Impact of modifications to antidementia drug reimbursement in France: Analysis of the FRA-DEM cohort.

AIMS: Alzheimer's disease and related diseases (ADRD) is a progressive and inexorable disease. In France, acetylcholinesterase inhibitors and memantine were reimbursed for subjects with ADRD, until 2 modifications of their reimbursement rate (2012, 2018). We aimed to study the consequences of these measures on ADRD subjects' healthcare use. METHODS: We analysed data from the FRA-DEM cohort, including subjects with presumed incident ADRD identified since 2011 in the French health insurance system. We studied the healthcare use of subjects identified with incident ADRD in 2011, 2013, 2015, 2017 and 2019, notably the annual number of defined daily doses of various psychotropic groups. We performed 2 multivariate multinomial logistic regressions with the subcohort year as the dependent variable. RESULTS: In total, 165 120 subjects were included. A progressive decrease in exposure to antidementia drugs was observed between 2011 and 2019. Consultations with private neurologists or psychiatrists, and exposure to risperidone, antidepressants and benzodiazepines increased in the 2019 subcohort, following the 2018 reimbursement withdrawal. Meanwhile, the use of nursing/allied healthcare and emergency care increased over the subcohort years, whereas we observed a decrease in general practitioner consultations. CONCLUSION: These results suggest increases in private neurologist or psychiatrist consultations and exposure to recommended drugs after the reimbursement withdrawal, contrary to the fears expressed. However, antidementia drug exposure decreased long before the reimbursement modifications, probably due to the growing evidence of the modest effect of these drugs, and exposure to benzodiazepines increased after the reimbursement withdrawal.

Role of Memantine in Limiting Cochleotoxicity in Rats.

Οur aim was to test whether amikacin's well-known cochleotoxic effects could be suppressed, depending on whether an NMDA-antagonist (memantine) was administered simultaneously with or after amikacin treatment. Forty Wistar rats were used in this experiment. Ten rats acted as controls and received no medication (group A). Amikacin (200 mg/kg) was administered intraperitoneally (i.p.) once daily for 14 days to 10 animals in group B; amikacin (200 mg/kg) was administered concurrently with memantine (10 mg/kg, i.p., once daily) to the same 10 animals in group C. Group D was given intraperitoneal memantine (10 mg/kg, once daily) for 14 days following a 2-week amikacin treatment. The cochlear activity of the right ear was tested using DPOAE in conscious animals. All animals were sacrificed at the conclusion of the experiment and both cochleae were collected for histological and immunohistochemical analysis. All groups treated with amikacin showed decreased cochlear activity, as testified by decreased DPOAE-amplitudes compared to the pre-treatment state. In the rats of group B, the DPOAE reduction was more pronounced. On histologic exam, the cochlear structures of group C rats and, although to a lesser extent, group D rats showed less severe cochlea damage. Memantine plays a protective role, resulting in restoring partially cochlear structures when administered either simultaneously with or after completion of amikacin i.p. treatment in rats.

Alzheimer's disease and its treatment-yesterday, today, and tomorrow.

Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-ß (Aß) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aß monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aß will benefit the majority of subjects with AD that the anti-Aß MABs are unlikely to be the "magic bullet". A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

Mitigating radiation-induced brain injury via NLRP3/NLRC4/Caspase-1 pyroptosis pathway: Efficacy of memantine and hydrogen-rich water.

