RESUMEN
BACKGROUND: Complications associated with liver cirrhosis are various and potentially fatal. The treatment options to counteract hepatic decompensation are limited. Therefore, the study aimed to explore the use of allopurinol in preventing the recurrence of liver cirrhosis-related complications. METHODS: One hundred patients with hepatic decompensation were randomized into 1:1 ratio to receive either allopurinol 300 mg or placebo tablets once daily for 6 months. The primary endpoint was the incidence of cirrhosis-related complications (overt ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, and hepatic encephalopathy). RESULTS: Six months following treatment, allopurinol reduced the relative risk (RR) of any first complication experienced after enrollment by 56% (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.27-0.62); P Ë .001). Allopurinol decreased the RR of overt ascites by 67% (HR 0.33; 95% CI, 0.0098-0.94); P = .039] and reduced the RR of spontaneous bacterial peritonitis by about 75% (HR 0.25; 95% CI, 0.05-0.76; P = .01). Likewise, allopurinol was linked to an 80% reduction in the RR of developing hepatorenal syndrome (HR 0.2; 95% CI, 0.04-0.87; P = .033). CONCLUSION: Allopurinol significantly decreased the recurrence of overall liver cirrhosis-related complications. Therefore, allopurinol may constitute a promising agent for patients with hepatic decompensation. These positive outcomes could be a result of its ability to reduce bacterial translocation and inflammation. GOV IDENTIFIER: NCT005545670.
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Várices Esofágicas y Gástricas , Síndrome Hepatorrenal , Peritonitis , Humanos , Alopurinol/uso terapéutico , Várices Esofágicas y Gástricas/complicaciones , Ascitis/etiología , Ascitis/prevención & control , Síndrome Hepatorrenal/tratamiento farmacológico , Síndrome Hepatorrenal/etiología , Síndrome Hepatorrenal/prevención & control , Hemorragia Gastrointestinal/etiología , Cirrosis Hepática/complicaciones , Peritonitis/prevención & control , Peritonitis/complicacionesRESUMEN
The toxic side effects of doxorubicin in cancer treatment are well established. Here we show that methanolic extract of the fungus Ganoderma applanatum offers protection against cardio- and hepatotoxicity induced by doxorubicin (DOX) in Dalton's Lymphoma Ascites (DLA) bearing mice. Treatment of DLA mice with 20 mg/kg of doxorubicin significantly increased the activities of serum toxicity markers including aspartate amino-transferase (AST), alanine amino-transferase (ALT) and lactate dehydrogenase (LDH). However, co-administration of doxorubicin (20 mg/kg) by intraperitoneal injection and G. applanatum (150 mg/kg) by oral gavage in DLA mice lowered the AST, ALT, and LDH activities when compared to DOX alone treatment. Treatment of DLA mice with DOX alone resulted in reduced GSH contents, and decreased the activities of glutathione-s-transferase (GST), catalase (CAT), and superoxide dismutase (SOD). Treatment of DOX-administered DLA mice with G. applanatum however increased the GSH content and elevated the activities of GST, CAT, and SOD. Among the various solvent extracts of G. applanatum, methanolic extract showed the highest phenolic (376.5 ± 15.24 mg GAE/g) and flavonoid (4717.79 ± 170.22 mg quercetin/g) contents compared to the aqueous (216.3 ± 7.33 mg GAE/g) and chloroform extracts (137.27 ± 1.03 mg GAE/g). Consistently, the methanolic extract was found to possess the highest free radical scavenging activities when compared to the aqueous and chloroform extracts as measured by ABTS and DPPH assays. Our results thus suggest that the protective roles of G. applanatum in DOX-induced toxicity could be an attribute of the antioxidant properties conferred by the high phenolic and flavonoid contents.
