Altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms.

The aim of this study is to assess a potential mechanism by which the serotonergic system can control the expression and activity of cytochrome (CYP) 2C11 and CYP3A isoforms during liver insufficiency. A rat model of diethylnitrosamine (DEN)-induced liver insufficiency was developed by administering 50 mg/kg of DEN twice a week for 7 weeks. Dysfunction of the serotonergic system was evoked by feeding the rats with a tryptophan-free diet for three weeks. Dysfunction of the serotonergic system during liver insufficiency decreased the level of proinflammatory cytokines (TGF-ß and IL-1ß) and increased the level of an anti-inflammatory cytokine (IL-4). Simultaneously, activation of the repressive mechanism IL-4/JAK1/STAT6/SOCS1 of the JAK2/STAT5b-mediated signal transduction pathway and the pERK1/2/GR/STAT6 signal transduction pathway resulted in the suppression of the CYP2C11 and CYP3A isoforms. Moreover, dysfunction of the serotonergic system during liver insufficiency equalized the level of testosterone to the basal level, did not change the steady state of the corticosterone level and significantly enhanced the reduced level of growth hormone. An altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms during liver insufficiency through mechanisms based on posttranscriptional and posttranslational processes.

The impact of serotonergic system dysfunction on the regulation of P4501A isoforms during liver insufficiency and consequences for thyroid hormone homeostasis.

This study aimed to evaluate the impact of serotonergic system dysfunction on the regulation of cytochrome P4501A (CYP1A) during liver insufficiency. A rat model of liver insufficiency with a dysfunctional serotonergic system was developed. To induce liver insufficiency, animals were treated with nitrosodiethylamine (DEN) at 50 mg/kg of body weight twice a week for 7 weeks. To induce serotonergic system dysfunction, the animals were fed a tryptophan-free diet for 3 days. Serotonergic system dysfunction during liver insufficiency generated the aryl hydrocarbon receptor (AhR) activation and the "superinduction" of the AhR target genes: CYP1A1, CYP1B1 and UGT1A, with a concomitant increase in CYP1A1 protein and activity. CYP1A2 gene expression was simultaneously down-regulated, with a concomitant decrease in CYP1A2 protein and activity. A significant reduction in TRß receptor levels, together with a simultaneous increase of TRα receptor gene and protein level (mainly TRα2 isoform) after serotonergic system dysfunction, suggests that the serotoninergic system is involved in the regulation of CYP1A isoforms without influence from thyroid hormones during liver insufficiency. The interplay between the serotonergic system and the regulation of CYP1A isoforms, which are downstream targets of AhR activation, is dependent on hepatic function and can be observed without influence from thyroid hormones.

Effects and toxicity of neoadjuvant chemotherapy preoperative followed by adjuvant chemoradiation in small cell neurdendocrine cervical carcinoma.

OBJECTIVE: To determine the efficacy and toxicity of a combined-modality regimen of neoadjuvant chemotherapy (NACT) before primary radical surgery followed by adjuvant chemoradiation in small cell neuroendocrine cervical cancer (SCNEC) patients. MATERIALS AND METHODS: The study was approved by the ethics committee of the present hospital. The records of 23 SCNEC patients who received NACT before primary radical surgery were reviewed at the Zhejiang Cancer Hospital between January 1998 and May 2010. All patients received one to four cycles of NACT and two to eight cycles of chemotherapy (NACT and adjuvant chemotherapy) on the basis of platinum, 17 (73.9%) patients received NACT using a regimen consisting of etoposide and cisplatin (EP). Eighteen (85.7%) patients received adjuvant chemotherapy using a regimen consisting of PE and EP. Kaplan-Meier and Cox regression methods were used for analyses. RESULTS: Of the 23 eligible patients, 18 had Stages I-IIA, five had Stages IIB-IIIB disease. Twelve patients (52.2%) developed grade 3 and 4 neutropenia. Fourteen patients (60.9%) developed grade 3 and 4 anemia. The majority of grade 3 and 4 neutropenia and non-hematologic toxicities were usually self-limited. Three patients (13.0%) who postoperative pathology showed pathologic complete response (CR) had better prognosis than those did not show pathologic CR; the median survival was 69.5 months (range, 51.1-177.1), 54.5 months (range: 7.3-81.5), respectively. In univariate analysis, lymphovascular space invasion (LSI) (p = 0.013), and deep stromal invasion (DSI) (p = 0.001) were considered poor prognostic factors. With a median follow-up for surviving patients was 40.8 months (range, 7-177), 12 patients recurred, 11 of which had died. The estimated three- and five-year overall survival (OS) rates for all patients were 55.8% and 39.9%, respectively. CONCLUSION: NACT before primary radical surgery followed by adjuvant chemoradiation or chemotherapy was well tolerated and seems to be effective for early stage SCNEC patients. Prospective clinical study is necessary and we hope that this research's results help to design a prospective clinical study.

