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1.
Acta Pharm ; 73(1): 91-105, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36692469

RESUMO

The effects of 3R,16S-2-hydroxyethyl apovincaminate (HEAPO, RGH-10885) compared with those of two cholinesterase inhibitors, donepezil and galantamine, were examined in naïve Wistar rats using standard active and passive avoidance tests. The active avoidance test (shuttle box) and two passive avoidance tests (step-through and step-down) were performed according to the experimental design. There were 10 groups of rats (n = 8) and the substances studied were applied orally before each testing session. In the active avoidance test, the number of conditioned stimuli (avoidances), unconditioned stimuli (escapes) and intertrial crossings were observed. In step-down and step-through passive avoidance tests, the latencies of reactions were observed. All the studied compounds showed positive effects in the learning and memory tests, compared to the controls. It was concluded that HEAPO, donepezil and galantamine had a memory-enhancing effect in active and passive avoidance tests.


Assuntos
Aprendizagem da Esquiva , Galantamina , Ratos , Animais , Donepezila/farmacologia , Ratos Wistar , Galantamina/farmacologia , Memória
2.
Mol Med ; 28(1): 148, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36494621

RESUMO

BACKGROUND: Autoinflammatory diseases, a diverse group of inherited conditions characterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine. METHODS: We tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF). Multiple chronic disease markers were evaluated in animals that received long-term galantamine treatment compared to vehicle. RESULTS: Long-term treatment with galantamine attenuated the associated splenomegaly and anemia which are characteristic features of this disease. Further, treatment reduced inflammatory cell infiltration into affected organs and a subcutaneous air pouch. CONCLUSIONS: These findings suggest that galantamine attenuates chronic inflammation in this mouse model of FMF. Further research is warranted to explore the therapeutic potential of galantamine in FMF and other autoinflammatory diseases.


Assuntos
Febre Familiar do Mediterrâneo , Camundongos , Animais , Febre Familiar do Mediterrâneo/tratamento farmacológico , Galantamina/farmacologia , Galantamina/uso terapêutico , Acetilcolinesterase/uso terapêutico , Modelos Animais de Doenças , Inflamação/tratamento farmacológico
3.
Int J Mol Sci ; 23(23)2022 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-36499171

RESUMO

Oxidative stress is an essential factor in the development and progression of Alzheimer's disease (AD). An excessive amount of reactive oxygen species (ROS) induces the peroxidation of lipid membranes, reduces the activity of antioxidant enzymes and causes neurotoxicity. In this study, we investigated the antioxidant and cholinesterase inhibitory potential of a novel galantamine-curcumin hybrid, named 4b, administered orally in two doses (2.5 mg/kg and 5 mg/kg) in scopolamine (SC)-induced neurotoxicity in mice. To evaluate the effects of 4b, we used galantamine (GAL) (3 mg/kg) and curcumin (CCN) (25 mg/kg) as positive controls. Ex vivo experiments on mouse brains showed that the higher dose of 4b (5 mg/kg) increased reduced glutathione (GSH) levels by 46%, catalase (CAT) and superoxide dismutase (SOD) activity by 57%, and glutathione peroxidase (GPx) activity by 108%, compared with the SC-treated group. At the same time, 4b (5 mg/kg) significantly reduced the brain malondialdehyde (MDA) level by 31% and acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities by 40% and 30%, respectively, relative to the SC-impaired group. The results showed that 4b acted as an antioxidant agent and brain protector, making it promising for further experimental research in the field of neurodegenerative diseases.


