RESUMO
OBJECTIVE: To determine the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentrations during insulin withdrawal in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: A double-blind, placebo-controlled crossover study with a 4-week washout period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the glucose Ra, Rd, and lipolysis. At isotopic steady state, insulin was withdrawn, and the study was terminated after 600 min or earlier if blood glucose reached 18 mmol/L, bicarbonate <15 mmol/L, venous pH <7.35, or capillary ketones >5.0 mmol/L. RESULTS: At baseline, glucose Ra was significantly higher for the dapagliflozin group than the placebo group. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and glucose Rd area under the curve (AUC)0-180 min and ß-hydroxybutyrate (BOHB) AUC0-180 min were significantly higher. There was a small but significantly higher glycerol Ra (measure of lipolysis) AUC0-180 min with dapagliflozin. Nonesterified fatty acid concentrations were not different between treatments. When divided by BMI >27 and <27 kg/m2, basal glucose Ra, BOHB, and glycerol Ra AUC0-180 min were significantly higher in the low-BMI group with dapagliflozin treatment versus the low-BMI group with placebo. CONCLUSIONS: During insulin withdrawal, the increase in BOHB with dapagliflozin may be partially due to increased lipolysis. However, reduced renal excretion, reduced BOHB uptake by peripheral tissues, or a metabolic switch to increased ketogenesis within the liver may also play a role.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucosídeos/uso terapêutico , Insulina/administração & dosagem , Insulina/deficiência , Cetose/induzido quimicamente , Adulto , Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Método Duplo-Cego , Esquema de Medicação , Substituição de Medicamentos , Feminino , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Cetose/sangue , Cetose/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Suspensão de TratamentoRESUMO
Sleep and its sub-states are assumed to be important for brain function across the lifespan but which aspects of sleep associate with various aspects of cognition, mood and self-reported sleep quality has not yet been established in detail. Sleep was quantified by polysomnography, quantitative Electroencephalogram (EEG) analysis and self-report in 206 healthy men and women, aged 20-84 years, without sleep complaints. Waking brain function was quantified by five assessments scheduled across the day covering objectively assessed performance across cognitive domains including sustained attention and arousal, decision and response time, motor and sequence control, working memory, and executive function as well as self-reports of alertness, mood and affect. Controlled for age and sex, self-reported sleep quality was negatively associated with number of awakenings and positively associated with the duration of Rapid Eye Movement (REM) sleep, but no significant associations with Slow Wave Sleep (SWS) measures were observed. Controlling only for age showed that associations between objective and subjective sleep quality were much stronger in women than in men. Analysis of 51 performance measures demonstrated that, after controlling for age and sex, fewer awakenings and more REM sleep were associated significantly with better performance on the Goal Neglect task, which is a test of executive function. Factor analysis of the individual performance measures identified four latent variables labeled Mood/Arousal, Response Time, Accuracy, and Visual Perceptual Sensitivity. Whereas Mood/Arousal improved with age, Response Times became slower, while Accuracy and Visual perceptual sensitivity showed little change with age. After controlling for sex and age, nominally significant association between sleep and factor scores were observed such that Response Times were faster with more SWS, and Accuracy was reduced where individuals woke more often or had less REM sleep. These data identify a positive contribution of SWS to processing speed and in particular highlight the importance of sleep continuity and REM sleep for subjective sleep quality and performance accuracy across the adult lifespan. These findings warrant further investigation of the contribution of sleep continuity and REM sleep to brain function.
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BACKGROUND: The provision of clinically assisted hydration at the end-of-life is one of the most contentious issues in medicine. AIM: The aim of this feasibility study was to answer the question 'can a definitive (adequately powered) study be done?' DESIGN: The study was a cluster randomised trial, with sites randomised on a one-to-one basis to intervention 'A' (regular mouth care and usual other care) or intervention 'B' (clinically assisted hydration, mouth care and usual other care). Participants were assessed every 4 h, and data collected on clinical problems, therapeutic interventions and overall survival. SETTING/PARTICIPANTS: The study was conducted at 12 sites/'clusters' with specialist palliative care teams (4 cancer centres and 8 hospices), and participants were cancer patients in the last week of life who were unable to maintain sufficient oral fluid intake. RESULTS: The study achieved its pre-determined criteria for success. Two hundred patients were recruited to the study, and 199 participants completed the study, over a 1-year period. A total of 38.5% participants discontinued clinically assisted hydration due to adverse effects: none of these adverse events were rated as 'severe' or worse in intensity. The primary reasons for discontinuation were site problems ( n = 2), localised oedema ( n = 13), generalised oedema ( n = 5), respiratory secretions ( n = 6) and nausea and vomiting ( n = 1). CONCLUSION: The results of this feasibility study suggest that a definitive study can be done, but that minor changes are needed to the protocol to standardise the administration of clinically assisted hydration (which may reduce the incidence of certain adverse effects).
