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1.
Emergencias ; 36(2): 88-96, 2024 Apr.
Artigo em Espanhol, Inglês | MEDLINE | ID: mdl-38607301

RESUMO

OBJECTIVES: To develop and validate a risk model for 1-year mortality based on variables available from early prehospital emergency attendance of patients with infection. MATERIAL AND METHODS: Prospective, observational, noninterventional multicenter study in adults with suspected infection transferred to 4 Spanish hospitals by advanced life-support ambulances from June 1, 2020, through June 30, 2022. We collected demographic, physiological, clinical, and analytical data. Cox regression analysis was used to develop and validate a risk model for 1-year mortality. RESULTS: Four hundred ten patients were enrolled (development cohort, 287; validation cohort, 123). Cumulative mortality was 49% overall. Sepsis (infection plus a Sepsis-related Organ Failure Assessment score of 2 or higher) was diagnosed in 29.2% of survivors vs 56.7% of nonsurvivors. The risk model achieved an area under the receiver operating characteristic curve of 0.89 for 1-year mortality. The following predictors were included in the model: age; institutionalization; age-adjusted Charlson comorbidity index; PaCO2; potassium, lactate, urea nitrogen, and creatinine levels; fraction of inspired oxygen; and diagnosed sepsis. CONCLUSION: The model showed excellent ability to predict 1-year mortality based on epidemiological, analytical, and clinical variables, identifying patients at high risk of death soon after their first contact with the health care system.


OBJETIVO: Diseñar y validar un modelo de riesgo con variables determinadas a nivel prehospitalario para predecir el riesgo de mortalidad a largo plazo (1 año) en pacientes con infección. METODO: Estudio multicéntrico, observacional prospectivo, sin intervención, en pacientes adultos con sospecha infección atendidos por unidades de soporte vital avanzado y trasladados a 4 hospitales españoles entre el 1 de junio de 2020 y el 30 de junio de 2022. Se recogieron variables demográficas, fisiológicas, clínicas y analíticas. Se construyó y validó un modelo de riesgo para la mortalidad a un año usando una regresión de Cox. RESULTADOS: Se incluyeron 410 pacientes, con una tasa de mortalidad acumulada al año del 49%. La tasa de diagnóstico de sepsis (infección e incremento sobre el SOFA basal $ 2 puntos) fue del 29,2% en supervivientes frente a un 56,7% en no supervivientes. El modelo predictivo obtuvo un área bajo la curva de la característica operativa del receptor para la mortalidad a un año fue de 0,89, e incluyó: edad, institucionalización, índice de comorbilidad de Charlson ajustado por edad, presión parcial de dióxido de carbono, potasio, lactato, nitrógeno ureico en sangre, creatinina, saturación en relación con fracción inspirada de oxígeno y diagnóstico de sepsis. CONCLUSIONES: El modelo desarrollado con variables epidemiológicas, analíticas y clínicas mostró una excelente capacidad predictiva, y permitió identificar desde el primer contacto del paciente con el sistema sanitario, a modo de evento centinela, casos de alto riesgo.


Assuntos
Serviços Médicos de Emergência , Sepse , Adulto , Humanos , Estudos Prospectivos , Ambulâncias , Ácido Láctico , Sepse/diagnóstico
2.
Emergencias (Sant Vicenç dels Horts) ; 36(2): 88-96, Abr. 2024. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-231793

