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SILYMARIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Silybum marianum, from the genus silybum, is a stout thistle and a member of the daisy family (Asteraceae, Compositae). Silymarin, a mixture of three isomeric flavonolignans (silibinin (silybin), silicristin (silychristin), and silidianin), is isolated from milk thistle (silybum marianum) seeds.

Specific Substances

    A) SILYBUM MARIANUM
    1) Bull Thistle
    2) Cardo blanco
    3) Cardo de blanco
    4) Cardui mariae frutus
    5) Carduus marianum L.
    6) Carduus marianus L.
    7) Chardon-Marie
    8) Frauendistelfruechte
    9) Fructus Silybi mariae
    10) Fruit de chardon Marie
    11) Holy Thistle
    12) Isosilibinin
    13) Kanger
    14) Kocakavkas
    15) Kuub
    16) Lady's Thistle
    17) Marian Thistle
    18) Mariana mariana
    19) Mariendistel
    20) Mariendistelfruechte
    21) Marienkoerner
    22) Mary Thistle
    23) Mild Thistle
    24) Silibinin (Silybin, Silibide)
    25) Silicristin (Silychristin)
    26) Silidianin
    27) Silymarin
    28) St. Mary's Thistle
    29) Variegated Thistle
    30) MILK THISTLE
    31) SILIBININ
    32) SILIBININE
    33) SILYBIN
    34) CAS 22888-70-6
    1.2.1) MOLECULAR FORMULA
    1) Silymarin: C(25)H(22)O(10)

