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1.
PLoS One ; 15(1): e0227781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978146

RESUMO

BACKGROUND: Memantine, currently available for the treatment of Alzheimer's disease, is an uncompetitive antagonist of the N-methyl-D-aspartate type of glutamate receptors. Under normal physiologic conditions, these unstimulated receptor ion channels are blocked by magnesium ions, which are displaced after agonist-induced depolarization. In humans, memantine administration is associated with different gastrointestinal dysmotility side effects (vomiting, diarrhoea, constipation, motor-mediated abdominal pain), thus limiting its clinical use. Mechanism of these motility disorders has not been clarified yet. Pigs can be used in various preclinical experiments due to their relatively very similar gastrointestinal functions compared to humans. The aim of this study was to evaluate the impact of a single and repeated doses of memantine on porcine gastric myoelectric activity evaluated by means of electrogastrography (EGG). METHODS: Six adult female experimental pigs (Sus scrofa f. domestica, mean weight 41.7±5.0 kg) entered the study for two times. The first EGG was recorded after a single intragastric dose of memantine (20 mg). In the second part, EGG was accomplished after 7-day intragastric administration (20 mg per day). All EGG recordings were performed under general anaesthesia. Basal (15 minutes) and study recordings (120 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Running spectral analysis based on Fourier transform was used. Results were expressed as dominant frequency of gastric slow waves (DF) and power analysis (areas of amplitudes). RESULTS: Single dose of memantine significantly increased DF, from basic values (1.65±1.05 cycles per min.) to 2.86 cpm after 30 min. (p = 0.008), lasting till 75 min. (p = 0.014). Basal power (median 452; inter-quartile range 280-1312 µV^2) raised after 15 min. (median 827; IQR 224-2769; p = 0.386; NS), lasting next 30 min. Repetitively administrated memantine caused important gastric arrhythmia. Basal DF after single and repeated administration was not different, however, a DF increase in the second part was more prominent (up to 3.18±2.16 after 15 and 30 min., p<0.001). In comparison with a single dose, basal power was significantly higher after repetitively administrated memantine (median 3940; IQR 695-15023 µV^2; p<0.001). Next dose of 20 mg memantine in the second part induced a prominent drop of power after 15 min. (median 541; IQR 328-2280 µV^2; p<0.001), lasting till 120 min. (p<0.001). CONCLUSIONS: Both single and repeated doses of memantine increased DF. Severe gastric arrhythmia and long-lasting low power after repeated administration might explain possible gastric dysmotility side effects in the chronic use of memantine.


Assuntos
Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Gastroenteropatias/induzido quimicamente , Motilidade Gastrointestinal/efeitos dos fármacos , Memantina/efeitos adversos , Estômago/efeitos dos fármacos , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Animais , Modelos Animais de Doenças , Eletromiografia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/fisiopatologia , Motilidade Gastrointestinal/fisiologia , Humanos , Memantina/administração & dosagem , Estômago/fisiopatologia , Sus scrofa
2.
J Clin Psychopharmacol ; 39(6): 634-638, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688396

RESUMO

PURPOSE/BACKGROUND: This double-blind, placebo-controlled clinical trial was designed to assess the efficacy and safety of memantine augmentation to standard regimen of antipsychotic treatment on psychotic symptoms and cognitive function in individuals with chronic schizophrenia for 8 weeks. METHODS/PROCEDURES: Forty stabilized individuals with chronic schizophrenia were randomized in a 1:1 ratio to memantine (20 mg/d) and control (placebo) groups, along with their antipsychotic regimen for 8 weeks. The efficacy of treatment was assessed by the Positive and Negative Syndrome Scale (PANSS) and Brief Assessment of Cognition Scale, and the safety was measured by the Abnormal Involuntary Movement Scale and Barnes Akathisia Rating Scale at baseline and at weeks 4 and 8. FINDINGS/RESULTS: No significant differences were observed in demographic or clinical variables between both groups at baseline. During the study, all subscales and total scores of PANSS decreased significantly within both groups, except the subscale score in memantine, which was found to be positive. Reduction in general subscale and total scores of PANSS was significantly higher in the control group compared with the memantine group. All subscale scores of the Brief Assessment of Cognition Scale increased significantly only in the memantine group. The increase in the Verbal Memory, Working Memory, Verbal Fluency Letter, and Verbal Fluency Total subscale scores was significantly higher in the memantine group than in the control group. There was no significant difference in the Abnormal Involuntary Movement Scale and Barnes Akathisia Rating Scale scores between the 2 groups during the study. IMPLICATIONS/CONCLUSIONS: This study showed that adjunctive memantine to antipsychotic regimen improved the verbal memory, learning, verbal letter fluency, and working memory without improvement on psychotic symptoms in individuals with chronic schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Memantina/farmacologia , Nootrópicos/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Antipsicóticos/administração & dosagem , Doença Crônica , Disfunção Cognitiva/etiologia , Método Duplo-Cego , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Memantina/administração & dosagem , Pessoa de Meia-Idade , Nootrópicos/administração & dosagem , Esquizofrenia/complicações , Adulto Jovem
3.
Psychiatry Res ; 282: 112602, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31630042

