RESUMO
Since the development of the "cholinergic hypothesis" as an important therapeutic approach in the treatment of Alzheimer's disease (AD), the scientific community has made a remarkable effort to discover new and effective molecules with the ability to inhibit the enzyme acetylcholinesterase (AChE). The natural function of this enzyme is to catalyze the hydrolysis of the neurotransmitter acetylcholine in the brain. Thus, its inhibition increases the levels of this neurochemical and improves the cholinergic functions in patients with AD alleviating the symptoms of this neurological disorder. In recent years, attention has also been focused on the role of another enzyme, butyrylcholinesterase (BChE), mainly in the advanced stages of AD, transforming this enzyme into another target of interest in the search for new anticholinesterase agents. Over the past decades, Nature has proven to be a rich source of bioactive compounds relevant to the discovery of new molecules with potential applications in AD therapy. Bioprospecting of new cholinesterase inhibitors among natural products has led to the discovery of an important number of new AChE and BChE inhibitors that became potential lead compounds for the development of anti-AD drugs. This review summarizes a total of 260 active compounds from 142 studies which correspond to the most relevant (IC 50 ≤ 15 µM) research work published during 2012-2022 on plant-derived anticholinesterase compounds, as well as several potent inhibitors obtained from other sources like fungi, algae, and animals.
RESUMO
The multifactorial nature of Alzheimer's disease (AD) is now widely recognized, which has increased the interest in compounds that can address more than one AD-associated targets. Herein, we report the inhibitory activity on the human cholinesterases (acetylcholinesterase, hAChE and butyrylcholinesterase, hBChE) and on the AChE-induced ß-amyloid peptide (Aß) aggregation by a series of peptide derivatives designed by mutating aliphatic residues for aromatic ones. We identified peptide W3 (LGWVSKGKLL-NH2 ) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC50 value against hAChE reported for a peptide (0.99±0.02â µM) and inhibited 94.2 %±1.2 of AChE-induced Aß aggregation at 10â µM. Furthermore, it inhibited hBChE (IC50 , 15.44±0.91â µM), showed no inâ vivo toxicity in brine shrimp and had shown moderated radical scavenging and Fe2+ chelating capabilities in previous studies. The results are in line with multiple reports showing the utility of the indole moiety for the development of cholinesterase inhibitors.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Relação Estrutura-Atividade , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Doença de Alzheimer/tratamento farmacológicoRESUMO
Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H3 and dopamine D3 receptors (H3R and D3R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H3R and D3R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the Ki and IC50 values. Results showed that several compounds were ligands at H3R (n = 10), D3R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (Ki H3R 2.8 µM; D3R 0.7 µM; IC50 BChE 26.3 µM) and LINS05015 (Ki H3R 1.1 µM; D3R 3.1 µM; IC50 AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.
Assuntos
Disfunção Cognitiva , Receptores Histamínicos H3 , Humanos , Histamina , Dopamina , Ligantes , Butirilcolinesterase/metabolismo , Receptores Histamínicos H3/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Inibidores da Colinesterase/química , Relação Estrutura-AtividadeRESUMO
Background: The response to cholinesterase inhibitors (ChEIs) treatment is variable in patients with Alzheimer's disease (AD). Patients and physicians would benefit if these drugs could be targeted at those most likely to respond in a clinical setting. Therefore, this study aimed to evaluate the ability of cerebrospinal fluid (CSF) AD biomarkers, hippocampal volumes, and Default Mode Network functional connectivity to predict clinical response to ChEIs treatment in mild AD. Methods: We followed up on 39 mild AD patients using ChEIs at therapeutic doses. All subjects underwent clinical evaluation, neuropsychological assessment, magnetic resonance imaging examination, and CSF biomarkers quantification at the first assessment. The Mini-Mental Status Examination (MMSE) was used to measure the global cognitive status before and after the follow-up. "Responders" were considered as those who have remained stable or improved the MMSE score between evaluations and "Nonresponders" as those who have worsened the MMSE score. We performed univariate and multivariate logistic regressions to predict the clinical response from each biomarker. Results: About 35.89% of patients were classified as "Responders" to ChEIs treatment after the follow-up. The multivariate model with measures of Right Hippocampus (RHIPPO), adjusted for gender and interval between assessments, was significant (odds ratio: 1.09 [95% confidence interval, 1.00-1.19], p = 0.0392). This model achieved an accuracy of 77.60%. Conclusion: Our findings suggest that the functional connectivity of RHIPPO might be an early imaging biomarker to predict clinical response to ChEIs drugs in mild AD. Impact statement The functional connectivity of the right hippocampus showed a direct relationship with the clinical response to cholinesterase inhibitors (ChEIs) treatment in patients with mild Alzheimer's disease. Transposing our findings to clinical settings could allow physicians to prescribe ChEIs for patients for whom treatment would be most beneficial.
Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Imageamento por Ressonância Magnética , Encéfalo , Hipocampo/diagnóstico por imagem , BiomarcadoresRESUMO
This work presents a frequency matched observational study comparing flower farmers exposed to pesticides and unexposed individuals as controls. All subjects were interviewed before plasma and urine collection. Manganese and Zinc were measured in theses samples by using dynamic reaction cell inductively coupled mass spectrometry. Cholinesterase activity was analyzed through spectrophotometry by using a modified version of the Ellman method. Seventy-eight percent of subjects reported occupational contact with pesticides, from which 37% reported exposure for over 9 years. Flower farms farmers had increased odds of having headache and irritability, respectively, by factors of 6.2 and 2.4 than the control subjects. While the odds of exposed subjects to have insomnia was smaller than control subjects by a factor of 0.34. Exposure to pesticides had a significant effect regarding the plasmatic plasma and urinary manganese levels and whole blood cholinesterase activity (p < 0.05). High levels of plasma and urinary manganese, as well as cholinesterase inhibition in whole blood, were evident in the flower farmers who participated in the study.
Assuntos
Exposição Ocupacional , Praguicidas , Brasil , Colinesterases , Fazendeiros , Flores/química , Humanos , Manganês/análise , Manganês/toxicidade , Metais , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Praguicidas/análise , Praguicidas/toxicidadeRESUMO
In this sense the objective of assessing the levels of pesticide poisoning in rural farmers of San Sebastian and take AL, using acetylcholinesterase enzymes Erythrocyte and plasma as biological indicator of intoxication. This is a prospective, transversal and descriptive variables analyzed were: year whose, sex, age group, education, location, condition, route of exposure. The data were acquired by collecting blood samples and socio demographic information of farmers. Was put as the determining factor the type of conventional and organic farming, and periods of drought and rainy. 56 volunteers were analyzed. The analyses were performed in the automatic biochemical Analyzer Cobas Integra 400 plus®. According to the results of the analyses, it was the largest number of individuals with reduced values of cholinesterase, specifically the Group of conventional farming, the period of greatest change index was in the rainy season, where the activity of AChE, expressive values presented in the city of São Sebastião, with 80% result of intoxicated, in the city of the foot take, 21.73% over the same period. On analysis of the AChP, São Sebastião has obtained the highest number of contaminated with 18.75% and 30% respectively, in the District Take Foot stood between 10 and 21.73% of reduced levels of cholinesterase. This sets the organic system of cultivation, as the best alternative for prevention of future diseases, in addition to bringing quality of life for rural workers, as well as for consumers.(AU)
Nesse sentido objetivou-se avaliar os níveis de intoxicação por agrotóxicos em agricultores rurais de São Sebastião e Pé Leve - AL, utilizando as enzimas acetilcolinesterase Eritrocitária e Plasmática, como indicador biológico de intoxicação. Trata - se de um estudo prospectivo, transversal e descritivo cujas variáveis analisadas foram: ano, sexo, faixa etária, escolaridade, local, circunstância, via de exposição. Os dados foram adquiridos através da coleta das amostras de sangue e das informações sócio demográficas dos agricultores. Foi posto como fator determinante o tipo de cultivo convencional e orgânico, e os períodos de estiagem e chuvoso. Foram analisados 56 voluntários. As análises foram realizadas no analisador automático de bioquímica Cobas Integra® 400 plus. De acordo com os resultados das análises, percebeu-se maior número de indivíduos com valores diminuídos da colinesterase, especificamente no grupo de cultivo convencional, o período de maior índice de alteração foi na época chuvosa, onde a atividade da AChE, apresentou valores expressivos na cidade de São Sebastião, com resultado de 80% de intoxicados, na cidade do Pé Leve, obteve-se 21,73% no mesmo período. Na análise da AChP, São Sebastião obteve maior número de contaminados com 18,75% e 30% respectivamente, já no Distrito Pé Leve ficou entre 10 e 21,73% de níveis diminuídos da colinesterase. Isso define o sistema orgânico de cultivo, como a melhor alternativa para prevenção de futuras patologias, além de trazer qualidade de vida para os trabalhadores rurais, como também para os consumidores.(AU)
