Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Aprovação de Drogas , Placa Amiloide , Doença de Alzheimer/diagnóstico , Biomarcadores , Indústria Farmacêutica/ética , Humanos , Relações Interprofissionais , Placa Amiloide/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Fatores de Tempo , Estados Unidos , United States Food and Drug AdministrationAssuntos
Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Encéfalo , Relação Dose-Resposta a Droga , Placa Amiloide/diagnóstico por imagem , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/economia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Tomada de Decisões , Aprovação de Drogas/métodos , Humanos , Infusões Intravenosas/métodos , Imageamento por Ressonância Magnética/métodos , Nootrópicos/administração & dosagem , Nootrópicos/efeitos adversos , Nootrópicos/economia , Tomografia por Emissão de Pósitrons/métodos , Vigilância de Produtos Comercializados , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do Tratamento , Estados UnidosAssuntos
Doença de Alzheimer , Aprovação de Equipamentos , Medicare/economia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/economia , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/economia , Análise Custo-Benefício , Publicidade Direta ao Consumidor , Custos de Medicamentos , Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Humanos , Nootrópicos/administração & dosagem , Nootrópicos/efeitos adversos , Nootrópicos/economia , Estados Unidos , United States Food and Drug Administration/normasRESUMO
Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and ß-amyloid (Aß1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02)â µm], has strong antioxidant activity (3.61â µmol Trolox equivalents), and moderate Aß1-42 antiaggregating power (40.3 %).
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/síntese química , Inibidores da Colinesterase/uso terapêutico , Colinesterases/metabolismo , Iminas/química , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/química , Antioxidantes/uso terapêutico , Sítios de Ligação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Colinesterases/química , Humanos , Iminas/síntese química , Iminas/uso terapêutico , Ligantes , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Estrutura Terciária de ProteínaAssuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos/uso terapêutico , Doença de Alzheimer/metabolismo , Anticorpos/metabolismo , Ensaios Clínicos Fase III como Assunto/métodos , Indústria Farmacêutica/métodos , Indústria Farmacêutica/tendências , HumanosRESUMO
Trypanosoma cruzi strains from distinct geographic areas show differences in drug resistance and association between parasites genetic and treatment response has been observed. Considering that benznidazole (BZ) can reduce the parasite burden and tissues damage, even in not cured animals and individuals, the goal is to assess the drug response to BZ of T. cruzi II strains isolated from children of the Jequitinhonha Valley, state of Minas Gerais, Brazil, before treatment. Mice infected and treated with BZ in both phases of infection were compared with the untreated and evaluated by fresh blood examination, haemoculture, polymerase chain reaction, conventional (ELISA) and non-conventional (FC-ALTA) serologies. In mice treated in the acute phase, a significant decrease in parasitaemia was observed for all strains. Positive parasitological and/or serological tests in animals treated during the acute and chronic (95.1-100%) phases showed that most of the strains were BZ resistant. However, beneficial effect was demonstrated because significant reduction (p < 0.05%) and/or suppression of parasitaemia was observed in mice infected with all strains (acute phase), associated to reduction/elimination of inflammation and fibrosis for two/eight strains. BZ offered some benefit, even in not cured animals, what suggest that BZ use may be recommended at least for recent chronic infection of the studied region.
Assuntos
Humanos , Descoberta de Drogas , Resíduos Industriais/análise , Nootrópicos/isolamento & purificação , Extratos Vegetais/química , Brotos de Planta/química , Estilbenos/isolamento & purificação , Vitis/química , Agricultura/economia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/análise , Benzofuranos/química , Benzofuranos/economia , Benzofuranos/isolamento & purificação , Cromatografia Líquida de Alta Pressão , França , Resíduos Industriais/economia , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/economia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Nootrópicos/química , Nootrópicos/economia , Nootrópicos/farmacologia , Agregação Patológica de Proteínas , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Fenóis/química , Fenóis/economia , Extratos Vegetais/economia , Agregados Proteicos/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Estilbenos/análise , Estilbenos/química , Estilbenos/economia , Estilbenos/farmacologiaRESUMO
BACKGROUND: Viticultural residues from commercial viticultural activities represent a potentially important source of bioactive stilbenes such as resveratrol. The main aim of the present study was therefore to isolate, identify and perform biological assays against amyloid-ß peptide aggregation of original stilbenes from Vitis vinifera shoots. RESULTS: A new resveratrol oligomer, (Z)-cis-miyabenol C (3), was isolated from Vitis vinifera grapevine shoots together with two newly reported oligostilbenes from Vitis vinifera shoots, vitisinol C (1) and (E)-cis-miyabenol C (2), and six known compounds: piceatannol, resveratrol, (E)-ε-viniferin (trans-ε-viniferin), ω-viniferin, vitisinol C and (E)-miyabenol C. The structures of these resveratrol derivatives were established on the basis of detailed spectroscopic analysis including nuclear magnetic resonance experiments. All the newly reported compounds were tested for their anti-aggregative activity against amyloid-ß fibril formation. Vitisinol C was found to exert a significant activity against amyloid-ß aggregation. CONCLUSION: Vitis vinifera grapevine shoots are potentially interesting as a source of new bioactive stilbenes, such as vitisinol C.
