RESUMO
OBJECTIVES: The objectives of this study were to assess the risk of severe coronavirus disease 2019 (COVID-19) outcomes in patients with mature B-cell non-Hodgkin lymphoma (mature B-cell NHL) compared with other cancers and to identify risk factors associated with severe COVID-19. METHODS: This study used Optum's electronic health record database. Risk factors were evaluated using multivariable logistic regression. RESULTS: Patients with mature B-cell NHL were more likely to be hospitalized or die from COVID-19 (age- and sex-standardized risk: 15.6%, 2.1%, respectively) than those without cancer (9.5%, 1.2%), or with solid tumors (9.7%, 1.3%). In patients with mature B-cell NHL, factors associated with severe COVID-19 outcomes included: greater age (75-84 years, adjusted odds ratio, 1.6 [95% CI, 1.3-2.0]; ≥85, 2.6 [2.0-3.4]), male sex (1.4 [1.2-1.6]), chronic kidney disease (1.4 [1.1-1.7]), chronic obstructive pulmonary disease (1.3 [1.0-1.6]), type 2 diabetes (1.3 [1.1-1.5]), and receiving treatment for NHL (1.5 [1.1-2.1]). CONCLUSIONS: These data suggest that patients with mature B-cell NHL are at a higher risk of severe COVID-19 than patients with solid tumors or without cancer and that risk factors are largely consistent with those in the general population.
Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Linfoma não Hodgkin , Neoplasias , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , COVID-19/complicações , COVID-19/epidemiologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/epidemiologia , Registros Eletrônicos de Saúde , Fatores de RiscoRESUMO
BACKGROUND: Women with a BRCA1 or BRCA2 mutation have high lifetime risks of developing breast and ovarian cancers. We sought to estimate the prevalence of cancer-related distress and to identify predictors of distress in an international sample of unaffected women with a BRCA mutation. METHODS: Women with a BRCA1/2 mutation and no previous cancer diagnosis were recruited from the United States, Canada, the United Kingdom, Australia and from a national advocacy group. Using an online survey, we asked about cancer risk reduction options and screening, and we measured cancer-related distress using the Impact of Event Scale. RESULTS: Among 576 respondents, mean age was 40.8 years (SD = 8.1). On average 4.9 years after a positive test result, 16.3% of women reported moderate-to-severe cancer-related distress. Women who had undergone risk-reducing breast and ovarian surgery were less likely to have (moderate or severe) cancer-related distress compared to other women (22.0% versus 11.4%, P value = 0.007). Women recruited from the advocacy group were more likely to have cancer-related distress than other women (21.6% versus 5.3%, P value = 0.002). CONCLUSIONS: Approximately 16% of women with a BRCA1 or BRCA2 mutation experience distress levels comparable to those of women after a cancer diagnosis. Distress was lower for women who had risk-reducing surgery.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/psicologia , Neoplasias Ovarianas/psicologia , Angústia Psicológica , Adulto , Austrália , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Canadá , Feminino , Testes Genéticos , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Fatores de Risco , Reino UnidoRESUMO
BACKGROUND: The putative benefits of cinacalcet therapy for management of secondary hyperparathyroidism (SHPT) are thought to be most manifested when patients are taking it consistently and as prescribed. Real-world descriptions of cinacalcet prescription discontinuation and reinitiation in European hemodialysis patients are lacking. To address this knowledge gap, we used Dialysis Outcomes and Practice Patterns Study (DOPPS) data, based on dialysis facility medical records, from seven European countries to estimate rates and predictors of cinacalcet prescription discontinuation and reinitiation in hemodialysis patients and to describe the trajectories of CKD-MBD laboratory values after discontinuation. METHODS: Cox regression analyses were used to predict (1) cinacalcet discontinuation among 613 patients with ≥3 consecutive months without cinacalcet prescription immediately prior to a new cinacalcet prescription and (2) cinacalcet reinitiation among 415 patients with a newly discontinued cinacalcet prescription immediately after ≥3 consecutive months of prescribed use. RESULTS: Cinacalcet was discontinued in 21 and 35% of new users after 6 and 12 months, respectively. Cinacalcet was reinitiated in 38 and 49% of newly-discontinued users after 6 and 12 months, respectively. Predictors of discontinuation included lower parathyroid hormone (PTH) in the previous month (< 150 pg/ml vs. 150-299, HR = 2.57 [95% CI: 1.52-4.33]) and lower serum calcium in the previous month (< 8.4 mg/dl vs. 8.4-10.19, HR = 1.67 [95% CI: 1.08-2.59]). Predictors of reinitiation included higher PTH in the previous month (300-599 pg/ml vs. 150-299, HR = 1.88 [95% CI = 1.19-2.97]; 600+ pg/ml, HR = 3.02 [95% CI = 1.92-4.76]). After cinacalcet discontinuation, mean serum PTH increased from 408 to 510 pg/ml, mean serum calcium briefly rose from 9.12 to 9.22 mg/dl before declining to 9.06 mg/dl, and mean serum phosphorus showed little change. CONCLUSIONS: Nephrologist discontinuation of cinacalcet therapy is common in European countries. Additional research is needed to identify optimal cinacalcet treatment strategies for SHPT management, including comparisons of intermittent cinacalcet therapy versus sustained treatment with reduced dose or frequency.