Radiation-induced brain injury (RIBI) is a significant challenge in radiotherapy for head and neck tumors, impacting patients' quality of life. In exploring potential treatments, this study focuses on memantine hydrochloride and hydrogen-rich water, hypothesized to mitigate RIBI through inhibiting the NLRP3/NLRC4/Caspase-1 pathway. In a controlled study involving 40 Sprague-Dawley rats, divided into five groups including a control and various treatment groups, we assessed the effects of these treatments on RIBI. Post-irradiation, all irradiated groups displayed symptoms like weight loss and salivation, with notable variations among different treatment approaches. Particularly, hydrogen-rich water showed a promising reduction in these symptoms. Histopathological analysis indicated substantial hippocampal damage in the radiation-only group, while the groups receiving memantine and/or hydrogen-rich water exhibited significant mitigation of such damage. Molecular studies, revealed a decrease in oxidative stress markers and an attenuated inflammatory response in the treatment groups. Immunohistochemistry further confirmed these molecular changes, suggesting the effectiveness of these agents. Echoing recent scientific inquiries into the protective roles of specific compounds against radiation-induced damages, our study adds to the growing body of evidence on the potential of memantine and hydrogen-rich water as novel therapeutic strategies for RIBI.

Anti-dementia drugs: what is the evidence in advanced stages?

Dementia is a major public health concern due to its increasing prevalence, substantial caregiver burden, and high financial costs. Currently, the anti-dementia drugs aim only at a symptomatic effect. The subject of prescribing these drugs in advanced stages is a matter of considerable debate, with different countries making distinct recommendations. In this review article, we analyzed the evidence regarding cognitive and functional outcomes, adverse events, health-related costs, and caregiver burden in patients with advanced Alzheimer disease (AD) and mixed dementia. We included 35 studies. Most studies are heterogeneous, focus exclusively on AD, and show small benefits in terms of cognitive and functional scales. The overall evidence seems to suggest a benefit in introducing or maintaining anti-dementia drugs in patients with advanced dementia, but clinical meaningfulness is difficult to ascertain. The issue of costs and caregiver burden is significantly underexplored in this field but also seems to favor treatment continuation, despite a reduced overall effect. The decision of introducing or withdrawing anti-dementia drugs in advanced stages of dementia should be individualized. Future studies with homogeneous designs and outcomes are warranted.

Synthesis, characterization, and biological evaluation of novel cinnamic acid derivatives: cinnamoyl-metronidazole ester and cinnamoyl-memantine amide.

In this study, two derivatives, namely the ester derivative cinnamoyl metronidazole and the amide derivative cinnamoyl memantine, were synthesized from cinnamic acid and respective drugs for the purpose of exploring their potential as novel and efficient antimicrobial agents in the quest of prevailing the global antimicrobial resistance challenge. The synthesis process involved two steps: first, the chlorination of cinnamic acid using thionyl chloride, and second, the esterification of metronidazole or the amidation of memantine. These steps resulted in the formation of cinnamoyl metronidazole/memantine. Optimal reaction conditions were established, and chromatographic techniques were used to separate the synthesized compounds. Confirmation of successful synthesis was achieved through FT-IR analysis, which readily distinguished the chlorinated product and derivatives based on distinctive bands, including mainly the one of carbonyl group. Additionally, molecular structures were validated using 1H NMR and 13C NMR, with all peaks further confirming the successful esterification/amidation of cinnamoyl and drug moieties. Upon evaluating the biological activity, the parent compounds exhibited negligible effects within the tested concentration range. However, the derivatives demonstrated significant activity. The ester derivative exhibited potent activity against the Gram-positive bacterium Staphylococcus aureus, as evidenced by a zone of inhibition measuring 12-15 mm in diameter. Conversely, the amide derivative displayed appreciable biological activity against Candida fungi, with an inhibition zone measuring 11-14 mm.

Neuroprotection in radiotherapy of brain metastases: A pattern-of-care analysis in Germany, Austria and Switzerland by the German Society for radiation Oncology - working group Neuro-Radio-Oncology (DEGRO AG-NRO).

