Milk Thistle Plus 175 mg Standardized Extract With Artichoke by Martin Avenue Pharmacy

POSSIBLY EFFECTIVE

• Dyspepsia. Oral artichoke leaf extract may improve symptoms in patients with functional dyspepsia or dyspepsia associated with biliary disease. Details: Several clinical trials in patients with functional dyspepsia or dyspepsia associated with biliary disease show that taking artichoke leaf extract can reduce symptoms such as nausea, vomiting, flatulence, and abdominal pain. Improvement seems to occur after 2 to 8 weeks of treatment (2056,11429,12208). The validity of some of this evidence is limited by a small sample size (2056) or lack of a control group (11429). However, a higher-quality clinical trial in patients with mild dyspepsia shows that taking artichoke leaf extract 640 mg three times daily for 6 weeks improves overall symptom and quality of life scores. Specifically, patient ratings for flatulence, feelings of fullness, and early satiety were reduced when compared with placebo. Further, for every 12 patients treated with this extract over placebo, one additional patient reported markedly or completely improved symptoms (12208). Some studies have used a specific extract called ALE LI 220 (Hepar-SL forte, Serturner Arzneimittel GmbH) at doses ranging from 320-640 mg three times daily for up to 8 weeks (2056,12208). Another study has used a different artichoke leaf extract (Cynara SL, Lichtwer Pharma) at a dose of 320-640 mg daily for 2 months (11429). Some clinical research has also assessed artichoke extract in combination with ginger extract. Results show that taking 2 capsules of a specific product containing artichoke leaf extract 100 mg and ginger extract 20 mg (ProDigest, Indena) daily for 4 weeks markedly or completely improves symptoms such as nausea, fullness, pain, and bloating in about 1.5-fold more patients with functional dyspepsia when compared with placebo (91474).
• Hyperlipidemia. Most research shows that oral artichoke lowers cholesterol and triglyceride levels in patients with hyperlipidemia. However, frozen artichoke juice does not appear to have these effects. Details: Multiple meta-analyses and clinical studies in patients who are either healthy or have hyperlipidemia, nonalcoholic fatty liver disease, or pre-obesity show that taking artichoke leaf extract or concentrated artichoke juice capsules daily for 4-24 weeks reduces total cholesterol by 13-18 mg/dL, low-density lipoprotein (LDL) cholesterol by 15-17 mg/dL, and triglycerides by 9-18 mg/dL, but does not increase high-density lipoprotein (HDL) cholesterol, when compared with placebo (104132,108713,111560,111564). While the five studies including non-hyperlipidemic patients in one of these analyses reported mixed results, all four of the studies evaluating artichoke leaf extract in patients with hyperlipidemia showed significant reductions in total cholesterol and LDL cholesterol when compared with placebo (104132). Additionally, a dose-response analysis suggests that baseline cholesterol levels are a stronger predictor of benefit than dose and treatment duration (108713). The validity of these findings is limited due to the high heterogeneity of studies included in meta-analyses. Another clinical study in patients with mild hypercholesterolemia shows that taking artichoke extract 250 mg twice daily for 8 weeks decreases LDL cholesterol by about 11% and increases HDL cholesterol by about 10% when compared with placebo (91478). Other formulations have also been evaluated, including cynarin, a constituent of artichoke, and artichoke juice. Some older, small clinical studies suggest that taking cynarin 20 mg three times daily for 2-7 months reduces total cholesterol and triglyceride levels when compared to baseline in patients with hypercholesterolemia and/or hypertriglyceridemia (52222,52223,52236). However, cynarin does not appear to reduce cholesterol levels in patients with familial type II hyperlipoproteinemia (1424). In patients with hyperlipidemia, consuming frozen artichoke juice 20-30 mL daily for 6-12 weeks does not appear to reduce total or LDL cholesterol levels and may even increase triglyceride levels (52216,52234). Artichoke leaf extract has also been evaluated in combination with other ingredients. Clinical research shows that taking a product containing red yeast rice extract, artichoke leaf extract, and other ingredients (Limicol, Laboratoire Lescuyer) 3 or 6 tablets daily for 4-16 weeks decreases LDL cholesterol by 14% to 21% in patients with hyperlipidemia. However, the red yeast in this product contains monacolin K (lovastatin), which likely contributed to the cholesterol-lowering effect (89451,89452,89454). Another specific product (Vazguard; Indena SpA), containing artichoke leaf extract (Indena SpA) 100 mg and bergamot phytosome 600 mg, has also shown benefit in patients with mild hypercholesterolemia when taken twice daily for 2 months (108712). However, it is unclear if this effect is due to artichoke leaf, bergamot, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Biliary disorders. Although there has been interest in using oral artichoke for various biliary disorders, including for the treatment of cholestasis or prevention of gallstones, there is insufficient reliable information about the clinical effects of artichoke for these conditions.
