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Traumatic brain injury (TBI) is a prevalent and debilitating condition, which often leads to the development of post-traumatic epilepsy (PTE), a condition that yet lacks preventive strategies. Biperiden, an anticholinergic drug, is a promising candidate that has shown efficacy in murine models of PTE. MicroRNAs (miRNAs), small regulatory RNAs, can help in understanding the biological basis of PTE and act as TBI- and PTE-relevant biomarkers that can be detected peripherally, as they are present in extracellular vesicles (EVs) that cross the blood-brain barrier. This study aimed to investigate miRNAs in serum EVs from patients with TBI, and their association with biperiden treatment and PTE. Blood samples of 37 TBI patients were collected 10 days after trauma and treatment initiation in a double-blind clinical trial. A total of 18 patients received biperiden, with three subjects developing PTE, and 19 received placebo, with two developing PTE. Serum EVs were characterized by size distribution and protein profiling, followed by high-throughput sequencing of the EV miRNome. Differential expression analysis revealed no significant differences in miRNA expression between TBI patients with and without PTE. Interestingly, miR-9-5p displayed decreased expression in biperiden-treated patients compared to the placebo group. This miRNA regulates genes enriched in stress response pathways, including axonogenesis and neuronal death, relevant to both PTE and TBI. These findings indicate that biperiden may alter miR-9-5p expression in serum EVs, which may play a role in TBI resolution.
Assuntos
Lesões Encefálicas Traumáticas , Regulação para Baixo , Vesículas Extracelulares , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/sangue , MicroRNAs/metabolismo , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/tratamento farmacológico , Vesículas Extracelulares/metabolismo , Masculino , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Adulto , Pessoa de Meia-Idade , Método Duplo-Cego , Epilepsia Pós-Traumática/sangue , Adulto JovemRESUMO
Introduction: Paroxetine is an older "selective" serotonin reuptake inhibitor (SSRI) that is notable for its lack of selectivity, resulting in a cholinergic adverse-effect profile, especially among older adults (65+). Methods: Paroxetine prescription rates and costs per state were ascertained from the Medicare Specialty Utilization and Payment Data. States' annual prescription rate, corrected per thousand Part D enrollees, outside 95% confidence interval were considered significantly different from the average. Results: There was a steady decrease in paroxetine prescriptions (-34.52%) and spending (-16.69%) from 2015-2020 but a consistent, five-fold state-level difference. From 2015-2020, Kentucky (194.9, 195.3, 182.7, 165.1, 143.3, 132.5) showed significantly higher prescriptions rates relative to the national average, and Hawaii (42.1, 37.9, 34.3, 31.7, 27.7, 26.6) showed significantly lower prescription rates. North Dakota was often a frequent elevated prescriber of paroxetine (2016: 170.7, 2018: 143.3), relative to the average. Neuropsychiatry and geriatric medicine frequently prescribed the largest amount of paroxetine prescriptions, relative to the number of providers in that specialty, from 2015-2020. Discussion: Despite the American Geriatrics Society prohibition against paroxetine use in the older adults and many effective treatment alternatives, paroxetine was still commonly used in this population, especially in Kentucky and North Dakota and by neuropsychiatry and geriatric medicine. These findings provide information on the specialty types and states where education and policy reform would likely have the greatest impact on improving adherence to the paroxetine prescription recommendations.
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Introducción: los pacientes con 65 años o más, por su condición fisiológica, tienen mayor probabilidad de estar expuestos a reacciones adversas a medicamentos. Algunos riesgos están asociados a la carga anticolinérgica de la medicación, y otros al perfil de seguridad de cada uno de los fármacos. Objetivo: realizar un análisis de los tratamientos farmacológicos para los pacientes ≥65 años y su posible implicancia en la clínica, por los riesgos potenciales debido a reacciones adversas. Método: se realizó un estudio descriptivo, transversal, observacional, naturalístico, del tratamiento farmacológico de los pacientes ≥65 años de la policlínica del Hospital Vilardebó, entre mayo y agosto de 2021. Se calculó la carga anticolinérgica de los tratamientos y se efectuó una comparación de dicha carga con la de una muestra de pacientes menores de 65 años. Resultados: 356 pacientes (83,0%) ≥65 años tenían un riesgo alto de tener algún efecto por su carga anticolinérgica y este riesgo fue similar a los pacientes menores de 65 años. Un total de 344 pacientes estaban en tratamiento con alguna benzodiazepina, destacándose el uso de flunitrazepam (47,6%) y clonazepam (32,6%). A 289 pacientes (67,4%) se le prescribió algún antipsicótico y nueve pacientes estaban con más de dos antipsicóticos. Dos pacientes estaban en tratamiento con imipramina y 49 pacientes recibían algún antiparkisoniano. Conclusiones: los pacientes mayores de 65 años están expuestos a riesgos altos de padecer reacciones adversas a medicamentos como consecuencia de una alta carga anticolinérgica (similar a la de la población más joven estudiada) y de una acentuada polifarmacia. Además, se deberían evitar algunas prácticas, como la prescripción de ciertos tipos de benzodiacepinas, así como minimizar el uso de imipramina y antiparkisonianos. Es necesario buscar estrategias de formación que disminuyan o minimicen este potencial riesgo que repercute adversamente en la salud de los pacientes.