Background and purpose: Many patients with solid tumors develop brain metastases (BM). With more patients surviving long-term, preservation of neurocognitive function gains importance. In recent years, several methods to delay cognitive deterioration have been tested in clinical trials. However, knowledge on the extent to which these neuroprotective strategies have been implemented in clinical practice is missing. Materials and methods: We performed an online survey regarding treatment patterns of BM in German-speaking countries, focused on the use of neuroprotective approaches. The survey was distributed among radiation oncologists (ROs) registered within the database of the German Society for Radiation Oncology (DEGRO). Results: Physicians of 78 centers participated in the survey. Whole brain radiotherapy (WBRT) is still preferred by 70 % of ROs over stereotactic radiotherapy (SRT) in patients with 6-10 BM. For 4-5 BM WBRT is preferred by 23 % of ROs. The fraction of ROs using hippocampal sparing (HS) in WBRT has increased to 89 %, although the technique is used on a regular basis only by a minority (26 %). The drug memantine is not widely prescribed (14% of ROs). A trend was observed for university hospitals to implement neuroprotective approaches more frequently. Conclusion: There is considerable heterogeneity regarding the treatment of BM in German-speaking countries and a general standard of care is lacking. Neuroprotective strategies are not yet standard approaches in daily clinical routine, although usage is increasing. Further clinical trials, as well as improvement of technical opportunities and reimbursement, might further shift the treatment landscape towards neuroprotective radiation treatments in the future.

Efficacy and safety evaluation of combined therapies incorporating whole-brain radiotherapy in patients with brain metastases: a systematic review and meta-analysis.

BACKGROUND: Whole-brain radiotherapy (WBRT) is a standard and effective approach for brain metastases, but it is linked to neurocognitive complications, specifically issues related to the hippocampus. Innovative strategies are being explored to enhance outcomes. However, a consensus is yet to be reached in this field. Our aim is to investigate the efficacy and safety of WBRT combined with simultaneous integrated boost (SIB), memantine, and hippocampal avoidance (HA) techniques in treatment of brain metastases. METHODS: In this systematic review and meta-analysis, we comprehensively searched PubMed, MEDLINE, Embase, and Cochrane for studies reporting the efficacy and toxicity of WBRT-based combination therapies from inception to September 19, 2023. Data were pooled using random-effects models. Results were reported as risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes, along with their 95% confidence intervals (CIs). Heterogeneity was evaluated using the I2 statistic. RESULTS: Among 2175 articles, 29 studies involving 3460 patients were included. The meta-analysis revealed that compared to WBRT alone, combination therapies significantly mitigated neurocognitive function decline (RD = -0.09, 95% CI [-0.18-0.01]; P = 0.03) and intracranial control failure (RR = 0.86, 95% CI [0.52-1.44]; P = 0.02), without increasing the risk of hippocampal recurrence or high-grade toxicities. Notably, HA-WBRT + SIB/memantine demonstrated improved neurocognitive outcomes and survival benefits. CONCLUSION: WBRT-based combination therapies demonstrate improved efficacy and comparable safety to WBRT alone, with specific emphasis on the effectiveness of HA-WBRT + Memantine and HA-WBRT + SIB in optimizing therapeutic outcomes for brain metastases.

Cholinesterase inhibitors and memantine are associated with a reduced mortality in nursing home residents with dementia: a longitudinal observational study.

BACKGROUND: A large proportion of nursing home (NH) residents suffer from dementia and effects of conventional anti-dementia drugs on their health is poorly known. We aimed to investigate the associations between exposure to anti-dementia drugs and mortality among NH residents. METHODS: This retrospective longitudinal observational study involved 329 French NH and the residents admitted in these facilities since 2014 and having major neurocognitive disorder. From their electronic health records, we obtained their age, sex, level of dependency, Charlson comorbidity index, and Mini mental examination score at admission. Exposure to anti-dementia drugs was determined using their prescription into 4 categories: none, exposure to acetylcholinesterase inhibitors (AChEI) alone, exposure to memantine alone, exposure to AChEI and memantine. Survival until the end of 2019 was studied in the entire cohort by Cox proportional hazards. To alleviate bias related to prescription of anti-dementia drugs, we formed propensity-score matched cohorts for each type of anti-dementia drug exposure, and studied survival by the same method. RESULTS: We studied 25,358 NH residents with major neurocognitive disorder. Their age at admission was 87.1 + 7.1 years and 69.8% of them were women. Exposure to anti-dementia drugs occurred in 2,550 (10.1%) for AChEI alone, in 2,055 (8.1%) for memantine alone, in 460 (0.2%) for AChEI plus memantine, whereas 20,293 (80.0%) had no exposure to anti-dementia drugs. Adjusted hazard ratios for mortality were significantly reduced for these three groups exposed to anti-dementia drugs, as compared to reference group: HR: 0.826, 95%CI 0.769 to 0.888 for AChEI; 0.857, 95%CI 0.795 to 0.923 for memantine; 0.742, 95%CI 0.640 to 0.861 for AChEI plus memantine. Results were consistent in propensity-score matched cohorts. CONCLUSION: The use of conventional anti-dementia drugs is associated with a lower mortality in nursing home residents with dementia and should be widely used in this population.