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Ganoderma , Linfoma , Animales , Antioxidantes/farmacología , Ascitis/tratamiento farmacológico , Ascitis/patología , Ascitis/prevención & control , Cloroformo/uso terapéutico , Doxorrubicina/toxicidad , Flavonoides , Linfoma/tratamiento farmacológico , Metanol , Ratones , Fenoles , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Superóxido DismutasaRESUMEN
The anti-metastasis effect of oridonin in combination with oxaliplatin on colorectal cancer liver metastasis was studied using a BALB/c nude mouse model. The liver condition, bloody ascites, cholestasis, and liver metastasis scores in the three groups receiving oxaliplatin combined with oridonin were significantly milder than in the control group and importantly the anti-migratory effect of oxaliplatin combined with oridonin was obviously the strongest (p<0.05). Oridonin possessed no hepatotoxicity; instead, it effectively alleviated liver injury caused by oxaliplatin. Oridonin alone or in combination with oxaliplatin significantly decreased serum levels of α-fetoprotein and carcinoembryonic antigen. Therefore, oridonin combined with oxaliplatin displays great potential to markedly increase the anti-metastasis effect of oxaliplatin in the treatment of liver metastases of colorectal cancer.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Diterpenos de Tipo Kaurano/farmacología , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/secundario , Oxaliplatino/farmacología , Animales , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ascitis/prevención & control , Antígeno Carcinoembrionario/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Colestasis/prevención & control , Sinergismo Farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia/prevención & control , Oxaliplatino/efectos adversos , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND & AIMS: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. METHODS: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. RESULTS: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. CONCLUSIONS: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. LAY SUMMARY: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS. GOV IDENTIFIER: NCT03205345.
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Ascitis , Hemorragia Gastrointestinal , Encefalopatía Hepática , Cirrosis Hepática , Pruebas de Función Hepática/métodos , Enfermedad del Hígado Graso no Alcohólico , Ácidos Pentanoicos , Peritonitis , Ascitis/etiología , Ascitis/prevención & control , Inhibidores de Caspasas/administración & dosificación , Inhibidores de Caspasas/efectos adversos , Progresión de la Enfermedad , Monitoreo de Drogas/métodos , Enfermedad Hepática en Estado Terminal/etiología , Enfermedad Hepática en Estado Terminal/prevención & control , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/fisiopatología , Femenino , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Ácidos Pentanoicos/administración & dosificación , Ácidos Pentanoicos/efectos adversos , Peritonitis/etiología , Peritonitis/prevención & control , Resultado del TratamientoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Malignant ascites (MA) effusion is mainly caused by hepatocellular, ovarian, and breast cancer etc. It has been reported that Euphorbia kansui (EK), the root of Euphorbia kansui S.L.Liou ex S.B.Ho, possessing a therapeutic effect on MA. However, the clinical applications of EK are seriously restricted for its severe toxicity. Although studies demonstrated that vinegar-processing can reduce the toxicity and retain the water expelling effect of EK, its specific mechanism remains unknown. AIM OF THE STUDY: This study aims to explore the underlying mechanisms of toxicity reduction without compromising the pharmacological effects of EK stir-fried with vinegar (VEK). MATERIALS AND METHODS: 3-O-(2'E,4'Z-decadienoyl)-20-O-acetylingenol (3-O-EZ), a major diterpenoid of EK, could convert into ingenol after processing EK with vinegar. The H22 mouse hepatoma ascites model was replicated, and were given 3-O-EZ and ingenol seven days (110.14, 50.07 and 27.54 mg/kg). The histopathological observation, serum liver enzymes, serum Renin-Angiotensin-Aldosterone System (RAAS) levels, ascites volumes, pro-inflammatory cytokines levels and H22 cells apoptosis in ascites were examined. Then the intestine (Aquaporin 8, AQP8) and kidney (Aquaporin 2, AQP2; Vasopressin type 2 receptor, V2R) protein expression were detected, as well as the metabolomics of serum were analyzed. Finally, the content of 3-O-EZ and ingenol in EK and VEK were investigated. RESULTS: 3-O-EZ and ingenol can relieve hepatic and gastrointestinal injuries, reduce ascites volumes, enhance the H22 cells apoptosis, ameliorate abnormal pro-inflammatory cytokines and RAAS levels, and down-regulate the expression of AQP8, AQP2, V2R. The involved metabolic pathways mainly included glycerophospholipid metabolism and arachidonic acid metabolism. And the decreasing rate of 3-O-EZ in VEK was 19.14%, the increasing rate of ingenol in VEK was 92.31%. CONCLUSION: 3-O-EZ and ingenol possess significant effect in treating MA effusion, while ingenol has lower toxicity compared with 3-O-EZ. And provide evidence for the mechanism of attenuation in toxicity without compromising the pharmacological effects of VEK.
