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.

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.

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.

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.

Febuxostat: drug review and update.

INTRODUCTION: Gouty arthritis and hyperuricemia have ailed humans for centuries. Recent advances in understanding of the mechanism(s) of their development have changed our perception of the disease process. Despite these gains, the treatment options available are limited. The FDA approval of febuxostat for the treatment of hyperuricemia in gout has been a significant step forward. Since its approval in 2009, febuxostat has proven to be safe and efficacious although concerns remain regarding its long-term effects and superiority to other uricosuric agents, such as allopurinol. AREAS COVERED: A comprehensive literature review of PubMed and Ovid examining clinical trials and post-marketing studies yielded congruent findings on efficacy and safety in elderly populations and those with mild-to-moderate renal/hepatic impairment. A lack of literature and clinical studies was found with regard to comparison of febuxostat to FDA-approved high-dose allopurinol (> 300 mg), the safety of febuxostat in the treatment of severe renal/hepatic impairment and the benefit in the treatment of secondary cases of hyperuricemia. EXPERT OPINION: Febuxostat is effective in the treatment of mild-to-moderate renal/hepatic impairment with dramatic effects on the serum urate level. It can be used safely in patients with hypersensitivity reactions to allopurinol. Further research is needed to determine the long-term benefits and risks.

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.

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.

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.

Hepatotoxicidad de rizatriptán. Descripción de un caso clínico / Rizatriptan-induced liver toxicity. Report of a case

Los triptanes son un grupo farmacológico con reconocida eficacia en el tratamiento agudo de la cefalea migrañosa, del que el primer componente fue el sumatriptán, y surgieron posteriormente diferentes derivados. Hasta la actualidad, solo ha sido reportado un caso de toxicidad hepática con zolmitriptán. Presentamos un cuadro de hepatotoxicidad relacionado con otro fármaco de este grupo, el rizatriptán (AU)

Triptans are a class of drugs with proven efficacy in the acute treatment of migraine headache. The first component of these drugs was sumatriptan, with various derivatives subsequently emerging. Until now, there has only been one reported case of liver toxicity with zolmitriptan. We now present a case of hepatotoxicity related to another drug in this group: rizatriptan (AU)

Hepatotoxicidad por levofloxacino / Levofloxacin hepatotoxicity

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[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.

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.

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.

Anti-nociceptive activity and toxicity evaluation of Cu(II)-fenoprofenate complexes in mice.

The proposed curative properties of copper(II)-non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous copper(II)-NSAID complexes with enhanced anti-inflammatory activity. In this work, the antinociceptive and toxic effects of two new coordination complexes: Cu2(fen)4(caf)2 [fen: fenoprofenate anion; caf: caffeine] and Cu2(fen)4(dmf)2 [dmf: N-N'-dimethylformamide] were evaluated in mice. The antinociceptive effect was evaluated with two models: acetic acid-induced writhing response and formalin test. For the sub-acute exposure, the complexes were added to the diet at different doses for 28days. Behavioral and functional nervous system parameters in a functional observational battery were assessed. Also, hematological, biochemical and histopathological studies were performed. Cu2(fen)4(caf)2 and Cu2(fen)4(dmf)2 significantly decreased the acetic acid-induced writhing response and the licking time on the late phase in the formalin test with respect to the control and fenoprofen salt groups. The sub-acute exposure to Cu2(fen)4(caf)2 complex increased the motor activity, the number of rearings and the arousal with respect to the control and fenoprofen salt groups. These impaired parameters in mice exposed to Cu2(fen)4(caf)2 can be attributable to the presence of caffeine as stimulating agent. On the other hand, all exposed groups decreased the urine pools in the functional observational battery and increased the plasmatic urea. These effects could be due to the decrease in the glomerular filtration caused by NSAIDs. In conclusion, both complexes Cu2(fen)4(dmf)2 and Cu2(fen)4(caf)2 were more potent antinociceptive agents than fenoprofen salt. Sub-acute exposure to different doses of these complexes did not produce significant changes in the parameters that evaluate toxicity.