Summary: Introduction: patients aged 65 years or older are at increased risk for exposure to adverse drug reactions because of their physiological status. Some risks are associated with the anticholinergic burden of medication, and others with the safety profile of each drug. Objective: to perform an analysis of pharmacological treatments for patients aged 65 years old or older and their possible clinical implications, given the potential risks of adverse drug reactions. Method: a descriptive, cross-sectional, observational, naturalistic, observational study of the pharmacological treatment of users aged 65 years old or older of the outpatient service at Vilardebó Hospital, between May and August 2021, was performed. A calculation was made of the anticholinergic burden of treatments and a comparison of this burden was made with a sample of patients under 65 years of age. Results: 356 patients (83.0%) ≥ 65 years old were at high risk of having some kind of effect from their anticholinergic burden and this risk was similar to patients younger than 65 years. A total of 344 patients were in treatment with a benzodiazepine. The prescription of flunitrazepam (47.6%) and clonazepam (32.6%) stood out. While 289 patients (67.4%) were in treatment with an antipsychotic, 9 patients were on more than 2 antipsychotics. Two patients were on imipramine and 49 patients were in treatment with some antiparkinsonian drugs. Conclusions: patients older than 65 years old are exposed to a high risk of suffering adverse drug reactions as a consequence of a high anticholinergic load (similar to that of the younger population studied) and a marked polypharmacy. In addition, some practices should be avoided, such as the prescription of certain types of benzodiazepines used in this population, as well as minimizing the use of imipramine and antiparkinsonian drugs. It is necessary to look for training strategies to minimize this potential risk that adversely affects the health of patients.
Introdução: pacientes com 65 anos ou mais, devido à sua condição fisiológica, estão mais propensos a serem expostos a reações adversas a medicamentos. Alguns riscos estão associados à carga anticolinérgica do fármaco e outros ao perfil de segurança de cada um dos medicamentos. Objetivo: realizar uma análise dos tratamentos farmacológicos para pacientes ≥ 65 anos de idade e sua possível implicação clínica, devido aos riscos potenciais decorrentes de reações adversas. Método: foi realizado um estudo descritivo, transversal, observacional, naturalístico do tratamento farmacológico de pacientes ≥ 65 anos da Policlínica Hospitalar de Vilardebó, entre maio e agosto de 2021. A carga anticolinérgica dos tratamentos foi calculada e foi feita uma comparação com a de uma amostra de pacientes com menos de 65 anos. Resultados: 356 pacientes (83,0%) ≥ 65 anos apresentaram alto risco de ter algum efeito devido à sua carga anticolinérgica e esse risco foi semelhante aos pacientes com menos de 65 anos. Um total de 344 pacientes estava em tratamento com algum benzodiazepínico, com destaque para o uso de flunitrazepam (47,6%) e clonazepam (32,6%). 289 pacientes (67,4%) receberam algum antipsicótico e 9 pacientes estavam tomando mais de 2 antipsicóticos. Dois pacientes estavam sendo tratados com imipramina e 49 estavam recebendo um antiparkisoniano. Conclusões: pacientes com mais de 65 anos estão expostos a um alto risco de sofrer reações adversas a medicamentos em decorrência de uma carga anticolinérgica elevada (semelhante à da população mais jovem estudada) e de uma polifarmácia acentuada. Além disso, algumas práticas devem ser evitadas, como a prescrição de determinados tipos de benzodiazepínicos que são utilizados nessa população, além de minimizar o uso de imipramina e antiparkinsonianos. É necessário buscar estratégias de formação que reduzam ou minimizem esse risco potencial que afeta negativamente a saúde dos pacientes.