Assuntos
Calcimiméticos/administração & dosagem , Cinacalcete/administração & dosagem , Diálise Renal/tendências , Suspensão de Tratamento/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Previsões , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Influenza vaccines are most effective when the antigens in the vaccine match those of circulating strains. However, antigens contained in the vaccines do not always match circulating strains. In the present work we aimed to examine the vaccine efficacy (VE) afforded by influenza vaccines when they are not well matched to circulating strains. METHODS: We identified randomized clinical trials (RCTs) through MEDLINE, EMBASE, the Cochrane Library, and references of included RCTs. RCTs reporting laboratory-confirmed influenza among healthy participants vaccinated with antigens of matching and non-matching influenza strains were included. Two independent reviewers screened citations/full-text articles, abstracted data, and appraised risk of bias. Conflicts were resolved by discussion. A random effects meta-analysis was conducted. VE was calculated using the following formula: (1 - relative risk × 100%). RESULTS: We included 34 RCTs, providing data on 47 influenza seasons and 94,821 participants. The live-attenuated influenza vaccine (LAIV) showed significant protection against mismatched (six RCTs, VE 54%, 95% confidence interval (CI) 28% to 71%) and matched (seven RCTs, VE 83%, 95% CI 75% to 88%) influenza strains among children aged 6 to 36 months. Differences were observed between the point estimates for mismatched influenza A (five RCTs, VE 75%, 95% CI 41% to 90%) and mismatched influenza B (five RCTs, VE 42%, 95% CI 22% to 56%) estimates among children aged 6 to 36 months. The trivalent inactivated vaccine (TIV) also afforded significant protection against mismatched (nine RCTs, VE 52%, 95% CI 37% to 63%) and matched (eight RCTs, VE 65%, 95% CI 54% to 73%) influenza strains among adults. Numerical differences were observed between the point estimates for mismatched influenza A (five RCTs, VE 64%, 95% CI 23% to 82%) and mismatched influenza B (eight RCTs, VE 52%, 95% CI 19% to 72%) estimates among adults. Statistical heterogeneity was low (I2 <50%) across all meta-analyses, except for the LAIV meta-analyses among children (I2 = 79%). CONCLUSIONS: The TIV and LAIV vaccines can provide cross protection against non-matching circulating strains. The point estimates for VE were different for matching versus non-matching strains, with overlapping CIs.
