The involvement of neuroinflammation in an animal model of dementia and depression.

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

Inhibitory effect of galantamine and donepezil combination against cholinesterase: An in silico and in vitro study.

This study aimed to evaluate the in silico and in vitro inhibitory effect of the combined use of galantamine (GAL) and donepezil (DON) against acetylcholinesterase and butyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysis were carried out for GAL and DON alone and combined. Molecular modeling studies were carried out (docking analysis, molecular dynamics simulation, and quantum theory of atoms in molecules). Cholinesterase's inhibitory activities by modified Ellman's method and the drug combination effect using the Chou-Talalay method were assayed. GAL/DON combination showed the co-occupancy of the ligands in both enzymes through in silico studies. Regarding in vitro BuChE inhibition analyses, three of five combinations showed an interaction between GAL and DON at the threshold of additive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higher concentrations. This is the first report showing the efficacy of the GAL/DON combinations inhibiting BuChE, showing the importance of analyzing the behavior of different ligands when co-occupancy into the active site is possible. These combinations might be a possible therapy to improved efficacy, reduced doses, minor side effects, and high levels of the neurotransmitter in the synaptic space for Alzheimer's disease.

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach.

Acetylcholinesterase (AChE) enzymes play an essential role in the development of Alzheimer's disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the hAChE B site of the human acetylcholinesterase (hAChE) enzyme employed in this investigation, which was obtained from the Protein Data Bank (PDB ID 4EY6), allowed for the prediction of the binding affinity and free binding energy between the protein and the ligand. Virtual screening was performed to obtain structures similar to Galantamine (GNT) with potential hAChE activity. The top 200 hit compounds were prioritized through the use of filters in ZincPharmer, with special features related to the pharmacophore. Critical analyses were carried out, such as hierarchical clustering analysis (HCA), ADME/Tox predictions, molecular docking, molecular simulation studies, synthetic accessibility (SA), lipophilicity, water solubility, and hot spots to confirm the stable binding of the two promising molecules (ZINC16951574-LMQC2, and ZINC08342556-LMQC5). The metabolism prediction, with metabolites M3-2, which is formed by Glutathionation reaction (Phase II), M1-2, and M2-2 formed from the reaction of S-oxidation and Aliphatic hydroxylation (Phase I), were both reactive but with no side effects. Theoretical synthetic routes and prediction of synthetic accessibility for the most promising compounds are also proposed. In conclusion, this study shows that in silico modeling can be used to create new drug candidate inhibitors for hAChE. The compounds ZINC16951574-LMQC2, and ZINC08342556-LMQC5 are particularly promising for oral administration because they have a favorable drug-likeness profile, excellent lipid solubility, high bioavailability, and adequate pharmacokinetics.

Consumption of drugs for Alzheimer's disease on the Brazilian private market / Consumo de medicamentos para doença de Alzheimer no mercado privado brasileiro

ABSTRACT OBJECTIVE To analyze the consumption of drugs for Alzheimer's disease on the Brazilian private market and its geographical distribution from 2014 to 2020. METHODS National data from the Brazilian National System of Controlled Product Management were used, regarding sales of donepezil, galantamine, rivastigmine, and memantine from January 2014 to December 2020. Sales data were used as a proxy for drug consumption and expressed as defined daily dose/1,000 inhabitants/year at national, regional, federative unit and microregion levels. RESULTS Drug consumption went from 5,000 defined daily doses/1,000 inhabitants, in 2014, to more than 16,000/1,000 inhabitants, in 2020, and all federative units showed positive variation. The Brazilian Northeast had the highest cumulative consumption in the period but displayed microregional disparities while the North region had the lowest consumption. Donepezil and memantine were the most consumed drugs, with the highest growth in consumption from 2014 to 2020. CONCLUSION The consumption of medicines indicated to treat Alzheimer's disease tripled in Brazil between 2014 and 2020, which may relate to the increase in the prevalence of the disease in the country, greater access to health services, and inappropriate use. This challenges managers and healthcare providers due to population aging and the increased prevalence of chronic-degenerative diseases.