Assuntos
Inibidores da Colinesterase , Praguicidas/toxicidade , Agroquímicos/toxicidade , FazendeirosRESUMO
Abstract In this sense the objective of assessing the levels of pesticide poisoning in rural farmers of San Sebastian and take AL, using acetylcholinesterase enzymes Erythrocyte and plasma as biological indicator of intoxication. This is a prospective, transversal and descriptive variables analyzed were: year whose, sex, age group, education, location, condition, route of exposure. The data were acquired by collecting blood samples and socio demographic information of farmers. Was put as the determining factor the type of conventional and organic farming, and periods of drought and rainy. 56 volunteers were analyzed. The analyses were performed in the automatic biochemical Analyzer Cobas Integra 400 plus®. According to the results of the analyses, it was the largest number of individuals with reduced values of cholinesterase, specifically the Group of conventional farming, the period of greatest change index was in the rainy season, where the activity of AChE, expressive values presented in the city of São Sebastião, with 80% result of intoxicated, in the city of the foot - take, 21.73% over the same period. On analysis of the AChP, São Sebastião has obtained the highest number of contaminated with 18.75% and 30% respectively, in the District Take Foot stood between 10 and 21.73% of reduced levels of cholinesterase. This sets the organic system of cultivation, as the best alternative for prevention of future diseases, in addition to bringing quality of life for rural workers, as well as for consumers.
Resumo Nesse sentido objetivou-se avaliar os níveis de intoxicação por agrotóxicos em agricultores rurais de São Sebastião e Pé Leve - AL, utilizando as enzimas acetilcolinesterase Eritrocitária e Plasmática, como indicador biológico de intoxicação. Trata - se de um estudo prospectivo, transversal e descritivo cujas variáveis analisadas foram: ano, sexo, faixa etária, escolaridade, local, circunstância, via de exposição. Os dados foram adquiridos através da coleta das amostras de sangue e das informações sócio demográficas dos agricultores. Foi posto como fator determinante o tipo de cultivo convencional e orgânico, e os períodos de estiagem e chuvoso. Foram analisados 56 voluntários. As análises foram realizadas no analisador automático de bioquímica Cobas Integra® 400 plus. De acordo com os resultados das análises, percebeu-se maior número de indivíduos com valores diminuídos da colinesterase, especificamente no grupo de cultivo convencional, o período de maior índice de alteração foi na época chuvosa, onde a atividade da AChE, apresentou valores expressivos na cidade de São Sebastião, com resultado de 80% de intoxicados, na cidade do Pé - Leve, obteve-se 21,73% no mesmo período. Na análise da AChP, São Sebastião obteve maior número de contaminados com 18,75% e 30% respectivamente, já no Distrito Pé Leve ficou entre 10 e 21,73% de níveis diminuídos da colinesterase. Isso define o sistema orgânico de cultivo, como a melhor alternativa para prevenção de futuras patologias, além de trazer qualidade de vida para os trabalhadores rurais, como também para os consumidores.
Assuntos
Humanos , Praguicidas , Exposição Ocupacional/análise , Acetilcolinesterase , Qualidade de Vida , Estudos Prospectivos , FazendeirosRESUMO
Alzheimer's disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder affecting cognition, behavior, and function, being one of the most common causes of mental deterioration in elderly people. Once thought as being just developed because of ß amyloid depositions or neurofibrillary Tau tangles, during the last decades, numerous AD-related targets have been established, the multifactorial nature of AD became evident. In this context, the one drug-one target paradigm has resulted in being inefficient in facing AD and other disorders with complex etiology, opening the field for the emergence of the multitarget approach. In this review, we highlight the recent advances within this area, emphasizing in hybridization tools of well-known chemical scaffolds endowed with pharmacological properties concerning AD, such as curcumin-, resveratrol-, chromone- and indole-. We focus mainly on well established and incipient AD therapeutic targets, AChE, BuChE, MAOs, ß-amyloid deposition, 5-HT4 and Serotonin transporter, with the aim to shed light about new insights in the AD multitarget therapy.
