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.

Herbs and liver injury: a clinical perspective.

Despite a perception that herbal and dietary supplements are safe, devastating liver injury has been reported to result from their use. The difficulty in characterizing liver injury attributable to herbal and dietary supplements stems from the permissive regulatory environment, the complexity of marketed products, and underreporting by the patients who use them. Despite these limitations, researchers, clinicians, and regulators have increasing awareness of the need for study in this area.

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.

[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.

Phytochemical screening, and assessment of ameliorating effect of aqueous and ethanolic extracts of Gmelina arborea on drug induced hepatic and renal insufficiency in rats.

Phytochemical screening of stem bark and leaves of Gmelina arborea; and effect of aqueous and ethanolic extracts of Gmelina arborea stembark on hepatic and renal insufficiency in rats was assessed in this study. Phytochemical screening was carried out on the air-dried leaf, oven-dried leaf, air-dried stembark and oven-dried stembark samples. Sixty five (65) wister albino rats, (50.7-117.5 g) were divided into thirteen groups of five animals each. Three groups serve as Controls and were administered Cisplatin (5mg/kg b.w; i.p), Paracetamol (200mg/kg b.w; i.p) and Normal saline (0.002 ml/kg b.w; oral). Other groups were administered, either, cisplatin and extracts (1g/kg b.w; oral); Paracetamol and extracts (1g/kg b.w; oral); extracts alone; or drugs and combination of extracts. Animals were starved, 24 hours prior to sacrifice and sacrificed on the 9th day after commencement of treatment. Phytochemical screening results show the presence of alkaloid, flavonoid, tannin, saponin, cyanogenic glycoside, phytate, and carbohydrate. Saponin and carbohydrate were shown to be much higher in concentration than other phytochemicals. The percentage composition of cyanogenic glycoside and phytate were highest in air-dried stembark and oven-dried leaf samples, respectively. All the Gmelina arborea extracts and extract mixture administered to both paracetamol and cisplatin treated animals, significantly, lowers both the activities of the SGOT and SGPT, and the levels of serum creatinine and urea. When administered alone, the aqueous and ethanolic extracts show little or no sign of toxicity. Thus Gmelina arborea extracts may have ameliorating effect on hepatic and renal insufficiency caused by paracetamol and cisplatin respectively, and any inherent toxicity may be reduced or eliminated through adequate heat treatment.

[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.

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.

Safety of fluoroquinolone use in patients with hepatotoxicity induced by anti-tuberculosis regimens.

BACKGROUND: Fluoroquinolones are frequently used to replace agents in first-line anti-tuberculosis (anti-TB) regimens in patients with TB who have drug-induced hepatic dysfunction. We investigated the safety of using fluoroquinolone in an area where TB is endemic and where there is a high incidence of drug-induced liver injury. METHODS: From September 2003 through August 2006, patients who had aspartate aminotransferase and/or alanine aminotransferase levels >3 times the upper limit of normal in the presence of hepatitis symptoms or who had aspartate aminotransferase and/or alanine aminotransferase levels >5 times the upper limit of normal after receipt of anti-TB treatment were enrolled. The control group received ethambutol, with or without streptomycin; study groups received either (1) ethambutol plus levofloxacin, with or without streptomycin; or (2) ethambutol plus moxifloxacin, with or without streptomycin. The outcome measurement was the time from onset of hepatitis to normalization of liver functions. RESULTS: One hundred thirty-four (11.3%) of 1191 patients received a diagnosis of hepatotoxicity and needed to stop anti-TB treatment. The risk factor was abnormal baseline transaminase levels. Twenty-two of the 134 patients received the control medication, 40 received levofloxacin, and 45 received moxifloxacin; the remaining patients were excluded from the study. There were no significant prestudy differences between groups. Time to liver function normalization was almost the same for all groups (mean +/- standard deviation, 29.1+/-21.4, 25.5+/-17.6, and 29.7+/-14.3 days, respectively). CONCLUSIONS: Abnormal baseline transaminase levels are the independent risk factors for anti-TB therapy-induced hepatitis. Levofloxacin and moxifloxacin caused no additional hepatotoxicity when they were used by patients with hepatitis induced by first-line anti-TB drugs.

Selective Associations of Recent Low Concentrations of Perfluoroalkyl Substances With Liver Function Biomarkers: NHANES 2011 to 2014 Data on US Adults Aged ≥20 Years.

