RESUMO
Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).
Assuntos
Anestesia/efeitos adversos , Anestesia/psicologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Complicações Pós-Operatórias/psicologia , Terminologia como Assunto , Transtornos Cognitivos/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Delírio do Despertar/psicologia , Humanos , Incidência , Testes Neuropsicológicos , Cobertura de Condição Pré-Existente , Projetos de PesquisaRESUMO
Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100âyr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5âyr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).
Assuntos
Anestesia/efeitos adversos , Transtornos Cognitivos/classificação , Cognição/fisiologia , Complicações Pós-Operatórias/classificação , Terminologia como Assunto , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Humanos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Fatores de TempoRESUMO
Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).
Assuntos
Anestesia/efeitos adversos , Disfunção Cognitiva/etiologia , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Terminologia como Assunto , Idoso , Anestesia/métodos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Disfunção Cognitiva/diagnóstico , Técnica Delphi , Manual Diagnóstico e Estatístico de Transtornos Mentais , Humanos , Incidência , Complicações Pós-Operatórias/diagnóstico , Procedimentos Cirúrgicos Operatórios/métodos , Fatores de TempoRESUMO
Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).
Assuntos
Anestesia/efeitos adversos , Transtornos Cognitivos/classificação , Cognição , Delírio/classificação , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Terminologia como Assunto , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/psicologia , Consenso , Delírio/diagnóstico , Delírio/epidemiologia , Delírio/psicologia , Técnica Delphi , Humanos , Incidência , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines (Diagnostic and Statistical Manual for Mental Disorders, fifth edition [DSM-5] and National Institute for Aging and the Alzheimer Association [NIA-AA]) are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).
Assuntos
Anestesia/efeitos adversos , Transtornos Cognitivos/induzido quimicamente , Complicações Pós-Operatórias/induzido quimicamente , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Terminologia como Assunto , Idoso , HumanosRESUMO
BACKGROUND: More than half of the cells in the brain are glia and yet the impact of general anaesthetics on these cells is largely unexamined. We hypothesized that astroglia, which are strongly implicated in neuronal well-being and synapse formation and function, are vulnerable to adverse effects of isoflurane. METHODS: Cultured rat astrocytes were treated with 1.4% isoflurane in air or air alone for 4 h. Viability, proliferation, and cytoskeleton were assessed by colorimetric assay, immunocytochemistry, or a migration assay at the end of treatment or 2 days later. Also, primary rat cortical neurones were treated for 4 days with conditioned medium from control [astrocyte-conditioned media (ACM)], or isoflurane-exposed astrocytes (Iso-ACM) and synaptic puncta were assessed by synapsin 1 and PSD-95 immunostaining. RESULTS: By several measures, isoflurane did not kill astrocytes. Nor, based on incorporation of a thymidine analogue, did it inhibit proliferation. Isoflurane had no effect on F-actin but reduced expression of α-tubulin and glial fibrillary acidic protein both during exposure (P<0.05 and P<0.001, respectively) and 2 days later (P<0.01), but did not impair astrocyte motility. ACM increased formation of PSD-95 but not synapsin 1 positive puncta in neuronal cultures, and Iso-ACM was equally effective. CONCLUSIONS: Isoflurane decreased expression of microtubule and intermediate filament proteins in astrocytes in vitro, but did not affect their viability, proliferation, motility, and ability to support synapses.
Assuntos
Anestésicos Inalatórios/farmacologia , Astrócitos/efeitos dos fármacos , Isoflurano/farmacologia , Sinapses/efeitos dos fármacos , Animais , Astrócitos/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches.