Assuntos
Doença de Alzheimer , Preparações Farmacêuticas , Idoso , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Química Farmacêutica , Inibidores da Colinesterase , Objetivos , Humanos , LigantesRESUMO
BACKGROUND: Currently approved Alzheimer's disease medications mainly comprise acetylcholinesterase inhibitors. Many of these inhibitors are either natural compounds or synthetic molecules inspired in natural compounds. Hybrid molecules that can interact with different target sites of the enzyme could lead to the discovery of effective multitarget drugs. OBJECTIVE: To design, synthesize, and evaluate a series of new aza-resveratrol analogs as in vitro acetyl- and butyrylcholinesterase inhibitors. METHODS: The synthesis is achieved by a simple and efficient microwave-assisted method, from commercially available starting materials. Compounds are designed as hybrids of an aza-stilbene nucleus (Schiff base) connected to a tertiary amine by a hydrocarbon chain of variable length, designed to interact both with the peripheric anionic site and the catalytic site of the enzyme. RESULTS: All the derivatives inhibit both enzymes in a concentration-dependent manner, acting as moderate to potent cholinesterase inhibitors. The most potent inhibitors are compounds 12b (IC50 = 0.43 µM) and 12a (IC50 = 0.31 µM) for acetyl- and butyrylcholinesterase, respectively. Compounds 12a and 12b also exhibit significant acetylcholinesterase inhibition in SH-SY5Y human neuroblastoma cells without cytotoxic properties. Enzyme kinetic studies and molecular modeling reveal that inhibitor 12b targets both the catalytic active site and the peripheral anionic site of acetylcholinesterase what makes it able to modulate the self-induced ß-amyloid aggregation. Furthermore, the molecular modeling analysis helps to assess the impact of the linker length in the inhibitory activity of this family of new cholinesterase inhibitors. CONCLUSION: These compounds have the potential to serve as a dual binding site inhibitor and might provide a useful template for the development of new anti-Alzheimer's disease agents.
Assuntos
Inibidores da Colinesterase/síntese química , Resveratrol/síntese química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Sítios de Ligação , Butirilcolinesterase/metabolismo , Humanos , Micro-Ondas , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
Resumen Introducción: La intoxicación aguda por plaguicidas, asociada al suicidio, es un problema de salud pública cuyo estudio es primordial por los organismos estatales. Objetivo: Establecer la relación de intencionalidad en pacientes con intoxicación aguda por plaguicidas, junto a la descripción de algunas características sociodemográficas y de exposición registrados en un hospital de Ibagué desde 2013 a 2016. Materiales y métodos: Se realizó un estudio observacional descriptivo de corte transversal retrospectivo en 137 registros notificados con intoxicación aguda por plaguicida según los códigos del CIE 10. Desarrollo de análisis estadístico descriptivo y estratificado para encontrar la asociación de características con la intencionalidad de la intoxicación. Resultados: El 50% de los casos correspondían a personas menores de 20 años; el 79,6% de las intoxicaciones tenían fines suicidas y se observó que el 45% realizaron un intento de suicidio previo; un nivel educativo alto correspondió a un bajo riesgo de envenenamiento intencional [OR=0,05; IC95% (0,01-0,56); p=0,01]. Conclusiones: Es necesaria la cooperación entre las autoridades en salud e instituciones públicas para implementar medidas de control y demás estrategias que prevengan las intoxicaciones con plaguicidas, particularmente la exposición voluntaria asociada al suicidio, fenómeno creciente en esta ciudad.
Abstract Introduction: Acute pesticide poisoning associated with suicide is a public health problem that requires special attention by state agencies. Objective: To establish the relationship of patient's intent with acute pesticide poisoning and describe some sociodemographic and exposure characteristics registered by a hospital in Ibagué (Colombia), from 2013 to 2016. Materials and methods: A retrospective, cross-sectional, descriptive, observational study was conducted on 137 reports of acute pesticide poisoning that were registered according to ICD 10 codes. A descriptive and stratified statistical analysis was applied to establish the association between characteristics of poisoning intentionality. Results: 50% of the cases corresponded to people who were under 20 years of age. 79.6% of the poisonings were due to suicide attempt and 45% had had a previous attempt. A high educational level corresponded to a lower risk of intentional poisoning [OR=0.05; IC95% (0.01-0.56); p=0.01]. Conclusions: Cooperation between health care authorities and public institutions is necessary to implement measures and strategies in order to prevent acute pesticide poisoning events, especially those associated with suicide attempts, the frequency of which is growing in this city.
