Research in Japanese Botanical Medicine and Immune Modulating Cancer Therapy
Japanese botanical medicine, known as Kampo, is part of the east Asian Chinese medicine tradition. The word “Kampo” means “Han method,” a reference to Chinese culture of the Han era (206BC-220AD). Kampo is fundamentally a clinical system based on the classical medical literature dating back to the Han era. Kampo is an older tradition preserved in Japan and distinct from Traditional Chinese Medicine (TCM) practiced today in China. TCM is the modern system of treatment developed in mainland China in the 1950s, based on a consensus on the traditional principles of evaluation and treatment. In Japan, Kampo has been in almost continuous use for centuries as a system of medicine with the exception of the Meiji era (1866 – 1912) when traditional medicine was banned. It was during the Meiji era, however, when pharmacological research was first used to validate the use of the herb mao (Chinese ma huang L. Ephedra sinica). In 1885 Dr. Nagayoshi Nagai isolated the alkaloid ephedrine from this herb, frequently used in fo rmulas for bronchial asthma and arthritis. The pharmacological action of ephedrine was explained by Dr. Kinnosuke Miura in a German medical journal and ephedrine subsequently became a mainstream pharmaceutical for the treatment of bronchial asthma in Europe and North America as well.
Kampo was validated as a clinical system in the 20th century. By the late 1960s, in large part due to public demand, Kampo was integrated into the medical mainstream. Today the large majority of physicians use at least some of the traditional formulas, which are available in almost all pharmacies by prescription, or under the advice of specially trained pharmacists. The Japanese national health insurance plan covers the use of many of the traditional formulas.
Hundreds of papers were published on the pharmacology of the herbs of the traditional pharmacopoeia even before the turn of the 20th century, but in recent decades clinical and animal research has been undertaken on a large scale by university hospitals and private clinics throughout Japan as well as hospitals and research institutes in China. Research in Japan has been more rigorous by western standards. In many ways Chinese research is more practical. The aim of research is often developmental, with clinical problem-solving as the chief aim. In China trials on herbal combinations are often designed to refine a clinical approach or test a formula before using it on hospital patients, rather than to validate a specific endpoint to convince skeptical colleagues. Japanese research, on the other hand, is more academic in the mold of conventional western pharmaceutical research. Japanese research on botanical medicine also uses substances that are pharmaceutical grade according to western standards.
Since 1994, Japanese manufacturers of traditional herbal medicines have been required to conform to the same standards of quality as other pharmaceutical companies. This requires that all formulas are tested for any contaminants and are “standardized” for specific levels of key chemical constituents that are used as “markers” of plant quality. This means that the herbs used in the formulas must have the required levels of at least two marker components in order for the formula to be approved as a medicament. This places the onus for quality control on the herb buyers for the Japanese manufacturers, because a single herb can have several “active” components and herbs grown in different climatic regions can have dramatically different chemical compositions. The amount of saikosaponins, important constituents of the herb Bupleurum falcatum, can vary considerably. According to one Japanese herb buyer, “Bupleurum from one region may contain seven times the saikosaponins of bupleurum from a different region. We hav e to get the best quality when we purchase because we can’t afford to buy seven times as much herb to get the required level of saikosaponins in our products.”
One widely researched combination that holds promise for cancer treatment is called Minor Bupleurum Combination or sho-saiko-to in Japanese, and TJ-9 in some of the research literature. Shosaiko-to has been used in Japan for over a thousand years and is probably the most popular herb formula in Japan today. Over a million Japanese patients take it every year for various complaints, but particularly for hepatitis C. There are specific symptoms and signs that indicate the use of Sho-saiko-to for various health problems. The combination is recommended when the appropriate symptoms and signs are presented at the examination. It has been used for a variety of medical diagnoses including gastroenteritis, migraine headaches, lingering colds, chronic bronchitis, bronchial asthma, gallstones, cholecystitis, epilepsy, malaria and even just to strengthen the physical constitution. Its potentially beneficial effect on cancer is attributed to its ability to regenerate liver function as well as to stimulate cytokine and NK cell activity.
According to the principles of Kampo, and Traditional Chinese Medicine in general, formulas are matched to symptoms and signs in order to individualize treatment. Therefore Shosaiko-to would not be indicated for all cases of hepatitis C. There are other variations of this formula for different body types and symptom patterns that could be used for the same diseases In different patients. In a controlled research trial, however, the requirement is to find a formula to match a medical diagnosis to stabilize repeatability in the research design.
