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Background: Neonates affected by isoimmune hemolytic disease (HDN) are at risk of developing severe hyperbilirubinemia. Studies show that increasing levels of bilirubin impact neonatal neurodevelopment. To avoid complications associated with exchange transfusion, intravenous immunoglobulin G (IVIG) is used to treat hyperbilirubinemia. We included all infants who received more than two doses of IVIG treatment for isoimmune hemolytic disease. We analyzed the incidence of side effects associated with IVIG treatment and the rate of exchange transfusion., Methods: A retrospective chart review performed between October 2011-October 2022 at East Carolina University Health identified neonates who received more than two doses IVIG for HDN. Neonates of postmenstrual age greater than 28 days old, receiving less than three doses of IVIG or received IVIG for other indications were excluded. The occurrences of adverse events, demographics and use of other medical therapies were reviewed., Results: Eleven neonates were included in the case series. Most common cause of severe hyperbilirubinemia was attributed to ABO incompatibility. Six patients (54%) received three doses of IVIG, and five patients (45%) received four doses of IVIG with bilirubin levels decreasing below exchange transfusion. No treatment exceeding four doses of IVIG was reported, nor adverse events during treatment., Conclusions: In this cohort of neonates with HDN, bilirubin levels decreased after treatment with multiple doses of IVIG. Future research on recommendations of optimal total number doses of IVIG to reduce the risk for exchange transfusion.

Background/aim: Prolonged jaundice is one of the most common problems during neonatal period. The aim of this study was to evaluate the efficiency of ursodeoxycholic acid (UDCA) treatment in newborn infants with prolonged unconjugated hyperbilirubinemia., Materials and Methods: The present study included 27 patients who were fed by breast milk and followed up in the outpatient clinic due to prolonged jaundice without any underlying etiological factor; 10 mg/kg/day UDCA was administrated in two doses for 7 days. Furthermore, 20 newborns diagnosed with prolonged jaundice with same characteristics were enrolled as the control group. The control group was also given a placebo; demographic characteristics, liver functions tests before and after the treatment, bilirubin decrease rates, and hemogram parameters of groups were compared., Results: Total bilirubin levels in the study and control groups before the treatment were 16.02 ± 1.41 mg/dL and 15.93 ± 1.66 mg/dL, respectively (P = 0.84). Total bilirubin levels in the study and control groups at day 7 after UDCA treatment were detected 8.18 ± 2.31 mg/dL and 13.92 ± 2.66 mg/dL, respectively (P < 0.001), and at day 14 after the treatment were 5.45 ± 2.59 mg/dL and 11.91 ± 2.83 mg/dL, respectively (P < 0.001). Furthermore, serum aspartate aminotransferase (AST) was detected <21 U/L in the ROC analysis after UDCA treatment (P = 0.04)., Conclusion: The study outcomes indicated that an efficient reduction in total bilirubin levels may be achieved, and outpatient clinic follow-up period may be reduced in patients whom UDCA was administrated. Moreover, it may be speculated that AST can be used to evaluate the efficacy after treatment. However, studies with larger sample sizes are needed for the routine use of UDCA in the treatment of prolonged jaundice., Competing Interests: None

Objective: Inflammation-induced free radical release is important in the pathogenesis of several diseases, including atherosclerosis and sepsis. Heme oxygenase (HO) breaks down heme into carbon monoxide, iron, and biliverdin. Biliverdin IXα is directly converted to bilirubin by biliverdin reductase. Unconjugated bilirubin is a powerful antioxidant, and elevated levels have beneficial effects in preclinical models and human cardiovascular disease. However, its impact during acute inflammation in humans is unknown. In the present study, we investigated the impact of atazanavir-induced (unconjugated) hyperbilirubinemia on antioxidant capacity, inflammation, and vascular dysfunction in human experimental endotoxemia., Approach and Results: Following double-blinded four-day treatment with atazanavir 2dd300 mg (or placebo), twenty healthy male volunteers received 2 ng/kg Escherichia coli lipopolysaccharide intravenously. Blood was drawn to determine the bilirubin levels, antioxidant capacity, and cytokine response. It was demonstrated that following atazanavir treatment, total bilirubin concentrations increased to maximum values of 4.67 (95%CI 3.91-5.59) compared to 0.82 (95%CI 0.64-1.07) mg/dL in the control group (p<0.01). Furthermore, the anti-oxidant capacity, as measured by the ferric-reducing ability of plasma (FRAP), was significantly increased with 36% in hyperbilirubinemia subjects (p<0.0001), and FRAP concentrations correlated strongly to bilirubin concentrations (R2 = 0.77, p<0.001). Hyperbilirubinemia attenuated the release of interleukin-10 from 377 (95%CI 233-609) to 219 (95%CI 152-318) pg/mL (p=0.01), whereas the release of pro-inflammatory cytokines remained unaltered. In vitro , in the absence of hyperbilirubinemia, atazanavir did not influence lipopolysaccharide-induced cytokine release in a whole blood assay. Vascular function was assessed using forearm venous occlusion plethysmography after intra-arterial infusion of acetylcholine and nitroglycerin. Hyperbilirubinemia completely prevented the LPS-associated blunted vascular response to acetylcholine and nitroglycerin., Conclusions: Atazanavir-induced hyperbilirubinemia increases antioxidant capacity, attenuates interleukin-10 release, and prevents vascular hyporesponsiveness during human systemic inflammation elicited by experimental endotoxemia., Clinical Trial Registration: http://clinicaltrials.gov, identifier NCT00916448., Competing Interests: Authors DD, FW, and PS have a patent about the therapeutic use of the anti-inflammatory and anti-oxidative potential of atazanavir. WO/2011/037467 The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dorresteijn, Dekker, Zwaag, Heemskerk, Roelofs, Smits, van der Hoeven, Wagener and Pickkers.)