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Humanos , Idoso , Idoso de 80 Anos ou mais , Prescrições de Medicamentos , Idoso , Segurança do Paciente , Psicotrópicos/administração & dosagemRESUMO
OBJECTIVES: Using multiple drugs with anticholinergic properties is common and might lead to cumulative anticholinergic toxicity and increased risk of cognitive impairment. Therefore, we sought to investigate the association between the Anticholinergic Cognitive Burden (ACB) Scale and cognitive performance among middle-aged and older adults. METHODS: In this cross-sectional study with 13,065 participants from the baseline visit of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), mean age was 51.7 ± 9.0 years old, 55% women, and 53% white. The ACB was calculated based on the medications in use. We investigated the association of ACB with global cognition and memory, verbal fluency (VF), and trail-making test version B (TMT-B) z-scores, using multiple linear regression models adjusted for sociodemographic and clinical variables. RESULTS: Overall, 16% of participants had an ACB score greater than 0. ACB was associated with poor cognitive performance in all tests in crude analysis. After adjustment for sociodemographic characteristics, the association remained significant for the global cognitive score, as well as the memory and the TMT-B z-scores. However, after further adjustments for clinical variables, only trend associations of ACB with poor memory (ß = - 0.02, 95% Cl = - 0.05, 0.00, p = 0.056) and the TMT-B z-scores (ß = - 0.02, 95% Cl = - 0.04, 0.00, p = 0.054) were found. In stratified analyses by age groups, ACB was associated with poor cognitive performance on the TMT-B (ß = - 0.03, 95% Cl = - 0.05, - 0.01, p = 0.005) in individuals aged less than 65 years old. CONCLUSION: Although the ACB was associated with poor executive function only among middle-aged adults in adjusted analysis, residual confounding may partly explain our results.
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Antagonistas Colinérgicos , Cognição , Adulto , Idoso , Brasil/epidemiologia , Antagonistas Colinérgicos/efeitos adversos , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Before the advent of L-DOPA, the gold standard symptomatic therapy for Parkinson's disease (PD), anticholinergic drugs (muscarinic receptor antagonists) were the preferred antiparkinsonian therapy, but their unwanted side effects associated with impaired extrastriatal cholinergic function limited their clinical utility. Since most patients treated with L-DOPA also develop unwanted side effects such as L-DOPA-induced dyskinesia (LID), better therapies are needed. Recent studies in animal models demonstrate that optogenetic and chemogenetic manipulation of striatal cholinergic interneurons (SCIN), the main source of striatal acetylcholine, modulate parkinsonism and LID, suggesting that restoring SCIN function might serve as a therapeutic option that avoids extrastriatal anticholinergics' side effects. However, it is still unclear how the altered SCIN activity in PD and LID affects the striatal circuit, whereas the mechanisms of action of anticholinergic drugs are still not fully understood. Recent animal model studies showing that SCINs undergo profound changes in their tonic discharge pattern after chronic L-DOPA administration call for a reexamination of classical views of how SCINs contribute to PD symptoms and LID. Here, we review the recent advances on the circuit implications of aberrant striatal cholinergic signaling in PD and LID in an effort to provide a comprehensive framework to understand the effects of anticholinergic drugs and with the aim of shedding light into future perspectives of cholinergic circuit-based therapies.