RESUMO

A considerable proportion of obsessive-compulsive disorder (OCD) patients receiving first-line pharmacological therapy, fail to fully respond to treatment and continue to exhibit significant symptoms. In this systematic review, we evaluate the efficacy of memantine, as a glutamate-modulating agent, in moderate to severe OCD. Single and double blinded as well as open-label trials of memantine augmentation in adults with OCD were considered. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores were the primary outcome measure. The electronic databases of PubMed, Scopus, Embase and Google Scholar were searched for relevant trials using keywords 'obsessive-compulsive disorder OR OCD' AND 'memantine'. The meta-analysis of eight studies involving 125 OCD subjects receiving memantine augmentation exhibited a significant overall mean reduction of 11.73 points in Y-BOCS scores. The categorical analysis of treatment response (a minimum of 35% reduction in Y-BOCS) in four double-blind placebo-controlled studies indicated that OCD patients receiving memantine augmentation were 3.61 times more likely to respond to treatment than those receiving placebo. We found that 20 mg/day memantine augmentation to first-line pharmacological treatment for a period of at least 8 weeks is a safe and effective intervention for moderate to severe OCD.


Assuntos
Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Memantina/administração & dosagem , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Resultado do Tratamento
4.
J Pharmacol Sci ; 140(3): 295-299, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31474556

RESUMO

We have previously reported that mice received intracerebroventricular injection of ouabain, an inhibitor of Na+, K+-ATPase, exhibited hyperactivity via overactivation of glutamatergic neurons. Here we investigated the effects of memantine, a blocker of N-methyl-d-aspartate receptors, on ouabain-induced hyperactivity. In mice that received ouabain injection, chronic memantine administration prevented the hyperactivity and the decrease in the Na+, K+-ATPase activity in the hippocampus. Memantine also protected neurons without affecting glial activation in the hippocampus of these mice. Our results suggest that memantine improves hyperactivity via the maintenance of Na+, K+-ATPase activity and neurons in the hippocampus in this mouse model.


Assuntos
Hipocampo/efeitos dos fármacos , Memantina/administração & dosagem , Ouabaína/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
5.
PLoS Negl Trop Dis ; 13(9): e0007226, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31536489

RESUMO

Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5-6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversion in infected people when used in the acute phase; however, their use in the chronic phase (the time when the majority of cases are diagnosed) is limited due to their serious side effects. Memantine is a glutamate receptor antagonist in the central nervous system of mammals that has been used for the treatment of Alzheimer's disease. Our group previously reported memantine as a trypanocidal drug that is able to induce apoptosis-like death in T. cruzi. In the present work, we further investigated the effects of memantine on the infection of RAW 264.7 macrophages and in vivo (in BALB/c mice). Here, we showed that memantine is able to diminish NO and Ca2+ entry in both LPS-activated and non-activated cells. These results, together with the fact that memantine was also able to reduce the infection of macrophages, led us to propose that this drug is able to activate a pro-oxidant non-NO-dependent cell defense mechanism. Finally, infected mice that were treated with memantine had diminished parasitemia, cardiac parasitic load, and inflammatory infiltrates. In addition, the treated mice had an increased survival rate. Taken together, these results indicate memantine to be a candidate drug for the treatment of Chagas disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Memantina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Cálcio/metabolismo , Doença de Chagas/parasitologia , Feminino , Coração/parasitologia , Lipopolissacarídeos/farmacologia , Macrófagos/parasitologia , Memantina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Óxidos de Nitrogênio/metabolismo , Carga Parasitária , Parasitemia , Células RAW 264.7 , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tripanossomicidas/administração & dosagem
6.
Medicine (Baltimore) ; 98(34): e16920, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441874