Objective: To evaluate the effect of intravenous (IV) ceftriaxone on free bilirubin concentrations in infants with unconjugated hyperbilirubinemia born at term., Study Design: A prospective study was performed with subjects serving as their own controls. Our inclusion criteria were infants born at term <7 days old with sepsis and receiving IV antibiotics for >3 days and resolving hyperbilirubinemia with total serum bilirubin levels between 6 and12 mg/dL by day 4 of life. Free bilirubin concentrations were measured by the peroxidase method using a UB analyzer and a Zone Fluidics device before (baseline) and 15 minutes after (follow-up) IV ceftriaxone administration on postnatal days 4 to 6. Paired measurements of free bilirubin were analyzed using a Student paired t-test or Wilcoxon signed-rank test., Results: In total, 27 infants were studied. The mean free bilirubin (μg/dL) at follow-up was not different from that at baseline when measured by the UB analyzer (P = .78). The mean free bilirubin was significantly lower at follow-up compared with baseline when measured by the Zone Fluidics device (P = .02). The ratio of a free bilirubin with and without ceftriaxone, an index of displacing effect, was 1.02 (95% CI 0.89-1.14) using the UB analyzer and 0.58 (95% CI 0.30-0.86) using the Zone Fluidics device., Conclusions: Ceftriaxone is not associated with a bilirubin-displacing effect in infants with a mild unconjugated hyperbilirubinemia. Home therapy with once-daily intramuscular ceftriaxone may be an alternative option for management of sepsis in asymptomatic infants with a mild unconjugated hyperbilirubinemia born at term., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Bictegravir (BIC) co-formulated with emtricitabine (FTC) and tenofovir alafenamide (TAF) is approved by Federal Food and Drug Administration in 2018 for both treatment-naïve and experienced persons living with HIV (PLWH)., Case Presentation: A young man with recently diagnosed human immunodeficiency virus (HIV) infection presented with jaundice. Blood work was significant for mild anemia and grade 4 unconjugated hyperbilirubinemia. A comprehensive evaluation for hemolytic anemia failed to reveal any etiology. Other causes of hyperbilirubinemia were negative. Four months prior, patient was started on antiretroviral therapy with a single tablet regimen containing bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), brand name Biktarvy ® , and the medication was suspected to be the cause. The medication was held, and the hyperbilirubinemia improved., Conclusion: Severe hyperbilirubinemia can be found in the patient using BIC/FTC/TAF. The data for this adverse reaction is scarce, and more studies are needed on this possible side effect. The mechanism of unconjugated hyperbilirubinemia by INSTI remains undefined., (© 2023. The Author(s).)

A total of 548 patients (age range: 1-22 years, 60.4% Hispanic, 55.8% male) diagnosed with acute lymphoblastic leukemia were reviewed for pegaspargase-associated hypersensitivity (14.8%), hyperbilirubinemia (9.7%), venous thromboembolism (VTE, 9.7%), and pancreatitis (5.3%). Odds ratios (OR) and 95% confidence intervals (CI) evaluated associations between clinical factors and each toxicity, cumulative number of toxicities, and toxicity clusters identified using k-mode analysis. Most (68.9%) did not experience any toxicity, 24.6% experienced one toxicity, and 6.3% two or more. Age >10 years was associated with hyperbilirubinemia (OR = 3.83; 95% CI: 1.64-8.95), pancreatitis (OR = 3.72; 95% CI: 1.29-10.68), VTE (OR = 4.65; 95% CI: 1.96-11.02), and cumulative toxicity burden (OR = 3.28, 95% CI: 1.97-5.47); high-risk therapy with hypersensitivity (OR 2.25; 95% CI 1.25-4.05); and overweight with cumulative toxicity burden (OR = 1.76, 95% CI: 1.20-2.57). Eight unique toxicity profiles were identified. Older age, overweight, and treatment intensity contribute to pegaspargase-associated toxicities.

Purpose: To investigate the relationships between tumor absorbed dose (TAD) or normal tissue absorbed dose (NTAD) and clinical outcomes in hepatocellular carcinoma (HCC) treated with yttrium-90 glass microspheres., Methods: TARGET was a retrospective investigation in 13 centers across eight countries. Key inclusion criteria: liver-dominant HCC with or without portal vein thrombosis, < 10 tumors per lobe (at least one ≥ 3 cm), Child-Pugh stage A/B7, BCLC stages A-C, and no prior intra-arterial treatment. Multi-compartment pre-treatment dosimetry was performed retrospectively. Primary endpoint was the relationship between ≥ grade 3 hyperbilirubinemia (such that > 15% of patients experienced an event) without disease progression and NTAD. Secondary endpoints included relationships between (1) objective response (OR) and TAD, (2) overall survival (OS) and TAD, and (3) alpha fetoprotein (AFP) and TAD., Results: No relationship was found between NTAD and ≥ grade 3 hyperbilirubinemia, which occurred in 4.8% of the 209 patients. The mRECIST OR rate over all lesions was 61.7%; for the target (largest) lesion, 70.8%. Responders and non-responders had geometric mean total perfused TADs of 225.5 Gy and 188.3 Gy (p = 0.048). Probability of OR was higher with increasing TAD (p = 0.044). Higher TAD was associated with longer OS (HR per 100 Gy increase = 0.83, 95% CI: 0.71-0.95; p = 0.009). Increased TAD was associated with higher probability of AFP response (p = 0.046 for baseline AFP ≥ 200 ng/mL)., Conclusion: Real-world data confirmed a significant association between TAD and OR, TAD and OS, and TAD and AFP response. No association was found between ≥ grade 3 hyperbilirubinemia and NTAD., Trial Registration Number: NCT03295006., (© 2022. The Author(s).)

Background: Lenalidomid ranks among immunomodulatory drugs. There are a few of the more common side effects, like a higher risk of venous trombembolism or diarrhea. Other side effects are rare. The hyperbilirubinemia described in this article can be assigned to them. In our case, the increase of bilirubin was associated with unrecognized Gilbert syndrome., Case Description: We report a patient with multiple myeloma and necrobio-tic xanthogranuloma (NXG) of the skin and liver. After the treatment with bortezomib, lenalidomid and dexamethasone, complete remission was attained after 4 cycles with decrease of monoclonal immunoglobulin to an unmeasurable concentration. At the same time, the dis-appearance of cutaneous and hepatic lesions of NXG on FDG-PET/CT was evident. The administration of bortezomib was stopped after 8 cycles and only continued with lenalidomide as a maintenance therapy. However, after four cycles of this therapy, bilirubin increased above the upper limit and the increase continued till the 11th month of lenadomide administration, when bilirubin reached the highest concentration of 75 &#956;mol/l (more than the three-fold of the upper limit, grade III toxicity). The patient had asymptomatic hyperbilirubinemia with no underlying liver disease or renal impairment while being on lenalidomide therapy. Genetic studies proved mutation; insertion in the promotor gene UGT1A1 typical for Gilbert syndrome. Hyperbilirubinemia may be attributed to the unmasking of previously undia-gnosed Gilbert syndrome. Therefore, the therapy with lenalidomide was interrupted after 11 months. The bilirubin level decreased after the discontinuation of the drug., Conclusion: NXG disappeared after fulfilling complete remission of multiple myeloma with disappearance of monoclonal immunoglobulin. This observation supports the hypothesis that monoclonal immunoglobulin has a crucial role in the ethiopathogenesis of NXG and suggests the treatment of monoclonal gammopathy if present in a patient with NXG, hoping that this will result in xantogranuloma disappearance.

Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study, we aimed to clarify the effects of oridonin (Ori), an active diterpenoid extracted from Rabdosia rubescens, on hyperbilirubinemia and revealed the underlying molecular mechanism in vivo and in vitro. Here, we showed that liver X receptor alpha (LXRα) deletion eliminated the protective effect of Ori on phenylhydrazine hydrochloride-induced hyperbilirubinemia mice, indicating that LXRα acted as a key target for Ori treatment of hyperbilirubinemia. Ori significantly increased the expression of LXRα and UDP-glucuronosyltransferase 1A1 (UGT1A1) in the liver of wild-type (WT) mice, which were lost in LXRα -/- mice. Ori or LXR agonist GW3965 also reduced lipopolysaccharide/D-galactosamine-induced hyperbilirubinemia via activating LXRα/UGT1A1 in WT mice. Liver UGT1A1 enzyme activity was elevated by Ori or GW3965 in WT mice. Further, Ori up-regulated LXRα gene expression, increased its nuclear translocation and stimulated UGT1A1 promoter activity in HepG2 cells. After silencing LXRα by siRNA, Ori-induced UGT1A1 expression was markedly reduced in HepG2 cells and primary mouse hepatocytes. Taken together, Ori stimulated the transcriptional activity of LXRα, resulting in the up-regulation of UGT1A1. Therefore, Ori or its analogs might have the potential to treat hyperbilirubinemia-related diseases through modulating LXRα-UGT1A1 signaling., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: This study aimed to investigate the effect of adding ursodeoxycholic acid (UDCA) to phototherapy in neonates with glucose-6-phosphate dehydrogenase (G6PD) deficiency and hyperbilirubinaemia. G6PD deficiency is a common cause of severe hyperbilirubinaemia in neonates., Methods: This study was a triple blind, clinical trial study of 40 neonates with G6PD deficiency and hyperbilirubinaemia who admitted for phototherapy in hospitals affiliated to the University of Medical Sciences. The treatment group (n = 20) received UDCA 10 mg/kg (2 cc/kg) daily divided into 2 doses every 12 h. The control group (n = 20) received the same volume of placebo syrup. The drug and placebo treatments were continued until the bilirubin level dropped below 171 μmol/L. Both the control and treatment group received continuous phototherapy. Independent sample t-test, survival analysis and logrank test were used to statistically analyse the results., Results: The mean total bilirubin level was 231.9 ± 18.8 μmol/L and 184.3 ± 18.6 μmol/L in the control and intervention group respectively, 24 h after drug administration and 209.7 ± 19.3 μmol/L and 157.4 ± 16.4 μmol/L, respectively, 48 h after intervention (P < 0.05). The median length of hospitalisation in the treatment group was approximately 1 day lower than the control group (logrank test P value: <0.001)., Conclusion: The study showed that the addition of UDCA to phototherapy accelerates the reduction of total bilirubin level in neonates with G6PD deficiency and can reduce the duration of hospitalisation., (© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Yinzhihuang oral liquid (YZH) is a traditional Chinese medicine that has been widely used in Asia to prevent and treat neonatal hyperbilirubinemia, but the published preclinical studies on its anti-hyperbilirubinemia effect are conducted in adult animals, partly due to the lack of preclinical neonatal hyperbilirubinemia animal models. In the present study, we tested six reagents to induce hyperbilirubinemia in neonatal rats, and established two appropriate neonatal hyperbilirubinemia rat models by subcutaneous injection of δ-Aminolevulinic acid (ALA, 200 mg/kg) or novobiocin (NOVO, 200 mg/kg). Oral treatment of YZH (80, 160 and 320 mg/kg) significantly decreased serum conjugated bilirubin levels in ALA-treated neonatal rats and serum unconjugated bilirubin levels in NOVO-treated neonatal rats, respectively. Additionally, pre-treatment of YZH also prevented the increase of serum bilirubin levels in both ALA- and NOVO-treated rats. Mechanistically, YZH significantly up-regulated the mRNA expression of genes involved in hepatic bilirubin disposition (organic anion-transporting polypeptide 1b2, Oatp1b2; multidrug resistance-associated protein 2, Mrp2) and bilirubin conjugation (UDP-glucuronosyltransferase 1a1, Ugt1a1). Additionally, YZH up-regulated the mRNA expression of cytochrome P450 1A1 (Cyp1a1), the target gene of aryl hydrocarbon receptor (AhR), and increased the nuclear protein levels of AhR in livers of neonatal rats. YZH and its two active ingredients, namely baicalin (BCL) and 4'-hydroxyacetophenone (4-HT), up-regulated the mRNA expression of AhR target genes (CYP1A1 and UGT1A1) and increased nuclear protein levels of AhR in HepG2 cells. In conclusion, the present study provides two neonatal hyperbilirubinemia animal models and evaluates the anti-hyperbilirubinemia effect and mechanisms of YZH in neonatal animals., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

A 52 year old previously healthy woman from Mumbai presented with fever and jaundice of 10 days duration. At admission, she was jaundiced with tachycardia, tachypnea, hypoxia, hypotension, conjunctival congestion and mild erythematous flush over the skin. She had very high WBC counts and CRP's with direct hyperbilirubinemia and azotemia. Investigations for infectious causes of fever were negative. RT-PCR for SARS-CoV-2 in the nasopharynx was negative. However her SARS-CoV-2 antibodies were reactive. She also had echocardiographic and biochemical evidence of cardiac dysfunction. The diagnosis of Multisystem inflammatory syndrome-Adult (MIS-A) was thus established. She rapidly improved with intravenous immunoglobulin (2 gm/kg) and high dose steroids., (Copyright © 2021 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Aim: To optimize the Zinc oxide nanoparticles (ZnONPs)-catalyzed in vitro photolysis of bilirubin and to test their effect on bilirubin clearance in vivo . Materials & methods: ZnONPs, synthesized in an alkaline medium, were characterized. Response surface methodology was used to optimize the in vitro photolysis catalyzed by the nanoparticles (NPs). Blood samples from phenylhydrazine-induced hyperbilirubinemic rabbits which had been administered ZnONPs and UV light were analyzed to assess in vivo clearance of bilirubin. Results: The ZnONP-assisted UV treatment showed the linear and quadratic positive effects on the in vitro bilirubin photolysis with an optimal photolysis of bilirubin at 225 mg dl -1 concentration of ZnONPs and a UV exposure of 1.80 h. The ZnONP-assisted phototherapy of hyperbilirubinemic animals was also found to be more effective for in vivo clearance of bilirubin than phototherapy alone. Conclusion: After further trials, ZnONP-assisted phototherapy could be a potential treatment for hyperbilirubinemia in humans.

