Memantine Therapy Research Articles

Changes in dementia treatment patterns associated with changes in the National Policy in South Korea among patients with newly diagnosed Alzheimer’s disease between 2011 and 2017: results from the multicenter, retrospective CAPTAIN study

BackgroundThe South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014, eligibility for mandatory long-term care insurance (LTCI) was extended to people with dementia enabling access to appropriate long-term care including the cognitive function training program and home nursing service. This study aimed to investigate changes in treatment patterns for Alzheimer’s disease (AD) between July 2011 and June 2017 which spanned the 2014 revision.MethodsThis multicenter, retrospective, observational study of patients with newly diagnosed AD analyzed electronic medical records from 17 general hospitals across South Korea. Based on their time of AD diagnosis, subjects were categorized into Cohort 1 (1 July 2011 to 30 June 2014) and Cohort 2 (1 July 2014 to 30 June 2017).ResultsSubjects (N=3,997) divided into Cohorts 1 (n=1,998) and 2 (n=1,999), were mostly female (66.4%) with a mean age of 84.4 years. Cohort 1 subjects were significantly older (P<0.0001) and had a lower number of comorbidities (P=0.002) compared with Cohort 2. Mean Mini-Mental State Examination (MMSE) scores in Cohorts 1 and 2 at the time of AD diagnosis or start of initial treatment were 16.9 and 17.1, respectively (P=0.2790). At 1 year, mean MMSE scores in Cohorts 1 and 2 increased to 17.9 and 17.4, respectively (P=0.1524). Donepezil was the most frequently administered medication overall (75.0%), with comparable rates between cohorts. Rates of medication persistence were ≥98% for acetylcholinesterase inhibitor or memantine therapy. Discontinuation and switch treatment rates were significantly lower (49.7% vs. 58.0%; P<0.0001), and mean duration of initial treatment significantly longer, in Cohort 2 vs. 1 (349.3 vs. 300.2 days; P<0.0001).ConclusionsComparison of cohorts before and after revision of the national LTCI system for dementia patients found no significant difference in mean MMSE scores at the time of AD diagnosis or start of initial treatment. The reduction in the proportion of patients who discontinued or changed their initial treatment, and the significant increase in mean duration of treatment, were observed following revision of the LTCI policy which enabled increased patient access to long-term care.

Memantine Therapy as an Augmentation in Treatmentresistant Depression: A Case Report

Abstract Evidence suggests that treatment-resistant depression (TRD), defined as the occurrence of an insufficient clinical response after adequate antidepressant therapy among patients diagnosed with major depression, is one of the most important public health problems and is associated with significant disability and psychosocial impairment. Here we present a case of depression resistance to the treatment of a 22-year-old man and the effects of Memantine augmentation. The first symptoms of depression appeared in January 2019, and pharmacotherapeutic treatment began in March of the same year. He was in a bad mood, sad, hopeless, tense, lacked energy, lost interest, and decreased libido. During his twoyear pharmacotherapeutic therapy, he took SSRIs, SNRIs, TeCAs, SARIs, atypical antipsychotics with antidepressant effects, such as aripiprazole and cariprazine. Since the patient still did not have adequate therapeutic response and new drugs were available, the choice fell on Memantine after researching several databases and collecting the data listed at the beginning of the article. The initial dose was 5 mg daily and was gradually increased by 5 mg each week to a maximum of 20 mg. After 2 weeks at a stable dose, the patient reported feeling a little better. Significant improvement in symptoms was observed in the MADRS score, which was then applied to assess the effects of augmentation. After four weeks of therapy, he entered remission which is still ongoing.

A causal inference study: The impact of the combined administration of Donepezil and Memantine on decreasing hospital and emergency department visits of Alzheimer's disease patients.

Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimer's disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimer's Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.