RESUMO OBJETIVO Analisar o consumo de medicamentos para a doença de Alzheimer no mercado privado brasileiro e sua distribuição geográfica entre os anos de 2014 e 2020. MÉTODOS Foram utilizados dados do Sistema Nacional de Gerenciamento de Produtos Controlados relativos às vendas de donepezila, galantamina, rivastigmina e memantina, entre janeiro de 2014 a dezembro de 2020, em todo o território nacional. Os dados de venda foram utilizados como proxy para o consumo dos medicamentos, avaliado em dose diária definida (DDD)/1.000 habitantes/ano em nível nacional, regional, por unidade federativa e microrregião. RESULTADOS O consumo dos medicamentos passou de 5.000 DDD/1.000 habitantes em 2014 para mais de 16.000 DDD/1.000 habitantes em 2020, e todas as unidades de federação apresentaram variação positiva. A região Nordeste apresentou o maior consumo acumulado no período, porém exibiu disparidades microrregionais. A região Norte apresentou o menor consumo. Os medicamentos mais consumidos foram donepezila e memantina, os quais também apresentaram maior crescimento do consumo no intervalo de tempo entre os anos de 2014 e 2020. CONCLUSÃO O consumo de medicamentos para o tratamento da doença de Alzheimer triplicou no Brasil entre os anos de 2014 e 2020, o que pode estar relacionado ao aumento da prevalência da doença no país e/ou maior acesso a serviços de saúde, assim como estar ligado, também, à utilização inapropriada destes medicamentos. Este é um desafio para gestores e profissionais de saúde num cenário de envelhecimento populacional e aumento da prevalência de doenças crônico-degenerativas.

Influence of galantamine in the inflammatory process and tissular lesions caused by Trypanosoma cruzi QM2 strain.

INTRODUCTION: Trypanosoma cruzi infection triggers an inflammatory process with exacerbated production of cytokines that stimulate inflammatory and anti-inflammatory signals, including the efferent anti-inflammatory signal known as the anti-inflammatory cholinergic pathway. Thus, the use of anticholinesterase drugs, such as galantamine, could minimize the inflammatory process caused by this disease. METHODS: For the study at 30, 60, and 90 days, 120 Swiss mice were divided into three groups. Each group was subdivided into four subgroups: uninfected/untreated (CTRL), uninfected/treated (GAL), infected/untreated (INF), and infected/treated (GAL/INF). The infected groups were inoculated intraperitoneally with 0.1 ml of mouse blood containing 5 × 104 trypomastigote forms of the T. cruzi QM2 strain. The galantamine-treated groups received 5 mg/kg of galantamine orally, through pipetting. From each subgroup, the parameters of parasitemia, histopathological analysis, butyrylcholinesterase activity (BuChE), and functional study of the colon were evaluated. RESULTS: BuChE performance was observed when AChE was suppressed, with increased activity in the GAL/INF group similar to the INF group on the 30th day post infection, thus corroborating the absence of a significant difference in parasitic curves and histopathological analysis. CONCLUSIONS: The presence of an inflammatory process and nests of amastigotes, as well as evidence of reactivity to ACh and NOR, suggest that galantamine did not interfere with the colonic inflammatory response or even in colonic tissue parasitism at this stage of Chagas disease.

The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial.

Background: The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS. Trial Design and Methods: The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (n = 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment. Results: Galantamine treatment significantly increased antioxidant enzyme activities, including SOD [+1.65 USOD/mg protein, [95% CI 0.39-2.92], P = 0.004] and CAT [+0.93 nmol/mg, [95% CI 0.34-1.51], P = 0.01], decreased lipid peroxidation [thiobarbituric acid reactive substances [log scale 0.72 pmol/mg, [95% CI 0.46-1.07], P = 0.05], and systemic nitrite levels [log scale 0.83 µmol/mg protein, [95% CI 0.57-1.20], P = 0.04] compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment. Conclusion: Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.