This study was performed to evaluate the effects of selenium supplementation on gene expression related to insulin and lipid metabolism, and pregnancy outcomes in patients with gestational diabetes mellitus (GDM). The current randomized, double-blind, placebo-controlled clinical trial was conducted in 36 patients with GDM. Participants were randomly divided into two groups to intake either 200 μg/day selenium supplements as selenium yeast or placebo (n = 18 each group) for 6 weeks. Selenium supplementation upregulated peroxisome proliferator-activated receptor gamma (P = 0.03) and glucose transporter 1 (GLUT-1) (P = 0.01) in lymphocytes of subjects with GDM compared with the placebo. Selenium supplementation did not affect gene expression of low-density lipoprotein receptor (LDLR) and lipoprotein(a) [Lp(a)]. Supplementation with selenium had a significant decrease in incidence of newborns' hyperbilirubinemia (5.6% vs. 33.3%, P = 0.03) and newborns' hospitalization (5.6% vs. 33.3%, P = 0.03) compared with the placebo. Overall, we found that selenium supplementation for 6 weeks among patients with GDM significantly increased PPAR-γ and GLUT-1 expression, but did not affect gene expression of LDLR and LP(a). It also reduced incidence of newborns' hyperbilirubinemia and newborns' hospitalization. Clinical trial registration number: http://www.irct.ir: IRCT20170513033941N35.

We present a teetotaler with compensated non-alcoholic fatty-liver-disease related cirrhosis who presented with acute worsening of his chronic liver disease. The acute event was not discernible even after extensive work up and finally a transjugular liver biopsy revealed features suggestive of severe alcoholic hepatitis. The patient and the family denied occult alcohol use when questioned over multiple times and finally, the culprit 'alcohol' was found to be the homoeopathy medicines that the patient was consuming over a month for treatment of Gilbert's syndrome. We retrieved and tested the homoeopathy drug for alcohol content and found an alarming 18% ethanol in the same, confirming our diagnosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

BACKGROUND Hyperbilirubinemia is a common event that occurs after liver transplantation. Hyperbilirubinemia is usually caused by early allograft dysfunction. Glucocorticoid is widely used for immunosuppression, but few studies have analyzed the effects of steroid therapy on posttransplantation hyperbilirubinemia. The aim of this study was to assess whether glucocorticoid was beneficial in treating hyperbilirubinemia caused by early allograft dysfunction. MATERIAL AND METHODS Patients with postoperative hyperbilirubinemia (those with conditions such as biliary complications and rejections were excluded) were randomly assigned, in a 2: 1 ratio, to the steroid and control groups. Patients in the steroid group were treated with glucocorticoid combined with ursodeoxycholic acid, whereas patients in the control group were only treated with ursodeoxycholic acid. The primary endpoint was decrease in bilirubin and the secondary endpoint was safety. RESULTS From 1st June 2016 to 30th April 2018, 40 patients were enrolled into the steroid group, and 20 were enrolled into the control group. Donor, recipient, and operative data were similar between the 2 groups. The decrease in bilirubin levels in the steroid group was significantly greater than that in the control group on the first day after the intervention was finished (9.25±1.30 mg/dL vs. 3.11±1.45 mg/dL, p=0.005), and after 2 weeks (15.01±1.20 mg/dL vs. 8.88±1.98 mg/dL, p=0.007). The steroid group did not have a higher complication rate but it did have a shorter postoperative hospital stay than in the control group. CONCLUSIONS Low-dose steroid therapy was effective and safe for treating hyperbilirubinemia caused by early graft dysfunction, and it improved liver function.

Background: Although prophylactic glucocorticoids have been used before liver resection to minimize liver dysfunction, it is unknown whether treatment with glucocorticoids will accelerates recovery from hyperbilirubinemia after liver resection., Methods: In this open-label, randomized, controlled trial, patients with hyperbilirubinemia (>2.5 × and ≤5 × the upper limit of normal) within 7 days after hepatic resection were assigned randomly to the dexamethasone or control groups. For the dexamethasone group, 10 mg, 10 mg, and 5 mg dexamethasone were administered intravenously on days 0, 1, and 2, respectively, after randomization. For the control group, patients received standard treatment only. The primary outcome was time to recovery from hyperbilirubinemia defined as the period from the day of randomization to the day when serum bilirubin decreased to ≤1.5 times that of the upper limit of normal. Secondary outcomes were the prevalence of postoperative complications, postoperative hospital stay, and hospital expense., Results: Between March 2016 and December 2017, 76 participants were enrolled (38 in each group). Median time to recovery from hyperbilirubinemia was less in the dexamethasone group than in the control group (2 vs 4 days, P < .001). Serum bilirubin levels were less in the dexamethasone group on days 1-3 after randomization (P < .05). The prevalence of infection, posthepatectomy liver failure, postoperative hospital stay, and hospital expense were not different between the groups., Conclusion: Dexamethasone accelerated recovery from hyperbilirubinemia and decreased serum bilirubin levels without causing more side effects in patients after hepatectomy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Drug-induced liver injury (DILI) is a common cause of hepatotoxicity associated with prescription-based and over-the-counter exposure to medications and herbal supplements. Use of unapproved and inadequately tested herbal supplements can cause DILI. Therefore, thorough history-taking on exposure to herbal supplements must be an integral part of clinical evaluation of DILI. Kratom is an herbal supplement or remedy that has been known for its analgesic effects and has also been used for self-treatment of opiate withdrawals. A 52-year-old man was seen for evaluation of yellow discoloration of the eyes and skin. He reported taking kratom for right shoulder strain for at least a couple of months. On workup, his total bilirubin was noted to be 23.2 mg/dL, which peaked at 28.9 mg/dL. He was noted to have mild elevation of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Extensive laboratory tests were ordered and known causes of chronic liver disease ruled out. Magnetic resonance imaging of the abdomen was unremarkable without stigmata of portal hypertension or signs of chronic liver disease. He demonstrated no evidence of coagulopathy or hepatic encephalopathy during his illness. He underwent liver biopsy, which demonstrated histologic evidence of acute cholestatic hepatitis highly suspicious of DILI. He was advised to avoid kratom or other herbal supplements in future and prescribed ursodeoxycholic acid with significant improvement in his liver chemistries. Kratom is associated with significant liver enzymes derangements leading to DILI. Kratom is not approved for use in the United States and should be avoided.

Hyperbilirubinemia is the most frequent clinical problem neonatologists must deal with during the newborn period. It has been suggested that bilirubin is involved in the balance between antioxidant and pro-oxidant agents due to its antioxidant properties. However, the relevance of these effects in vivo in term and preterm infants is still debated. We performed a literature review of studies that investigated the association between total serum bilirubin (TSB) and oxidative stress in newborn infants. We found that studies in term infants give contradictory results, while studies in preterm infants suggest that the TSB increase is associated with an oxidative stress increase due to concurrent factors other than bilirubin level, such as heme oxygenase (HO) activity. Moreover, it could be speculated that low physiologic TSB values are associated with antioxidant effects, while high pathologic TSB values are associated with pro-oxidant effects. Literature data do not allow the establishment of whether if the antioxidant properties of bilirubin are important from a clinical point of view and can affect the outcome in ill infants.

Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially ameliorate the mitochondrial toxicity of asparaginase. In this retrospective case series, we describe the clinical presentation and management of six pediatric and young adult patients (mean age 12.7, range 9-24 years) with ALL who developed Grade 3-4 hyperbilirubinemia following administration of asparaginase as part of induction/re-induction therapy. Five of these patients were treated with levocarnitine with subsequent improvement of hyperbilirubinemia, while one patient was given levocarnitine prophylactically during induction and developed Grade 3 hyperbilirubinemia, but did not require therapy adjustments or delays. Increased awareness in the pediatric oncology community regarding asparaginase-associated hepatic toxicity and the potential role of levocarnitine in management is warranted.

A 52-year-old man presented to our hospital for further workup of fever of unknown origin after an extensive workup at an outside hospital had failed to reveal a diagnosis. At the outside hospital, he underwent excisional biopsy of the left supraclavicular lymph node, which showed non-necrotising granulomatous changes, and a bone marrow biopsy which showed a normocellular marrow. He was discharged without a diagnosis with recommendations to present to a tertiary hospital. During his admission, his hospital course was complicated by new direct hyperbilirubinaemia and eosinophilia, prompting liver and skin biopsies which showed CD30+ and CD3+ cells. He subsequently underwent left axillary lymph node biopsy, which was reported as 'classic Hodgkin's lymphoma'. With worsening lab values and T cells noted on liver and skin biopsies, excisional lymph node biopsy was sent to the National Institute of Health, where it was confirmed patient had peripheral T cell lymphoma., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We aimed to identify potent biliverdin reductase (BVRA) inhibitors as a novel concept for the treatment of severe unconjugated hyperbilirubinemia. 1280 FDA-approved compounds were screened in vitro for their ability to inhibit human and rat BVRA activity and 26 compounds were identified as BVRA inhibitors. Montelukast and Disulfiram were selected as potentially clinically applicable drugs and tested to reduce serum unconjugated bilirubin (UCB) levels in the Ugt1a1-deficient rat, a model for chronic unconjugated hyperbilirubinemia. Oral administration of Disulfiram was toxic in the Ugt1a1-deficient rat (weight loss, transaminase elevation). Oral Montelukast administration led to low serum concentrations and did not alter serum UCB levels. Intraperitoneal injections of Montelukast resulted in concentrations up to 110 μmol/L in serum and 400 μmol/L in the liver. Still, serum UCB levels remained unaltered. This first study on biliverdin reductase inhibition as a novel concept for treatment of unconjugated hyperbilirubinemia identified putative in vitro BVRA inhibitors. Montelukast, the clinically most suitable inhibitor, did not result in reduction of serum UCB in the Ugt1a1-deficient rat. The proposed treatment strategy will not result in amelioration of severe unconjugated hyperbilirubinemia in humans without the identification or development of more potent BVRA inhibitors.

We report 2 cases of systemic steroid therapy for hyperbilirubinemia after right hepatic lobectomy for liver metastases from colorectal cancer.One of the patients was a 65-year-old man, diagnosed with transverse colon cancer with multiple liver metastases.After surgery for the primary lesion and chemotherapy(FOLFOX plus bevacizumab, FOLFIRI plus panitumumab), he underwent right hepatic lobectomy for the liver metastasis.His preoperative ICG 15 min was 8%.Conjugated hyperbilirubinemia without biliary stenosis occurred after the hepatectomy.Two courses of pulse steroid therapy were effective for only a limited period.After initiation of oral prednisolone therapy, his hyperbilirubinemia decreased.The other patient was a 66- year-old man with rectal cancer who underwent a low anterior resection.Postoperatively, a liver metastasis appeared.After CapeOX therapy, he underwent right hepatic lobectomy.His preoperative ICG 15 min was 5%.Conjugated hyperbilirubinemia occurred after hepatectomy.Pulse steroid therapy was effective for only a limited period.After initiation of prednisolone therapy, his hyperbilirubinemia decreased.In both cases, fatty changes in the liver were detected.Chemotherapy -associated hepatotoxicity may induce hyperbilirubinemia after hepatectomy.The effectiveness of systemic steroid therapy for hyperbilirubinemia is demonstrated by these cases.

DDI could be caused by the inhibition of OATP-mediated hepatic uptakes. The aim of this study is to set the risk criteria for the compounds that would cause DDI via OATP inhibition at the drug discovery stage. The IC 50 values of OATP inhibitors for human OATP-mediated atorvastatin uptake were evaluated in the expression system. In order to set the risk criteria for OATP inhibition, the relationship was clarified between OATP inhibitory effect and severe adverse effects of OATP substrates, rhabdomyolysis, hyperbilirubinemia and jaundice. Rhabdomyolysis would be caused in the atorvastatin AUC more than 9-fold of that at a minimum therapeutic dose. The atorvastatin AUC was 6- to 9-fold increased with the OATP inhibitors of which IC 50 values were ≤1 μmol/L. Hyperbilirubinemia and jaundice would be caused with the OATP inhibitors of which IC 50 values were ≤6 μmol/L. This investigation showed that the compounds with IC 50 of ≤1 μmol/L would have high risk for OATP-mediated DDI that would cause severe side effects. Before the detailed analysis based on the dosage, unbound fraction in blood and effective concentration to evaluate the clinical DDI potency, this criteria enable high throughput screening and optimize lead compounds at the drug discovery stage., (Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Aims: The aim of this study was to evaluate the bilirubin lowering and wound healing property of aqueous extract of Calotropis procera (AECP) leaves in Wistar rats., Materials and Methods: Albino Wistar rats of either sex were used for the study. Bilirubin lowering property of C. procera leaves was evaluated using phenylhydrazine and paracetamol as inducing agents followed by measuring the concentration of serum total bilirubin in hyperbilirubinemic rats. Wound healing property was evaluated using incision and excision models by measuring tensile breaking strength, percentage wound contractions, and epithelization days, respectively., Statistical Analysis: Statistical comparison between groups in each experiment was done with one-way analysis of variance followed by Dunnett's test., Results: AECP showed a significant (P < 0.05) decrease in concentrations of serum total bilirubin in hyperbilirubinemic rats as well as significant (P < 0.05) increase in breaking strength and percentage wound contractions with decreased epithelization period when compared to control groups., Conclusions: AECP showed significant bilirubin lowering and wound healing property in Wistar rats.

