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1.
BMC Neurol ; 20(1): 183, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404068

RESUMO

BACKGROUND: Pisa syndrome (PS) is characterized by an abnormally sustained posture, with flexion of the body and head to one side and slight rotation of the trunk. Although PS most commonly arises as an adverse effect of antipsychotic drugs, choline-esterase inhibitors (ChEIs) are also sometimes known to induce PS. Despite the fact that the precise mechanism remains unclear, cholinergic-dopaminergic imbalance has been considered as a possible pathophysiologic mechanism underlying the genesis of PS. CASE PRESENTATION: We hereby report the case of a 60-year-old woman with Alzheimer's disease who presented with the signs of PS after her treatment was switched to galantamine, a type of ChEI, even though she had received donepezil, another type of ChEI, for 5 years without any complications. To the best of our knowledge, this is the first report of PS associated with treatment switch from one to another type of ChEI. Galantamine, but not other ChEIs, can enhance striatal dopamine release through allosteric modulation of the nicotinic acetylcholine receptor, and has weaker muscarinic effects than donepezil. Therefore, we propose two novel hypotheses to explain the development of PS, as follows; galantamine, which enhances dopamine release, can induce imbalance of dopamine levels in the striatum of patients with dementia, resulting in PS, and the weaker muscarinic effects of the drug could be one of the factors predisposing to the development of PS. CONCLUSION: The present case suggests that treatment with galantamine is associated with a higher risk of development of PS than that with other ChEIs, such as donepezil, despite the pharmacological profile of galantamine as a dopamine modulator. Also, this report provides novel insight into another plausible mechanism underlying the development of PS, besides cholinergic-dopaminergic imbalance, namely, dopamine imbalance in the striatum with muscarinic-nicotinic imbalance.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/efeitos adversos , Galantamina/efeitos adversos , Discinesia Tardia/induzido quimicamente , Donepezila/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade
2.
Anesthesiology ; 132(6): 1371-1381, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32282427

RESUMO

BACKGROUND: Five percent of adult patients undergoing noncardiac inpatient surgery experience a major pulmonary complication. The authors hypothesized that the choice of neuromuscular blockade reversal (neostigmine vs. sugammadex) may be associated with a lower incidence of major pulmonary complications. METHODS: Twelve U.S. Multicenter Perioperative Outcomes Group hospitals were included in a multicenter observational matched-cohort study of surgical cases between January 2014 and August 2018. Adult patients undergoing elective inpatient noncardiac surgical procedures with general anesthesia and endotracheal intubation receiving a nondepolarizing neuromuscular blockade agent and reversal were included. Exact matching criteria included institution, sex, age, comorbidities, obesity, surgical procedure type, and neuromuscular blockade agent (rocuronium vs. vecuronium). Other preoperative and intraoperative factors were compared and adjusted in the case of residual imbalance. The composite primary outcome was major postoperative pulmonary complications, defined as pneumonia, respiratory failure, or other pulmonary complications (including pneumonitis; pulmonary congestion; iatrogenic pulmonary embolism, infarction, or pneumothorax). Secondary outcomes focused on the components of pneumonia and respiratory failure. RESULTS: Of 30,026 patients receiving sugammadex, 22,856 were matched to 22,856 patients receiving neostigmine. Out of 45,712 patients studied, 1,892 (4.1%) were diagnosed with the composite primary outcome (3.5% sugammadex vs. 4.8% neostigmine). A total of 796 (1.7%) patients had pneumonia (1.3% vs. 2.2%), and 582 (1.3%) respiratory failure (0.8% vs. 1.7%). In multivariable analysis, sugammadex administration was associated with a 30% reduced risk of pulmonary complications (adjusted odds ratio, 0.70; 95% CI, 0.63 to 0.77), 47% reduced risk of pneumonia (adjusted odds ratio, 0.53; 95% CI, 0.44 to 0.62), and 55% reduced risk of respiratory failure (adjusted odds ratio, 0.45; 95% CI, 0.37 to 0.56), compared to neostigmine. CONCLUSIONS: Among a generalizable cohort of adult patients undergoing inpatient surgery at U.S. hospitals, the use of sugammadex was associated with a clinically and statistically significant lower incidence of major pulmonary complications.