Assuntos
Praguicidas , Substâncias Tóxicas , Compostos Organofosforados , Tentativa de Suicídio , Inibidores da ColinesteraseRESUMO
Alzheimer's disease (AD), the most common form of dementia, is a growing problem worldwide, with 10 million incident cases registered every year. The complex etiology of AD has not been clarified yet and represents an active research topic. In this work, we studied the inhibitory properties of Hp-1935, a natural peptide extracted from the skin secretions of an Argentinian frog (Boana pulchella). It was initially isolated as an antimicrobial peptide by our group, but we later discovered its anti-AChE action. Since not many peptides with this activity have been reported, we focused on defining the basis of its inhibitory mechanism against acetylcholinesterase (AChE) and on finding the primary portion for the inhibitory activity in its sequence, through the combination of an experimental strategy of design and synthesis with molecular dynamics simulations. We also tested its cytotoxicity. We found that Hp-1935 is an interesting sequence for the development of new AChE inhibitors. This peptide is a peripheral anionic site inhibitor with an inhibitory activity that collocates it between the most potent natural amino acids peptides against AChE reported. We also demonstrate that its inhibitory activity is concentrated on the central part of the sequence.
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Inibidores da Colinesterase/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Anuros , Células CHO , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cricetulus , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Relação Estrutura-AtividadeRESUMO
Alzheimer's disease (AD) is clearly linked to the decline of acetylcholine (ACh) effects in the brain. These effects are regulated by the hydrolytic action of acetylcholinesterase (AChE). Therefore, a central palliative treatment of AD is the administration of AChE inhibitors although additional mechanisms are currently described and tested for generating advantageous therapeutic strategies. In this work, we tested new arylamides and arylimides as potential inhibitors of AChE using in silico tools. Then, these compounds were tested in vitro, and two selected compounds, C7 and C8, as well as propranolol showed inhibition of AChE. In addition, they demonstrated an advantageous acute toxicity profile compared to that of galantamine as a reference AChE inhibitor. in vivo evaluation of memory performance enhancement was performed in an animal model of cognitive disturbance with each of these compounds and propranolol individually as well as each compound combined with propranolol. Memory improvement was observed in each case, but without a significant additive effect with the combinations.
Assuntos
Amidas/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Imidas/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Amidas/síntese química , Amidas/química , Amidas/uso terapêutico , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Simulação por Computador , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Imidas/síntese química , Imidas/química , Imidas/uso terapêutico , Masculino , Conformação Molecular , Simulação de Acoplamento Molecular , Propranolol , RatosRESUMO
Abstract In this sense the objective of assessing the levels of pesticide poisoning in rural farmers of San Sebastian and take AL, using acetylcholinesterase enzymes Erythrocyte and plasma as biological indicator of intoxication. This is a prospective, transversal and descriptive variables analyzed were: year whose, sex, age group, education, location, condition, route of exposure. The data were acquired by collecting blood samples and socio demographic information of farmers. Was put as the determining factor the type of conventional and organic farming, and periods of drought and rainy. 56 volunteers were analyzed. The analyses were performed in the automatic biochemical Analyzer Cobas Integra 400 plus®. According to the results of the analyses, it was the largest number of individuals with reduced values of cholinesterase, specifically the Group of conventional farming, the period of greatest change index was in the rainy season, where the activity of AChE, expressive values presented in the city of São Sebastião, with 80% result of intoxicated, in the city of the foot take, 21.73% over the same period. On analysis of the AChP, São Sebastião has obtained the highest number of contaminated with 18.75% and 30% respectively, in the District Take Foot stood between 10 and 21.73% of reduced levels of cholinesterase. This sets the organic system of cultivation, as the best alternative for prevention of future diseases, in addition to bringing quality of life for rural workers, as well as for consumers.
Resumo Nesse sentido objetivou-se avaliar os níveis de intoxicação por agrotóxicos em agricultores rurais de São Sebastião e Pé Leve - AL, utilizando as enzimas acetilcolinesterase Eritrocitária e Plasmática, como indicador biológico de intoxicação. Trata - se de um estudo prospectivo, transversal e descritivo cujas variáveis analisadas foram: ano, sexo, faixa etária, escolaridade, local, circunstância, via de exposição. Os dados foram adquiridos através da coleta das amostras de sangue e das informações sócio demográficas dos agricultores. Foi posto como fator determinante o tipo de cultivo convencional e orgânico, e os períodos de estiagem e chuvoso. Foram analisados 56 voluntários. As análises foram realizadas no analisador automático de bioquímica Cobas Integra® 400 plus. De acordo com os resultados das análises, percebeu-se maior número de indivíduos com valores diminuídos da colinesterase, especificamente no grupo de cultivo convencional, o período de maior índice de alteração foi na época chuvosa, onde a atividade da AChE, apresentou valores expressivos na cidade de São Sebastião, com resultado de 80% de intoxicados, na cidade do Pé Leve, obteve-se 21,73% no mesmo período. Na análise da AChP, São Sebastião obteve maior número de contaminados com 18,75% e 30% respectivamente, já no Distrito Pé Leve ficou entre 10 e 21,73% de níveis diminuídos da colinesterase. Isso define o sistema orgânico de cultivo, como a melhor alternativa para prevenção de futuras patologias, além de trazer qualidade de vida para os trabalhadores rurais, como também para os consumidores.