Donepezil-induced psychosis: a cautionary report of a rare adverse reaction

IntroductionDonepezil is an acetylcholinesterase inhibitor approved by the Food and Drug Administration for the treatment of dementia in Alzheimer’s disease. While it is not curative for Alzheimer’s disease, donepezil has been shown to improve symptoms and slow disease progression; however, cases of rare psychiatric adverse effects, including hallucinations, mania, and increased confusion, have been reported. This report presents a case of donepezil-induced psychosis, which quickly resolved following cessation of the offending medication.ObjectivesTo illustrate a unique case of donepezil-induced psychosisMethodsThe patient is an 81-year-old male with a history of late-onset Alzheimer’s disease, mild depression, hypertension, hyperlipidemia, gastroesophageal reflux disease, and myocardial infarction. The patient was prescribed oral donepezil 10mg twice daily to manage his late-onset Alzheimer’s disease. Subsequently, he began developing persecutory delusions, increased agitation toward his family, and auditory hallucinations. His symptoms were worse at night after taking the donepezil, and he regularly requested to have a firearm for self-defense in the late hours of the night. His symptoms progressed for several weeks before his family brought him into the geriatric psychiatry clinic to address his psychosis. The family recognized that these new symptoms started shortly after the patient began taking donepezil and had already started decreasing the dose to half of what was originally prescribed.ResultsThis patient experienced symptom remission from psychosis immediately upon discontinuation of donepezil. The patient and his family reported significant improvement with no continuation of hallucinations or paranoia. There was also reported improvement in mood and irritability, and the patient appeared significantly better upon follow-up with geriatric psychiatry. Due to this immediate improvement, the suspected causative factor in the precipitation of psychosis in this patient is the anticholinesterase activity of the donepezil. Although the prescribing information of donepezil details inadequate data proving an association between donepezil and psychotic symptoms, two other published case reports (Yorston GA et al. J Psychopharmacol 2000;14:303-4, Pozzi FE et al. Case Rep Neurol 2022; 14:359-365), along with this one, provide evidence of a causal relationship between the two. The patient was switched to memantine therapy and has remained free of psychotic symptoms thus far.ConclusionsThis case demonstrates the caution required among clinicians when prescribing donepezil for the treatment of Alzheimer’s disease. There needs to be a more focused risk evaluation of potential psychiatric adverse effects in patients treated with donepezil.Disclosure of InterestNone Declared

Alzheimer's disease and COVID-19

In elderly patients with COVID-19 cognitive functions decline; it has been suggested that SARS-CoV-2 infection may lead to the development of Alzheimer's disease (AD) and other long-term neurological consequences. We review several parallels between AD and COVID-19 in terms of pathogenetic mechanisms and risk factors. Possible mechanisms through which COVID-19 can initiate AD are discussed. These include systemic inflammation, hyperactivation of the renin-angiotensin system, innate immune activation, oxidative stress, and direct viral damage. It has been shown that increased expression of angiotensin-renin receptors (ACE2) may be a risk factor for COVID-19 in patients with AD. When entering the central nervous system, the SARS-CoV-2 virus can directly activate glial cell-mediated immune responses, which in turn can lead to the accumulation of beta-amyloid and the subsequent onset or progression of current AD. The involvement of inflammatory biomarkers, including interleukins (IL): IL6, IL1, as well as galectin-3, as a link between COVID-19 and AD is discussed. The rationale for the use of memantine (akatinol memantine) in patients with COVID-19 in order to prevent the development of cognitive deficits is discussed. Memantine has been shown to have a positive effect on neuroinflammatory processes in the onset or exacerbation of cognitive deficits, in reducing cerebral vasospasm and endothelial dysfunction in viral infections. Memantine therapy may improve everyday activity and reduce the risk of severe SARS-CoV-2 infection.

CO104 Efficacy of Memantine in Preventing Neurocognitive Dysfunction Induced By Radiation Therapy in Patients with Brain Metastases: A Systematic Review of Clinical Trials

Neurocognitive impairment affects about 50-90% of brain metastases patients who receive radiation therapy. However, literature search revealed that memantine had potential to prevent neurocognitive impairments induced by radiation therapy. However, due to lack of comprehensive data on memantine in prevention of neurocognitive impairments following radiation therapy, we conduct this systematic review to gather the safety and efficacy data of memantine therapy in prevention of neurocognitive dysfunction induced by radiation therapy in brain metastases patients.

Virtual Therapy with the NMDA Antagonist Memantine in Hippocampal Models of Moderate to Severe Alzheimer's Disease, in Silico Trials.

