Integral pharmacokinetics of multiple lignan components in normal, CCl4-induced hepatic injury and hepatoprotective agents pretreated rats and correlations with hepatic injury biomarkers

Although pharmacokinetic alternations by hepatic injury have been extensively studied, little is known about the potential influence of hepatoprotective agent's treatment. This study was aimed to investigate the holistic pharmacokinetics of multiple lignans, CYP3A regulations, and their correlations with hepatic injury biomarkers, in hepatic injured rats pretreated with or without schisandra lignan extract (SLE) and dimethyl-diphenyl-bicarboxylate (DDB). Integral pharmacokinetics of multiple lignans based on an AUC-weighting approach was determined in normal, CCl4 induced hepatic injury rats pretreated with or without SLE and DDB. Protein expression and activities of CYP3A were determined. Pharmacokinetic parameters and CYP3A activities were correlated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. CCl4 induced acute hepatic injury resulted in a nearly 8-fold enhancement of integral plasma exposures of multiple lignans, which was caused by the significant down-regulation of CYP3A. SLE and DDB pretreatment exhibited potent hepatoprotective effects, accompanied with the restored expression and activity of CYP3A, and the recovery of the respective and integral pharmacokinetics of lignans components. The integral AUC_0-tn and CYP3A activities correlated well with ALT and AST. This study suggested that the pharmacokinetic regulating effects of hepatoprotective agent's on themselves and co-prescribed drugs should be of concern, and hepatic injury biomarkers may serve as good predictors.     

Combination therapy with andrographolide and d-penicillamine enhanced therapeutic advantage over monotherapy with d-penicillamine in attenuating fibrogenic response and cell death in the periportal zone of liver in rats during copper toxicosis

Long treatment regime with d-penicillamine is needed before it can exert clinically meaningful benefits in the treatment of copper toxicosis. The consequence of long-term d-penicillamine treatment is associated with numerous side effects. The limitations of d-penicillamine monotherapy prompted us to search for more effective treatment strategies that could decrease the duration of d-penicillamine therapy. The present study was designed to evaluate the therapeutic potential of d-penicillamine in combination with another hepatoprotective drug, andrographolide in treatment of copper toxicosis in rats. d-penicillamine treatment led to the excretion of copper through urine. Addition of andrographolide to d-penicillamine regime appeared to increase protection of liver by increasing the biliary excretion of copper and reduction in cholestatic injury. The early removal of the causative agent copper during combination treatment was the most effective therapeutic intervention that contributed to the early rectification of fibrosis in liver. Combination treatment reduced Kupffer cells accumulation and TNFα production in liver of copper exposed rats. In particular, andrographolide mediated the anti-inflammatory effect by inhibiting the cytokine production. However, another possible mechanism of cytoprotection of andrographolide was decreasing mitochondrial production of superoxide anions that resulted in better restoration of mitochondrial dysfunction during combination therapy than monotherapy. Furthermore, ROS inhibition by combination regimen resulted in significant decline in activation of caspase cascade. Inhibition of caspases attenuated apoptosis of hepatocytes, induced by chronic copper exposure. In summary, this study suggested that added benefit of combination treatment over use of either agent alone in alleviating the hepatotoxicity and fibrosis associated with copper toxicosis.     

Targeting maladaptive glutathione responses in lung disease

The lung is unique being exposed directly to the atmospheric environment containing xenobiotics, pathogens, and other agents which are continuously inhaled on a daily basis. Additionally, the lung is exposed to higher ambient oxygen levels which can promote the formation of a complex number of reactive oxygen and nitrogen species. Due to this constant barrage of potential damaging agents, the lung has developed a high degree of plasticity in dealing with ever changing conditions. In the present commentary, we will focus on glutathione (GSH) as a key antioxidant in the lung airways and discuss mechanisms by which the lung uses GSH to adapt to its rapidly changing environment. We will then examine the evidence on how defective and inadequate adaptive responses can lead to lung injury, inflammation and disease. Lastly, we will examine some of the recent attempts to alter lung GSH levels with therapies in a number of human lung diseases and discuss some of the limitations of such approaches.     

Decreased small dense LDL levels in Gilbert's syndrome

Objective

To investigate the role of small dense low density lipoprotein cholesterol (sd-LDL-C) in the mechanism of decreased incidence of cardiovascular disease in Gilbert's syndrome (GS).

Design and methods

sd-LDL-C, ox-LDL, and high sensitive C reactive protein (hs-CRP) levels were investigated in subjects with GS (n = 42) and compared to healthy controls (n = 52).

Results

Age, gender and body mass index (BMI) distributions were similar between the two groups. sd-LDL-C, ox-LDL and hs-CRP levels were lower in GS than the healthy controls (p < 0.001, p < 0.001 and p = 0.001, respectively). Unconjugated bilirubin was negatively correlated with sd-LDL-C, ox-LDL and hs-CRP (r = −0.594, p < 0.001; r = −0.249, p = 0.016 and r = − 0.373, p < 0.001 respectively). In addition, sd-LDL-C was positively correlated with ox-LDL (r = 0.307, p = 0.003).

Conclusions

The findings of this preliminary study suggest that reduced sd-LDL-C, ox-LDL and hs-CRP levels may have a role in preventing atherosclerosis in subjects with GS.     