Assuntos
Desidratação/terapia , Neoplasias , Cuidados Paliativos , Doente Terminal , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de PesquisaRESUMO
Dietary sugars are linked to the development of non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia, but it is unknown if NAFLD itself influences the effects of sugars on plasma lipoproteins. To study this further, men with NAFLD (n = 11) and low liver fat 'controls' (n = 14) were fed two iso-energetic diets, high or low in sugars (26% or 6% total energy) for 12 weeks, in a randomised, cross-over design. Fasting plasma lipid and lipoprotein kinetics were measured after each diet by stable isotope trace-labelling.There were significant differences in the production and catabolic rates of VLDL subclasses between men with NAFLD and controls, in response to the high and low sugar diets. Men with NAFLD had higher plasma concentrations of VLDL1-triacylglycerol (TAG) after the high (P<0.02) and low sugar (P<0.0002) diets, a lower VLDL1-TAG fractional catabolic rate after the high sugar diet (P<0.01), and a higher VLDL1-TAG production rate after the low sugar diet (P<0.01), relative to controls. An effect of the high sugar diet, was to channel hepatic TAG into a higher production of VLDL1-TAG (P<0.02) in the controls, but in contrast, a higher production of VLDL2-TAG (P<0.05) in NAFLD. These dietary effects on VLDL subclass kinetics could be explained, in part, by differences in the contribution of fatty acids from intra-hepatic stores, and de novo lipogenesis. The present study provides new evidence that liver fat accumulation leads to a differential partitioning of hepatic TAG into large and small VLDL subclasses, in response to high and low intakes of sugars.
Assuntos
Carboidratos da Dieta/administração & dosagem , Gorduras/metabolismo , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Triglicerídeos/metabolismo , Adulto , Idoso , Estudos Cross-Over , Carboidratos da Dieta/farmacologia , Ensaio de Imunoadsorção Enzimática , Jejum/sangue , Humanos , Lipídeos/sangue , Lipoproteínas VLDL/sangue , Fígado/efeitos dos fármacos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Avaliação de Resultados em Cuidados de Saúde , Fatores de Tempo , Triglicerídeos/sangueRESUMO
BACKGROUND: The provision of clinically assisted hydration at the end of life is one of the most contentious issues in medicine, and indeed within the general population. The reasons for contention include: a) the lack of evidence for or against; b) the disparate opinions of healthcare professionals; and c) the generally positive opinions of patients and their carers about clinically assisted hydration. METHODS/DESIGN: The study is a cluster randomised trial to assess the feasibility of conducting an adequately powered, randomised controlled trial of clinically assisted hydration in patients with cancer in the last days of life. Twelve sites, four National Health Service (NHS) hospitals and eight NHS/voluntary sector hospices in the United Kingdom, will be randomised to give either standard intervention A: continuance of oral intake and regular mouth care, or standard intervention B: continuance of oral intake, regular mouth care and clinically assisted hydration. Patients will be included if they: i) have a diagnosis of cancer; ii) are aged ≥ 18 yr; iii) have an estimated prognosis of ≤ 1 week and iv) are unable to maintain sufficient oral intake (1 L per day, measured/estimated); and v) are able to give informed consent. Patients will be excluded if they have contra-indications to receiving clinically assisted hydration. The primary endpoint of interest is the frequency of hyperactive delirium ('terminal agitation'), and this will be assessed using the Modified Richmond Agitation and Sedation Scale (administered every four hours). Other data to be collected include the frequency of pain, respiratory secretions ('death rattle'), dyspnoea, nausea and vomiting, adverse effects to clinically assisted hydration and overall survival. In addition, data will be collected on the use of anti-psychotic drugs, sedative drugs, analgesics, anti-secretory drugs and other end-of-life medication. The study has obtained full ethical approval. DISCUSSION: A randomised controlled trial of clinically assisted hydration in end-of-life care is urgently required. This feasibility study will allow methodological and ethical issues to be understood and addressed to ensure that a robust, adequately powered, randomised controlled trial is designed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02344927 (registered 4 June 2014).
