per month. Patients who progressed faster than -0.5 ALSFRS points per month had an average baseline CSF tau concentration of 574 pg/ml, while those who progressed slower than -0.5 ALSFRS points per month had CSF tau levels that averaged 298 pg/ml (p = 0.006). After therapy with memantine, patients had a 27% decline in CSF tau levels (p = 0.04) and four patients whose CSF tau dropped to healthy control levels lost only -0.42 ALSFRS points per month. In conclusion, memantine was well tolerated in patients with ALS. Patients receiving memantine and riluzole lost on average -0.73 ALSFRS points per month. Furthermore, levels of CSF tau at baseline could be correlated with how rapidly a patient's disease progressed.

A review comparing the safety and tolerability of memantine with the acetylcholinesterase inhibitors

Alzheimer's disease (AD) is prevalent among elderly people, who often have comorbid conditions, and may be prescribed multiple medications. Drug safety and tolerability is paramount in maximising efficacy and optimising patient and carer quality of life, as patients are vulnerable to adverse events (AEs) and/or compliance difficulties. The two principal categories of drug used in the treatment of AD are the acetylcholinesterase inhibitors (AChEIs) and the NMDA-receptor antagonist, memantine. This paper reviews the most recent safety data for memantine in comparison with the AChEIs. Review of most recent safety/tolerability data for memantine and AChEIs, derived from meta-analyses, pooled analyses, European SPCs and EMEA publications. Memantine was found to have a favourable tolerability profile when used as monotherapy or in combination with other agents. AChEIs were found to be fairly well tolerated. All treatments commonly or very commonly produce dizziness and/or headache. AChEIs are associated with many more types of AEs than memantine, particularly in the gastrointestinal category. Agitation is a less common AE when comparing memantine treatment to placebo, but just as common when comparing AChEI treatment to placebo. Withdrawals in memantine-treated groups are comparable to placebo, and more common in AChEI-treated groups compared to placebo. Overall, drug-drug interactions, contraindications and warnings were fewer for memantine than AChEIs. In both the clinical and naturalistic setting, memantine displays a safety and tolerability profile that is favourable and distinct from that of AChEIs. Safety and tolerability profiles should be given careful consideration when selecting treatment for AD patients.

The efficacy and tolerability of memantine in the therapy of schizophrenia

The efficacy and tolerability of memantine in the therapy of schizophrenia

Memantine Efficacy and Safety in Patients With Acute Mania Associated With Bipolar I Disorder

Evaluate the efficacy and tolerability of memantine (20, 30, and 40 mg/d) in the acute treatment of adults with bipolar I disorder hospitalized for mania. This multicenter, open-label, pilot trial included adults with bipolar I disorder (manic or mixed episode, with and without psychotic features). Patients were assigned to 21 days of treatment: cohort 1, 20 mg/d (range, 20-30 mg/d); cohort 2, 30 mg/d (range, 30-40 mg/d); cohort 3, 40 mg/d (range, 30-50 mg/d). Efficacy measures included the Young Mania Rating Scale (YMRS) and the Mania Rating Scale (>or=50% reduction in total score from baseline). The change from baseline was also assessed using the Positive and Negative Syndrome Scale in patients with psychiatric symptoms, Positive and Negative Syndrome Scale-Excited Component, Clinical Global Impression Severity and Improvement scores, and Montgomery Asberg Depression Rating Scale. A total of 35 patients were enrolled; 33 patients received at least 1 dose of memantine and had at least 1 postbaseline assessment using YMRS. Greatest improvement occurred in cohort 1 where half of the patients responded to memantine based on YMRS and Mania Rating Scale. At day 21, a response was observed in all patient cohorts. Treatment-emergent adverse events were reported in 19 patients (54.3%). The most frequently reported adverse events (>or=4 patients) included constipation, nausea, and headache. The response to memantine combined with its tolerability support conducting large-sized randomized controlled trials to investigate further the use of memantine monotherapy in the treatment of mania.