Influence of galantamine in the inflammatory process and tissular lesions caused by Trypanosoma cruzi QM2 strain

Abstract INTRODUCTION: Trypanosoma cruzi infection triggers an inflammatory process with exacerbated production of cytokines that stimulate inflammatory and anti-inflammatory signals, including the efferent anti-inflammatory signal known as the anti-inflammatory cholinergic pathway. Thus, the use of anticholinesterase drugs, such as galantamine, could minimize the inflammatory process caused by this disease. METHODS For the study at 30, 60, and 90 days, 120 Swiss mice were divided into three groups. Each group was subdivided into four subgroups: uninfected/untreated (CTRL), uninfected/treated (GAL), infected/untreated (INF), and infected/treated (GAL/INF). The infected groups were inoculated intraperitoneally with 0.1 ml of mouse blood containing 5 × 104 trypomastigote forms of the T. cruzi QM2 strain. The galantamine-treated groups received 5 mg/kg of galantamine orally, through pipetting. From each subgroup, the parameters of parasitemia, histopathological analysis, butyrylcholinesterase activity (BuChE), and functional study of the colon were evaluated. RESULTS: BuChE performance was observed when AChE was suppressed, with increased activity in the GAL/INF group similar to the INF group on the 30th day post infection, thus corroborating the absence of a significant difference in parasitic curves and histopathological analysis. CONCLUSIONS: The presence of an inflammatory process and nests of amastigotes, as well as evidence of reactivity to ACh and NOR, suggest that galantamine did not interfere with the colonic inflammatory response or even in colonic tissue parasitism at this stage of Chagas disease.

Genistein and Galantamine Combinations Decrease ß-Amyloid Peptide (1-42)-Induced Genotoxicity and Cell Death in SH-SY5Y Cell Line: an In Vitro and In Silico Approach for Mimic of Alzheimer's Disease.

Alzheimer's disease (AD) is the primary dementia-causing disease worldwide, involving a multifactorial combination of environmental, genetic, and epigenetic factors, with essential participation of age and sex. Biochemically, AD is characterized by the presence of abnormal deposition of beta amyloid peptide (Aß(1-42)), which in the brain is strongly correlated with oxidative stress, inflammation, DNA damage, and cholinergic impairment. The multiple mechanisms involved in its etiology create significant difficulty in producing an effective treatment. Neuroprotective properties of genistein and galantamine have been widely demonstrated through different mechanisms; however, it is unknown a possible synergistic neuroprotective effect against Aß(1-42). In order to understand how genistein and galantamine combinations regulate the mechanisms of neuroprotection, we conducted a set of bioassays in vitro to evaluate cell viability, clonogenic survival, cell death, and anti-genotoxicity. Through molecular docking and therapeutic viability assays, we analyzed the inhibitory activity exerted by genistein on three major protein targets (AChE, BChE, and NMDA) involved in AD. The results showed that genistein and galantamine afforded significant protection at higher concentrations; however, combinations of sub-effective concentrations of both compounds provided marked neuroprotection when they were combined. In silico approaches showed that genistein has higher scores than the positive controls and low toxicity levels; nevertheless, the therapeutic viability indicated that unlike galantamine, genistein cannot undergo the action by P glycoprotein (PGP) and probably may be unable to cross the blood-brain barrier. In conclusion, our results show that genistein and galantamine exert neuroprotective by decreasing genotoxicity and cell death. In silico analysis, suggest that genistein modulates positively the expression of AChE, BChE, and NMDA. In this context, a combination of two or more drugs could inspire an attractive therapeutic strategy.

Aporphinoid Alkaloids Derivatives as Selective Cholinesterases Inhibitors: Biological Evaluation and Docking Study.

Alzheimer's dementia is a neurodegenerative disease that affects the elderly population and causes memory impairment and cognitive deficit. Manifestation of this disease is associated to acetylcholine decrease; thus, Cholinesterase inhibition is the main therapeutic strategy for the treatment of Alzheimer's disease. In the present study, a series of aporphinoid alkaloids were tested as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors in vitro. Alkaloids liriodenine (3) and cassythicine (10) were the best inhibitors of both cholinesterases with IC50 values lower than 10 µM. In addition, these alkaloids demonstrated better inhibition of BChE than reference drug galantamine. In addition, some alkaloids showed selective inhibition. Laurotetatine clorhydrate (13) selectively inhibit AChE over BChE. On the contrary, pachyconfine (7) interacted more efficiently with BChE active site. Molecular modelling studies were performed in order to illustrate key interactions between most active compounds and the enzymes and to explain their selectivity. These studies reveal that the benzodioxole moiety exhibits strong interactions due to hydrogen bonds that form with the Glu201 (AChE) and Tyr440 (BChE) residues, which is reflected in the IC50 values.

