- Antibiotic-induced Elevations of Plasma Bile Acids in Rats Independent of Bsep Inhibition. [Journal Article]
- TSToxicol Sci 2017 Jan 20
- Drug-induced liver injury (DILI) is a common toxicity observed in drug development and can lead to withdrawal of approved drugs from the market. To better understand the numerous mechanisms of DILI, ...
Drug-induced liver injury (DILI) is a common toxicity observed in drug development and can lead to withdrawal of approved drugs from the market. To better understand the numerous mechanisms of DILI, recent efforts have focused on transporter inhibition, specifically liver canalicular bile salt export pump (Bsep) as one mechanism of DILI, and on the potential use of plasma bile acids as monitorable mechanism-based biomarkers of Bsep inhibition. To explore alternative mechanisms of bile acid increases in plasma, six antibiotic and two non-antibiotic drugs unlikely to be Bsep inhibitors were evaluated in rat studies. Surprisingly, all six antibiotics demonstrated 2- to 14-fold increases of plasma taurocholic acid (TCA). Also, unconjugated primary bile acids and secondary bile acids (both taurine-conjugated and unconjugated) were decreased in rat plasma after antibiotic treatments, but not with the non-antibiotic drugs. These results suggest alternative mechanisms of bile acids regulation such as attenuation of bacterial deconjugation of bile acids following reduction of gut microflora by antibiotics. Measurements of TCA transport in rat hepatocytes and Bsep-containing membrane vesicles suggest that inhibition of uptake into hepatocytes could also contribute to increases in plasma bile acid concentrations, while excluding inhibition of Bsep as a mechanism. These studies further demonstrate that there are several mechanisms that can lead to conjugated bile acid increases in plasma. By carefully considering the time course and magnitude of changes of individual bile acids relative to any changes seen in transaminases and bilirubin, interpretations and conclusions of the involvement of Bsep inhibition are enabled.
- Effects of Soybean Lipid Infusion on Unbound Free Fatty Acids and Unbound Bilirubin in Preterm Infants. [Journal Article]
- JPedJ Pediatr 2017 Jan 12
- CONCLUSIONS: Increasing intralipid doses result in increasing FFAu levels, which are associated with increased Bf independent of TSB. In infants born extremely preterm (<28 weeks of gestation), phototherapy effectively reduces TSB but not Bf.
- The role of heme-oxygenase-1 in pathogenesis of cerebral malaria in the co-culture model of human brain microvascular endothelial cell and ITG Plasmodium falciparum-infected red blood cells. [Journal Article]
- APAsian Pac J Trop Med 2017; 10(1):20-24
- CONCLUSIONS: Results provide at least in part, insight into the contribution of HO-1 on CM pathogenesis and need to be confirmed in animal model.
- Validation of a Modified Child-Turcotte-Pugh Classification System Utilizing Insulin-Like Growth Factor-1 for Patients with Hepatocellular Carcinoma in an HBV Endemic Area. [Journal Article]
- PlosPLoS One 2017; 12(1):e0170394
- CONCLUSIONS: The IGF-CTP classification was slightly better than the original CTP classification for predicting survival of patients with HCC in a chronic hepatitis B endemic area. This is most likely due to the fact that serum IGF-1 levels reflect underlying HCC status.
- Early Posthepatoportoenterostomy Predictors of Native Liver Survival in Biliary Atresia. [Journal Article]
- JPJ Pediatr Gastroenterol Nutr 2017; 64(2):203-209
- CONCLUSIONS: Serum TB and albumin levels 3 months post-HPE independently predicted native liver survival in BA when controlling for center. Serum albumin level <35 g/L in infants with BA who were no longer jaundiced at 3 months post-HPE was a poor prognostic indicator. Poorer linear growth and absence of significant coagulopathy suggest a role for early aggressive nutritional therapy in this group.
- Pretransplant Serum Hyaluronic Acid Can Be a Biomarker as a Prognostic Predictor in Adult-to-Adult Living Donor Liver Transplantation. [Journal Article]
- TPTransplant Proc 2017 Jan - Feb; 49(1):102-108
- CONCLUSIONS: Preoperative HA level can be a prognostic risk factor. Patients with high HA levels are vulnerable and should be carefully managed after LDLT.