Available Forms Sources

    A) FORMS
    1) PARENTERAL
    a) Silibinin is not available as a licensed drug in the US. It is widely available, under a variety of trade names, in Europe and South America.
    b) Silibinin (silybin) ampules for intravenous use are available (Legalon(R)SIL (Madaus AG, Germany):
    1) CLINICAL TRIAL: An open-label, multicenter, clinical trial (start date: February 2010; anticipated end date December, 2015), sponsored by Madaus Inc, (a division of Madaus GmbH, Cologne, Germany), is evaluating the safety and efficacy of intravenous silibinin (Legalon(R) SIL) for treating patients with amatoxin mushroom poisoning diagnosed by history, GI symptoms, elevated liver enzymes, and/or diagnostic assay. Patients will be treated with 5 mg/kg loading dose of silibinin followed by 20 mg/kg/day via continuous infusion. Treatment will be discontinued when coagulopathy has resolved, and when liver enzyme concentrations have significantly improved. Patients will be monitored for 7 to 14 days after the end of silibinin therapy with follow up lab studies. For more information on this clinical trial, check the following website: http://clinicaltrials.gov/ct2/show/NCT00915681 (Madaus Inc., 2009).
    2) To obtain silibinin, a 24-hour hotline is available for physicians: 866-520-4412 (Madaus Inc., 2009).
    2) ORAL
    a) In the US, milk thistle extracts, tablets, capsules or tincture containing 70% to 80% silymarin, are available as commercial preparations (Thisilyn (Nature's Way)) (Javed et al, 2011; Anon, 1997).
    1) Most clinical trials have used daily oral dosages of 420 to 480 mg silymarin, divided into 2 or 3 doses daily (Rainone, 2005).
    3) HERBAL TEA
    a) TEA: Silymarin is poorly soluble in water; thus it is generally less effective when water is used for extraction and administrations. A tea of Milk thistle would likely be less effective (Grauds, 1996).
    B) USES
    1) ORAL: Milk thistle (silymarin) has been used as a hepatoprotectant and as a supportive treatment of toxic liver damage by chemicals. In addition, it has been used to treat Amanita phalloides mushroom poisoning, jaundice, chronic inflammatory liver diseases, hepatic cirrhosis, hepatitis and fatty infiltration by alcohol and industrial chemical, loss of appetite, dyspeptic and gallbladder complaints, hangover, diseases of the spleen, prostate cancer, pleurisy, malaria, depression, uterine complaints, stimulating breast milk flow, and stimulating menstrual flow (Arteel et al, 2003; Flora et al, 1998; Anon, 1997; Leng-Peschlow, 1996). Milk thistle may have a role as a renoprotective agent against such therapy as cisplatin and aminoglycosides that can induce nephrotoxicity (Dashti-Khavidaki et al, 2012).
    2) PARENTERAL: Milk thistle (Silymarin) has been used as an antidote for Amanita phalloides mushroom poisoning (Madaus Inc., 2009; Hruby et al, 1983).
    a) Actual absorption of silymarin from the gastrointestinal tract is thought to be about 23% to 47%. Silymarin is best administered parenterally for maximum absorption (Anon, 1997; Tyler , 1994).
    b) In a study of 60 patients with severe Amanita mushroom poisoning who were given 20 mg/kg of silybin (syn. silibinin) IV, no patients died (Vogel, 1981). Death rates for this type of mushroom poisoning vary widely but may reach up to 40% or 50%.
    c) Hruby et al reported on a total of 18 cases of poisoning by Amanita phalloides that were treated by combined chemotherapy. After attempted primary elimination, all patients received silibinin (16 intravenously, 2 orally). All patients survived except one, who received a massive dose of toxin with suicidal intent. Using severe liver damage as a marker, silibinin given within 48 hours of mushroom ingestion appeared to be an effective prophylactic measure. The earlier the silibinin was given, the more benign the subsequent clinical course of mushroom poisoning. A dose of 20 to 50 mg/kg/day, given within the first 48 hours, may have helped prevent severe liver damage (Hruby et al, 1983; Hruby et al, 1983a).
    d) Silymarin (syn. silibinin) and high-dose penicillin G were used to treat a 7-year-old girl with severe Amanita phalloides poisoning (prothrombin-time less than 10% and hepatic coma). The child responded favorably to the treatment (Rambousek et al, 1993).
    3) FOOD USES: In Europe, the de-spined leaves have been used in fresh salads and as a spinach substitute. The pealed and soaked young stalks have been eaten like asparagus. In addition, the flower-heads were eaten like those of the artichoke. Milk thistle seeds (fruit) were used as a coffee substitute (Anon, 1997; Awang, 1993).
    4) AMANITA PHALLOIDES MUSHROOM POISONING: The hepatoprotective and antagonist effects of silibinin against amatoxins have been confirmed in experimental models. Silibinin is thought to inhibit the penetration of the amatoxins into liver cells (Jahn et al, 1980; Faulstich et al, 1980a; Floersheim, 1987). The efficacy of silibinin is difficult to evaluate because it is often combined with other therapies, such as penicillin, ascorbic acid, and hemodialysis(Lheureux et al, 1992), however the results appear to be positive in the treatment of mushroom poisoning.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: ANTIDOTE: Silybum marianum (also known as milk thistle) has been used intravenously (Legalon(R) SIL) as an antidote for Amanita phalloides mushroom poisoning. It is available in the US based on compassionate use under an FDA sanctioned Open Treatment IND. ORAL THERAPY: As an herbal supplement it is widely used for its hepatoprotective effect and has been used in the treatment of toxic liver damage (ie, commonly prescribed for cirrhosis and viral hepatitis). FOOD: The de-spined leaves, the young stalks of the plant and the flower-heads have all been used as a food source.
    B) PHARMACOLOGY: Silybum marainum is part of the family Asteraceae. Silymarin is a lipohilic extract and the active part of the plant. It has been suggested that it acts as an antiinflammatory. Extracts of the plant usually contain 70% to 80% silymarin and contain 3 isomers of flavonolignans (ie, silybin, silydianin and silychristin) and 2 flavonoids (taxifolin and quercetin) and the remaining portion (20% to 30%) is made up of polyphenolic compounds.
    C) EPIDEMIOLOGY: Exposure is not common. Serious toxicity has not been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Silymarin is usually well tolerated.
    2) ORAL: Nausea, diarrhea, dyspepsia, flatulence, abdominal bloating, fullness or pain, and anorexia have been reported. Urticaria and allergic reactions to silymarin may occur. INFREQUENT: Pruritus, headache, exanthema, malaise, asthenia and vertigo may develop. Intermittent episodes of sweating, nausea and vomiting, colicky abdominal pain, diarrhea, weakness, and collapse occurred in a woman following daily administration of milk thistle capsules for 2 months.
    3) INTRAVENOUS: No serious adverse reactions have been reported with intravenous therapy. Flushing has been reported during infusion; effects have been mild.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: No overdose data available.
    0.2.20) REPRODUCTIVE
    A) Silymarin has been used to treat mothers with intrahepatic cholestasis of pregnancy for as long as three weeks.