RESUMO

RATIONALE: Vascular cognitive impairment (VCI) is a common cause of dementia. Research suggests that hereditary factors (gene mutations) play an important role in the pathogenesis of VCI, and a mutation of the NOTCH3 locus is frequently identified in affected patients. Herein, we report the case of a patient with confirmed VCI associated with a NOTCH3 exon 33 gene mutation and review the relevant VCI literature. PATIENT CONCERNS: A 48-year-old man presented to our neurology clinic with gradually progressive cognitive impairment. DIAGNOSES: Brain magnetic resonance imaging revealed multiple punctate hyperintensities in the patient's periventricular white matter. Genetic analysis showed a c.6744C > T, p. Ala2223Val substitution in exon 33 of the NOTCH3 gene. We diagnosed thepatient with VCI secondary to a NOTCH3 gene mutation. INTERVENTIONS: Donepezil (5 mg) and memantine (5 mg) daily. OUTCOMES: The patient showed symptom improvement at his 3-month and 6-month follow-up appointments. LESSONS: This patient may have a new type of mutation that is different from the one seen in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, although it involves a NOTCH3 defect. We propose that the entire NOTCH3 gene should be sequenced in patients with suspected hereditary VCI. This practice could facilitate the discovery of newpathogenic mutations and diseases.


Assuntos
Demência Vascular/genética , Receptor Notch3 , Disfunção Cognitiva/etiologia , Demência Vascular/complicações , Demência Vascular/tratamento farmacológico , Donepezila/administração & dosagem , Humanos , Masculino , Memantina/administração & dosagem , Pessoa de Meia-Idade , Mutação , Nootrópicos/administração & dosagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
7.
Drug Des Devel Ther ; 13: 2677-2688, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447547

RESUMO

Purpose: Intravenous ketamine is often prescribed in severe neuropathic pain. Oral N-methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine. Patients and methods: A multicenter randomized controlled clinical trial included 60 patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine infusion. The primary endpoint was pain intensity at one month. Secondary endpoints included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations up to 12 weeks. Results: At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Scale: 4.01±1.87 to 4.05±2.61, p=0.53) and diminished pain paroxysms (p=0.03) while pain intensity increased significantly with memantine and placebo (p=0.04). At 3 months, pain remained lower than at inclusion (p=0.001) and was not significantly different in the three groups. Significant benefits were observed on cognitive-affective domains and quality of life for dextromethorphan and memantine (p<0.05). Conclusions: Oral dextromethorphan given after ketamine infusion extends pain relief during one month and could help patients to better cope with pain. Future studies should include larger populations stratified on pharmacogenetics screening. Optimization of an oral drug that could extend ketamine antihyperalgesia, with fewer hospital admissions, remains a prime challenge in refractory neuropathic pain.


Assuntos
Analgesia , Dextrometorfano/uso terapêutico , Ketamina/uso terapêutico , Memantina/uso terapêutico , Neuralgia/tratamento farmacológico , Administração Oral , Adulto , Idoso , Dextrometorfano/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Ketamina/administração & dosagem , Masculino , Memantina/administração & dosagem , Pessoa de Meia-Idade
8.
Mol Neurobiol ; 56(12): 8573-8588, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31280448

RESUMO

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aß) deposits and causes cerebral hemorrhages and dementia in elderly people. Memantine is used in Alzheimer's disease to inhibit the glutamatergic system by blocking N-methyl-D-aspartate receptors. Its therapeutic effects in CAA are unclear, however. Here, we used APP23 transgenic mice (CAA model) to investigate whether memantine has direct therapeutic effects on cerebrovascular Aß deposits. We treated APP23 mice and age-matched wild-type littermates with memantine at ages 6-18 months. We counted the numbers of vessels with Aß and hemosiderin deposits. We measured soluble and insoluble Aß40 and Aß42 levels and levels of amyloid precursor protein (APP), APP-processing enzymes (α-, ß-, γ-secretase), and Aß-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Memantine reduced cerebrovascular Aß and hemosiderin deposits in APP23 mice. Compared with controls, memantine-treated APP23 mice had reduced Aß40 levels and increased levels of hippocampal and vascular IDE. Our results suggest that memantine reduces cerebrovascular Aß deposits by enhancing Aß-cleaving IDE expression. The clinical availability of memantine may allow its use as a novel therapeutic agent in CAA.