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Ácido Acético/química , Antineoplásicos Fitogénicos/farmacología , Ascitis/prevención & control , Carcinoma Hepatocelular/tratamiento farmacológico , Cromatografía Líquida de Alta Presión , Culinaria , Diterpenos/farmacología , Euphorbia , Neoplasias Hepáticas/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Acuaporina 2/metabolismo , Acuaporinas/metabolismo , Ascitis/metabolismo , Ascitis/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Citocinas/metabolismo , Diterpenos/aislamiento & purificación , Euphorbia/química , Femenino , Calor , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos ICR , Extractos Vegetales/aislamiento & purificación , Receptores de Vasopresinas/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Transducción de SeñalRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia kansui (EK) is the dried root of Euphorbia kansui S.L.Liou ex S.B.Ho. Clinically, processing with vinegar is for reducing toxicity of EK, and EK stir-fried with vinegar (VEK) is used to treat ascites and edema. VEK has been confirmed to reduce ascites by accelerating the promotion of intestinal contents. AIM OF THE STUDY: The study aimed to investigate whether gut microbiota could affect the expelling water retention effects and the intestinal oxidative damage of EK and VEK on malignant ascites effusion (MAE) rats. MATERIALS AND METHODS: Pseudo-germ-free (PGF) MAE rats or probiotic intervented MAE rats were treated with EK/VEK. Related indicators such as serum, ascites, urine, feces, gastrointestinal tissues were analyzed, and the structure of the gut microbiota were also studied. The relationship between gut microbiota and the expelling water retention effects of EK/VEK where then further investigated. RESULTS: VEK reduce the volume of ascites by promoting urine and feces excretion, AQP8 protein and mRNA expression, when comparing with the MAE rats, also VEK could regulate the disordered gut microbiota in MAE rats. Mixed antibiotics could diminish VEK's expelling water retention effects in MAE rats, but increased oxidative damage in intestine. While existence of gut microbiota (especially probiotics) played an important role in the protection of intestines in VEK treated MAE rats. CONCLUSION: VEK had obvious pharmacological effect on MAE and could regulate gut microbiota, but gut microbiota was not a necessary condition for its pharmacological effects. The probiotics played a synergistic role with VEK in the effects of expelling water retention and intestinal protection.
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Ácido Acético/química , Ascitis/prevención & control , Bacterias/efectos de los fármacos , Culinaria , Euphorbia , Microbioma Gastrointestinal/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Acuaporinas/genética , Acuaporinas/metabolismo , Ascitis/etiología , Ascitis/microbiología , Ascitis/patología , Bacterias/crecimiento & desarrollo , Línea Celular Tumoral , Defecación/efectos de los fármacos , Euphorbia/química , Calor , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Intestino Delgado/patología , Masculino , Neoplasias/complicaciones , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/aislamiento & purificación , Probióticos/farmacología , Ratas Sprague-Dawley , Micción/efectos de los fármacosRESUMEN
Many blood glucose-lowering drugs cannot be used once patients with type 2 diabetes (T2D) and nonalcoholic fatty liver disease develop nonalcoholic steatohepatitis (NASH). Therefore, such patients often require insulin treatment. We aimed to determine the effect of sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin monotherapy on glucose metabolism in a mouse model of NASH/T2D, with a focus on its diuretic effects. To imitate ascites and to determine its severity by imaging, meglumine sodium amidotrizoate (MSA) was infused into the abdominal cavities of mice. The reduction in ascites induced by dapagliflozin was compared with that induced by furosemide using microcomputed tomography. The effects of each drug on hemodynamics were also compared. A dapagliflozin-related improvement in glucose tolerance was achieved in mice fed a high-fat diet (HFD) or an HFD + methionine-and-choline-deficient diet (MCDD). In dapagliflozin-treated NASH mice, hypoglycemia was not identified during 24-hour casual blood glucose monitoring. In the dapagliflozin and furosemide-treated groups, the time taken for the resolution of artificial ascites was significantly shorter than in the untreated group, and there were no significant differences between these groups. Furosemide significantly reduced the blood pressure and significantly increased the heart rate of the mice. Dapagliflozin caused a mild decrease in systolic, but not diastolic blood pressure, and the heart rate and circulating catecholamine and renin-aldosterone concentrations were unaffected. Dapagliflozin treatment improved glycemic control in the NASH mice versus untreated mice. Thus, dapagliflozin had a prompt diuretic effect but did not adversely affect the hemodynamics of mice with NASH and T2D. Therefore, it may be useful for the treatment of patients with both T2D and liver cirrhosis.