Assuntos
Hidratação/métodos , Neoplasias/terapia , Cuidados Paliativos/métodos , Assistência Terminal/métodos , Equilíbrio Hidroeletrolítico , Protocolos Clínicos , Delírio/etiologia , Delírio/prevenção & controle , Estudos de Viabilidade , Hidratação/efeitos adversos , Nível de Saúde , Humanos , Neoplasias/complicações , Neoplasias/fisiopatologia , Higiene Bucal , Polimedicação , Projetos de Pesquisa , Fatores de Tempo , Resultado do Tratamento , Reino UnidoRESUMO
Pre-eclampsia is a serious hypertensive condition of pregnancy associated with high maternal and fetal morbidity and mortality. Se intake or status has been linked to the occurrence of pre-eclampsia by our own work and that of others. We hypothesised that a small increase in the Se intake of UK pregnant women of inadequate Se status would protect against the risk of pre-eclampsia, as assessed by biomarkers of pre-eclampsia. In a double-blind, placebo-controlled, pilot trial, we randomised 230 primiparous pregnant women to Se (60 µg/d, as Se-enriched yeast) or placebo treatment from 12 to 14 weeks of gestation until delivery. Whole-blood Se concentration was measured at baseline and 35 weeks, and plasma selenoprotein P (SEPP1) concentration at 35 weeks. The primary outcome measure of the present study was serum soluble vascular endothelial growth factor receptor-1 (sFlt-1), an anti-angiogenic factor linked with the risk of pre-eclampsia. Other serum/plasma components related to the risk of pre-eclampsia were also measured. Between 12 and 35 weeks, whole-blood Se concentration increased significantly in the Se-treated group but decreased significantly in the placebo group. At 35 weeks, significantly higher concentrations of whole-blood Se and plasma SEPP1 were observed in the Se-treated group than in the placebo group. In line with our hypothesis, the concentration of sFlt-1 was significantly lower at 35 weeks in the Se-treated group than in the placebo group in participants in the lowest quartile of Se status at baseline (P= 0·039). None of the secondary outcome measures was significantly affected by treatment. The present finding that Se supplementation has the potential to reduce the risk of pre-eclampsia in pregnant women of low Se status needs to be validated in an adequately powered trial.
Assuntos
Suplementos Nutricionais , Pré-Eclâmpsia/prevenção & controle , Selênio/uso terapêutico , Selenoproteína P/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Fermento Seco/uso terapêutico , Adulto , Biomarcadores/análise , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Incidência , Unhas/química , Estado Nutricional , Projetos Piloto , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/etiologia , Gravidez , Primeiro Trimestre da Gravidez , Risco , Selênio/análise , Selênio/sangue , Selênio/deficiência , Reino Unido/epidemiologia , Fermento Seco/químicaRESUMO
OBJECTIVE: To describe patterns of prehospital ECG (PHECG) use and determine its association with processes and outcomes of care in patients with ST-elevation myocardial infarction (STEMI) and non-STEMI. METHODS: Population-based linked cohort study of a national myocardial infarction registry. RESULTS: 288â 990 patients were admitted to hospitals via emergency medical services (EMS) between 1 January 2005 and 31 December 2009. PHECG use increased overall (51% vs 64%, adjusted OR (aOR) 2.17, 95% CI 2.12 to 2.22), and in STEMI (64% vs 79%, aOR 2.34, 95% CI 2.25 to 2.44). Patients who received PHECG were younger (71â years vs 74â years, P<0.0001); and less likely to be female (33.1% vs 40.3%, OR 0.87, 95% CI 0.86 to 0.89), or to have comorbidities than those who did not. For STEMI, reperfusion was more frequent in those having PHECG (83.5% vs 74.4%, p<0.0001). PHECG was associated with more primary percutaneous coronary intervention patients achieving call-to-balloon time <90â min (27.9% vs 21.4%, aOR 1.38, 95% CI 1.24 to 1.54) and more patients who received fibrinolytic therapy achieving door-to-needle time <30â min (90.6% vs 83.7%, aOR 2.13, 95% CI 1.91 to 2.38). Patients with PHECG exhibited significantly lower 30-day mortality rates than those who did not (7.4% vs 8.2%, aOR 0.94, 95% CI 0.91 to 0.96). CONCLUSIONS: Findings from this national MI registry demonstrate a survival advantage in STEMI and non-STEMI patients when PHECG was used.