Assuntos
Curcumina , Síndromes Neurotóxicas , Animais , Camundongos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Butirilcolinesterase , Escopolamina/farmacologia , Acetilcolinesterase/metabolismo , Curcumina/farmacologia , Peroxidação de Lipídeos , Galantamina/farmacologia , Superóxido Dismutase/metabolismo , Catalase/metabolismo , Estresse Oxidativo , Glutationa Peroxidase/metabolismo , Glutationa/metabolismo
4.
Medicine (Baltimore) ; 101(45): e31625, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397447

RESUMO

To examine the real-world effects of the cholinesterase inhibitors (AChEI) on all-cause mortality. A nationwide, retrospective cohort study. Participants were diagnosed with incident AD in Denmark from January 1, 2000 to December 31, 2011 with follow-up until December 31, 2012. A total of 36,513 participants were included in the current study with 22,063 deaths during 132,426 person-years of follow-up. At baseline, patients not treated with AChEI (n = 28,755 [9961 males (35%)]) had a mean age ±â€…standard deviation (SD) of 80.33 ±â€…7.98 years (78.97 ±â€…8.26 for males and 81.04 ±â€…7.98 for females), as compared to 79.95 ±â€…7.67 (78.87 ±â€…7.61 for males and 80.61 ±â€…7.63 for females) in the group exposed at baseline. Patients treated with AChEI had a beneficial hazard ratio (HR) of 0.69, 95% confidence interval (CI) (0.67-0.71) for all-cause mortality as compared to patients not treated, with donepezil (HR 0.80, 95% CI [0.77-0.82]) and galantamine (HR 0.93,95% CI [0.89-0.97]) having beneficial effects on mortality rate as compared to non-treatment, whereas rivastigmine (HR 0.99, 95% CI [0.95-1.03]) was associated with a mortality rate comparable to non-treatment with AChEI. Patients were primarily exposed to donepezil (65.8%) with rivastigmine (19.8%) and galantamine (14.4%) being used less often. These findings underscore the effect of AChEI on not only reducing speed of cognitive decline but also directly prolonging life, which could result in changes in treatment recommendation for when to stop treatment.


Assuntos
Doença de Alzheimer , Galantamina , Masculino , Feminino , Humanos , Rivastigmina/uso terapêutico , Donepezila/uso terapêutico , Galantamina/uso terapêutico , Galantamina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/induzido quimicamente , Indanos/uso terapêutico , Indanos/farmacologia , Estudos Retrospectivos , Fenilcarbamatos/uso terapêutico , Piperidinas/efeitos adversos
5.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232533

RESUMO

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC50 values of 1.94 ± 0.13 µM and 28.37 ± 1.85 µM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC50 values of 9.07 ± 1.34 µM and 6.05 ± 1.17 µM, respectively, which were superior to the control, Trolox (IC50 = 11.03 ± 0.76 µM). It is worth noting that 3-aminoquinoline derivatives 12a-12d exhibited better drug-like properties.


Assuntos
Doença de Alzheimer , Hidroxiquinolinas , Acetilcolinesterase/metabolismo , Aminas/farmacologia , Aminoquinolinas/farmacologia , Benzotiazóis , Carbono , Inibidores da Colinesterase/farmacologia , Galantamina , Humanos , Cinética , Simulação de Acoplamento Molecular , Morfolinas , Relação Estrutura-Atividade , Ácidos Sulfônicos
6.
Molecules ; 27(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36234916

RESUMO

New resveratrol-thiophene and resveratrol-maltol hybrids were synthesized as cholinesterase inhibitors and antioxidants. As with photostability experiments, biological tests also found remarkable differences in the properties and behavior of thiophene and maltol hybrids. While resveratrol-thiophene hybrids have excellent inhibitory and antioxidant properties (similar to the activity of reference drug galantamine), maltols have been proven to be weaker inhibitors and antioxidants. The molecular docking of selected active ligands gave insight into the structures of docked enzymes. It enabled the identification of interactions between the ligand and the active site of both cholinesterases. The maltols that proved to be active cholinesterase inhibitors were able to coordinate Fe3+ ion, forming complexes of 1:1 composition. Their formation constants, determined by spectrophotometry, are very similar, lgK = 11.6-12.6, suggesting that Fe3+ binds to the common hydroxy-pyranone moiety and is hardly affected by the other aromatic part of the ligand. Accordingly, the characteristic bands in their individual absorption spectra are uniformly red-shifted relative to those of the free ligands. The crystal structures of two new resveratrol-maltol hybrids were recorded, giving additional information on the molecules' intermolecular hydrogen bonds and packing. In this way, several functionalities of these new resveratrol hybrids were examined as a necessary approach to finding more effective drugs for complicated neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Oligoelementos , Doença de Alzheimer/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Quelantes/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Galantamina , Humanos , Ligantes , Simulação de Acoplamento Molecular , Pironas , Resveratrol , Relação Estrutura-Atividade , Tiofenos
7.
Molecules ; 27(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36234964