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Ascitis/prevención & control , Compuestos de Bencidrilo/farmacología , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacología , Hemodinámica/efectos de los fármacos , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Animales , Ascitis/etiología , Ascitis/fisiopatología , Biomarcadores/sangre , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Modelos Animales de Enfermedad , Diuresis/efectos de los fármacos , Quimioterapia Combinada , Furosemida/farmacología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacologíaRESUMEN
Postparacentesis circulatory dysfunction (PCD) is one of the commonest complications encountered in patients with refractory or recurrent ascites. Alpha agonists like clonidine and midodrine have been studied in various clinical trials for the prevention of PCD with varied results. This meta-analysis was done to evaluate the effect of alpha agonists on prevention of PCD in patients of refractory or recurrent ascites. A standard meta-analysis protocol was developed and registered in the International Prospective register of Ongoing Systematic Reviews. After performing a comprehensive literature search in MEDLINE, Cochrane, and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from five relevant articles. Preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines were followed in selection, analysis, and reporting of findings. Random effects model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool and meta-regression for probable variables affecting effect size. The random effect model analysis revealed a mean reduction of 2.63 ng/ml/h (95% CI: -4.46 to -0.8; P = 0.005) in plasma renin activity (PRA), mean reduction of 255.37 pg/ml (95% CI: -441.23 to -69.5; P = 0.007) in plasma aldosterone levels, and a mean increase of 0.14 mg/dl (95% CI: -0.13 to 0.41; P = 0.32) in serum creatinine levels favouring add-on alpha agonist group. In meta-regression, change in PRA (P = 0.79) and plasma aldosterone (P = 0.93) did not show a significant difference due to variation in follow-up duration across various studies. Add-on alpha agonists bring about a significant reduction in PRA and plasma aldosterone compared to standard medical treatment and thus prevents the occurrence of PCD in patients with refractory or recurrent ascites.
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Midodrina , Choque , Aldosterona , Ascitis/etiología , Ascitis/prevención & control , Humanos , Midodrina/efectos adversosAsunto(s)
Antibacterianos , Bacterias , Infecciones Bacterianas , Farmacorresistencia Microbiana , Peritonitis , Antibacterianos/clasificación , Antibacterianos/uso terapéutico , Ascitis/etiología , Ascitis/prevención & control , Bacterias/clasificación , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/etiología , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peritonitis/diagnóstico , Peritonitis/epidemiología , Peritonitis/microbiología , Peritonitis/terapiaRESUMEN
BACKGROUND AND AIM: The nuclear farnesoid X receptor (FXR) regulates critical pathways of hepatic metabolism, inflammation, and gut mucosal barrier. Thus, we investigated the association of FXR-single nucleotide polymorphism (SNPs) with hepatic decompensation and liver-related mortality in patients with advanced chronic liver disease. METHODS: Two FXR-SNPs (rs56163822 G > T and rs35724 G > C) were genotyped in a cohort of 402 prospectively characterized patients with hepatic venous pressure gradient (HVPG) ≥ 6 mmHg. RESULTS: Only 19 patients (4.7%) harbored a rs56163822 T-allele and had less pronounced liver disease as indicated by lower Child-Pugh score (CPS, 6 ± 1 vs 7 ± 2 points, P = 0.034) and higher albumin levels (38.9 ± 4.9 vs 35.9 ± 5.9 g/L, P = 0.026). In contrast, n = 267 (66.4%) patients harbored minor rs35724 allele (G/C or C/C) and had more advanced liver disease, as indicated by a higher model of end-stage liver disease (11 ± 4 vs 10 ± 3, P = 0.016), while other baseline characteristics were similar across FXR-SNP genotypes. In compensated CPS-A patients, the rs35724 minor allele was independently protective for the development of ascites (adjusted hazard ratio [aHR] = 0.411, 95% confidence interval (95% CI): 0.191-0.885; P = 0.023) and tended to reduce the risk of hepatic decompensation (aHR = 0.625, 95% CI: 0.374-1.044, P = 0.072) in multivariate analyses. Of note, transplant-free survival was longer in patients with rs35724 minor allele and HVPG ≥ 10 mmHg (at 5 years: 68.2% vs 55.8%, P = 0.047) and those with HVPG ≥ 16 mmHg (63.3% vs 44.0%, P = 0.021). After adjusting for established risk factors, the rs35724 minor allele was independently associated with reduced liver-related mortality in the overall cohort (aHR = 0.658, 95% CI: 0.434-0.998, P = 0.049), in compensated CPS-A patients (aHR = 0.488, 95% CI: 0.252-0.946, P = 0.034), in patients with HVPG ≥ 10 mmHg (aHR = 0.547, 95% CI: 0.346-0.864, P = 0.010), and in patients with HVPG ≥ 16 mmHg (aHR = 0.519, 95% CI: 0.307-0.878, P = 0.014). CONCLUSION: The FXR-SNP rs35724 was associated with a reduced risk for development of ascites and liver-related mortality in patients with advanced chronic liver disease.