Synergistic effect of black tea and curcumin in improving the hepatotoxicity induced by aflatoxin B1 in rats.

Aflatoxin B1 (AFB1) is a toxic compound commonly found as a contaminant in human food. It is carcinogenic due its potential in inducing the oxidative stress and distortion of the most antioxidant enzymes. Since black tea possesses strong antioxidant activity, it protects cells and tissues against oxidative stress. Curcumin (CMN), a naturally occurring agent, has a combination of biological and pharmacological properties that include antioxidant activity. Therefore, the present study was carried out to investigate the possible role of separate and mixed supplementation of black tea extract and CMN in the hepatotoxicity induced by AFB1 in rats. A total of 48: adult male Sprague Dawley rats were randomly divided into eight groups with six rats in each group. Group 1 (normal control) includes rats that received no treatment. Groups 2, 3, and 4 (positive control) include rats that received olive oil, black tea extract, and CMN, respectively. Group 5 includes rats that received AFB1 at a dose of 750 µg/kg body weight (b.w.) dissolved in olive oil. Groups 6, 7, and 8 include rats that received AFB1 along with 2% black tea extract, CMN at a dose of 200 mg/kg b.w., and both black tea extract and CMN at the same previous doses, respectively. After 90 days, biochemical and histopathological examination was carried out for the blood samples and liver tissues. A significant decrease in the antioxidant enzymes and a significant increase in the lipid peroxidation and hydrogen peroxide in the rats treated with AFB1 were observed. Moreover, there were dramatic changes in the liver function biomarkers, lipid profile, and liver architecture. Supplementation of black tea extract or CMN showed an efficient role in repairing the distortion of the biochemical and histological changes induced by AFB1 in liver. This improvement was more pronounced when both CMN and black tea were used together.

Phase I study of carboplatin combined with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVE: The primary objective of this study was to evaluate the safety and tolerability of carboplatin plus pemetrexed for elderly patients (≥75 years) with chemotherapy-naïve advanced non-squamous non-small cell lung cancer. METHODS: Patients received escalated doses of carboplatin at an area under the concentration-time curve of 4 (Level 1) or 5 (Level 2) plus pemetrexed (500 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation was decided according to whether dose-limiting toxicity occurred in the first cycle of chemotherapy. RESULTS: A total of 20 patients (6 at Level 1, 14 at Level 2) were enrolled. No dose-limiting toxicities were observed in patients at Level 1 or the first six patients at Level 2, and therefore the combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was considered to be the recommended dose. Among a total of 14 patients in Level 2, only 1 patient experienced dose-limiting toxicity: Grade 3 febrile neutropenia and urticaria. The major toxicities were neutropenia, thrombocytopenia and anemia. Liver dysfunction, fatigue and anorexia were also common, but generally manageable. Six patients showed partial responses, giving the overall response rate of 30%. The median progression-free survival period was 4.8 months (95% confidence interval 2.9-6.7 months). CONCLUSIONS: The combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was determined as the recommended dose in chemotherapy-naïve elderly patients (≥75 years) with advanced non-squamous non-small cell lung cancer, in view of overall safety and tolerability.

κ-Selenocarrageenan prevents microcystin-LR-induced hepatotoxicity in BALB/c mice.