Assuntos
Síndrome Coronariana Aguda/diagnóstico , Eletrocardiografia , Serviços Médicos de Emergência/métodos , Serviço Hospitalar de Emergência , Infarto do Miocárdio/diagnóstico , Avaliação de Processos e Resultados em Cuidados de Saúde , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Eletrocardiografia/tendências , Serviços Médicos de Emergência/tendências , Serviço Hospitalar de Emergência/tendências , Inglaterra , Feminino , Humanos , Modelos Logísticos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Razão de Chances , Avaliação de Processos e Resultados em Cuidados de Saúde/tendências , Intervenção Coronária Percutânea , Valor Preditivo dos Testes , Sistema de Registros , Fatores Sexuais , Terapia Trombolítica , Fatores de Tempo , Tempo para o Tratamento , Resultado do Tratamento , País de GalesRESUMO
OBJECTIVE: Chronic diabetic peripheral neuropathic pain (DPNP) is difficult to treat, with treatment regimens often inadequate at controlling pain and limited by side effects and drug tolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful DPNP management. The objectives of this study were to compare the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on polysomnographic sleep, daytime functioning, and quality of life in patients with DPNP. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, parallel group investigation of type 1 and 2 diabetic subjects with DPNP. Each treatment group had a single-blind, 8-day, placebo run-in followed by 14 days of lower-dose and 14 days of higher-dose medication. At the end of each dose titration period, subjective pain, sleep, and daytime functioning were assessed during a 2-day residential period. RESULTS: All medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group. CONCLUSIONS: There was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin. However, there were significant differences in the secondary parameters, which may be of relevance when deciding the optimal treatment for DPNP.
Assuntos
Amitriptilina/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Dor/tratamento farmacológico , Dor/etiologia , Sono/fisiologia , Tiofenos/uso terapêutico , Ácido gama-Aminobutírico/análogos & derivados , Idoso , Neuropatias Diabéticas/fisiopatologia , Método Duplo-Cego , Cloridrato de Duloxetina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pregabalina , Qualidade de Vida , Resultado do Tratamento , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
The effect of light on circadian rhythms and sleep is mediated by a multi-component photoreceptive system of rods, cones and melanopsin-expressing intrinsically photosensitive retinal ganglion cells. The intensity and spectral sensitivity characteristics of this system are to be fully determined. Whether the intensity and spectral composition of light exposure at home in the evening is such that it delays circadian rhythms and sleep also remains to be established. We monitored light exposure at home during 6-8wk and assessed light effects on sleep and circadian rhythms in the laboratory. Twenty-two women and men (23.1±4.7yr) participated in a six-way, cross-over design using polychromatic light conditions relevant to the light exposure at home, but with reduced, intermediate or enhanced efficacy with respect to the photopic and melanopsin systems. The evening rise of melatonin, sleepiness and EEG-assessed sleep onset varied significantly (P<0.01) across the light conditions, and these effects appeared to be largely mediated by the melanopsin, rather than the photopic system. Moreover, there were individual differences in the sensitivity to the disruptive effect of light on melatonin, which were robust against experimental manipulations (intra-class correlation=0.44). The data show that light at home in the evening affects circadian physiology and imply that the spectral composition of artificial light can be modified to minimize this disruptive effect on sleep and circadian rhythms. These findings have implications for our understanding of the contribution of artificial light exposure to sleep and circadian rhythm disorders such as delayed sleep phase disorder.