The variability in clinical trial results on memantine treatment of Alzheimer’s disease remains incompletely explained. The aim of this in silico study is a virtual memantine therapy for Alzheimer’s disease that provides a different perspective on clinical trials; An in silico randomised trial using virtual hippocampi to treat moderate to severe Alzheimer’s disease with doses of memantine 3–30 µM compared to placebo. The primary endpoint was the number of impulses (spikes). Secondary endpoints included interspike interval and frequency; The number of virtual moderate-AD hippocampal spikes was significantly lower, at 1648.7 (95% CI, 1344.5–1952.9), versus those treated with the 3 µM dose, 2324.7 (95% CI, 2045.9–2603.5), and the 10 µM dose, 3607.0 (95% CI, 3137.6–4076.4). In contrast, the number of virtual spikes (spikes) of severe AD of the hippocampus was significantly lower, at 1461.8 (95% CI, 1196.2–1727.4), versus those treated with the 10 µM dose, at 2734.5 (95% CI, 2369.8–3099.2), and the 30 µM dose, at 3748.9 (95% CI, 3219.8–4278.0). The results of the analysis of secondary endpoints, interspike intervals and frequencies changed statistically significantly relative to the placebo; The results of the in silico study confirm that memantine monotherapy is effective in the treatment of moderate to severe Alzheimer’s disease, as assessed by various neuronal parameters.

Computational Modeling of Therapy with the NMDA Antagonist in Neurodegenerative Disease: Information Theory in the Mechanism of Action of Memantine.

(1) Background: in patients with neurodegenerative diseases, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists provide neuroprotective advantages. We performed memantine therapy and proved mathematical and computer modeling of neurodegenerative disease in this study. (2) Methods: a computer simulation environment of the N-methyl-D-aspartate receptor incorporating biological mechanisms of channel activation by high extracellular glutamic acid concentration. In comparison to controls, pathological models were essentially treated with doses of memantine 3–30 µM. (3) Results: the mean values and 95% CI for Shannon entropy in Alzheimer’s disease (AD) and memantine treatment models were 1.760 (95% CI, 1.704–1.818) vs. 2.385 (95% CI, 2.280–2.490). The Shannon entropy was significantly higher in the memantine treatment model relative to AD model (p = 0.0162). The mean values and 95% CI for the positive Lyapunov exponent in AD and memantine treatment models were 0.125 (95% CI, NE–NE) vs. 0.058 (95% CI, 0.044–0.073). The positive Lyapunov exponent was significantly higher in the AD model relative to the memantine treatment model (p = 0.0091). The mean values and 95% CI for transfer entropy in AD and memantine treatment models were 0.081 (95% CI, 0.048–0.114) vs. 0.040 (95% CI, 0.019–0.062). The transfer entropy was significantly higher in the AD model relative to the memantine treatment model (p = 0.0146). A correlation analysis showed positive and statistically significant correlations of the memantine concentrations and the positive Lyapunov exponent (correlation coefficient R = 0.87, p = 0.0023) and transfer entropy (TE) (correlation coefficient R = 0.99, p < 0.000001). (4) Conclusions: information theory results of simulation studies show that the NMDA antagonist, memantine, causes neuroprotective benefits in patients with AD. Our simulation study opens up remarkable new scenarios in which a medical product, drug, or device, can be developed and tested for efficacy based on parameters of information theory.

The Computer Simulation of Therapy with the NMDA Antagonist in Excitotoxic Neurodegeneration in an Alzheimer's Disease-like Pathology.