RESUMO

Data on alkaloid interactions with the physiologically important transition metals, iron and copper, are mostly lacking in the literature. However, these interactions can have important consequences in the treatment of both Alzheimer's disease and cancer. As isoquinoline alkaloids include galanthamine, an approved drug for Alzheimer's disease, as well as some potentially useful compounds with cytostatic potential, 28 members from this category of alkaloids were selected for a complex screening of interactions with iron and copper at four pathophysiologically relevant pH and in non-buffered conditions (dimethyl sulfoxide) by spectrophotometric methods in vitro. With the exception of the salts, all the alkaloids were able to chelate ferrous and ferric ions in non-buffered conditions, but only five of them (galanthine, glaucine, corydine, corydaline and tetrahydropalmatine) evoked some significant chelation at pH 7.5 and only the first two were also active at pH 6.8. By contrast, none of the tested alkaloids chelated cuprous or cupric ions. All the alkaloids, with the exception of the protopines, significantly reduced the ferric and cupric ions, with stronger effects on the latter. These effects were mostly dependent on the number of free aromatic hydroxyls, but not other hydroxyl groups. The most potent reductant was boldine. As most of the alkaloids chelated and reduced the ferric ions, additional experimental studies are needed to elucidate the biological relevance of these results, as chelation is expected to block reactive oxygen species formation, while reduction could have the opposite effect.


Assuntos
Doença de Alzheimer , Citostáticos , Quelantes/química , Cobre/química , Dimetil Sulfóxido , Galantamina , Humanos , Radical Hidroxila , Ferro/química , Isoquinolinas/farmacologia , Espécies Reativas de Oxigênio , Substâncias Redutoras , Sais
8.
Molecules ; 27(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36296692

RESUMO

Alzheimer's disease is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment due to a severe loss of cholinergic neurons in specific brain areas. It is the most common type of dementia in the aging population. Although many anti-acetylcholinesterase (AChE) drugs are already available on the market, their performance sometimes yields unexpected results. For this reason, research works are ongoing to find potential anti-AChE agents both from natural and synthetic sources. In this study, 90 extracts from 30 native and naturalized medicinal plants are tested by TLC and Ellman's colorimetric assay at 250, 125 and 62.5 µg/mL in order to determine the inhibitory effect on AChE. In total, 21 out of 90 extracts show high anti-AChE activity (75-100% inhibition) in a dose-dependent manner. Among them, ethanolic extract from aerial parts of O. vulgare ssp. vulgare shows an IC50 value 7.7 times lower than galantamine. This research also establishes the chemical profile of oregano extract by TLC, HPLC-DAD and LC-MS, and twenty-three compounds are identified and quantified. Dihydroxycinnamic acids and flavonoids are the most abundant ones (56.90 and 25.94%, respectively). Finally, total phenolic compounds and antioxidant properties are quantified by colorimetric methods. The total phenolic content is 207.64 ± 0.69 µg/mg of extract. The antioxidant activity is measured against two radicals, DPPH and ABTS. In both assays, the oregano extract shows high activity. The Pearson correlation matrix shows the relationship between syringic acids, a type of dihydroxybenzoic acid, and anti-AChE (r2 = -0.9864) and antioxidant activity (r2 = 0.9409 and 0.9976). In conclusion, the results of this study demonstrate promising potential new uses of these medicinal herbs for the treatment of Alzheimer's. Origanum vulgare ssp. vulgare and syringic acids, which have anti-AChE activity and beneficial antioxidant capacity, can be highlighted as potential candidates for the development of drugs for the treatment of Alzheimer's disease and other diseases characterized by a cholinergic deficit.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Origanum , Plantas Medicinais , Origanum/química , Inibidores da Colinesterase/química , Plantas Medicinais/química , Antioxidantes/química , Doença de Alzheimer/tratamento farmacológico , Galantamina , Espanha , Extratos Vegetais/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Fenóis/química , Acetilcolinesterase/uso terapêutico
9.
Molecules ; 27(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36144504

