Liver Bilirubin Research Articles

Multicenter extension and switch study evaluating the safety of long-term treatment with abiraterone acetate fine particle formulation (AAFP) in patients with metastatic castration-resistant prostate cancer (mCRPC): The STAAR-E study.

181 Background: The STAAR-study results showed novel AAFP 500 mg is therapeutically equivalent to originator abiraterone acetate (OAA) 1000 mg in men with mCRPC (Stein et al. Urologic Oncol). This STAAR-extension study evaluates the safety of ≤ 1 year of additional AAFP treatment in men with mCRPC. Methods: Patients were enrolled in the extension if they had: 1) mCRPC; 2) successfully completed 84 days of treatment with either AAFP + methylprednisolone (MP) or OAA + prednisone (PDN) in the STAAR-study; and 3) received their last dose of STAAR-study treatment < 45 days of starting this extension study. All patients continued or switched to AAFP 500 mg QD + 4 mg MP BID. Serum testosterone and PSA levels are measured at 6 and 12 months. Safety evaluations include adverse event (AE) incidence, clinical laboratory test results, and vital signs. Results: 20 patients were enrolled in the ongoing study (11 were switched to AAFP from OAA and 9 continued on AAFP). Median age is 76.5 years, and median AAFP treatment duration (STAAR + STAAR-E) is 178 days as of 8/16/17. Ten patients have been treated with AAFP > 9 months; 3 of these for > 1 year. Three patients discontinued due to progressive disease (n=1), fatigue (n=1), and a fall (non-AAFP related) resulting in death (n=1). No adverse events related to liver enzyme or bilirubin increases have been reported (Table). Conclusions: In this extension study in men with mCRPC, the safety profile of AAFP, regardless of prior treatment with OAA or AAFP, is consistent with that of OAA reported in the literature. Based on these results, longer-term treatment with AAFP + MP has acceptable safety, and patients on OAA + PDN treatment can switch to AAFP + MP successfully. Clinical trial information: NCT02962284. [Table: see text]

Predictors of Seven-Day Mortality in Patients with Advanced Oncologic Liver Disease Admitted to a Palliative Care Unit

Context and objectives: A specific prognostic tool is lacking for end-stage oncological liver diseases. In addition to various factors, bilirubin, which reflects the severity of liver dysfunction, may be associated with mortality in this population. We aimed to assess how bilirubin influence survival in patients admitted in palliative care units with advanced oncologic liver diseases and to develop a prognostic model combining bilirubin with other factors. Methods: Data were collected retrospectively from 652 patients with oncologic liver diseases, accounting for 25% of all admissions in our palliative care units from 2011 to 2016. Age, gender, chronic liver diseases, infections including spontaneous bacterial peritonitis, gastrointestinal bleeding, encephalopathy, Eastern Cooperative Oncology Group score (ECOG), oral intake, jaundice, dyspnea, bilirubin, albumin and urea variables collected within 24 hours before or after admission were analyzed. Univariate and multivariate survival analyses were performed to identify the predictive value of bilirubin and other variables for 7-day survival. Results: Bilirubin value was collected in 398 patients. Univariate analysis showed that male sex, chronic liver diseases, encephalopathy, ECOG, oral intake, jaundice, bilirubin and urea blood levels, were associated with 7-day survival. Multivariate analysis showed that bilirubin>25 μ mol/L, urea>15 mmol/L, ECOG=4 and reduced oral intake, were independently correlated with survival. Accuracy of the model based on these factors to predict 7-day mortality is high (AUC=0.90). Conclusion: Bilirubin is an independent prognostic factor for 7 day-survival among patients with end-stage oncologic liver disease. Combining bilirubin, urea, ECOG and oral intake increases short term prognostication accuracy in this subgroup of patients.