Laboratory Monitoring

    A) Therapeutic or toxic blood levels have not been established.
    B) Systemic toxicity, requiring monitoring of liver, kidney or hematologic factors, has NOT been reported.
    C) Monitor fluid and electrolytes in patients with prolonged vomiting or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Silymarin overdose information is limited. Treatment is symptomatic and supportive. In patients with significant gastrointestinal symptoms (ie, nausea, vomiting or diarrhea); replace fluids as necessary. IV fluids may be indicated in patients with significant dehydration.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Allergic reactions (ie, rash to possible anaphylaxis) are rarely reported with milk thistle exposure. For MILD to MODERATE symptoms administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    C) DECONTAMINATION
    1) PREHOSPITAL: Acute toxicity has not been reported after silymarin overdose. Gastrointestinal decontamination is generally not indicated. Activated charcoal should only be considered after very large ingestions or exposures where more toxic coingestants are involved.
    2) HOSPITAL: Gastrointestinal decontamination is generally not indicated. Activated charcoal should only be considered after very large ingestions or exposures where more toxic coingestants are involved.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary unless the patient develops severe anaphylaxis requiring aggressive airway management.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) There is no information regarding the effectiveness of enhanced elimination (ie, hemodialysis or hemoperfusion) for the removal of silymarin from plasma.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children with unintentional ingestions (1 or 2 tablets) can be observed at home with a responsible adult. Asymptomatic adults with inadvertent ingestion of 1 to 2 extra doses can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve.
    3) ADMISSION CRITERIA: Patients demonstrating severe fluid and electrolyte imbalance or severe hypersensitivity reaction should be admitted.
    4) CONSULT CRITERIA: Consult with a medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established.
    B) SUGGESTED THERAPEUTIC DOSE: ORAL: Most clinical trials have used oral daily dosages of 420 to 480 mg silymarin, divided into 2 or 3 doses daily. PARENTERAL: AMATOXIN TOXICITY: Loading dose of 5 mg/kg IV followed by and infusion of 20 mg/kg/day.