Assuntos
Neostigmina/efeitos adversos , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Complicações Pós-Operatórias/induzido quimicamente , Transtornos Respiratórios/induzido quimicamente , Sugammadex/efeitos adversos , Inibidores da Colinesterase/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Medicine (Baltimore) ; 99(11): e19443, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176074

RESUMO

INTRODUCTION: Alzheimer disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction, which is mainly manifested as memory impairment and a reduced ability to self-care, often accompanied by neuropsychiatric and behavioral disorders. Donepezil is the second drug to be approved by the US FDA for the treatment of AD. Of the five FDA-approved drugs for AD treatment, donepezil is currently the most widely used. Here, we report an extrapyramidal adverse reaction to donepezil in an elderly patient with AD. PATIENT CONCERNS: An 87-year-old woman presented with a 1-year history of forgetfulness that was aggravated since the past 2 months. She had a long-term history of multiple major conditions, including hypertension, diabetes, osteoporosis, and arterial plaques. Brain imaging showed age-related changes, and her Mini Mental State Examination score was 20. Other tests revealed no abnormalities apart from multiple thyroid nodules on ultrasonography. DIAGNOSIS: She was diagnosed with AD, hypertension, type 2 diabetes mellitus, diabetic neuropathy, osteoporosis, carotid and lower-extremity arterial plaques, thyroid nodules. INTERVENTIONS: She was treated with donepezil (5 mg/day), amlodipine besylate (5 mg/day), glimepiride (4 mg/day), methylcobalamin (1.5 mg/day), calcium carbonate D3 (600 mg/day), simvastatin (20 mg/day) and enteric-coated aspirin (100 mg/day). OUTCOMES: Four days later, she experienced fatigue, panic, sweating, and one episode of vomiting. On the 5th day, she developed increased muscle tension, speech difficulty, and involuntary tremors. Imaging and blood tests revealed no obvious abnormality, and the patient was not receiving psychotropic drugs. An extrapyramidal adverse reaction to donepezil was considered, and the drug was discontinued, after which the symptoms gradually disappeared. CONCLUSION: Serious adverse reactions to donepezil can occur in elderly patients, who typically require multiple medications for a variety of comorbidities. In particular, extrapyramidal reactions have occurred when donepezil is administered in combination with psychotropic drugs. However, in our patient, an extrapyramidal adverse reaction occurred in the absence of psychotropic drugs. Thus, clinicians must be aware of inter-individual differences in drug actions and possible serious adverse reactions, and carefully monitor these patients to ensure the timely detection of adverse events and their safe treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/efeitos adversos , Donepezila/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Idoso de 80 Anos ou mais , Feminino , Humanos
4.
PLoS One ; 15(2): e0227820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32032361

RESUMO

Cognitive impairment is a common complication observed after a stroke. Currently there are no definitively proven pharmacologic therapies for recovery from post-stroke cognitive impairment and vascular dementia. In this meta-analysis, we evaluated the efficacy and safety of cholinesterase inhibitors in their improvement of cognition in patients with post-stroke cognitive impairment and vascular dementia. We conducted a meta-analysis using seven eligible studies from 305 published articles. We investigated the differences in Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, before and after cholinergic augmentation in patients with post-stroke cognitive impairment and vascular dementia. MMSE and ADAS-cog scores were also compared during the subsequent follow-up periods. MMSE score of patients with post-stroke cognitive impairment was increased after cholinergic augmentation throughout the 24 weeks with mean differences [MD] of 3.000, 1.732, 1.578 1.516, and 1.222, at 4, 4-8, 8-12, 12-18, and 18-24 weeks, respectively. In addition, ADAS-cog scores decreased at 6, 12, 18, and 24 weeks by pharmaceutical augmentation, but not with placebo with mean differences [MD] of -2.333, -2.913, -2.767, -2.416, and -1.859, respectively. This meta-analysis shows that acetylcholinesterase inhibitors maintain a stable pattern of improved cognitive function in patients with post stroke cognitive impairment and vascular dementia without the increased risk of side effects.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Demência Vascular/tratamento farmacológico , Demência Vascular/etiologia , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/farmacologia , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade
6.
Expert Opin Drug Saf ; 19(2): 147-157, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31976781