Evaluation of the hepato-protective potential of Sarcocephalus latifolius leaf methanol extracts in paracetamol-induced liver damage of mice

Sarcocephalus latifolius, the African peach, is one greatly cherished, eaten and widely distributed shrubs mainly in the closed woodland savannah, and has been used to treat diverse diseases in some African and Asia populations. In Southern Nigeria, ‘herbal doctors’ include its leaves in decoctions given to patients of varying degrees of suspected liver damage. However, there is no scientific substantiation of their claim and use in literature. To evaluate the possible hepato-protective activity of S. latifolius leaves extract in paracetamol-induced hepato-compromised animal model as information is lacking. Adult mice were for 3 consecutive days orally administered methanol extracts of S. latifolius (SLM) at doses below any that is toxic, or Silymarin reference standard (100 mg/kg) prior to a high oral dose of paracetamol (2000 mg/kg) to damage the liver. Sacrificed animals 12 h after paracetamol treatment were bled. Serum obtained from clotted blood was used to biochemically quantify liver function enzymes, total protein and bilirubin levels as well as perform in vivo antioxidant studies. No acutely toxic signs or deaths were seen following oral administration of SLM extract. Orally given SLM extract at low doses produced a significant reduction in liver enzyme markers against the reference, as well as dose-dependent decreases in antioxidant parameters and total protein levels (p < 0.05). Our results portend that SLM extract possesses hepato-protective and antioxidant activity in paracetamol-induced hepato-compromised mice without any obvious untoward kidney damages suggesting that its use in the management of the liver diseases may be appropriate.

Coinfections of Human Immunodeficiency Virus and Sexually Transmitted Infections among HIV Seropositive Pregnant Women at Healthcare Centres in Akure, Southwestern Nigeria

Background: Sexually transmitted infections (STIs) represent significant risk factors for HIV transmission and adverse fetal complications in pregnancy. We tested 240 pregnant women for their HIV serostatus and for the effects of HIV-STI coinfections on CD4+ cell counts and on HIV plasma viral load. The study was conducted at four antenatal clinics in Akure, Ondo State of Nigeria between November 2014 and December 2015. Methods: The HIV-1/2 strip was used for preliminary determination of HIV serostatus and this was followed by a confirmatory Abbott enzyme-linked immunosorbent assay (ELISA) procedure. CD4+ T-cell counts were done by cytometric analysis while viral load was determined by COBAS® AmpliPrep TaqMan HIV-1 procedure. Liver enzymes were determined by an automated chemistry analyzer. Detection of hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus-6 (HPV-6) and herpes simplex virus type-2 (HSV-2) were determined by ELISA. The syphilis VDRL test was done by the rapid plasma reagin procedure, while Trichomonas vaginalis infection was demonstrated by the wet mount procedure. Infections with Chlamydia trachomatis and Neisseria gonorrhoeae were determined respectively by ELISA and by culture on proteose peptone agar supplemented with 5% serum. Results: The results show prevalence of STIs in 33.3% of the 240 study participants; 77.5% for HIV seropositive and 22.5% for seronegative subjects. Trichomonas vaginalis constituted the highest isolate Coinfections in 50% of HIV seropositive subjects and 22.2% for seronegative controls. HIV-HBV coinfection occurred among 7 individuals while HIVHBV-TV coinfection occurred in 4 individuals. The results also showed elevated titers of alanine aminotransferase (ALT), creatinine and total bilirubin liver enzymes in both HIV-HBV coinfection and HBV monoinfection. HIV viral loads were twice as high in HIV-HBV coinfection relative to HBV mono- infection. Conclusion: The prevalence of STIs was significantly high at 54.4% among HIV seropositive pregnant women as compared to 14.3% for HIV seronegative pregnant women. T. vaginalis was the highest isolate at 50% in HIV seropositive subjects and may therefore be a driving factor for HIV transmission and susceptibility as very few T. vaginalis infections were recorded in control subjects.