• Diabetes. Several small clinical studies suggest that oral artichoke extract may slightly reduce fasting blood glucose, but may not improve glycated hemoglobin (HbA1c) or other measures of glycemic control, in patients with diabetes. Details: A meta-analysis of 9 small clinical trials shows that taking artichoke leaf extract for 8-12 weeks reduces fasting blood glucose by around 5 mg/dL, but does not improve HbA1c, insulin levels, or markers of insulin resistance, when compared with placebo (105768). The generalizability of these findings to patients with diabetes is limited; only 2 of the 9 studies specifically enrolled patients with diabetes. The other studies included patients who were overweight or with liver disease, hyperlipidemia, or metabolic syndrome. In contrast, a post-hoc analysis of clinical research in overweight adults at risk for developing diabetes shows that taking a specific artichoke leaf product (Altilix, Bionap S.r.l.) 50 mg daily for 6 months reduces HbA1c by around 0.9% and improves measures of insulin resistance and beta-cell function when compared with placebo (111564).
• Hangover. It is unclear if oral artichoke extract is beneficial for the prevention of hangover. Details: A small clinical study in healthy adults shows that taking artichoke extract 960 mg immediately before and after alcohol consumption does not prevent alcohol-induced hangover when compared with placebo (11774).
• Hepatitis C. It is unclear if oral artichoke is beneficial in patients with hepatitis C. Details: One small clinical study in patients with chronic hepatitis C shows that taking artichoke leaf extract 3200 mg daily for 12 weeks does not normalize liver enzyme levels or reduce viral load when compared to baseline. Although symptoms such as fatigue, abdominal discomfort, and joint problems appear to improve in the first 4 weeks, the improvement is not maintained over 12 weeks (91475). However, another small clinical study shows that drinking a tea infusion of wild artichoke three times daily for 3 months normalizes liver enzymes and serum virus levels in 12 of 15 patients with hepatitis C (97717). The validity of these findings is limited by the lack of a control group.
• Hypertension. Analyses of small clinical studies suggest that oral artichoke may slightly reduce blood pressure in patients with hypertension; however, individual study results are conflicting, and the improvements in blood pressure may not be clinically significant. Details: Evidence regarding an association between artichoke consumption and hypertension is conflicting (91477,104133,105767,111561). Two meta-analyses include many of the same studies yet reach contradictory conclusions. One meta-analysis of 8 small clinical trials shows that taking artichoke leaf extract, powder, or juice for 8-12 weeks does not reduce systolic blood pressure (SBP) or diastolic blood pressure (DBP). However, subgroup analysis in patients with documented hypertension shows that artichoke reduces SBP by around 3 mmHg and DBP by around 2 mmHg when compared with placebo (105767). In contrast, another meta-analysis of 7 small clinical trials shows that taking artichoke 50-2700 mg daily for 4-12 weeks reduces SBP by about 2 mmHg and DBP by about 1.5 mmHg. Subgroup analysis shows that the greatest reductions in SBP and DBP occur in doses of 500 mg daily or less, at durations longer than 8 weeks, and in patients under 50 years old (111561). Discrepancies between the results of the meta-analyses with overlapping studies may be due to the former meta-analysis including artichoke supplementation in combination with other ingredients, while the latter meta-analysis focused on artichoke supplementation alone.
• Irritable bowel syndrome (IBS). It is unclear if oral artichoke leaf extract is beneficial in patients with IBS. Details: Some observational research in patients with IBS has found that taking a specific artichoke leaf extract (Hepar-SL forte, Serturner Arzneimittel GmbH) 640 mg three times daily for 6 weeks is associated with reductions in abdominal pain, cramping, bloating, flatulence, and constipation when compared to baseline (2562). Also, a small clinical study in patients with IBS shows that taking a different specific artichoke leaf extract (Cynara SL, Lichtwer Pharma) 320-640 mg daily for 2 months reduces the incidence of IBS symptoms in patients with dyspepsia by about 26% when compared to baseline. Patients taking this extract also had improved quality of life (15204). The validity of these findings is limited by the lack of a control group.
• Metabolic syndrome. It is unclear if oral artichoke leaf extract is beneficial in patients with metabolic syndrome. Details: A small clinical trial in patients with metabolic syndrome shows that taking artichoke leaf extract 1800 mg daily for 12 weeks does not improve fasting blood glucose, insulin resistance, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or blood pressure when compared with placebo. However, taking artichoke extract does reduce triglycerides by around 27 mg/dL when compared with placebo (100935).