RESUMO
A series of 44 hybrid compounds that included in their structure tetrahydroquinoline (THQ) and isoxazole/isoxazoline moieties were synthesized through the 1,3-dipolar cycloaddition reaction (1,3-DC) from the corresponding N-allyl/propargyl THQs, previously obtained via cationic Povarov reaction. In vitro cholinergic enzymes inhibition potential of all compounds was tested. Enzyme inhibition assays showed that some hybrids exhibited significant potency to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Especially, the hybrid compound 5n presented the more effective inhibition against AChE (4.24 µM) with an acceptable selectivity index versus BChE (SI: 5.19), while compound 6aa exhibited the greatest inhibition activity on BChE (3.97 µM) and a significant selectivity index against AChE (SI: 0.04). Kinetic studies were carried out for compounds with greater inhibitory activity of cholinesterases. Structure-activity relationships of the molecular hybrids were analyzed, through computational models using a molecular cross-docking algorithm and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy approach, which indicated a good correlation between the experimental inhibition values and the predicted free binding energy.
Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Isoxazóis/química , Quinolinas/química , Acetilcolinesterase/química , Sítios de Ligação , Domínio Catalítico , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Ativação Enzimática/efeitos dos fármacos , Humanos , Ligação de Hidrogênio , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
AIM: Alzheimer's disease is a common cause of dementia, and is usually treated with medications that elevate acetylcholine levels. The objective of the present study was to identify drugs with anticholinergic properties prescribed to patients diagnosed with Alzheimer's disease in Colombia. METHODS: A cross-sectional study was carried out in outpatients diagnosed with Alzheimer's disease who were identified from a population database from Colombia, and had been treated with cholinesterase inhibitors and glutamate N-methyl-D-aspartate receptor antagonists. The anticholinergic burden was evaluated using the Anticholinergic Cognitive Burden scale, and patients were classified on a scale of 0-3 points according to anticholinergic potential, and were grouped into those with mild-to-moderate (1-2 points) or high (≥3 points) anticholinergic load. RESULTS: The study included 4134 Alzheimer's disease patients. The mean age was 81.50 ± 8.16 years, and 67.8% were women. At least 22.9% of patients took anticholinergic drugs. Of these, the most frequently prescribed medication was quetiapine (8.6%). Age >85 years was associated with a high risk of having an anticholinergic burden ≥3 points (OR 2.19, 95%CI 1.159-4.162). Potential interactions between cholinesterase inhibitors and anticholinergic drugs were identified in 7.8% of patients. CONCLUSIONS: The majority of patients who were prescribed anticholinergic drugs were older women, had a significant total anticholinergic burden and had frequent pharmacological interactions with cholinesterase inhibitors. The use of anticholinergics reduces the clinical effectiveness of antidementia drugs and increases the risk of adverse reactions. Geriatr Gerontol Int 2019; 19: 913-917.
Assuntos
Doença de Alzheimer , Inibidores da Colinesterase/uso terapêutico , Prescrição Inadequada , Antagonistas Muscarínicos/uso terapêutico , Fumarato de Quetiapina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/epidemiologia , Antagonistas Colinérgicos/uso terapêutico , Colômbia/epidemiologia , Estudos Transversais , Feminino , Humanos , Prescrição Inadequada/prevenção & controle , Prescrição Inadequada/estatística & dados numéricos , Masculino , Conduta do Tratamento Medicamentoso/normas , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Pacientes Ambulatoriais/estatística & dados numéricos , Farmacovigilância , Lista de Medicamentos Potencialmente Inapropriados , Psicotrópicos/uso terapêuticoRESUMO
Plants of the Amaryllidaceae family are well-known (not only) for their ornamental value but also for the alkaloids that they produce. In this report, the first phytochemical study of Clinanthus genus was carried out. The chemical composition of alkaloid fractions from Clinanthus microstephium was analyzed by GC/MS and NMR. Seven known compounds belonging to three structural types of Amaryllidaceae alkaloids were identified. An epimeric mixture of a haemanthamine-type compound (6-hydroxymaritidine) was tested as an inhibitor against acetyl- and butyrylcholinesterase enzymes (AChE and BChE, respectively), two enzymes relevant in the treatment of Alzheimer's disease, with good results. Structure-activity relationships through molecular docking studies with this alkaloid and other structurally related compounds were discussed.