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Hipertensión Portal/genética , Cirrosis Hepática/genética , Polimorfismo de Nucleótido Simple , Receptores Citoplasmáticos y Nucleares/genética , Adulto , Anciano , Ascitis/etiología , Ascitis/genética , Ascitis/mortalidad , Ascitis/prevención & control , Austria/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Portal/etiología , Hipertensión Portal/mortalidad , Hipertensión Portal/fisiopatología , Estimación de Kaplan-Meier , Cirrosis Hepática/complicaciones , Cirrosis Hepática/mortalidad , Cirrosis Hepática/fisiopatología , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Presión Portal/fisiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Clinical decompensation of cirrhosis is associated with poor prognosis. Clinically significant portal hypertension (CSPH), defined by a hepatic venous pressure gradient (HVPG) ≥10 mm Hg, is the strongest predictor of decompensation. This study aimed at assessing whether lowering HVPG with ß blockers could decrease the risk of decompensation or death in compensated cirrhosis with CSPH. METHODS: This study on ß blockers to prevent decompensation of cirrhosis with portal hypertension (PREDESCI) was an investigator-initiated, double-blind, randomised controlled trial done in eight hospitals in Spain. We enrolled patients with compensated cirrhosis and CSPH without high-risk varices. All participants had HVPG measurements with assessment of acute HVPG-response to intravenous propranolol. Responders (HVPG-decrease ≥10%) were randomly assigned to propranolol (up to 160 mg twice a day) versus placebo and non-responders to carvedilol (≤25 mg/day) versus placebo. Doses were individually determined during an open-label titration period after which randomisation was done with 1:1 allocation by a centralised web-based system. The primary endpoint was incidence of cirrhosis decompensation (defined as development of ascites, bleeding, or overt encephalopathy) or death. Since death in compensated cirrhosis is usually unrelated to the liver, an intention-to-treat analysis considering deaths unrelated to the liver as competing events was done. This study is registered with ClinicalTrials.gov, number NCT01059396. The trial is now completed. FINDINGS: Between Jan 18, 2010, and July 31, 2013, 631 patients were evaluated and 201 were randomly assigned. 101 patients received placebo and 100 received active treatment (67 propranolol and 33 carvedilol). The primary endpoint occurred in 16 (16%) of 100 patients in the ß blockers group versus 27 (27%) of 101 in the placebo group (hazard ratio [HR] 0·51, 95% CI 0·26-0·97, p=0·041). The difference was due to a reduced incidence of ascites (HR=0·44, 95%CI=0·20-0·97, p=0·0297). The overall incidence of adverse events was similar in both groups. Six patients (four in the ß blockers group) had severe adverse events. INTERPRETATION: Long-term treatment with ß blockers could increase decompensation-free survival in patients with compensated cirrhosis and CSPH, mainly by reducing the incidence of ascites. FUNDING: Spanish Ministries of Health and Economy.
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Antagonistas Adrenérgicos beta/administración & dosificación , Carvedilol/administración & dosificación , Hipertensión Portal/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Propranolol/administración & dosificación , Administración Oral , Adulto , Anciano , Ascitis/prevención & control , Método Doble Ciego , Femenino , Hemorragia Gastrointestinal/prevención & control , Encefalopatía Hepática/prevención & control , Humanos , Hipertensión Portal/complicaciones , Hipertensión Portal/mortalidad , Cirrosis Hepática/complicaciones , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Índice de Severidad de la EnfermedadRESUMEN
Due to the restrictions of liver transplantation, complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis. This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications, together with discussion of current controversies and potential future directions. PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety, efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis. Non-selective beta-blockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices, but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation. Recent observational studies suggest protective, haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation. The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy; recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis. Diuretics remain the mainstay of uncomplicated ascites treatment, and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites. Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications. Despite initial hepatotoxicity concerns, safety of statin administration has been demonstrated in compensated cirrhosis. Furthermore, statins are suggested to have protective effects upon fibrosis progression, decompensation and mortality. Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting. Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis, and may impede hepatic fibrogenesis and decompensation. Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management, nutritional optimisation and patient education.