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Discinesia Induzida por Medicamentos , Doença de Parkinson , Animais , Antiparkinsonianos , Antagonistas Colinérgicos , Corpo Estriado , Modelos Animais de Doenças , Humanos , Levodopa , Oxidopamina , Doença de Parkinson/tratamento farmacológicoRESUMO
ABSTRACT Objective: A very small amount of Atropa belladonna (AB) can lead to serious symptoms of poisoning and can cause death in children. In this study, demographic, clinic and laboratory results of AB poisoning were evaluated. Methods: A total of 108 cases with belladonna poisoning were retrospectively evaluated. At time of admission, age, age groups, gender, signs and symptoms caused by poisoning, duration of stay in hospital, laboratory data, intensive care needs, and applied treatments were recorded. Results: Approximately 44.4% were females and 55.6% were males. While the most common symptoms were xeroderma and flushing, the most frequent findings were tachycardia and mydriasis. Eight patients complained about astasis and five of them were taken into the intensive care unit. Astasis complaint was relatively higher (p < 0.01) in the patients who needed intensive care than those who did not. Creatine kinase levels were relatively higher (p = 0.06) in the intensive care patients as compared to non-intensive care patients. Neostigmine was given to all patients. Five patients, who failed to respond to therapy, were taken into the intensive care and respond to treatment successfully with physostigmine. Conclusion: Atropa belladonna poisoning may seriously progress in the act of late diagnosis and treatment in childhood. Thus, it is crucial to realize that AB poisoning should be taken into consideration in the patients with flushing, xeroderma with mydriasis, tachycardia, tremor, abdominal pain, and fever symptoms. Patients with astasis complaints should be evaluated carefully in terms of intensive care need. Patients with a Glasgow Coma Scale lower than 12 should be observed in the intensive care.
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RESUMEN Introducción: los fármacos con potencial efecto anticolinérgico son prescritos frecuentemente en la población mayor de 65 años. Existen varias escalas para calcular la carga anticolinérgica: Anticholinergic Drug Scale, Anticholinergic Risk Scale y Anticholinergic Cognitive Burden. Objetivo: caracterizar la carga anticolinérgica en pacientes mayores de 65 años con polifarmacia que son formulados ambulatoriamente. Métodos: estudio de corte transversal, retrospectivo con información de prescripción registrada desde abril hasta septiembre de 2016. Se utilizó la base de datos transaccional de prescripción de una EPS nacional registrada en la plataforma tecnológica de un PBM (Pharmacy Benefit Management). Se analizaron los medicamentos con propiedades anticolinérgicas y carga anticolinérgica. Resultados: fueron 115.713 los pacientes formulados, con una edad media de 74 años. Los grupos terapéuticos más asociados con carga anticolinérgica moderada fueron, en un 6,5 %, dimenhidrinato, amantadina, biperideno y quetiapina. Un 13,1 % con carga anticolinérgica alta donde se encuentran el butil bromuro de hioscina y la amitriptilina. Discusión: el manejo de las patologías en los pacientes adultos mayores es compleja y se llega hasta el punto de requerir prescripción de múltiples medicamentos; por lo cual, se hace fundamental evaluar la necesidad del uso de estos, además de verificar su pertinencia y las posibles interacciones farmacológicas de alta significancia clínica, para evitar la presencia de eventos adversos. Por esto se han desarrollado escalas que permiten mejorar el resultado terapéutico especialmente en fármacos con carga anticolinérgica.
SUMMARY Background: Drugs with potential anticholinergic effect are usually prescribed to the population over 65 years. There are several scales created to calculate anticholinergic burden: Anticholinergic Drug Scale, Anticholinergic Risk Scale, and Anticholinergic Cognitive Burden. Objective: To characterize the anticholinergic burden in patients older than 65 years with polypharmacy who are prescribed in ambulatory settings. Methods: Retrospective cross-sectional study with information registered from April to September 2016. The database of prescription records of a health management organization (HMO), with national registries in the Pharmacy Benefit Management (PBM) technology platform, was used. Medicines were analyzed by its anticholinergic properties and anticholinergic burden. Results: There were 115,713 patients with a median age of 74 years. The medicines with moderate anticholinergic burden were dimenhydrinate, amantadine, biperidene and quetiapine in 6.5 %, and with high anticholinergic burden hyoscine butylbromide and amitryptiline in 13.1 %. Discussion: The medical attention of diseases of the elderly is complex and requires the prescription of multiple medications. It is important to evaluate the medicines and verify their relevance and possible pharmacological interactions, to avoid the presence of adverse events. For this reason, scales have been developed, they allow improving therapeutic results, and especially in medicines with anticholinergic burden and systems of clinical alerts that promotes correct formulation.
