New Articles/Silmarin,IR

2009 Dec 3. [Epub ahead of print]
Silibinin and Related Compounds are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase.

Ahmed-Belkacem A, Ahnou N, Barbotte L, Wychowski C, Pallier C, Brillet R, Pohl RT, Pawlotsky JM.

Research Team "Pathophysiology and Therapy of Chronic Viral Hepatitis", INSERM U955, Créteil, France.

BACKGROUND & AIMS:: Silymarin is a mixture of flavonolignans extracted from the milk thistle. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Intravenous infusion of silibinin induces dose-dependent reduction of hepatitis C virus (HCV) RNA levels. The aim of this study was to test the principal isomers contained in silymarin preparations for their ability to inhibit HCV enzymatic functions and replication in different models. METHODS:: The inhibitory activity of silymarin components was tested in HCV RNA-dependent RNA polymerase and NS3/4A protease enzyme assays. Their ability to inhibit replication of an HCV genotype 1b replicon model and the JFH1 infectious HCV model in cell culture was also studied. RESULTS:: Silibinin A, silibinin B, their water-soluble dihydrogen succinate forms and Legalon SIL(R), a commercially available intravenous preparation of silibinin, inhibited HCV RNA-dependent RNA polymerase function, with inhibitory concentrations 50% of the order of 75-100 muM. Silibinin A and silibinin B also inhibited HCV genotype 1b replicon replication and HCV genotype 2a strain JFH1 replication in cell culture. None of these compounds inhibited HCV protease function. CONCLUSIONS:: Silibinin A and silibinin B, as well as Legalon SIL(R), inhibit HCV replicon and JFH1 replication in cell culture. This effect is at least partly explained by the ability of these compounds to inhibit HCV RNA-dependent RNA polymerase activity. Our results provide a basis for the optimization and subsequent development of members of the Flavonoid family as specific HCV antivirals.

2009 Dec 3.
Chronic Hepatitis C is Associated with Peripheral rather than Hepatic Insulin Resistance.
Milner KL, van der Poorten D, Trenell M, Jenkins AB, Xu A, Smythe G, Dore GJ, Zekry A, Weltman M, Fragomeli V, George J, Chisholm DJ.

Garvan Institute for Medical Research, University of New South Wales, Sydney, Australia.

BACKGROUND & AIMS:: Chronic Hepatitis C (CHC) is associated with insulin resistance (IR), liver steatosis (genotype 3) and increased diabetes risk. The site and mechanisms of IR are unclear. METHODS:: We compared cross-sectionally 29 non-obese, normoglycemic males with CHC (genotype 1 and 3) to 15 adiposity and age matched controls using a two step hyperinsulinemic-euglycemic clamp with [6,6-(2)H(2)] glucose to assess insulin sensitivity in liver and peripheral tissues and (1)H -magnetic resonance spectroscopy to evaluate liver and intramyocellular lipid (IMCL). Insulin secretion was assessed after intravenous glucose. RESULTS:: Insulin secretion was not impaired in CHC. Peripheral insulin sensitivity was 35% higher in controls versus CHC (P< .001) during high (264.3+/-25(SE) mU/L) dose insulin (P< .001); this was negatively associated with viral load (R(2) = .12, P= .05) and subcutaneous fat (R(2)= .41, P< .001). IR was similar in both genotypes despite three-fold increased hepatic fat in genotype 3 (P< .001). Hepatic glucose production (P= .25) and nonesterified free fatty acid (P = .84) suppression with insulin were not different between CHC and controls inferring no adipocyte IR, and suggesting IR is mainly in muscle. In CHC IMCL was non-significantly increased but levels of Glucagon (73.8+/-3.6 versus 52.8+/-3.1 ng/mL; P< .001), soluble Tumor Necrosis Factor Receptor 2 (3.1+/-0.1 versus 2.3+/-0.1 ng/mL; P< .001) and Lipocalin-2 (36.4+/-2.9 versus 19.6+/-1.6 ng/mL; P< .001) were elevated. CONCLUSIONS:: CHC represents a unique infective/inflammatory model of IR which is predominantly in muscle, correlates with subcutaneous, not visceral, adiposity and is independent of liver fat.