- No negative impact of serum IgG4 levels on clinical outcome in 435 patients with primary sclerosing cholangitis from Japan. [Journal Article]
- JHJ Hepatobiliary Pancreat Sci 2017 Jan 19
- CONCLUSIONS: The current study showed that serum IgG4 levels at diagnosis do not affect PSC prognosis in a Japanese cohort that excluded patients with IgG4-SC. This article is protected by copyright. All rights reserved.
- Risks and benefits of phase I liver dysfunction studies: should patients with severe liver dysfunction be included in these trials? [Journal Article]
- INInvest New Drugs 2017 Jan 19
- Introduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical bene...
Introduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical benefit is not well established. Methods We reviewed 170 patients across 15 liver dysfunction studies at our institution, grouped based on the NCI-Organ Dysfunction Working Group criteria or Child-Pugh Score. Results The median survival for the entire cohort was two months and just one month amongst patients with severe liver dysfunction. Patients with normal or mild liver dysfunction, absence of tumor in liver, good performance status, higher serum albumin and lower bilirubin, aspartate transaminase and alkaline phosphatase had improved survival by univariate analysis. Serum albumin and liver function classification remained significant by multivariate analysis. Conclusion Given poor survival of patients with liver dysfunction, we need better criteria, such as albumin levels, for optimally selecting patients for liver dysfunction studies.
- Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment. [Journal Article]
- SRSci Rep 2017 Jan 19; 7:41032
- The neurologic manifestations of neonatal hyperbilirubinemia in the central nervous system (CNS) exhibit high variations in the severity and appearance of motor, auditory and cognitive symptoms, whic...
The neurologic manifestations of neonatal hyperbilirubinemia in the central nervous system (CNS) exhibit high variations in the severity and appearance of motor, auditory and cognitive symptoms, which is suggestive of a still unexplained selective topography of bilirubin-induced damage. By applying the organotypic brain culture (OBC: preserving in vitro the cellular complexity, connection and architecture of the in vivo brain) technique to study hyperbilirubinemia, we mapped the regional target of bilirubin-induced damage, demonstrated a multifactorial toxic action of bilirubin, and used this information to evaluate the efficacy of drugs applicable to newborns to protect the brain. OBCs from 8-day-old rat pups showed a 2-13 fold higher sensitivity to bilirubin damage than 2-day-old preparations. The hippocampus, inferior colliculus and cerebral cortex were the only brain regions affected, presenting a mixed inflammatory-oxidative mechanism. Glutamate excitotoxicity was appreciable in only the hippocampus and inferior colliculus. Single drug treatment (indomethacin, curcumin, MgCl2) significantly improved cell viability in all regions, while the combined (cocktail) administration of the three drugs almost completely prevented damage in the most affected area (hippocampus). Our data may supports an innovative (complementary to phototherapy) approach for directly protecting the newborn brain from bilirubin neurotoxicity.
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- [Repeated yellowing of the skin and sclera for 2 years]. [Journal Article]
- ZDZhongguo Dang Dai Er Ke Za Zhi 2017; 19(1):77-80
- A two-year-old girl was admitted due to repeated yellowing of the skin and sclera for 2 years and had no other specific symptoms or signs. The use of phenobarbital could relieve the symptoms of jaund...
A two-year-old girl was admitted due to repeated yellowing of the skin and sclera for 2 years and had no other specific symptoms or signs. The use of phenobarbital could relieve the symptoms of jaundice. Multiple examinations showed increased indirect bilirubin levels, and the results of aminotransferases and liver imaging were normal. There was no evidence of hemolysis. The analysis of UGT1A1 gene in her family found that this child had double homozygous mutation of c.211G>A(G71R) and c.1456T>G(Y486D), which had been reported as the pathogenic mutation for Gilbert syndrome. Her parents carried double heterozygous mutation of G71R and Y486D and had no symptom of jaundice. The child was diagnosed as having Gilbert syndrome. It is concluded that as for patients with unconjugated hyperbilirubinemia which cannot be explained by liver damage and hemolysis, their family history should be investigated in detail and gene analysis should be performed as early as possible, in order to identify congenital bilirubin metabolic disorders.