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Humanos , Pacientes Ambulatoriais , Polimedicação , Síndrome Anticolinérgica , IdosoRESUMO
The fucosterol has been reported numerous biological activities. In this study, the activity in vitro of the fucosterol from Sargassum horridum as potential human acetylcholinesterase inhibitor was evaluated. The structural identification was obtained by nuclear magnetic resonance (NMR) spectroscopy and based on experimental data, we combined docking and molecular dynamics simulations coupled to the molecular-mechanics-generalized-born-surface-area approach to evaluating the structural and energetic basis for the molecular recognition of fucosterol and neostigmine at the binding site of acetylcholinesterase (AChE). In addition, the Lineweaver-Burk plot showed the nature of a non-competitive inhibition. The maximum velocity (Vmax) and the constant of Michaelis-Menten (Km) estimated for fucosterol (0.006 µM) were 0.015 1/Vo (ΔA/h and 6.399 1/[ACh] mM-1, respectively. While, for neostigmine (0.14 µM), the Vmax was 0.022 1/Vo (ΔA/h) and Km of 6.726 1/[ACh] mM-1, these results showed a more effective inhibition by fucosterol respect to neostigmine. Structural analysis revealed that neostigmine reaches the AChE binding site reported elsewhere, whereas fucosterol can act as a no-competitive and competitive acetylcholinesterase inhibitor, in agree with kinetic enzymatic experiments. Binding free energy calculations revealed that fucosterol reaches the acetylcholinesterase binding site with higher affinity than neostigmine, which is according to experimental results. Whereas the per-residue decomposition free energy analysis let us identify crucial residues involved in the molecular recognition of ligands by AChE. Results corroborate the ability of theoretical methods to provide crucial information at the atomic level about energetic and structural differences in the binding interaction and affinity from fucosterol with AChE. Communicated by Ramaswamy H. Sarma.
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Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Sargassum/química , Estigmasterol/análogos & derivados , Sítios de Ligação/efeitos dos fármacos , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Estigmasterol/farmacologiaRESUMO
ABSTRACT Objective To develop a scale of anticholinergic activity drugs used in Brazil, to be applied in health care and pharmacoepidemiology research. Methods We performed a literature review on PubMed/MEDLINE® to identify previously published scales of anticholinergic drugs. This scale started with anticholinergic drugs, and those with known anticholinergic activity as per the 4th level, chemical-therapeutic subgroup, of the Anatomical Therapeutic Chemical classification. We also included drugs with high anticholinergic activity, as described in a list of potentially inappropriate medications for use in older adults, according to the 2015 American Geriatrics Society Beers Criteria. Drugs listed in at least two anticholinergic scales were added. Then we verified which drugs in the previous steps were marketed in Brazil. We assigned a score of 1, 2 and 3, based on their anticholinergic action. Results A total of 273 anticholinergic drugs were identified, of which 125 were included in the scale. We identified 45 (36.0%) drugs with a score of 3, 13 (10.4%) with a score of 2, and 67 (53.6%) with a score of 1. Drugs for the nervous and respiratory systems were the most frequent in the scale. Eight drugs were not present in previous scales. Conclusion The methodology used for development of the Brazilian anticholinergic activity scale is simple, systematized, reproducible and easy to update. The scale allows evaluating the impact of anticholinergic burden on health outcomes, and can potentially contribute to pharmacoepidemiology research, leading to more accurate measurements of anticholinergic activity.
RESUMO Objetivo Desenvolver uma escala de atividade anticolinérgica abrangendo os medicamentos utilizados no Brasil, para aplicação no cuidado em saúde e em pesquisas farmacoepidemiológicas. Métodos Realizou-se revisão da literatura no PubMed/MEDLINE®para identificação das escalas de mensuração da atividade anticolinérgica. Iniciou-se a escala com os fármacos anticolinérgicos e aqueles com atividade anticolinérgica conhecida, relacionados segundo o nível 4, subgrupo químico, na classificação da Anatomical Therapeutic Chemical . Incluíram-se os fármacos com atividade anticolinérgica alta, descritos na lista de medicamentos potencialmente inapropriados para idosos, segundo o 2015 American Geriatrics Society Beers Criteria . Adicionaram-se os medicamentos que constavam em, no mínimo, duas escalas anticolinérgicas. Em seguida, verificaram-se os medicamentos constantes nas etapas anteriores comercializados no Brasil. A magnitude da atividade anticolinérgica foi estabelecida em escores com os valores de 1, 2 e 3. Resultados Foram identificados 273 medicamentos com atividade anticolinérgica, sendo 125 incluídos na escala. Destes, 45 (36,0%) receberam pontuação 3, 13 (10,4%) tiveram pontuação 2, e 67 (53,6%) pontuação 1. A maioria dos medicamentos da escala atuava nos sistemas nervoso e respiratório. Oito fármacos não constavam em escalas prévias. Conclusão A metodologia de desenvolvimento da escala brasileira de atividade anticolinérgica é simples, sistematizada, reprodutível e de fácil atualização. A escala permite avaliar o impacto da carga anticolinérgica nos resultados em saúde e pode contribuir com as pesquisas farmacoepidemiológicas, propiciando mensurações mais exatas da atividade anticolinérgica.