Hepatotoxicity following separate administration of two phosphodiesterase-5 inhibitors (sildenafil and tadalafil) and opioid (tramadol); evaluation of possible reversal following their withdrawal

The use of phosphodiesterase-5 inhibitors (PDE5i) and tramadol in the absence of erectile and ejaculatory dysfunctions in Nigeria has become a norm. In this study, we comparatively assess the effects of chronic use of these drugs on hepatotoxicity. Fifty male albino wistar rats weighing 180–200g were randomly assigned into 5 groups (n=10) as follows; control, sildenafil (1mg/100g b.w), tadalafil (1mg/100g b.w), tramadol (2mg/100g b.w) and sildenafil+tramadol treated group (1mg/100g and 2mg/100g b.w, respectively). Drugs were orally administered, once, every two days for 8weeks, at the end of which five animals were sacrificed per group (batch 1), while the remaining five animals per group were allowed for another 8weeks without drug administration (batch 2). Serum concentration of liver enzymes (AST, ALT and ALP) and bilirubin were assessed in both batches. Serum concentrations of AST, ALT, ALP, total bilirubin and unconjugated bilirubin were significantly (p

Hepatoprotective Effect of Calotropis procera in Isoniazid and Rifampicin Induced Hepatotoxicity

Objective: In this study anti-tubercular (Anti-TB) drugs (isoniazid [INH] and rifampicin [RMP]) induced liver toxicity has been studied for the hepatoprotective effect of hydroethanolic extract of Calotropis procera (CP) fl owers in rats. Materials and Methods: Animals were divided into four groups, group A was given normal saline (1 ml/kg), group B received INH (50 mg/kg) and RMP (100 mg/kg) group C received INH (50 mg/kg), RMP (100 mg/kg) and CP (150 mg/kg) orally for 14 days. Results: Biochemical markers of liver toxicity such as aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and bilirubin and tissue histology were done inall groups. Anti-TB drugs (INH 50 mg/kg and RMP 100 mg/kg) have enhanced the ALT, AST, ALP, bilirubin and histological changes in liver, whereas co-administration of anti-TB drugs with CP has reduced these levels within the normal range. Conclusion: Findings of this study showed the hepatoprotective effect of CP against INH and RMP administration to reduce the liver damage for chronic treatment.

Effect of Methanolic Extract of Stem Bark of Anogeissus Leiocarpus on Liver Function of Mice Infected with Plasmodium Berghei

The effect of methanolic extract of Anogeissus leiocarpus on the liver funtion of Plasmodium berghe–infected mice was examined. Results showed that serum and liver alanine aminotransferase, aspartate aminotransferase, and bilirubin levels were higher in a group treated with 200 mg.kg−1 than those treated with 100 mg.kg−1. P. berghei infection caused noticeable liver impairment that was ameliorated by 100 mg.kg−1 of A. leiocarpus. Treatment of malaria with A. leiocarpus in doses higher than 200 mg.kg−1 body weight must be carefully monitored to avoid liver toxicity.

Assessment of serum bilirubin and hepatic enzymes in malaria patients

Objectives:-The present study was conducted on malaria patients to observe the correlation between liver enzymes (SGOT, SGPT & ALP) and bilirubin. Material & Methods:-The study population contained 100 subjects divided into two groups, 60 malaria patients and 40 healthy control subjects of varying age groups and both sex. All biochemical parameters Total bilirubin, Direct bilirubin, Indirect bilirubin, SGOT (aspartate transaminase), SGPT (alanine transaminase) & ALP (alkaline phosphatise) were analyzed by semiautoanalyser. Statistical analysis was done by, science (SPSS 16) Software Results: - In our study we have found that (Mean ± SD) of Total serum bilirubin in malaria patients were 1.63±2.27 & controls were 0.67±0.08, Direct bilirubin in malarial patients were 0.92±1,3 & control were 0.37±0.07, Indirect bilirubin in malarial patients was 0.68±0.95. We observed that (Mean ±SD) of SGOT in malaria patients was 48.29±28.89 & in control were 29.28±7.44, the level of SGPT in malarial subjects were 44.9±27.15 & control subjects were 29.98±7.77 & the level of ALP in malarial patients were 98.47±60.67 & in control 71.4±25.12. We also found that both aminotransferases (SGOT & SGPT) showed significance positive correlation with serum total bilirubin levels whereas in case of ALP, significance correlation could not be obtained. Conclusion: Our study indicates that liver enzymes SGOP, SGPT and ALP significantly increases in malaria patients as compared to control subjects Therefore these enzymes may be useful in diagnosis of malaria subjects.