Assuntos
Relógios Circadianos , Melatonina/metabolismo , Fotoperíodo , Opsinas de Bastonetes/metabolismo , Transtornos do Sono do Ritmo Circadiano , Sono , Adulto , Estudos Transversais , Eletroencefalografia , Feminino , Humanos , Masculino , Estimulação Luminosa , Transtornos do Sono do Ritmo Circadiano/etiologia , Transtornos do Sono do Ritmo Circadiano/metabolismo , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Fatores de TempoRESUMO
AMPA receptor modulation is a potential novel approach to enhance cognitive performance. CX717 is a positive allosteric modulator of the AMPA receptor that has shown efficacy in rodent and primate cognition models. CX717 (100 mg, 300 mg and 1000 mg) and placebo were studied in 16 healthy male volunteers (18-45 years) in a randomized, crossover study. Cognitive function, arousal and recovery sleep (by polysomnography) were assessed during the extended wakefulness protocol. Placebo condition was associated with significant decrements in cognition, particularly at the circadian nadir (between 03:00 and 05:00). Pre-specified primary and secondary analyses (general linear mixed modelling, GLMM) at each separate time point did not reveal consistent improvements in performance or objective alertness with any dose of CX717. Exploratory repeated measures analysis, a method used to take into account the influence of individual differences, demonstrated an improvement in attention-based task performance following the 1000 mg dose. Analysis of the recovery sleep showed that CX717 1000 mg significantly reduced stage 4 and slow-wave sleep (p ≤ 0.05) with evidence of reduced electroencephalogram (EEG) slow-wave and spindle activity. The study suggests that CX717 only at the 1000 mg dose may counteract effects of sleep deprivation on attention-based tasks and that it may interfere with subsequent recovery sleep.
Assuntos
Nível de Alerta/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Isoxazóis/uso terapêutico , Desempenho Psicomotor/efeitos dos fármacos , Privação do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Adolescente , Adulto , Regulação Alostérica/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Ondas Encefálicas/fisiologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/fisiopatologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Eletroencefalografia/psicologia , Humanos , Isoxazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nootrópicos/efeitos adversos , Nootrópicos/uso terapêutico , Polissonografia/efeitos dos fármacos , Polissonografia/métodos , Desempenho Psicomotor/fisiologia , Receptores de AMPA/agonistas , Sono/fisiologia , Privação do Sono/complicações , Privação do Sono/fisiopatologia , Vigília/fisiologiaRESUMO
OBJECTIVE: Insulin detemir lacks the usual propensity for insulin to cause weight gain. We investigated whether this effect was a result of reduced energy intake and/or increased energy expenditure. RESEARCH DESIGN AND METHODS: A 32-week, randomized crossover design trial was undertaken in 23 patients with type 1 diabetes. Patients on a basal-bolus regimen (with insulin aspart as the bolus insulin) were randomly assigned to insulin detemir or NPH insulin as a basal insulin for 16 weeks, followed by the other basal insulin for 16 weeks. At the end of each 16-week period, total energy expenditure, resting energy expenditure, diet-induced thermogenesis, activity energy expenditure, energy intake, weight change, glycemic control, hypoglycemic episodes, and hormones that affect satiety and fuel partitioning were measured. RESULTS: After 16 weeks, weight change was -0.69±1.85 kg with insulin detemir and +1.7±2.46 kg with NPH insulin (P<0.001). Total energy intake was significantly less with insulin detemir (2,016±501 kcal/day) than with NPH insulin (2,181±559 kcal/day) (P=0.026). There was no significant difference in any measure of energy expenditure, HbA1c percentage, or number of hypoglycemic episodes. Leptin was lower and resistin was higher with insulin detemir compared with NPH insulin (P=0.039, P=0.047). After the meal, ghrelin and pancreatic polypeptide levels (P=0.002, P=0.001) were higher with insulin detemir. CONCLUSIONS: The reduced weight gain with insulin detemir compared with NPH insulin is attributed to reduced energy intake rather than increased energy expenditure. This may be mediated by a direct or indirect effect of insulin detemir on the hormones that control satiety.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Isófana/uso terapêutico , Insulina/análogos & derivados , Aumento de Peso/efeitos dos fármacos , Adulto , Glicemia/metabolismo , Estudos Cross-Over , Ingestão de Alimentos , Ingestão de Energia , Feminino , Humanos , Insulina/uso terapêutico , Insulina Detemir , Insulina de Ação Prolongada , MasculinoRESUMO