Assuntos
Angiopatia Amiloide Cerebral/tratamento farmacológico , Angiopatia Amiloide Cerebral/enzimologia , Insulisina/metabolismo , Memantina/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Angiopatia Amiloide Cerebral/complicações , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Insulisina/genética , Aprendizagem em Labirinto , Memantina/administração & dosagem , Memantina/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Solubilidade
9.
Pharmacol Biochem Behav ; 183: 6-13, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31175916

RESUMO

Several studies have reported on the beneficial effects of memantine on behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease. However, the effects of memantine on BPSD-like behaviors in animals have not been well addressed. Here, the effects of memantine on memory disturbance and BPSD-like behaviors were evaluated in thiamine-deficient (TD) mice. Memantine (3 and 10 mg/kg, b.i.d.) was orally administered to ddY mice fed a TD diet for 22 days. During the treatment period, the forced swimming test, elevated plus-maze test, passive avoidance test, and locomotor activity test were performed. Neurotransmitter levels in the brain were analyzed after the treatment period. Daily oral administration of memantine ameliorated the memory disturbances, anxiety-like behavior, and depression-like behavior observed in TD mice. Memantine did not have a significant effect on monoamine levels, but increased glutamate levels in the hippocampus in TD mice. These results suggest that memantine prevents or suppresses the progression of BPSD-like behaviors that develop due to TD. This effect may be mediated in part by the enhancement of glutamatergic neuron activity in the hippocampus.


Assuntos
Comportamento Animal/efeitos dos fármacos , Demência/induzido quimicamente , Demência/psicologia , Memantina/farmacologia , Memória/efeitos dos fármacos , Deficiência de Tiamina/psicologia , Administração Oral , Animais , Ansiedade/tratamento farmacológico , Monoaminas Biogênicas/metabolismo , Peso Corporal/efeitos dos fármacos , Demência/tratamento farmacológico , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memantina/administração & dosagem , Camundongos
10.
Restor Neurol Neurosci ; 37(3): 245-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31177251

RESUMO

BACKGROUND: Altered glutamatergic neurotransmission after traumatic brain injury (TBI) contributes to excitotoxic cell damage and death. Prevention or suppression of such changes is a desirable goal for treatment of TBI. Memantine (3,5-dimethyl-1-adamantanamine), an uncompetitive NMDA receptor antagonist with voltage-dependent open channel blocking kinetics, was reported to be neuroprotective in preclinical models of excitotoxicity, brain ischemia, and in TBI when administered prophylactically, immediately, or within minutes after injury. METHODS: The current study examined effects of memantine administered by single intraperitoneal injection to adult male rats at a more clinically relevant delay of one hour after moderate-severe controlled cortical impact (CCI) injury or sham surgery. Histopathology was assessed on days 1, 7, 21, and 90, vestibulomotor function (beam balance and beam walk) was assessed on days 1-5 and 71-75, and spatial memory (Morris water maze test, MWM) was assessed on days 14-21 and 83-90 after CCI injury or sham surgery. RESULTS: When administered at 10 mg/kg, but not 2.5 or 5 mg/kg, memantine preserved cortical tissue and reduced neuronal degeneration 1 day after injury, and attenuated loss of synaptophysin immunoreactivity in the hippocampus 7 days after injury. No effects of 10 mg/kg memantine were observed on histopathology at 21 and 90 days after CCI injury or sham surgery, or on vestibulomotor function and spatial memory acquisition assessed during any of the testing periods. However, 10 mg/kg memantine resulted in trends for improved search strategy in the MWM memory retention probe trial. CONCLUSIONS: Administration of memantine at a clinically-relevant delay after moderate-severe CCI injury has beneficial effects on acute outcomes, while more significant improvement on subacute and chronic outcomes may require repeated drug administration or its combination with another therapy.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/lesões , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memantina/farmacologia , Atividade Motora/efeitos dos fármacos , Degeneração Neural/prevenção & controle , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Memória Espacial/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Masculino , Memantina/administração & dosagem , Ratos , Fatores de Tempo
11.
Geriatr Gerontol Int ; 19(7): 654-659, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31074090