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Ascitis/tratamiento farmacológico , Várices Esofágicas y Gástricas/tratamiento farmacológico , Hemorragia Gastrointestinal/tratamiento farmacológico , Encefalopatía Hepática/tratamiento farmacológico , Hipertensión Portal/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Antibacterianos/uso terapéutico , Profilaxis Antibiótica/métodos , Anticoagulantes/uso terapéutico , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Ascitis/etiología , Ascitis/prevención & control , Enfermedad Crónica/tratamiento farmacológico , Modelos Animales de Enfermedad , Diuréticos/uso terapéutico , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/prevención & control , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión Portal/etiología , Hipertensión Portal/prevención & control , Cirrosis Hepática/complicaciones , Inhibidores de la Bomba de Protones/uso terapéutico , Prevención Secundaria/métodos , Resultado del TratamientoRESUMEN
High levels of guanidinoacetate acid (GAA) deteriorate growth response in broiler chickens. We propose using coenzyme Q10 , an antioxidant, and taurine (TAU), a methyl donor, to cope with the situation when high level of GAA included in diet. GAA was supplemented at 0 (control), 0.75, 1.5 and 2.25 g/kg in isoenergetic and isonitrogenous diets and fed to broilers (Cobb 500) from 1 to 40 days post-hatch. Three additional diets were prepared by adding CoQ10 (40 mg/kg), TAU (40 mg/kg) or their combination (both CoQ10 and TAU at 40 mg/kg) to the 2.25 g/kg GAA group. The experimental design used was a completely randomized design. While weight gain (p = 0.038) and feed conversion ratio (p = 0.024) improved when GAA added at 1.5 g/kg, higher supplementation (2.25 g/kg) deteriorated these responses. These responses, however, were significantly restored by using CoQ10 , TAU or their combination. Abdominal fat deposition was significantly decreased when TAU added to broiler diets by virtue of upregulating peroxisome proliferator-activated receptor alpha. Supplementing broiler diets with CoQ10 and TAU or their combination significantly decrease ascites mortality. In conclusion, CoQ10 and TAU have shown beneficial effects when high level of GAA included in broiler diets.
Asunto(s)
Ascitis/veterinaria , Pollos/crecimiento & desarrollo , Glicina/análogos & derivados , Taurina/farmacología , Ubiquinona/análogos & derivados , Alimentación Animal/análisis , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Ascitis/mortalidad , Ascitis/prevención & control , Dieta/veterinaria , Quimioterapia Combinada , Regulación de la Expresión Génica/efectos de los fármacos , Glicina/administración & dosificación , Glicina/farmacología , Masculino , Taurina/administración & dosificación , Ubiquinona/administración & dosificación , Ubiquinona/farmacologíaRESUMEN
BACKGROUND: Statin has been more and more widely used in chronic liver disease, however, existed studies have attained contradictory results. According to the present study, we aimed to test the efficacy and safety of statin via a meta-analysis. METHODS: Different databases were searched for full-text publication based on inclusion and exclusion criteria. For data-pooling, fixed-effect model was applied if heterogeneity wasn't detected. Otherwise, random-effect model was adopted. Heterogeneity was detected by I squire (I2) test. All results of analysis were illustrated as forest plots. Publication bias was assessed using the Begg's adjusted rank correlation test. Standard mean difference (SMD) was calculated in continuous variables. Pooled hazard ratio or odds ratio was calculated in catergorical variables. RESULTS: Seventeen clinical studies were finally included. Hepatic portal hemodynamic parameters were improved in statin users for a short-term response. For a long-term follow-up, statin treatment surprisingly decreased mortality rate (HR = 0.782, 95% CI: 0.718-0.846, I2 > 50%) and lower the occurrence of hepatocellular carcinoma (HR = 0.75, 95% CI: 0.64-0.86, I2 > 50%) in liver cirrhosis. Statin seemed not to decrease the risk of esophageal variceal bleeding and spontaneous bacterial peritonitis. However, statin was proved to decrease the risk of hepatic encephalopathy and ascites. Incidence of drug related adverse events didn't increase in statin users. Dose-dependent effects of statin on hepatocellular carcinoma development, decompensated cirrhosis events occurrence, and liver cirrhosis progression. CONCLUSION: Statin influenced parameters of hepatic portal vessel pressure in short-term treatment. Prognosis of liver cirrhosis benefited from statin treatment in long term follow-up. The efficacy and safety of statin in liver cirrhosis treatment is confirmed. To date, similar study is hardly seen before.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Cirrosis Hepática/tratamiento farmacológico , Ascitis/prevención & control , Carcinoma Hepatocelular/prevención & control , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Várices Esofágicas y Gástricas/complicaciones , Hemorragia Gastrointestinal/prevención & control , Encefalopatía Hepática/prevención & control , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Cirrosis Hepática/mortalidad , Neoplasias Hepáticas/prevención & control , Ensayos Clínicos Controlados no Aleatorios como Asunto , Peritonitis/microbiología , Peritonitis/prevención & control , Presión Portal/efectos de los fármacos , Sesgo de Publicación , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