Clinical Effects

Summary Of Exposure

    A) USES: ANTIDOTE: Silybum marianum (also known as milk thistle) has been used intravenously (Legalon(R) SIL) as an antidote for Amanita phalloides mushroom poisoning. It is available in the US based on compassionate use under an FDA sanctioned Open Treatment IND. ORAL THERAPY: As an herbal supplement it is widely used for its hepatoprotective effect and has been used in the treatment of toxic liver damage (ie, commonly prescribed for cirrhosis and viral hepatitis). FOOD: The de-spined leaves, the young stalks of the plant and the flower-heads have all been used as a food source.
    B) PHARMACOLOGY: Silybum marainum is part of the family Asteraceae. Silymarin is a lipohilic extract and the active part of the plant. It has been suggested that it acts as an antiinflammatory. Extracts of the plant usually contain 70% to 80% silymarin and contain 3 isomers of flavonolignans (ie, silybin, silydianin and silychristin) and 2 flavonoids (taxifolin and quercetin) and the remaining portion (20% to 30%) is made up of polyphenolic compounds.
    C) EPIDEMIOLOGY: Exposure is not common. Serious toxicity has not been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Silymarin is usually well tolerated.
    2) ORAL: Nausea, diarrhea, dyspepsia, flatulence, abdominal bloating, fullness or pain, and anorexia have been reported. Urticaria and allergic reactions to silymarin may occur. INFREQUENT: Pruritus, headache, exanthema, malaise, asthenia and vertigo may develop. Intermittent episodes of sweating, nausea and vomiting, colicky abdominal pain, diarrhea, weakness, and collapse occurred in a woman following daily administration of milk thistle capsules for 2 months.
    3) INTRAVENOUS: No serious adverse reactions have been reported with intravenous therapy. Flushing has been reported during infusion; effects have been mild.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: No overdose data available.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Two-month history of intermittent episodes of sweating, nausea and vomiting, colicky abdominal pain, diarrhea, weakness, and collapse occurred in a 57-year-old woman following daily administration of milk thistle capsules for 2 months. The duration of each episode was approximately 24 hours. The patient recovered spontaneously following discontinuation of the capsules; however, rechallenge with one milk thistle capsule resulted in a recurrence of symptoms (Anon, 1999).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL COMPLICATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Intermittent episodes of sweating, nausea and vomiting, colicky abdominal pain, diarrhea, weakness, and collapse occurred in a 57-year-old woman following daily administration of milk thistle capsules for 2 months. The duration of each episode was approximately 24 hours. The patient recovered spontaneously following discontinuation of the capsules; however, rechallenge with one milk thistle capsule resulted in a recurrence of symptoms (Anon, 1999).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DIARRHEA
    a) Silibinin and silymarin, at doses between 100 and 200 mg/kg intraperitoneally, reduced the intestinal transit time from 23% to 41% in mice. This effect was antagonized between 87% to 96% by yohimbine and between 87% and 91% by phentolamine. No change in the decreased transit time was seen when prazosin, propranolol, atropine, hexamethonium, mepyraine, cyproheptadine, and naloxone were administered (Di Carlo et al, 1993).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) URTICARIA
    1) WITH POISONING/EXPOSURE
    a) There has been one report of possible urticaria (Mironets et al, 1990).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH POISONING/EXPOSURE
    a) Allergic reactions to silymarin may occur (Anon, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Silymarin has been used to treat mothers with intrahepatic cholestasis of pregnancy for as long as three weeks.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF EFFECT
    1) Silymarin has been used to treat mothers with intrahepatic cholestasis of pregnancy for as long as three weeks (Ladas & Kelly, 2003; Reyes & Simon, 1993).
    2) No studies were found describing the effects of silymarin used in early pregnancy (during organogenesis).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS65666-07-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS22888-70-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Therapeutic or toxic blood levels have not been established.
    B) Systemic toxicity, requiring monitoring of liver, kidney or hematologic factors, has NOT been reported.
    C) Monitor fluid and electrolytes in patients with prolonged vomiting or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients demonstrating severe fluid and electrolyte imbalance or severe hypersensitivity reaction should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children with unintentional ingestions (1 or 2 tablets) can be observed at home with a responsible adult. Asymptomatic adults with inadvertent ingestion of 1 to 2 extra doses can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult with a medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve.
    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients demonstrating severe fluid and electrolyte imbalance or severe hypersensitivity reaction should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Asymptomatic children with unintentional ingestions (1 or 2 tablets) can be observed at home with a responsible adult. Asymptomatic adults with inadvertent ingestion of 1 to 2 extra doses can be monitored at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult with a medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve.