Efficacy and tolerability of Memantine in Alzheimer's disease - results of an observational study

Efficacy and tolerability of Memantine in Alzheimer's disease - results of an observational study

Randomized controlled trial of memantine in dementia associated with Parkinson's disease

The objective of this study is to investigate the safety and tolerability of memantine, a glutamatergic modulator, in patients suffering from dementia associated with Parkinson's disease (PDD), an increasingly common complication of PD. This was a 22-week trial of 25 participants with a DSM-IV diagnosis of PDD who were randomized to either placebo or 20 mg/day of memantine. Memantine was well tolerated by participants at 20 mg/day dosing. No participant was withdrawn due to memantine-related adverse events. Six weeks after drug withdrawal, a significantly greater proportion (P = 0.04) of memantine-treated participants deteriorated globally compared with those treated with placebo. These findings suggest that continued treatment with memantine may be needed to maintain global level of functioning over time. Based on the findings of this pilot study, memantine is safe and very well-tolerated in PDD.

Memantine in Moderately-Severe-to-Severe Alzheimerʼs Disease

Postmarketing surveillance studies (PMS) are an important tool for evaluating a drug's effectiveness and safety in clinical practice. To our knowledge, no PMS on memantine monotherapy for moderately-severe-to-severe Alzheimer's disease (AD) according to National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association criteria has been conducted to date. The Lombardy Health Office, Italy, promoted this PMS to evaluate the effectiveness and safety of memantine in the treatment of moderately-severe-to-severe AD in clinical practice. A total of 451 patients with moderately-severe-to-severe AD (mean age 77 +/- 7 years; 72% female), free of cholinergic medication, received memantine (standard titration to 10 mg twice daily). After 6 months of therapy, treatment effectiveness was evaluated according to two definitions of response ('no deterioration' and 'improvement'), as measured by changes in baseline scores on the Clinical Global Impression of Change, Mini-Mental State Examination, Neuropsychiatric Inventory and Activities of Daily Living scales. The safety measure was the frequency of adverse events (AEs). At 6-month assessment, 26.8% of subjects showed no deterioration and 3.8% showed improvement. In those showing no deterioration, response to treatment at the 3-month assessment was associated with a greater probability of a response at 6 months (adjusted odds ratio = 8.54; 95% CI 4.54, 16.05). Seventy patients (15.5%) experienced at least one AE and 39 (8.6%) discontinued treatment prematurely because of an AE. Of those who experienced an AE, 27 (38.6%) manifested behavioural and psychological symptoms of dementia. The proportion of responders to memantine treatment in this PMS was similar to that reported in a previous randomized clinical trial (26.8% vs 29%, respectively). The proportion of patients who discontinued treatment prematurely because of an AE (8.6%) was similar to that reported in two previous randomized clinical trials (10% and 12.4%). This PMS provides additional evidence that both the effectiveness and the tolerability of memantine may be transferred into real world medicine, where AD patients receiving treatment are not selected according to strict criteria.

Memantine in the Preventive Treatment of Refractory Migraine

To assess the efficacy and tolerability of memantine(MEM)in the preventive treatment of refractory migraine. Glutamate is of importance in migraine pathophysiology and may be related to progression from episodic to chronic migraine. Furthermore, individuals with chronic pain often report cognitive problems. MEM has the potential to address both issues, justifying this pilot study. We included subjects with refractory migraine (episodic migraine with 8-14 days of headache per month or transformed migraine, who had previously failed at least 2 trials of adequate preventive therapy). Other preventive drugs were allowed if the patient had been on a stable dose for more than 30 days. MEM dose ranged from 10 mg to 20 mg per day. The treatment phase lasted 3 months. The primary endpoint was number of days with headache at month 3. Cognitive performance was assessed with the trail making tests A and B (TMT-A and B). Statistical analyses were performed on the intent-to-treat (ITT) population, using data subjected to the last observation carried forward algorithm.We also conducted per protocol analyses. In the ITT population (n = 28), monthly headache frequency was reduced from 21.8 days at baseline to 16.1 (P < .01) at 3 months. The mean number of days with severe pain was reduced from 7.8 to 3.2 at 3 months (P < .01). The mean disability scores were significantly reduced at 3 months, compared with baseline (36.6 vs 54.9, P < .01). There was a significant reduction in the time to complete TMT-A at termination vs baseline (28.4 vs 23.2,P = .02) and also TMT-B (70.1 vs 50.4,P = .04). Side effects were present in 37.5% of the patients; 5.5% dropped out the study because of poor tolerability. Most adverse events were mild. This study offers preliminary evidence for the use of MEM in the prevention of refractory migraine.Double-blind studies are now required.