La hipertensión portal (HTP) es una condición clínica definida por una presión hidrostática >5mmHg en el territorio venoso portal, siendo clínicamente significativa cuando es ≥10mmHg. A partir de este umbral pueden desarrollarse complicaciones, como sangrado de varices esofágicas, aparición de ascitis o encefalopatía hepática. Las técnicas de imagen tienen un papel importante como método no invasivo para determinar la presencia de HTP. En este artículo se analizan varios hallazgos radiológicos que pueden sugerir HTP y contribuir a definir su etiología, gravedad y posibles complicaciones
Portal hypertension is a clinical entity defined by a hydrostatic pressure greater than 5mm Hg in the portal territory, being clinically significant when it is greater than or equal to 10mm Hg. Starting from this threshold, complications can develop, such as the bleeding of esophageal varices, the appearance of ascites, or hepatic encephalopathy. Imaging techniques play an important role as a noninvasive method for determining whether portal hypertension is present. This article analyzes various imaging findings that can suggest the presence of portal hypertension and can help to define its etiology, severity, and possible complications
Asunto(s)
Humanos , Hipertensión Portal/diagnóstico por imagen , Diagnóstico por Imagen de Elasticidad/métodos , Cirrosis Hepática/diagnóstico por imagen , Índice de Severidad de la Enfermedad , Ascitis/prevención & control , Várices Esofágicas y Gástricas/diagnóstico por imagen , Encefalopatía Hepática/diagnóstico por imagen , Biomarcadores/análisis , Derivación Portosistémica Intrahepática Transyugular , Circulación ColateralRESUMEN
Castleman's disease (CD) is a rare lymphoproliferative disorder, and its prevalence in Thailand is not known. This 10-year period study investigated the prevalence of CD in Thailand, and the clinical characteristics and outcomes of Thai CD patients, with special focus on the existence and prevalence of TAFRO syndrome. TAFRO syndrome is defined as CD with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. Thirty-three CD patients diagnosed and treated at Siriraj Hospital during January 2007 to December 2016 were included. The prevalence of CD was 1.4 per 1,000,000 patients/10 years. Median age was 46 years, with slight female predominance. Six patients were assigned to the TAFRO group. A high proportion of TAFRO syndrome (18.2%) was found among Thai adult CD patients. In addition to routine TAFRO diagnostic criteria, significantly lower hemoglobin and albumin levels were observed in the TAFRO group than in the non-TAFRO group. Treatment outcomes of CD patients were complete remission (52%), stable disease (30%), and death (13%). Three-year overall survival in the non-TAFRO group and TAFRO group was 88 and 50%, respectively. While most CD patients had a good prognosis, severe cases with TAFRO syndrome had poor outcome.
Asunto(s)
Enfermedad de Castleman/fisiopatología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Ascitis/etiología , Ascitis/prevención & control , Enfermedad de Castleman/diagnóstico , Enfermedad de Castleman/tratamiento farmacológico , Enfermedad de Castleman/epidemiología , Edema/etiología , Edema/prevención & control , Femenino , Fiebre/etiología , Fiebre/prevención & control , Estudios de Seguimiento , Hospitales de Enseñanza , Humanos , Perdida de Seguimiento , Masculino , Persona de Mediana Edad , Derrame Pleural/etiología , Derrame Pleural/prevención & control , Prevalencia , Pronóstico , Inducción de Remisión , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Tailandia/epidemiología , Trombocitopenia/etiología , Trombocitopenia/prevención & controlRESUMEN
A hypothesis was tested that eggshell temperature manipulations during incubation and in ovo injection of thyroxine (T4) would help their progeny chicks to better survive the ascites-inducing condition during the growing period. In experiment 1, a total of 4,800 hatching eggs was randomly arranged in a 2 × 4 factorial design (8 replicates of 75 eggs per treatment), in which the eggs were incubated at a constant eggshell temperature (EST) of 37.8°C throughout the incubation period (CON) or were exposed to 15°C for one h on d 11, 13, 15, and 17 of incubation (EST manipulations; ESTM), and 4 treatment groups of 3 control groups (no injection; INJN, needle pricked; INJP, and sterilized distilled water injection; INJW) and one T4 treatment group (injected with sterilized distilled water containing 65 ng of T4; INJT4). In experiment 2, 240 one-day-old male broiler chicks from 2 temperature conditions and injection (INJN and INJT4) treatment groups were reared for 42 d in a completely randomized design with a 2 × 2 factorial arrangement. To induce ascites, all chicks were exposed to a 15°C room temperature from 14 d onwards. Results from experiment 1 showed that second-grade chicks and yolk sac weight were decreased, and body weight at hatch was increased in the ESTM and INJT4 groups. Also, final body weight was increased in the ESTM group. Ascites mortality rate was decreased in the ESTM and INJT4 groups. In the ESTM and INJT4 groups, the red blood cell (RBC) and the packed cell volume (PCV) count were decreased. In conclusion, the results showed that the ESTM and INJT4 treatments during incubation were associated with improved chick quality, productive performance of broilers, and a decreased incidence of cold-induced ascites in broiler chickens.