Assuntos
Descoberta de Drogas , Resíduos Industriais/análise , Nootrópicos/isolamento & purificação , Extratos Vegetais/química , Brotos de Planta/química , Estilbenos/isolamento & purificação , Vitis/química , Agricultura/economia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/análise , Benzofuranos/química , Benzofuranos/economia , Benzofuranos/isolamento & purificação , Cromatografia Líquida de Alta Pressão , França , Humanos , Resíduos Industriais/economia , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/economia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Nootrópicos/química , Nootrópicos/economia , Nootrópicos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Fenóis/química , Fenóis/economia , Extratos Vegetais/economia , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Estilbenos/análise , Estilbenos/química , Estilbenos/economia , Estilbenos/farmacologia , EstilbestroisAssuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Ensaios Clínicos como Assunto/métodos , Adulto , Idade de Início , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/análise , Ensaios Clínicos como Assunto/economia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Progressão da Doença , Predisposição Genética para Doença , Humanos , Internacionalidade , Pessoa de Meia-Idade , Fatores de TempoAssuntos
Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Vacinas contra Alzheimer/imunologia , Vacinas contra Alzheimer/uso terapêutico , Peptídeos beta-Amiloides/antagonistas & inibidores , Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Vacinas contra Alzheimer/efeitos adversos , Amiloide/antagonistas & inibidores , Amiloide/química , Amiloide/imunologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/efeitos adversos , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Ensaios Clínicos como Assunto , Humanos , Imunoglobulinas Intravenosas/economia , Camundongos , Proteínas tau/antagonistas & inibidores , Proteínas tau/química , Proteínas tau/metabolismoRESUMO
The leading mechanistic theory of Alzheimer's disease (AD) is the "amyloid hypothesis" which states that the accumulation of the amyloid ß protein (Aß), and its subsequent aggregation into plaques, is responsible for the initiation of a cascade of events resulting in neurodegeneration and dementia. The anti-amyloid disease-modifying approach, based on the decrease in the production of Aß, gained thus a paramount importance. The aim of this study was the design and synthesis of a new series of acetylcholinesterase inhibitors (AChEIs) endowed with anti-Aß aggregating capability. These dual binding inhibitors, being able to interact both with the peripheral anionic site (PAS) of AChE and the catalytic subsite, proved to be able to inhibit the AChE-induced Aß aggregation. Thus, starting from the lead compound 1, an AChEI composed by a benzophenone scaffold and a N,N'-methylbenzylamino group, a substantial modification aimed at targeting the PAS was performed. To this aim, different amino-terminal side chains were incorporated into this main framework, in order to mimic the diethylmethylammonium alkyl moiety of the pure PAS ligand propidium. The synthesized compounds proved to effectively and selectively inhibit AChE. Moreover, compounds 16a-c and 18a,b, with a propoxy and a hexyloxy tether respectively, showed a good activity against the AChE-induced Aß aggregation. In particular, molecular modeling studies confirmed that compounds carrying the diethylaminopropoxy and the diethylaminohexyloxy side chains (compounds 16a and 19a, respectively) could suitably contact the PAS pocket of the enzyme.
