Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.483
Filtrar
1.
Clin Ter ; 172(2): 116-118, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33763670

RESUMO

ABSTRACT: Over the last few years reports have indicated an increase in the number, type and availability of new psychoactive substances belonging to the benzodiazepine class. These molecules may pose high risks to users, since the majority have never undergone clinical trials or tests so their pharmacology and toxicology is largely unknown. However the new drug scenario emerging from the COVID-19 global pandemic seems to play a role in increasing the diversion of prescribed benzodiazepines and Z-drug. A brief presentation of this phenomenon is hereby presented. The awareness and response activities at national and international levels related to this issue should be enforced.


Assuntos
Benzodiazepinas/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Benzodiazepinas/administração & dosagem , Fármacos do Sistema Nervoso Central/administração & dosagem , Fármacos do Sistema Nervoso Central/efeitos adversos , Humanos , Desvio de Medicamentos sob Prescrição/tendências
2.
Res Social Adm Pharm ; 17(1): 2005-2008, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33317769

RESUMO

BACKGROUND: Healthcare access has changed drastically during the COVID-19 pandemic. Elective medical procedures, including routine office visits, were restricted raising concerns regarding opioid and benzodiazepine provider and prescription availability. OBJECTIVE: To examine how the cancelation of elective medical procedures due to COVID-19 impacted the dispensing of opioid and benzodiazepine prescriptions in Texas. METHODS: Interrupted time series analyses were preformed to examine changes in prescription trends for opioids and benzodiazepines before and after the restriction on elective medical procedures. Samples of patients who filled an opioid or benzodiazepine prescription from January 5, 2020 to May 12, 2020 were identified from the Texas Prescription Monitoring Program. Elective medical procedures were restricted starting March 23, 2020 indicating the beginning of the intervention period. RESULTS: Restricting elective procedures was associated with a significant decrease in the number of patients (ß = -6029, 95%CI = -8810.40, -3246.72) and prescribers (ß = -2784, 95%CI = -3671.09, -1896.19) filling and writing opioid prescriptions, respectively. Also, the number of patients filling benzodiazepine prescriptions decreased significantly (ß = -1982, 95%CI = -3712.43, -252.14) as did the number of prescribers (ß = -708.62, 95%CI = -1190.54, -226.71). CONCLUSION: Restricting elective procedures resulted in a large care gap for patients taking opioid or benzodiazepine prescriptions.


Assuntos
Analgésicos Opioides/administração & dosagem , Benzodiazepinas/administração & dosagem , Padrões de Prática Médica/estatística & dados numéricos , Prescrições de Medicamentos , Política de Saúde , Acesso aos Serviços de Saúde , Humanos , Análise de Séries Temporais Interrompida , Programas de Monitoramento de Prescrição de Medicamentos , Texas
3.
Ann Pharmacother ; 55(1): 15-24, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32567359

RESUMO

BACKGROUND: Approximately 17% of intensive care unit (ICU) patients are prescribed at least 1 home neuropsychiatric medication (NPM). When abruptly discontinued, withdrawal symptoms may occur manifesting as agitation or delirium in the ICU setting. OBJECTIVE: To evaluate the impact of early reinitiation of NPMs. METHODS: This was a retrospective, observational cohort of adult ICU patients in a tertiary care hospital. Patients were included if admitted to the ICU and prescribed a NPM prior to arrival. Study groups were based on the timing of reinitiation of at least 50% of NPMs: ≤72 hours (early group) versus >72 hours (late group). RESULTS: The primary outcome was the proportion of patients with at least 1 agitation or delirium episode in the first 72 hours. Agitation and delirium were defined as at least 1 RASS assessment between +2 to +4 and a positive CAM-ICU assessment, respectively. A total of 300 patients were included, with 187 (62%) and 113 (38%) in the early and late groups, respectively. There was no difference in agitation or delirium (late 54 [48%] vs early 62 [33%]; adjusted odds ratio [aOR] = 1.5; 95% CI = 0.8-2.8; P = 0.193). Independent risk factors found to be associated with the primary outcome were restraints (aOR = 12.9; 95% CI = 6.9-24.0; P < 0.001) and benzodiazepines (BZDs; aOR = 2.0; 95% CI = 1.0-3.7; P = 0.038). CONCLUSIONS: After adjustment for baseline differences, there was no difference in agitation or delirium. Independent risk factors were restraint use and newly initiated BZDs.