RESUMO

Introduction: Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders with a prevalence in the US of about 5.7 million in 2018. With the disease burden projected to increase dramatically in the coming years, it is imperative to review the current available treatment regimens for their safety and utility. The cholinesterase inhibitors (ChEIs) have continued to play a pivotal role in managing the symptoms and possibly slowing the rate of progression of AD since 1993. Owing to their being a mainstay in the treatment of AD, the safety and efficacy of prescribing these drugs needs to be reviewed often, especially with the approval of new formulations and doses.Areas covered: The three ChEIs currently approved by the FDA are donepezil, rivastigmine and galantamine. This article will review the safety and tolerability of these ChEIs and analyze the potential disease modifying properties of these drugs. The authors have reviewed all recent literature including review articles, meta-analyzes, clinical trials and more.Expert opinion: These ChEIs differ subtly in their mechanisms of action, in their tolerability and safety and FDA-approved indications. All are considered first-line, symptomatic treatments of the various phases of AD and may even have potentially disease-modifying effects.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/administração & dosagem , Doença de Alzheimer/fisiopatologia , Animais , Inibidores da Colinesterase/efeitos adversos , Donepezila/administração & dosagem , Donepezila/efeitos adversos , Galantamina/administração & dosagem , Galantamina/efeitos adversos , Humanos , Rivastigmina/administração & dosagem , Rivastigmina/efeitos adversos
7.
Toxicol Appl Pharmacol ; 389: 114879, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31931016

RESUMO

In a previous work we showed that the organophosphate pesticide (OP) chlorpyrifos (CPF) reduces the protective chemoreflex and baroreflex responses in rats. However, whether the antidotes atropine (ATR) and pralidoxime (2-PAM) are capable of restoring these reflex functions remains unexplored. Rats were poisoned with CPF (30 mg.kg-1, i.p.) and one hour after the intoxication, ATR (10 mg.kg-1, i.p.) and 2-PAM (40 mg.kg-1, i.p.) were administrated separately or in combination. Cardiorespiratory parameters were recorded in awake rats 24 h after CPF. Systolic blood pressure (SBP) and heart rate (HR) variability and spontaneous baroreflex sensitivity (sBRS) were derived from undisturbed recordings (30 min), while chemoreflex was assessed through potassium cyanide (KCN) i.v. injections (10, 20, 40, 80 µg/rat). CPF poisoning increased SBP variability and low frequency/high frequency (LF/HF) ratio of the HR variability spectrum, indicating autonomic imbalance with increased cardiac sympathetic tone. sBRS was not changed. Treatment with 2-PAM restored SBP variability, whilst both antidotes increased LF/HF ratio. CPF poisoning reduced the hypertensive, bradycardic and tachypneic chemoreflex responses. Chemoreflex-induced hypertensive response was restored by 2-PAM treatment, while ATR recovered the bradycardic response. Both antidotes restored the chemoreflex tachypneic response. Our data show distinct effects of ATR and 2-PAM on cardiorespiratory parameters affected by OP poisoning. While 2-PAM rescued the chemoreflex hypertensive response, ATR reversed chemoreflex bradycardic dysfunction. Although 2-PAM clinical use is questioned in some countries, our data indicate that summation of effects of both antidotes appears beneficial on the cardiorespiratory system and peripheral chemoreflex function.


Assuntos
Antídotos/farmacologia , Atropina/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Clorpirifos/efeitos adversos , Intoxicação por Organofosfatos/tratamento farmacológico , Compostos de Pralidoxima/farmacologia , Sistema Respiratório/efeitos dos fármacos , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/tratamento farmacológico , Inibidores da Colinesterase/efeitos adversos , Frequência Cardíaca/efeitos dos fármacos , Inseticidas/efeitos adversos , Masculino , Ratos , Ratos Wistar
8.
Br J Anaesth ; 124(2): 154-163, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791621

RESUMO

BACKGROUND: Although cases of anaphylaxis caused by sugammadex have been reported, its incidence remains uncertain. Conversely, no studies have evaluated the incidence of anaphylaxis to neostigmine. METHODS: This was a retrospective multicentre observational study of patients who underwent surgery under general anaesthesia between 2012 and 2016 to compare the incidence of anaphylaxis with sugammadex with that of neostigmine at four tertiary hospitals in Japan. To ensure the quality of diagnosis, only cases with a clinical history suggestive of anaphylaxis, along with positive results from in vitro or in vivo testing, were assessed. RESULTS: From a total of 49 532 patients who received general anaesthesia included in this study, 18 cases of anaphylaxis were reported, of which six were attributable to sugammadex and none to neostigmine. There were no fatalities attributable to anaphylaxis. The incidence of anaphylaxis caused by all drugs or by sugammadex was calculated as 0.036% (95% confidence interval [CI]: 0.022-0.057%) and 0.02% (of the number of sugammadex cases) (95% CI: 0.007-0.044%), respectively. CONCLUSIONS: The results suggest that neostigmine might be safer than sugammadex when assessing only the incidence of anaphylaxis. We believe that there is room for reconsideration of the choice of reversal agent for neuromuscular blocking agents by all anaesthetists. CLINICAL TRIAL REGISTRATION: UMIN000022365; UMIN000033561.