RESUMO

Objetivo: Diseñar y validar un modelo de riesgo con variables determinadas a nivel prehospitalario para predecir el riesgo de mortalidad a largo plazo (1 año) en pacientes con infección. Métodos: Estudio multicéntrico, observacional prospectivo, sin intervención, en pacientes adultos con sospecha infección atendidos por unidades de soporte vital avanzado y trasladados a 4 hospitales españoles entre el 1 de junio de 2020 y el 30 de junio de 2022. Se recogieron variables demográficas, fisiológicas, clínicas y analíticas. Se construyó y validó un modelo de riesgo para la mortalidad a un año usando una regresión de Cox.Resultados: Se incluyeron 410 pacientes, con una tasa de mortalidad acumulada al año del 49%. La tasa de diagnóstico de sepsis (infección e incremento sobre el SOFA basal $ 2 puntos) fue del 29,2% en supervivientes frente a un 56,7% en no supervivientes. El modelo predictivo obtuvo un área bajo la curva de la característica operativa del receptor para la mortalidad a un año fue de 0,89, e incluyó: edad, institucionalización, índice de comorbilidad de Charlson ajustado por edad, presión parcial de dióxido de carbono, potasio, lactato, nitrógeno ureico en sangre, creatinina, saturación en relación con fracción inspirada de oxígeno y diagnóstico de sepsis.Conclusiones: El modelo desarrollado con variables epidemiológicas, analíticas y clínicas mostró una excelente capacidad predictiva, y permitió identificar desde el primer contacto del paciente con el sistema sanitario, a modo de evento centinela, casos de alto riesgo.(AU)


Objectives: To develop and validate a risk model for 1-year mortality based on variables available from earlyprehospital emergency attendance of patients with infection. Methods: Prospective, observational, noninterventional multicenter study in adults with suspected infection transferred to 4 Spanish hospitals by advanced life-support ambulances from June 1, 2020, through June 30, 2022. We collected demographic, physiological, clinical, and analytical data. Cox regression analysis was used to develop and validate a risk model for 1-year mortality. Results: Four hundred ten patients were enrolled (development cohort, 287; validation cohort, 123). Cumulative mortality was 49% overall. Sepsis (infection plus a Sepsis-related Organ Failure Assessment score of 2 or higher) was diagnosed in 29.2% of survivors vs 56.7% of nonsurvivors. The risk model achieved an area under the receiver operating characteristic curve of 0.89 for 1-year mortality. The following predictors were included in the model: age; institutionalization; age-adjusted Charlson comorbidity index; PaCO2; potassium, lactate, urea nitrogen, and creatinine levels; fraction of inspired oxygen; and diagnosed sepsis. Conclusions: The model showed excellent ability to predict 1-year mortality based on epidemiological, analytical, andclinical variables, identifying patients at high risk of death soon after their first contact with the health care system.(AU)


Assuntos
Humanos , Masculino , Feminino , Prognóstico , Serviços Médicos de Emergência , Serviços Pré-Hospitalares , /mortalidade , Sepse/mortalidade , Tomada de Decisão Clínica , Estudos Prospectivos , Espanha , Suporte Vital Cardíaco Avançado
3.
Proc Natl Acad Sci U S A ; 121(7): e2315069121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38315851

RESUMO

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery.


Assuntos
Doenças Transmissíveis , Descoberta de Drogas , Camundongos , Animais , Interações Medicamentosas , Modelos Animais de Doenças , Sistema Enzimático do Citocromo P-450/metabolismo , Aceleração
4.
Front Med (Lausanne) ; 10: 1149736, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37144037

RESUMO

Background: Nowadays, there is no gold standard score for prehospital sepsis and sepsis-related mortality identification. The aim of the present study was to analyze the performance of qSOFA, NEWS2 and mSOFA as sepsis predictors in patients with infection-suspected in prehospital care. The second objective is to study the predictive ability of the aforementioned scores in septic-shock and in-hospital mortality. Methods: Prospective, ambulance-based, and multicenter cohort study, developed by the emergency medical services, among patients (n = 535) with suspected infection transferred by ambulance with high-priority to the emergency department (ED). The study enrolled 40 ambulances and 4 ED in Spain between 1 January 2020, and 30 September 2021. All the variables used in the scores, in addition to socio-demographic data, standard vital signs, prehospital analytical parameters (glucose, lactate, and creatinine) were collected. For the evaluation of the scores, the discriminative power, calibration curve and decision curve analysis (DCA) were used. Results: The mSOFA outperformed the other two scores for mortality, presenting the following AUCs: 0.877 (95%CI 0.841-0.913), 0.761 (95%CI 0.706-0.816), 0.731 (95%CI 0.674-0.788), for mSOFA, NEWS, and qSOFA, respectively. No differences were found for sepsis nor septic shock, but mSOFA's AUCs was higher than the one of the other two scores. The calibration curve and DCA presented similar results. Conclusion: The use of mSOFA could provide and extra insight regarding the short-term mortality and sepsis diagnostic, backing its recommendation in the prehospital scenario.