RESUMO

Aiming to find Amaryllidaceae alkaloids against breast cancer, including the highly aggressive triple-negative breast cancer, the phytochemical study of Pancratium maritimum was carried out. Several Amaryllidaceae-type alkaloids, bearing scaffolds of the haemanthamine-, homolycorine-, lycorine-, galanthamine-, and tazettine-type were isolated (3-11), along with one alkamide (2) and a phenolic compound (1). The antiproliferative effect of compounds (1-11) was evaluated by the sulforhodamine B assay against triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468, breast cancer cells MCF-7, and the non-malignant fibroblast (HFF-1) and breast (MCF12A) cell lines. The alkaloids 3, 5, 7, and 11 showed significant growth inhibitory effects against all breast cancer cell lines, with IC50 (half-maximal inhibitory concentration) values ranging from 0.73 to 16.3 µM. The homolycorine-type alkaloid 7 was selected for further investigation in MDA-MB-231 cells. In the annexin-V assay, compound 7 increased cell death by apoptosis, which was substantiated, in western blot analyses, by the increased expression of the pro-apoptotic protein Bax, and the decreased expression of the anti-apoptotic protein Bcl-xL. Consistently, it further stimulated mitochondrial reactive oxygen species (ROS) generation. The antiproliferative effect of compound 7 was also associated with G2/M cell cycle arrest, which was supported by an increase in the p21 protein expression levels. In MDA-MB-231 cells, compound 7 also exhibited synergistic effects with conventional chemotherapeutic drugs such as etoposide.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Alcaloides/farmacologia , Amaryllidaceae/metabolismo , Alcaloides de Amaryllidaceae/farmacologia , Anexinas , Apoptose , Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Etoposídeo/farmacologia , Feminino , Galantamina/farmacologia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína X Associada a bcl-2/metabolismo
10.
Molecules ; 27(18)2022 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-36144637

RESUMO

Sweroside is a secoiridoid glycoside and belongs to a large group of naturally occurring monoterpenes with glucose sugar attached to C-1 in the pyran ring. Sweroside can promote different biological activities such as antifungal, antibacterial, hepatoprotective, gastroprotective, sedative and antitumor, antioxidant, and neuroprotective activities. Zebrafish were given sweroside (12.79, 8.35, and 13.95 nM) by immersion once daily for 8 days, along with scopolamine (Sco, 100 µM) 30 min before the initiation of the behavioral testing to cause anxiety and memory loss. Employing the novel tank diving test (NTT), the Y-maze, and the novel object recognition test (NOR), anxiety-like reactions and memory-related behaviors were assessed. The following seven groups (n = 10 animals per group) were used: control, Sco (100 µM), sweroside treatment (2.79, 8.35, and 13.95 nM), galantamine (GAL, 2.71 µM as the positive control in Y-maze and NOR tests), and imipramine (IMP, 63.11 µM as the positive control in NTT test). Acetylcholinesterase activity (AChE) and the antioxidant condition of the brains were also evaluated. The structure of sweroside isolated from Schenkia spicata was identified. Treatment with sweroside significantly improved the Sco-induced decrease of the cholinergic system activity and brain oxidative stress. These results suggest that sweroside exerts a significant effect on anxiety and cognitive impairment, driven in part by the modulation of the cholinergic system activity and brain antioxidant action.