In Chinese research on hepatitis, patients with hepatitis all receive identical laboratory tests but are then subdivided into cohorts with different TCM diagnoses, e.g. blood stasis, liver qi congestion, spleen dampness, etc. In Japan, Dr. Shigeru Arichi of Kinki University, who carried out research on hepatitis, diabetes, treatment of side effects of steroid withdrawal and numerous other types of pathology in a hospital setting, used a similar strategy.
The formula he would select for a hepatitis patient was based on the patient’s pulse quality, pattern of abdominal tension and the appearance of the tongue. He also used the individualization of patients’ treatments to train physicians interested in Kampo in grand rounds based on these clinical observations rather than on the medical diagnosis or blood test results. Dr. Arichi’s research results were quite successful, but his research strategy was criticized for lack of controls.
For the purpose of clinical research, Sho-saiko-to is an obvious choice to be selected as a one-size-fits-all hepatitis formula for several reasons. The combination contains the herbs bupleurum (Bupleurum falcatum), ginseng (Panax ginseng), Scute (Scutellaria baicalensis), licorice (Glycyrrhiza uralensis),ju jube (Zizyphus jujuba), pinellia (Pinellia ternata) and ginger (Zingiber officinalis). The herb bupleurum has been shown to accelerate the regeneration of liver cells and four saikosaponins, important components of bupleurum, were shown by Dr. Arichi to improve physical and psychological symptoms in intractable cases of hepatitis B. Ginseng saponins have also been shown to protect liver cells, even against damage from carbon tetrachloride. Ginseng has also been found to accelerate the regeneration of liver cells. Licorice has been found to increase gamma-interferon production. One of its components (glycyrrhizin) has been used intravenously for hepatitis B and improves liver function with occasional comp lete recovery. Scutellaria was found to increase the production of interleukin 10 (IL-10), a cytokine which hepatitis patients do not produce sufficiently.
Sho-saiko-to holds promise in the treatment of hepatocellular carcinoma (HCC) as well as hepatitis. It was found to have a preventive effect on HOC in patients with liver cirrhosis, a population in which HCC incidence is high. The formula appears to induce production of tumor necrosis factor (TNF-a) and granulocyte colony stimulating factor in patients with HOC. Other studies indicate that Sho-saiko-to protects the liver from fibrosis, inhibits the growth of malignant melanoma cells, induces apoptosis of cells infected with HIV and stimulates NK (Natural Killer) cell activity.
There is no reason why other bupleurum formulas would not be equally effective as Sho-saiko-to if properly prescribed. The fact that several of its components had been studied individually and found useful for improving liver function and immune status made it the combination of choice, but the synergies of herbs often create effects that can’t always be predicted by taking an inventory of the chemical constituents. Traditional practitioners have used numerous formulas for hepatitis, many of them containing bupleurum.
The formula Major Bupleurum Combination, or Dal-saiko-to is traditionally indicated for almost all of the same diseases for which Sho-saiko-to has been used. Dai-saiko-to is typically used for a more robust “sthenic” individual than Sho-saiko-to. Both formulas contain bupleurum, pinellia, scute, ginger and jujube, but instead of ginseng and licorice, Dal-saiko-to has rhubarb (Rheum palmatum), aurantium (Citrus aurantium) and white peony (Paeonia lactiflora). White peony induces interferon production and rhubarb has anti-tumor properties. It is likely that there are many more traditional formulas that could have anti-cancer properties beside the few that have been widely researched, but exploiting this potential would require new research designs that could make allowances for matching patients to the clinical indications of specific formulas.
Another traditional formula considered to hold great promise in cancer treatment is called Ginseng and Tang-kuei Ten Combination, also called Ten Ingredient Great Supplementing Combination and Juzen-taiho-to in Japanese. Juzen-taiho-to contains the ten herbs ginseng (Panax ginseng), white peony (Paeonia lactiflora), tangkuei (An gelica sinensis), lico rice (Glycyrrhiza uralensis), astragalus (Astragalus membranaceous), poria (Poria cocos), onidium (Ligusticum wallichii), atractylodes (Atractylodes alba), rehmannia (Rehmannia glutinosa) and cinnamon (Cinnamomum, zeylanicum). It is used to treat fatigue, anemia, loss of appetite, poor digestion, cachexia and general lack of vitality in chronic disease. It has traditionally been used for patients recovering from severe illness, injury, surgery or other debilitation.