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Humanos , Idoso , Antagonistas Colinérgicos/normas , Antagonistas Colinérgicos/farmacologia , Padrões de Referência , Brasil , Reprodutibilidade dos Testes , Farmacoepidemiologia , Medição de Risco , Antagonistas Colinérgicos/classificaçãoRESUMO
ABSTRACT CONTEXT: The seeds from Lupinus mutabilis Sweet, also called "chocho", are an important part of the diet in several countries in South America. Prior to consumption, processing is required to remove toxic alkaloids. These alkaloids are known to have pharmacological properties as antiarrhythmics, antimuscarinics and hypoglycemics. CASE REPORT: We report a case in which a one-year-old male initially presented with altered mental status and respiratory distress and subsequently developed symptoms of anticholinergic toxicity, after ingesting a large amount of chocho seeds. CONCLUSION: In spite of going through a difficult clinical condition, the subject evolved favorably through receiving supportive treatment. The seeds from Lupinus mutabilis provide nutritional benefits when consumed, but people need to know their risks when these seeds are consumed without proper preparation.
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Humanos , Masculino , Lactente , Lupinus/intoxicação , Ingestão de Alimentos , Síndrome Anticolinérgica/etiologia , Doenças Transmitidas por Alimentos/etiologia , Antagonistas Colinérgicos , Alcaloides/intoxicação , Síndrome Anticolinérgica/diagnóstico , Síndrome Anticolinérgica/sangue , Doenças Transmitidas por Alimentos/diagnóstico , Doenças Transmitidas por Alimentos/sangue , HipoglicemiantesRESUMO
BACKGROUND/OBJECTIVE: To determine the association between the use of anticholinergic drugs and the risk of falls with hip fracture in a population older than 60 years. METHODS: A case-control study in patients older than 60 years with a diagnosis of hip fracture. All drugs dispensed during the previous 30 days were identified. Sociodemographic, clinical, pharmacological (drugs according to the Anticholinergic Risk Scale [ARS]), and polypharmacy variables were analyzed. MEASUREMENTS: Falls with hip fracture and type of drug according to the ARS. RESULTS: A total of 300 patients with hip fracture and 600 controls were included. The mean age was 81.6 ± 8.9 years, with female predominance (71.3%). The use of drugs with moderate (odds ratio [OR]: 1.97, 95% confidence interval [CI]: 1.19-3.27) or high ARS scores (OR: 1.83, 95% CI: 1.13-2.96) increased the probability of fracture. CONCLUSIONS: There was an association between the use of drugs with anticholinergic properties and the probability of hip fracture in elderly patients and it was possible to establish the level of risk.
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Acidentes por Quedas/estatística & dados numéricos , Antagonistas Colinérgicos/efeitos adversos , Idoso Fragilizado/psicologia , Fraturas do Quadril/epidemiologia , Prescrição Inadequada , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Colômbia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Risco , Resultado do TratamentoRESUMO
Brain injuries are often associated with the later development of epilepsy. Evidence suggests that morphological and functional changes occur in the remaining neural tissue during a silent (or latent) period in which no seizures are expressed. It is believed that this silent (reorganization) period may provide a therapeutic window for modifying the natural history of disease progression. Here we provide evidence that biperiden, a muscarinic anticholinergic agent, is able to alter disease progression in an animal model of epilepsy. We observed that biperiden was capable of slowing the manifestation of the first spontaneous epileptic seizure and effectively reduced the severity and number of recurrent, spontaneous epileptic seizures during the animals' lifespan. Biomolecular (microdialysis) and electrophysiological (extracellular field recordings) studies determined that biperiden was capable of elevating the threshold of hippocampal excitability, thereby making the hippocampal glutamatergic pathways less responsive to stimuli when high concentrations of potassium were used in vivo or in vitro. Notably, there was no hindrance of long-term memory or learning (a potential problem given the amnestic nature of biperiden). We conclude that biperiden has antiepileptogenic potential and may represent an opportunity for the prevention of post-traumatic epilepsy.