Assuntos
Antipsicóticos/administração & dosagem , Delírio/prevenção & controle , Unidades de Terapia Intensiva , Agitação Psicomotora/prevenção & controle , Prevenção Secundária/métodos , Síndrome de Abstinência a Substâncias/prevenção & controle , Adulto , Idoso , Antipsicóticos/uso terapêutico , Benzodiazepinas/administração & dosagem , Benzodiazepinas/uso terapêutico , Estudos de Coortes , Cuidados Críticos , Delírio/diagnóstico , Substituição de Medicamentos , Feminino , Humanos , Masculino , Reconciliação de Medicamentos , Pessoa de Meia-Idade , Agitação Psicomotora/diagnóstico , Estudos Retrospectivos , Síndrome de Abstinência a Substâncias/diagnóstico
5.
Emergencias (Sant Vicenç dels Horts) ; 32(5): 353-362, oct. 2020. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-197088

RESUMO

El presente documento de consenso se ha desarrollado con el objetivo de optimizar el tratamiento de pacientes con crisis epilépticas (CE) en los ámbitos de urgencias prehospitalario y hospitalario. Un equipo multidisciplinar formado por urgenciólogos, neurólogos y neuropediatras de tres sociedades científicas, la Sociedad Española de Epilepsia (SEEP), la Sociedad Española de Urgencias y Emergencias (SEMES) y la Sociedad Española de Neurología (SEN), elaboró un listado de preguntas clínicas y revisó la literatura científica sobre el tratamiento urgente del paciente con CE. Después de un periodo de trabajo individual dando respuesta a las preguntas planteadas, se discutieron y consensuaron en una reunión con expertos de las tres sociedades los contenidos del presente documento. Las recomendaciones y los protocolos que se proponen tratan de unificar el tratamiento urgente de los pacientes con CE. Se han revisado conceptos y definiciones previas y se ha propuesto una nueva definición de CE urgente, planteando diferentes recomendaciones terapéuticas según los escenarios clínicos, incluyendo una propuesta de código crisis


This consensus statement was developed to optimize the emergency management of epileptic seizures in prehospital and hospital settings. A list of clinical questions was drafted and the literature on the emergency treatment of epileptic seizures was reviewed by a multidisciplinary team of emergency physicians, neurologists, and pediatric neurologists from 3 associations: the Spanish Epilepsy Society (SEEP), the Spanish Society of Emergency Medicine (SEMES), and the Spanish Neurology Society (SEN). The team members first answered the questions individually and then discussed them during a meeting of experts from the 3 associations, to reach consensus on the content of the present statement. The recommendations and protocols proposed attempt to standardize the emergency management epileptic seizures. Earlier concepts and definitions are reviewed, a new definition of an epileptic seizure emergency is proposed, treatment options are described for different clinical scenarios, and a crisis code for seizures is also set out


Assuntos
Humanos , Conferências de Consenso como Assunto , Epilepsia/terapia , Serviços Médicos de Emergência , Sociedades Médicas/normas , Assistência Pré-Hospitalar/normas , Benzodiazepinas/administração & dosagem , Anestesia Intravenosa/métodos
6.
PLoS One ; 15(9): e0238723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32916693

RESUMO

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.


Assuntos
Acidentes por Quedas , Azepinas/efeitos adversos , Indenos/efeitos adversos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Azepinas/administração & dosagem , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Estudos Cross-Over , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Indenos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sono/efeitos dos fármacos , Sono/fisiologia , Triazóis/administração & dosagem
7.
Neurology ; 95(19): e2683-e2696, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913024

RESUMO

OBJECTIVE: To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation. METHODS: This was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation. RESULTS: We included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49; p = 0.012), older age (OR 1.1, 95% CI 1.05-1.17; p < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23-3.69; p = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24-3.94; p = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57-0.95). CONCLUSION: BZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.