5.
Dis Markers ; 2022: 5351137, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35242244

RESUMO

BACKGROUND: The aim of this study was to assess the role of prehospital point-of-care N-terminal probrain natriuretic peptide to predict sepsis, septic shock, or in-hospital sepsis-related mortality. METHODS: A prospective, emergency medical service-delivered, prognostic, cohort study of adults evacuated by ambulance and admitted to emergency department between January 2020 and May 2021. The discriminative power of the predictive variable was assessed through a prediction model trained using the derivation cohort and evaluated by the area under the curve of the receiver operating characteristic on the validation cohort. RESULTS: A total of 1,360 patients were enrolled with medical disease in the study. The occurrence of sepsis, septic shock, and in-hospital sepsis-related mortality was 6.4% (67 cases), 4.2% (44 cases), and 6.1% (64 cases). Prehospital National Early Warning Score 2 had superior predictive validity than quick Sequential Organ Failure Assessment and N-terminal probrain natriuretic peptide for detecting sepsis and septic shock, but N-terminal probrain natriuretic peptide outperformed both scores in in-hospital sepsis-related mortality estimation. Application of N-terminal probrain natriuretic peptide to subgroups of the other two scores improved the identification of sepsis, septic shock, and sepsis-related mortality in the group of patients with low-risk scoring. CONCLUSIONS: The incorporation of N-terminal probrain natriuretic peptide in prehospital care combined with already existing scores could improve the identification of sepsis, septic shock, and sepsis-related mortality.


Assuntos
Mortalidade Hospitalar , Peptídeo Natriurético Encefálico , Escores de Disfunção Orgânica , Fragmentos de Peptídeos , Valor Preditivo dos Testes , Sepse/epidemiologia , Sepse/mortalidade , Idoso , Serviços Médicos de Emergência , Serviço Hospitalar de Emergência , Feminino , Hospitalização , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Sepse/diagnóstico
6.
ACS Infect Dis ; 8(3): 557-573, 2022 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-35192346

RESUMO

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of ß-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 ß-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of ß-lactams screened were active against Mtb, many without a ß-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.


Assuntos
COVID-19 , Mycobacterium tuberculosis , Animais , Indústria Farmacêutica , Camundongos , SARS-CoV-2 , Universidades , beta-Lactamas/farmacologia
7.
J Adv Nurs ; 78(6): 1618-1631, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34519377

RESUMO

AIMS: To assess the prognostic accuracy of comorbidity-adjusted National Early Warning Score in suspected Coronavirus disease 2019 patients transferred from nursing homes by the Emergency Department. DESIGN: Multicentre retrospective cohort study. METHODS: Patients transferred by high-priority ambulances from nursing homes to Emergency Departments with suspected severe acute respiratory syndrome coronavirus 2 infection, from March 12 to July 31 2020, were considered. Included variables were: clinical covariates (respiratory rate, oxygen saturation, systolic blood pressure, heart rate, temperature, level of consciousness and supplemental oxygen use), the presence of comorbidities and confirmatory analytical diagnosis of severe acute respiratory syndrome coronavirus 2 infection. The primary outcome was a 2-day mortality rate. The discriminatory capability of the National Early Warning Score was assessed by the area under the receiver operating characteristic curve in two different cohorts, the validation and the revalidation, which were randomly selected from the main cohort. RESULTS: A total of 337 nursing homes, 10 advanced life support units, 51 basic life support units and 8 hospitals in Spain entailing 1,324 patients (median age 87 years) was involved in this study. Two-day mortality was 11.5% (152 cases), with a positivity rate of severe acute respiratory syndrome coronavirus 2 of 51.2%, 77.7% of hospitalization from whom 1% was of intensive care unit admission. The National Early Warning Score results for the revalidation cohort presented an AUC of 0.771, and of 0.885, 0.778 and 0.730 for the low-, medium- and high-level groups of comorbidities. CONCLUSION: The comorbidity-adjusted National Early Warning Score provides a good short-term prognostic criterion, information that can help in the decision-making process to guide the best strategy for each older adult, under the current pandemic. IMPACT: What problem did the study address? Under the current coronavirus disease 2019 pandemic, targeting older adults at high risk of deterioration in nursing homes remains challenging. What were the main findings? Comorbidity-adjusted National Early Warning Score helps to forecast the risk of clinical deterioration more accurately. Where and on whom will the research have impact? A high NEWS, with a low level of comorbidity is associated with optimal predictive performance, making these older adults likely to benefit from continued follow up and potentially hospital referral under the current coronavirus disease 2019 pandemic.