C.15.03 Pharmacology of memantine

Until recently, acetylcholinesterase inhibitors were the only approved agents for the treatment of Alzheimer's disease (AD). These medications have also been used in the treatment of vascular dementia (VD). Memantine, the first N-methyl-d-aspartate (NMDA)—receptor antagonist to be well tolerated, has been approved for the treatment of moderate to severe AD.The aim of this study was to review the current literature on the efficacy and tolerability of memantine in the treatment of AD and VD.A MEDLINE search of the English-language literature from January 1970 to March 2004 was conducted to identify randomized, double-blind, placebo-controlled, parallel-group trials in which memantine was administered to patients with VD or AD. The search terms were memantine, NMDA inhibitor, and NMDA antagonist.Excessive glutamate, the brain's major excitatory neurotransmitter, can cause excitotoxicity by allowing too much calcium to enter neuronal cells. Moderate-affinity NMDA-receptor antagonists such as memantine block pathologic activity of glutamate while allowing physiologic activity. Use of memantine has been associated with significant improvements in measures of cognition, function, and behavior in both VD and AD. Adverse events associated with memantine have been comparable to those with placebo, with the exception of an increased incidence of dizziness, constipation, cataracts, nausea, dyspnea, confusion, headache, and urinary incontinence.Memantine seems to be promising and well tolerated in the treatment of moderate to severe VD or AD, either as monotherapy or in combination with donepezil. It appears to be particularly effective in improving cognitive, functional, and global outcomes in moderate to severe AD and in improving cognitive end points in mild to moderate VD. More research is needed on important clinical questions, including whether memantine can prolong patients' ability to provide self-care and delay institutional placement.

P.5.a.006 Long-term safety and tolerability of memantine: an open-label extension study in patients with mild to moderate Alzheimer's disease

P.5.a.006 Long-term safety and tolerability of memantine: an open-label extension study in patients with mild to moderate Alzheimer's disease

Memantine (Ebixa®) in Clinical Practice – Results of an Observational Study

Background/Aims: In a post-marketing observational study, the efficacy and tolerability of memantine were examined in patients with moderate to severe Alzheimer’s disease. Methods: The patients were treated with 20 mg/day of memantine for a 6-month period. The efficacy of memantine was evaluated using the Mini-Mental State Examination, the Nurses’ Observation Scale for Geriatric Patients (NOSGER) and the Explorationsmodul Demenz (EMD) scale. In addition, a global assessment was made by the physician. Results: After 6 months of open-label treatment with memantine, the patients’ cognitive function, ability to perform daily activities and global performance all showed a marked improvement. In the overall evaluation by the physician, improvement or stabilisation had been achieved by 78.8% of patients after 6 months of therapy. Memantine also demonstrated an excellent tolerability profile. Conclusion: The results of this naturalistic study support the significant efficacy and tolerability of memantine that has been previously demonstrated in randomised, controlled clinical Alzheimer’s disease trials.

Open label, multicenter, 28-week extension study of the safety and tolerability of memantine in patients with mild to moderate Alzheimer’s disease

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be safe and to have beneficial effects on cognition, function, behavior, and global patient status in patients with Alzheimer's disease (AD) in studies lasting 3-6 months. It is approved in the U.S. and Europe for the treatment of moderate to severe AD and is currently under investigation for mild to moderate AD. To evaluate the long-term safety of memantine in patients with mild to moderate AD and to investigate the tolerability of once-daily dose administration. This 28-week study enrolled 314 patients with mild to moderate AD who had completed a 24-week, double-blind, placebo-controlled lead-in clinical trial of memantine in AD. Following an 8-week double-blind dose titration phase (used to assess the tolerability of different dosing regimens), subjects were assigned to continuous open label memantine (10 mg, bi.d.) treatment for 20 weeks. Safety outcome measures included treatment-emergent adverse events (AEs), deaths, vital signs, electrocardiograms, and laboratory parameters. During the 28-week study (Phase A+Phase B), the most common AEs were falls and other injuries (both 10.8%). AEs resulted in treatment discontinuation in 6.7% of patients. Discontinuations due to AEs were similar in the once-daily dosing groups compared to the twice-daily dosing groups. During dose titration, completion rates were greater than 90% for both groups. Conversion to once-daily dosing in patients already receiving twice-daily doses of memantine was also well tolerated. Memantine monotherapy in patients with mild to moderate AD is safe and well tolerated for at least one year. Once-daily dosing during titration and short-term maintenance therapy is safe and well tolerated.