Efecto de Petiveria alliacea y drogas colinérgicas sobre la habituación / Effects of Petiveria alliacea and cholinergic drugs on the habituation cognitive behavior

Petiveria alliacea (PA) have anxiolytic, antidepressant and cognitive effects. In the present paper the effect of PA water infusion and cholinergic drugs on cognitive behavior were studied. For that, 40 male NMRI mice were divided in 4 groups: Control (n=10), Drug Control (n=10), PA (n=10) and PA plus Drug (n=10). PA 1% was administered orally (7.59±1.39 ml/day); while scopolamine (2 mg/Kg), galantamine (1 mg/Kg) and nicotine (0.1 mg/Kg) were administered intraperitoneally. Behavioral tests included: anxiety maze (AM), open field (OF) and marble burying (MB). Habituation cognitive behavior was evaluated in 4 sessions, one week each session. PA had anxiolytic and antidepressant effect effect in AM, combined with nicotine potentiated an anxiogenic effect in AM, galantamine favored habituation in OF. Scopolamine potentiated the habituation in LA and decreased the obsessive-compulsive behavior in OF. In conclusion; PA had an anxiolytic effect and favored deshabituation, combined with nicotine induced an anxiogenic effect, galantamine favored habituation and scopolamine decreased obsessive-compulsive behavior and favored motor habituation indicated a possible anxiolytic effect.

La Petiveria alliacea (PA) está relacionada con efectos ansiolíticos, antidepresivos y cognitivos. El presente trabajo estudió el efecto de la infusión de PA y drogas colinérgicas sobre la habituación. 40 ratones NMRI machos fueron divididos en 4 grupos: Control (n=10), Control Drogas (n=10), PA (n=10) y PA plus Drogas (n=10). La PA (1%) fue administrada vía oral (7.59±1.39 ml/día); escopolamina (2 mg/Kg), galantamina (1 mg/Kg) y nicotina (0.1 mg/Kg) fueron administrados vía intraperitoneal. Los ensayos conductuales incluyeron: laberinto de ansiedad (LA), campo abierto (CA) y enterramiento aversivo (EA). La habituación fue evaluada en 4 sesiones con duración de una semana cada una. PA mostró un efecto ansiolítico en el LA, combinada con nicotina potenció un efecto ansiogénico en el LA. Galantamina favoreció la habituación en CA, y escopolamina potenció el fenómeno de habituación en LA y disminuyó la conducta obsesivo-compulsiva en CA. En conclusión, la PA mostró un efecto ansiolítico y antidepresivo que potencia la deshabituación, combinada con nicotina indujo un efecto ansiogénico, galantamina favoreció la habituación y escopolamina disminuyó la conducta obsesivo­ compulsiva y favoreció la habituación motora indicando un posible efecto ansiolítico.

A novel on-flow mass spectrometry-based dual enzyme assay.

This work describes a new simultaneous on-flow dual parallel enzyme assay based on immobilized enzyme reactors (ICERs) with mass spectrometry detection. The novelty of this work relies on the fact that two different enzymes can be screened at the same time with only one single sample injection and in less than 6 min. The system consisted of two immobilized capillary enzyme reactors (ICERs). More specifically, the ICERs comprised two different enzymes that were accommodated in parallel and were placed between a liquid chromatography (LC) system and a mass spectrometer (MS). The resulting system could be adapted to other types of enzyme reactors with different supports. All the elements in the system were interfaced by means of two 10-port/two-position switching valves. Different tubing dimensions allowed us to monitor the activity of each enzyme independently during the same analysis. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) bioreactors were chosen as proof of concept. Acetylcholine (ACh) was used as substrate; the area of its protonated enzymatic hydrolysis product ion, choline, [M+H]+m/z 104.0, was monitored in the presence and absence of the standard cholinesterase inhibitor galantamine. This method proved to be an interesting tool for fast, simultaneous, and independent label-free dual enzyme inhibitor assay.

[Patterns of antidemential drug use in a group of patients from Colombia]. / Patrones de uso de farmacos antidemencia en un grupo de pacientes de Colombia.

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.