Assuntos
Escopolamina , Peixe-Zebra , Acetilcolinesterase/metabolismo , Animais , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antioxidantes/efeitos adversos , Encéfalo/metabolismo , Colinérgicos/farmacologia , Galantamina/farmacologia , Glucose/farmacologia , Hipnóticos e Sedativos/farmacologia , Imipramina/farmacologia , Inosina Monofosfato/farmacologia , Glucosídeos Iridoides/farmacologia , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Estresse Oxidativo , Escopolamina/efeitos adversos , Açúcares , Peixe-Zebra/metabolismo
11.
J Phys Chem B ; 126(40): 7797-7805, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36170055

RESUMO

Traditional drug discovery is based on a binding affinity (thermodynamics)-driven paradigm. Numerous examples, however, demonstrated that drug efficacy does not always depend only on binding affinity but positively correlates with binding kinetics, that is, the dissociation rate constant (koff). Binding free energy landscape (BFEL) constructor is a computational binding kinetics prediction method, previously developed by us, that estimates the binding kinetics for ligand-protein based on their constructed binding free energy landscape, but it also reveals the detailed molecular mechanism of the binding event, hence, providing the position of transition states at the molecular level to modify/improve the binding kinetics. Acetylcholinesterase (AChE) is a well-known Alzheimer's disease (AD) target for which there is still not an ideal drug on the market. Therefore, to improve the drug design strategy for AD, the binding kinetics and binding molecular mechanisms of the four inhibitors of AChE, that is, E2020 (Aricept), HupA, Rivastigmine, and Galantamine, were studied. Also, the differentiation of the binding kinetics between mAChE and TcAChE was studied to evaluate the sensitiveness of BFEL constructor. The flexibility of molecules has a noticeable effect on the nature of BFEL. To the same target, flexible molecules (i.e., E2020 and Rivastigmine) which contain more rotatable bonds tend to have more complicated BFELs reflecting more complicated molecular action mechanisms than the rigid ones (i.e., HupA and Galantamine), which therefore could be more challenging to be optimized. The binding kinetics is highly dependent on the structure of the molecules, such as the length and the functional groups. Therefore, E2020 presents better binding kinetic and thermodynamic properties with either TcAChE or mAChE. Therefore, it is the most promising lead drug for binding kinetics-based drug design. In addition, the binding kinetics of a drug may present different values in the proteins of different organisms because the residue compositions of the binding gorges of the targets are variant, that is, E2020 shows lower binding affinity and association energy barrier in binding with mAChE than TcAChE. However, HupA presents a better binding property with TcAChE than mAChE.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/química , Inibidores da Colinesterase/química , Donepezila , Galantamina , Humanos , Cinética , Ligantes , Rivastigmina
12.
Chem Biol Interact ; 365: 110092, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-35987277

RESUMO

Complex neurological disorders, including Alzheimer's disease, are one of the major therapeutic areas to which multitarget drug discovery strategies have been applied in the last twenty years. Due to the complex multifactorial etiopathogenesis of Alzheimer's disease, it has been proposed that to be successful the pharmaceutical agents should act on multiple targets in order to restore the complex disease network and to provide disease modifying effects. Here we report on the synthesis and the anticholinergic activity profiles of seven multitarget anti-Alzheimer compounds designed by combining galantamine, a well-known acetylcholinesterase inhibitor, with different peptide fragments endowed with inhibitory activity against BACE-1. A complementary approach based on molecular docking simulations of the galantamine-peptide derivatives in the active sites of acetylcholinesterase and of the related butyrylcholinesterase, as well as on inhibition kinetics, by global fitting of the reaction progress curves, allowed to gain insights into the enzyme-inhibitor mechanism of interaction. The resulting structure-activity relationships pave the way towards the design of more effective pharmacodynamic/pharmacokinetic multitarget inhibitors.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Galantamina/farmacologia , Galantamina/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fragmentos de Peptídeos , Relação Estrutura-Atividade
13.
Fitoterapia ; 162: 105268, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35963483

RESUMO

The main objective of our present research work was to explore molecular insight for potentially active new acetylcholinesterase inhibitor from the aerial parts of Delphinium uncinatum. New norditerpenoid alkaloids, uncinatine-A, was isolated from the basic alkaloidal fraction of D. uncinatum, based on bioactivity guided isolation. The structure of uncinatine-A was determined through latest spectroscopic techniques including single X-Ray diffraction technique. The structural data and electronic properties of uncinatine-A was also calculated by Density Functional Theory (DFT) using B3LYP/6-31þ G (p) basis set. The isolated natural product was evaluated for their acetyl cholinesterase inhibitory potential in dose dependent protocol (62.5-1000 µg/mL), followed by molecular docking studies. Significant competitive type inhibition activity (IC50 = 207.73 ± 0.3) was shown by isolated natural norditerpenoid against cholinesterase targets in comparison with standard drugs available in the market such as galanthamine. The molecular docking results showed that isolated natural product was well accommodated by AChE in the active site with docking scores -11.0326. This is the first report indicating uncinatine-A as a potent acetylcholinesterase inhibitor and can be used as a target drug in cerebral dementia and Alzheimer diseases.


