~Hepatitis C, Part 5 - Botanical Medicines

Botanical Medicines

Comparing conventional pharmaceutical drugs to herbal products can be problematic. As a rule, pharmaceuticals have one or two well-understood synthetic ingredients. Herbal ingredients are complex mixtures of dozens of plant chemicals, each with a different action. The constituents responsible for therapeutic effects are frequently unknown or only partly understood. At times, the true usefulness of a botanical is obscured by folklore. Many herbal products are touted as remedies and widely marketed for a wide range of disorders with no trial data to backup claims—or their applications are inferred from other plants with similar chemical components. There are many synthetic and natural antioxidants available, but their activity, bioavailability, and efficacy differ widely. The antioxidants discussed in this section have a broad spectrum of biological, pharmacological and therapeutic activities and are proven to be suited to defend against free radicals and oxidative stress caused by HCV infection.

Grape Seed Skin Extract. Grape seeds contain many chemical compounds, including polyphenols and flavonoids. Proanthocyanidins are mixtures of polyphenols that are closely related to flavonoids.308 Their potent antioxidant and free-radical scavenging309 and vasoprotective effects have been proven in many studies and trials. Proanthocyanidins exert their protective effect partially by increasing the activity of endogenous antioxidants such as glutathione and superoxide dismutase.310 Proanthocyanidins are twice as potent as vitamin E and four times as potent as vitamin C.40,309,311 Proanthocyanidins possess an impressive list of actions, including the ability to inhibit lipid oxidation and platelet aggregation, to promote nitric oxide production, to arrest tumor growth, and to inhibit carcinogenesis. Proanthocyanidins also exert an immunomodulatory effect. In laboratory studies, proanthocyanidins increased the cytotoxicity of natural killer cells, enhanced the production of IL-2, and decreased production of IL-6.312 A diet supplemented with proanthocyanidins increased T- and B-cell activity in mice with age-associated immune deficits.313 Dosing animals with grape seed extract before giving them hepatotoxic doses of acetaminophen significantly attenuated DNA damage and apoptotic and necrotic cell death of liver cells.314 Today grape seed extract is commonly used for prevention and treatment of edema and chronic venous insufficiency.314,315

Proanthocyanidins are generally considered nontoxic and adverse events are rare. There were no adverse effects seen in dogs who were given 130 mg daily of proanthocyanidins from grape seeds per pound of body weight for 1 year. Individuals with bleeding disorders or those who are taking anticoagulant medication or anticipating surgery should not use grape seed extract because of its effect on platelet coagulation.204

Milk Thistle. Silybum marianum, commonly know as milk thistle, has been a treatment for liver diseases for more than 2000 years.316 Its hepatoprotective component is silymarin;317 most research is directed at silybin, silymarin's most biologically active component. As an antioxidant, silymarin reduces free radical production and lipid peroxidation in the liver and slows glutathione depletion.318 In the laboratory, silymarin displayed marked hepatoprotective effects. It significantly reduced hepatic necrosis in rats caused by toxic doses of acetaminophen319 and protected liver cell membranes exposed to an array of hepatotoxins.320,321 It also demonstrated the ability to regenerate hepatic tissue322 and enhanced liver detoxification.323

Silymarin is used commercially as a hepatoprotectant and a treatment for chronic inflammatory liver disorders such as cirrhosis, hepatitis, and alcohol-related fatty liver disease.324 It is well known as a treatment for liver damage caused by toxic chemicals and for occupational liver diseases325 and as an antidote to mushroom poisoning.

Milk thistle extract has been the subject of more than 200 placebo-controlled clinical trials. It is very difficult to sort out the results because doses and treatment protocols were not consistent among studies. Trials lasted from 7 days to 2 years and methods to judge improvement and follow-up varied widely. Unfortunately, many of the studies were poorly designed. In all the trials, the most frequent benefit was lowering of liver enzyme levels. Trials to study alcoholic liver disease showed widely divergent results. Some studies reported normalization of liver function tests, improvements in liver tissue, and significantly lower death rates with silymarin,326-328 while others found no effect on survival or clinical course of liver disease.329,330 Several studies that evaluated the effects of milk thistle on viral hepatitis showed improvement in liver enzymes, but none in liver function.331,332 Two other studies found that the reverse was true.333,334 There are some positive trends in studies of patients with alcoholic and nonalcoholic cirrhosis.329,330 Although silymarin has significant anti-cancer activity in laboratory studies, there have been no studies evaluating milk thistle as a treatment for hepatocellular carcinoma.335,336 Unfortunately, it is not known how silymarin interacts with interferon or ribavirin. A large study of milk thistle therapy in hepatitis funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases is underway.

Milk thistle is safe; there were no signs of toxicity in studies when dogs were given very high doses for 1 year.337 Side effects are mild, and their incidence is low.329 GI disturbances, mild allergic reactions, and laxative effects have occasionally been reported.338

Licorice Root. Licorice root has been an important part of herbal medicine for thousands of years, but today it is most well known as a treatment for peptic ulcers. Licorice root contains a variety of compounds; glycyrrhizin is responsible for most of its pharmacological activity. Glycyrrhizin is converted into glychyrrhetic acid in the body by an enzymatic reaction. Glycyrrhizin has various immune-modulating actions339 as well as potent anti-inflammatory,340 antioxidant, antiviral, and anti-tumor constituents.341 The mechanisms of actions are not fully understood. It is known that glycyrrhizin stabilizes lysosomal membranes.342 It also inhibits the enzyme that breaks down cortisol, resulting in a prolongation of its anti-inflammatory effects.343 Glychyrrhetic acid inhibits the complement cascade344 and might potentate the anti-inflammatory effects of cortisol.343