(1) Background: The use of uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists results in neuroprotective benefits in patients with moderate to severe Alzheimer’s disease. In this study, we demonstrated mathematical and computer modelling of the excitotoxicity phenomenon and performed virtual memantine therapy. (2) Methods: A computer simulation environment of the N-methyl-D-aspartate receptor combining biological mechanisms of channel activation by means of excessive extracellular glutamic acid concentration in three models of excitotoxicity severity. The simulation model is based on sliding register tables, where each table is associated with corresponding synaptic inputs. Modelling of the increase in extracellular glutamate concentration, through over-stimulation of NMDA receptors and exacerbation of excitotoxicity, is performed by gradually increasing the parameters of phenomenological events by the power function. Pathological models were virtually treated with 3–30 µM doses of memantine compared to controls. (3) Results: The virtual therapy results of memantine at doses of 3–30 µM in the pathological models of excitotoxicity severity show statistically significant neuroprotective benefits in AD patients with moderate severity, 1.25 (95% CI, 1.18–1.32) vs. 1.76 (95% CI, 1.71–1.80) vs. 1.53 (95% CI, 1.48–1.59), (p < 0.001), to severe, 1.32 (95% CI, 1.12–1.53) vs. 1.77 (95% CI, 1.72–1.82) vs. 1.73 (95% CI, 1.68–1.79), (p < 0.001), in the area of effects on memory. A statistically significant benefit of memantine was demonstrated for all neuronal parameters in pathological models. In the mild severity model, a statistically significant increase in frequency was obtained relative to virtual memantine treatment with a dose of 3 µM, which was 23.5 Hz (95% CI, 15.5–28.4) vs. 38.8 Hz (95% CI, 34.0–43.6), (p < 0.0001). In the intermediate excitotoxicity severity model, a statistically significant increase in frequency was obtained relative to virtual memantine therapy with a 3 µM dose of 26.0 Hz (95% CI, 15.7–36.2) vs. 39.0 Hz (95% CI, 34.2–43.8) and a 10 µM dose of 26.0 Hz (95% CI, 15.7–36.2) vs. 30.9 Hz (95% CI, 26.4–35.4), (p < 0.0001). A statistically significant increase in frequency was obtained in the advanced excitotoxicity severity model as in the medium. (4) Conclusions: The NMDA antagonist memantine causes neuroprotective benefits in patients with moderate to severe AD. One of the most important benefits of memantine is the improvement of cognitive function and beneficial effects on memory. On the other hand, memantine provides only symptomatic and temporary support for AD patients. Memantine is prescribed in the US and Europe if a patient has moderate to severe AD. Memantine has also been approved for mild to moderate AD patients. However, its very modest effect provides motivation for further research into new drugs in AD. We are the first to present a mathematical model of the NMDA receptor that allows the simulation of excitotoxicity and virtual memantine therapy.

Preventives for oxaliplatin-induced peripheral neuropathy in colorectal cancer patients.

83 Background: For colorectal cancer patients treated with the chemotherapy drug oxaliplatin, oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect. We conducted an observational comparative effectiveness study to evaluate whether several potential preventives reduced the rate of OIPN diagnosis in the two years following chemotherapy initiation. Methods: This was a retrospective cohort study that utilized the Surveillance, Epidemiology, and End Results database combined with Medicare claims (SEER-Medicare). Eligible patients were diagnosed with colorectal cancer between 2007-2015, 66 years of age or older, and received at least two cycles of oxaliplatin. We used two definitions to denote diagnosis of OIPN: OIPN 1 (diagnosis codes specific to CIPN) and OIPN 2 (additional codes for peripheral neuropathy). Multinomial propensity score weighting was used to balance potential confounders. The Fine-Gray subdistribution hazards model was used to perform a competing risk, time to event analysis for diagnosis of OIPN. Results: There were 4,482 subjects analyzed for the outcome of OIPN 1 (n = 477, 10.1%), and 4,561 for OIPN 2 (n = 1,191, 26.1%). Duloxetine, venlafaxine (marginally significant for OIPN 1), opioids, and minocycline were associated with a decreased rate of OIPN according to both definitions. In addition, memantine and neuromuscular therapy were associated with a decreased rate of OIPN 1 but not OIPN 2. Gabapentin and pregabalin exposure was associated with an increased rate of OIPN diagnosis according to both definitions. Mixed results were obtained for nortriptyline and cannabinoids. Conclusions: This study revealed several potentially effective preventive options for OIPN in colorectal cancer patients receiving oxaliplatin. A limitation of this study is the observational design which cannot directly inform treatment guidelines. However, evidence from this study may serve as preliminary data to support a future randomized clinical trial.[Table: see text]

Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations

BackgroundATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. AimWe aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. MethodsA retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program. ResultsPatients (age 2.5–20 years) had symptom onset at an early age (6 days–1 year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks–4.8 years) with some improvements reported in all five. ConclusionsOur observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure–function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.