NMDA Receptor Antagonist Memantine Ameliorates Experimental Autoimmune Encephalomyelitis in Aged Rats.

Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is expected to increase. In addition to neurons, N-methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronal cells, such as immune cells. The aim of this study was to investigate the role of NMDARs in experimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and aged Dark Agouti rats from day 7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease, reactivation, and apoptosis of CD4+ T cells in the target organ of aged EAE rats. The expression of the fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent in aged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes' mRNA expression in brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advanced oxidation protein products in brain tissue were consistent with previous results. Overall, our results suggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats.

Memantine suppresses the excitotoxicity but fails to rescue the ataxic phenotype in SCA1 model mice.

Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder of the cerebellum and brainstem. Memantine has been proposed as a potential treatment for SCA1. It blocks N-methyl-D-aspartate (NMDA) receptors on neurons, reduces excitotoxicity and decreases neurodegeneration in Alzheimer models. However, in cerebellar neurodegenerative diseases, the potential value of memantine is still unclear. We investigated the effects of memantine on motor performance and synaptic transmission in the cerebellum in a mouse model where mutant ataxin 1 is specifically targeted to glia. Lentiviral vectors (LVV) were used to express mutant ataxin 1 selectively in Bergmann glia (BG). In mice transduced with the mutant ataxin 1, chronic treatment with memantine improved motor activity during initial tests, presumably due to preserved BG and Purkinje cell (PC) morphology and numbers. However, mice were unable to improve their rota rod scores during next days of training. Memantine also compromised improvement in the rota rod scores in control mice upon repetitive training. These effects may be due to the effects of memantine on plasticity (LTD suppression) and NMDA receptor modulation. Some effects of chronically administered memantine persisted even after its wash-out from brain slices. Chronic memantine reduced morphological signs of neurodegeneration in the cerebellum of SCA1 model mice. This resulted in an apparent initial reduction of ataxic phenotype, but memantine also affected cerebellar plasticity and ultimately compromised motor learning. We speculate that that clinical application of memantine in SCA1 might be hampered by its ability to suppress NMDA-dependent plasticity in cerebellar cortex.

Detection and analysis of signals of adverse events of memantine based on the US food and drug administration adverse event reporting system.

BACKGROUND: Despite its widespread use, the adverse effects (AEs) of memantine have not been well documented, and there is a need to find new ways to analyze the AEs of memantine. RESEARCH DESIGN AND METHODS: AEs in which the primary suspected drug was memantine were retrieved from the FAERS database. The proportional report ratio (PRR), reporting odds ratio (ROR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM) were used to detect potential positive signals between memantine and AEs. SAS, MySQL, EXCEL, and R language software were used for data processing and statistical analysis. RESULTS: This study gathered a total of 5808 reports of AEs associated with memantine. Of these reports, a greater proportion of female patients (51.17%) than male patients (36.33%) had AEs. The AEs reported by FAERS were mainly in psychiatric category (n = 2157, IC025 = 2.69), various neurologic disorders (n = 1608, IC025 = 2.04), systemic disorders and various site reactions (n = 842, IC025 = 1.29). Unexpected ocular adverse events have been reported, ophthalmic vein thrombosis (n = 4, IC025 = 3.47) and scleral discolouration (n = 7, IC025 = 3.1), which may worsen glaucoma. CONCLUSIONS: This study observed conceivable new AEs signals and may supply important assist for scientific monitoring and threat identification of memantine.

