RESUMEN
Hepatic encephalopathy (HE) is a common complication of acute and chronic liver disease associated with exposure of brain tissue to excessive levels of ammonia produced by intestinal bacteria. Clinical manifestations range from subtle neurologic abnormalities to coma. Because development of HE can reduce survival probability, guidelines for evaluating patients for liver transplantation suggest that patients who develop HE should be considered for transplantation. Various patient factors before transplantation, including the presence of HE and reduced nutritional status, may increase the risk of poor outcomes after transplantation. Therefore, effective management of HE before transplantation, while minimizing the potential impact of negative predictive factors, may improve transplantation outcomes. The most common HE treatments are directed toward reducing systemic ammonia levels, thereby reducing brain exposure to this neurotoxin. The administration of nonabsorbable disaccharides is considered as a first-line therapy for HE, and the antibiotics neomycin and metronidazole are frequently administered, despite a lack of clinical data supporting their efficacy. These agents are associated with adverse events that may reduce nutritional status in patients awaiting transplantation and could contribute to poor posttransplantation outcomes. The nonsystemic antibiotic rifaximin has demonstrated efficacy for the treatment of HE and has a favorable safety profile. Given these data, nonsystemic antibiotics may also provide a safe and effective option for treating HE in the pretransplant setting. This article reviews treatments for HE and the potential impact these treatments may have on pretransplantation status of patients awaiting liver transplantation and on posttransplantation outcomes.
Asunto(s)
Antibacterianos/uso terapéutico , Disacáridos/uso terapéutico , Encefalopatía Hepática/terapia , Hepatopatías/cirugía , Trasplante de Hígado , Antibacterianos/efectos adversos , Disacáridos/efectos adversos , Encefalopatía Hepática/etiología , Humanos , Hepatopatías/complicaciones , Trasplante de Hígado/efectos adversos , Donadores Vivos , Estado Nutricional , Guías de Práctica Clínica como Asunto , Cuidados Preoperatorios , Resultado del TratamientoRESUMEN
Cdc25 phosphatases are important in cell cycle control and activate cyclin-dependent kinases (Cdk). Efforts are currently under way to synthesize specific small-molecule Cdc25 inhibitors that might have anticancer properties. NSC 95397, a protein tyrosine phosphatase antagonist from the National Cancer Institute library, was reported to be a potent Cdc25 inhibitor. We have synthesized two hydroxyl derivatives of NSC 95397, monohydroxyl-NSC 95397 and dihydroxyl-NSC 95397, which both have enhanced activity for inhibiting Cdc25s. The new analogues, especially dihydroxyl-NSC 95397, potently inhibited the growth of human hepatoma and breast cancer cells in vitro. They influenced two signaling pathways. The dual phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) was induced, likely due to inhibition of the ERK phosphatase activity in Hep 3B cell lysate but not the dual specificity ERK phosphatase MKP-1. They also inhibited Cdc25 enzymatic activities and induced tyrosine phosphorylation of the Cdc25 target Cdks. Addition of hydroxyl groups to the naphthoquinone ring thus enhanced the potency of NSC 95397. These two new compounds may be useful probes for the biological functions of Cdc25s and have the potential for disrupting the cell cycle of growing tumor cells.
Asunto(s)
Antineoplásicos/farmacología , Naftoquinonas/farmacología , Fosfatasas cdc25/metabolismo , Biotinilación , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Hepatocelular/tratamiento farmacológico , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Sistema Libre de Células , ADN/química , Fosfatasa 1 de Especificidad Dual , Flavonoides/farmacología , Citometría de Flujo , Humanos , Proteínas Inmediatas-Precoces/metabolismo , Inmunoprecipitación , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Fosforilación , Proteína Fosfatasa 1 , Proteínas Tirosina Fosfatasas/metabolismo , Transducción de Señal , Factores de Tiempo , Transfección , Tirosina/químicaRESUMEN
BACKGROUND/AIMS: Short-term efficacy of local gamma interferon delivered via a single injection of an adenovirus-gamma interferon vector has been reported in immunocompetent animals which develop spontaneous liver cancer. However the long-term outcome was not examined. The aim of this randomized trial was to assess in an immunodeficient mouse ectopic model the benefit, if any, of the long-term efficacy of intratumoral injections of gamma interferon itself. METHODOLOGY: 77 mice were randomly assigned to 4 groups. Gamma interferon treated groups received a dose of 5000, 10000 or 20000 IU per animal versus phosphate-buffered saline. The follow-up lasted 46 days. RESULTS: Significant differences were noted in mice receiving 20000 IU compared to controls: increase in survival (p=0.0485), slowing down of tumor growth in large tumors (p=0.009), increase in necrosis (p=0.004). The preferential staining in necrotic areas with anti-Class II antibody and the accumulation of nuclear debris indicated that neutrophils were involved. CONCLUSIONS: Gamma interferon could accentuate the migration of non-specific immune cells to necrotic areas which occur spontaneously in large tumors. These results in animals bearing large tumor suggest that it may be worthwhile to explore local gamma interferon delivery to patients with extensive hepatocarcinoma.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Interferón gamma/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Anticuerpos/análisis , Carcinoma Hepatocelular/patología , División Celular/efectos de los fármacos , Línea Celular , Núcleo Celular/patología , Modelos Animales de Enfermedad , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inyecciones Intralesiones , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , Necrosis , Neutrófilos , Análisis de SupervivenciaRESUMEN
We report on the fluorinated form of Cpd 5 as a cell growth inhibitor. This compound is 3-fold more potent than the parent Cpd 5 and is predicted, using the semi-empirical AM1 method to be only an arylator of cysteine-containing proteins, without generating reactive oxygen species.