Assuntos
Anafilaxia/induzido quimicamente , Inibidores da Colinesterase/efeitos adversos , Neostigmina/efeitos adversos , Sugammadex/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Humanos , Incidência , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
9.
Anesth Analg ; 130(3): 685-695, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-30896593

RESUMO

BACKGROUND: The anticholinesterase neostigmine and the muscarinic inhibitor glycopyrrolate are frequently coadministered for the reversal of neuromuscular blockade. This practice can precipitate severe bradycardia or tachycardia, but whether it affects the incidence of cardiovascular complications remains unclear. We hypothesized that anticholinesterase reversal with neostigmine and glycopyrrolate versus no anticholinesterase reversal increases the risk of postoperative cardiovascular complications among adult patients undergoing noncardiac surgery with general anesthesia. METHODS: We conducted a prespecified retrospective analysis of hospital registry data from a major health care network for patients undergoing surgery with general anesthesia from January 2007 to December 2015. The primary outcome was a composite of cardiac dysrhythmia, acute heart failure, transient ischemic attack, ischemic stroke, and acute myocardial infarction within 30 days after surgery. We performed sensitivity analyses in subgroups and propensity score adjustment and explored the association between exposure and outcome in subgroups of patients with high risk of cardiovascular complications. RESULTS: Of the 98,147 cases receiving neuromuscular blockade, 73,181 (74.6%) received neostigmine and glycopyrrolate, while 24,966 (25.4%) did not. A total of 5612 patients (7.7%) in the anticholinesterase reversal group and 1651 (6.6%) in the control group (P < .001) experienced the primary outcome. After adjustment for clinical covariates, neostigmine and glycopyrrolate exposure was significantly associated in a dose-dependent fashion (P for trend <.001, respectively) with tachycardia (adjusted odds ratio = 2.1 [95% CI, 1.97-2.23]; P < .001) and bradycardia (adjusted odds ratio = 2.84 [95% CI, 2.49-3.24]; P < .001) but not with postoperative cardiovascular complications (adjusted odds ratio = 1.03 [95% CI, 0.97-1.1]; P = .33). We identified a significant effect modification of anticholinesterase reversal by high age, high-risk surgery, and history of atrial fibrillation (P for interaction = .002, .001, and .02, respectively). By using linear combinations of main effect and exposure-risk interaction terms, we detected significant associations between anticholinesterase reversal and cardiovascular complications toward a higher vulnerability in these patient subgroups. CONCLUSIONS: Neuromuscular blockade reversal with neostigmine and glycopyrrolate was associated with an increased incidence of intraoperative tachycardia and bradycardia but not with 30-day postoperative cardiovascular complications. Exploratory analyses suggest that a high postoperative cardiovascular complication risk profile may modify the effects of anticholinesterase reversal toward clinical relevance.


Assuntos
Anestesia Geral/efeitos adversos , Bradicardia/induzido quimicamente , Inibidores da Colinesterase/efeitos adversos , Glicopirrolato/efeitos adversos , Frequência Cardíaca/efeitos dos fármacos , Antagonistas Muscarínicos/efeitos adversos , Neostigmina/efeitos adversos , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Taquicardia/induzido quimicamente , Adulto , Idoso , Boston/epidemiologia , Bradicardia/diagnóstico , Bradicardia/epidemiologia , Bradicardia/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taquicardia/diagnóstico , Taquicardia/epidemiologia , Taquicardia/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
10.
J Enzyme Inhib Med Chem ; 35(1): 118-128, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31694418

RESUMO

A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 µM for eeAChE; IC50 = 0.16 µM for hAChE), and it was also the best inhibitor to AChE-induced Aß aggregation (29.02% at 100 µM) and an efficient inhibitor to self-induced Aß aggregation (30.67% at 25 µM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Quinolonas/química , Tiocarbamatos/química , Animais , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Desenho de Fármacos , Feminino , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos
11.
Psiquiatr. biol. (Internet) ; 26(3): 99-104, sept.-dic. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-191660