OBJECTIVE: To assess whether actigraphy is sensitive to benzodiazepine-induced changes in cognitive and psychomotor performance and sleep. METHODS: Healthy young volunteers (n = 23; 11 males), were randomised to a double-blind, placebo-controlled, crossover trial. Actigraphy was used to record motor activity continuously. Following dosing at 18.00 h with 2.5 mg lorazepam (LZP), psychomotor and cognitive assessments were made at hourly intervals post-dose for 4 h and after sleep at 14.5 h post-dose. RESULTS: Activity levels were significantly reduced after LZP for 5 h post-dose (p = 0.0104), during sleep (5-13 h) (p < 0.02) and the following morning, 13-14.5 h post-dose (p < 0.02). At the same time cognitive and psychomotor performance was also significantly impaired (p < 0.05). LZP also significantly increased actigraphic sleep efficiency and sleep per cent (p < 0.02). CONCLUSION: This study showed that activity levels were significantly reduced following dosing with a benzodiazepine and these changes coincided with impairment of cognitive and psychomotor performance. Actigraphy, therefore, appears to be able to reflect the psychopharmacological effects of a benzodiazepine in changes in daytime function and nocturnal behaviour, which, without waking the subject, is beyond the power of conventional psychometrics.
Assuntos
Ansiolíticos/farmacologia , Cognição/efeitos dos fármacos , Lorazepam/farmacologia , Atividade Motora/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Psicometria , Sono/efeitos dos fármacos , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: To evaluate next-day driving ability, as assessed by brake reaction time (BRT), and cognitive/psychomotor function following nighttime administration of 3 mg eszopiclone. METHODS: Two randomized, double-blind, placebo-controlled, cross-over studies were performed in healthy volunteers (n = 32) and patients with primary insomnia (n = 32). Study participants received nighttime dosing of 3 mg eszopiclone or placebo. BRT and a psychometric test battery were used to assess the next-day effects of eszopiclone treatment. RESULTS: In both studies, driving ability and measures of cognitive and psychomotor function were not impaired the morning after eszopiclone, as compared to placebo. All eszopiclone subjects reported improved ease in getting to sleep and quality of sleep with no significant changes in behavior upon awakening. A significant increase in next-day feelings of sedation was reported in healthy volunteers, but not in patients with primary insomnia, following eszopiclone treatment relative to placebo. Sleep induction, maintenance, duration, and efficiency, as assessed by PSG, were significantly improved following eszopiclone treatment in patients with insomnia. CONCLUSIONS: Nighttime administration of 3 mg eszopiclone improved objective and subjective sleep measures in patients with insomnia (and subjective sleep measures in healthy patients) and did not impair next-day driving-related skills or measures of cognition in either study population relative to placebo.
Assuntos
Condução de Veículo , Compostos Azabicíclicos/efeitos adversos , Cognição/efeitos dos fármacos , Hipnóticos e Sedativos/efeitos adversos , Piperazinas/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adulto , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/uso terapêutico , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Zopiclona , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacosRESUMO
Cognitive and psychomotor performance have traditionally been assessed in the laboratory. There is a need for an objective portable assessment tool to assess cognitive and psychomotor performance. This study investigated the viability of a portable psychometric test battery, in a controlled laboratory environment, possibly leading to use in the field. A randomised, double-blind placebo controlled, three-way crossover design was employed. 16 subjects received 50 mg/100 ml and 80 mg/100 ml of alcohol and alcohol placebo. Performance was assessed with a tracking task, and an attention task presented on a small ruggedised handheld computer. The attention task showed no significant training effects; however, an element of the tracking task did. Statistical significance, effect size, and test-retest reliability analyses are presented indicating sensitivity of the portable psychometric test battery to the impairing effects of two separate doses of alcohol. Ability to undertake wide-scale impairment testing in the field with meaningful results in the absence of baseline data collection may have wide reaching implications, particularly in relation to the assessment of drivers impaired by drug use.