Assuntos
Alcaloides , Produtos Biológicos , Delphinium , Diterpenos , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase , Delphinium/química , Teoria da Densidade Funcional , Galantamina , Simulação de Acoplamento Molecular , Estrutura Molecular
14.
J Alzheimers Dis ; 89(2): 721-731, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35964196

RESUMO

BACKGROUND: Dysphagia has been reported as an adverse event for patients receiving rivastigmine for Alzheimer's disease (AD) treatment. OBJECTIVE: The purpose of this study was to determine the association between dysphagia and the usage of rivastigmine by using the pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS). METHODS: The risk of dysphagia in patients who took rivastigmine was compared with those of patients who took other medications. In addition, this study sought to determine if the dysphagia risk was influenced by sex, age, dosage, and medication routes of administration. RESULTS: When compared to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. The dysphagia risk in individuals prescribed rivastigmine is comparable to individuals prescribed penicillamine but significantly higher than clozapine, drugs of which have been previously shown to be associated with elevated dysphagia likelihood. Individuals older than 80 were 122% more likely to report having dysphagia after being prescribed rivastigmine than patients that were 50-70 years of age. Oral administration of rivastigmine was associated with approximately 2 times greater likelihood of reporting dysphagia relative to users of the transdermal patch. In addition, dysphagia showed higher association with pneumonia than other commonly reported adverse events. CONCLUSION: Patients prescribed rivastigmine were at greater risk of reporting dysphagia as an adverse event than patients prescribed many other medicines. This increase in dysphagia occurrence may be attributed to the dual inhibition of both acetylcholinesterase and butyrylcholinesterase.


Assuntos
Doença de Alzheimer , Clozapina , Transtornos de Deglutição , Acetilcolinesterase , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase , Inibidores da Colinesterase/efeitos adversos , Clozapina/uso terapêutico , Transtornos de Deglutição/induzido quimicamente , Transtornos de Deglutição/tratamento farmacológico , Transtornos de Deglutição/epidemiologia , Donepezila/uso terapêutico , Galantamina/uso terapêutico , Humanos , Memantina/uso terapêutico , Penicilamina/uso terapêutico , Gestão de Riscos , Rivastigmina/efeitos adversos , Estados Unidos , United States Food and Drug Administration
15.
Sci Rep ; 12(1): 13700, 2022 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953692

RESUMO

Leucojum aestivum is known for its ability to biosynthesize alkaloids with therapeutic properties, among which galanthamine used for the treatment of Alzheimer's disease. New sources of this alkaloid are still being explored. In this study, a novel strain PLV of endophytic bacterium Paenibacillus lautus was isolated from in vitro L. aestivum plants. We report the whole genome sequence of that strain and its capacity to produce alkaloids and growth regulators. The effect of elicitation with autoclaved bacteria on the production of alkaloids was examined. Ten alkaloids were identified in bacteria extracts: galanthamine, lycorine, ismine, lycoramine, haemanthamine, tazettine, galanthine, homolycorine, 1,2-dihydrochlidanthine, and hippeastrine. The mean contents of galanthamine and lycorine were 37.51 µg/g of dry weight (DW) and 129.93 µg/g of DW, respectively. Moreover, isolated P. lautus strain synthesized: indole-3-acetic acid, t-zeatin, c-zeatin, kinetin, gibberellin A1, abscisic acid, salicylic acid, benzoic acid. In vitro elicitation of cultures with P. lautus increased dry biomass, stimulated galanthamine and lycorine production, contributed to 8,9-desmethylenebis (oxy)-7,9 dimethoxy-crinan biosynthesis, change pigments content, and antioxidant enzymes activities. Our findings for the first time point out that galanthamine can be synthesized by an microorganism. Moreover isolated strain can be used as a new elictor of Amaryllidaceae alkaloids biosynthesis.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Liliaceae , Bactérias , Galantamina , Zeatina
17.
Biomolecules ; 12(7)2022 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-35883449