RESUMO

AIM: To evaluate the prevalence of potentially inappropriate prescribing (PIP), as defined by the internationally validated Screening Tool of Older Person's Prescriptions (STOPP) criteria, in 12 months before and after initiation of medicines for dementia. METHODS: A retrospective cohort study was carried out involving people with their first claim for dispensing of medicines for dementia (cholinesterase inhibitor or memantine) between 1 January 2015 and 31 December 2015, aged ≥65 years at 1 January 2016 and alive at the end of 2016. The index date was defined as the date of first supply of medicines for dementia. PIP was identified using the Screening Tool of Older Person's Prescriptions criteria, and PIP prevalence was compared in the 12 months pre- and post-index date. The McNemar's test was used to test differences in the prevalence of PIP between the two time periods. RESULTS: The cohort included 1176 patients: 60% were women and the median age was 80 years. The overall PIP prevalence was 85% in the 12 months pre-initiation of medicines for dementia compared with 89% in the 12 months post-initiation (P < 0.0001). The median number of Screening Tool of Older Person's Prescriptions criteria was two (interquartile range 1-4) in the 12 months pre-initiation of medicines for dementia, increasing to three (range 2-4) in the 12 months post-initiation. CONCLUSIONS: PIP was common in people dispensed medicines for dementia, with a significant increase in prevalence post-initiation of medicines for dementia compared with pre-initiation. These results highlight the need for targeted interventions to minimize inappropriate use of medicines in people with dementia. Geriatr Gerontol Int 2019; 19: 654-659.


Assuntos
Inibidores da Colinesterase , Demência/tratamento farmacológico , Prescrições de Medicamentos , Prescrição Inadequada/prevenção & controle , Memantina , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Demência/diagnóstico , Demência/epidemiologia , Demência/psicologia , Prescrições de Medicamentos/normas , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Prescrição Inadequada/efeitos adversos , Masculino , Memantina/administração & dosagem , Memantina/efeitos adversos , Nootrópicos/administração & dosagem , Nootrópicos/efeitos adversos , Seleção de Pacientes , Lista de Medicamentos Potencialmente Inapropriados/normas , Prevalência , Estudos Retrospectivos
12.
Rev. neurol. (Ed. impr.) ; 68(10): 409-416, 16 mayo, 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-180736

RESUMO

Introducción. Los beneficios del manejo farmacológico con medicamentos antidemencia aún no están del todo demostrados, e incluso hay carencia de trabajos que describan su perfil de utilización. El presente trabajo buscó determinar los patrones de prescripción de fármacos antidemencia en una población de Colombia. Pacientes y métodos. Estudio descriptivo de corte transversal. Mediante una base de datos sistematizada de 3,5 millones de afiliados al sistema de salud colombiano, se seleccionó a pacientes con dispensaciones ininterrumpidas de fármacos antidemencia entre agosto y octubre de 2016. Se analizaron variables sociodemográficas, farmacológicas y comedicaciones. Se estimaron los costes de las terapias a partir del precio de referencia de los medicamentos. Resultados. Se identificó a 8.372 pacientes con una edad media de 79,5 ± 8,7 años; el 65,3% (n = 5.471) fueron mujeres. El fármaco más utilizado fue la rivastigmina (69,6%), principalmente en presentación transdérmica, seguida de la memantina (31,4%). En general, la dosis media administrada por día fue inferior a la dosis diaria definida. Solamente 568 pacientes (6,7%) usaron terapia combinada. El 84,3% de los pacientes (n = 7.061) usó medicamentos para alguna comorbilidad y el 54,2% (n = 4.535) tenía otro neurofármaco. El coste por 1.000 habitantes/día de la rivastigmina fue de 3,47 dólares, y de la memantina, de 0,30 dólares. Conclusión. Los pacientes con medicamentos antidemencia los están empleando en dosis inferiores a las definidas y presentan una importante frecuencia de comorbilidades y comedicaciones