Assuntos
COVID-19 , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Comorbidade , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Casas de Saúde , Estudos Retrospectivos , Medição de Risco/métodos
8.
Pediatr. aten. prim ; 22(86): 153-159, abr.-jun. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-198528

RESUMO

OBJETIVOS: analizar el empleo de los test de detección rápida de antígeno estreptocócico en Pediatría de Atención Primaria (AP), su impacto en la prescripción de antibióticos y la reducción de costes del tratamiento antibiótico. MATERIAL Y MÉTODOS: estudio descriptivo transversal, en menores de 15 años atendidos en AP, en 24 centros de salud, desde abril de 2017 hasta febrero de 2018. Se elaboró un protocolo de utilización del test de detección rápida de antígeno estreptocócico (TDRS). Se incluyeron pacientes con escala Centor mayor o igual a 2 puntos. Se extrajeron del sistema de facturación de recetas datos del número de dosis diaria definida (DDD) e importe de antibióticos en dicha temporada, comparándose con el gasto en los 12 meses previos. RESULTADOS: se realizaron 819 TDRS. Resultaron positivos 250 (30,5%), negativos 557 (68%) y 12 no valorables (1,5%). Se prescribió antibiótico al 33% de los pacientes (todos los positivos, 18 negativos, 3 no valorables). En 539 pacientes (97%) con resultado negativo no se instauró antibiótico. El número de DDD total disminuyó en 21 960 (12%), de las cuales 19 023 (86,6%) corresponden a los antibióticos más utilizados (penicilinas, amoxicilina, amoxicilina-clavulánico y azitromicina). La reducción económica fue de 11 320 € (12,5%) y el gasto en TDRS fue de 991 €, lo que supone un ahorro de 10 329€. CONCLUSIONES: la introducción del TDRS en consultas de Pediatría de AP ha permitido que se eviten un elevado número de tratamientos antibióticos. Su utilización ha demostrado ser eficiente en la optimización del consumo de antibióticos, consiguiendo reducir su utilización, evitar efectos adversos y reducir el gasto farmacéutico innecesario


OBJECTIVE: the aim of the study was to analyse the use of the rapid Streptococcus antigen detection test in primary care paediatrics, its impact on antibiotic prescription of and the associated decrease in antibiotic treatment costs. MATERIAL AND METHODS: we conducted a cross-sectional descriptive study in children aged less than 15 years managed in 24 primary care centres between April 2017 and February 2018. We developed a protocol for the use of the rapid strep test (RST). We included patients with a Centor score equal to or greater than 2 points. We collected data on the number of daily defined doses (DDDs) and amount antibiotics prescribed in the study period from the prescription billing system and compared it with the costs corresponding to the previous 12-month period. RESULTS: 819 TDRS were performed. The results were positive in 250 (30.5%), negative in 557 (68%) and inconclusive in 12 (1.5%). Antibiotics were prescribed to 33% of the patients (all patients with a positive test, 18 with a negative test and 3 with an inconclusive test). Antibiotherapy was not prescribed to 539 of the patients with a negative result (97%). The total number of prescribed DDDs decreased by 21 960 (12%), of which 19 023 (86.6%) corresponded to the most frequently prescribed antibiotics (penicillins, amoxicillin, amoxicillin-clavulanic acid and azithromycin). We found a reduction of €11 320 in antibiotherapy costs (12.5%), while the total cost of rapid testing was € 991, corresponding to total savings of €10 329. CONCLUSIONS: the introduction of the RST in primary care paediatrics has achieved a reduction in the frequency of antibiotherapy. Its use has proven effective in optimising antibiotic use, reducing antibiotic prescription and therefore preventing associated adverse events and reducing unnecessary pharmacotherapy costs