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Ascitis/veterinaria , Pollos , Frío , Cáscara de Huevo/fisiología , Óvulo/fisiología , Enfermedades de las Aves de Corral/prevención & control , Tiroxina/administración & dosificación , Animales , Ascitis/epidemiología , Ascitis/etiología , Ascitis/prevención & control , Incidencia , Inyecciones/veterinaria , Irán/epidemiología , Masculino , Enfermedades de las Aves de Corral/epidemiología , Enfermedades de las Aves de Corral/etiologíaRESUMEN
Even though hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic cell transplantation (HCT), there is paucity of research on the management of associated multiorgan dysfunction. To help provide standardized care for the management of these patients, the HCT Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators and the Supportive Care Committee of the Pediatric Blood and Marrow Transplant Consortium, collaborated to develop evidence-based consensus guidelines. After conducting an extensive literature search, in part 2 of this series we discuss the management of fluids and electrolytes, renal dysfunction; ascites, pleural effusion, and transfusion and coagulopathy issues in patients with VOD. We consider the available evidence using the GRADE criteria.
Asunto(s)
Humanos , Niño , Adolescente , Derrame Pleural/prevención & control , Ascitis/prevención & control , Enfermedad Veno-Oclusiva Hepática/prevención & control , Trasplante de Médula Ósea/efectos adversos , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Enfermedad Veno-Oclusiva Hepática/etiología , Manejo de la EnfermedadRESUMEN
AIM: To evaluate the effect of initial stent position on transjugular intrahepatic portosystemic shunt (TIPS). METHODS: We studied 425 patients from January 2004 to January 2015 with refractory ascites or variceal bleeding who required TIPS placement. Patients were randomly divided into group A (stent in hepatic vein, n = 57), group B (stent extended to junction of hepatic vein and inferior vena cava, n = 136), group C (stent in left branch of portal vein, n = 83) and group D (stent in main portal vein, n = 149). Primary unassisted patency was compared using Kaplan-Meier analysis, and incidence of recurrence of bleeding, ascites and hepatic encephalopathy (HE) were analyzed. RESULTS: The mean primary unassisted patency rate in group B tended to be higher than in group A at 3, 6 and 12 mo (P = 0.001, 0.000 and 0.005), and in group D it tended to be lower than in group C at 3, 6 and 12 mo (P = 0.012, 0.000 and 0.028). The median shunt primary patency time for group A was shorter than for group B (5.2 mo vs 9.1 mo, 95%CI: 4.3-5.6, P = 0.013, log-rank test), while for group C it was longer than for group D (8.3 mo vs 6.9 mo, 95%CI: 6.3-7.6, P = 0.025, log-rank test). Recurrence of bleeding and ascites in group A was higher than in group B at 3 mo (P = 0.014 and 0.020), 6 mo (P = 0.014 and 0.019) and 12 mo (P = 0.024 and 0.034. Recurrence in group D was higher than in group C at 3 mo (P = 0.035 and 0.035), 6 mo (P = 0.038 and 0.022) and 12 mo (P = 0.017 and 0.009). The incidence of HE was not significantly different among any of the groups (P = 0.965). CONCLUSION: The initial stent position can markedly affect stent patency, which potentially influences the risk of recurrent symptoms associated with shunt stenosis or occlusion.