Assuntos
Intoxicação Alcoólica/psicologia , Computadores de Mão , Testes Neuropsicológicos/estatística & dados numéricos , Sistemas Automatizados de Assistência Junto ao Leito , Psicometria/instrumentação , Adolescente , Adulto , Intoxicação Alcoólica/diagnóstico , Atenção , Condução de Veículo/psicologia , Testes Respiratórios , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Etanol/sangue , Estudos de Viabilidade , Feminino , Humanos , Masculino , Polícia , Desempenho Psicomotor , Tempo de Reação , Movimentos SacádicosRESUMO
BACKGROUND: The effects of the selective H1-receptor antagonist fexofenadine have been widely demonstrated in Western populations; however, to date, limited data comparing the effects of fexofenadine with other antihistamines have been reported in Japanese subjects. OBJECTIVE: To investigate the effect of fexofenadine and loratadine on the histamine-induced cutaneous wheal and flare response in healthy Japanese volunteers. METHODS: Eighteen healthy male and female Japanese volunteers aged 20-53 years were randomized to receive fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily or placebo in a 1-day, three-period, double-blind, crossover study. For each treatment, the wheal and flare response to 100 mg/mL histamine was assessed at baseline and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, 12 and 24 hours post-dose. Blood samples were taken for pharmacokinetic analysis. RESULTS: Fexofenadine produced significantly greater percentage suppression of the overall wheal response compared with placebo and loratadine (43.1% versus 10.0% and 15.2%, respectively; p < 0.001). Similarly, fexofenadine significantly suppressed the overall flare response compared with placebo and loratadine (43.0% versus 3.5% and -8.9%, respectively; p < 0.01). Loratadine was statistically no different from placebo in terms of both overall wheal and flare suppression. Area under the curve analysis for wheal and flare reduction (0-12 hours post-dose) confirmed these findings. For wheal inhibition, fexofenadine had a significantly faster onset of action (defined as time to > or = 35% inhibition) compared with placebo (p < 0.001) and loratadine (p < 0.01); for flare, fexofenadine had a significantly faster onset of action than loratadine (p < 0.01). Mean maximum inhibition (the mean of the greatest inhibition achieved from baseline for each treatment) for wheal was achieved significantly faster with fexofenadine than loratadine (p < 0.01), and fexofenadine had a significantly longer duration of effect on suppressing wheal and flare compared with placebo and loratadine (p < 0.05 for all). The antihistamine effects of fexofenadine correlated significantly with its Cmax, while loratadine activity did not correlate significantly with its plasma levels. CONCLUSIONS: Fexofenadine is a potent suppressor of the histamine-induced wheal and flare response in healthy Japanese volunteers. These results support findings in Caucasian subjects, and confirm that fexofenadine has greater antihistaminergic activity than loratadine in this human model.
Assuntos
Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Loratadina/uso terapêutico , Terfenadina/análogos & derivados , Urticária/tratamento farmacológico , Adulto , Quimioterapia Combinada , Feminino , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Humanos , Japão/etnologia , Loratadina/administração & dosagem , Loratadina/farmacocinética , Masculino , Pessoa de Meia-Idade , Placebos , Estudos Prospectivos , Terfenadina/administração & dosagem , Terfenadina/farmacocinética , Terfenadina/uso terapêutico , Reino Unido , Urticária/induzido quimicamenteAssuntos
Doença de Alzheimer/diagnóstico , Cognição , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Interpretação Estatística de Dados , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Testes Neuropsicológicos , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica , Análise e Desempenho de TarefasRESUMO
Dementia represents a significant burden on the resources of both the National Health Service and Social Services as well as a great strain on the caregivers. The ability to predict, at diagnosis, those dementia patients that will deteriorate rapidly would allow a more effective allocation of resources as well as enabling the families and caregivers to make appropriate preparations. We performed discriminant analysis on a placebo data set of over 5,000 patients with Alzheimer's disease in order to create a model that predicts the rate of cognitive decline in Alzheimer's disease from simple demographic data and the baseline score on the cognitive subscale of the Alzheimer's Disease Assessment Scale or the Mini Mental State Examination. This model has 96-97% sensitivity and 92-93% specificity. The potential benefits of this model argue for its validation in a prospective study.