Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

Clinical Assistant Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, CB #7360, Kerr Hall Rm 3310, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
The Journal of Clinical Pharmacology (Impact Factor: 2.48). 10/2009; 50(4):434-49. DOI: 10.1177/0091270009347475
Source: PubMed


Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

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    • "They ranged from 0.3 to 2.5 nmol/g tissue in the liver, and from 20 to 141 nmol/g tissue in colorectal tissue. In addition, enterohepatic cycling was observed in healthy volunteers [23] and in patients [45], particular in patients with NAFLD [48], confirming the data observed in rats. "
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    ABSTRACT: The increasing prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) worldwide is becoming a challenge for the modern global care system. The lipotoxic process is characterized by an oxidative stress followed by a burst of the inflammatory response, prompting the wound healing process (fibrosis), which can ultimately lead to the development of cirrhosis and the subsequent complications. There is no consensus concerning an effective pharmacological treatment. Therefore, there is a need for effective therapeutic compounds. Silibinin the major active compound of Milk Thistle may be a potential candidate mainly due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. In spite of the large number of data obtained in experimental models, the translation of the evidence in clinical setting is far to be conclusive. The aim of this paper is to critically review the aspects of the use of the different formulations of Silibinin in several experimental and clinical settings and to provide hints on the needed future studies.
    Current Medicinal Chemistry 07/2015; 22(25). DOI:10.2174/0929867322666150729114235 · 3.85 Impact Factor
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    • "In view of suggestive in vitro evidence, a phased-study approach was developed by the SyNCH Study Group (Figure 1) to study the potential role of silymarin in research participants with chronic hepatitis C who were previously refractory to conventional therapy. Since preliminary dosing and pharmacokinetic data on the product were not available, a Phase I dose-ranging study in research participants with chronic HCV was performed initially by the study team [22]. The research participants were randomized to one of four silymarin doses covering a fivefold range (140, 280, 560 and 700 mg, thrice daily), to assess safety and dose–exposure relationships in HCV patients who were previously treatment nonresponders. "
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    ABSTRACT: Background Chronic hepatitis C is associated with significant morbidity and mortality as a consequence of progression to cirrhosis, hepatocellular carcinoma, and liver failure. Current treatment for chronic hepatitis C with pegylated interferon (IFN) and ribavirin is associated with suboptimal responses and numerous adverse effects. A number of botanical products have been used to treat hepatic disorders. Silymarin, extracted from the milk thistle plant, Silybum marianum (L) Gaertn. (Asteraceae), has been most widely used for various liver disorders, including chronic hepatitis C, B, and alcoholic liver disease. However, the safety and efficacy of silymarin have not been studied systematically in chronic hepatitis C.
    Clinical Trials 11/2011; 9(1):102-12. DOI:10.1177/1740774511427064 · 1.93 Impact Factor
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    • "Alterations in the expression and function of hepatobiliary transporters may be a more plausible explanation for the decrease in flavonolignan conjugates and the higher plasma concentrations of parent flavonolignans observed in the NAFLD cohorts. Evidence for extensive enterohepatic cycling of silymarin and their conjugates has been observed at high doses of silymarin (Schrieber et al., 2008; Hawke et al., 2010). Enterohepatic cycling is regulated by hepatobiliary transporters involved in the active uptake of anionic and cationic compounds from the blood such as the organic anion-transporting polypeptides, OATP1B1 and OATP2B1, located on the basolateral membrane of the hepatocyte (Chandra and Brouwer, 2004). "
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    ABSTRACT: Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single- and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC(0-8 h)) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC(0-8 h) was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC(0-8 h) (p < 0.05) and 42% lower C(max) (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.
    Drug metabolism and disposition: the biological fate of chemicals 08/2011; 39(12):2182-90. DOI:10.1124/dmd.111.040212 · 3.25 Impact Factor
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