We showed in this study that rifampicin therapy is more effective than plasmapheresis and steroid treatment in diseases associated with severe hyperbilirubinemia. In our opinion, rifampicin treatment may suitable especially for patients with persistent hyperbilirubinemia, and it would be appropriate to use rifampicin as a challenge therapy to patients with severe hyperbilirubinemia, but liver function tests in these patients must be monitored closely., (© Acta Gastro-Enterologica Belgica.)

In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years, new treatment options such as the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in patients with good performance status. Unfortunately, patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients, have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical treatment of this patient group is limited. In a meeting of German medical oncology experts, the available clinical evidence and own clinical experience regarding the management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present publication summarises the discussion outcomes with regard to appropriate management of these patients, including consensus-based recommendations for nab-paclitaxel/gemcitabine treatment, according to the best available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the experts provide advice for an initial dose reduction of chemotherapy with nab-paclitaxel/gemcitabine based on the total bilirubin level in patients with biliary obstruction or extensive liver metastasis., (© 2015 S. Karger GmbH, Freiburg.)

Aim: Testing the potential of citrate-capped Mn3O4 nanoparticles (NPs) as a therapeutic agent for alternative rapid treatment of hyperbilirubinemia through direct removal of bilirubin (BR) from blood in mice., Materials & Methods: NPs were synthesized and the mechanism of BR degradation in presence and absence of biological macromolecules were characterized in vitro. To test the in vivo BR degradation ability of NPs, CCl4-intoxicated mice were intraperitoneally injected with NPs., Results: We demonstrated ultrahigh efficacy of the NPs in symptomatic treatment of hyperbilirubinemia for rapid reduction of BR in mice compared with conventional medicine silymarin without any toxicological implications., Conclusion: These findings may pave the way for practical clinical use of the NPs as safe medication of hyperbilirubinemia in human subjects.

Aim: Mild, temporary hepatic failure (MTHF) may be completely asymptomatic or cause minimal signs and symptoms. This common clinical problem is very diffuse and, in case of repeated episodes may cause a chronic impairment in liver function. The aim of this registry was to evaluate the evolution of MTHF in subjects using Liverubin (a new standardized Silymarin preparation) over a 4-week period., Methods: Patients with MTHF were observed in a registry study. In all subjects viral hepatitis markers were negative at inclusion. Different possible causes of MTHF had been considered, documented or excluded. The role of alcohol was mainly as a "facilitator" and not definitely determinant as a single factor in causing the MTHF episode. The registry included patients with MTHF characterized by: decreased albumin levels; increased total bilirubin; altered hepatic functions enzymes; increased oxidative stress. Two management groups were created: a. standard management (SM) only; b: SM and Liverubin; 25 Liverubin patients and 23 SM subjects completed the registry. The average follow-up period was 32.2;1.3 days in the supplement group and 32.1;2 days in controls., Results: The distribution of symptoms and ultrasound results were comparable. Most symptoms observed at inclusion were disappeared or attenuated at 4 weeks in both groups. At inclusion, the values in the two groups were comparable. The increase in albumin levels was significantly (P<0.05 at 4 weeks) faster and the final values were higher in the Liverubin group. Total bilirubin was reduced in the supplement group better than in controls (P<0.05). Direct bilirubin values improved more in the supplement group at 4 weeks (P<0.05). The decrease of ALT-SGPT and AST-ASAT was more evident in the supplement group (P<0.05). Improvement in controls was more limited. Alkaline phosphatase value was normalized at 4 weeks in Liverubin patients; values decreased less in controls (P<0.05). Gamma GT decreased and were normal at 4 weeks with Liverubin. ESR was decreased in both groups (significantly more in the Liverubin group: P<0.05). There was a less important decrease in controls without normalization at 4 weeks. The white cell count was also better at 4 weeks in the supplement group; P<0.05). Plasma free radicals were significantly elevated in both groups at inclusion. A more significant decrease in the supplement group was observed at 4 weeks. Persisting, elevated values were seen in controls (P<0.05 in comparison with normal range). Platelets values improved in the Liverubin group (P<0.05) better than in controls. All other blood tests values (including hematocrit, renal function tests) were within the normal range at inclusion and at 4 weeks in both groups. Hepatitis markers were negative at inclusion and at 4 weeks. Compliance. Ninety-six percent of the Liverubin capsules were correctly used. Safety and tolerability were optimal (no side effect was registered)., Conclusion: In conclusion, data from this pilot, registry study indicate a significant activity of Liverubin associated with a very good safety profile, in patients with temporary hepatic failure. The recovery of hepatic function is faster and more effective with Liverubin compared to the best "standard" management.

Children with hematologic malignancies may be challenged with life-threatening, invasive fungal infections by organisms that would otherwise have a low potential for virulence in healthy hosts. Presented is a case of a 15-year-old adolescent with B-cell acute lymphoblastic leukemia who was receiving steroids and chemotherapy. He developed cough associated with left chest pain with suspicion for fungal pneumonia. He began systemic antifungal therapy, underwent computed tomography of the chest demonstrating a large cavitary lesion (reversed halo sign) in the left lung. Over a 48-hour period the patient clinically deteriorated with worsening pneumonia and required left thoracotomy with nonanatomic pulmonary resection. This case illustrates the aggressive nature of Cunninghamella pneumonia in patients with hematologic malignancies, and the multidisciplinary approach required to have the greatest possible outcome.

Background: Despite several advances in the treatment of Epstein-Barr virus (EBV) in recent years, patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) do not always show satisfactory outcomes. We here conducted a nationwide survey in Japan to identify prognostic factors of EBV-HLH in children with this disease in an effort to improve the management and the outcomes of these patients., Procedure: Between January 2003 and June 2008, we enrolled 98 children younger than 18 years of age who were diagnosed with EBV-HLH. We then studied the clinical characteristics and laboratory findings at the time of diagnosis with the aim to identify prognostic factors for EBV-HLH., Results: The mean age of onset of EBV-HLH was 3.9 ± 2.8 years. Most of our patients presented with fever, hepatosplenomegaly, lymphadenopathy, and hemophagocytosis of bone marrow. Sixty-two percent of patients showed T cell clonality, and 97% had EBV infection in either T or natural killer cells. Most patients (60%) were treated with a multi-agent chemotherapeutic regimen, including corticosteroid, etoposide, and cyclosporine. After initial treatment, 90.3% of patients were in remission, and 7 patients (8.2%) experienced recurrence of EBV infection. Among several prognostic factors, patients with both hyperbilirubinemia (>1.8 mg/dl) and hyperferritinemia (>20,300 ng/ml) at the time of diagnosis had significantly poorer outcomes than those with low serum bilirubin and ferritin levels., Conclusions: These findings suggest that the therapeutic strategy for children with EBV-HLH could be tailored according to the laboratory findings at diagnosis., (© 2014 Wiley Periodicals, Inc.)