Assuntos
Vacinas contra Influenza/genética , Vacinas contra Influenza/uso terapêutico , Influenza Humana/genética , Influenza Humana/prevenção & controle , Proteção Cruzada/genética , Humanos , Influenza Humana/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Especificidade da Espécie , Resultado do Tratamento , Vacinas Atenuadas/genética , Vacinas Atenuadas/uso terapêuticoRESUMO
Introduction: The COVID-19 pandemic has caused over 6 million deaths worldwide and is a significant cause of mortality. Mortality dynamics vary significantly by country due to pathogen, host, social and environmental factors, in addition to vaccination and treatments. However, there is limited data on the relative contribution of different explanatory variables, which may explain changes in mortality over time. We, therefore, created a predictive model using orthogonal machine learning techniques to attempt to quantify the contribution of static and dynamic variables over time. Methods: A model was created using Partial Least Squares Regression trained on data from 2020 to rank order the significance and effect size of static variables on mortality per country. This model enables the prediction of mortality levels for countries based on demographics alone. Partial Least Squares Regression was then used to quantify how dynamic variables, including weather and non-pharmaceutical interventions, contributed to the overall mortality in 2020. Finally, mortality levels for the first 60 days of 2021 were predicted using rolling-window Elastic Net regression. Results: This model allowed prediction of deaths per day and quantification of the degree of influence of included variables, accounting for timing of occurrence or implementation. We found that the most parsimonious model could be reduced to six variables; three policy-related variables - COVID-19 testing policy, canceled public events policy, workplace closing policy; in addition to three environmental variables - maximum temperature per day, minimum temperature per day, and the dewpoint temperature per day. Conclusion: Country and population-level static and dynamic variables can be used to predict COVID-19 mortality, providing an example of how broad temporal data can inform a preparation and mitigation strategy for both COVID-19 and future pandemics and assist decision-makers by identifying population-level contributors, including interventions, that have the greatest influence in mitigating mortality, and optimizing the health and safety of populations.
Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , Teste para COVID-19 , Pandemias , Febre , Política PúblicaRESUMO
The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. Site-directed mutagenesis (SDM) and domain exchange (chimera) studies have provided important insight into key features of the OX1 and OX2 binding sites. However, the precise determinants of antagonist binding and selectivity are still not fully known. In this work, we used homology modeling of OX receptors to direct further SDM studies. These SDM studies were followed by molecular dynamics (MD) simulations to rationalize the full scope of the SDM data and to explain the role of each mutated residue in the binding and selectivity of a set of OX antagonists: Almorexant (dual OX1 and OX2 antagonist), SB-674042 (OX1 selective antagonist), EMPA (OX2 selective antagonist), and others. Our primary interest was focused on transmembrane helix 3 (TM3), which is identified as being of great importance for the selectivity of OX antagonists. These studies revealed conformational differences between the TM3 helices of OX1 and OX2, resulting from differences in amino acid sequences of the OX receptors that affect key interhelical interactions formed between TM3 and neighboring TM domains. The MD simulation protocol used here, which was followed by flexible docking studies, went beyond the use of static models and allowed for a more detailed exploration of the OX structures. In this work, we have demonstrated how even small differences in the amino acid sequences of GPCRs can lead to significant differences in structure, antagonist binding affinity, and selectivity of these receptors. The MD simulations allowed refinement of the OX receptor models to a degree that was not possible with static homology modeling alone and provided a deeper rationalization of the SDM data obtained. To validate these findings and to demonstrate that they can be usefully applied to the design of novel, very selective OX antagonists, we show here two examples of antagonists designed in house: EP-109-0092 (OX1 selective) and EP-009-0513 (OX2 selective).
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/química , Neuropeptídeos/antagonistas & inibidores , Neuropeptídeos/química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Neuropeptídeos/metabolismo , Orexinas , Conformação Proteica , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Reactions of the allyltin trichloride 45 generated from (4S)-4-benzyloxypent-2-enyl(tributyl)stannane 1 with imines prepared from glyoxylates proceed with useful levels of 1,5-stereocontrol in favour of (4E)-2,6-anti-2-(alkylamino)-6-benzyloxyhept-4-enoates 49. This stereoselectivity, controlled by the chirality of the stannane, dominates over any intrinsic stereochemical bias of the imine although a small amount of matching and mis-matching was observed. The allyltin trichloride 77 prepared from (4S)-4-(tert-butyldimethylsilyloxy)pent-2-enyl(tributyl)stannane 52 reacts with 1-alkoxycarbonylimines with the opposite 1,5-stereoselectivity to give the (4E)-2,6-syn-diastereoisomers 79. Matching and mismatching was more pronounced for tin(IV) chloride mediated reactions of (4R)-5-benzyloxy-4-methylpent-2-enyl(tributyl)stannane 80 with chiral 1-alkoxycarbonylimines but useful stereoselectivity in favour of (4E)-2,6-syn-2-alkyl- and arylthio-amino-7-benzyloxy-6-methylhept-4-enoates 177 was observed for reactions with achiral imines and similar, but reduced, stereoselectivity was observed for the 5-tert-butyldimethylsilyloxypentenylstannane 82. However, excellent 1,5-stereocontrol in favour of the (4E)-2,6-anti-isomers 179 was found using the 4,5-bis-alkoxypent-2-enylstannane 106. Modest (4E)-2,7-anti-stereoselectivity was observed in the analogous tin(IV) bromide mediated reactions of (S)-5-methoxy- and (S)-5-hydroxyhex-2-enyl(tributyl)stannanes (S)-123 and (S)-122 with achiral 1-alkoxycarbonylimines but in this series the intrinsic stereochemical bias of the imine controls the facial selectivity of reactions of chiral 1-alkoxycarbonylimines. Useful (4E)-2,6-anti-stereoselectivity was also observed in the tin(IV) chloride promoted reaction of the 4-benzyloxypent-2-enylstannane 1 with an oxime O-benzyl ether.