Assuntos
Alcaloides/química , Alcaloides de Amaryllidaceae/química , Amaryllidaceae/química , Inibidores da Colinesterase/química , Fenantridinas/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Alcaloides/metabolismo , Alcaloides/farmacologia , Amaryllidaceae/metabolismo , Sítios de Ligação , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Relação Estrutura-AtividadeRESUMO
ABSTRACT In light of the high cost of dementia treatment, there is legislation authorizing free distribution of cholinesterase inhibitors to those suffering from Alzheimer's disease in Brazil. However, the existence of this free distribution does not guarantee adequate distribution. Objectives The present study aimed to investigate the trends of prescriptions and the coverage of Alzheimer's disease treatment using cholinesterase inhibitors from public pharmacies dispensing high-cost drugs in Brazil. Methods This was a retrospective study that collected data from the Brazilian public Unified Health System. All cholinesterase inhibitors distributed at no cost to Brazilians during the year 2014, as well as the estimated number and percentages of patients who used these medications, were evaluated and compared to data from the year 2008. Results Our estimates indicated that 9.7% of the population having dementia syndromes used cholinesterase inhibitors, as well as 16.1% of those with Alzheimer's disease in Brazil. A clear disparity was noted between the use and distribution of cholinesterase inhibitors, depending on the region in which they were found. Over time, an increase in the distribution of cholinesterase inhibitors has been noted. In 2008, that use was 12.0% whereas, in 2014, it was 16.1%, an increase of 34% in six years. Conclusion It was estimated that 16.1% of patients with Alzheimer's disease in Brazil use cholinesterase inhibitors. These values have increased and, in spite of not being satisfactory, they indicate a potential for improvement. However, there is still a significant disparity among the regions.
RESUMO Devido ao custo alto de tratamento, existe uma legislação autorizando a distribuição sem custo de anticolinesterásicos para pacientes com doença de Alzheimer no Brasil. Entretanto, a existência dessa distribuição gratuita nem sempre garante uma distribuição adequada. Objetivos O presente estudo objetiva investigar a distribuição e desigualdades no uso de anticolinesterásicos (AChE) dispensados pelo Sistema de Saúde Público do Brasil. Métodos Estudo retrospectivo que coletou dados do Sistema Único de Saúde brasileiro. Foram avaliados todos os anticolinesterásicos distribuídos sem custo no Brasil durante o ano de 2014, assim como o número estimado e a porcentagem de pacientes que usavam essa medicação. Esses dados foram comparados com o ano de 2008. Resultados Estima-se que 9,7% da população que possui síndromes demenciais usa anticolinesterásicos, assim como 16,1% dos pacientes com doença de Alzheimer. Uma clara desigualdade entre o uso e a distribuição dos anticolinesterásicos foi encontrada, variando de acordo com a região. Houve um aumento na distribuição de anticolinesterásicos ao longo do tempo. Em 2008, o uso era de 12% e, em 2014, foi de 16,1%, resultando em um aumento de 34% em 6 anos. Conclusão Estima-se que 16,1% dos pacientes com doença de Alzheimer no Brasil usam anticolinesterásicos. Esses valores tiveram um aumento e, embora ainda não sejam satisfatórios, eles indicam um potencial de melhora. Entretanto, ainda foi evidenciada uma significante desigualdade entre as regiões.