Assuntos
Anestesia Geral/efeitos adversos , Anestésicos Gerais/efeitos adversos , Encéfalo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Publicações Periódicas como Assunto , Idoso , Idoso de 80 Anos ou mais , Animais , Áustria , Transtornos Cognitivos/induzido quimicamente , Humanos , Lactente , Reino UnidoRESUMO
Post-operative cognitive dysfunction (POCD) is a decline in cognitive function from pre-operative levels, which has been frequently described after cardiac surgery. The purpose of this study was to examine the variability in the measurement and definitions for POCD using the framework of a 1995 Consensus Statement on measurement of POCD. Electronic medical literature databases were searched for the intersection of the search terms 'thoracic surgery' and 'cognition, dementia, and neuropsychological test.' Abstracts were reviewed independently by two reviewers. English articles with >50 participants published since 1995 that performed pre-operative and post-operative psychometric testing in patients undergoing cardiac surgery were reviewed. Data relevant to the measurement and definition of POCD were abstracted and compared with the recommendations of the Consensus Statement. Sixty-two studies of POCD in patients undergoing cardiac surgery were identified. Of these studies, the recommended neuropsychological tests were carried out in less than half of the studies. The cognitive domains measured most frequently were attention (n=56; 93%) and memory (n=57; 95%); motor skills were measured less frequently (n=36; 60%). Additionally, less than half of the studies examined anxiety and depression, performed neurological exam, or accounted for learning. Four definitions of POCD emerged: per cent decline (n=15), standard deviation decline (n=14), factor analysis (n=13), and analysis of performance on individual tests (n=12). There is marked variability in the measurement and definition of POCD. This heterogeneity may impede progress by reducing the ability to compare studies on the causes and treatment of POCD.
Assuntos
Procedimentos Cirúrgicos Cardíacos/psicologia , Transtornos Cognitivos/diagnóstico , Testes Neuropsicológicos , Complicações Pós-Operatórias/diagnóstico , Idoso , Transtornos Cognitivos/etiologia , Conferências de Consenso como Assunto , Ponte de Artéria Coronária/psicologia , Fidelidade a Diretrizes , Humanos , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Guias de Prática Clínica como Assunto , Padrões de ReferênciaRESUMO
The purpose of this analysis was to determine if postoperative delirium was associated with early postoperative cognitive dysfunction (at 7 days) and long-term postoperative cognitive dysfunction (at 3 months). The International Study of Postoperative Cognitive Dysfunction recruited 1218 subjects >or= 60 years old undergoing elective, non-cardiac surgery. Postoperatively, subjects were evaluated for delirium using the criteria of the Diagnostic and Statistical Manual. Subjects underwent neuropsychological testing pre-operatively and postoperatively at 7 days (n = 1018) and 3 months (n = 946). Postoperative cognitive dysfunction was defined as a composite Z-score > 2 across tests or at least two individual test Z-scores > 2. Subjects with delirium were significantly less likely to participate in postoperative testing. Delirium was associated with an increased incidence of early postoperative cognitive dysfunction (adjusted risk ratio 1.6, 95% CI 1.1-2.1), but not long-term postoperative cognitive dysfunction (adjusted risk ratio 1.3, 95% CI 0.6-2.4). Delirium was associated with early postoperative cognitive dysfunction, but the relationship of delirium to long-term postoperative cognitive dysfunction remains unclear.
Assuntos
Transtornos Cognitivos/etiologia , Delírio/etiologia , Complicações Pós-Operatórias , Idoso , Transtornos Cognitivos/epidemiologia , Delírio/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Complicações Pós-Operatórias/epidemiologia , Período Pós-Operatório , Prognóstico , Medição de RiscoRESUMO
The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.
Assuntos
Acetilcolina/metabolismo , Cognição/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Piperazinas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Frequência Cardíaca/efeitos dos fármacos , Masculino , Camundongos , Microdiálise , Estrutura Molecular , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M2 , Saimiri , Escopolamina/farmacologia , Fatores de TempoRESUMO
The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
Assuntos
Compostos de Benzilideno/química , Dioxóis/química , Dioxóis/farmacologia , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Sulfonas/química , Sulfonas/farmacologia , Acetilcolina/análise , Acetilcolina/metabolismo , Administração Oral , Animais , Área Sob a Curva , Compostos de Benzilideno/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Humanos , Macaca fascicularis , Microdiálise , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Antagonistas Muscarínicos/sangue , Ratos , Receptor Muscarínico M2 , Relação Estrutura-AtividadeRESUMO
The long-term response to neurotropic drugs depends on drug-induced neuroplasticity and underlying changes in gene expression. However, alterations in neuronal gene expression can be observed even following single injection. To investigate the extent of these changes, gene expression in the medial striatum and lumbar part of the spinal cord was monitored by cDNA microarray following single injection of morphine. Using robust and resistant linear regression (MM-estimator) with simultaneous prediction confidence intervals, we detected differentially expressed genes. By combining the results with cluster analysis, we have found that a single morphine injection alters expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins. RNAs for these proteins were mostly downregulated both in the medial striatum and in lumbar part of the spinal cord. These transitory changes were prevented by coadministration of the opioid antagonist naloxone. Data indicate that microarray analysis by itself is useful in describing the effect of well-known substances on the nervous system and provides sufficient information to propose a potentially novel pathway mediating its activity.