RESUMO

OBJETIVOS: Evaluar si los inhibidores de la colinesterasa pueden inducir manía, y determinar si este efecto puede estar relacionado con estados u otras características previas de los pacientes. MÉTODO: Se realizó una revisión sistemática, incluyendo artículos publicados en ISI Web of Knowledge y PubMed, desde enero de 1990 a marzo de 2018, siguiendo criterios PRISMA. RESULTADOS: De 326 estudios identificados, se incluyeron en la revisión 16. En los casos comunicados hay una correlación entre la introducción de un inhibidor de la colinesterasa y la aparición de un episodio maníaco/hipomaníaco. El riesgo parece ser mayor si el paciente tiene antecedentes de trastorno afectivo y si está tomando medicación antidepresiva. CONCLUSIONES: Los inhibidores de la colinesterasa pueden inducir manía en algunos pacientes. Más estudios son necesarios para una mejor comprensión de este fenómeno; se deben tomar precauciones al prescribir estos fármacos en pacientes de riesgo


AIMS: To evaluate if cholinesterase inhibitors can induce mania, and if so to determine if this effect could be related to pre-existing conditions and other patient characteristics. METHODS: A systematic review was conducted that included articles published in PubMed and ISI Web of Knowledge from January 1990 to March 2018, following PRISMA guidelines. RESULTS: From a total of 326 studies found, 16 were included in the review. In the reported cases, there was a correlation between the introduction of a cholinesterase inhibitor and the development of a manic/ hypomanic episode. The risk appears to be higher if the patient had a history of affective disorder and if he/she was taking antidepressant medication. CONCLUSIONS: Cholinesterase inhibitors may induce mania in some patients. Further studies are needed for a better understanding of this phenomenon. Care should be taken when prescribing these drugs in specific patients


Assuntos
Masculino , Humanos , Feminino , Inibidores da Colinesterase/efeitos adversos , Transtorno Bipolar/induzido quimicamente , Donepezila/efeitos adversos , Galantamina/efeitos adversos , Rivastigmina/efeitos adversos , Fatores de Risco
12.
Biomarkers ; 24(8): 771-775, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31642715

RESUMO

Background: Farmers and their workers are exposed to a wide variety of pesticides. The use of pesticides has been documented to lead to several adverse health effects. Inhibition of cholinesterase, primarily butyrylcholinesterase is a good indicator of occupational exposure to organophosphates and carbamates.Objective: This case-control study aims to study the risks associated with pesticide exposure among farmers and agricultural workers in the Souss Massa region by analyzing variations in the response of a pesticides exposure biomarker: Serum Cholinesterase Activity (butyrylcholinesterase (BChE)).Materials and methods: This was a prospective study conducted on 133 participants (71 farmers and 62 non-farmers). A structured questionnaire was applied collecting socio-demographic information and determining knowledge and work practices in relation to pesticide use. The activity of Serum cholinesterase was measured by the butyrulthiocholine method a spectrophotometric assay.Results: The mean age of the participants was 42.5 ± 10.66 years. The study demonstrated significantly lower BChE activity, respectively, in the plasma of farmers exposed to pesticides, compared to the control group (p < 0.05). The measured mean level of BChE activity was (7304.80 ± 1939.99 U/L) and (9746.42 ± 1699.85 U/L) in the farmers and the control group (non-farmers), respectively. In addition, a high proportion of farmers reported that empty containers are burned in the open (74.6%) for waste disposal. A proportion (11.3%) of farmers also reported that empty container waste is spilled on the farm.Conclusions: The decrease in BChE indicates a serious public health problem among farmers who use organophosphate pesticides. This study suggests that regular monitoring for blood cholinesterase and effective interventions to reduce pesticide exposure to prevent health effects should be provided to farmers.


Assuntos
Biomarcadores/sangue , Butirilcolinesterase/sangue , Fazendeiros , Exposição Ocupacional/efeitos adversos , Adulto , Estudos de Casos e Controles , Inibidores da Colinesterase/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Organofosfatos/efeitos adversos , Praguicidas/efeitos adversos , Estudos Prospectivos
13.
JAMA ; 322(16): 1589-1599, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31638686

RESUMO

Importance: Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million. Observations: Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the United States, Alzheimer disease, one cause of dementia, affects 5.8 million people. Dementia is commonly associated with more than 1 neuropathology, usually Alzheimer disease with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a thorough mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (eg, symptoms present, but normal examination findings), neuropsychological testing can help determine whether dementia is present. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing may be considered in atypical dementia cases, such as age of onset younger than 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients may benefit from nonpharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For Alzheimer disease, this includes an acetylcholinesterase inhibitor such as donepezil for mild to severe dementia, and memantine (used alone or as an add-on therapy) for moderate to severe dementia. Rivastigmine can be used to treat symptomatic Parkinson disease dementia. Conclusions and Relevance: Alzheimer disease currently affects 5.8 million persons in the United States and is a common cause of dementia, which is usually accompanied by other neuropathology, often cerebrovascular disease such as brain infarcts. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both nonpharmacologic and pharmacologic approaches, although efficacy of available treatments remains limited.