Introduction. The benefits of pharmacological therapy with anti-dementia drugs are not yet fully demonstrated and there is even a lack of publications describing their use profile. The present work sought to determine the prescription patterns of anti-dementia drugs in a Colombian population. Patients and methods. Descriptive cross-sectional study. Through a systematized database of 3.5 million affiliates to the Colombian health system, patients with uninterrupted dispensing of anti-dementia drugs between August-October/2016 were selected. Sociodemographic, pharmacological and comedication variables were analyzed. The costs of the therapies were estimated from the reference price of the medicines. Results. We identified 8372 patients with a mean age of 79.5 ± 8.7 years and 65.3% (n = 5471) were women. The most widely used medication was rivastigmine (69.6%), mainly in transdermal presentation, followed by memantine (31.4%). In general, the average dose administered per day was lower than the defined daily dose. Only 568 patients (6.7%) used combination therapy. 84.3% of patients (n = 7061) used some additional medication and 54.2% (n = 4535) had another neurologic medication. The cost per 1000 inhabitants/day of rivastigmine was 3.47 USD and for memantine 0.30 USD. Conclusion. Patients with anti-dementia drugs are using them at doses lower than those defined and they present an important frequency of comorbidities and comedications


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Demência/tratamento farmacológico , Rivastigmina/administração & dosagem , Memantina/administração & dosagem , Galantamina/administração & dosagem , Estudos Transversais , Estudo Observacional , Fatores Socioeconômicos , Colômbia
13.
Naunyn Schmiedebergs Arch Pharmacol ; 392(6): 685-695, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30759264

RESUMO

There is increasing evidence of a link between type 2 diabetes mellitus (T2DM) and cognitive decline. T2DM has been recognized as a risk factor for Alzheimer's disease (AD). The aim of this research was to investigate the biochemical and physiological effects of vildagliptin treatment alone, and in combination with memantine, in a rat model of combined T2DM and AD. The experimental study was carried out on 75 male Wistar rats weighing 180-200 g. The rats were divided into five groups (n = 15): normal group, Alzheimer diabetic control, treated with vildagliptin (10 mg/kg/day), treated with memantine (30 mg/kg/day), and treated with combination of drugs. Serum glucose, lipid profile, acetylcholinesterase (AChE), homocysteine (Hcy), and amyloid beta peptide (Aß) were determined. Lipid peroxidation was measured in brain tissue. Expression of amyloid precursor protein (APP) in the brain was assessed by q-PCR, and expression of total and phosphorylated tau was determined by Western Blotting. Vildagliptin alone and in combination with memantine caused a decrease in blood glucose, HOMA-IR, lipid profile, Hcy, malanodialdhyde, and acetylcholinesterase, and an increase in apolipoprotein E. Expression of APP and phosphorylated tau protein was decreased with combined vildagliptin and memantine treatment. In conclusion, vildagliptin treatment, either alone or in combination with memantine, modulates AD-associated biochemical changes and downregulates amyloid precursor protein and phosphorylated tau expression in diabetic rats.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Memantina/administração & dosagem , Vildagliptina/administração & dosagem , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulação para Baixo , Lipídeos/sangue , Masculino , Fosforilação , Ratos , Ratos Wistar , Estreptozocina
14.
Med J Aust ; 210(4): 174-179, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30771226

RESUMO

INTRODUCTION: Cholinesterase inhibitors (ChEIs) and memantine are medications used to treat the symptoms of specific types of dementia. Their benefits and harms can change over time, particularly during long term use. Therefore, appropriate use of ChEIs and memantine involves both prescribing these medications to individuals who are likely to benefit, and deprescribing (withdrawing) them from individuals when the risks outweigh the benefits. We recently developed an evidence-based clinical practice guideline for deprescribing ChEIs and memantine, using robust international guideline development processes. MAIN RECOMMENDATIONS: Our recommendations aim to assist clinicians to: identify individuals who may be suitable for a trial of deprescribing ChEIs and memantine (such as those who do not have an appropriate indication, those who have never experienced a benefit, those who appear to be no longer benefitting, and those who have severe or end-stage dementia); and taper treatment and monitor individuals during the deprescribing process. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: Deprescribing ChEIs and memantine through shared decision making with individuals and their caregivers by: ▶determining their treatment goals; ▶discussing benefits and harms of continuing and ceasing medication, from the start of therapy and throughout; and ▶engaging them in monitoring after discontinuation, while informing carers that the individual will continue to decline after discontinuation. This approach may reduce adverse drug reactions and medication burden, leading to improved quality of life in people with dementia.


