Shosaiko-to and other Kampo (Japanese herbal) medicines: a review of their immunomodulatory activities

Journal of Ethnopharmacology 73 (2000) 1 – 13 www.elsevier.com/locate/jethpharm

Review

Shosaiko-to and other Kampo (Japanese herbal) medicines: a review of their immunomodulatory activities Andrea T. Borchers a, Shinya Sakai a,b, Gary L. Henderson a,b, Martha R. Harkey a,b, Carl L. Keen c, Judy S. Stern a,c, Katsutoshi Terasawa d, M. Eric Gershwin a,* a

Department of Internal Medicine, Di6ision of Rheumatology, Allergy and Clinical Immunology, School of Medicine, Uni6ersity of California, TB 192, Da6is, CA 95616, USA b Department of Medical Pharmacology and Toxicology, Uni6ersity of California, Da6is, CA, USA c Department of Nutrition, Uni6ersity of California, Da6is, CA, USA d Department of Japanese Traditional Medicine, Toyama Medical and Pharmaceutical Uni6ersity, 2630 Sugitani, Toyama 930 -01 94, Japan Received 1 January 2000; received in revised form 7 April 2000; accepted 10 April 2000

Abstract The use of alternative medicine, including consumption of herbal products and dietary supplements, has been increasing substantially both in the United States and in Western Europe. One area that is garnering increased attention is the use of Oriental Medicine including Kampo, or Japanese herbal medicine. Herein, we review representative examples of research available on the most common use of Kampo medicinals, namely to improve the immune response. We also provide an extensive background on the history of Kampo. There are more than 210 different Kampo formulae used in Japan and most uses of Kampo are to modulate the immune response, i.e. to improve immunity. We have extracted data on seven common Kampo medicinals, and the data are reviewed with respect to in vitro and in vivo activities for both humans and experimental animals; the ingredients as well as the problems with classification of these materials are presented. Research suggests that Kampo herbals are biologically active and may have therapeutic potential. While it is believed that Kampo medicines have few side effects, there is a paucity of data on their toxicity as well as a relative lack of knowledge of the bioactive constituents and potential drug interactions of these agents. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Immunomodulation; Kampo; Chinese medical philosophy; Shosaiko-to

* Corresponding author. Tel.: + 1-530-7522884; fax: + 1-530-7524669. E-mail address: [email protected] (M.E. Gershwin). 0378-8741/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 8 7 4 1 ( 0 0 ) 0 0 3 3 4 - 2

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1. Introduction Traditional Chinese medical philosophy is one of the oldest medical traditions in the world and has a long-standing history in the usage of herbal medicinals (Ergil, 1996). Chinese medicine was introduced into Japan between the 6th and 8th century where, as Kampo medicine, it constituted the official medical system until the Meiji Restoration (starting 1868). Although during that period, Western customs, including Western medicine, began to supersede older Japanese traditions (Yamamura, 1988; Terasawa, 1993), Kampo medicine never completely fell out of use, and is being practiced today again by a growing number of Japanese physicians trained in Western medicine. In 1976, the manufacture of Kampo herbal preparations was officially approved by the Japanese ministry of Health and Welfare, and prescriptions for Kampo formulae are currently covered by the National Health Insurance Plan (Terasawa, 1993; Audet, 1994). Although Japanese physicians today practice predominantly the Western medicine, surveys conducted in 1993 and 1998 indicate that approximately 75% of the responding physicians (response rate  21%) prescribed Kampo medicine to their patients (reported in Anonymous, 1994, 1999). Sales of Kampo formulae increased from 310 million to 1.5 billion between 1980 and 1990 (Anonymous, 1999). Both consumer surveys and industry reports indicate that the use of complementary/alternative medicine (CAM) and especially the consumption of botanicals has been increasing rapidly worldwide, including in the United States (Eisenberg et al., 1993, 1998; Goldbeck-Wood et al., 1996; Scimone and Scimone, 1998). The reasons for the use of CAM, particularly botanicals, have been explored only incompletely (Astin, 1998; Baldwin, 1998; Cherkin, 1998; Lawler, 1998). There are indications, however, that the ineffectiveness of Western medicine in the treatment of chronic diseases, as well as the side effects often associated with conventional Western therapies, contribute to the decision of many patients to explore CAM, and in particular medicinal botanicals (Astin, 1998; Hilsden et al., 1998).