Background: Accumulating evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. We previously reported evidence of schizophrenia-like behaviors and microglial activation in Gunn rats. We concluded that the Gunn rat, which exhibits a high concentration of unconjugated bilirubin, may be useful as an animal model of schizophrenia. On the other hand, there have been numerous reports that minocycline is effective in treating schizophrenia., Methods: In the present study, we investigated the effects of minocycline on performance of behavioral tests (prepulse inhibition (PPI) and novel object recognition test (NORT)) after animals received either 40mg/kg/d of minocycline or vehicle by intraperitoneal (i.p.) injection for 14 consecutive days. Furthermore, we examined the effects of minocycline on microglial activation in the hippocampal dentate gyrus of Gunn rats and Wistar rats., Results: We found that administration of minocycline for 14days significantly increased the exploratory preference in retention sessions and tended to improve the PPI deficits in Gunn rats. Immunohistochemistry analysis revealed that microglial cells in the minocycline-treated Gunn rat group showed less expression of CD11b compared to vehicle-treated Gunn and Wistar groups., Conclusions: Our findings suggest that minocycline improves recognition memory and attenuates microglial activation in the hippocampal dentate gyrus of Gunn rats. Therefore, minocycline may be a potential therapeutic drug for schizophrenia., (Copyright © 2013. Published by Elsevier Inc.)

No effective medication for hyperbilirubinemia yet exists. Taurine is believed to exert a neuroprotective action. The aim of the present study was to determine whether taurine protected neurons of the rat anteroventral cochlear nucleus (AVCN) against bilirubin-induced neuronal hyperexcitation. AVCN neurons were isolated from 13 to 15-day-old Sprague-Dawley rats. The effects of bilirubin on the spontaneous excitatory postsynaptic currents (sEPSCs) and action potential currents were compared with those exerted by bilirubin and taurine together. Bilirubin dramatically increased the frequencies of sEPSCs and action potential currents, but not sEPSC amplitude. Taurine suppressed the enhanced frequency of action potentials induced by bilirubin, in a dose-dependent manner. In addition, taurine decreased the amplitude of voltage-dependent calcium channel currents that were enhanced upon addition of bilirubin. We explored the mechanism of the protective effects exerted by taurine using GABAA and glycine receptor antagonists, bicuculline and strychnine, respectively. Addition of bicuculline and strychnine eliminated the protective effects of taurine. Neither bilirubin nor taurine affected the sensitivity of the glutamate receptor. Our findings thus indicate that taurine protected AVCN neurons against bilirubin-induced neuronal hyperexcitation by activating the GABAA and glycine receptors and inhibiting calcium flow through voltage-gated channels. Thus, taurine may be effective in treatment of neonatal hyperbilirubinemia., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

Background: Phenylhydrazine, a hemolytic agent, is widely used as a model of experimental hyperbilirubinemia. Palm tocotrienol-rich fraction (TRF) was shown to exert beneficial effects in hyperbilirubinemic rat neonates., Aim: To investigate the effects of palm TRF supplementation on hepatic bilirubin-metabolizing enzymes and oxidative stress status in rats administered phenylhydrazine., Methods: Twenty-four male Wistar rats were divided into two groups; one group was intraperitoneally injected with palm TRF at the dose of 30 mg/kg/day, while another group was only given vehicle (control) (vitamin E-free palm oil) for 14 days. Twenty-four hours after the last dose, each group was further subdivided into another two groups. One group was administered phenylhydrazine (100 mg/kg, intraperitoneally) and another group was administered normal saline. Twenty-four hours later, blood and liver were collected for biochemical parameter measurements., Results: Phenylhydrazine increased plasma total bilirubin level and oxidative stress in the erythrocytes as well as in the liver, which were reduced by the pretreatment of palm TRF. Palm TRF also prevented the increases in hepatic heme oxygenase, biliverdin reductase and UDP-glucuronyltransferase activities induced by phenylhydrazine., Conclusion: Palm tocotrienol-rich fraction was able to afford protection against phenylhydrazine-induced hyperbilirubinemia, possibly by reducing oxidative stress and inhibiting bilirubin-metabolizing enzymes in the liver.

Background: Free bilirubin (Bf), the unbound fraction of unconjugated bilirubin (UCB), can induce neurotoxicity, including impairment of the auditory system, which can be assessed by brainstem auditory evoked potentials (BAEPs). We hypothesized that albumin might reduce the risk of neurotoxicity by decreasing Bf and its translocation into the brain., Aim: To determine the effects of albumin on BAEPs and brain bilirubin content in two Gunn rat pup models of acute hyperbilirubinemia., Methods: We used Gunn rat pups, which have a deficiency of the bilirubin-conjugating enzyme UGT1A1. We induced haemolysis by injection of phenylhydrazine (phz) into 14-days old pups. Subsequently, pups were treated with either i.p. human serum albumin (HSA; 2.5 g/kg; n = 8) or saline (control, n = 8). We induced acute neurotoxicity by injecting 16-days old pups with sulphadimethoxine (sulpha) and treated them with either HSA (n = 9) or saline (control, n = 10). To assess bilirubin neurotoxicity, we used the validated BAEP method and compared relevant parameters; i.e. peak latency values and interwave interval (IWI) between peak I and peak II, a marker of acute neurotoxicity., Results: Phz and sulpha significantly increased IWI I-II by 26% and 29% (P < 0.05) in the haemolysis and the displacement model, respectively. Albumin completely prevented the increase of IWI I-II in either model. The beneficial effect of albumin in the displacement-model by means of normal BAEPs was in line with less bilirubin in the brain (NS). Interestingly, in the haemolysis model the accumulation of total bilirubin in the brain was unaltered, and BAEPs still appeared normal. This might advocate for a role of brain Bf which was calculated and showed that albumin treatment non-significantly reduces Bf concentrations in brain, compared with saline treatment., Conclusions: Albumin treatment is neuroprotective in acute hyperbilirubinemia in Gunn rat pups. Our present results underline the importance of functional diagnostic test of neurotoxicity above biochemical concentrations., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Atazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO(4). HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25 mmol/liter received 125 mg daily of ZnSO(4) as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4 initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4 were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO(4) was well tolerated. Statistically significant declines in total bilirubin C(max) and AUC(0-24) of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubin Cmax and AUC(0-24) of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for C(trough), C(max), and AUC(0-24) were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO(4) decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO(4) supplementation may be useful in management of ATV-related HBR in selected patients.