TITLE: Patrones de uso de farmacos antidemencia en un grupo de pacientes de Colombia.Introduccion. Los beneficios del manejo farmacologico con medicamentos antidemencia aun no estan del todo demostrados, e incluso hay carencia de trabajos que describan su perfil de utilizacion. El presente trabajo busco determinar los patrones de prescripcion de farmacos antidemencia en una poblacion de Colombia. Pacientes y metodos. Estudio descriptivo de corte transversal. Mediante una base de datos sistematizada de 3,5 millones de afiliados al sistema de salud colombiano, se selecciono a pacientes con dispensaciones ininterrumpidas de farmacos antidemencia entre agosto y octubre de 2016. Se analizaron variables sociodemograficas, farmacologicas y comedicaciones. Se estimaron los costes de las terapias a partir del precio de referencia de los medicamentos. Resultados. Se identifico a 8.372 pacientes con una edad media de 79,5 ± 8,7 años; el 65,3% (n = 5.471) fueron mujeres. El farmaco mas utilizado fue la rivastigmina (69,6%), principalmente en presentacion transdermica, seguida de la memantina (31,4%). En general, la dosis media administrada por dia fue inferior a la dosis diaria definida. Solamente 568 pacientes (6,7%) usaron terapia combinada. El 84,3% de los pacientes (n = 7.061) uso medicamentos para alguna comorbilidad y el 54,2% (n = 4.535) tenia otro neurofarmaco. El coste por 1.000 habitantes/dia de la rivastigmina fue de 3,47 dolares, y de la memantina, de 0,30 dolares. Conclusion. Los pacientes con medicamentos antidemencia los estan empleando en dosis inferiores a las definidas y presentan una importante frecuencia de comorbilidades y comedicaciones.

An improved immobilized enzyme reactor-mass spectrometry-based label free assay for butyrylcholinesterase ligand screening.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are key cholinesterase enzymes responsible for the hydrolysis of acetylcholine into choline and acetic acid, an essential process for the restoration of the cholinergic neuron. The loss of cholinergic function in the central nervous system contributes to the cognitive decline associated with advanced age and Alzheimer's disease (AD). Inhibitions assays represent a significant role in the drug discovery process. Herein, we describe an improved label free method to screen and characterize new BChE ligands. The liquid chromatography system uses an immobilized capillary enzyme reactor (ICER) as a low affinity and high selectivity column coupled to a mass spectrometer (MS). The enzyme activity was evaluated by monitoring the choline's precursor ion [M + H]+m/z 104 for a brief period. The method was validated using two known cholinesterase inhibitors tacrine and galanthamine. The IC50 values were 0.03 ±â€¯0.006 µM and 0.88 ±â€¯0.2 for tacrine and galanthamine respectively, and Ki was 0.11 ±â€¯0.2 for galanthamine. The efficient combination of the huBChE-ICER with sensitive enzymatic assay detection such as MS, improved the reliable, fast identification of new ligands. Moreover, specific direct quantitation of the product contributes to the reduction of false positive and negative results.

Characteristics of Pediatric Exposures to Antidementia Drugs Reported to a Poison Control System.

OBJECTIVE: To characterize pediatric exposures to the antidementia drugs donepezil, memantine, rivastigmine, and galantamine by reviewing a poison control system's database. STUDY DESIGN: A retrospective review of a statewide poison control system's database identified cases of pediatric (less than 19 years of age) exposures to antidementia drugs over an 11-year period. Data collected included age, sex, drug(s) involved, route of exposure, reason for exposure, symptoms, and interventions. RESULTS: There were 189 cases identified (53% male, median age: 2.3 years, 99% unintentional exposures). Donepezil was the most commonly reported exposure (106 cases), followed by memantine (57), galantamine (18), oral rivastigmine (16), and transdermal rivastigmine (3). Coingestants were reported in 68 (36%) cases. Symptoms were reported in 38 (20%) cases. Gastrointestinal symptoms were most common (n = 21) followed by central nervous system depression (n = 15). Oral rivastigmine was associated with higher rates of symptoms. No bradycardia, seizures, or fasciculations were reported. Eighty-nine cases (47%) were evaluated at a health care facility, and 13 (7%) were admitted to a hospital. Oral rivastigmine exposures were associated with increased rate of health care facility evaluation. Activated charcoal was administered in 28 cases. Atropine was given only once, for drooling. There were no serious outcomes or deaths in this series. CONCLUSIONS: Reported pediatric exposures to antidementia drugs resulted in minimal morbidity and no mortality. Oral rivastigmine exposures were found to be associated with more symptoms and health care facility evaluations.