Little statistical data exist on the utilization of traditional Chinese medicine (TCM), including Chinese herbal medicine, in the United States. However, according to the American Association of Oriental Medicine, there are over 10 000 licensed practitioners of Oriental medicine in the United States, and their number has been increasing by about 1000 per year since 1995. A recent survey supports this growing interest in Oriental medicine and indicates that non-Asian populations constitute the largest user group (Cassidy, 1998a,b). Although Chinese herbal preparations and their Japanese counterpart, Kampo medicinals, are extensively studied in China and Japan, such research is only beginning to become available to Western scientists, largely due to the efforts of Japanese research groups to publish their results in English-language journals. The diagnostic criteria of Kampo medicine are rooted in the complex medical philosophy of TCM, which perceives disease not as an isolated biological disturbance, but as an imbalance of the forces and energies within the body (Terasawa, 1993; Ergil, 1996). Therapeutic approaches, of which herbal medicine is only one, are aimed at restoring balance. As a result, it is not the symptoms that are treated but the whole patient. Thus, even though two patients might present with the same symptoms, varied therapeutic approaches might be chosen because of differences in their overall conditions. Furthermore, as a patient’s condition changes, the therapeutic approach might be adjusted accordingly. Therefore, Chinese herbal, and thus Kampo, medicines do not easily lend themselves to randomized, double-blind, placebo-controlled trials. Nonetheless, a number of such studies have been conducted by the Research Institute for Wakan-Yaku (Oriental Medicine) of Toyama Medical and Pharmaceutical University in Japan (reported in Okada, 1996). Kampo preparations are crude drugs, in that they are prepared from medicinal plants with only minimal processing. They use the same combinations of medicinal botanicals as Chinese herbal formulae but usually in lower concentrations. Most commonly, several different specific plant parts are dried, mixed in precise proportions, and taken as teas by the patient. (Table 1 lists the

b

a

2.0 3.0 3.0

2.0

1.0 2.0 2.0 2.0

4.0

1.0

Keishi-bushi-to

2.0 2.0

2.0 2.0 2.0

Juzen-taiho-to

2.0 6.0

5.0

1.0 4.0

3.0 5.0 5.0 3.0

3.0

5.0 5.0 6.0

3.0

10.0

2.0

Keishi-ni-eppi-ichi-toka-ryo-jutsubu

5.0

Keishi-ni-eppi-ichi-to

Kampo formulae are offered in the United States under the romaji version of their Japanese designation. pH Neutralizer, not a plant.

Aconitii tuber Alismatis rhizoma Angelicae radix Astragali radix Atractylodis rhizoma Bupleuri radix Cinnamomi cortex Cnidii rhizoma Coptidis rhizoma Ephedrae herba Gardeniae fructus Glycyrrhizae radix Gypsum Fibrosumb Hoelen Paeoniae radix Panax ginseng radix Phellodendri cortex Pinelliae tuber Rehmanniae radix Scutellariae radix Zingiberis rhizoma Zizyphi fructus

Plant name and part

Table 1 Botanical sources and their proportions in seven Kampo medicine formulaea

3.0 1.0 3.0

5.0

3.0

2.0

7.0

Sho-saiko-to

4.0 4.0

3.0

4.0

4.0 3.0

Toki-shaku-yaku-san

3.0 1.5

1.5

3.0

1.5

3.0 1.5

3.0

Unsei-in

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plants and their proportions used to prepare the seven Kampo formulae reviewed here. Table 2 provides a list of indications for the seven Kampo formulae reviewed below.) Although over 210 different Kampo formulae are prescribed in Japan, the number of medicinal plants used in their preparation is limited, but their proportions and precise combinations differ from one formula to the next. The extract of even one single plant is an inordinately complex mixture of chemical constituents, making pharmacological studies difficult. This complexity is potentiated in Kampo formulae where anywhere from three to ten or more plant extracts are combined. Nonetheless, in recent years, scientists have attempted to elucidate the active principles as well as the mechanisms of action of Kampo formulae. The wide range of indications of most Kampo medicines is reflected in the great diversity of studies attempting to elucidate their mechanisms. For example, Tokishakuyaku-san (TSS) is most commonly prescribed for dysmenorrhea and menopausal complaints, and research into the possible mechanisms of this effect is ongoing (Ota et al., 1995; Iizuka et al., 1998). In addition, however, and Table 2 Clinical indications of seven commonly used Kampo formulae Compound