• Nausea and vomiting. Although there has been interest in using oral artichoke for nausea and vomiting, there is insufficient reliable information about the clinical effects of artichoke for this purpose.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral artichoke leaf extract is beneficial in patients with NAFLD. Details: Meta-analyses of 12 clinical studies in adults with a variety of metabolic disorders, including NAFLD, show that taking artichoke 50-2700 mg daily for 4-24 weeks reduces alanine aminotransferase (ALT) and aspartate aminotransferase (AST) when compared with placebo (111560,111563). These effects are greater for ALT in trials lasting 8 weeks or longer and for AST at doses over 500 mg daily (111563). The validity of these findings is limited by significant heterogeneity among the included studies. A small clinical trial in patients with NAFLD shows that taking a specific artichoke leaf extract (Cynarol, Niak Pharmaceuticals), standardized to contain cynarin 2%, as 200 mg three times daily for 2 months improves NAFLD severity, reduces liver size, and increases hepatic vein flow when compared with placebo. The severity of NAFLD improved in 82% of patients taking artichoke, compared with 5% taking placebo. NAFLD severity did not worsen in any patients taking artichoke, compared with 27.5% of those taking placebo. Serum levels of liver transaminases, total bilirubin, and lipids were also improved with artichoke when compared with placebo (100934). However, the validity of these findings is limited by inappropriate randomization, the use of a per-protocol analysis, and significant differences between groups at baseline. Artichoke leaf extract has also been evaluated in combination with conventional therapies. A clinical trial shows that taking metformin 500 mg twice daily and/or vitamin E 400 IU once daily along with a specific artichoke leaf extract (Tishoke; Goldaru Company) 400 mg twice daily, providing 40 mg chlorogenic acid daily, for 12 weeks improves NAFLD severity and reduces liver size when compared with baseline. However, these improvements were similar to those seen in patients taking metformin with vitamin E. After 12 weeks, the number of patients with no fat accumulation (steatosis grade 0) increased by 23% in the artichoke and metformin group, 17% in the artichoke and vitamin E group, and 10% in the metformin and vitamin E group (108714)
• Obesity. A meta-analysis of several small clinical studies suggests that oral artichoke extract may slightly reduce waist circumference, but not body weight or body mass index (BMI), in patients who are overweight or obese. Details: A meta-analysis of 10 small clinical trials shows that taking artichoke leaf extract, powder, or juice for 8-12 weeks reduces waist circumference by 1.11 cm, but does not improve body weight or BMI, when compared with placebo (105766). The generalizability of these findings to patients who are overweight or obese is limited by the fact that only 3 of the 10 trials specifically enrolled patients because they were overweight. Other studies evaluated patients with liver disease, metabolic syndrome, diabetes, hyperlipidemia, or hypertension. In contrast, a post-hoc analysis of clinical research in adults with overweight shows that taking an artichoke leaf supplement (Altilix, Bionap S.r.l.) 150 mg daily for 6 months reduces body weight by around 2.3 kg but does not improve waist circumference when compared with placebo (111564).
• Osteoarthritis. Although there has been interest in using oral artichoke for osteoarthritis, there is insufficient reliable information about the clinical effects of artichoke for this purpose. More evidence is needed to rate artichoke for these uses.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Artichoke has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Artichoke extract has been used with apparent safety at doses up to 3200 mg daily for up to 12 weeks (6282,15204,52235,91475,91478,100934). Artichoke leaf powder has been used with apparent safety at a dose of 1000 mg daily for up to 8 weeks (104133). Cynarin, a constituent in artichoke extract, has been used with apparent safety at daily doses of 750 mg daily for up to 3 months or 60 mg daily for up to 7 months (1423,1424,52222,52223,52236).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of artichoke when used in medicinal amounts during pregnancy or lactation; avoid amounts greater than those found in foods.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, artichoke leaf extract may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details A meta-analysis of small clinical studies shows that taking artichoke leaf extract for 8-12 weeks can modestly reduce fasting plasma glucose when compared with placebo (105768).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, artichoke leaf extract may increase the risk of hypotension when taken with antihypertensive drugs.  Details A meta-analysis of small clinical studies in patients with hypertension shows that taking artichoke can reduce systolic blood pressure by around 3 mmHg and diastolic blood pressure by around 2 mmHg when compared with placebo (105767).