Microcystins (MCs) are a family of cyclic heptapeptides that are produced by blooming algae Microcystis. MCs have been implicated in the development of liver cancer, necrosis and even intrahepatic bleeding. Effective prophylactic approaches and complete removal of MCs are urgently needed. Accumulating evidence suggests that microcystin-LR (MC-LR)-induced damage is accompanied by oxidative stress. Supplementation of Se can enhance resistance to oxidative stress. Therefore, in the present study, we investigated the protective effects of κ-Selenocarrageenan (Se-Car), a kind of organic Se compound, in Balb/c mice exposed to MC-LR. Our results proved that Se-Car could significantly ameliorate the hepatic damage induced by MC-LR, including serum markers of liver dysfunction, oxidative damages and histological alterations. Furthermore, Se-Car could significantly alleviate the up-regulation of the molecular targets indicating mitochondrial dysfunction and endoplasmic reticulum stress induced by MC-LR. In conclusion, Se-Car showed clear protection against toxicity induced by MC-LR. Thus, Se-Car could be useful as a new category of anti-MC-LR toxicity reagent.

[Statin-induced adverse effects -- facts and genes]. / Statin okozta mellékhatások -- tények és gének.

Statin therapy is considered to be safe and rarely associated with serious adverse events. However, a significant proportion of patients on statin therapy show some degree of intolerance which can lead to decreased adherence to statin therapy. The authors summarize the symptoms, signs and frequencies of the most common statin-induced adverse effects and their most important risk factors including some single nucleotide polymorphisms and gene mutations. Also, they review the available approaches to detect and manage the statin-intolerant patients.

[Effect of domestic gas on morphological and functional state of parenchymatous organs in rats].

The work is devoted to a study of morphological and functional changes in liver and kidneys in the simulation of subacute toxic exposure of rats to domestic gas in the experiment. In the course of studies found that the subacute intoxication by domestic gas and its metabolites were shown to causes profound structural and metabolic lesions of the liver and kidneys that can progress to develop the chronic liver and kidney insufficiency.

Fat content in liver and skeletal muscle changes in a reciprocal manner in patients with acromegaly during combination therapy with a somatostatin analog and a GH receptor antagonist: a randomized clinical trial.

CONTEXT: Pegvisomant is a GH antagonist, which is used for the treatment of acromegalic patients. It effectively blocks the hepatic and peripheral effects of GH, but transient elevations in circulating liver enzymes of unknown pathogenesis may occur, which seems to be more prevalent when the treatment is combined with a somatostatin analog (SA). Accumulation of intrahepatic lipid is a known cause of elevated liver enzymes, and there is evidence to suggest that GH impacts lipid content in liver and skeletal muscle. OBJECTIVE: Our objective was to measure lipid content in liver and skeletal muscle in acromegalic patients before and after cotreatment with pegvisomant and SA as compared with SA monotherapy. DESIGN: Eighteen acromegalic patients well controlled on SA monotherapy were randomized in a parallel study over 24 wk to 1) unchanged SA monotherapy, or 2) cotreatment with pegvisomant (15-30 mg twice a week) and SA (half the usual dosage). SETTING: This was an investigator-initiated study in a single tertiary referral center. MAIN OUTCOME MEASURES: Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) was assessed by ¹H magnetic resonance spectroscopy. RESULTS: IHL increased in the cotreatment group compared with SA only (P = 0.002). The increase was positively correlated to weekly pegvisomant dose (r² = 0.52; P = 0.01). By contrast, IMCL decreased in the cotreatment group compared with SA only (P = 0.01). These changes related neither to insulin sensitivity nor inflammatory markers. CONCLUSION: Cotreatment with pegvisomant and a reduced SA dose increase IHL and decrease IMCL compared with SA monotherapy. The clinical implications remain unclear, but increased IHL may be causally linked to the transient elevations in liver enzymes observed during pegvisomant treatment.

Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases.