Assuntos
Anticonvulsivantes/administração & dosagem , Benzodiazepinas/administração & dosagem , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Fidelidade a Diretrizes/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Estado Epiléptico/tratamento farmacológico , Tempo para o Tratamento/estatística & dados numéricos , Adolescente , Fatores Etários , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Epilepsia Resistente a Medicamentos/fisiopatologia , Feminino , Humanos , Lactente , Levetiracetam/uso terapêutico , Masculino , Análise Multivariada , Fenobarbital/uso terapêutico , Fenitoína/análogos & derivados , Fenitoína/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores Sexuais , Estado Epiléptico/fisiopatologia
8.
Medicine (Baltimore) ; 99(30): e21414, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791758

RESUMO

Agoraphobia is frequently accompanied by panic disorder and causes considerable suffering. The aim of this study was to compare clinical features and treatment courses between patients with and without agoraphobia in panic disorder.In this retrospective study, 87 patients with panic disorder were divided into two groups depending on the presence of agoraphobia: patients with agoraphobia (PDA, n = 41) and patients without agoraphobia (PD, n = 46). Agoraphobia subscale score of the Albany Panic and Phobia Questionnaire was used to identify correlations between agoraphobia and panic and affective symptoms.The PDA group showed more severe panic and affective symptoms than the PD group. Patients with PDA were more likely to be younger at the age of onset, take benzodiazepines for longer durations, and be treated with antipsychotics augmentation. Agoraphobia subscale was associated with panic symptoms, depression, anxiety, and the duration of benzodiazepines use.The findings suggest that patients with PDA experienced more severe panic symptoms, more profound psychiatric comorbidity, and worse illness progression than those with PD.


Assuntos
Agorafobia/complicações , Transtorno de Pânico/complicações , Adulto , Agorafobia/psicologia , Benzodiazepinas/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/tratamento farmacológico , Transtorno de Pânico/psicologia , Estudos Retrospectivos , Adulto Jovem
9.
Yakugaku Zasshi ; 140(8): 1025-1033, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741860

RESUMO

Additional fees for ward pharmacists' services have been valued for hospitals in Japan. However, the calculation period for services provided to inpatients in the psychiatric ward is limited to 8 weeks. This study aimed to reveal the need for the services of pharmacists in the hospital ward for inpatients hospitalized for >8 weeks in the psychiatric ward. Patients who were hospitalized in the psychiatric ward from September 2016 to February 2017 were analyzed retrospectively. The pharmacists suggested prescriptions for inpatients admitted for >8 weeks, similar to those admitted for <9 weeks, and this supported pharmacotherapy without exacerbating patient outcomes. Moreover, significant decreases in benzodiazepine doses were found between the prior and post prescription suggestions of the pharmacist for inpatients >8 weeks of admission. Healthcare expenditures were also reduced. These results suggest that the prescriptions suggested by pharmacists for inpatients admitted for >8 weeks in the psychiatric ward were useful. In conclusion, our findings show that ward pharmacists' services were necessary not only for the inpatients hospitalized for <9 weeks, but also for those hospitalized for >8 weeks.


Assuntos
Pacientes Internados , Transtornos Mentais/tratamento farmacológico , Farmacêuticos , Serviço de Farmácia Hospitalar , Prescrições , Sugestão , Benzodiazepinas/administração & dosagem , Benzodiazepinas/economia , Custos de Cuidados de Saúde , Japão , Transtornos Mentais/economia , Prescrições/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Tempo
10.
JAMA Netw Open ; 3(6): e205860, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32568398