Optimizing Neuroprotective Nano-structured Lipid Carriers for Transdermal Delivery through Artificial Neural Network.

BACKGROUND: Dementia associated with Alzheimer's disease (AD) is a neurological disorder. AD is a progressive neurodegenerative condition that predominantly impacts the elderly population, although it can also manifest in younger people through the impairment of cognitive functions, such as memory, cognition, and behaviour. Donepezil HCl and Memantine HCl are encapsulated in Nanostructured Lipid Carriers (NLCs) to prolong systemic circulation and minimize the systemic side effects. OBJECTIVE: This work explores the use of data mining tools to optimize the formulation of NLCs comprising of Donepezil HCl and Memantine HCl for transdermal drug delivery. Neuroprotective drugs and excipients are utilized for protecting the nervous system against damage or degeneration. METHOD: The NLCs were formulated using a high-speed homogenization technique followed by ultrasonication. NLCs were optimized using Box Behnken Design (BBD) in Design Expert Software and artificial neural network (ANN) in IBM SPSS statistics. The independent variables included the ratio of solid lipid to liquid lipid, the percentage of surfactant, and the revolutions per minute (RPM) of the high-speed homogenizer. RESULTS: The NLCs that were formulated had a mean particle size ranging from 67.0±0.45 to 142.4±0.52nm. Both drugs have a %EE range over 75%, and Zeta potential was determined to be - 26±0.36mV. CryoSEM was used to do the structural study. The permeation study showed the prolonged release of the formulation. CONCLUSION: The results indicate that NLCs have the potential to be a carrier for transporting medications to deeper layers of the skin and reaching systemic circulation, making them a suitable formulation for the management of Dementia. Both ANN and BBD techniques are effective tools for systematically developing and optimizing NLC formulation.

Uso de antipsicóticos en los pacientes con demencia en España: comparación con la prescripción de los inhibidores de la acetilcolinesterasa y de la memantina, y análisis de las asociaciones / Use of antipsychotics in patients with dementia in Spain: Comparison with prescription of acetylcholinesterase inhibitors and memantine and analysis of associations

Objetivo: Se ha analizado la prevalencia de antipsicóticos, inhibidores de la acetilcolinesterasa (IACE) y memantina en pacientes con demencia en España y la influencia de estas asociaciones en su prescripción. Método: Estudio descriptivo, retrospectivo y transversal de la base BIFAP de 2017 en los mayores de 65 años con demencia. Se recogieron las prescripciones de antipsicóticos, los IACE y la memantina. Para los antipsicóticos también se recogieron, la duración del tratamiento y el tiempo desde el diagnóstico de demencia, al de prescripción. Resultados: Se recuperaron 1.327.792 sujetos, 89.464 (6,73%) con demencia. El 31,76% tuvieron prescritos antipsicóticos; los más frecuentes: quetiapina (58,47%), risperidona (21%) y haloperidol (19,34%). Las prescripciones de IACE y memantina fueron más frecuentes en los menores de 84 años y las de antipsicóticos en los mayores de 85 años (p<0,001). Los antipsicóticos se mantuvieron una media de 1.174,5 días. En el 26,4% de los casos se prescribieron aislados, OR: 0,61 (IC 95%: 0,59-0,62), en el 35,85% asociados a IACE, OR: 1,26 (IC 95%: 1,22-1,30) y en el 42,4% a memantina, OR: 1,69 (IC 95%: 1,62-1,78); p<0,000). Desde el diagnóstico de demencia transcurrieron de 461 días (±1.576,5) cuando se prescribieron aislados; 651 días (±1.574,25) asociados a IACE y 1.224 (±1.779) a memantina. Conclusiones: Una tercera parte de los pacientes con demencia tuvieron prescritos antipsicóticos, mayoritariamente atípicos, más frecuentemente en los mayores de 85 años y durante periodos prolongados. La prescripción de IACE y memantina se asoció al incremento del riesgo de uso de antipsicóticos, pero paradójicamente, a la prolongación del tiempo hasta su prescripción.(AU)