Hepatitis E virus infection results in acute graft failure after liver transplantation: a case report

Hepatitis E virus (HEV) infection in most individuals is known as a self-limiting, acute, icteric hepatitis, but evidence shows HEV is responsible for choric hepatitis and rapid progressed liver cirrhosis in immuno-compromised patients. We present the case of a patient whose diagnosis of acute graft failure was due to a HEV infection 7 years after his first liver transplantation because of Wilson's disease. The process showed severe jaundice with fatigue, poor appetite and continually rising serum aminopherase. The blood serum was found positive for the anti-HEV IgG antibody but negative for anti-HEV IgM or other infections. Cholangiole cholestasis was detected in graft biopsy. Triple hepato-protective drugs (Transmetil, Polyene Phosphatidylcholine, and Compound Ammonium Glycyrrhetate S) alongside five times Artificial Liver Support System (ALSS) did not improve the patient's condition, but the total bilirubin level rose to more than 900umol/L. So re-transplantation was performed. Blood testing shows normal liver enzymes and bilirubin with persisting anti-HEV IgG antibody positive at the 3-month follow-up.

Effects of N-Butanol Fraction of Gongronema Latifolium Leave Extract on Some Liver Function and Histological Parameters in Ccl4-Induced Oxidative Damage in Wistar Albino Rats

Effects of n-butanol fraction of Gongronema latifolium leave extract on some liver function and histological parameters in CCl4-induced oxidative damage in Wistar albino rats were assessed. Fifty-four (54) Wistar albino rats were divided into treatment group and LD50 groups. Group A (normal control) was given feed and water, Group B (vehicle control) was injected with olive oil intraperitoneally, while the rest groups (C, D, E, F and G) were injected intraperitoneally with a single dose of CCl4 (148 mg/kg) as a 1:1 (v/v) solution in olive oil and all the animals were fasted for 36 hours. This was repeated once every week for a period of four (4) weeks. At the end of 28 days of treatment, liver marker enzymes studies showed that there was significant (p 0.05) difference of these liver marker enzymes and bilirubin levels between the normal control and induced treated groups. Antioxidant assay on the liver homogenate showed that there was significant (p 0.05) difference between the normal control and induced treated groups. These findings suggested that n-butanol fraction of methanolic leave extract of G. latifolium may have anti-hepatotoxic and antioxidative effects against CCl4-induced liver damage in rats.

Acute hepatitis with concomitant graves\ disease

Acute hepatitis A with concomitant Graves’ disease was reported rarely in the literature. To our knowledge there is one case in the literature from New York in which acute hepatitis A infection was not thought predominant. It is difficult to manage these cases because of the limited therapy options especially when cholestasis occurs. A 36-year-old male presented with severe cholestasis who was diagnosed as acute hepatitis A infection together with Graves’ disease. He had severe cholestasis with elevated liver enzymes and bilirubin levels. Thyroid functions tests decreased to normal levels with plasmapheresis therapy and then he was sent to general surgery for thyroidectomy. Plasmapheresis is an alternative therapy option for thyrotoxicosis in patients with Graves’ disease concomitant with acute HAV infection.