Assuntos
Demência/diagnóstico , Demência/terapia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Memantina/efeitos adversos , Memantina/uso terapêutico , Neuroimagem , Testes Neuropsicológicos
14.
Anesth Analg ; 129(4): 1124-1129, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31584918

RESUMO

BACKGROUND: Sugammadex, with its novel mechanism of action of encapsulation and noncompetitive binding of aminosteroid neuromuscular-blocking agents (rocuronium and vecuronium), may offer distinct advantage to pediatric patients where residual neuromuscular blockade may be poorly tolerated. Data describing its use in the pediatric population are limited, and no large-scale studies are available evaluating the occurrence of adverse event across the full spectrum of ages. We sought to measure the occurrence of adverse events, assess the severity and clinical significance of the events, and quantify a surrogate measure of efficacy of sugammadex compared to neostigmine in a large population and in the full age range of children. METHODS: Beginning in September 2016 through initiation of data collection, we identified from our data warehouse that all patients were treated with sugammadex for reversal of neuromuscular blockade, from birth through adolescence, and retrospectively matched, by case type and age group, to historical neostigmine-treated controls. From subsequent chart review, we quantified occurrence of adverse events and administration of medications to treat adverse events. All cases in the originally identified cohort treated with epinephrine after administration of sugammadex underwent chart review to elicit the cause, in the event that an infrequently occurring event was not captured after the case-matching process. "End-Interval Time," the time from administration of reversal agent to time out of the procedure room, was measured as an indirect assessment of efficacy. RESULTS: Fewer cases of bradycardia were observed in the sugammadex group compared to the neostigmine group in the overall cohort (P < .001) and in the subgroups of older children (P < .001) and adolescents (P < .001). End-interval time, the time measured from administration of neuromuscular blockade (NMB) reversal agent to time out of the operating room, was significantly shorter in sugammadex-treated groups in the overall cohort (mean difference, 2.8; 95% CI, 1.85-3.77; P < .001) and all age groups except for first year (31 days through 12 months). This observation was most pronounced in the neonatal subgroup (mean difference, 11.94 minutes; 95% CI, 4.79-19.1; P < .001). No other adverse events measured were found to be different between treatment groups. CONCLUSIONS: This study provides data supporting the safe and effective use of sugammadex for reversal of neuromuscular blockade throughout the entire range of ages in the pediatric population. Within age groups, sugammadex demonstrates faster completion of operation compared with neostigmine, with the greatest difference observed in the neonatal population.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Neostigmina/uso terapêutico , Bloqueio Neuromuscular , Sugammadex/uso terapêutico , Adolescente , Fatores Etários , Período de Recuperação da Anestesia , Bradicardia/induzido quimicamente , Bradicardia/fisiopatologia , Criança , Pré-Escolar , Inibidores da Colinesterase/efeitos adversos , Data Warehousing , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neostigmina/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Sugammadex/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
15.
Am J Case Rep ; 20: 1418-1421, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31554781

RESUMO

BACKGROUND Pyridostigmine is a quaternary amine parasympathomymetic which inhibits acetylcholinesterase for the treatment of various conditions such as myasthenia gravis. Previously, no cases of pyridostigmine toxicity in human beings have been reported except the cases reported among the troops of Persian Gulf War. CASE REPORT A 47-year-old female intentionally ingested a high dose of pyridostigmine (Mestinon) and developed its toxic symptoms within 1 hour of ingestion. She was treated with injections of atropine and pralidoxime. The patient made an excellent recovery and responded to the classical treatment using atropine and pralidoxime. She was discharged on the second day of admission. CONCLUSIONS The authors demonstrated that pyridostigmine poisoning is self-limiting and well tolerated by young adults; however, unwanted effects of pyridostigmine on the heart has still to be considered which may become profound to the point of generating heart failure, syncope, or stress particularly in elderly patients. As the literature on human toxicity with pyridostigmine is scarce, not much data is available on its toxicity. However, prompt and specific management of pyridostigmine toxicity promises safety.