Clinical indications

Juzen-taiho-to

Anemia, general fatigue, loss of appetite, chronic disease, chemotherapy, or surgery, colds Rheumatoid arthritis Colds, rheumatoid arthritis, osteoarthritis, eczema Rheumatoid arthritis, Behc¸et’s disease, eczema Chronic gastroenteritis, chronic hepatitis, chronic tonsillitis, orthostatic hypotension, bronchial asthma, psychological problems General fatigue, cold limbs, anemia, headache, menopausal syndrome, sterility, chronic nephritis, edema Allergic dermatitis, psoriasis, eczema, gastritis, Behc¸et’s disease, urticaria

Keishi-bushi-to Keishi-ni-eppi-ichi-to Keishi-ni-eppi-ichi-to-karyo-jutsubu Shosaiko-to

Toki-shakuyaku-san

Unsei-in

largely without providing a clear rationale for their research, several laboratories have examined the ability of TSS to scavenge free radicals and to affect neurotransmitter levels (Stefek and Benes, 1994; Ueda et al., 1996; Itoh et al., 1998). A majority of the research on Kampo formulae, however, appears to focus on their ability to modulate the host immune system. Herein, we review studies of the immunomodulatory activities of seven Kampo formulae indicated for diseases which are often not successfully treated with standard Western medical practices, such as hepatitis and other viral infections, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). We focus particularly on studies demonstrating the complex interactions between the individual herbal constituents of these preparations.

2. Shosaiko-to (Chinese name, Xiao-Chai-Hu-Tang) Shosaiko-to (alternate designations; Sho-saikoto, Syosaiko-to, TJ-9) consists of a mixture of seven different medicinal plants (listed in Table 1) and is used primarily in the treatment of liver diseases, specifically chronic hepatitis as well as cancer, but it is also prescribed for bronchial asthma. Shosaiko-to appears to have direct cytostatic or even cytotoxic effects on some hepatocellular carcinoma cell lines (Yano et al., 1994). However, current research suggests that most of its medicinal effects in liver diseases are mediated by modulation of various host immune responses, including research on Shosaiko-to, which suggests that beneficial effects in hepatitis B might be due to its ability to induce interferons (IFNs) and to activate natural killer activity (Borchers et al., 1997). There are indications that, in addition to IFNs, Shosaiko-to can modulate the production of numerous other cytokines. For example, Shosaiko-to, dose-dependently, increased the production of granulocyte colony-stimulating factor (G-CSF) by peripheral blood mononuclear cells (PBMC) from healthy subjects (Yamashiki et al., 1992) with similar increases observed in PBMC from patients with hepatitis C mediated liver cir-

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rhosis with or without liver cancer (Yamashiki et al., 1996). In another study by the same authors, however, low concentrations of Shosaiko-to restored the decreased synthesis of G-CSF found in patients with hepatitis B and C to levels seen in healthy controls, but concentrations of 50 or 200 mg/ml induced very high levels of G-CSF in patients with hepatitis C compared with the other two groups (Yamashiki et al., 1997a). Similar and equally conflicting results were reported for TNFa (Yamashiki et al., 1996, 1997a). Interestingly, several studies mention, without an original citation, that plasma levels of Shosaiko-to in patients taking the commonly prescribed dose of 7.5 g/day for one week are between 200 and 500 mg/ml (Hattori et al., 1995). PBMC from patients with hepatitis B or C produced lower levels of interleukin (IL)-1b and IL-10 (Yamashiki et al., 1997b) than those of healthy controls both in the absence and presence of Shosaiko-to or pokeweed mitogen (PWM). The stimulation of cytokine synthesis achieved with Shosaiko-to was similar to that observed with PWM. In contrast, synthesis of IL-4 and IL-5 in response to concanavalin A stimulation was significantly higher in both groups of hepatitis patients than in healthy controls and was reduced when Shosaiko-to was added to the culture medium (Yamashiki et al., 1997b). If Shosaiko-to has similar effects in vivo, it might exert beneficial effects on the course of viral hepatitis by correcting imbalances in cytokine production. Animal studies have been conducted to elucidate which of the herbal constituents of Shosaikoto participates in its various effects on cytokine production. Intraperitoneal (i.p.) administration of Shosaiko-to induced interferon (IFN)-a/b and IL-6 activity in the sera of treated mice (Matsuura et al., 1993). Among the individual herbal constituents of Shosaiko-to, the i.p. injection of Glycyrrhizae radix induced almost 3-fold higher levels of IFN-a/b than did Shosaiko-to itself, while Pinelliae tuber and Bupleuri radix stimulated IFNproduction only slightly. Ginseng radix and Zizyphi fructus made essentially no contribution to the induction of IL-6 activity, while Pinelliae tuber was the strongest inducer among the other herbal constituents.