ObjectiveWe have analyzed the prevalence of antipsychotics in patients with dementia in Spain, their age distribution and the influence of treatment with IACEs and memantine on their prescription. Method: Descriptive, retrospective and cross-sectional study of the 2017 BIFAP database in over 65 years of age with dementia. Prescriptions of antipsychotics, IACEs and memantine were collected. For antipsychotics were also collected, the duration of treatment and time from dementia diagnosis to prescription. Results: A total of 1,327,792 subjects were retrieved, 89,464 (6.73%) with dementia. Antipsychotics were prescribed in 31.76%; by frequency: quetiapine (58.47%), risperidone (21%) and haloperidol (19.34%). Prescriptions of IACEs and memantine were clustered in those younger than 84 years and antipsychotics in those older than 85 (P<.001). Antipsychotics were maintained for a mean of 1174.5 days. In 26.4% of cases they were prescribed alone, OR 0.61 (95% CI: 0.59-0.62), in 35.85% associated with IACEs, OR 1.26 (95% CI: 1.22-1.30) and in 42.4% with memantine, OR 1.69 (95% CI: 1.62-1.78) (P<.000). From the diagnosis of dementia, 461 days (±1576.5) elapsed when isolated drugs were prescribed; 651 days (±1574.25) associated with IACEs and 1224 (±1779) with memantine. Conclusions: One third of patients with dementia were prescribed antipsychotics, mostly atypical, more frequently in those older than 85 years and for prolonged periods. IACEs and memantine were associated with the risk of antipsychotic prescription, but paradoxically, with prolonged time to onset.(AU)

[Multi-center open comparative randomized study of efficacy and safety of Akatinol Memantine 20 mg (single-doses) vs Akatinol Memantine 10 mg (double-doses) in patients with vascular dementia]. / Mnogotsentrovoe otkrytoe sravnitel'noe randomizirovannoe issledovanie effektivnosti i bezopasnosti primeneniya preparata Akatinol Memantin, 20 mg (odnokratnyi priem) v sravnenii s preparatom Akatinol Memantin, 10 mg (dvukratnyi priem) u patsientov s sosudistoi dementsiei.

OBJECTIVE: Evaluation of the efficacy and safety of the drug Acatinol Memantine, 20 mg (once daily) in comparison with the drug Acatinol Memantine, 10 mg (twice daily) in patients with moderate to moderate severe vascular dementia. MATERIAL AND METHODS: The study included 130 patients aged 50-85 years of both sexes with instrumentally and clinically confirmed vascular dementia. The patients were randomized into 2 groups. Group I consisted of 65 patients receiving Akatinol Memantine, 20 mg once daily, group II - 65 patients receiving Akatinol Memantine, 10 mg twice daily for 24 weeks. Clinical, parametric and statistical research methods were used. The Alzheimer's disease assessment scale, the cognitive subscale (ADAS-cog), the short mental Status Assessment Scale (MMSE) and the general clinical impression scale for patients condition and illness severity (CGI-C and CGI-S) and the Hamilton Depression Rating scale (HAM-D) were used. Adverse events were collected and analyzed. RESULTS: At week 24, both groups showed statistically significant positive change in ADAS-cog total score: in group I the total score was 27.2±8.76 points (absolute difference from baseline 3.5 points; p<0.01), and in group II - 26.1±7.86 points (absolute difference from baseline 2.5 points; p<0.01) with no statistically significant differences between groups. Evaluation of secondary efficacy criteria (change in ADAS-cog total score at week 12 and MMSE at weeks 4, 12, and 24) also revealed statistically significant benefit in both groups compared to baseline with no significant differences between groups. Statistically significant improvement was noticed on CGI-S and CGI-C scales in both groups. Akatinol Memantine was safe and well tolerated in both groups. CONCLUSION: The study showed no lesser efficacy and safety of Akatinol Memantine, 20 mg (once daily) compared to Akatinol Memantine, 10 mg (twice daily) in patients with moderate and moderately severe vascular dementia.