OBJECTIVE: Perfluoroalkyl substances (PFAS) and liver function biomarkers were reexamined for relatively lower serum concentrations of PFAS observed in recent years. METHODS: National Health and Nutrition Examination Survey 2011 to 2014 data were analyzed for obese and nonobese participants for serum perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA) as well as four liver function biomarkers in risk-adjusted analysis. RESULTS: Among obese participants only, alanine aminotransferase (ALT) was positively associated with PFOA (ß = 0.07065, P < 0.01), PFHxS (ß = 0.051349, P < 0.01), and with PFNA (ß = 0.072742, P < 0.01). PFOA (ß = 0.07422, P = 0.03) and PFNA (ß = 0.077995, P < 0.01) were associated with gamma glutamyl transferase (GGT) in obese participants. CONCLUSIONS: Recent lower levels of PFOA, PFHxS, and PFNA are associated with higher serum liver functions but only among obese participants. The findings are consistent with PFAS animal toxicology concerning steatosis.

Fenofibrate prevents orotic acid--induced hepatic steatosis in rats.

The experiments performed in this report were designed to investigate the mechanisms involved in the metabolic alterations associated with orotic acid-induced hepatic steatosis and the effect of fenofibrate, a stimulant of peroxisome proliferators-activated receptor alpha (PPARalpha), on these alterations. Male Wistar rats were divided into three experimental groups: 1) fed a balanced diet (C); 2) fed a balanced diet supplemented with 1% orotic acid (OA); 3) fed OA diet containing 100 mg.kg(-1) bw.day(-1) fenofibrate (OA+F), for 9 days. Administration of OA to rats induced significant increase in the hepatic total lipids content, marked microvesicular steatosis and decrease in plasma lipids concentrations compared to control group. Fenofibrate treatment prevented fatty liver induction, caused an additional reduction on plasma lipids concentrations and caused a 40% decrease in the lipogenic rate in adipose tissue. The results also showed a 40% increase in lipoprotein lipase (LPL) activity in adipose tissue from OA treated group and fenofibrate administration induced a 50% decrease in LPL activity. The liver mRNA expression of PPARalpha and ACO (acyl CoA oxidase) were 85% and 68% decreased in OA group when compared to control, respectively. Fenofibrate treatment increased the PPARalpha and ACO expressions whereas the CPT-1 (carnitine palmitoyl transferase-1) expression was not altered. Our results have shown that fenofibrate treatment decreases the hepatic lipid content induced by OA which is mediated by an important increase in fatty acid oxidation consequent to an increase in hepatic mRNA expression of PPARalpha and ACO.

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.

[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.

[The models of hepatic insufficiency and encephalopathy in animals].

The majority of the investigation methods of biochemical, morphological and metabolic disorders in hepatic insufficiency and encephalopathy occurrence are inadequate in use in clinical conditions because their invasiveness frequently creates dangerous situations to the patient life and health. That's why, to characterize the mechanisms, constituting the hepatic and cerebral damages base, for testing of a new medicinal preparations, aprobation of a new theoretical and clinical hypotheses, the models of an acute and chronic hepatic insufficiency are applied on the animals, permitting to unify the age, genetic peculiarities and physiological parameters of the individuals involved in experiments, the pathology character, its severity and longevity. Homogeneity of these indexes permits to estimate molecular, structural and functional disorders, laying in the base of pathological process. We have analyzed the experimental models of hepatic insufficiency, basing on the hepatotoxins usage--acetaminophen (paracetamol), carbon tetrachloride, thioacetamide, D-galactosamine, concanavalin A, lipopolysaccharides. Every existing pharmacological model of hepatic insufficiency and encephalopathy for animals owes its own advantages and faults. The choice of a model depends on tasks of the investigation and of the animal species, involved in the procedures.

[Peritoneal dialysis with allogenic hepatic cell suspension in treatment of hepatic insufficiency].