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Antibacterianos/uso terapêutico , Tonsilite/tratamento farmacológico , Streptococcus pyogenes/isolamento & purificação , Infecções Estreptocócicas/microbiologia , Faringite/tratamento farmacológico , Prescrições de Medicamentos/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Estudos Transversais , Testes Imediatos/estatística & dados numéricos , Custos de Medicamentos/estatística & dados numéricos
9.
J Med Chem ; 63(10): 5367-5386, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32342688

RESUMO

In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against Mycobacterium. tuberculosis. The compounds were found to be noncovalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-ß-d-ribose-2'-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined submicromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising noncovalent lead series for the discovery of novel antituberculosis agents.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Hidantoínas/química , Hidantoínas/farmacologia , Oxirredutases do Álcool/metabolismo , Animais , Antituberculosos/metabolismo , Proteínas de Bactérias/metabolismo , Feminino , Células Hep G2 , Humanos , Hidantoínas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Ressonância Magnética Nuclear Biomolecular/métodos , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo
10.
J Med Chem ; 63(5): 2557-2576, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31922409

RESUMO

Decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) is an essential enzyme in Mycobacterium tuberculosis and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a novel series of morpholino-pyrimidine DprE1 inhibitors. These were derived from a phenotypic high-throughput screening (HTS) hit with suboptimal physicochemical properties. Optimization strategies included scaffold-hopping, synthesis, and evaluation of fragments of the lead compounds and property-focused optimization. The resulting optimized compounds had much improved physicochemical properties and maintained enzyme and cellular potency. These molecules demonstrated potent efficacy in an in vivo tuberculosis murine infection model.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/farmacologia , Tuberculose/tratamento farmacológico , Oxirredutases do Álcool/metabolismo , Animais , Antituberculosos/química , Antituberculosos/uso terapêutico , Proteínas de Bactérias/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Camundongos , Morfolinas/química , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Mycobacterium tuberculosis/enzimologia , Pirimidinas/química , Pirimidinas/uso terapêutico , Tuberculose/microbiologia
11.
J Med Chem ; 61(15): 6592-6608, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29944372

RESUMO

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino-thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure-activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.


Assuntos
Citocromos c/metabolismo , Morfolinas/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Oxirredutases/metabolismo , Tiofenos/química , Tiofenos/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Chlorocebus aethiops , Camundongos , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/toxicidade , Células Vero
12.
Rev. esp. cardiol. (Ed. impr.) ; 71(6): 450-457, jun. 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-178557

RESUMO

Introducción y objetivos: Los individuos con tasa de filtrado glomerular estimada (TFGe) disminuida tienen mayor riesgo de muerte por todas las causas (MT) y cardiovascular; se debate si los sujetos mayores con TFGe entre 45 y 59 ml/min/1,73 m2 también tienen un riesgo aumentado. Se evaluó la asociación entre la TFGe y la MT y los eventos cardiovasculares (ECV) en individuos de edad 60-74 y ≥ 75 años en un área de baja incidencia de enfermedad coronaria. Métodos: Se realizó un estudio retrospectivo de cohortes utilizando registros electrónicos de atención primaria y hospital. Se incluyó a 130.233 individuos de 60 o más años con una determinación de creatinina entre el 1 de enero de 2010 y el 31 de diciembre de 2011 y una TFGe según la fórmula de la Chronic Kidney Disease Epidemiology Collaboration. Las asociaciones independientes entre la TFGe y la MT y el ingreso por ECV se evaluaron mediante modelos de regresión de Cox y Fine-Gray respectivamente. Resultados: Media de edad, 70 años; el 56,1% eran mujeres. El 13,5% tenía una TFGe < 60 (el 69,7%, TFGe 45-59). Durante una mediana de seguimiento de 38,2 meses, 6.474 participantes fallecieron y 3.746 presentaron ECV. Tanto para la MT como para los ECV, las HR ajustadas de los participantes de 75 o más años fueron significativas con TFGe < 60. Con TFGe 45-59, para MT fueron HR = 1,61; IC95%, 1,37-1,89 y HR = 1,19; IC95%, 1,10-1,28 en los grupos de edad de 60-74 y ≥ 75 años respectivamente, y para ECV, HR = 1,28; IC95%, 1,08-1,51 y HR = 1,12; IC95%, 0,99-1,26. Conclusiones: En un área de baja incidencia de enfermedad coronaria, el riesgo de muerte y ECV fue de mayor a menor TFGe. A edades ≥ 75 años, la categoría de TFGe 45-59, en el límite significativo de ECV, incluyó a muchos individuos sin riesgo adicional significativo