Assuntos
Aminoácidos/química , Iminas/química , Compostos de Estanho/química , Catálise , Oximas/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.
Assuntos
Antivirais/química , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos , Oligopeptídeos/química , Linhagem Celular , Humanos , Serpinas/química , Proteínas Virais/químicaRESUMO
A series of potent and subtype selective H3 receptor antagonists containing a novel tetrazole core and diamine motif is reported. A one-pot multi-component Ugi reaction was utilised to rapidly develop the structure-activity relationships (SAR) of these compounds. Optimisation for liver microsome stability (t(1/2)>60 min), minimal CYP inhibition (IC(50)>50 microM) and high cell permeability (Caco-2 P(app) >20x10(-6) cm/s) identified several compounds with drug-like properties.
Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacologia , Tetrazóis/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular , Descoberta de Drogas , Meia-Vida , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
A novel series of 2-aminobenzimidazole inhibitors of BACE1 has been discovered using fragment-based drug discovery (FBDD) techniques. The rapid optimization of these inhibitors using structure-guided medicinal chemistry is discussed.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Humanos , Modelos Moleculares , Inibidores de Proteases/química , Relação Estrutura-AtividadeRESUMO
RATIONALE: It is commonly stated that mortality from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is decreasing. OBJECTIVES: To systematically review the literature assessing ARDS mortality over time and to determine patient- and study-level factors independently associated with mortality. METHODS: We searched multiple databases (MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL) for prospective observational studies or randomized controlled trials (RCTs) published during the period 1984 to 2006 that enrolled 50 or more patients with ALI/ARDS and reported mortality. We pooled mortality estimates using random-effects meta-analysis and examined mortality trends before and after 1994 (when a consensus definition of ALI/ARDS was published) and factors associated with mortality using meta-regression models. MEASUREMENTS AND MAIN RESULTS: Of 4,966 studies, 89 met inclusion criteria (53 observational, 36 RCTs). There was a total of 18,900 patients (mean age 51.6 years; 39% female). Overall pooled weighted mortality was 44.3% (95% confidence interval [CI], 41.8-46.9). Mortality decreased with time in observational studies conducted before 1994; no temporal associations with mortality were demonstrated in RCTs (any time) or observational studies (after 1994). Pooled mortality from 1994 to 2006 was 44.0% (95% CI, 40.1-47.5) for observational studies, and 36.2% (95% CI, 32.1-40.5) for RCTs. Meta-regression identified study type (observational versus RCT, odds ratio, 1.36; 95% CI, 1.08-1.73) and patient age (odds ratio per additional 10 yr, 1.27; 95% CI, 1.07-1.50) as the only factors associated with mortality. CONCLUSIONS: A decrease in ARDS mortality was only seen in observational studies from 1984 to 1993. Mortality did not decrease between 1994 (when a consensus definition was published) and 2006, and is lower in RCTs than observational studies.