Monitoring

    A) Therapeutic or toxic blood levels have not been established.
    B) Systemic toxicity, requiring monitoring of liver, kidney or hematologic factors, has NOT been reported.
    C) Monitor fluid and electrolytes in patients with prolonged vomiting or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Acute toxicity has not been reported after silymarin overdose. Gastrointestinal decontamination is generally not indicated. Activated charcoal should only be considered after very large ingestions or exposures where more toxic coingestants are involved.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Acute toxicity has not been reported after silymarin overdose. Gastrointestinal decontamination is generally not indicated. Activated charcoal should only be considered after very large ingestions or exposures where more toxic coingestants are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no antidote for silymarin overdose; treatment is symptomatic and supportive.
    2) In patients with significant gastrointestinal symptoms (ie, nausea, vomiting or diarrhea); replace fluids as necessary. IV fluids may be indicated in patients with significant dehydration.
    3) Allergic reactions (ie, rash to possible anaphylaxis) are rarely reported with milk thistle exposure.
    B) MONITORING OF PATIENT
    1) Therapeutic or toxic blood levels have not been established.
    2) Systemic toxicity, requiring monitoring of liver, kidney or hematologic factors, has NOT been reported.
    3) Monitor fluid and electrolytes in patients with prolonged diarrhea and/or vomiting.
    C) HYPERSENSITIVITY REACTION
    1) Allergic reactions (ie, rash to possible anaphylaxis) are rarely reported with milk thistle exposure (Rainone, 2005).
    2) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    3) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    4) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    5) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    6) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    7) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    8) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    9) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    10) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    11) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    12) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    13) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) There is no information regarding the effectiveness of enhanced elimination (ie, hemodialysis or hemoperfusion) for the removal of silymarin from plasma.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established.
    B) SUGGESTED THERAPEUTIC DOSE: ORAL: Most clinical trials have used oral daily dosages of 420 to 480 mg silymarin, divided into 2 or 3 doses daily. PARENTERAL: AMATOXIN TOXICITY: Loading dose of 5 mg/kg IV followed by and infusion of 20 mg/kg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) SUMMARY
    1) Dosing of herbal preparations is highly dependent on a variety of factors, such as growing and harvesting conditions, plant parts and extraction methods used and the dosage form chosen by the manufacturer. Standardization to single constituent markers has proven unreliable. Since no official standards have been established to date to regulate the production of herbal medicines in the United States, dosage ranges must be employed as guidelines.
    2) The concentration of silymarin in silybum marianum varies by geographic location (Corti et al, 1990). Products are usually standardized to 70% to 80% (not milligrams) of silymarin, but with no governmental regulation, silymarin concentrations may vary considerably (Flora et al, 1998; Hobbs, 1997).
    B) ORAL
    1) Most clinical trials have used daily oral dosages of 420 to 480 mg silymarin, divided into 2 or 3 doses daily (Rainone, 2005).
    2) EXTRACT: Hepatoprotection: 420 mg/day of standardized to 70% to 80% silymarin, divided into 3 doses for 6 to 8 weeks, then a maintenance dose of 280 mg/day (Hobbs, 1997).
    C) PARENTERAL
    1) CYCLOPEPTIDE MUSHROOM POISONING
    a) The usual dose is 5 mg/kg loading dose of silibinin followed by 20 mg/kg/day via continuous infusion. It should be administered as soon as possible after ingestion of cyclopeptide mushroom poisoning as early therapy is associated with increased likelihood of survival (Mengs et al, 2012).
    b) Silibinin is NOT available as a licensed drug in the US; it has been available in Europe under the trade names Legalon (R) and Legalon(R) SIL. However, the antidote is available as part of a study protocol for use in the US. The drug is provided at no charge to treat patients with amatoxin poisoning; physicians can obtain the drug by contacting a 24 hour hotline number at 866-520 4412 (Madaus Inc., 2013).
    1) An open-label, multicenter, clinical trial (start date: February 2010; anticipated end date December, 2015), sponsored by Madaus Inc, (a division of Madaus GmbH, Cologne, Germany), is evaluating the safety and efficacy of intravenous silibinin (Legalon(R) SIL) for treating patients with amatoxin mushroom poisoning diagnosed by history, GI symptoms, elevated liver enzymes, and/or diagnostic assay. Patients will be treated with 5 mg/kg loading dose of silibinin followed by 20 mg/kg/day via continuous infusion. Treatment will be discontinued when coagulopathy has resolved, and when liver enzyme concentrations have significantly improved. Patients will be monitored for 7 to 14 days after the end of silibinin therapy with follow up lab studies. For more information on this clinical trial, check the following website: http://clinicaltrials.gov/ct2/show/NCT00915681 (Madaus Inc., 2009).
    2) To obtain silibinin, a 24-hour hotline is available for physicians: 866-520-4412 (Madaus Inc., 2009).
    c) The hepatoprotective and antagonist effects of silibinin against amatoxins have been confirmed in experimental models. Silibinin is thought to inhibit the penetration of the amatoxins into liver cells (Jahn et al, 1980; Faulstich et al, 1980a; Floersheim, 1987).