RESUMO

Importance: Understanding the safety profile of medications used in pregnancy is crucial for clinical decision-making. Few studies exist on the associations of exposure to benzodiazepines and benzodiazepine-like hypnotic drugs (z-hypnotics) in pregnancy with pregnancy outcomes. Objective: To determine whether exposure to benzodiazepines or z-hypnotics in pregnancy is associated with greater risk of negative immediate pregnancy outcomes compared with nonexposure. Design, Setting, and Participants: This questionnaire-based cohort study used data from the Norwegian Mother, Father and Child cohort study (MoBa), which also includes data from the Medical Birth Registry of Norway. Pregnant women were recruited from all over Norway from 1999 and 2008. The first child was born in October 1999 and the last in July 2009. This analysis included women who completed 3 questionnaires, twice during pregnancy and once 6 months after delivery. Data analyses were conducted from September to November 2019. Exposures: Self-reported exposure to benzodiazepines or z-hypnotics during pregnancy, characterized in terms of any exposure, timing (ie, early, middle, or late), and duration of exposure. Main Outcomes and Measures: The main outcomes were gestational age at delivery, risk of preterm delivery, birth weight, birth weight relative to gestational age and sex, risk of being small for gestational age, head circumference, Apgar score less than 7 at 5 minutes, and risk of neonatal respiratory distress. Continuous outcomes are reported using effect estimates as mean differences, and binary outcomes are reported using risk ratios. Results: The MoBa study included 114 234 mother-child dyads. This analysis of MoBa data includes 82 038 singleton pregnancies among 69 434 unique women. Mean (SD) maternal age was 30.2 (4.5) years, and 37 641 pregnancies (45.9%) were in primiparous women. Exposure to benzodiazepines or z-hypnotics was reported in 679 pregnancies (0.8%). After adjusting for all measured baseline and postbaseline confounders, benzodiazepine or z-hypnotic use during pregnancy was associated with lower birth weight (mean difference, -79.3 [95% CI, -126.7 to -31.9] g), lower gestational age at birth (mean difference, -2.1 [95% CI, -3.3 to -0.9] days), and higher risk of preterm birth (risk ratio, 1.41 [95% CI, 1.03 to 1.94]). We found no significant association of exposure to benzodiazepines or z-hypnotics with the child's birth weight relative to gestational age and sex (z score), or any of the other immediate birth outcomes. Conclusions and Relevance: These findings suggest that the magnitude of the association of exposure to benzodiazepines or z-hypnotics with gestational age is not necessarily clinically significant. The absence of an association of exposure to benzodiazepines or z-hypnotics with z score for birth weight relative to gestational age and sex suggests that association of exposure to benzodiazepines or z-hypnotics with birth weight could be explained by earlier delivery rather than impaired intrauterine growth.


Assuntos
Benzodiazepinas/uso terapêutico , Peso ao Nascer , Hipnóticos e Sedativos/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Índice de Apgar , Benzodiazepinas/administração & dosagem , Feminino , Idade Gestacional , Cabeça/anatomia & histologia , Humanos , Hipnóticos e Sedativos/administração & dosagem , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Noruega/epidemiologia , Gravidez , Trimestres da Gravidez , Nascimento Prematuro/epidemiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologia , Sexo , Inquéritos e Questionários
12.
Br J Anaesth ; 125(1): 38-46, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32416996

RESUMO

BACKGROUND: Delirium is common after cardiac surgery and is associated with adverse outcomes. Perioperative benzodiazepine use is associated with delirium and is common during cardiac surgery, which may increase the risk of postoperative delirium. We undertook a pilot study to inform the feasibility of a large randomised cluster crossover trial examining whether an institutional policy of restricted benzodiazepine administration during cardiac surgery (compared with liberal administration) would reduce delirium. METHODS: We conducted a two-centre, pilot, randomised cluster crossover trial with four 4 week crossover periods. Each centre was randomised to a policy of restricted or liberal use, and then alternated between the two policies during the remaining three periods. Our feasibility outcomes were adherence to each policy (goal ≥80%) and outcome assessment (one delirium assessment per day in the ICU in ≥90% of participants). We also evaluated the incidence of intraoperative awareness in one site using serial Brice questionnaires. RESULTS: Of 800 patients undergoing cardiac surgery during the trial period, 127/800 (15.9%) had delirium. Of these, 355/389 (91.3%) received benzodiazepines during the liberal benzodiazepine periods and 363/411 (88.3%) did not receive benzodiazepines during the restricted benzodiazepine periods. Amongst the 800 patients, 740 (92.5%) had ≥1 postoperative delirium assessment per day in the ICU. Of 521 patients screened for intraoperative awareness, one patient (0.2%), managed during the restricted benzodiazepine period (but who received benzodiazepine), experienced intraoperative awareness. CONCLUSIONS: This pilot study demonstrates the feasibility of a large, multicentre, randomised, cluster crossover trial examining whether an institutional policy of restricted vs liberal benzodiazepine use during cardiac surgery will reduce postoperative delirium. CLINICAL TRIAL REGISTRATION: NCT03053869.