Assuntos
Inibidores da Colinesterase/normas , Demência/tratamento farmacológico , Desprescrições , Memantina/normas , Idoso , Idoso de 80 Anos ou mais , Inibidores da Colinesterase/administração & dosagem , Feminino , Humanos , Masculino , Memantina/administração & dosagem , Guias de Prática Clínica como Assunto
15.
PLoS One ; 14(1): e0210954, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689644

RESUMO

Understanding expression levels of proteins and their interactions is a key factor to diagnose and explain the Down syndrome which can be considered as the most prevalent reason of intellectual disability in human beings. In the previous studies, the expression levels of 77 proteins obtained from normal genotype control mice and from trisomic Ts65Dn mice have been analyzed after training in contextual fear conditioning with and without injection of the memantine drug using statistical methods and machine learning techniques. Recent studies have also pointed out that there may be a linkage between the Down syndrome and the immune system. Thus, the research presented in this paper aim at in silico identification of proteins which are significant to the learning process and the immune system and to derive the most accurate model for classification of mice. In this paper, the features are selected by implementing forward feature selection method after preprocessing step of the dataset. Later, deep neural network, gradient boosting tree, support vector machine and random forest classification methods are implemented to identify the accuracy. It is observed that the selected feature subsets not only yield higher accuracy classification results but also are composed of protein responses which are important for the learning and memory process and the immune system.


Assuntos
Síndrome de Down/genética , Síndrome de Down/psicologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Teorema de Bayes , Simulação por Computador , Modelos Animais de Doenças , Síndrome de Down/imunologia , Expressão Gênica , Humanos , Fenômenos do Sistema Imunológico/genética , Fenômenos do Sistema Imunológico/fisiologia , Aprendizagem/fisiologia , Memantina/administração & dosagem , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Redes Neurais de Computação , Máquina de Vetores de Suporte , Trissomia
16.
Cancer ; 125(3): 424-433, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30359477

RESUMO

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas , Glioblastoma , Mefloquina/administração & dosagem , Memantina/administração & dosagem , Metformina/administração & dosagem , Temozolomida/administração & dosagem , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Quimioterapia Adjuvante , Ensaios Clínicos Fase II como Assunto/métodos , Feminino , Glioblastoma/diagnóstico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Masculino , Dose Máxima Tolerável , Mefloquina/efeitos adversos , Memantina/efeitos adversos , Metformina/efeitos adversos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Radioterapia Adjuvante , Projetos de Pesquisa , Temozolomida/efeitos adversos , Resultado do Tratamento , Adulto Jovem
17.
Clin Pharmacol Ther ; 105(1): 121-130, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29717478

RESUMO

Memantine and the Acetylcholinesterase inhibitors (AChEIs) are two classes of drugs that are used to treat patients with Alzheimer's disease. We conducted a network meta-analysis of randomized controlled trials to compare the treatment effectiveness of monotherapy or combination therapy A total of 23,707 AD patients in 76 randomized trials were identified. In patients with mild-to-moderate AD, monotherapy with donepezil, galantamine or rivastigmine were superior to placebo in enhancing cognitive functions and activities of daily living (ADL), whereas monotherapy with donepezil or memantine were superior to placebo in improving behavioral symptoms. However, combination therapy with AChEIs and memantine did not show additional benefit than monotherapy. In patients with moderate-to-severe AD, neither monotherapy nor combination therapy were superior to placebo in any domain measurement. Combination therapy with memantine and AChEIs is confirmed to have no additional benefits over monotherapy. This article is protected by copyright. All rights reserved.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/administração & dosagem , Dopaminérgicos/administração & dosagem , Memantina/administração & dosagem , Nootrópicos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Humanos , Metanálise em Rede , Resultado do Tratamento
18.
J Oncol Pharm Pract ; 25(3): 657-662, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30200844