Introduction and objectives: Individuals with a decreased estimated glomerular filtration rate (eGFR) are at increased risk of all-cause (ACM) and cardiovascular mortality; there is ongoing debate about whether older individuals with eGFR 45 to 59 mL/min/1.73 m2 are also at increased risk. We evaluated the association between eGFR and ACM and cardiovascular events (CVE) in people aged 60 to 74 and ≥ 75 years in a population with a low coronary disease incidence. Methods: We conducted a retrospective cohort study by using primary care and hospital electronic records. We included 130 233 individuals aged ≥ 60 years with creatinine measurement between January 1, 2010 and December 31, 2011; eGFR was estimated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. The independent association between eGFR and the risk of ACM and hospital admission due to CVE were determined with Cox and Fine-Gray regressions, respectively. Results: The median was age 70 years, and 56.1% were women; 13.5% had eGFR < 60 (69.7% eGFR 45-59). During a median follow-up of 38.2 months, 6474 participants died and 3746 had a CVE. For ACM and CVE, the HR in older individuals became significant at eGFR < 60. Fully adjusted HR for ACM in the eGFR 45 to 59 category were 1.61; 95%CI, 1.37-1.89 and 1.19; 95%CI, 1.10-1.28 in 60- to 74-year-olds and ≥ 75-year-olds, respectively; for CVE HR were 1.28; 95%CI, 1.08-1.51 and 1.12; 95%CI, 0.99-1.26. Conclusions: In a region with low coronary disease incidence, the risk of death and CVE increased with decreasing eGFR. In ≥ 75-year-olds, the eGFR 45 to 59 category, which had borderline risk for CVE, included many individuals without significant additional risk


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Taxa de Filtração Glomerular , Doenças Cardiovasculares/fisiopatologia , Doença das Coronárias/epidemiologia , Fatores de Risco , Estudos Retrospectivos , Testes de Função Renal/estatística & dados numéricos
13.
Rev Esp Cardiol (Engl Ed) ; 71(6): 450-457, 2018 Jun.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29111335

RESUMO

INTRODUCTION AND OBJECTIVES: Individuals with a decreased estimated glomerular filtration rate (eGFR) are at increased risk of all-cause (ACM) and cardiovascular mortality; there is ongoing debate about whether older individuals with eGFR 45 to 59mL/min/1.73 m2 are also at increased risk. We evaluated the association between eGFR and ACM and cardiovascular events (CVE) in people aged 60 to 74 and ≥ 75 years in a population with a low coronary disease incidence. METHODS: We conducted a retrospective cohort study by using primary care and hospital electronic records. We included 130 233 individuals aged ≥ 60 years with creatinine measurement between January 1, 2010 and December 31, 2011; eGFR was estimated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. The independent association between eGFR and the risk of ACM and hospital admission due to CVE were determined with Cox and Fine-Gray regressions, respectively. RESULTS: The median was age 70 years, and 56.1% were women; 13.5% had eGFR < 60 (69.7% eGFR 45-59). During a median follow-up of 38.2 months, 6474 participants died and 3746 had a CVE. For ACM and CVE, the HR in older individuals became significant at eGFR < 60. Fully adjusted HR for ACM in the eGFR 45 to 59 category were 1.61; 95%CI, 1.37-1.89 and 1.19; 95%CI, 1.10-1.28 in 60- to 74-year-olds and ≥ 75-year-olds, respectively; for CVE HR were 1.28; 95%CI, 1.08-1.51 and 1.12; 95%CI, 0.99-1.26. CONCLUSIONS: In a region with low coronary disease incidence, the risk of death and CVE increased with decreasing eGFR. In ≥ 75-year-olds, the eGFR 45 to 59 category, which had borderline risk for CVE, included many individuals without significant additional risk.