Assuntos
Anestesia em Procedimentos Cardíacos/métodos , Benzodiazepinas/administração & dosagem , Delírio/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Idoso , Canadá , Análise por Conglomerados , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Projetos Piloto
13.
Rev Saude Publica ; 54: 40, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294666

RESUMO

OBJECTIVE: In recent decades there has been an increase in the use of antidepressants (AD) and a decrease in the use of benzodiazepines (BDZ). Prevalence, cumulative incidence, and factors associated with the incidence of AD and BDZ use in a Brazilian population were estimated in this article. METHODS: Data were collected with a self-administered questionnaire in a cohort of employees from a university in Rio de Janeiro. The prevalence of the use of AD and BDZ was calculated for 1999 (4,030), 2001 (3,574), 2006-07 (3,058), and 2012 (2,933). The cumulative incidences of the use of AD and BDZ between 1999 and 2007 were estimated by the Poisson models with robust variance estimates. RESULTS: In 1999, the prevalence of the use of AD and BDZ were 1.4% (95%CI: 1.1-1.8) and 4.7% (95%CI: 4.1-5.4), respectively; in 2012, they were 5.4% (95%CI: 5.5-6.2) and 6.8% (95%CI: 6.0-7.8). The incidence of use, between 1999 and 2007, was 4.9% (95%CI: 4.2-5.7) for AD and 8.3% (95%CI: 7.3-9.3) for BDZ. The incidences of AD and BDZ use were higher among women and participants with a positive General Health Questionnaire. CONCLUSION: In this population, the increase in the use of AD was not accompanied by a decrease in the use of BDZ, showing the prescriptions for psychotropic medication do not follow the currently recommended guidelines for treatment of common mental health disorders.


Assuntos
Antidepressivos/administração & dosagem , Benzodiazepinas/administração & dosagem , Uso de Medicamentos/tendências , Adulto , Fatores Etários , Brasil , Estudos de Coortes , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicotrópicos , Fatores Sexuais , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-32179516

RESUMO

BACKGROUND: High-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL) levels. We evaluated the impact of treatment with evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial. METHODS AND RESULTS: Time to first occurrence of any component of the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, revascularization, and hospitalization for unstable angina was compared among patients with DM randomized to treatment with evacetrapib (n=4127) or placebo (n=4109) over a median of 26 months of follow-up. The mean baseline LDL at initiation was 80 mg/dL with a mean baseline HDL of 44 mg/dL. In patients with DM, evacetrapib resulted in a 131% mean increase in HDL levels and a 32% mean decrease in LDL at 3 months that was sustained during the course of the trial. At 6 months, hemoglobin A1c (HbA1c) levels were lower with evacetrapib than placebo (7.08% vs 7.15%, p=0.023). Composite event rates were higher in patients with DM than without DM (Kaplan-Meier estimates: 15.2% vs 10.6%, HR 1.46, 95% CI 1.30 to 1.64, p<0.001). In the DM group, event rates for the composite endpoint (14.5% evacetrapib vs 16% placebo, HR 0.95, 95% CI 0.85 to 1.07, p=0.38) and individual components of the composite were similar for both evacetrapib and placebo groups. No significant treatment interaction between treatment assignment and diabetes status was noted. CONCLUSION: Despite a favorable increase in HDL, and decreases in LDL and HbA1c levels in patients with DM, we observed no benefits of treatment with evacetrapib on prespecified clinical outcomes in this high-risk population.


Assuntos
Anticolesterolemiantes/administração & dosagem , Benzodiazepinas/administração & dosagem , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Idoso , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/análise , LDL-Colesterol/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
16.
J Exp Clin Cancer Res ; 39(1): 50, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164732