RESUMO

Whole brain radiotherapy is the mainstay of treatment for patients suffering from stage IV malignancies that have metastasized to the brain. Although this therapy is often effective at reducing tumor size and burden, it is associated with a spectrum of toxicities that often result in irreversible cognitive decline. Various drug and non-drug therapies have been evaluated to treat this neurotoxicity after whole brain radiotherapy is administered; however, currently available options have shown little benefit or come with side effects themselves that may outweigh the benefits of their use. For this reason, current investigations are focusing on preventing cognitive decline, rather than attempting to attenuate symptoms after they occur. Memantine has consistently shown promise in both in-vitro and in-vivo studies as a neuroprotective agent that may improve cognitive outcomes in patients undergoing whole brain radiotherapy. Memantine use prior to and during whole brain radiotherapy has been shown to significantly delay time to cognitive failure and reduce the rate of decline in memory, cognitive function, and processing speed. Its use has also been linked to significant decreases in brain edema, brain infarct size, and brain vasculature changes following whole brain radiotherapy. Memantine offers a promising safety profile with high tolerability and limited side effects. The objective of this article is to provide an overview of the target patient population, the neurotoxic effects of WBRT, current treatment options, and a summary of the available literature surrounding the use of memantine in this setting.


Assuntos
Neoplasias Encefálicas/radioterapia , Irradiação Craniana/métodos , Memantina/administração & dosagem , Neoplasias Encefálicas/secundário , Cognição/efeitos da radiação , Humanos , Memória/efeitos da radiação , Estadiamento de Neoplasias
19.
Neuroscience ; 390: 241-255, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30176321

RESUMO

Adult neurogenesis has potential to ameliorate a number of disorders that negatively impact the hippocampus, including age-related cognitive decline, depression, and schizophrenia. A number of treatments enhance adult neurogenesis including exercise, NMDA receptor antagonism, antidepressant drugs and environmental enrichment. Despite the chronic nature of many disorders, most animal studies have only examined the efficacy of neurogenic treatments over short timescales (≤1 month). Also, studies of neurogenesis typically include only 1 sex, even though many disorders differentially impact males and females. We tested whether two known neurogenic treatments, running and the NMDA receptor antagonist, memantine, could cause sustained increases in neurogenesis in male and female rats. We found that continuous access to a running wheel (cRUN) initially increased neurogenesis, but effects were minimal after 1 month and completely absent after 5 months. Similarly, a single injection of memantine (sMEM) transiently increased neurogenesis before returning to baseline at 1 month. To determine whether neurogenesis could be increased over a 2-month timeframe, we next subjected rats to interval running (iRUN), multiple memantine injections (mMEM), or alternating blocks of iRUN and mMEM. Two months of iRUN increased DCX+ cells in females and iRUN followed by mMEM increased DCX+ cells in males, indicating that neurogenesis was increased in the later stages of the treatments. However, thymidine analogs revealed that neurogenesis was minimally increased during the initial stages of the treatments. These findings highlight temporal limitations and sex differences in the efficacy of neurogenic manipulations, which may be relevant for designing plasticity-promoting treatments.


Assuntos
Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Hipocampo/fisiologia , Memantina/administração & dosagem , Neurogênese , Condicionamento Físico Animal , Caracteres Sexuais , Animais , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Neurogênese/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
20.
Expert Opin Drug Saf ; 17(10): 1053-1061, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30222469

RESUMO

INTRODUCTION: Currently, five pharmacotherapeutic options are available to treat Alzheimer's disease: memantine; the three cholinesterase inhibitors donepezil, galantamine, and rivastigmine; and combination treatments with memantine and one cholinesterase inhibitor. Selection of the best course of treatment is based upon the evidence gathered by systematic reviews and meta-analyses of randomized controlled trials. Areas covered: This article provides a risk-benefit analysis of these treatments using evidence from meta-analyses on their safety and their efficacy. Expert opinion: Memantine improves cognitive functions and behavioral disturbances more efficiently than the placebo, both as monotherapy and in combination with donepezil. Although memantine monotherapy and combination therapy are associated with a few individual adverse events such as somnolence, it is well-tolerated and its safety (all-cause discontinuation) is comparable or superior to that of the placebo (agitation). Pooled cholinesterase inhibitors are superior to the placebo in the improvement of cognitive functions, but not behavioral disturbances and they are not well-tolerated, as evaluated by the high discontinuation rate. Donepezil (10 mg/day) and oral rivastigmine and galantamine monotherapies carry the risk for some adverse events including gastrointestinal symptoms. Therefore, we consider that combined treatment with memantine and donepezil is the most useful treatment for Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Memantina/administração & dosagem , Doença de Alzheimer/fisiopatologia , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Cognição/efeitos dos fármacos , Donepezila , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Humanos , Indanos/administração & dosagem , Indanos/efeitos adversos , Memantina/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
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