Page 1153 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 64 Dietary Supplements & Herbal Medications 1139

kappa B (NF-κB), an inflammatory response mediator. One of clinical trial in patients with hepatitis C refractory to interferon
the most unusual mechanisms claimed for milk thistle involves treatment failed to show a benefit with 24 weeks of milk thistle,
an increase in RNA polymerase I activity in nonmalignant hepa- 420 mg/d and 700 mg/d, on reduction of serum alanine amino-
tocytes but not in hepatoma or other malignant cell lines. By transferase levels. Milk thistle also had no effect on mean serum
increasing this enzyme’s activity, enhanced protein synthesis and hepatitis C virus (HCV) RNA levels at 24 weeks. In contrast, the
cellular regeneration might occur in healthy but not malignant intravenous use of silybinin succinate has shown some benefit in
cells. In an animal model of cirrhosis, it reduced collagen accu- reducing HCV RNA levels and alanine aminotransferase levels in
mulation, and in an in vitro model it reduced expression of the patients with treatment-resistant hepatitis C infection. Prospective
fibrogenic cytokine transforming growth factor-β. If confirmed, pilot studies have also shown benefits with intravenous silybinin
milk thistle may have a role in the treatment of hepatic fibrosis. before and after liver transplantation treatment in patients with
In animal models, silymarin has a dose-dependent stimulatory HCV cirrhosis. Potent antiviral activity was demonstrated with
effect on bile flow that could be beneficial in cases of cholestasis. significant reductions in HCV-RNA levels during treatment com-
To date, however, there is insufficient evidence to warrant the use pared to placebo or nontreated controls when given for at least
of milk thistle for these indications. 14 days before transplantation and 7 days after liver transplanta-
tion. HCV-RNA relapsed, however, after silibinin withdrawal.
2. Chemotherapeutic effects—Preliminary in vitro and animal This suggests that formulation and poor oral bioavailability may
studies of the effects of silymarin and silybinin have been carried influence treatment outcomes.
out with several cancer cell lines. In murine models of skin cancer, Although milk thistle has not been confirmed as an antidote
silybinin and silymarin were said to reduce tumor initiation and following acute exposure to liver toxins in humans, intrave-
promotion. Induction of apoptosis has also been reported using nous silybinin is marketed and used in Europe (Legalon SIL)
silymarin in a variety of malignant human cell lines (eg, mela- as an antidote in Amanita phalloides mushroom poisoning.
noma, prostate, colon, leukemia cells, bladder transitional-cell This use is based on favorable outcomes reported in case-
papilloma cells, cervical and hepatoma cells). Inhibition of cell control studies.
growth and proliferation by inducing a G cell cycle arrest has
1
also been claimed in cultured human breast and prostate cancer Adverse Effects
cell lines. The use of milk thistle in the clinical treatment of can-
cer has not yet been adequately studied but preliminary trials in Milk thistle has rarely been reported to cause adverse effects
patients undergoing chemotherapy show that it may improve liver when used at recommended doses. In clinical trials, the inci-
function (ie, reduced liver transaminase concentrations in blood). dence of adverse effects (eg, gastrointestinal upset, dermatologic,
There are insufficient data to support use in patients with cancer. headaches) was comparable to that of placebo. At high doses
The antioxidant potential of milk thistle should be taken into con- (>1500 mg), it can have a laxative effect caused by stimulation of
sideration prior to administration with chemotherapeutic agents bile flow and secretion.
that may be affected by antioxidant compounds.
Drug Interactions, Precautions, & Dosage
3. Lactation—Historically, milk thistle has been used by herbal- Milk thistle does not significantly alter the pharmacokinetics
ists and midwives to induce lactation in pregnant or postpartum of other drugs transported by the P-glycoprotein transporter
women. In female rats, milk thistle increases prolactin production. or metabolized by cytochrome enzymes. In a recent review, the
As such, it is possible that it could have an effect on human breast impact of the herb was listed as “posing no risk for drug interac-
milk production. Clinical trial data are lacking, however, for this tions in humans.” Recommended oral dosage is 280–420 mg/d,
indication, as are safety data on nursing mothers and infants. calculated as silybin, in three divided doses.
Until further data become available, milk thistle should not be
used for this indication.

Clinical Trials ST. JOHN’S WORT (HYPERICUM
Oral milk thistle has been used to treat acute and chronic viral PERFORATUM)
hepatitis, alcoholic liver disease, and toxin-induced liver injury Chemistry
in human patients. A systematic review of 13 randomized trials
involving 915 patients with alcoholic liver disease or hepatitis B St. John’s wort, also known as hypericum, contains a variety of
or C found no significant reductions in all-cause mortality, liver constituents that might contribute to its claimed pharmacologic
histopathology, or complications of liver disease with 6 months of activity in the treatment of depression. Hypericin, a marker of
use. A significant reduction in liver-related mortality was claimed standardization for currently marketed products, was thought to
using the data from all the surveyed trials, but not when the be the primary antidepressant constituent. Recent attention has
data were limited to trials of better design and controls. It was focused on hyperforin, but a combination of several compounds is
concluded that the effects of oral milk thistle in improving liver probably involved. Commercial formulations are usually prepared
function or mortality from liver disease are currently poorly sub- by soaking the dried chopped flowers in methanol to create a
stantiated. A recent multicenter, double-blind, placebo-controlled hydroalcoholic extract that is then dried.