RESUMO

BACKGROUND: Inhibition of ABC transporters is considered the most effective way to circumvent multidrug resistance (MDR). In the present study, we evaluated the MDR modulatory potential of ERK5-IN-1, a potent extracelluar signal regulated kinase 5 (ERK5) inhibitor. METHODS: The cytotoxicity and MDR reversal effect of ERK5-IN-1 were assessed by MTT assay. The KBv200-inoculated nude mice xenograft model was used for the in vivo study. Doxorubicin efflux and accumulation were measured by flow cytometry. The modulation of ABCB1 activity was measured by colorimetric ATPase assay and [125I]-iodoarylazidoprazosin (IAAP) photolabeling assay. Effect of ERK5-IN-1 on expression of ABCB1 and its downstream markers was measured by PCR and/or Western blot. Cell surface expression and subcellular localization of ABCB1 were tested by flow cytometry and immunofluorescence. RESULTS: Our results showed that ERK5-IN-1 significantly increased the sensitivity of vincristine, paclitaxel and doxorubicin in KBv200, MCF7/adr and HEK293/ABCB1 cells, respectively. This effect was not found in respective drug sensitive parental cell lines. Moreover, in vivo combination studies showed that ERK5-IN-1 effectively enhanced the antitumor activity of paclitaxel in KBv200 xenografts without causing addition toxicity. Mechanistically, ERK5-IN-1 increased intracellular accumulation of doxorubicin dose dependently by directly inhibiting the efflux function of ABCB1. ERK5-IN-1 stimulated the ABCB1 ATPase activity and inhibited the incorporation of [125I]-iodoarylazidoprazosin (IAAP) into ABCB1 in a concentration-dependent manner. In addition, ERK5-IN-1 treatment neither altered the expression level of ABCB1 nor blocked the phosphorylation of downstream Akt or Erk1/2. No significant reversal effect was observed on ABCG2-, ABCC1-, MRP7- and LRP-mediated drug resistance. CONCLUSIONS: Collectively, these results indicated that ERK5-IN-1 efficiently reversed ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function. The use of ERK5-IN-1 to restore sensitivity to chemotherapy or to prevent resistance could be a potential treatment strategy for cancer patients.


Assuntos
Benzodiazepinas/administração & dosagem , Doxorrubicina/administração & dosagem , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Células HEK293 , Células HL-60 , Humanos , Camundongos , Camundongos Nus , Proteína Quinase 7 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Ann Palliat Med ; 9(2): 542-557, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32036672

RESUMO

Opioids and benzodiazepines are increasingly used alone or in combination. However, the combined use of these agents increases the risk for potentially lethal respiratory depression. This review summarizes current evidence on the effects of the combined use of opioids and benzodiazepines on mortality and severe respiratory adverse events. The results of 29 included manuscripts showed that concomitant use of opioids and benzodiazepines increased the risk for these outcomes in most of clinical and non-clinical settings. However, the risk for harm and benefit of the drug combination strongly correlates to its context and there are situations, such as in the hospice setting, where benefits may outweigh the risks.


Assuntos
Analgésicos Opioides/efeitos adversos , Benzodiazepinas/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Transtornos Relacionados ao Uso de Opioides/etiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Analgésicos Opioides/administração & dosagem , Benzodiazepinas/administração & dosagem , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Humanos , Transtornos Relacionados ao Uso de Opioides/mortalidade , Doença Pulmonar Obstrutiva Crônica/mortalidade
18.
Leukemia ; 34(8): 2150-2162, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32060401

RESUMO

To target mechanisms critical for multiple myeloma (MM) plasma cell adaptations to genomic instabilities and further sustain MM cell killing, we here specifically trigger DNA damage response (DDR) in MM cells by a novel BCMA antibody-drug conjugate (ADC) delivering the DNA cross-linking PBD dimer tesirine, MEDI2228. MEDI2228, more effectively than its anti-tubulin MMAF-ADC homolog, induces cytotoxicity against MM cells regardless of drug resistance, BCMA levels, p53 status, and the protection conferred by bone marrow stromal cells and IL-6. Distinctly, prior to apoptosis, MEDI2228 activates DDRs in MM cells via phosphorylation of ATM/ATR kinases, CHK1/2, CDK1/2, and H2AX, associated with expression of DDR-related genes. Significantly, MEDI2228 synergizes with DDR inhibitors (DDRi s) targeting ATM/ATR/WEE1 checkpoints to induce MM cell lethality. Moreover, suboptimal doses of MEDI2228 and bortezomib (btz) synergistically trigger apoptosis of even drug-resistant MM cells partly via modulation of RAD51 and accumulation of impaired DNA. Such combination further induces superior in vivo efficacy than monotherapy via increased nuclear γH2AX-expressing foci, irreversible DNA damages,  and tumor cell death, leading to significantly prolonged host survival. These results indicate leveraging MEDI2228 with DDRi s or btz as novel combination strategies, further supporting ongoing clinical development of MEDI2228 in patients with relapsed and refractory MM.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Antígeno de Maturação de Linfócitos B/imunologia , Bortezomib/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Imunoconjugados/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Benzodiazepinas/administração & dosagem , Linhagem Celular Tumoral , Dano ao DNA , Sinergismo Farmacológico , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Pirróis/administração & dosagem
19.
Med J Aust ; 212(7): 309-313, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32045014