Assuntos
Humanos , Inibidores da Colinesterase/uso terapêutico , Disparidades em Assistência à Saúde/estatística & dados numéricos , Doença de Alzheimer/tratamento farmacológico , Sistemas de Medicação/estatística & dados numéricos , Brasil , Saúde Pública , Estudos RetrospectivosRESUMO
A set of triterpenoids with different grades of oxidation in the lupane skeleton were prepared and evaluated as cholinesterase inhibitors. Allylic oxidation with selenium oxide and Jones's oxidation were employed to obtain mono-, di- and tri-oxolupanes, starting from calenduladiol (1) and lupeol (3). All the derivatives showed a selective inhibition of butyrylcholinesterase over acetylcholinesterase (BChE vs. AChE). A kinetic study proved that compounds 2 and 9, the more potent inhibitors of the series, act as competitive inhibitors. Molecular modeling was used to understand their interaction with BChE, the role of carbonyl at C-16 and the selectivity towards this enzyme over AChE. These results indicate that oxidation at C-16 of the lupane skeleton is a key transformation in order to improve the cholinesterase inhibition of these compounds.
Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Triterpenos/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxirredução , Relação Estrutura-Atividade , Torpedo , Triterpenos/síntese química , Triterpenos/químicaRESUMO
Therapeutic botulinum toxin injections are commonly performed in pediatric otolaryngology. Aerodigestive complications from botulinum toxin injections, although rare, may be serious. Oral pyridostigmine is effective in the symptomatic treatment of these complications. We report 2 cases of aerodigestive complications arising from injection of botulinum toxin that were successfully treated with pyridostigmine.
Assuntos
Toxinas Botulínicas Tipo A/efeitos adversos , Inibidores da Colinesterase/uso terapêutico , Fármacos Neuromusculares/efeitos adversos , Brometo de Piridostigmina/uso terapêutico , Criança , Transtornos de Deglutição/induzido quimicamente , Transtornos de Deglutição/tratamento farmacológico , Feminino , Humanos , LactenteRESUMO
RESUMEN Objetivo Determinar niveles de colinesterasa sérica en caficultores del departamento de Caldas y su asociación con factores demográficos y ocupacionales. Metodología Se realizó un estudio descriptivo, muestra de 1 098 agricultores del Alto Oriente y Centro Sur del Departamento de Caldas, por medio de una encuesta en la que se analizaron características del trabajador agrícola de tipo: sociodemográfico, ocupacional, clínicos y concentración de colinesterasa determinada con el método de Ellman. Resultados A nivel ocupacional, el 90,8 % de los agricultores refirió riesgo de exposición directa a plaguicidas. El 3,8 % de las determinaciones analíticas de colinesterasa fueron anormales, se relacionó que el 75,6 % de los agricultores preparan la mezcla del insecticida, el 22,2 % tienen una frecuencia de aplicación en el cultivo más de dos veces por semana, el 37,8 % no emplea ropa de protección durante la jornada de fumigación. El tiempo de la última aplicación fue dentro del rango de uno a diez días demostrando que a menor tiempo de aplicación del insecticida, se presenta mayor inhibición de la enzima. Los plaguicidas más reportados fueron los de tipo organofos-forado (58,6 %). Conclusiones El control de la exposición a plaguicidas se torna difícil porque la mayoría de trabajadores son de tipo informal. Se requiere fortalecer los programas de capacitación y campañas de sensibilización sobre los efectos de los plaguicidas en la salud, las medidas de higiene y seguridad en el trabajo. Los niveles bajos de colinesterasa sérica indican la absorción de una cantidad mínima de insecticidas inhibidores de la colinesterasa.(AU)
ABSTRACT Objective To determine the levels of serum cholinesterase in coffee growers from the Caldas department and its association with demographic and labor factors. Methodology A descriptive study was carried out in a sample of 1 098 farmers from the Upper East and South Center of the Caldas department, through a survey that analyzed characteristics such as sociodemographic, labor, and clinical conditions, as well as cholinesterase levels, determined by Ellman's method. Results Regarding the occupational aspect, 90.8 % of farmers reported a risk of direct exposure to pesticides. 3.8 % of the analytical determinations of cholinesterase were abnormal, which was related to the fact that 75.6 % of the farmers themselves prepare the mixture of the insecticide, 22.2 % spread the insecticide over their crops more than twice a week, and 37.8 % do not wear protective clothing during the fumigation. The last fumigation was within the range of one to ten days, revealing that the shorter the time of application of the insecticide, the greater the inhibition of the enzyme. The most frequent pesticides were organophosphates (58.6 %). Conclusions Controlling pesticide exposure is difficult because most workers are self-employed. It is necessary to strengthen training programs and awareness campaigns regarding the effect of pesticides on health, as well as health and safety measures at the workplace. Low levels of serum cholinesterase indicate the absorption of a minimal amount of cholinesterase inhibiting insecticides.(AU)