RESUMO
BACKGROUND: Acute renal failure due to viral infections is rare. We assessed the development of acute kidney injury (AKI) in critically compromised patients due to the H1N1 influenza virus. METHODS: All patients with a PCR -confirmed diagnosis of H1N1 influenza infection admitted to the intensive care unit between May and July 2009 were retrospectively studied. Thereafter, the risk factors associated with the development of acute renal injury, the requirements of acute hemodialysis (HD) and death were analyzed. RESULTS: Twenty-two patients with H1N1 pneumonia were included: age: 52.91 ± 18.89 years; gender: males 11 (50%); chronic airway disease: 9 (41%); oncohematological disease: 8 (36.7%); cardiovascular disease 5 (22.7%); chronic renal insufficiency: 4 (18.2%); obesity 3 (13.6%); concomitant pregnancy: 2 (9.1%); diabetes mellitus: 2 (9.1%); previous influenza A vaccination: 9 (41%). All patients received oseltamivir within 48 hours of presumed diagnosis. Seventeen patients (77.3%) developed fever initially. Six patients (27.3%) required noninvasive ventilation assistance and 15 patients (68.2%) received invasive ventilatory support. Mean days on mechanical respiratory assistance: 11 ± 10.35. Arterial partial pressure of oxygen/fraction of inspired oxygen ratio: 140.11 ± 83.03 mmHg. Inotropic drugs were administered to 15 patients (68.2%). Fourteen patients (63.6%) developed AKI. Mean highest creatinine levels: 2.74 ± 2.83 mg/dl. Four patients (18.2%) needed renal replacement therapy with a mean duration of 15 ± 12 days. Six patients (42.9%) recovered renal function. AKI was associated with pregnancy, immunosuppression, high APAC HE, SOFA and MURRA Y scores, and less time on mechanical ventilation assistance, hemodynamical instability and thrombocytopenia. HD requirements were associated with elevated SOFA scores (12.25 ± 1.75 vs. 6.22 ± 0.8, p<0.05), elevated creatine phosphokinase (933 ± 436.6 vs. 189.9 ± 79.3 U/L, p<0.05) and alanine transferase levels (843.3 ± 778.8 vs. 85.33 ± 17.4 U/L, p<0.05). Twelve patients died (54.6%), 10 of whom had acute renal failure (83.3%) and 3 had been on acute HD (25%). Mortality was associated with higher APACHE, SOFA and Murray scores, a higher oseltamivir dose (253.1 ± 25.8 vs. 183.8 ± 27.6 mg, p<0.05), lower oxygen inspired fraction/alveolar pressure ratio (99.3 ± 12.2 vs. 196.3 ± 33.9 mmHg, p<0.01), thrombocytopenia (88966 ± 22977 vs. 141200 ± 17282 mm3, p<0.05), hypoalbuminemia (1.82 ± 0.1 vs. 2.61 ± 0.2 g/dl, p<0.01), acute renal failure (10 vs. 4, p<0.05), oligoanuria (5 vs. 0, p<0.05) and lack of recovery of renal function (2 vs. 4, p<0.01). Three out of 4 (75%) of the hemodialyzed patients died. CONCLUSIONS: In the critically ill due to H1N1 pneumonia, renal insufficiency was a frequent complication, demanding renal replacement therapy in 18% of cases. The need for HD was associated with an elevated risk of death. Mortality was mainly associated with multiple organ failure, oligoanuria, acute renal injury and a lack of recovery of renal function.
Assuntos
Injúria Renal Aguda/etiologia , Estado Terminal , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/complicações , Adulto , Idoso , Creatina Quinase/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.
Assuntos
Antineoplásicos/química , Fenóis/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Piridinas/química , Sítio Alostérico , Antineoplásicos/farmacologia , Concentração Inibidora 50 , Melanoma/tratamento farmacológico , Mutação de Sentido Incorreto , Fenóis/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
BRAF, a serine/threonine kinase, plays a key role in the development of certain types of cancer, particularly melanoma. 2-(3,4,5-Trimethoxyphenylamino)-6-(3-acetamidophenyl)-pyrazine, 1, was identified as a low micromolar (IC 50 = 3.5 microM) BRAF inhibitor from a high-throughput screen of a library of 23000 compounds. This compound was chosen as the starting point of a program aimed at developing inhibitors of mutant (V600E)BRAF. We have already reported on the optimization of the trimethoxyphenylamino moiety of 1. In this paper, we describe the synthesis of a series of compounds derived from 1 with the purpose of optimization of the pyrazine central core and the phenylacetamido moiety in order to increase the potency against (V600E)BRAF compared to CRAF. The biological activity of the new inhibitors was assessed against mutant (V600E)BRAF in vitro. Several compounds were identified with IC 50s of 300-500 nM for (V600E)BRAF, and all compounds that were assessed showed selectivity for (V600E)BRAF compared to CRAF by 5-->86-fold.
Assuntos
Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazinas/síntese química , Bases de Dados Factuais , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-raf/química , Pirazinas/química , Relação Estrutura-AtividadeRESUMO
B-RAF, a serine/threonine kinase, plays an important role in the development of certain classes of cancer, especially melanoma. As a result of high-throughput screening of a 23,000 compound library, 2-(3,4,5-trimethoxyphenylamino)-6-(3-acetamidophenyl)pyrazine, 1, was identified as a low micromolar (IC(50) = 3.5 microM) B-RAF inhibitor. This compound was chosen as the starting point of a program aimed at producing potent inhibitors of B-RAF. We have synthesized a series of 40 novel compounds, which involved extensive modifications to the 2-(3,4,5-trimethoxyphenylamino) moiety (ring A) of 1. Their biological profiles against isolated B-RAF and mutated B-RAF in a cellular assay have been determined. These efforts led to the identification of two compounds exhibiting activities lower than 800 nM against B-RAF.
Assuntos
Acetanilidas/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazinas/farmacologia , Acetanilidas/síntese química , Acetanilidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Relação Estrutura-AtividadeRESUMO
A new series of dendrimers containing a central cavitand core with four appended Fréchet-type dendrons, linked to the core through 4,4'-bipyridinium (viologen) subunits, have been synthesized, characterized and their electrochemical properties investigated using cyclic voltammetric measurements.
Assuntos
Anestesia , Anestésicos/farmacologia , Sistema Imunitário/efeitos dos fármacos , Anestesia/efeitos adversos , Formação de Anticorpos/efeitos dos fármacos , Depressão Química , Humanos , Imunidade Celular/efeitos dos fármacos , Síndromes de Imunodeficiência/etiologia , Linfócitos/classificação , Linfócitos/efeitos dos fármacosRESUMO
Se realizó un estudio prospectivo con la finalidad de determinar la utilidad de la evaluación nutricional preoperatoria como índice pronóstico en cirugía mayor electiva. Utilizamos los siguientes parámetros: Porciento del peso corporal ideal y del peso corporal habitual, perímetro mesobraquial, pliegue cutáneo a nivel del tríceps, área muscular del brazo, albúmina sérica, transferrina sérica, cuenta de linfocitos periféricos totales y pruebas cutáneas de sensibilidad a antígenos comunes. Se estudiaron con 25 pacientes en quienes se realizó cirugía del aparato digestivo, con morbilidad del 20% y mortalidad del 16%. Los parámetros con significancia estadística como índice pronóstico fueron: El porciento del peso corporal habitual (p <.05), la albúmina sérica (p <.03) y las pruebas cutáneas de sensibilidad (p <.005). Nuestros resultados preliminares coinciden con los publicados en la literatura mundial