Умеренные когнитивные расстройства: некоторые аспекты диагностики и терапии

Objective of the Paper: To describe the modern approaches to diagnosis and management of moderate cognitive disorders (MCD). Key Points. MCD is a transition between normal characteristics of cognitive functions and dementia. Prevalence of MCD is extremely high; with improper diagnosis and management, the condition can develop to dementia. Currently there are no generally accepted recommendations on MCD medications. We have used an example of a MCD patient to demonstrate cognitive defect stabilisation within 1 year with memantine therapy. The use of the medicine at pre-dementia stage of Alzheimer's disease is discussed. Conclusion. Timely diagnosis and proper management of MCD syndrome are very important taking into account a high risk of their progression to dementia. Memantine is a promising medication possessing neuroprotective activity and prolonging the period of patient independence. Clinical studies of memantine for non-dementia cognitive disorders should be conducted, where the duration of therapy is sufficient to assess its neuroprotective effects. Keywords: cognitive disorders, moderate cognitive disorders, memantine.

A pilot clinical phase II trial MemSID: Acute and durable changes of red blood cells of sickle cell disease patients on memantine treatment.

An increase in abundance and activity of N‐methyl D‐aspartate receptors (NMDAR) was previously reported for red blood cells (RBCs) of sickle cell disease (SCD) patients. Increased Ca2+ uptake through the receptor supported dehydration and RBC damage. In a pilot phase IIa‐b clinical trial MemSID, memantine, a blocker of NMDAR, was used for treatment of four patients for 12 months. Two more patients that have enrolled into the study did not finish it. One of them had psychotic event following the involuntary overdose of the drug, whereas the other had vertigo and could not comply to the trial visits schedule. Acute and durable responses of RBCs of SCD patients to daily oral administration of memantine were monitored. Markers of RBC turnover, changes in cell density, and alterations in ion handling and RBC morphology were assessed. Acute transient shifts in intracellular Ca2+, volume and density, and reduction in plasma lactate dehydrogenate activity were observed already within the first month of treatment. Durable effects of memantine included (a) decrease in reticulocyte counts, (b) reduction in reticulocyte hemoglobinization, (c) advanced membrane maturation and its stabilization as follows from reduction in the number of NMDAR per cell and reduction in hemolysis, and (iv) rehydration and decrease in K+ leakage from patients’ RBC. Memantine therapy resulted in reduction in number of cells with sickle morphology that was sustained at least over 2 months after therapy was stopped indicating an improvement in RBC longevity.

The Concentration of Memantine in the Cerebrospinal Fluid of Alzheimer's Disease Patients and Its Consequence to Oxidative Stress Biomarkers.

Memantine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist utilized as a palliative cure for Alzheimer’s disease. This is the second study examining the memantine concentrations in cerebrospinal fluid. The previously published study enrolled six patients, and three of them were theoretically in a steady state. In our study, we enrolled 22 patients who regularly used a standard therapeutic dose of memantine (20 mg/day, oral administration) before the sample collection. Patients were divided into four groups, according to the time of plasma and cerebrospinal fluid collection: 6, 12, 18, and 24 h after memantine administration. The cerebrospinal fluid samples were also assessed for selected oxidative stress parameters (malondialdehyde, 3-nitrotyrosine, glutathione, non-protein thiols, and non-protein disulfides). The plasma/cerebrospinal fluid (CSF) ratio for all time intervals were within the range of 45.89% (6 h) to 55.60% (18 h), which corresponds with previously published findings in most patients. The other aim of our study was to deduce whether the achieved “real” memantine concentration in the central compartment was sufficient to block NMDA receptors. The IC50 value of memantine as an NMDA antagonist is in micromolar range; the lowest limit is 112 ng/ml (GluN2C), and this value was achieved only in three cases. The memantine cerebrospinal fluid concentration did not reach one quarter of the IC50 value in five cases (one patient was excluded for noncompliance); therefore, the potency of memantine as a therapeutic effect in patients may be questionable. However, it appears that memantine therapy positively affected the levels of some oxidative stress parameters, especially non-protein thiols and 3-nitrotyrosine.

Application value of serum biomarkers for choosing memantine therapy for moderate AD.