Assuntos
Doenças Cardiovasculares/mortalidade , Taxa de Filtração Glomerular/fisiologia , Idoso , Doenças Cardiovasculares/fisiopatologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia
15.
J Med Chem ; 58(16): 6448-55, 2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-26222445

RESUMO

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (1), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of 1 led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue 44 displayed potent in vitro activity (IC50 = 10 nM) and oral activity in a SCID mouse model of Pf infection with an ED50 of 100 and ED90 of between 100 and 150 mg kg(-1), respectively. The results presented encourage further investigations to identify the target of these highly active compounds.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Animais , Antimaláricos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Técnicas In Vitro , Malária/tratamento farmacológico , Malária/psicologia , Malária Falciparum/tratamento farmacológico , Camundongos , Camundongos SCID , Microssomos Hepáticos/metabolismo , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Inibidores de Serino Proteinase/metabolismo , Relação Estrutura-Atividade , Triazóis/metabolismo
16.
Aten. prim. (Barc., Ed. impr.) ; 47(4): 236-245, abr. 2015. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-135395

RESUMO

OBJETIVO: Conocer la prevalencia y los estadios de la enfermedad renal crónica según la estimación del filtrado glomerular (eFG), y los factores de riesgo asociados en individuos ≥ 60 años. DISEÑO: Estudio observacional transversal. Emplazamiento: Atención Primaria. PARTICIPANTES: Sujetos ≥ 60 años de 40 centros de Atención Primaria con determinación de creatinina sérica entre 1 enero-31 diciembre de 2010. Criterios de exclusión: trasplante renal, atención domiciliaria. MEDICIONES PRINCIPALES: Variables sociodemográficas, antropométricas, factores de riesgo y enfermedad cardiovascular según registro en historia clínica electrónica, concentración de creatinina sérica según método Jaffé cinético compensado estandarizado y eFG según MDRD-4 IDMS y CKD-EPI. RESULTADOS: Fueron analizados 97.665 individuos (57,3% mujeres, mediana de edad 70,0 [Q1: 65,0; Q3: 77,0]). Prevalencia de eFG-MDRD < 60 = 15,1% (16,6% en mujeres, 13,2% en hombres; p < 0,001) con aumento progresivo con la edad. El análisis multivariante detectó una asociación positiva entre eFG-MDRD < 60 y edad (OR = 1,74; IC 95% 1,70-1,77), HTA (OR = 2,18; IC 95% 2,08-2,30), insuficiencia cardiaca (OR = 2,03; IC 95% 1,83-2,25), fibrilación auricular (OR = 1,57; IC 95% 1,41-1,76), cardiopatía isquémica (OR = 1,40; IC 95% 1,30-1,50), arteriopatía periférica (OR = 1,31; IC 95% 1,09-1,57), dislipidemia (OR = 1,28; IC 95% 1,23-1,33), DM (OR = 1,26; IC 95% 1,17-1,34) y AVC (OR = 1,17; IC 95% 1,09-1,25). El modelo con eFG-CKD-EPI mostró un aumento de la OR con la edad y sexo masculino, que cobró significación como factor de riesgo. CONCLUSIONES: La enfermedad renal crónica presenta una importante prevalencia en pacientes ≥ 60 años atendidos en Atención Primaria, mayor en mujeres que en hombres, y aumentando con la edad. La HTA, más que la DM, fue el principal factor de riesgo cardiovascular asociado