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Daily administration of Shosaiko-to in the drinking water of ddY mice for 2 weeks resulted in a slight but significant increase in serum TNFa-activity (Haranaka et al., 1985). Interestingly, four of its individual herbal constituents, Bupleuri radix, Angelicae radix, Cnidii rhizoma, and particularly Cinnamomi cortex, induced several-fold higher levels of TNF-a activity, suggesting that other ingredients act to downregulate TNF-a production. Despite the fact that Shosaiko-to induces TNF-a synthesis, oral pretreatment with Shosaiko-to had a protective effect against some toxic effects of exogenous rTNF-a (Sakaguchi et al., 1991, 1996). A total of 260 patients with cirrhosis was treated with Shosaiko-to over a period of 5 years in order to assess its ability to prevent hepatocellular carcinoma (Oka et al., 1995). Although this study is cited frequently as demonstrating the chemopreventive effects of Shosaiko-to, the study was neither double-blind nor placebo-controlled. Furthermore, although the cumulative incidence of hepatocellular carcinoma was lower, and the survival rate higher, in the Shosaiko-to-treated group, these differences failed to reach significance unless the group of patients with HBeAg was removed from statistical analysis. Although Shosaiko-to has long been considered to have very few, and only minor, side effects, in recent years a number of cases of acute pneumonitis have been reported in patients with chronic active hepatits treated either with interferon, Shosaiko-to, or a combination of the two (Ishizaki et al., 1996). Similar complications have occurred after treatment with G-CSF, the production of which is upregulated by Shosaiko-to in vitro (Yamashiki et al., 1997b). It, therefore, seems plausible that G-CSF is an important mediator in the acute pneumonitis occurring in some patients after ingestion of Shosaiko-to. In addition, increased cellular infiltration was observed not only in renal tumors, but also in the lungs of tumor-bearing mice treated with Shosaiko-to (Huang et al., 1997). Chemokines play an important role in such cellular infiltration events, among them IL-8, a cytokine chemotactic for neutrophils (Graves and Jiang, 1995). In vitro, Shosaiko-to induced IL-8 production by lung

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fibroblasts from control subjects as well as patients with interstitial pneumonia (Suganuma et al., 1994). In controls, IFN-a suppressed IL-8 production; however, in two (of four) of the patients, IFN-a upregulated IL-8 production, and the combination of Shosaiko-to and IFN-a resulted in higher levels of IL-8 than were seen with either agent alone in all patients.

3. Juzen-taiho-to (Chinese name, Si-Quan-Da-Bu-Tang) Juzen-taiho-to (TJ-48) consists of the extract of ten different plant parts (Table 1). It is commonly used as a tonic for patients recovering from surgery, or suffering from anemia or cachexia, or given as a general immunostimulant for patients with compromised immune systems due to chemotherapy. In vitro, Juzen-taiho-to activated complement activity, and stimulated the proliferation of mouse spleen cells (Yamada et al., 1992). Several of its herbal constituents (Astragali radix, Actylodis lanceae rhizoma, and Glycyrrhizae radix) induced mitogenic activity to the same extent as did Juzen-taiho-to, however, the omission of one of these herbs from the total extract resulted in only minor decreases in the proliferative response. Similarly, several individual herbal extracts exhibited higher anti-complementary activity than did Juzen-taiho-to, yet their omission from the total extract reduced this activity in some cases, had little effect in others, and even increased it in yet another case. Thus, in vitro, the activity of the combination of all ten extracts clearly results from complex interactions of the individual components. Such studies of the pharmacological and immunomodulatory effects of single botanical components of Kampo medicinal formulae, and even some of their isolated chemical constituents, are common (Wang et al., 1995). Somewhat unusual, however, is the route taken by Yamada et al. who fractionated the combined extract of all ten ingredients contained in Juzentaiho-to (Yamada et al., 1990; Kiyohara et al., 1991). The pectic polysaccharide fraction F-5-2 possessed not only stronger anti-complementary,