Assuntos
Síndrome do Desconforto Respiratório/mortalidade , Saúde Global , Humanos , Taxa de Sobrevida/tendências , Fatores de TempoRESUMO
Novel nonpeptidic inhibitors of beta-secretase (BACE1) have been discovered by employing a fragment-based biochemical screening approach. A diverse library of 20000 low-molecular weight compounds were screened and yielded 26 novel hits that were confirmed by biochemical and surface plasmon resonance secondary assays. We describe here fragment inhibitors cocrystallized with BACE1 in a flap open and flap closed conformation as determined by X-ray crystallography.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/químicaRESUMO
Protein crystallography has proven to be an effective method of obtaining high-resolution structures of protein-ligand complexes. However, in certain cases only apoprotein structures are readily available and the generation of crystal complexes is more problematic. Some crystallographic systems are not amenable to soaking of ligands owing to crystal-packing effects and many protein-ligand complexes do not crystallize under the same conditions as used for the apoprotein. Using crystals of human phosphodiesterase 10a (hPDE10a) as an example of such a challenging crystallographic system, the structure of the complex with papaverine was obtained to 2.8 A resolution using protein crystals cross-linked by glutaraldehyde prior to soaking of the ligand. Inspection of the electron-density maps suggested that the correct mode of binding was obtained in one of the two monomers in the asymmetric unit and inspection of crystal-packing contacts explained why cocrystallization experiments and soaking of crystals that were not cross-linked were unsuccessful.
Assuntos
Complexos Multiproteicos/química , Papaverina/química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/química , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/metabolismo , Cristalização , Cristalografia por Raios X , Glutaral/química , Glutaral/metabolismo , Humanos , Ligantes , Complexos Multiproteicos/metabolismo , Papaverina/metabolismo , Inibidores de Fosfodiesterase/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Ligação Proteica , Conformação ProteicaRESUMO
BACKGROUND: Since Mehta et al. reported the first successful use of regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) in 1990, RCA is increasingly used for CRRT because it provides filter patency with minimal risk of bleeding. However, RCA has been associated with significant metabolic complications including hypocalcemia, hypernatremia, metabolic alkalosis, and citrate toxicity. OBJECTIVE: To describe our experience with a newly implemented RCA protocol with acid citrate dextrose formula A (ACD-A) and intravenous calcium gluconate, for use with PrismaFlex CRRT in critically ill patients with acute kidney injury. METHODS: A retrospective chart review was conducted from May 1, 2006, until May 1, 2007, in a 16-bed medical-surgical university-affiliated intensive care unit. Data collected included dialysis filter life, patient and circuit metabolic parameters, and units of packed red blood cells transfused. RESULTS: Forty-eight patients received dialysis with citrate (n = 178 filters). Circuit clotting occurred in 24% of all filters. Mean +/- SD filter life was 38.4 +/- 25.9 hours, and filter survival at 48 hours was 38.2%. Persistent metabolic alkalosis while on CRRT was identified in 6 of 45 (13.3%) patients. Mild hypocalcemia (ionized calcium <3.6 mg/dL) occurred in 11 (23%) patients, but no patient had an ionized calcium level less than 2.8 mg/dL. Six patients, 3 with acute leukemia, required transfusion of 2 or more units of packed red blood cells in 24 hours. CONCLUSIONS: We found that anticoagulation of PrismaFlex CRRT with ACD-A and intravenous calcium gluconate provided reasonable filter patency, but with minor metabolic complications. Close monitoring of electrolyte and acid-base balance is required to minimize metabolic derangements.