Although the FDA already has approved two types of drug therapies for Alzheimer's disease, in regard to moderate AD, there is no clear research to support the best choice of drug treatment. The goal of this study was to examine the levels of serum biomarkers in moderate-AD patients and to explore the value of these serum biomarkers for the diagnosis of memantine sensitivity in AD patients who are significantly affected by MEM. In our study, 177 patients with moderate AD were enrolled and divided into memantine-sensitive AD (n = 90) and memantine-insensitive AD (n = 87) groups. The sera from all patients were collected, and seven serum biomarkers were analysed. Then, 120 patients were used to establish a diagnostic model that was built with a binary logistic regression analysis, and 57 patients were used to validate our model. In addition, the area under the receiver operating characteristic (ROC) curve was established. From the seven serum biomarkers, the four serum biomarkers that were selected in to establish the regression model were VEGF, BDNF, IL-6 and IL-1β. The ROC curve of best combined detection was 0.899. The diagnostic ratio of the logistic model was 0.825. This study suggests that the logistic regression model (LRM) and the ROC curve based on patients' serum levels of VEGF, BDNF, IL-6 and IL-1β is a promising research for diagnosing and choosing the best course of treatment for moderate AD.

Memantine treatment of juvenile rats with kaolin-induced hydrocephalus

Memantine is a selective, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that has previously been shown to have neuroprotective qualities in some animal models of neurologic disease. We hypothesized that memantine therapy would improve behavioral, neuropathological, and/or biochemical outcomes in juvenile rats with kaolin-induced hydrocephalus. Three-week old rats received an injection of kaolin (aluminum silicate) into the cisterna magna. Magnetic resonance imaging was performed one week later to assess ventricle size and stratify rats to three treatment groups. Rats were blindly treated daily for three weeks with saline or 10 or 30 mg/kg/day memantine. Behavior measures were performed weekly. Histologic and biochemical evaluations were performed at termination. Hydrocephalic rats showed no differences in weight among treatment groups. Memantine treatment stabilized ventricular enlargement in both low and high dose groups. The high dose group exhibited increased motor activity in open field chambers compared to the vehicle-treated group. However, there were no significant differences between the three hydrocephalic treatment groups for other behavioral tasks. Ventriculomegaly was associated with periventricular white matter damage. Glial fibrillary acidic protein (GFAP) content was higher in the low dose memantine group compared to vehicle-treated group, but there were no differences in GFAP-immunoreactive astrocytes or Iba-1- immunoreactive microglia between groups. Memantine therapy stabilized ventricular expansion and improved some behavioral measures but did not reduce brain tissue changes in juvenile rats with kaolin-induced hydrocephalus.

Prophylactic Cranial Irradiation for Limited-Stage Small-Cell Lung Cancer: Survey of US Radiation Oncologists on Current Practice Patterns

PurposeProphylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer (LS-SCLC) is considered the standard of care. Meta-analysis of 7 clinical trials indicates a survival benefit to PCI, but all of these trials were conducted in the pre–magnetic resonance imaging (MRI) era. Therefore, routine brain imaging with MRI before PCI—as recommended by National Comprehensive Cancer Network guidelines—is not directly supported by the evidence. Current US practice patterns for patients with LS-SCLC are unknown. Materials and MethodsWe surveyed practicing US radiation oncologists via an institutional review board–approved online questionnaire. Questions covered demographic information and treatment recommendations for LS-SCLC. ResultsWe received 309 responses from US radiation oncologists. Ninety-eight percent recommended PCI for patients with LS-SCLC, 96% obtained brain MRI before PCI, 33% obtained serial brain imaging with MRI after PCI to detect new metastases, and 35% recommended memantine for patients undergoing PCI. Recommending memantine was associated with fewer years of practice (P < .001), fewer lung cancer patients treated per year (P = .045), and fewer LS-SCLC patients treated per year (P = .024). ConclusionAlmost all responding radiation oncologists recommended PCI and pre-PCI brain MRI for LS-SCLC patients with disease responsive to initial therapy. Only a third of respondents followed these patients with serial brain MRI. Approximately one third provided memantine therapy to try to limit neurocognitive effects of PCI. Further research is warranted to determine the best treatment for patients with LS-SCLC. This survey can inform the development of future trials that depend on participation from radiation oncologists.

The Effects of Memantine on Glutamic Receptor-Associated Nitrosative Stress in a Traumatic Brain Injury Rat Model.