OBJECTIVE: To determine the prevalence of chronic kidney disease and associated risk factors in subjects over 60 years of age, as well as its staging by determining the glomerular filtration rate (GFR). DESIGN: Cross-sectional observational study. SETTING: Primary Health Care. PARTICIPANTS: Patients ≥ 60 years of age who were seen in 40 Primary Health Care centres with serum creatinine measured in a central laboratory between January 1 and December 31, 2010. Exclusion criteria: kidney transplant, home care. Main measures: Social-demographic and anthropometric data, cardiovascular risk factors, and diseases established according to electronic clinical records. Serum creatinine was measured using standardised Jaffe kinetic method, and GFR estimated with MDRD-4-IDMS and CKD-EPI. RESULTS: A total of 97,665 subjects (57.3% women, median age 70.0 years [Q1: 65.0, Q3: 77.0]). GFR-MDRD prevalence < 60 = 15.1% (16.6% in women, 13.2% in men; P < .001) and increased with age. Multivariate analysis showed a positive association between GFR-MDRD < 60 and age (OR = 1.74; 95% CI 1.70 to 1.77), hypertension (OR = 2.18; 95% CI 2.08 to 2.30), heart failure (OR = 2.03; 95% CI 1.83 to 2.25), atrial fibrillation (OR = 1.57; 95% CI 1.41 to 1.76), ischaemic heart disease (OR = 1.40; 95% CI 1.30 to 1.50), peripheral arterial disease (OR = 1.31; 95% CI 1.09 to 1.57), dyslipidaemia (OR = 1.28; 95% CI 1.23 to 1.33), diabetes (OR = 1.26; 95% CI 1.17 to 1.34), and stroke (OR = 1.17; 95% CI 1.09 to 1.25). The GFR-CKD-EPI model showed an increase in OR with age and male sex, that became significant as a chronic kidney disease risk factor. CONCLUSIONS: Chronic kidney disease has considerable prevalence in subjects ≥ 60 years seen in Primary Health Care, more in women, and increasing with age. Hypertension, more than diabetes, was the main associated cardiovascular risk factor


Assuntos
Humanos , Masculino , Feminino , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transplante de Rim/métodos , Transplante de Rim/psicologia , Assistência Domiciliar/métodos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Transplante de Rim/classificação , Transplante de Rim/instrumentação , Assistência Domiciliar , Insuficiência Cardíaca/complicações , Estudo Observacional
17.
Aten Primaria ; 47(4): 236-45, 2015 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-25212720

RESUMO

OBJECTIVE: To determine the prevalence of chronic kidney disease and associated risk factors in subjects over 60 years of age, as well as its staging by determining the glomerular filtration rate (GFR). DESIGN: Cross-sectional observational study. SETTING: Primary Health Care. PARTICIPANTS: Patients≥60 years of age who were seen in 40 Primary Health Care centres with serum creatinine measured in a central laboratory between January 1 and December 31, 2010. EXCLUSION CRITERIA: kidney transplant, home care. MAIN MEASURES: Social-demographic and anthropometric data, cardiovascular risk factors, and diseases established according to electronic clinical records. Serum creatinine was measured using standardised Jaffe kinetic method, and GFR estimated with MDRD-4-IDMS and CKD-EPI. RESULTS: A total of 97,665 subjects (57.3% women, median age 70.0 years [Q1: 65.0, Q3: 77.0]). GFR-MDRD prevalence<60=15.1% (16.6% in women, 13.2% in men; P<.001) and increased with age. Multivariate analysis showed a positive association between GFR-MDRD<60 and age (OR=1.74; 95% CI 1.70 to 1.77), hypertension (OR=2.18; 95% CI 2.08 to 2.30), heart failure (OR=2.03; 95% CI 1.83 to 2.25), atrial fibrillation (OR=1.57; 95% CI 1.41 to 1.76), ischaemic heart disease (OR=1.40; 95% CI 1.30 to 1.50), peripheral arterial disease (OR=1.31; 95% CI 1.09 to 1.57), dyslipidaemia (OR=1.28; 95% CI 1.23 to 1.33), diabetes (OR=1.26; 95% CI 1.17 to 1.34), and stroke (OR=1.17; 95% CI 1.09 to 1.25). The GFR-CKD-EPI model showed an increase in OR with age and male sex, that became significant as a chronic kidney disease risk factor. CONCLUSIONS: Chronic kidney disease has considerable prevalence in subjects≥60 years seen in Primary Health Care, more in women, and increasing with age. Hypertension, more than diabetes, was the main associated cardiovascular risk factor.


Assuntos
Insuficiência Renal Crônica/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Atenção Primária à Saúde , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco
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