Assuntos
Analgésicos Opioides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Morfina/farmacologia , Animais , Encéfalo/metabolismo , Corpo Estriado/metabolismo , DNA Complementar/genética , Masculino , Camundongos , Camundongos Endogâmicos , NADH Desidrogenase/genética , Análise de Sequência com Séries de Oligonucleotídeos , RNA/genética , RNA/metabolismo , Estatística como AssuntoRESUMO
Current treatment of Alzheimer's Disease (AD) requires acetylcholinesterase inhibition to increase acetylcholine (ACh) concentrations in the synaptic cleft. Another mechanism by which ACh levels can be increased is blockade of presynaptic M2 muscarinic autoreceptors that regulate ACh release. An antagonist designed for this purpose must be highly selective for M2 receptors to avoid blocking postsynaptic M1 receptors, which mediate the cognitive effects of ACh. Structure-activity studies of substituted methylpiperadines led to the synthesis of 4-[4-[1(S)-[4-[(1,3-benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-1-piperazinyl]-4-methyl-1-(propylsulfonyl)piperidine. This compound, SCH 72788, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 0.5 nM, and its affinity at M1 receptors is 84-fold lower. SCH 72788 is a functional M2 antagonist that competitively inhibits the ability of the agonist oxotremorine-M to inhibit adenylyl cyclase activity. In an in vivo microdialysis paradigm, SCH 72788 increases ACh release from the striatum of conscious rats. The compound is also active in a rodent model of cognition, the young rat passive avoidance response paradigm. The effects of SCH 72788 suggest that M2 receptor antagonists may be useful for treating the cognitive decline observed in AD and other dementias.
Assuntos
Acetilcolina/metabolismo , Antagonistas Muscarínicos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Receptores Muscarínicos/metabolismo , Sinapses/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Humanos , Cinética , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Estrutura Molecular , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/uso terapêutico , Oxotremorina/farmacologia , Piperazinas/síntese química , Piperazinas/metabolismo , Piperazinas/uso terapêutico , Piperidinas/síntese química , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Ensaio Radioligante , Ratos , Receptor Muscarínico M2 , Transdução de Sinais/fisiologia , Sinapses/metabolismoRESUMO
AIMS: To measure the prevalence and independent associations of heavy and problematic use of alcohol and recreational drugs among a household-based sample of urban MSM (men who have sex with men). DESIGN: Cross-sectional survey. PARTICIPANTS: Men who identified as being gay or bisexual or who reported sex with another man in the prior 5 years were included in this analysis (n = 2172). SETTING: A probability telephone sample of MSM was taken within Zip Codes of four large American cities (Chicago, Los Angeles, New York and San Francisco) estimated to have total concentrations of at least 4% of all households with one resident MSM. MEASUREMENTS: Standard measures of alcohol use, problems associated with alcohol use, and recreational drug use were administered by trained telephone interviewers. FINDINGS: Both recreational drug (52%) and alcohol use (85%) were highly prevalent among urban MSM, while current levels of multiple drug use (18%), three or more alcohol-related problems (12%), frequent drug use (19%) and heavy-frequent alcohol use (8%) were not uncommon. The associations of heavy and/or problematic substance use are complex, with independent multivariate associations found at the levels of demographics, adverse early life circumstances, current mental health status, social and sexual practices and connection to gay male culture. CONCLUSIONS: The complex pattern of associations with heavy and/or problematic substance use among urban MSM suggests that heavy and/or problematic substance use is grounded in multiple levels: the individual, the interpersonal and the socio-cultural.
Assuntos
Homossexualidade Masculina/psicologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Estudos Transversais , Soropositividade para HIV/epidemiologia , Soropositividade para HIV/psicologia , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Identificação Social , Apoio Social , Estatística como Assunto , Transtornos Relacionados ao Uso de Substâncias/psicologia , Estados Unidos/epidemiologiaRESUMO
Identification of a number of highly potent M2 receptor antagonists with >100-fold selectivity against the M1 and M3 receptor subtypes is described. In the rat microdialysis assay, this series of compounds showed pronounced enhancement of brain acetylcholine release after oral administration.
Assuntos
Antagonistas Muscarínicos/síntese química , Piperidinas/síntese química , Receptores Muscarínicos/fisiologia , Acetilcolina/metabolismo , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Desenho de Fármacos , Microdiálise , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Ratos , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptores Muscarínicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.