BACKGROUND: The optimal duration, safety, and benefit of preoperative chemotherapy in patients with colorectal liver metastases (CLM) are unclear. We evaluated the association between the duration of preoperative chemotherapy with 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX) ± bevacizumab, pathologic response, and hepatotoxicity after hepatic resection for CLM. METHODS: A total of 219 patients underwent hepatic resection following FOLFOX with or without bevacizumab and were divided into 2 groups according to the chemotherapy duration: 1-8 cycles (short duration [SD]; N = 157) and ≥9 cycles (long duration [LD]; N = 62). The frequency of complete or major pathologic response, sinusoidal injury, and major postoperative morbidity were compared. RESULTS: Treatment consisting of ≥9 cycles was not associated with an increase in complete or major pathologic response (SD vs. LD, 57% vs. 55%; P = .74). The incidence of sinusoidal injury was higher in the LD group (26% vs. 42%; P = .017). The incidence of liver insufficiency was higher in the LD group (4% vs. 11%; P = .035). Sinusoidal injury did not predict postoperative liver insufficiency; multivariate analysis revealed ≥9 cycles was the only independent predictor of postoperative liver insufficiency (P = .031; odds ratio = 3.90). Chemotherapy including bevacizumab was associated with a significantly higher frequency of complete or major response in both SD and LD groups. CONCLUSIONS: Extended preoperative chemotherapy increases the risk of hepatotoxicity in CLM without improving the pathologic response. The type of chemotherapy (FOLFOX with bevacizumab) has more impact on pathologic response than the duration of chemotherapy.

[Preliminary study on the effects of an artificial liver support system in the treatment of medicamentous liver insufficiency].

OBJECTIVES: To study the effectiveness of an artificial liver support system. METHODS: Thirty-two patients with medicamentous liver insufficiency were treated with an artificial liver support system in addition to the routine medicinal therapy. Thirty patients treated with routine medicinal therapy only served as controls. RESULTS: The clinical symptoms (e.g. hepatic encephalopathy) and the laboratory indices (serum total bilirubin and prothrombin time) of the treatment group patients were obviously improved compared with those of the control group patients (P < 0.05). The cure rate and hospitalization days were 90.6% (26/32) and 47 days respectively in the treatment group, and 43.3% (13/30) and 72 days in the control group (P < 0.05). CONCLUSION: Using an artificial liver support system combined with routine medicinal therapy is more effective than using medication alone.

Relationship between iron replacement and hepatic functions in hepatitis C virus-positive chronic haemodialysis patients.

AIM: To investigate the effects of intravenous (i.v.) iron replacement on hepatic functions of hepatitis C virus (HCV)-positive haemodialysis patients. METHODS: The present retrospective study included 89 HCV-positive and 57 HCV-negative haemodialysis patients. Alanine aminotransferase (ALT) levels were accepted as sustained high if the last three values were >/=20 U/L. All patients and the HCV-positive group were dichotomised into subgroups by the median for dialysis duration, the amounts of i.v. iron administered per year and totally. RESULTS: Sustained high levels of ALT were significantly more frequent in the HCV-positive group (P < 0.001). In HCV-positive patients, the subgroup with ALT levels >/=20 U/L had significantly higher serum iron levels and mean amounts of i.v. iron administered per year and totally (P < 0.001) and the subgroup with the high mean total amount of i.v. iron had significantly higher serum ALT and iron levels (P < 0.001). Significant positive correlations were found in HCV-positive patients between ALT and serum iron levels (P < 0.001), as well as between ALT both with the mean amounts of i.v. iron administered per year (P = 0006) and totally (P = 0.015). Regression analysis showed that the main parameters effecting ALT were the serum iron level (P < 0.0001) and the mean amount of parenteral iron administered per year (P = 0.032). CONCLUSION: We conclude that parenteral iron replacement might contribute to hepatocellular injury in HCV-positive haemodialysis patients.

Hepatite associada à aspirina / Hepatitis associated with aspirin

Os autores relatam um caso de hepatite em paciente tomando altas doses de aspirina por longo período e fazem uma breve revisäo da literatura pertinente.