Sa1309 Prospective Clinical Short and Long Term Study on Critically Ill Patients With Sclerosing Cholangitis (SC-CIP)

Secundary sclerosing cholangitis is an important clinical entity in critically ill patients (SCCIP) with severe polpyraumas and shock symptoms. Most current data come from transplant centers at the end stage of the disease. The aim of this study was to indentify all patients with SC-CIP, to characterize imaging modalities such as US,MS-CT,MRCP, EUS and ERC for the diagnosis and therapy (ERC). We included 57 patients (m=41, f=16, age median 53y) from a large Bavarian trauma center from 2/2005-11/2009 retrospective (n=28) and 12/2009 -11/2011 prospective (n=29). SC-CIP-diagnosis of all patients (n=57) was confirmed by ERC by typical bile duct changes and by extraction and histology of cast material. Underlying disorders were 26 (46%) intracerebral bleeding, 17 (30%) severe polytrauma with MOF, 10 (17%) with severe septic schock, 4 (7%) with severe burning . At admission all patients except one had a NACA score . 3 and a SOFA score of median 8 (63.5% of the patients . 7). Intensive care stay lasted 44 days (range 23-298 days). SOFA score further increased to 11 on day 4 of admission. Patients had normal liver enzymes and gGT (median 32 U/l ) and AP values at admission and on day 1-4 of ICU stay. There was a characteristic rise of gGT on day 6 (median 98 U/l) reaching maximum values on days 11-13 (median 669 U/l). AP showed a linear increase also starting on day 5, whereas liver enzymes and bilirubin in median increased gradually. Abdominal US initially showed no dilation of the external or internal bile ducts, but showed intraluminal reflexes. With time intrahepatic segmental dilatation occurred. EUS showed echodense material with typical double-linear contours, characterized as cast material by ERC. ERC was performed median on day 53 of the ICU stay. In 35 (60%) of the patients both sides of the biliary systems were affected, whereas in 23 patients only one side was affected. In all patients papillotomy was performed and cast material was removed when present, strictures of the main duct and both hepatici were balloon dilated, all patients received antibiotics. 51/57 patients (89%) were followed by routine follow up, readmission, telephone contact or questionnaire with a follow up of 34.7 month. 27 patients had a favorable (n=8) or stable course (n=19). 3 patients received LTX, 5 patients have a negative course of the liver disease being listed for LTX, 16 Patients died during follow up, 4/16 died as a consequence of the SC-CIP. In conclusion: This study describes in a prospective manner in a single center study the clinical signs, course and parameters of SC-CIP patients. Mandatory interventional ERC removed biliary casts and stricutes and determined a long term outcome (2,6 years) with a letality of 14.5%, LTX rate of 5.1% and listing for LTX of 8.6%. This study adds new important clinical information to the initial course of this disease.

Sa1310 Long-Term Outcomes of Hepatolithiasis After Treatment; Risk Factors for Incomplete Clearance and Recurrence of Stone