Assuntos
Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Benzofenonas/farmacologia , Inibidores da Colinesterase/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Acetilcolinesterase/química , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Benzofenonas/síntese química , Benzofenonas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Método de Monte Carlo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid ß-peptide (Aß) production, aggregation, or accumulation. Translational models suggest that anti-Aß therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aß therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Aß aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/prevenção & controle , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto , Progressão da Doença , Necessidades e Demandas de Serviços de Saúde , Humanos , Pesquisa Translacional BiomédicaRESUMO
We provide the first evidence for the capability of a high-resolution positron emission tomographic (PET) imaging system in quantitatively mapping amyloid accumulation in living amyloid precursor protein transgenic (Tg) mice. After the intravenous administration of N-[11C]methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [11C]PIB for "Pittsburgh Compound-B") with high-specific radioactivity, the Tg mice exhibited high-level retention of radioactivity in amyloid-rich regions. PET investigation for Tg mice over an extended range of ages, including longitudinal assessments, demonstrated age-dependent increase in radioligand binding consistent with progressive amyloid accumulation. Reduction in amyloid levels in the hippocampus of Tg mice was also successfully monitored by multiple PET scans along the time course of anti-amyloid treatment using an antibody against amyloid beta peptide (Abeta). Moreover, PET scans with [18F]fluoroethyl-DAA1106, a radiotracer for activated glia, were conducted for these individuals parallel to amyloid imaging, revealing treatment-induced neuroinflammatory responses, the magnitude of which intimately correlated with the levels of pre-existing amyloid estimated by [11C]PIB. It is also noteworthy that the localization and abundance of [11C]PIB autoradiographic signals were closely associated with those of N-terminally truncated and modified Abeta, AbetaN3-pyroglutamate, in Alzheimer's disease (AD) and Tg mouse brains, implying that the detectability of amyloid by [11C]PIB positron emission tomography is dependent on the accumulation of specific Abeta subtypes. Our results support the usefulness of the small animal-dedicated PET system in conjunction with high-specific radioactivity probes and appropriate Tg models not only for clarifying the mechanistic properties of amyloidogenesis in mouse models but also for preclinical tests of emerging diagnostic and therapeutic approaches to AD.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Emaranhados Neurofibrilares/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Fatores Etários , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/imunologia , Compostos de Anilina , Animais , Anticorpos/uso terapêutico , Feminino , Inflamação/diagnóstico por imagem , Inflamação/patologia , Inflamação/terapia , Estudos Longitudinais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Emaranhados Neurofibrilares/patologia , TiazóisRESUMO
First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is currently treated by symptomatic drugs, the acetylcholinesterase inhibitors, based on the cholinergic hypothesis (1976). During the past decade, advances in neurobiology have conducted to the identification of new targets. Although some of these innovative approaches tend to delay onset of AD, others are still symptomatic. In this review, we present an overview of the several strategies and new classes of compounds against AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Aminoácidos/farmacologia , Aminoácidos/uso terapêutico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Colinérgicos/farmacologia , Colinérgicos/uso terapêutico , Desenho de Fármacos , Indústria Farmacêutica , Tratamento Farmacológico/tendências , Humanos , Estresse OxidativoRESUMO
The accumulation of the beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). Abeta removal from the brain by immune therapy shows promising potential for the treatment of patients with AD, although the mechanisms of the antibody action are incompletely understood. In this study we compared the biological activities of antibodies raised against various Abeta fragments for Abeta reduction in vitro and in vivo. Antibodies against Abeta enhanced the uptake of Abeta42 aggregates up to 6-fold by primary microglial cells in vitro. The kinetics of Abeta42 uptake varied considerably among antibodies. Based on the activity to mediate Abeta42 uptake by microglial cells, we identified a bioactive antibody that significantly reduced Abeta42 levels in the brains of transgenic mice with neuronal expression of an AD-related mutated amyloid precursor protein. This effect depended on the epitopes recognized by the antibody. Our data suggest that the ability to facilitate Abeta42 uptake by primary microglia cells in vitro can be used to predict the biological activity of the antibody by passive immunization in vivo. This protocol may prove useful for the rapid validation of the activity of antibodies designed to be used in immune therapy of AD.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos Bloqueadores/farmacologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Animais , Anticorpos Bloqueadores/análise , Western Blotting , Química Encefálica/efeitos dos fármacos , Células Cultivadas , Epitopos/imunologia , Humanos , Hibridomas , Imunização Passiva , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/imunologia , Microglia/metabolismo , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismoRESUMO
Alzheimer's disease is the single biggest unmet medical need in neurology. Current drugs are safe, but of limited benefit to most patients. This review discusses the scientific basis and current status of promising disease-modifying therapies in the discovery and development stages. I describe the major targets of anti-amyloid therapy and the main focus of disease modification approaches. In addition, two new potential treatment approaches supported by retrospective epidemiology are outlined.