Mike

[orphanedhawk]

Thanks Mike!
When I was in Thailand and not ready to start interferon treatment, the doctor suggested silymarin. They sell it there in pill form imported from Germany.

[jusjames]

i vant get my head around the term ;
Peripheral rather than Hepatic Insulin Resistance.
i/r is surely neither since its pancreatic, some what confussed by this

[mikesimon]

Milk Thistle Treats Chemotherapy-Induced Hepatoxicity
Nancy Fowler Larson

December 14, 2009 — Hepatoxicity caused by chemotherapy can be successfully treated with milk thistle (MT), according to a study of children with acute lymphoblastic leukemia (ALL) published online December 14 in Cancer.

"Currently, there are no substitute chemotherapy agents that provide the same effectiveness against ALL yet preserve liver function. There are also no hepatoprotective medications that allow chemotherapy to continue to be administered while preserving liver function," write Kara M. Kelly, MD, from the pediatric oncology department at Columbia University Medical Center, New York City, and colleagues. "Thus, adjunctive agents that may enable optimal doses of chemotherapy to be administered without necessitating a decrease in the recommended doses of chemotherapy are of clinical significance and may further improve survival in children with ALL."

Earlier studies have shown that MT reduces liver damage caused by cirrhosis or ingested toxins. The goal of this MT evaluation was to determine whether the herb can safely and effectively remedy chemotherapy-induced liver inflammation — a common adverse effect that can necessitate reduction or suspension of the cancer treatment.

The randomized controlled, double-blind study consisted of 50 children with ALL who were in the maintenance phase of therapy and had a hepatic toxicity of grade 2 or greater on amino alanine transferase (ALT), aspartate amino transferase (AST), or total bilirubin (TB) levels.

For a period of 28 days, patients received either MT (5.1 mg/kg/day) or a placebo. Patient visits and reports and chart reviews were used to monitor the safety of MT. Liver inflammation was determined by blood level increases of AST and ALT.

On day 28, there were no noteworthy alterations in mean ALT, AST, or TB levels. However, the authors write, "at day 56, the MT group had a significantly lower AST (P = .05) and a trend toward a significantly lower ALT (P = .07)." Ingesting MT seemed to produce no negative effects, and the herb did not reduce the effectiveness of chemotherapy. Furthermore, patients taking MT were more likely to maintain their prescribed chemotherapy dosages.

"Although not significantly different, chemotherapy doses were reduced in 61% of the MT group compared with 72% of the placebo group. In vitro experiments revealed no antagonistic interactions between MT and vincristine or L-asparaginase in CCRF-CEM cells," the authors write.

The study authors noted that their research was made stronger by product quality analysis, stability testing, and a goal of quantifying plasma levels of silibinin. They also reported several limitations. These included the study's small sample size and an MT dose that may have been smaller than necessary. They also acknowledged that those taking MT had a rate of compliance that was appreciably lower than that of the placebo group. Overall, however, they hailed their findings as an important step toward using MT to treat hepatotoxicity in cancer patients.

"Despite our study's limitations, it provides preliminary evidence that MT may be a safe, effective, supportive-care agent," the authors write. "Future investigations are needed to determine the appropriate dose and duration and to identify populations that may gain the largest clinical benefit."

The American Institute for Cancer Research, the Tamarind Foundation, and the National Cancer Institute supported this study. The study authors have disclosed no relevant financial relationships.

Cancer. Published online December 14, 2009.

[mikesimon]

Conclusion

"Our study shows that even HCV patients with chronic hepatitis but not cirrhosis have an increased prevalence of gallstones. Compared with the controls, gallstone disease is present in HCV patients at a younger age and in association with central obesity and liver steatosis, and is not related to gallstone heredity, dyslipidaemia, diabetes mellitus or metabolic syndrome. Although we could not establish a temporal relationship, the association between HCV infection and gallstone disease is real and appears to be causally linked at least in predisposed individuals, namely obese and with liver steatosis."