RESUMO

Amaryllidaceae alkaloids (AAs) are plant specialized metabolites with therapeutic properties exclusively produced by the Amaryllidaceae plant family. The two most studied representatives of the family are galanthamine, an acetylcholinesterase inhibitor used as a treatment of Alzheimer's disease, and lycorine, displaying potent in vitro and in vivo cytotoxic and antiviral properties. Unfortunately, the variable level of AAs' production in planta restricts most of the pharmaceutical applications. Several biotechnological alternatives, such as in vitro culture or synthetic biology, are being developed to enhance the production and fulfil the increasing demand for these AAs plant-derived drugs. In this review, current biotechnological approaches to produce different types of bioactive AAs are discussed.


Assuntos
Alcaloides de Amaryllidaceae , Amaryllidaceae , Acetilcolinesterase , Alcaloides de Amaryllidaceae/farmacologia , Inibidores da Colinesterase/farmacologia , Galantamina
18.
Eur J Clin Pharmacol ; 78(10): 1567-1587, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35881170

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia. In this umbrella systematic review (SR), we summarized the efficacy of different pharmacological interventions in improving cognitive function in patients with AD. METHODS: A systematic search was performed through the PubMed, Scopus, Embase, and Cochrane databases for SRs of studies assessing the efficacy of pharmacological interventions versus placebo in improving cognitive function in AD or mild cognitive impairment due to AD. The risk of bias (RoB) was assessed using the Risk of Bias in SRs (ROBIS) tool. RESULTS: Out of 1748 articles found through the database survey, 33 SR articles were included. These studies assessed effects of immunotherapy, cholinesterase inhibitors (ChEIs), memantine, statins, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), antidiabetic agents, Cerebrolysin, RAS-targeting antihypertensive drugs (ARBs and ACEIs), psychostimulants, glycogen synthase kinase 3 (GSK-3) inhibitors, melatonin, and herbal medications on cognitive function in AD patients. There was no notable overall RoB in 18 studies (54.5%), the RoB in 14 studies (42.4%) was high, and in one study (3.0%) it was unclear. CONCLUSIONS: The use of ChEIs, including rivastigmine, galantamine, and donepezil, as well as memantine has demonstrated a positive impact on improving cognitive outcomes of AD patients, but no considerable effects were found for immunotherapies. Melatonin, statins, antihypertensive drugs, antidiabetic agents, Cerebrolysin, psychostimulants, and some herbal drugs such as Danggui-Shaoyao-San and Ginkgo biloba seem to be effective in improving cognitive function of AD patients, but the evidence in this regard is limited.


Assuntos
Doença de Alzheimer , Inibidores de Hidroximetilglutaril-CoA Redutases , Melatonina , Doenças Neurodegenerativas , Doença de Alzheimer/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Donepezila/uso terapêutico , Galantamina/uso terapêutico , Quinase 3 da Glicogênio Sintase/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Indanos/uso terapêutico , Lítio/uso terapêutico , Melatonina/uso terapêutico , Memantina/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Rivastigmina , Revisões Sistemáticas como Assunto
19.
Neuropharmacology ; 217: 109191, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35835213