The main aim of this study is to elucidate whether the neuroprotective effect of memantine, a noncompetitive N-methyl-d-aspartate receptor 2B (NR2B) antagonist, affects neuronal nitrosative stress, apoptosis, and NR2B expression and improves functional outcomes. Immediately after the onset of fluid percussion traumatic brain injury (TBI), anesthetized male Sprague-Dawley rats were divided into sham-operated, TBI+ vehicle, and TBI+ memantine groups. TBI rats were treated with a memantine intraperitoneal injection dose of 20 mg/kg intraperitoneally and then 1 mg/kg every 12 hours intraperitoneally for 6 doses. The motor function, proprioception, infarction volume, and neuronal apoptosis were then measured. Immunofluorescence was used to evaluate astrogliosis, microgliosis, nitrosative stress, and NR2A and NR2B expression in cortical cells. All the parameters were assessed 72 hours after TBI. Compared with the sham-operated controls, the TBI-induced motor and proprioception deficits, and increased infraction volume after TBI were significantly attenuated by memantine therapy. The TBI-induced neuronal apoptosis, astrogliosis, and microgliosis, the numbers of neuronal NO synthase and 3-nitro-l-tyrosine expression in neurons, and inducible NO synthase expression in microglia and astrocyte cells in the ischemic cortex after TBI were significantly improved by memantine therapy. Simultaneously, without affecting the NR2A expression in neuronal cells, the NR2B expression significantly decreased after memantine therapy, as evaluated by an immunofluorescence stain. Intraperitoneal injection of memantine in the acute stage may ameliorate TBI in rats by affecting NR2B expression and decreasing neuronal apoptosis and nitrosative stress in the injured cortex. These effects might represent 1 mechanism by which functional recovery occurred.

Evidence for accuracy of pain assessment and painkillers utilization in neuropsychiatric symptoms of dementia in Calabria region, Italy.

During the clinical course of dementia, beside cognitive impairment and memory loss, a very complex challenge is posed by the neuropsychiatric symptoms (NPSs). Accurate evaluation and treatment of pain impacts positively the agitation of demented patients aged ≥ 65 years. To gather information on the utilization of pain killers in demented patients a preliminary survey has been conducted in collaboration with the Calabrian Pharmacovigilance Territorial Service of the health district of Catanzaro (Italy). The study has taken into consideration the prescriptions of acetylcholinesterase inhibitors and memantine during the period ranging from July 2015 to June 2016 and the percentage of patients treated against pain with non steroidal antinflammatory drugs, opioids, and anticonvulsants have been monitored. The latter have been evaluated statistically for difference between the treatment before (pre) and after (post) the settlement of acetylcholinesterase inhibitors (AChEI) or memantine therapy. The results do support accuracy in painkillers utilization in the course of dementia in the regional population of Calabria (Italy).

Memantine, an NMDA Receptor Antagonist, Prevents Thyroxin-induced Hypertension, but Not Cardiac Remodeling.

Stimulation of glutamatergic tone has been causally linked to myocardial pathogenesis and amplified systemic blood pressure (BP). Memantine, a noncompetitive N-methyl-D-aspartate glutamatergic receptor (NMDA-R) antagonist, has been proposed to be an active cardioprotective drug. However, the efficacy of memantine and subsequently the possible involvement of the NMDA-R in the thyroxin (T4)-induced cardiovascular complications have never been investigated. We examined the effect of memantine (30 mg·kg·d) on the T4 (500 μg·kg·d)-provoked increase in mouse BP, cardiac hypertrophy indicated by enlarged overall myocardial mass, and reformed reactions of the contractile myocardium both in vivo and ex vivo after 2 weeks of treatment. Memantine alone did not result in any cardiovascular pathology in mice. Instead, memantine significantly prevented the T4-triggered systemic hypertension. But, it did not reverse cardiac hypertrophy, coupled in vivo left ventricular dysfunction (LV) or ex vivo right ventricular (RV) papillary muscle contractile alterations of the T4-treated mice. Our results openly direct the cardiovascular safety and tolerability of memantine therapy. Yet, extra research is necessary to endorse these prospective advantageous outcomes. Also, we believe that this is the first study to inspect the possible role of NMDA-R in the T4-stimulated cardiovascular disorders and concluded that NMDA-R could play a key role in the T4-induced hypertension.