but also mitogenic activity than Juzen-taiho-to (Yamada et al., 1990). Furthermore, F-5-2 was found to be an unusual mitogen in that, in vitro, it stimulated the proliferation of B cells without inducing class switching from IgM to IgG production (Takemoto et al., 1994). In vivo, oral administration of F-5 (the polysaccharide fraction of Juzen-taiho-to from which F-5-2 is derived by further purification) increased significantly the number of plaqueforming cells (PFC), both IgM and IgG, against sheep red blood cells (SRBC) in SRBC-immunized Balb/c mice (Kiyohara et al., 1995). Interestingly, it suppressed the carrageenan-induced upregulation of the anti-SRBC antibody response but normalized the depressed anti-SRBC response after treatment with cisplatin. It is now well-established that numerous fungus- or plantderived polysaccharides, for example from various mushrooms (Mizuno et al., 1986) but also from Echinacea (Roesler et al., 1991a,b), exert immunomodulatory activities. But while some of these polysaccharides are ineffective when given orally (Suzuki et al., 1991; Mizuno et al., 1995), others modulate immune function following oral administration (Morinaga et al., 1994). One possibility is that their contact with circulating cellular components of the gut-associated lymphoid tissue (GALT) is sufficient to activate the cells, which subsequently can migrate to other tissues and exert further immunomodulatory effects. Until recently, it had been assumed that polysaccharides are either (a) absorbed only after they have been digested into monosaccharides, or small oligosaccharides; or (b) not digested and, therefore not absorbed, at all due to the lack of necessary enzymes to break certain glycosidic linkages. In fact, it has been established by several research groups that at least a portion of some indigestible polysaccharides can be absorbed after oral ingestion; remnants with molecular weights as high 20 000 Da are detected in plasma or serum of experimental animals as well as humans (Volpi, 1996). It is, therefore, conceivable that polysaccharides exert some of the same immunomodulatory effects in vivo as they do in vitro.

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Much research on Juzen-taiho-to has focused on its ability to protect mice against the toxic effects of anticancer drugs (Aburada, 1988; Sugiyama et al., 1995; Ueda et al., 1998). This protection seems to be, at least partially, mediated by the stimulation of hematopoietic stem cells, a process in which free fatty acids contained in Juzen-taiho-to appear to play an important role (Hisha et al., 1997). However, Juzen-taiho-to itself possesses antitumor activity (Ito and Shimura, 1988; Ohnishi et al., 1996, 1998). Juzen-taiho-to increases the phagocytic activity of macrophages, and adoptive transfer of macrophages from Juzen-taiho-to-treated mice inhibited the growth of pulmonary metastases significantly (Ito and Shimura, 1988). Spleen cells from Juzen-taiho-to-treated mice exhibited significantly greater cytotoxicity than those of untreated controls (Kawamura et al., 1988). Further evidence for the ability of Juzen-taiho-to to activate both macrophages and T cells comes from the recent finding that the tumor-inhibitory effect of Juzen-taiho-to was abrogated in nude mice and in mice whose macrophages had been eliminated by treatment with 2-chloroadenosine (Ohnishi et al., 1998).

4. Keishi-ni-eppi-ichi-to Keishi-ni-eppi-ichi-to (TJS-064) is prepared as a hot-water extract from seven ingredients (Table 1). It is used to treat the common cold and ‘flu,’ headaches as well as arthritis and eczema (Table 2). When mice were treated orally with Keishi-nieppi-ichi-to 1 day before and 1 and 4 days after infection with a 5 LD50 dose of influenza A2(H2N2) virus, all of them survived over a 25day experimental period while all the salinetreated control mice died (Ball et al., 1994). Pulmonary consolidations, virus titers in lung tissues, and antibody titers in sera of infected mice treated with Keishi-ni-eppi-ichi-to were all significantly lower than those of infected mice treated with saline. However, Keishi-ni-eppi-ichi-to was not effective when the dose of influenza virus was 100 LD50 or higher. When each herbal component of Keishi-ni-eppi-ichi-to was tested indi-

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vidually, Cinnamomi cortex and Zizyphi fructus had no protective effect, while Paeoniae radix, Glycyrrhizae radix, Ephedrae herba, and Zingiberis rhizoma each resulted in a small increase in the mean survival time of infected mice. In contrast, the combination of these four extracts, or of all six extracts (which is Keishi-ni-eppi-ichito without the pH-neutralizing agent gypsum), provided significant protection against A2(H2N2) viral infection. Those results suggest that the antiviral effect of Keishi-ni-eppi-ichi-to in mice infected with influenza A2 virus is the result of the additive or synergistic effects of its herbal components rather than of any one individual constituent.