Once Daily Calcineurin Inhibitor Monotherapy in Pediatric Liver Transplantation

This report describes a group of pediatric liver transplant recipients who have undergone once daily calcineurin inhibitor (CNI) monotherapy at Children's Memorial Hospital, Chicago, between January 1, 2001 and November 30, 2008. We defined success as normal liver enzymes at 1 year after dose change, with normal enzymes throughout all follow‐up. Patients who did not meet the set criteria or had lost an organ to chronic rejection were not considered for this therapeutic strategy. There were 147 patients in our organ transplant tracking record (OTTR) who were ≥ 5 years post liver transplant. Of these, 56 underwent reduced dose, once daily CNI monotherapy. Patients who met the set criteria were placed on once daily calcineurin inhibitor at half their previous dose. Fifty patients successfully achieved this dose change, while six patients failed at a mean of 3.7 ± 3.2 months following the dosing change. The mean interval from transplant was significantly longer in those patients who were successful compared to those who failed dose change (p < 0.05). Importantly, there have been no graft losses. Reduced dose, once daily CNI monotherapy is safe in carefully selected recipients, with a longer interval post liver transplantation increasing the likelihood of success.     

Flaxseed lignan lowers blood cholesterol and decreases liver disease risk factors in moderately hypercholesterolemic men

The effects of flaxseed lignan (secoisolariciresinol diglucoside [SDG]) intake on hypercholesterolemia and liver disease risk factors in moderately hypercholesterolemic men were investigated. In a previous study, we reported that SDG attenuates high-fat, diet-induced hypercholesterolemia in mice. Here, we report a double-blinded, randomized, and placebo-controlled study in moderately hypercholesterolemic men in which we investigated the hypothesis that oral administration of SDG (20 or 100 mg) would decrease the level of blood cholesterol and liver disease risk factors induced by hypercholesterolemia in humans. Thirty men with total cholesterol levels of 4.65 to 6.21 mmol/L (180-240 mg/dL) were randomly assigned to 3 groups; 2 groups received flaxseed lignan capsules (SDG, 20 or 100 mg/d) and the other received placebo capsules for 12 weeks. We found that, compared to the subjects who received placebo, those who received 100 mg of SDG exhibited a significant reduction in the ratio of low-density lipoprotein/high-density lipoprotein cholesterol at baseline (P < .05) and at week 12 (P < .05). In addition, in SDG-treated subjects, we also observed a significant percentage decrease in the levels of glutamic pyruvic transaminase and γ–glutamyl transpeptidase relative to the levels at baseline (P < .01) and a significant percentage decrease in the level of γ–glutamyl transpeptidase relative to the placebo-treated group (P < .05). These results suggest that daily administration of 100 mg SDG can be effective at reducing blood level of cholesterol and hepatic diseases risk in moderately hypercholesterolemic men.     

Serum Carbohydrate Antigen 19-9 as an Indicator of LiverMetastasis in Colorectal Carcinoma Cases

Purpose: The liver is the organ to which colorectal carcinomas (CRCs) most commonly metastasize, andsurgical resection has been established as the most effective and potentially curative treatment for CRC withliver metastasis (LM). Therefore, surveillance of LM is vital for improvement of prognosis of CRC patients. Inthis study, we aimed to explore the potential value of carbohydrate antigen 19-9 (CA 19-9), carcinoembryonicantigen (CEA), and marker enzymes in indicating LM with CRC. Methods: Three groups of eligible patientswith metastatic cancers were retrospectively included: CRC patients with LM (CRC-LM) or without LM (CRCNLM),and non-CRC patients with LM (NCRC-LM). All metastatic lesions were identified by CT or MRI. Dataon characteristics of the patients, the primary site, the locations of metastasis, CA 19-9, CEA, and biochemicalparameters were collected for analysis. Results: A total of 493 patients were retrospectively included. Morealcohol consumption was found in CRC-LM than CRC-NLM. Some biochemical enzymes were found to besignificantly higher in groups with LM than without (CRC-LM or NCRC-LM v.s CRC-NLM). Both CEA andCA 19-9 were much higher in CRC-LM than CRC-NLM or NCRC-LM. For CRC patients, CA 19-9, γ-glutamyltranspeptidase, CEA and alcohol consumption were identified as independent factors associated with LM.Conclusion: Our analysis suggested the CA 19-9 might be a potential valuable indicator for LM of CRC in theclinic.     

PNPLA3 polymorphism influences the association between high-normal TSH level and NASH in euthyroid adults with biopsy-proven NAFLD

AimWe aimed to evaluate the association between serum thyroid stimulating hormone (TSH) levels, within the reference range, and the histological severity of nonalcoholic fatty liver disease (NAFLD), and whether this association was modulated by the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism.Materials and methodsWe enrolled 327 euthyroid individuals with biopsy-proven NAFLD, who were subdivided into two groups, i.e., a ‘strict-normal’ TSH group (TSH level 0.4 to 2.5 mIU/L; n = 283) and a ‘high-normal’ TSH group (TSH level 2.5 to 5.3 mIU/L with normal thyroid hormones; n = 44). Logistic regression analyses were performed to assess the association between TSH status and presence of nonalcoholic steatohepatitis (NASH) after stratifying subjects by PNPLA3 genotypes.ResultsCompared to strict-normal TSH group, patients with high-normal TSH levels were younger and had a greater prevalence of NASH and higher histologic NAFLD activity score. After stratifying by PNPLA3 genotypes, the significant association between high-normal TSH levels and presence of NASH was restricted only to carriers of the PNPLA3 G risk allele and remained significant even after adjustment for potential confounding factors (adjusted-odds ratio: 3.279; 95% CI: 1.298–8.284; P = 0.012).ConclusionIn euthyroid individuals with biopsy-proven NAFLD, we found a significant association between high-normal TSH levels and NASH. After stratifying by PNPLA3 rs738409 genotypes, this association was observed only among carriers of the PNPLA3 G risk allele.