Maximum Tolerated Exposure

    A) ORAL THERAPY
    1) Most clinical trials have used daily oral dosages of 420 to 480 mg silymarin, divided into 2 or 3 doses daily (Rainone, 2005).
    2) Silipide doses up to 360 mg (silybin equivalent) 3 times a day for 3 weeks have been given to normal volunteers without toxic effects (Marena & Lampertico, 1991).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Hepatoprotectant, 8 micrograms/milliliter (Conti et al, 1991).
    2) In an animal study, a 200-milligram/kilogram (as silybin) dose of silipide (the phosphatidylcholine complex of silymarin), produced a plasma concentration of about 8 to 74 micrograms/milliliter of unconjugated and total silybin . The test dose given corresponds to a therapeutic dose (Conti et al, 1991).
    3) AREA UNDER THE CURVE: Single doses of silymarin or silybin-phosphatidylcholine (IdB 1016), both equivalent to 360 milligrams of silybin, were given to 8 volunteers orally, producing an area under the curve between 257 ng/mL/h (silymarin dose) to 881 ng/mL/h (IdB 1016) (Barzaghi et al, 1990).
    4) In one study, single oral doses of IdB 1016 (equivalent to 360 mg silybin) and silymarin (equivalent to 336 mg silybin) were given to nine patients with liver cirrhosis, producing AUC values of 3,515 ng/mL/hour and 252 ng/mL/hour, respectively(Orlando et al, 1990).

Workplace Standards

    A) ACGIH TLV Values for CAS65666-07-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS22888-70-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS65666-07-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS22888-70-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS65666-07-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS22888-70-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS65666-07-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS22888-70-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) Approximately 1000 mg/kg (Desplaces et al, 1975)
    B) LD50- (INTRAPERITONEAL)RAT:
    1) Approximately 900 mg/kg (Desplaces et al, 1975)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Silymarin has been shown to have hepatoprotective actions against chemical, infectious, and environmental toxins. It has antioxidant, antihepatitis, and anticirrhotic effects (Vavreckova et al, 1997; Schuppan et al, 1995; Hikino et al, 1984).
    B) AMANITA PHALLOIDES MUSHROOM POISONING: The hepatoprotective and antagonist effects of silibinin against amatoxins have been confirmed in experimental models. Silibinin is thought to inhibit the penetration of the amatoxins into liver cells (Ladas & Kelly, 2003; Jahn et al, 1980; Faulstich et al, 1980a; Floersheim, 1987).
    C) Silymarin inhibits lipid peroxidation of hepatocyte, microsomal, and erythrocyte membranes as well as increasing hepatocyte protein synthesis via stimulation of ribosomal RNA (Flora et al, 1998).
    D) Silymarin decreases the activity of several tumor promoters (Flora et al, 1998).
    E) In one study, it was found that milk thistle is immunostimulatory in vitro; it increased lymphocyte proliferation, increased interferon gamma, interleukin (IL)-4 and IL-10 cytokines (Wilasrusmee et al, 2002).

Physicochemical

Molecular Weight

    1) SILICRISTIN 482.4
    2) SILIBININ 482.4
    3) SILIDIANIN 482.4

References

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