ABSTRACT
Risk factors and underlying mechanisms for liver injury associated with amiodarone remain elusive. This study aimed to investigate the drug-related covariates for acute liver injury by amiodarone-an intriguing compound of high lipophilicity, with a long half-life and notable efficacy.The medical, pharmacy, and laboratory records of new amiodarone users admitted to the cardiac or surgical intensive care units of a medical center were examined retrospectively. A Cox regression model with time-varying dose-related variables of amiodarone was utilized to estimate the hazard ratio (HR) of amiodarone-associated liver injury while adjusting for concomitant therapy and relevant covariates.Of the 131 eligible patients among 6,572 amiodarone users (46,402 prescriptions), 6 were identified as amiodarone-associated liver injury cases. In comparison to controls (nâ=â125), this liver injury cohort (nâ=â6) had significantly higher numbers of amiodarone-interacting (2.7â±â2.0 vs 0.9â±â0.9 drugs, Pâ=â.02) and hepatotoxic (3.8â±â0.8 vs 2.5â±â1.7 drugs, Pâ=â.03) comedications. The number of comedications with amiodarone-interacting potential (HR 2.07, 95% confidence interval [CI] 1.02-4.22, Pâ=â.04) and amiodarone cumulative doses standardized by body surface area (HR 6.82, 95% CI 1.72-27.04, Pâ=â.01) were independent risk factors for liver injury associated with amiodarone.Drug-related (amiodarone cumulative dose, interacting drugs) factors were significant predictors of amiodarone-associated acute liver injury. A prudent evaluation of each medication profile is warranted to attain precision medicine at the level of patient care, especially for those treated by medications with complex physicochemical and pharmacokinetic properties, such as amiodarone.
Subject(s)
Amiodarone/adverse effects , Anti-Arrhythmia Agents/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Adolescent , Adult , Aged , Drug Interactions , Female , Humans , Intensive Care Units , Male , Middle Aged , Polypharmacy , Proportional Hazards Models , Regression Analysis , Retrospective Studies , Risk Factors , Young AdultABSTRACT
Previous studies have identified that the expression of UK114 is tissue specific and the protein has been found to be most abundant in liver and kidney. However, the expression of UK114 in human hepatocellular carcinoma and its relationship to differentiation and transformation of hepatocellular carcinoma have not been studied. In this study, the expression of UK114 in human hepatocellular carcinoma was examined by Northern and Western blot analyses. We found that UK114 was significantly down-regulated in most of hepatocellular carcinoma tissues compared with adjacent nontumor tissues (72.7%) at both mRNA and protein levels. We looked into the possibility that this decreased expression of UK114 in the hepatocellular carcinoma tissues may play a role in the differentiation or tumorigenicity of hepatocellular carcinoma. Immunohistochemical staining showed that the reduced expression of UK114 in hepatocellular carcinoma tissues was correlated with the tumor differentiation status as graded by the Edmondson-Steiner classification. On the other hand, overexpression of UK114 was not able to suppress the proliferation of human hepatoma cells and tumorigenicity in nude mice. These results suggest that UK114 does not seem to act as a tumor suppressor gene; however, it may useful as a biomarker that will assist in the grading of the differentiation status of hepatocellular carcinoma samples.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Heat-Shock Proteins/metabolism , Liver Neoplasms/metabolism , Ribonucleases/metabolism , Biomarkers, Tumor/metabolism , Blotting, Northern , Blotting, Western , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic , Chi-Square Distribution , Down-Regulation , Humans , Immunoenzyme Techniques , Kidney/metabolism , Liver/metabolism , Liver Neoplasms/pathology , Tissue DistributionABSTRACT
To evaluate the potential of DNA vaccine against dengue (DEN) infection, we characterize the protective efficacy and immune responses of mice intramuscularly injected with plasmid encoding DEN-2 non-structural protein 1 (NS1). Intravenously challenged by lethal DEN-2, mice vaccinated with NS1-DNA exhibited a delay onset of paralysis, a marked decrease of morbidity, and a significant enhancement of survival. In addition to a moderate increase of NS1-specific antibody titer from immunized mice measured by ELISA, a strong priming effect on anti-NS1 response was also noticed in plasmid NS1-vaccinated mice by radioimmunoprecipitation (RIP) or immunoblot analysis. Interestingly, newborn mice from NS1-DNA-immunized dam showed stronger resistance to viral challenge, as compared to those from vector DNA or PBS-immunized dams, indicating the protective role of NS1-specific antibody. In contrast to humoral immune response, DNA immunization can elicit strong cellular immune responses, including NS1-specific T cell proliferation and cytolytic activity. The NS1-DNA-induced protection can be further augmented by co-injection of plasmid encoding interleukin 12 (IL-12), suggesting an effector role of Th1 immunity against DEN infection. In summary, our results suggest the potential of NS1-DNA vaccine against DEN infection, and indicate both NS1-specific humoral and cellular immune responses contribute to the protection.