Insuficiencia hepática aguda fulminante: presentación de un modelo canino por intoxicación con acetaminofeno / Acute fulminant liver failure: presentation of a dog model by acetaminofen poisoning

La carencia de donantes oportunos en casos de insuficiencia hepática aguda fulminante (IHAF) requiere contar con sistemas de soporte hepático transitorio. Para ensayarlos antes de su uso clínico es necesario tener modelos animales de IHAF estandarizados y reproducibles. Nuestro objetivo fue establecer un modelo canino de IHAF por intoxicación oral con acetaminofeno (ACE), para obtener una necrosis hepática (NH) superior al 60 por ciento y determinar los cambios en diferentes variables bioquímicas susceptibles de ser corregidas en modelos de soporte hepático. Para ello se utilizaron 22 perros a los cuales se les administró ACE por sonda gástrica en 3 grupos (Gr): A: 500 mg/kg (n= 5), B: 750 mg/kg (n= 10) y C: 1000 mg/kg (n= 7). En ellos se determinaron los valores basases de diferentes variables bioquímicas de función hepática. Los animales fueron observados clínicamente, y entre las 22 y 24 h post-intoxicación (po.i.) se realizó una 2º determinación de los mismos parámetros en los perros que sobrevivieron. Finalmente se realizó una biopsia hepática, y en los perros fallecidos una necropsia. Se analizó el grado de NH obtenida, su relación con la mortalidad y los resultados de las variables bioquímicas pre y po.i. con diferentes pruebas estadísticas. Resultados: Sobrevivieron 19 animales al procedimiento basal. De ellos, en 10 (52,6 por ciento) se obtuvo una NH >60 por ciento (0, 56 y 83 por ciento de los Gr A, B y C respectivamente, p< 0,05). El 80 por ciento de estos animales (5/6 del Gr C y 319 del Gr B) falleció entre las 14 y 26 h po.i. posterior a un cuadro clínico y bioquímico de falla hepática aguda. En 3 animales no se observó NH, todos del Gr A. No falleció ningún animal con NH < 60 por ciento (p< 0,01). El análisis de las variables bioquímicas pre y po.i. mostró un trastorno metálico importante en todos los animales intoxicados, dosis dependiente, con una mayor sensibilidad para los cambios en los niveles de bilirrubina y transaminasas. En conclusión, con dosis entre 750 y 1000 mg/kg de ACE oral se establece un modelo canino de 1 HAF válido para ser utilizado en la evaluación de sistemas de soporte hepático transitorio

Daño hepático por acetaminofeno: caso clínico / Hepatic damage due to acetaminophen: a clinical case

Se presenta el caso de una paciente de 27 años de edad, con el antecedente de ingesta excesiva de fármacos en forma voluntaria. Por sospecha de corresponder a una dosis alta de acetaminofeno, se evalúa con niveles plasmáticos de la droga (que confirman la ingesta) enzimas hepáticas y pruebas de coagulación, mostrando evolución rápida y progresiva al daño hepático agudo. No se obtuvo restos de fármacos del lavado gástrico efectuando al ingreso y no se pudo contar con el antídoto específico (n-acetilcisteína). La paciente evolucionó inicialmente soporosa, y luego con sensibilidad en hipocondrio derecho e ictericia. Se usó fitonodiona IM y plasma fresco congelado para corregir las alteraciones de coagulación, hidratación parenteral, ranitidina EV, dieta cero por boca. Se observó paulatina recuperación. Se revisa el mecanismo de daño hepático del acetaminofeno y se comentan las posibilidades terapéuticas

Antibioticos e insuficiência hepática / Antibiotics and liver failure

Säo revistos, de início, os principais mecanismos de metabolizaçäo hepática de drogas, descrevendo-se tais processos ao nível da fraçäo microssomal da célula. A seguir, analisam-se as diferentes formas de agressäo hepática causadas por drogas, distinguindo-se aquelas causadas por hepatotoxinas verdadeiras (lesöes previsíveis) daquelas ocasionadas por substâncias cuja açäo nociva é eventual (lesöes de sensibilizaçäo - imprevisíveis). Diferenciam-se principalmente as formas colestáticas das reaçöes tipo hepatite aguda. Por fim, säo estudados os principais grupos de antibióticos mais utilizados na prßtica clínica, procurando realçar a participaçäo do fígado, de modo mais importante ou näo, nos seus processos de metabolizaç1 , acentuando os possíveis potenciais de toxidez de cada grupo, bem como assinalando as restriçöes, quando existentes, de uso em vigência de hepatopatias.