Assuntos
Derivados de Benzeno/síntese química , Antagonistas Muscarínicos/síntese química , Receptores Muscarínicos/efeitos dos fármacos , Acetilcolina/metabolismo , Administração Oral , Alcaloides/química , Alcaloides/farmacologia , Animais , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dibenzazepinas/química , Dibenzazepinas/farmacologia , Desenho de Fármacos , Furanos , Humanos , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Naftalenos , Piperidinas , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor Muscarínico M2 , Receptores Muscarínicos/fisiologia , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Piperidine analogues of our previously described piperazine muscarinic antagonists are described. Piperidine analogues show a distinct structure-activity relationship (SAR) that differs from comparable piperazines. Compounds with high selectivity and improved potency for the M2 receptor have been identified. The lead compound, 12b, increases acetylcholine release in vivo. Compounds of this class may be useful for the treatment of cognitive disorders such as Alzheimer's disease (AD).
Assuntos
Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores Muscarínicos/metabolismo , Acetilcolina/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Estrutura Molecular , Antagonistas Muscarínicos/química , Piperidinas/química , Ratos , Receptor Muscarínico M2 , Relação Estrutura-AtividadeRESUMO
This analysis was undertaken to identify (a) the level of HIV sexual risk behaviors of men who drop out of treatment and (b) baseline variables associated with later treatment dropout. A cross-sectional sample of 340 gay/bisexual men were recruited from an outpatient substance abuse treatment facility in San Francisco. We compared participants who completed less than 15 visits with participants who graduated from the program. Men who dropped out were more likely than treatment graduates to report injection drug use, social problems related to substance use, self-blaming coping strategies, and more recent substance use prior to entering treatment and less likely to have a college degree, report using sex for tension relief, and have previously attended Alcoholics Anonymous or Narcotics Anonymous. Given the strong link between the substance abuse and HIV epidemics, substance abuse treatment agencies have been forced into addressing the issues of HIV sexual risk taking with their clients. Strategies toward reducing substance use relapse and HIV risk reduction are offered.
Assuntos
Bissexualidade , Infecções por HIV/epidemiologia , Homossexualidade Masculina , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Recusa do Paciente ao Tratamento , Adolescente , Adulto , Estudos Transversais , Demografia , Humanos , Masculino , Análise Multivariada , Fatores de RiscoRESUMO
Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.
Assuntos
Compostos de Benzilideno/metabolismo , Compostos de Benzilideno/farmacocinética , Receptores Muscarínicos/metabolismo , Acetilcolina/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Compostos de Benzilideno/síntese química , Encéfalo/metabolismo , Agonistas Colinérgicos/síntese química , Agonistas Colinérgicos/metabolismo , Agonistas Colinérgicos/farmacocinética , Cognição/efeitos dos fármacos , Estabilidade de Medicamentos , Humanos , Memória/efeitos dos fármacos , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacocinética , Ligação Proteica , Ratos , Receptor Muscarínico M2 , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To evaluate the effects of safe sex intervention at a substance use disorder treatment agency designed to serve gay men. METHOD: Of all eligible men, 456 (78%) were recruited as they entered treatment for a substance use disorder. This cohort was followed for five waves of data collection, each wave measuring the previous 90 days. Assigned to the experimental condition (treatment for substance use disorder plus a safe sex intervention) were 82 men; 65 were assigned to the regular substance use disorder treatment. RESULTS: Although levels of risk within each wave were never significantly different between the two treatment groups, reductions in unprotected anal intercourse (UAI) with a nonmonogamous partner for both groups from the baseline Wave-1 levels were uniformly significant (all p's < .05). Such high-risk sex in the year-long follow-up period was correlated with UAI reported at intake, enjoyment of UAI, relative youth, heavier concurrent use of alcohol or amphetamines and greater numbers of sexual partners. CONCLUSIONS: We conclude that: (1) substantial HIV risk reductions can occur after initiation of treatment for substance use disorder among gay men; (2) risk reductions begin soon after treatment begins; (3) lapses to unsafe sex are common during treatment; (4) continued UAI is most likely among those men who are riskier at intake, who continue to be more sexually active and who are more likely to combine substance use and sexual behavior; (5) AIDS prevention activities conducted at treatment agencies cannot reach all high-risk substance-using gay men.