Secundary sclerosing cholangitis is an important clinical entity in critically ill patients (SCCIP) with severe polpyraumas and shock symptoms. Most current data come from transplant centers at the end stage of the disease. The aim of this study was to indentify all patients with SC-CIP, to characterize imaging modalities such as US,MS-CT,MRCP, EUS and ERC for the diagnosis and therapy (ERC). We included 57 patients (m=41, f=16, age median 53y) from a large Bavarian trauma center from 2/2005-11/2009 retrospective (n=28) and 12/2009 -11/2011 prospective (n=29). SC-CIP-diagnosis of all patients (n=57) was confirmed by ERC by typical bile duct changes and by extraction and histology of cast material. Underlying disorders were 26 (46%) intracerebral bleeding, 17 (30%) severe polytrauma with MOF, 10 (17%) with severe septic schock, 4 (7%) with severe burning . At admission all patients except one had a NACA score . 3 and a SOFA score of median 8 (63.5% of the patients . 7). Intensive care stay lasted 44 days (range 23-298 days). SOFA score further increased to 11 on day 4 of admission. Patients had normal liver enzymes and gGT (median 32 U/l ) and AP values at admission and on day 1-4 of ICU stay. There was a characteristic rise of gGT on day 6 (median 98 U/l) reaching maximum values on days 11-13 (median 669 U/l). AP showed a linear increase also starting on day 5, whereas liver enzymes and bilirubin in median increased gradually. Abdominal US initially showed no dilation of the external or internal bile ducts, but showed intraluminal reflexes. With time intrahepatic segmental dilatation occurred. EUS showed echodense material with typical double-linear contours, characterized as cast material by ERC. ERC was performed median on day 53 of the ICU stay. In 35 (60%) of the patients both sides of the biliary systems were affected, whereas in 23 patients only one side was affected. In all patients papillotomy was performed and cast material was removed when present, strictures of the main duct and both hepatici were balloon dilated, all patients received antibiotics. 51/57 patients (89%) were followed by routine follow up, readmission, telephone contact or questionnaire with a follow up of 34.7 month. 27 patients had a favorable (n=8) or stable course (n=19). 3 patients received LTX, 5 patients have a negative course of the liver disease being listed for LTX, 16 Patients died during follow up, 4/16 died as a consequence of the SC-CIP. In conclusion: This study describes in a prospective manner in a single center study the clinical signs, course and parameters of SC-CIP patients. Mandatory interventional ERC removed biliary casts and stricutes and determined a long term outcome (2,6 years) with a letality of 14.5%, LTX rate of 5.1% and listing for LTX of 8.6%. This study adds new important clinical information to the initial course of this disease.

A case of Inherited Unconjugated Hyperbilirubinemia foran incidental surgery: Anesthetic management and Review

Congenital indirecthyperbilirubinemiaoccurs due to the relative deficiency or absence of the primary conjugating enzyme uridinediphosphate-glucuronyltransferase.The enzyme UDP glucuronyltransferase is responsible for the conjugation of bilirubin in liver. The enzyme is also essential for transport of many other substrates including drugs, hormones, toxins and neurotransmitters. Thus, anaesthetic management of such a case is quite challenging. Avoiding drugs which use this enzyme for its metabolism or excretion during the perioperative period allows safe conduct of anaesthesia for these patients. We report a case of inherited unconjugated hyperbilirubinemiafor an incidental surgery and review the different types of congenital indirect hyperbilirubinemias.

Antioxidant and toxicological evaluation ofCassia sopherain streptozotocin-induced diabetic Wistar rats

Background:Multiple-organ failure is the main cause of death in diabetes mellitus (DM). Hyperglycemia-induced oxidative stress is responsible for major diabetic complications, including multiple-organ failure. Medicinal plants possessing antioxidant activity may reduce oxidative stress and improve the functions of various organs affected by hyperglycemia.Objectives:This study was designed to evaluate the antioxidant effect of Aqueous Extract of Cassia sophera (AECS) in streptozotocin (STZ)-induced diabetic Wistar rats.Materials and Methods:AECS (200 mg/kg body weight (bw)) and the standard antidiabetic drug glibenclamide (10 mg/kgbw) were administered orally by gavaging for 28 days.Results:Oral administration of AECS inhibited STZ-induced increase in lipid peroxidation (LPO), aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, creatinine and urea in liver of diabetic rats. Significant increase in activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and a reduced level of glutathione (GSH), were observed in the liver, kidney, pancreas and testis on AECS treatment.Conclusion:The results demonstrate that AECS is not only useful in controlling blood glucose, but also has antioxidant potential to protect the liver, kidney, pancreas and testis against damage caused by hyperglycemia-induced oxidative stress.