Assuntos
Injúria Renal Aguda/terapia , Anticoagulantes/administração & dosagem , Ácido Cítrico/administração & dosagem , Glucose/análogos & derivados , Terapia de Substituição Renal/métodos , Adulto , Idoso , Alcalose/etiologia , Gluconato de Cálcio/administração & dosagem , Estado Terminal , Feminino , Glucose/administração & dosagem , Hospitais Universitários , Humanos , Hipocalcemia/etiologia , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Terapia de Substituição Renal/efeitos adversos , Estudos RetrospectivosRESUMO
OBJECTIVE: Protocolized sedation (PS) and daily sedative interruption (DI) in critically ill patients have both been shown to shorten the durations of mechanical ventilation (MV) and intensive care unit (ICU) stay. Our objective was to determine the safety and feasibility of a randomized trial to determine whether adults managed with both PS + DI have a shorter duration of MV than patients managed with PS alone. DESIGN: Prospective randomized, concealed, unblinded, multicenter, pilot trial. SETTING: Three university-affiliated medical-surgical ICUs. PATIENTS: Sixty-five adults anticipated to require MV >48 hrs and receiving sedative/analgesic infusions. INTERVENTIONS: Patients were randomized to PS alone, or PS + DI. PS was implemented by bedside nurses; sedatives/analgesics were titrated to achieve Sedation Agitation Score (SAS) 3-4. The PS + DI group also had infusions interrupted daily until the patients awoke. MEASUREMENTS AND MAIN RESULTS: Diagnosis, age [mean +/- SD] (53 +/- 18.3 vs. 62.1 +/- 16.7 yrs) and Acute Physiology and Chronic Health Evaluation II (27.7 +/- 8.4 vs. 26.6 +/- 8.4) were similar in the PS and PS + DI groups, respectively. The median duration of MV in the PS and PS + DI groups was 8.0 vs. 10.5 days, and ICU stay was 10.0 vs. 13.0 days, respectively. The SAS was within target range (3-4) in 59% of 9,611 measurements, and within an acceptable range (2-5) in 86% of measurements. Self-assessed nursing and respiratory therapist workload was low in the majority of the cohort. Adverse events were similar in both groups. Patient recruitment was slower than projected (1.5 patients/mo). CONCLUSION: This pilot trial comparing PS vs. PS + DI confirmed the safety and acceptability of the sedation protocol and DI, and guided important modifications to the protocol, thus enhancing the feasibility of a future multicenter trial. This trial was not designed to detect small but significant differences in clinically important outcomes.
Assuntos
APACHE , Sedação Consciente/efeitos adversos , Cuidados Críticos/métodos , Mortalidade Hospitalar , Midazolam , Morfina , Bloqueadores Neuromusculares/farmacologia , Respiração Artificial , Sono/efeitos dos fármacos , Idoso , Sedação Consciente/classificação , Sedação Consciente/métodos , Feminino , Humanos , Hipnóticos e Sedativos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Projetos Piloto , SegurançaRESUMO
BACKGROUND: The Intensive Care Unit (ICU) is a data-rich environment where information technology (IT) may enhance patient care. We surveyed ICUs in the province of Ontario, Canada, to determine the availability, implementation and variability of information systems. METHODS: A self-administered internet-based survey was completed by ICU directors between May and October 2006. We measured the spectrum of ICU clinical data accessible electronically, the availability of decision support tools, the availability of electronic imaging systems for radiology, the use of electronic order entry and medication administration systems, and the availability of hardware and wireless or mobile systems. We used Fisher's Exact tests to compare IT availability and Classification and Regression Trees (CART) to estimate the optimal cut-point for the number of computers per ICU bed. RESULTS: We obtained responses from 50 hospitals (68.5% of institutions with level 3 ICUs), of which 21 (42%) were university-affiliated. The majority electronically accessed laboratory data and imaging reports (92%) and used picture archiving and communication systems (PACS) (76%). Other computing functions were less prevalent (medication administration records 46%, physician or nursing notes 26%; medication order entry 22%). No association was noted between IT availability and ICU size or university affiliation. Sites used clinical information systems from15 different vendors and 8 different PACS systems were in use. Half of the respondents described the number of computers available as insufficient. Wireless networks and mobile computing systems were used in 23 ICUs (46%). CONCLUSION: Ontario ICUs demontrate a high prevalence of the use of basic information technology systems. However, implementation of the more complex and potentially more beneficial applications is low. The wide variation in vendors utilized may impair information exchange, interoperability and uniform data collection.