Effect of Donepezil, Tacrine, Galantamine and Rivastigmine on Acetylcholinesterase Inhibition in Dugesia tigrina.

Dugesia tigrina is a non-parasitic platyhelminth, which has been recently utilized in pharmacological models, regarding the nervous system, as it presents a wide sensitivity to drugs. Our trials aimed to propose a model for an in vivo screening of substances with inhibitory activity of the enzyme acetylcholinesterase. Trials were performed with four drugs commercialized in Brazil: donepezil, tacrine, galantamine and rivastigmine, utilized in the control of Alzheimer's disease, to inhibit the activity of acetylcholinesterase. We tested five concentrations of the drugs, with an exposure of 24 h, and the mortality and the inhibition of acetylcholinesterase planarian seizure-like activity (pSLA) and planarian locomotor velocity (pLMV) were measured. Galantamine showed high anticholinesterasic activity when compared to the other drugs, with a reduction of 0.05 µmol·min(-1) and 63% of convulsant activity, presenting screw-like movement and hypokinesia, with pLMV of 65 crossed lines during 5 min. Our results showed for the first time the anticholinesterasic and convulsant effect, in addition to the decrease in locomotion induced by those drugs in a model of invertebrates. The experimental model proposed is simple and low cost and could be utilized in the screening of substances with anticholinesterasic action.

Galantamine protects against lipopolysaccharide-induced acute lung injury in rats.

Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats.

Galantamine protects against lipopolysaccharide-induced acute lung injury in rats

Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats.

Effect of alpha-7 nicotinic acetylcholine receptor activation on beta-amyloid induced recognition memory impairment. Possible role of neurovascular function.

PURPOSE: To evaluate the effects of PHA-543613 (α7-nAChR agonist) and galantamine (acetylcholinesterase inhibitor (AChEI)) on recognition memory and neurovascular coupling (NVC) response in beta-amyloid (Aß) 25-35-treated mice. METHODS: PHA-543613 (1 mg/kg, i.p.), and galantamine (3 mg/kg, s.c.), effects were tested in Aß25-35 mice model of AD. α7-nAChR antagonist, methyllycaconitine (MLA) (1 mg/kg, i.p.), was used for evaluation of receptor blockade effects. Recognition memory in animals was assessed by the novel object recognition (NOR) task. NVC response was analyzed by laser-doppler flow meter in barrel cortex by whisker stimulation method. RESULTS: Both, PHA-543613 and galantamine improve recognition memory in Aß-treated animals. However, the advantageous effects of PHA-543613 were significantly higher than galantamine. Also, pretreatment with MLA reversed both galantamine and PHA-543613 effects on NOR. Impaired NVC response in AD animals was improved by PHA-543613 and galantamine. However, MLA pretreatment disrupts this function. CONCLUSION: Activation of α7-nAChR improved recognition memory possible through enhancement of neurovascular response in Alzheimer's disease in animals.

Effect of alpha-7 nicotinic acetylcholine receptor activation on beta-amyloid induced recognition memory impairment. Possible role of neurovascular function

PURPOSE: To evaluate the effects of PHA-543613 (α7-nAChR agonist) and galantamine (acetylcholinesterase inhibitor (AChEI)) on recognition memory and neurovascular coupling (NVC) response in beta-amyloid (Aβ) 25-35-treated mice. METHODS: PHA-543613 (1 mg/kg, i.p.), and galantamine (3 mg/kg, s.c.), effects were tested in Aβ25-35 mice model of AD. α7-nAChR antagonist, methyllycaconitine (MLA) (1 mg/kg, i.p.), was used for evaluation of receptor blockade effects. Recognition memory in animals was assessed by the novel object recognition (NOR) task. NVC response was analyzed by laser-doppler flow meter in barrel cortex by whisker stimulation method. RESULTS: Both, PHA-543613 and galantamine improve recognition memory in Aβ-treated animals. However, the advantageous effects of PHA-543613 were significantly higher than galantamine. Also, pretreatment with MLA reversed both galantamine and PHA-543613 effects on NOR. Impaired NVC response in AD animals was improved by PHA-543613 and galantamine. However, MLA pretreatment disrupts this function. CONCLUSION: Activation of α7-nAChR improved recognition memory possible through enhancement of neurovascular response in Alzheimer's disease in animals.