Assuntos
Inibidores da Colinesterase/efeitos adversos , Miastenia Gravis , Brometo de Piridostigmina/efeitos adversos , Tentativa de Suicídio , Atropina/administração & dosagem , Reativadores da Colinesterase/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Miastenia Gravis/tratamento farmacológico , Compostos de Pralidoxima/administração & dosagem
16.
Pharmacol Biochem Behav ; 185: 172758, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31430484

RESUMO

BACKGROUND: Acetylcholinergic (ACh) neurons interface with the mesolimbic dopamine pathway implicated in addiction, and acetylcholinesterase inhibitors (AChEis) have been shown to reduce the immediate effects of cocaine and amount used. Our study is the first to examine if the safe and low-interaction AChEi rivastigmine (riv) alters the subjective effects produced by cocaine administration. METHODS: Cocaine-dependent subjects were randomized to daily placebo, riv 3 mg, or riv 6 mg, administered inpatient for 10 days. On day 1 (pre-dose) and day 9, subjects received both IV cocaine 40 mg or placebo in a randomized order with subsequent serial assessments of visual analog scale (VAS) subjective effects and pharmacokinetic measurements. On day 10 all participants received one baseline dose of cocaine 20 mg with assessment of subjective effects, and were then able to purchase additional doses at 15 min intervals with study earnings. RESULTS: 40 subjects were randomized to placebo (n = 16), riv 3 mg (n = 13), or riv 6 mg (n = 12). All subjects completed the study and there were no demographic differences between treatment groups. Pre- and post- treatment, there were no significant pharmacokinetic differences (blood levels of cocaine, BE, EME) following cocaine administration. In a two-way ANOVA, IV cocaine significantly increased positive VAS category ratings compared to placebo, but rivastigmine treatment at either dose had no significant effect on any VAS category ratings. Similarly, there was no significant rivastigmine effect on any category in the day 10 cocaine administration, and no effect on number of subsequent doses participants purchased. CONCLUSION: Rivastigmine 3 or 6 mg had no significant effect on the subjective effects of cocaine after 9 days of treatment. This is an important finding as other drugs in the AChEi class (donepezil, Huperzine A) have produced significant results, but differ in their receptor specificity and PK parameters.


Assuntos
Comportamento Aditivo/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cocaína/administração & dosagem , Cocaína/farmacologia , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/farmacologia , Rivastigmina/farmacologia , Adulto , Análise de Variância , Pressão Sanguínea/efeitos dos fármacos , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Rivastigmina/administração & dosagem , Rivastigmina/efeitos adversos , Autoadministração , Escala Visual Analógica
17.
Expert Opin Drug Saf ; 18(10): 883-891, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359807

RESUMO

Introduction: Sugammadex is a modified cyclodextrin that is able to reverse neuromuscular block induced by aminosteroidal neuromuscular blocking drugs. Compared to reversal with neostigmine, it reverses neuromuscular block quicker and more predictable and without cholinergic side effects. However, there have been concerns about sugammadex ability to bind other drugs and its effects on QT interval and clotting times. In addition, sugammadex might induce hypersensitivity reactions more frequently than initially anticipated. This review summarizes current evidence with regard to these and other safety aspects of sugammadex. Areas covered: This review provides an overview of the efficacy of sugammadex in various patient populations, evaluates potential interactions with other drugs and discusses adverse effects and reactions that have been reported in the literature. Expert opinion: Sugammadex quickly reverses aminosteroid neuromuscular block with less side effects compared to neostigmine. As such, it has the potential to significantly reduce the incidence of residual neuromuscular block and to improve postoperative pulmonary outcome. Current safety concerns mainly focus on hypersensitivity reactions and cardiac arrhythmias. Although the absolute risk for these events is low, ongoing vigilance and research in this area are needed.