RESUMO

OBJECTIVE: To examine the prevalence of psychotropic medicine dispensing before and after older people enter residential care. DESIGN: Retrospective national cohort study; analysis of Registry of Senior Australians (ROSA) data. SETTING, PARTICIPANTS: All concession card-holding residents of government-subsidised residential aged care facilities in Australia who entered residential care for at least three months between 1 April 2008 and 30 June 2015. MAIN OUTCOME MEASURES: Proportions of residents dispensed antipsychotic, benzodiazepine, or antidepressant medicines during the year preceding and the year after commencing residential care, by quarter. RESULTS: Of 322 120 included aged care residents, 68 483 received at least one antipsychotic (21.3%; 95% CI, 21.1-21.4%), 98 315 at least one benzodiazepine (30.5%; 95% CI, 30.4-30.7%), and 122 224 residents at least one antidepressant (37.9%; 95% CI, 37.8-38.1%) during their first three months of residential care; 31 326 of those dispensed antipsychotics (45.7%), 38 529 of those dispensed benzodiazepines (39.2%), and 25 259 residents dispensed antidepressants (19.8%) had not received them in the year preceding their entry into care. During the first three months of residential care, the prevalence of antipsychotic (prevalence ratio [PR], 3.37; 95% CI, 3.31-3.43) and antidepressant dispensing (PR, 1.05; 95% CI, 1.04-1.07) were each higher for residents with than for those without dementia; benzodiazepine dispensing was similar for both groups (PR, 1.01; 95% CI, 0.99-1.02). CONCLUSIONS: Dispensing of psychotropic medicines to older Australians is high before they enter residential care but increases markedly soon after entry into care. Non-pharmacological behavioural management strategies are important for limiting the prescribing of psychotropic medicines for older people in the community or in residential care.


Assuntos
Antidepressivos/administração & dosagem , Benzodiazepinas/administração & dosagem , Uso de Medicamentos/estatística & dados numéricos , Instituição de Longa Permanência para Idosos/estatística & dados numéricos , Casas de Saúde/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Demência/tratamento farmacológico , Feminino , Instituição de Longa Permanência para Idosos/organização & administração , Humanos , Masculino , Mortalidade , Sistema de Registros , Estudos Retrospectivos
20.
Trials ; 21(1): 136, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014032

RESUMO

BACKGROUND: The GABAA-α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS). S44819 is currently evaluated in this indication; RESTORE brain study started in Dec 2016 and was completed in March 2019. METHODS/DESIGN: The study is a 3-month international, randomized, double-blind, parallel group, placebo-controlled phase II multicentre study. Patients in 14 countries who suffered an IS leading to a moderate or severe deficit defined by NIHSS score ranging from 7 to 20 and are aged between 18 to 85 years are included between 3 and 8 days after the stroke onset. Approximately 580 patients are to be included. The primary objective of the study is to demonstrate the superiority of at least one of the two doses of S44819 (150 or 300 mg bid) compared to placebo on top of usual care on functional recovery measured with the modified Rankin scale at 3 months. Comparisons between two doses of S44819 and placebo are assessed with ordinal logistic regression evaluating the odds of shifting from one category to the next in the direction of a better outcome at day 90. Secondary objectives include the evaluation of S44819 effects on neurological examination using the National Institute of Health Stroke Scale total score, activities of daily living using the Barthel Index total score, and cognitive performance using the Montreal Cognitive Assessment scale total score and Trail Making Test times. Safety and tolerability of the two doses of S44819 will also be analyzed. DISCUSSION: The RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS. TRIAL REGISTRATION: Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event, an international, multi-centre, randomized, double-blind placebo-controlled phase II study. ClinicalTrials.gov, NCT02877615; Eudract 2016-001005-16. Registered 24 August 2016.


Assuntos
Benzodiazepinas/administração & dosagem , Isquemia Encefálica/tratamento farmacológico , Antagonistas de Receptores de GABA-A/administração & dosagem , Hemorragias Intracranianas/tratamento farmacológico , Oxazóis/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Atividades Cotidianas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzodiazepinas/efeitos adversos , Método Duplo-Cego , Feminino , Antagonistas de Receptores de GABA-A/efeitos adversos , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Oxazóis/efeitos adversos , Recuperação de Função Fisiológica/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...