Assuntos
Difusão de Inovações , Pesquisas sobre Atenção à Saúde , Sistemas de Informação Hospitalar/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Sistemas de Informação em Farmácia Clínica/instrumentação , Sistemas de Informação em Farmácia Clínica/estatística & dados numéricos , Sistemas de Apoio a Decisões Clínicas/instrumentação , Sistemas de Apoio a Decisões Clínicas/estatística & dados numéricos , Humanos , Internet , Sistemas de Registro de Ordens Médicas/estatística & dados numéricos , Ontário , Telemetria/instrumentação , Telemetria/estatística & dados numéricosRESUMO
Non-selective benzodiazepines, such as diazepam, interact with equivalent affinity and agonist efficacy at GABA(A) receptors containing either an alpha1, alpha2, alpha3 or alpha5 subunit. However, which of these particular subtypes are responsible for the anticonvulsant effects of diazepam remains uncertain. In the present study, we examined the ability of diazepam to reduce pentylenetetrazoLe (PTZ)-induced and maximal electroshock (MES)-induced seizures in mice containing point mutations in single (alpha1H101R, alpha2H101R or alpha5H105R) or multiple (alpha125H-->R) alpha subunits that render the resulting GABA(A) receptors diazepam-insensitive. Furthermore, the anticonvulsant properties of diazepam, the alpha1- and alpha3-selective compounds zolpidem and TP003, respectively, and the alpha2/alpha3 preferring compound TP13 were studied against PTZ-induced seizures. In the transgenic mice, no single subtype was responsible for the anticonvulsant effects of diazepam in either the PTZ or MES assay and neither the alpha3 nor alpha5 subtypes appeared to confer anticonvulsant activity. Moreover, whereas the alpha1 and alpha2 subtypes played a modest role with respect to the PTZ assay, they had a negligible role in the MES assay. With respect to subtype-selective compounds, zolpidem and TP003 had much reduced anticonvulsant efficacy relative to diazepam in both the PTZ and MES assays whereas TP13 had high anticonvulsant efficacy in the PTZ but not the MES assay. Taken together, these data not only indicate a role for alpha2-containing GABA(A) receptors in mediating PTZ and MES anticonvulsant activity but also suggest that efficacy at more than one subtype is required and that these subtypes act synergistically.
Assuntos
Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Receptores de GABA-A/fisiologia , Convulsões/prevenção & controle , Animais , Sítios de Ligação , Convulsivantes , Diazepam/farmacologia , Eletrochoque , Agonistas de Receptores de GABA-A , Ligantes , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Pentilenotetrazol , Mutação Puntual , Subunidades Proteicas/agonistas , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Piridinas/farmacologia , Receptores de GABA-A/genética , Convulsões/etiologia , ZolpidemRESUMO
BACKGROUND: Nursing-directed sedation protocols have been shown to reduce the duration of mechanical ventilation and shorten the length of intensive care unit (ICU) stay among critically ill adult patients. METHODS: We designed a self-administered questionnaire to understand nurses' satisfaction with current sedation and analgesia practices as well as drug therapies in the ICU setting and the perceived relevance of sedation protocols to patient care and nursing autonomy. We surveyed nurses from 3 academic medical-surgical ICUs that were not using a sedation protocol or a sedation scale. Responses were based on a 5-point Likert scale and on text responses to open-ended questions. RESULTS: Of the 88 respondents, only 52.7% were satisfied (score, > or =4) overall with their local ICU's approach to sedation and analgesia. Nurses favored the use of morphine (85.0%), midazolam (71.2%), and fentanyl (59.6%) over that of lorazepam (38.6%) and haloperidol (15.4%). Some nurses (39.3%) were satisfied with the subjective methods used in their ICU to evaluate sedation adequacy. Almost all respondents believed that a nursing-directed sedation protocol combined with a sedation/agitation scoring system would be valuable to patient care (84.3%) as well as professional nursing practice (85.3%) and that a standardized approach by nurses and physicians was important (81.6%). CONCLUSIONS: In this survey of ICU nurses, we identified a perceived need for improvement in sedation and analgesia practices. Most respondents believed that the use of a nursing-directed sedation protocol in combination with a sedation scoring system would provide greater practice consistency among nurses and physicians and thus improve the care of critically ill patients.
Assuntos
Analgésicos/administração & dosagem , Atitude do Pessoal de Saúde , Protocolos Clínicos , Hipnóticos e Sedativos/administração & dosagem , Respiração Artificial/enfermagem , Adulto , Ansiedade/prevenção & controle , Pesquisas sobre Atenção à Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Unidades de Terapia Intensiva , Avaliação em Enfermagem , Ontário , Dor/prevenção & controle , Agitação Psicomotora/prevenção & controleRESUMO
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.
Assuntos
Ansiolíticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Subunidades Proteicas/fisiologia , Receptores de GABA-A/fisiologia , Animais , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Benzodiazepinas/farmacologia , Relação Dose-Resposta a Droga , Agonistas de Receptores de GABA-A , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , SaimiriRESUMO
A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.