P2-121: Safety & tolerability of memantine in the treatment of agitation in patients with Alzheimer’s disease: A pilot study in community dwelling patients presenting clinical & caregiver impressions

P2-121: Safety & tolerability of memantine in the treatment of agitation in patients with Alzheimer’s disease: A pilot study in community dwelling patients presenting clinical & caregiver impressions

Memantine hydrochloride: Pharmacological and clinical profile

Memantine (Axura, Merz Pharmaceuticals GmbH; Ebixa, H. Lundbeck A/S, Namenda, Forest Laboratories, Inc.) is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with low to moderate affinity for the (+)MK-801 binding site. It is characterized as a voltage-sensitive open-channel NMDA receptor blocker that antagonizes NMDA receptor-mediated inward currents in vitro with an IC50 of 1-3 microM. In animal models, memantine displays both neuroprotective (antiexcitotoxic) and cognition-enhancing properties at therapeutically relevant concentrations. The strong voltage dependency and rapid blocking/unblocking kinetics of memantine are thought to be the basis for its excellent clinical tolerability. Recently completed clinical studies demonstrate positive effects of memantine in Alzheimer's disease both as a monotherapy and in patients receiving continuous donepezil treatment. Memantine treatment also has demonstrated significant improvement of cognitive performance in patients suffering from vascular dementia. Furthermore, the safety and tolerability of memantine in clinical trials has been excellent, with the incidence of premature withdrawals due to adverse events no greater than placebo and overall low frequencies of total adverse events. In 2002, memantine was approved by the European Medicines Agency (EMEA) for the treatment of moderately severe to severe Alzheimer's disease. More recently, memantine was approved in the US for the treatment of moderate to severe Alzheimer's disease (October 2003). Here, we review the most recent pharmacological and clinical data in dementia patients that has emerged from the systematic evaluation of memantine.

P.4.020 Efficacy and tolerability of memantine in nursing home patients with moderate to severe dementia of the Alzheimer's type

The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that interacts with the low-density lipoprotein (LDL) receptor at the surface of hepatocytes to regulate circulating LDL cholesterol levels. High circulating PCSK9 levels have been associated with elevated LDL cholesterol. Recently, the Food and Drug Administration of the United States approved new LDL cholesterol–lowering drugs that specifically target the inhibition of PCSK9. Similar to most human proteins, PCSK9 exists in multiple forms as it is the target of posttranslational modifications (PTMs) such as proteolytic cleavage, phosphorylation, and others, which can affect its biological activity. However, commercially available assays, such as enzyme-linked immunosorbent assays, do not discriminate between these forms.To investigate, in 2 patient cohorts, the relationships between circulating levels of multiple forms of PCSK9 and cardiometabolic interventions or treatments known to reduce LDL cholesterol levels.PCSK9 forms were measured in plasma: (1) in 20 patients before and 6 months after bariatric surgery and (2) in 132 patients before and 12 months after daily statin treatment. A series of specific peptides used as surrogates for various PCSK9 forms were quantified by a novel semiautomated proteomic assay termed protein affinity capture coupled to quantitative mass spectrometry.Bariatric surgery resulted in a decrease in the plasma level of PCSK9 prodomain (P < .05), but did not result in a significant change in other measured PCSK9 forms. Statin treatment resulted in an increase in all measured plasma PCSK9 peptides (P < .001), but a 25% decrease in the phosphorylated state of PCSK9 at S688 (P < .05).These unexpected findings indicate that measuring the circulating levels of the various domains and PTMs of PCSK9 provides more in depth information than total PCSK9 and that the prodomain and the phosphorylated state of S688 may represent novel biomarkers to explore in cardiometabolic diseases and response to treatment. In addition, our data generated new hypotheses on the function of PCSK9 PTMs in health and disease.