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Biperideno/uso terapêutico , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Agonistas Muscarínicos/toxicidade , Antagonistas Muscarínicos/uso terapêutico , Pilocarpina/toxicidade , Potenciais de Ação/efeitos dos fármacos , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Epilepsia/patologia , Comportamento Exploratório/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/metabolismoRESUMO
BACKGROUND: Antipsychotics are essential for the treatment of schizophrenia. However, due to side effects, both continuity of treatment and patients' general health can be jeopardized. Some of these drugs, especially clozapine, have a class of side effects attributed to their antimuscarinic properties, such as dysmotility, a condition in which muscles of the digestive system become impaired. Dysmotility may also alter the speed, strength or coordination of the digestive organs, causing distention, disturbing gastrointestinal transit, leading to symptoms such as bloating, nausea, vomiting, and even malnutrition. In this study, our aim was to develop an in vivo assay capable of identifying and studying the antimuscarinic effects of antipsychotics in a zebrafish model. METHODS: We performed video recordings of in vivo 5-day postfertilization (dpf) zebrafish larvae gastrointestinal tracts and analyzed the frequency of spontaneous and regular cycles of contractions of the gut. KEY RESULTS: The assay was first validated with treatment with atropine. We showed that this antimuscarinic drug reduces peristaltic cycles. Subsequently, the larvae were treated with the antipsychotics haloperidol, risperidone, and clozapine. Neither haloperidol nor risperidone reduced gut motility, but clozapine significantly reduced the frequency of cycles of contractions (P<.0001), which confirms the existing clinical data. CONCLUSIONS & INFERENCES: We conclude that this zebrafish assay efficiently identifies anticholinergic side effects of antipsychotics, and can thus be a quick and useful way to screen for this property in new drugs.
Assuntos
Antipsicóticos/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Motilidade Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Animais , Atropina/administração & dosagem , Clozapina/administração & dosagem , Haloperidol/administração & dosagem , Larva , Antagonistas Muscarínicos/administração & dosagem , Risperidona/administração & dosagem , Peixe-ZebraRESUMO
OBJECTIVES: To evaluate the effect of a prolonged constant rate infusion (CRI) of fentanyl on the minimum alveolar concentration (MAC) of isoflurane (ISOMAC ) and to establish whether concurrent atropine administration influences ISOMAC in dogs. STUDY DESIGN: Prospective, crossover study. ANIMALS: Six healthy dogs weighing 13.0 ± 4.1 kg. METHODS: Dogs were anesthetized with isoflurane under conditions of normocapnia and normothermia. Arterial blood pressure was monitored invasively. Each dog was administered two treatments, on different occasions, in a crossover design. The dogs were administered intravenously (IV) an atropine bolus 0.02 mg kg(-1) and CRI at 0.04 mg kg(-1) hour(-1) (fentanyl-atropine treatment) or no atropine (fentanyl treatment). For each dog, baseline ISOMAC was measured in duplicate using a tail clamp technique. Subsequently, all dogs were administered a fentanyl bolus (5 µg kg(-1)) and CRI (9 µg kg(-1) hour(-1)) IV, and ISOMAC was re-determined at 120 and 300 minutes after initiation of the fentanyl CRI. RESULTS: Baseline ISOMAC values in the fentanyl and fentanyl-atropine treatments were 1.38 ± 0.16% and 1.39 ± 0.14%, respectively. Fentanyl significantly decreased the ISOMAC by 50 ± 9% and 47 ± 13% after 120 minutes and by 51 ± 14% and 50 ± 9% after 300 minutes (p < 0.001) in the fentanyl and fentanyl-atropine treatments, respectively. Compared with baseline, heart rate decreased significantly in the fentanyl treatment by 35% and 43% at 120 and 300 minutes, respectively. In the fentanyl-atropine treatment, heart rate did not change significantly over time. In both treatments, systolic arterial pressure increased from baseline after fentanyl. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, fentanyl reduced the ISOMAC by approximately 50%. The ISOMAC remained stable throughout the 300 minute CRI of fentanyl, suggesting no cumulative effect of the opioid. Atropine did not influence ISOMAC in dogs.