Glycyrrhizin is active against both DNA and RNA viruses and is effective against viral hepatitis A,345 hepatitis B,346 and hepatitis C in clinical and laboratory studies.347 In Japan, glycyrrhizin is widely used to treat chronic hepatitis B346 and lower ALT levels in patients with CHC.348 Its antiviral mechanism appears to be twofold: a direct inhibitory action on viral replication and function and stimulation of the host immune system T-cells to produce interferon-y.343 This has been demonstrated in several animal studies. When splenic T-cells were transferred from glycyrrhizin-treated mice to mice exposed to the influenza virus, all of the recipients and none of the controls survived. Another study with the same design resulted in improved resistance to herpes simplex virus.349 Glycyrrhizin increased production of IL-10 in the cells of mice with hepatitis.122

Glycyrrhizin lowers ALT levels122,350 and possesses a hepatoprotective effect against cirrhosis and a variety of carcinogens.338,351 A study that evaluated the effect of glycyrrhizin showed that long-term treatment of CHC patients prevented hepatocellular carcinoma. After 15 years, the incidence of hepatocellular carcinoma was 12% in patients treated with glycyrrhizin for a median time of 10 years and 25% for those who had used other supplements or herbal medicines. The relative risk of HCC in patients not treated with glycyrrhizin was higher than those who were.348

Combination treatment with interferon and glycyrrhizin for CHC is also being investigated. In a trial that enrolled patients who had not responded to interferon, 33% of those treated with interferon alone and 64% of those who received interferon plus glycyrrhizin achieved normal serum ALT levels. Histological improvement was not significant, but reversal of histological grade was more frequently in the interferon and glycyrrhizin group.352 In a study of patients who did not respond or were unlikely to respond to interferon, glycyrrhizin lowered serum ALT during treatment, but had no effect on HCV-RNA levels.353 Intravenous treatment with glycyrrhizin induced a significant ALT decrease in non-responders and difficult-to-treat patients, but the effect disappeared when the treatment was stopped.350 When ursodeoxycholic acid was added to glycyrrhizin in a 24-week trial, results showed a significant decrease in ALT levels, but no change in viral load in either group.354

Glycyrrhizin and glychyrrhetic acid inhibit the breakdown of cortisol which can result in the common side effects associated with licorice root: edema, sodium retention and low serum potassium levels, and high blood pressure.355 Patients with cardiovascular or renal disease should discuss the use of licorice root with their physicians.

Green Tea Extract. The Chinese have used the leaves of Camellia sinensis as a treatment for many diseases, for over 4000 years. Green tea contains flavonoids and B and C vitamins356,357 and is rich in the polyphenols, gallic acid and catechin, and their derivatives.358 Epigallocatechin-3-gallate (EGCG) is the major and the most active polyphenol in green tea extracts,359 other components of green tea, such as caffeine and tannin, have therapeutic applications as well.

The potent antioxidant activity of green tea catechins has been well researched. Green tea has a positive influence on lipid metabolism and exerts anti-mutagenic and anticancer effects. The polyphenols in green tea can influence the proliferative processes of the cells.360 Epidemiological studies have showed that green tea reduces the risk of cancer361 and is a successful adjunct to chemotherapy. However, a positive association between green tea consumption and development of stomach and colon cancer also has been reported.362

The hepatoprotective effect of green tea modulates the inflammatory processes and protects against DNA damage.363 Studies in mice showed that green tea inhibited chemical-induced hepatotoxicity.364 Green tea also is an effective treatment for hepatitis.365 Oxidative stress plays a part in activation of hepatic stellate cells during hepatic fibrogenesis. The polyphenols from green tea scavenge oxygen radicals and prevent activation of stellate cells, thereby minimizing liver fibrosis.359 Polyphenols from green tea are potent free radical scavengers.366 In the laboratory, epigallocatechin-3-gallate protected against oxidative stress and hepatotoxins toxicity created by cytochrome P450 enzymes.367

Tea drinking is safe. In fact, a Japanese longevity study that followed 3000 practitioners of the Japanese tea ceremony for 8 years showed a positive correlation between the regular drinking of green tea and a long life.365 There is some evidence that highly condensed tannins and catechins could induce esophageal cancer. Green tea might antagonize the effects of warfarin, an oral anticoagulant.368

Other Botanicals for Hepatitis C

Coffee. A population study of 6000 adults found a positive correlation between coffee and caffeine and a lower risk of liver injury in people with a high risk for liver disease. Individuals with CHC and iron overload were included in the high-risk population studied.369

Mistletoe. In a very small study, a combination treatment of Viscum album (mistletoe) and an extract of Solanum lycopersicum, Fragaria vesca, and Vitis vinifera (Hepatodoron) reduced fibrosis in five of eight patients with HCV infection370

Lycopene. Lycopene is a carotenoid found abundantly in tomatoes and in some red and orange vegetables. In an experiment to distinguish the effects of lycopene from tomato extract on acute liver injury, first rats were force-fed the oxidant carbon tetrachloride and then fed either lycopene or tomato extract. Results showed that that tomato extract, not lycopene, partially protected against acute liver injury due to chemically induced oxidant stress.371 In a clinical trial that enrolled 92 patients with chronic hepatitis C, a tomato-based functional food reduced the severity of ribavirin-related anemia and improved the tolerance to the full dose of ribavirin in patients with chronic hepatitis C.372

Continued . . .

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