The present study investigated the effect of the H2 antagonist cimetidine on the pharmacokinetics of a multi-targeted receptor tyrosine kinase (RTK) inhibitor, sunitinib, in Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic mutant rats (EHBR) lacking the efflux transporter, ATP-binding cassette C2 protein (ABCC2). Rats received an intraperitoneal injection of cimetidine (10 mg/kg) once a day for three days. On day 4, sunitinib (3 mg/kg) was administered intravenously 30 min after the final injection of cimetidine or saline to SD rats. Disappearance of sunitinib from plasma was significantly delayed by cimetidine. The pharmacokinetic parameter of sunitinib, systemic clearance (CLSYS), was significantly reduced and the half-life was significantly prolonged, with no change in the volume of distribution at steady-state (VSS). When the effect of cimetidine on the biliary excretion of sunitinib at steady-state condition was investigated in SD rats, cimetidine had no effect on some transporter-mediated biliary excretion of sunitinib. Furthermore, the contribution of ABCC2 to the biliary excretion of sunitinib was also examined in SD rats and EHBR. The biliary clearance of sunitinib was significantly lower in EHBR, but the biliary excretion rate of EHBR was not different from that of SD rats, and the contribution of biliary excretion to systemic elimination was small, suggesting that sunitinib is mainly eliminated by cytochrome P450 3A4 (CYP3A4)-mediated metabolism and is not excreted into the bile via ABCC2. These findings indicate that co-administration of cimetidine alters the pharmacokinetics of sunitinib probably due to inhibition of CYP3A4, suggesting the possibility that cimetidine should be used carefully for patients with cancer being treated with sunitinib therapy.

Objectives: Previous work showed that taurine protects neurons against unconjugated bilirubin (UCB)-induced neurotoxicity by maintaining intracellular calcium homeostasis, membrane integrity, and mitochondrial function, thereby preventing apoptosis from occurring, in primary neuron cultures. In this study, we investigated whether taurine could protect the auditory system against the neurotoxicity associated with hyperbilirubinemia in an in vivo model., Methods: Hyperbilirubinemia was established in neonatal guinea pigs by intraperitoneal injection of UCB. Hearing function was observed in electrocochleograms (ECochGs) and auditory brainstem responses (ABRs) recorded before and 1, 8, 24, and 72 h after UCB injection. For morphological evaluations, animals were sacrificed at 8h post-injection, and the afferent terminals beneath the inner hair cells (IHCs), spiral ganglion neurons (SGNs), and their fibers were examined., Results: It was found that UCB injection significantly increased latencies and inter-wave intervals, and thresholds of ABR and compound action potentials, and caused marked damage to type I SGNs, their axons, and terminals to cochlear IHCs. When baby guinea pigs were pretreated with taurine for 5 consecutive days and then injected with bilirubin, electrophysiological abnormalities and morphological damage were attenuated significantly in both the peripheral and central auditory system., Conclusions: From these observations, it was concluded that taurine limited bilirubin-induced neural damage in the auditory system. These findings may contribute to the development of taurine as a broad-spectrum agent for preventing and/or treating hearing loss in neonatal jaundice., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: 4Z,15Z-bilirubin-IXα (BR), an endogenous toxic compound that is sparingly soluble in water, binds human serum albumin (HSA) with high affinity in a flexible manner. Our previous findings suggest that both Lys195 and Lys199 in subdomain IIA are important for the high-affinity binding of BR, and especially Lys199 in stand-alone domain II plays a prominent role in the renal elimination of BR. Our hypothesis is that HSA-domain II with high BR binding would be a useful therapeutic agent to treat hyperbilirubinemia in patients with impaired liver function., Methods: Unbound BR concentrations were determined using a modified HRP assay. To evaluate the effect of pan3&#95;3-13 domain II mutant in promoting urinary BR excretion, the serum concentration and urinary excretion amount of BR were determined using bile duct ligation mice., Results: After three or six rounds of panning, pan3&#95;3-13 and pan6&#95;4 were found to have a significantly higher affinity for BR than wild-type domain II. Administration of pan3&#95;3-13 significantly reduced serum BR level and increased its urinary excretion in the disease model mice as compared to wild-type domain II treatment., Conclusions: These results suggest that pan3&#95;3-13 has great potential as a therapeutic agent that promotes urinary BR excretion in hyperbilirubinemia., General Significance: This is the first study to be applied to other HSA bound toxic compounds that are responsible for the progression of disease, thereby paving the way for the development of non-invasive and cost effective blood purification treatment methods., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Infants who are dependent on parenteral nutrition (PN) sometimes develop PN-associated cholestasis (PNAC). A compassionate use protocol, approved by the U.S. Food and Drug Administration and the institutional review board, guided enrollment of hospitalized infants with PNAC (<1 year of age, PN dependence for >3 weeks). Plasma concentrations of essential fatty acids were monitored before and after a soybean-based PN lipid, infused at 3 g/kg body weight/d, was replaced by an experimental fish oil-based intravenous fat emulsion (FO-IVFE) at 1.0 g/kg/d. All participants were born premature (n = 10; 20% male). At enrollment, infants were (mean ± SD) 86.5 ± 53.5 days of life and weighed 2.24 ± 0.87 kg; direct bilirubin was 5.5 ± 1.3 mg/dL. After treatment, blood concentrations significantly increased from baseline (P < .017) for circulating eicosapentaenoic acid (6.3 ± 3.0 to 147.8 ± 53.1 µg/mL), docosahexaenoic acid (20.7 ± 6.5 to 163.7 ± 43.4 µg/mL), pristanic acid (0.01 ± 0.01 to 0.17 ± 0.03 µg/mL), and phytanic acid (0.06 ± 0.03 to 0.64 ± 0.15 µg/mL). In contrast, total plasma ω-6 fatty acids (including linoleic acid) decreased (P < .017). The triene/tetraene ratio remained below the threshold value of 0.2 that defines ω-6 deficiency. No adverse effects were observed attributable to FO-IVFE. Discontinuation of FO-IVFE was typically due to infants (body weight 3.76 ± 1.68 kg) transitioning to enteral feeding rather than for resolution of hyperbilirubinemia (direct bilirubin 7.9 ± 4.8 mg/dL). These exploratory results suggest that FO-IVFE raises circulating ω-3 fatty acids in premature infants without development of ω-6 deficiency in the 8.3 ± 5.8-week time frame of this study.

This prospective randomized study incorporates 141 surgical department patients with hepatobiliary tumors. The 1st group patients received 800 ml/day of remaxol. The 2nd1 group patients received Ringer solution and 10% glucose at 1:1 ratio. The subgroups included: 1 subgroup-with pre-operative cholecysto- or choledochostomia and B-subgroup-without pre-operative interventions. The combined surgical and pharmaceutical correction of bile passage, bilirubinemia, cholestasis and cytolysis by remaxole leads to better hepatic dysfunction correction and allows better timing of chemotherapy in bile passage tumors.