Safety and Tolerability of EPs 7630 in Clinical Trials

Herbal medicines play an increasingly important role in the perception of physicians and patients looking for equally effective, albeit safer approaches to conventional management of certain diseases. The controversy surrounding effective management regimes for respiratory tract infections (RTI) has made many healthcare providers reconsider current therapeutic strategies. This review presenting the available evidence from clinical trials and non-interventional studies on the safety and tolerability profile of EPs 7630 is based on publications and study reports of 29 clinical trials and post-marketing surveillance studies completed by February 2010. It includes study data from 10,026 adults and children suffering from acute or chronic RTI such as acute tonsillopharyngitis, rhinopharyngitis, sinusitis, bronchitis, or COPD and from 31 healthy subjects. In 19 double-blind, placebo-controlled trials, the type and incidence rate of adverse events under EPs 7630 were similar to those in patients treated with placebo. For gastrointestinal complaints and epistaxis, event rate differences of 2.9% and of 0.6% against EPs 7630 were determined; hypersensitivity reactions and all other system groups showed rate differences <0.5%. For liver associated events, rate differences of 0.0% for all events and of 0.1% for potentially related events were observed. Patients treated with EPs 7630 did not exhibit increased liver enzyme or bilirubin values – neither in terms of a shift in the mean, nor according to individual deviations from the reference ranges. These findings were fully supported by the data from the post-marketing surveillance studies reviewed. EPs 7630 appears to be a well-tolerated herbal medicine in the management of RTI in adults and children alike. Evidence for hepatotoxic effects in humans during routine administration was neither provided in the literature, nor by our own analyses.

New insights in bilirubin metabolism and their clinical implications

Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.

Effect of S-allylcysteine, a sulphur containing amino acid on iron metabolism in streptozotocin induced diabetic rats

It is suggested that iron may play a role in the pathogenesis of diabetes. Iron is not only chaperoned through its essential functional pathways, but it also causes damage to biological systems by catalyzing the production of reactive oxygen species. So, the parenchymal tissues of several organs are subject to cell injury and functional insufficiency due to excess deposition of iron. The present study investigated the effects of S-allylcysteine (SAC), a sulphur containing amino acid derived from garlic on the changes in iron metabolism induced by oxidative stress in tissues, as well as on serum biochemical parameters of streptozotocin (STZ)-induced diabetic rats. SAC was administered orally for 45days to control and experimental diabetic rats. The effects of SAC on glucose, insulin, serum iron, ferritin, transferrin, serum bilirubin, heart heme oxygenase activity (HO) and δ-aminolevulinicacid dehydratase activity (δ-ALA-D) in liver and kidneys were studied. The levels of glucose, iron, ferritin, bilirubin and HO in liver were increased significantly (p<0.05) whereas the levels of insulin, transferrin and δ-ALA-D in tissues were decreased in diabetic rats. Administration of SAC to diabetic rats showed a decrease in blood glucose, iron, ferritin, bilirubin and HO. In addition, the levels of insulin, transferrin and δ-ALA-D activity in tissues were increased in SAC treated diabetic rats. These findings suggest that S-allylcysteine could have a protective effect against alterations in oxidative stress induced iron metabolism in the diabetic state which was evidenced by the capacity of this natural antioxidant to modulate parameters of iron metabolism.

Abstract LB-232: Preliminary results of a phase I study of the novel CRM1 inhibitors KPT-276 and KPT-335 in dogs with spontaneous cancer