Increasing prevalence of patients with liver diseases results in growth of morbidity caused by liver insufficiency. The comparative analysis of the different methods (hemosorption, hemofiltration, plasmapheresis, liver cell transplantation) for the treatment of the hepatic failure showed that the mortality rate of such patients remains to be high. Ex vivo blood treatment can be divided into three categories: passive detoxification, liver perfusion and bioartificial or cell-based systems. A cellular dialyzing fluid was used in rats to evaluate efficacy of peritoneal dialysis in the treatment of hepatic insufficiency. The results of treatment of animals suffering from acute toxic disease of the liver indicate to the high therapeutic effectiveness of such dialysis. Cellular peritoneal dialysis did not induce anaphylactic reactions in animals. Favorable dynamics of changes in the biochemical, clinical and morphological induces were noted, which allows this method to be recommended for clinical approbation.

Study design of the influence of SErotonin inhibition on patients with RENAl impairment or diabetes undergoing drug-eluting stent implantation (SERENADE) study: A multicenter, open-label, prospective, randomized study.

BACKGROUND: The rates of stent failure after percutaneous coronary intervention have decreased since the introduction of the drug-eluting stent (DES). However, chronic kidney disease (CKD) and diabetes mellitus (DM) remain strong clinical predictors of poor prognosis despite DES implantation. Sarpogrelate, a selective serotonin (5-hydroxytryptamine (HT)2a [5-HT2A]) receptor antagonist, has antiproliferative effects, reducing neointimal hyperplasia and smooth muscle cell proliferation, as well as potent antiplatelet action, inhibiting 5-HT-induced platelet aggregation. However, efficacy and safety data for sarpogrelate in patients with CKD or DM are limited. We aim to determine whether sarpogrelate has beneficial effects in patients with CDK or DM treated with DES implantation. METHODS/DESIGN: The SERENADE trial is a multicenter, open-label, prospective, randomized study that will test the superiority of triple anti-platelet therapy (TAT; aspirin, clopidogrel, and sarpogrelate) to conventional dual antiplatelet therapy (DAT; aspirin and clopidogrel) in preventing late lumen loss 9 months after the index procedure in patients with CKD or DM. A total of 220 patients diagnosed with coronary artery disease with DM or CKD will be randomized to the TAT or DAT groups (1:1 ratio) after DES implantation. The primary endpoint is late lumen loss at 9 months assessed by quantitative coronary angiography. Secondary efficacy endpoints are composites of major adverse cardiovascular events including cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Secondary safety endpoints are major bleeding events and hepatic or renal impairment. DISCUSSION: The SERENADE trial will provide insight on the efficacy of adjunctive therapy with sarpogrelate after DES implantation for patients with high-risk profiles such as CKD or DM. TRIAL REGISTRATION: National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov NCT02294643).

Relationship between structural alerts in NSAIDs and idiosyncratic hepatotoxicity: an analysis of spontaneous report data from the WHO database.

BACKGROUND: Idiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the drug molecule that are susceptible to bioactivation resulting in RMs. The relationship, however, between metabolic activation of SAs in drugs with in vivo toxicity measured as disproportionate reporting of adverse drug reactions (ADRs) to the WHO VigiBase™ database has never been studied. OBJECTIVE: The objective of this study was to investigate whether reported associations of hepatotoxicity between NSAIDs with SAs and NSAIDs with mitigated SAs are disproportionately present in the ADR reporting VigiBase™ database of the WHO collaborating center (the Uppsala Monitoring Centre). The extent of disproportionality of these associations is compared with associations of NSAIDs and hemorrhage, an ADR not associated with the forming of RMs. METHODS: We calculated the reporting odds ratios for five NSAIDs [bromfenac (withdrawn), lumiracoxib (withdrawn), diclofenac, ibuprofen, and naproxen] associated with the MedDRA preferred terms: hepatic failure, hepatic function abnormal, hepatic necrosis, and hepatitis. The disproportionality of the association of these ADRs is compared with the preferred term hemorrhage. RESULTS: The results show that hepatotoxicity is more disproportionately reported in the WHO database for NSAIDs with SAs (bromfenac, lumiracoxib, diclofenac) than for NSAIDs where SAs are mitigated (ibuprofen and naproxen). This difference in reporting between NSAIDs with SAs and with mitigated SAs is not observed for the ADR hemorrhage, an ADR not associated with the forming of RMs. CONCLUSIONS: This study shows that although spontaneous reports have many limitations, the findings are in line with previous research on the reactive metabolite concept. Whether SAs and the number of SAs in the NSAIDs actually play a role in the observed hepatotoxicity must be investigated in future studies.