Assuntos
Neostigmina/administração & dosagem , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Sugammadex/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Humanos , Neostigmina/efeitos adversos , Bloqueio Neuromuscular , Sugammadex/efeitos adversos , Sugammadex/farmacologia
18.
J Vet Pharmacol Ther ; 42(5): 548-555, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31328799

RESUMO

The combination of the organophosphate (OP) chlorpyrifos (CPF) and the pyrethroid cypermethrin (CPM) is commonly marketed as pour-on formulations for the control of sheep lice, ked, and blowflies. CPF irreversibly inhibits acetylcholinesterases (AChE), while pyrethroids are not AChE inhibitors. However, combinations of pyrethroids with OPs showed a highly synergistic effect on AChE inhibition. Thus, the aim of the current work was to evaluate in vitro and in vivo the inhibitory potency of both pesticides, alone and in combination with AChE and butyrylcholinesterase (BChE) activities in sheep blood. In vitro, IC50 values were similar after CPF or CPF plus CPM incubations. The pour-on coadministration of recommended doses of CPF and CPM did not cause a significant inhibition of AChE and BChE in sheep blood. Only slight percentages of inhibition of their catalytic activities were observed when both drugs were given at 4-fold higher dose rates. The lower systemic availability of topical administration of OPs in sheep may help to explain the lower degree of inhibition of blood AChE and BChE in vivo. The results emerged from this research are a further contribution to the knowledge of the risks of implementing higher dosage regimens of OPs-containing antiparasitic formulations.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Clorpirifos/efeitos adversos , Inibidores da Colinesterase/efeitos adversos , Piretrinas/efeitos adversos , Ovinos/sangue , Administração Tópica , Animais , Clorpirifos/administração & dosagem , Clorpirifos/uso terapêutico , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/uso terapêutico , Combinação de Medicamentos , Inseticidas/administração & dosagem , Inseticidas/efeitos adversos , Inseticidas/uso terapêutico , Masculino , Piretrinas/administração & dosagem , Piretrinas/uso terapêutico
19.
Z Gerontol Geriatr ; 52(4): 309-315, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161337

RESUMO

As a result of the aging population dementia is a growing challenge, especially in healthcare. Nevertheless, cognitive disorders are often not systematically evaluated, especially during hospital stays for other reasons; however, cognitive impairment is associated with a number of geriatric syndromes, including falls, delirium, dysphagia and lack of adherence to treatment plans. This article considers the current state of diagnosis and treatment of dementia. Non-pharmacological therapeutic approaches as well as current and future pharmacological treatment options are discussed. The drugs of choice for the symptomatic treatment of cognitive deficits in Alzheimer's disease and Parkinson-associated dementia are cholinesterase inhibitors and memantine; there is no specific pharmacological treatment for other types of dementia. Prevention and treatment of cardiovascular risk factors can potentially retard the progression of possibly all forms of dementia.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/terapia , Memantina/uso terapêutico , Idoso , Doença de Alzheimer , Inibidores da Colinesterase/efeitos adversos , Demência , Humanos
20.
Drugs Aging ; 36(8): 719-731, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31201687

RESUMO

Non-Alzheimer's dementias constitute 30% of all dementias and present with major cognitive and behavioral disturbances. Cholinesterase inhibitors improve memory by increasing brain acetylcholine levels and are approved symptomatic therapies for Alzheimer's disease (AD). They have also been investigated in other types of dementias with potential cholinergic dysfunction. There is compelling evidence for a profound cholinergic deficit in Lewy Body dementia (LBD) and Parkinson's disease dementia (PDD), even to a greater extent than AD. However, this deficit is difficult to objectivize in vascular dementia (VaD) given the increased comorbidity with AD. Furthermore, there is minimal to no evidence for cholinergic loss in frontotemporal dementia (FTD). Although cholinesterase inhibitors showed significant improvement in cognitive, behavioral, and functional measures in both LBD and PDD clinical trials, only rivastigmine is approved for PDD, due to the heterogeneity of the scales used, the duration of trials, and the limited sample sizes impacting data interpretation. Similarly, the interpretation of findings in VaD trials are limited by the lack of pre-defined inclusion criteria for 'pure VaD' and the wide heterogeneity of patients enrolled with respect to location and extent of cerebrovascular disease. In FTD patients, cholinesterase inhibitors were mostly associated with worsening of cognitive and behavioral symptoms. In non-AD dementias, cholinesterase inhibitors were well tolerated, with increased reports of mild to moderate cholinergic side effects and a non-significant trend for increased cardio and cerebrovascular events with rivastigmine in VaD, justifying their cautious use on a case-by-case basis, especially when there is evidence for cholinergic deficit.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Degeneração Lobar Frontotemporal/tratamento farmacológico , Doença por Corpos de Lewy/tratamento farmacológico , Rivastigmina/uso terapêutico , Acetilcolina/metabolismo , Idoso , Inibidores da Colinesterase/efeitos adversos , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Doença por Corpos de Lewy/metabolismo , Rivastigmina/efeitos adversos
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