Assuntos
Anestésicos Inalatórios/farmacocinética , Anestésicos Intravenosos/farmacologia , Atropina/administração & dosagem , Fentanila/farmacologia , Isoflurano/farmacocinética , Alvéolos Pulmonares/metabolismo , Anestésicos Intravenosos/administração & dosagem , Animais , Estudos Cross-Over , Cães , Fentanila/administração & dosagem , Infusões Intravenosas/veterinária , Estudos Prospectivos , Alvéolos Pulmonares/efeitos dos fármacosRESUMO
BACKGROUND: Asthma is a prevalent disease characterized by chronic inflammatory changes of the airway and marked by airway hyperresponsiveness, edema, and excess mucus production. Management of the disease has focused upon reversing the early airway changes and limiting the late effects of airway remodeling. Several classes of medications are available for the effective treatment and long-term control of asthma and novel therapeutic options are in development that hold promise in improving patient outcome. METHODS: A review of updated guidelines and current literature was conducted to identify available pharmacologic treatments of asthma and determine future directions in development of novel therapeutic options. RESULTS: Inhaled corticosteroids are the most effective medications in long-term asthma control with adjunct medications such as ß2-agonists, which can provide symptomatic relief. Other classes of asthma control medications including anticholinergics, cromolyns, and leukotriene receptor modifiers can also be used to develop an effective management strategy based on asthma severity. CONCLUSION: Several classes of medications are available for the effective management of asthma. Inhaled corticosteroids play a central role in control of inflammation and several other adjuncts are available to tailor therapy to the patient's symptoms. New therapeutic options that target downstream inflammatory mediators can provide increased efficacy while limiting side effects.
Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , HumanosRESUMO
PURPOSE: To evaluate the efficacy of botulinum toxin type A injections in the detrusor muscle in patients with spinal cord injury and urinary incontinence due to detrusor overactivity and refractory to anticholinergic agents. MATERIALS AND METHODS: We prospectively evaluated 22 patients with spinal cord injuries, whose bladders were emptied by intermittent catheterization. All patients had detrusor overactivity and urinary incontinence that proved difficult to treat, despite using high doses of two different anticholinergics. The pre-treatment assessment included a complete urodynamic study and ultrasonography of the kidneys and urinary tract. A one-month follow-up was completed with urodynamic evaluation and the clinical response was evaluated through outpatient consultations and telephone contact. RESULTS: After the procedure, the maximum cystometric capacity and the bladder reflex volume increased, whereas the maximum detrusor pressure and compliance decreased. The mean duration of continence was 7 ± 7 months. In 18 patients (81.8 percent), it was necessary to administer anticholinergics to achieve continence. Five patients (22.7 percent) had indication of reinjection, and augmentation cystoplasty was indicated in 9 patients (40.9 percent). CONCLUSION: The use of botulinum toxin in the treatment of neurogenic detrusor overactivity refractory to anticholinergics is an option before more invasive treatments, such as augmentation cystoplasty, are attempted. In our study as well as in the literature, there was improvement in most urodynamic parameters. Overall, 40.9 percent of patients underwent augmentation cystoplasty and 81.8 percent of patients needed anticholinergic agents to reach urinary continence. Further studies are necessary to improve the procedure and to achieve better clinical results.
Assuntos
Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Toxinas Botulínicas Tipo A/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Fármacos Neuromusculares/uso terapêutico , Traumatismos da Medula Espinal/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária/tratamento farmacológico , Seguimentos , Injeções Intramusculares , Fatores de Tempo , Resultado do Tratamento , Bexiga Urinaria Neurogênica/tratamento farmacológicoRESUMO
Acute psychosis and confusional states are known complications of treatment with anticholinergic agents in the elderly. We report an 87-year-old female patient presenting with acute neurobehavioral abnormalities requiring hospitalization immediately after starting treatment for openangle glaucoma with the topic cycloplegic muscarinic receptor blocker tropicamide. Case-effect relationship was confirmed. The authors make a review of the literature trying to identify the clinical manifestations and risk factors for this complication.
Tratamento com drogas anticolinérgicas é uma causa conhecida de alterações agudas do estado mental em idosos. Relata-se o caso de uma paciente de 87 anos de idade com alterações comportamentais agudas, que necessita de internamento imediatamente após início de terapia para glaucoma de ângulo aberto com tropicamida, um agente cicloplégico bloqueador de receptor muscarínico. A relação causa-efeito foi confirmada depois de a droga ter sido reiniciada durante o internamento. É apresentada uma revisão da literatura delineando as manifestações clínicas mais comuns e fatores de risco para essa complicação.