RESUMO

Postoperative delirium (POD) occurs in a few days after major surgery under general anesthesia and may cause serious health problems. However, effective intervention and treatment remain unavailable because the underlying mechanisms have far been elucidated. In the present study, we explored the role of the malfunctioned astrocytes in POD. Our results showed that mice with tibia fracture displayed spatial and temporal memory impairments, reduced LTP, and activated astrocytes in the hippocampus in early postoperative stage. Using electrophysiological and Ca2+ imaging techniques in hippocampal slices, we demonstrated the malfunctions of astrocytes in surgery mice: depolarized resting membrane potential, higher membrane conductance and capacitance, and attenuated Ca2+ elevation in response to external stimulation. The degraded calcium signaling in hippocampal astrocytes in surgery mice was restored by correcting the diminution of acetylcholine release with galantamine. Furthermore, pharmacologically blocking astrocyte activation with fluorocitrate and enhancing cholinergic inputs with galantamine normalized hippocampal LTP in surgery mice. Finally, inhibition of astrocyte activation with fluorocitrate in the hippocampus improved cognitive function in surgery mice. Therefore, the prevention of astrocyte activation may be a valuable strategy for the intervention of cognitive dysfunction in POD, and acetylcholine receptors may be valid drug targets for this purpose.


Assuntos
Astrócitos , Galantamina , Animais , Colinérgicos/farmacologia , Cognição , Galantamina/farmacologia , Hipocampo , Camundongos , Plasticidade Neuronal/fisiologia
20.
Mol Med ; 28(1): 60, 2022 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-35659521

RESUMO

BACKGROUND: African Americans (AAs) are disproportionately affected by cardiovascular disease (CVD), they are 20% more likely to die from CVD than whites, chronic exposure to inflammation and oxidative stress contributes to CVD. In previous studies, enhancing parasympathetic cholinergic activity has been shown to decrease inflammation. Considering that AAs have decreased parasympathetic activity compared to whites, we hypothesize that stimulating it with a central acetylcholinesterase (AChE) inhibitor, galantamine, would prevent lipid-induced oxidative stress. OBJECTIVE: To test the hypothesis that acute dose of galantamine, an AChE inhibitor, decreases lipid-induced oxidative stress in obese AAs. METHODS: Proof-of-concept, double-blind, randomized, placebo-controlled, crossover study that tested the effect of a single dose of 16 mg of galantamine versus placebo on lipid-induced oxidative stress in obese AAs. Subjects were studied on two separate days, one week apart. In each study day, 16 mg or matching placebo was administered before 20% intralipids infusion at doses of 0.8 mL/m2/min with heparin at doses of 200 U/h for 4 h. Outcomes were assessed at baseline, 2 and 4 h during the infusion. MAIN OUTCOME MEASURES: Changes in F2-isoprostane (F2-IsoPs), marker of oxidative stress, measured in peripheral blood mononuclear cells (PBMC) and in plasma at baseline, 2, and 4-h post-lipid infusion. Secondary outcomes include changes in inflammatory cytokines (IL-6, TNF alpha). RESULTS: A total of 32 obese AA women were screened and fourteen completed the study (age 37.8 ± 10.70 years old, BMI 38.7 ± 3.40 kg/m2). Compared to placebo, 16 mg of galantamine significantly inhibited the increase in F2-IsoPs in PBMC (0.007 ± 0.008 vs. - 0.002 ± 0.006 ng/sample, P = 0.016), and plasma (0.01 ± 0.02 vs. - 0.003 ± 0.01 ng/mL, P = 0.023). Galantamine also decreased IL-6 (11.4 ± 18.45 vs. 7.7 ± 15.10 pg/mL, P = 0.021) and TNFα levels (18.6 ± 16.33 vs. 12.9 ± 6.16 pg/mL, P = 0.021, 4-h post lipid infusion) compared with placebo. These changes were associated with an increased plasma acetylcholine levels induced by galantamine (50.5 ± 10.49 vs. 43.6 ± 13.38 during placebo pg/uL, P = 0.025). CONCLUSIONS: In this pilot, proof-of-concept study, enhancing parasympathetic nervous system (PNS) cholinergic activity with galantamine inhibited lipid-induced oxidative stress and inflammation induced by lipid infusion in obese AAs. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02365285.


Assuntos
Doenças Cardiovasculares , Galantamina , Acetilcolinesterase , Adulto , Colinérgicos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Galantamina/farmacologia , Galantamina/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Interleucina-6 , Leucócitos Mononucleares , Lipídeos , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Estresse Oxidativo
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