Because of its beneficial effects on asthenic patients, Juzen-taiho-to was researched as an immunoprotective agent for cancer patients undergoing cytotoxic chemotherapy, even drugs as strong as cis-platinum. It has been used successfully to prevent or mitigate the damaging effects of other toxic anticancer drugs. Other research has shown, however, that Ginseng and TK 10 is a powerful immunomodulator and itself has significant anti-tumor properties. It has been shown to activate NK cells, to increase macrophage activity accelerating phagocytosis and to modulate cytokine secretion. It has also been shown to inhibit liver metastasis of colon cancer cells. The formula also protects the bone marrow function, often preventing a precipitous drop in red cells, white cells and platelets.
Far from being rare or exotic, the herbs that comprise this formula are some of the most ubiquitous. Most of the classical formulas contain one or more of these herbs as ingredients. The antimetastatic properties of Juzen-taiho-to have been attributed to the presence of the four herbs tang-kuei, cnidium, rehmannia and white peony. These four herbs are commonly found in many traditional formulas, even as a group. These four herbs, known as the “four substances” are most frequently used in formulas for female complaints although they are also recommended for men. They are also found in formulas used for anemia, arthritic conditions and autoimmune disorders. They are considered to reinforce blood production and tissue repair. There is evidence that ginseng increases liver activity and by itself can prevent metastasis and relieve side effects of chemotherapy. The herb astragalus has also been used in China in concentrated extracts to prevent the collapse of the immune system in patients treated with chemotherapy for cancer. The herbs atractylodes and poria improve digestion and immunity. Atractylodes stimulates immunity and has tumor reduction properties, especially for tumors of the stomach, breast, cervix and uterus. Poria is an immune regulator that also has tumor reduction properties.
This formula is one of the most versatile for cancer because its clinical range of efficacy is for anemia, improving liver function, “Spleen” function (an important factor in immunity), improving digestive transport and absorption and strengthens adrenal cortex function building energy that gives stamina, not stimulation.
Another formula often used for similar purposes is called Hochu-ekki-to (Ginseng and Astragalus Combination). This formula contains Panax ginseng, Astragalus membranaceous Atractylodes alba, Glycyrrhiza uralensis, Angelica sinensis, Bupleurum falcatum, Zingiberis officinalis, Citrus reticulata, Zizyphus jujuba, and Cimicifuga foetida. There has been a lot written about both Juzen-taiho-to and Hochu-ekki-to and their tumor reduction properties. Hochuekki-to contains only one of the herbs in Juzen-taiho-to to which its tumor reduction properties have been attributed, which leaves the cancer researchers without a clear mechanism of action.
It may be that the herb components in these formulas don’t have a direct action on the actual tumors, and don’t directly inhibit metastasis. One speculation on the mechanism of these formulas for tumor reduction, from the standpoint of immunology, appears to be that they operate by means of activation of natural killer cells which can destroy tumor material, along with increased levels of tumor necrosis factor and various cytokines. Activating white blood cells appears to result in enhanced cytokine production. Cytokines that stimulate cellular immunity like gammainterferon and interleukin-12 are particularly powerful in tumor reduction. There are other cytokines that stimulate tumor growth. There may be a suppression of these cytokines by the formulas.
The use of these formulas can be of immeasurable value as an adjunct to chemotherapy as well as possibly useful on their own as a treatment. After surgery there is often immune suppression from the anesthesia. Surgically damaged organs secrete growth factors that can stimulate tumor growth and accelerate metastasis. Radiation can damage immune cells in the peripheral circulation, suppress immunity and bone marrow function. The immune system stays suppressed for a relatively long time. To have a nontoxic compound that can be used safely for a long period of time and protect the immune functions, prevent metastasis and perhaps reduce incipient tumor growth, would be of the utmost value.
The classical herbal formulas from the Chinese medicine tradition are increasingly used in the medical mainstream in Japan. These traditional formulas were developed for individualized treatment based on a patient’s symptoms and signs. The decision to focus cancer research on Sho-saiko-to and Juzen-taiho-to was not arbitrary, but because there are dozens of other traditional formulas using many of the same herbs, there is ample opportunity to refine cancer treatment using many of the other formulas from the traditional pharmacopoeia. The research that has taken place thus far on the treatment of cancer using traditional formulas is certainly only the tip of the iceberg. For more information about Kampo formulas, contact Honso USA of Tempe, Arizona (www.honso.com), Kampo Institute of River Forest, Illinois (www.kampoinstitute.com), or Tsumura Company of Tokyo, Japan (www.tsumura.co.jp).
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