Case report: a unique presentation of memantine overdose causing echolalia and hypertension.

BACKGROUND: Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored in other diseases like neuropathic pain, epilepsy, and mood disorders. Our case uniquely highlights two important adverse effects in a patient who overdosed on memantine. One is hypertension, which is easy to overlook as a medication side effect. The other is echolalia which is the repetition of words and phrases spoken by another person. It is commonly seen in children with autism spectrum disorder and has been reported in older adults with head injuries, delirium, and neurocognitive disorders. The aim of this patient story is to highlight the importance of medication reconciliation with caregivers and knowledge of adverse drug reactions in patient management. This case report has been presented previously in the form of an abstract at the American Geriatrics Society Presidential poster session in May 2023. CASE PRESENTATION: Our patient is an 86-year-old man with mild dementia and hypertension, who was brought to the emergency department (ED) due to abrupt onset of altered mental status and auditory hallucinations. Investigations including blood work, CT head and an electroencephalogram (EEG) did not reveal an etiology for this change in his condition. Due to elevated blood pressure on presentation, a nicardipine drip was started, and he was given IV midazolam to assist with obtaining imaging. While reviewing medications with his daughter, it was noted that sixty memantine pills were missing from the bottle. Poison control was contacted and they confirmed association of these features with memantine. With supportive care, his symptoms resolved in less than 100 h, consistent with the half-life of memantine. Notably, our patient was started on Memantine one month prior to this presentation. CONCLUSIONS: Hypertensive urgency and echolalia were the most striking symptoms of our patient's presentation. Though hypertension is a known sign of memantine overdose, it can easily be contributed to medication non-compliance in patients with dementia, being treated for hypertension. According to our literature review, this the first case of memantine overdose presenting with echolalia, a sign that is not commonly associated with adverse reactions to medications. This highlights the importance of an early medication review, especially with caregivers of people with dementia.

Efficacy of memantine premedication in alleviating postoperative pain- A systematic review and meta-analysis.

Many premedication agents with opioid-sparing properties have been used in patients undergoing various elective surgeries. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been used by many researchers as an opioid-sparing strategy. Various databases like PubMed, Scopus, Cochrane Library, and clinicaltrials.gov were searched after registering the review protocol in PROSPERO for randomized-controlled trials (RCTs) that investigated the efficacy and safety of memantine premedication in adult patients undergoing various elective surgeries. The risk of bias (RoB-2) scale was used to assess the quality of evidence. From the 225 articles that were identified after a database search, 3 studies were included for a qualitative systematic review and a quantitative meta-analysis. The pooled analysis revealed that the use of memantine provided better pain scores at 2nd (mean difference: -0.82, 95% CI: -1.60, -0.05, P = 0.04) with significant heterogeneity (P = 0.06; I² =71%), and 6 hours postoperatively (mean difference: -1.80, 95% CI: -2.23, -1.37, P < 0.00001), but not at 1 hour. The sedation scores at 1 hour were higher in the memantine group but comparable in the 2nd hour. The number of doses of rescue analgesia and nausea/vomiting in the postoperative period was comparable in both groups. The results of this review suggest that memantine premedication could provide better pain scores in the immediate postoperative period with acceptable adverse effects. However, the current evidence is insufficient to suggest the routine use of memantine as a premedication before elective surgeries.

Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer's disease therapy.

RATIONALE: The ß-secretase BACE1 initiates amyloid-ß (Aß) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aß reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. OBJECTIVES: We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. METHODS: The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aß deposition. RESULTS: Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the ß-amyloidogenic processing of amyloid precursor protein or Aß levels in 5XFAD mouse brains. CONCLUSIONS: A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.