Abstract Introduction: KPT-276 and KPT-335 are irreversible inhibitors of CRM1/XPO1, the major nuclear export protein in cells, forcing nuclear retention of key tumor suppressor and growth regulatory proteins ultimately resulting in tumor cell death. KPT-276 and KPT-335 demonstrate potent anti-tumor activity against tumor cells in vitro at nanomolar concentrations (IC50 &amp;lt; 500 nM) and in multiple mouse xenograft models at doses 5-25 mg/kg with minimal effects on normal cells in vitro (IC50 &amp;gt; 5 μM). In normal laboratory dogs, both KPT-276 and KPT-335 are well tolerated with mild reversible transaminase and bilirubin elevations and mild to moderate anorexia. The purpose of this Phase I study was to evaluate the clinical toxicities, establish the maximum tolerated dose and dosing regimen, and provide a preliminary assessment of biologic activity in dogs with spontaneous cancers that receive KPT-276 and KPT-335 Methods: Dogs with Non-Hodgkins lymphoma (NHL), metastatic osteosarcoma (OSA), melanoma (MEL) and mast cell tumor (MCT) were eligible for enrollment. Drug was administered at a starting dose of 30 mg/kg orally on a Monday/Wednesday/Thursday schedule for KPT-276 and at 3 mg/kg orally on a Monday/Thursday schedule for KPT-335. Complete blood count, serum chemistries, clotting times, drug peak plasma level and response to therapy were assessed at each visit. Results: The first four of dogs entered (MCT n=3 and NHL n=1) received KPT-276; the 3 dogs with MCT experienced progressive disease (PD, n=2) and stable disease (SD, n=1). The dog with NHL experienced a cytologic complete response (CR) of approximately 3 months duration despite having failed chemotherapy induction and prednisone treatment. Adverse events included vomiting, diarrhea, and anorexia (all grade 1-2) and elevations in liver function tests (LFTs, grade 1-3) and bilirubin (grade 1-2), as well as neutrophilic leukocytosis. Pharmacokinetic (PK) analysis indicated wide variation in oral bioavailability among dogs so the closely related analog, KPT-335, that is more potent and has better canine bioavailability was subsequently used. To date, 7 dogs have received KPT-335 (NHL, n=6, OSA, n=1) with responses consisting of PR (NHL n=2), SD (NHL n=2), and PD (NLH n=2 and OSA n=1). Adverse events included anorexia and weight loss (grade 1-3) and LFT elevations (grade 1-3) necessitating dpse reductions to 1-1.5 mg/kg on the M/Th schedule. PK analysis indicated more consistent drug absorption among dogs receiving KPT-335. Conclusions: The novel oral SINE CRM1 inhibitors KPT-276 and KPT-335 exhibit biologic activity in a relevant spontaneous large animal model of cancer. Adverse events associated with drug administration are tolerable and reversible with drug holiday. Enrollment in this clinical trial is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-232. doi:1538-7445.AM2012-LB-232

Ciprofibrate regulation of rat hepatic bilirubin glucuronidation and UDP-glucuronosyltransferases expression

Synthetic fibrates are hypolipidemic drugs known to stimulate hepatic peroxisome proliferation and bilirubin glucuronidation. This study was designed to estimate the effects of ciprofibrate simultaneously on rat hepatic bilirubin glucuronoconjugation and on hepatic expression of UGT1A1, UGT1A2 and UGT1A5, all of which belong to the bilirubin cluster. Hepatic bilirubin glucuronidation activity and UDP-glucuronosyltransferase expression (RT-PCR and Western blotting) were measured after a single-dose ciprofibrate treatment (5mg/kg by gastric intubation) in 36-h time course experiments. Ciprofibrate regulation of PPARα and UGT1A5 mRNA expression was also investigated in rat hepatocytes. Bilirubin conjugation activity was induced by ciprofibrate, reaching a maximum level (2.4×) 24h after the treatment. UGT1A1 and UGT1A5 mRNA expression was induced 1.5 times by ciprofibrate, with UGT1A5 reaching the basal level of UGT1A1. Although UGT1A2 mRNA was induced approximately threefold by ciprofibrate, its expression level remained low in comparison with basal or induced levels of UGT1A1 and UGT1A5 mRNA. In the 36-h time course experiment, bilirubin conjugation activity as well as UGT1A5 and PPARα mRNA expression presented a biphasic induction profile. Although a similar level of induction was observed in primary cultured hepatocyte experiments, such biphasic variation was not observed for both UGT1A5 and PPARα, and the induction of UGT1A5 mRNA expression by ciprofibrate required de novo protein synthesis. A single dose of ciprofibrate significantly induces rat liver bilirubin conjugation as well as UGT1A1, UGT1A5 and PPARα expression. The induction mechanism may involve PPARα, at least regarding UGT1A5 regulation.