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Introduction

  1. Pharmacology. Extracts of the milk thistle plant (Silybum marianum) have been used since ancient times to treat a variety of hepatic and biliary disorders, including cholestasis, jaundice, cirrhosis, acute and chronic hepatitis, and primary malignancies, and to protect the liver against toxin-induced injury. The extract of the ripe seeds and leaves contains 70-80% silymarin, a flavanolignan mixture of which silibinin is the most biologically active constituent. The hypothesized mechanism of action is twofold: alteration of hepatocyte cell membrane permeability, preventing toxin penetration; and increased ribosomal protein synthesis, promoting hepatocyte regeneration.Although the efficacy of silibinin has not been established in controlled studies in humans, it has been associated with reduced liver damage when administered intravenously in the treatment of amatoxin mushroom poisoning. Competitive inhibition of amatoxin entry via the membrane transport system for bile salts has been demonstrated. Silibinin also appears to inhibit tumor necrosis factor (TNF) release in the injured liver, thus slowing the process of amatoxin-induced apoptosis.
  2. Indications
    1. Intravenous silibinin (Legalon-SIL) is approved across Europe for the prevention and treatment of fulminant hepatic failure following ingestion of amatoxin-containing mushrooms (Introduction). Intravenous Legalon-SIL can be obtained in the United States only through emergency approval by the Food and Drug Administration (FDA, see VI.A. below).
    2. Although this indication is unproven, silibinin may be effective as adjuvant therapy in cases of acute hepatic injury caused by acetaminophen toxicity and potentially other chemical- and drug-induced liver diseases.
  3. Contraindications. None reported.
  4. Adverse effects are few and generally mild.
    1. Nausea, diarrhea, abdominal fullness or pain, flatulence, and anorexia may occur in users of oral preparations.
    2. Mild warmth and a flushing sensation are commonly reported during intravenous infusion.
    3. Milk thistle is a member of the Asteraceae (daisy) family and can cause an allergic reaction in ragweed-sensitive individuals, including rash, urticaria, pruritus, and anaphylaxis.
    4. Use in pregnancy. FDA Category B. Insufficient reliable information is available (Introduction).
  5. Drug or laboratory interactions. Although milk thistle has been shown to induce slight cytochrome P-450 enzyme inhibition in vitro, significant drug interactions with milk thistle extract have not been demonstrated in humans.
  6. Dosage and method of administration
    1. Parenteral. Dosing for amatoxin mushroom poisoning is 20-50 mg/kg/d by continuous intravenous infusion or in four divided doses administered over 2 hours each. Intravenous silibinin (Legalon-SIL) can be obtained in the US by application to the FDA for emergency use/expanded access:
      1. Step 1: alert the drug supplier by e-mail that the drug may be needed:
      2. Step 2: call the FDA to obtain an individual patient Expanded Access IND:
        1. During business hours: 1-301-796-2120.
        2. After hours/weekends: 1-866-300-4374.
      3. General information on obtaining an Expanded Access IND can be found at: https://www.fda.gov/news-events/expanded-access/expanded-access-how-submit-request-forms#PhysicianEmergency-sbs
    2. Oral. In the United States, milk thistle extracts are available as over-the-counter dietary supplements. Oral formulations include Legalon (standardized to contain 70% silibinin) and Silipide (silibinin complexed with phosphatidylcholine, which has a higher oral bioavailability). Because silymarin is poorly water-soluble, milk thistle tea is not considered an effective preparation. Oral doses used in published studies have ranged from 280 to 800 mg/d of standardized silymarin. A typical dose used for chronic hepatitis is 420 mg/d in two or three oral doses.