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, artichoke might increase serum levels of drugs metabolized by CYP2B6.  Details In vitro research shows that artichoke leaf extract inhibits CYP2B6 activity (97717). However, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, artichoke might increase serum levels of drugs metabolized by CYP2C19.  Details In vitro research shows that artichoke leaf extract inhibits CYP2C19 activity (97717). However, this interaction has not been reported in humans.

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General ...Orally, artichoke extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, flatulence, hunger, and nausea.
Topically: Contact dermatitis in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis to artichoke inulin has been reported in individuals sensitive to inulin.
Topically: Chest tightness, cough, and dyspnea after occupational exposure in sensitive individuals.

Dermatologic ...Artichoke can cause an allergic reaction in some patients. Patients sensitive to the Asteraceae/Compositae family may be at the greatest risk. Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs. Topically, allergic contact dermatitis can occur with the use of artichoke. This has been attributed to the constituent cynaropicrin (11,52206,52226,52230). Redness in the face (11774) and sweating (91475) have been reported rarely following oral use of artichoke extract.
Occupational or airborne exposure to artichoke may also cause allergic reactions. In one case, a 52-year-old male presented with severe spongiotic dermatitis in exposed areas that was recurrent over the past 8 years. A patch test confirmed allergies to artichokes and sesquiterpene lactones, a group of allergens from the Compositae family, and the patient confirmed occupational and airborne exposure to artichokes during the time of his symptoms. The patient improved considerably after treatment with dupilumab (111565).

Gastrointestinal ...Orally, artichoke extract might increase abdominal discomfort, flatulence, diarrhea, hunger, and nausea in some patients (2562,52238,91475). Abdominal pain and a bitter taste in the mouth were reported by a single person following oral use of a dietary supplement containing artichoke extract, as well as red yeast rice, pine bark extract, and garlic extract (89452). It is not clear if this adverse effect was due to artichoke, other ingredients, or the combination.
In one case report, the autopsy of an 84-year-old female revealed a colonic bezoar comprised of artichoke fiber and fragments. This bezoar caused complete intestinal obstruction, leading to fatal acute peritonitis. Although rare, patients who lack adequate teeth and/or who have a history of gastric surgery are at increased risk for fibrous bezoar formation (97716).

Pulmonary/Respiratory ...Following occupational exposure, allergic symptoms including dyspnea, cough, chest tightness, and asthma symptoms or exacerbation have been reported. The effects were attributed to sensitization to artichoke. Subsequent nasal challenge with artichoke extract caused reduced nasal patency in these patients (52210,52230).
Orally, severe anaphylactic shock in response to artichoke inulin as an ingredient in commercially available products has been reported (52217). Individuals with a noted sensitivity to artichokes should consume inulin with caution. While rare, individuals with a known inulin allergy should avoid artichoke and artichoke extract.

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