5. Keishi-ni-eppi-ichi-to-ka-ryo-jutsubu Keishi-ni-eppi-ichi-to-ka-ryo-jutsubu (KNEITRJB) consists of Hoelen, A. lanceae rhizoma and Aconitii tuber in addition to the seven constituents of Keishi-ni-eppi-ichi-to (see Table 1 for their identity and proportions). It is used for the treatment of rheumatoid arthritis (RA) and other arthropathies, but also used for colds and headaches (Table 2). In a clinical trial, KNEIT-RJB was given to 14 patients (three males, 11 females) with RA (Kogure et al., 1996). All patients received nonsteroidal anti-inflammatory drugs (NSAIDs) and seven took other medications (two, D-penicillamine; two, gold salts; and three, prednisolone (PSL; 4–10 mg/day), which were not altered during this trial. Both the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) decreased significantly 12 weeks after the start of treatment with KNEIT-RJB in comparison with baseline, and no adverse effects were observed. Nine of 14 patients responded to treatment with KNEIT-RJB by showing at least a 25% improvement by the Lansbury index. Although the sample size was small and the trial was not randomized, double-blind, or placebocontrolled, these encouraging results warrant further clinical trials with KNEIT-RJB in the treatment of RA.

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6. Keishi-bushi-to Keishi-bushi-to consists of only five of the ten ingredients used in the preparation of KNEITRJB, and these five plant extracts are mixed in different proportions (see Table 1). It is also indicated for the treatment of RA (Wakabayashi et al., 1997). Collagen-induced arthritis (CIA) is an animal (mouse or rat) model of RA that shares many of the characteristics of the human disease (Feldmann et al., 1996). Oral administration of Keishibushi-to, given prophylactically to Lewis rats, significantly delayed the onset and reduced the severity of CIA (Wakabayashi et al., 1997). When treatment with Keishi-bushi-to was started on the day of immunization, it slightly reduced the severity of arthritis, and this reduction became significant approximately 2 weeks after disease onset. Anti-collagen II antibodies (both IgM and IgG) were lower in the treated group compared with the controls. The clearance rate of exogenous anti-collagen II antibodies was faster in the first 24 h after their injection, but serum levels were similar in the two groups after 96 h. However, since the contribution of autoantibodies to the disease course of RA is as yet undetermined, the significance of these findings is uncertain.

7. Toki-shakuyaku-san Toki-shakuyaku-san (TSS), a Kampo formula traditionally administered as a powder (‘san’ means powder) of six different plants (Table 1), is also taken as a tea. Toki-shakuyaku-san (TSS) is most commonly prescribed for ovarian dysfunction and post-menopausal syndrome (Table 2). Recently, however, some immunomodulatory effects of TSS have also been proposed. Based on the findings that some Kampo formulae can ameliorate symptoms of systemic lupus erythematosus (SLE) in animal models, four such preparations were tested for their ability to reduce circulating immune complexes (Iijima et al., 1993, 1994). Among the formulae tested, only TSS significantly enhanced the binding of an immune complex consisting of peroxidase-anti-peroxidase

to macrophages in vitro; Angelicae radix and A. lanceae rhizoma were the individual herbal constituents primarily responsible for this effect (Iijima et al., 1993). In vivo, TSS administered orally to MRL Mp-lpr/lpr mice, a model of human SLE, for 6 weeks accelerated the clearance of intravenously (i.v.) delivered glucose oxidase-antiglucose-oxidase complexes (GAG) (Iijima et al., 1994). The half-life (t1/2) of GAG in the circulation was significantly shortened in the TSS-treated group, and this effect was abolished by the omission of either Angelicae radix or A. lanceae rhizoma from the extract. However, none of the individual herbal constituents of TSS had any significant effect on GAG-clearance.

8. Unsei-in (Chinese name, Wen-Quing-Yin) Unsei-in consists of the hot-water extract of eight different medicinal plants (Table 1). It is used extensively in Japan for treatment of allergic dermatitis, eczema, psoriasis, and Behc¸et’s disease (Table 2). In vitro, Unsei-in reduced the rheological activity (adhesion, deformability, and aggregation) of leukocytes obtained from normal individuals only when the leukocytes had been stimulated by Nformyl-methionyl-leucyl-phenylalanine (FMLP; Iijima et al., 1995). In contrast, Unsei-in reduced the rheological activity of unstimulated, but not of stimulated, leukocytes obtained from patients with Behc¸et’s disease. A plausible explanation would be that the leukocytes of patients with Behc¸et’s disease were already strongly activated and that Unsei-in was unable to overcome the further stimulation by FMLP. Oral pretreatment for 5 days with either Unseiin or Oren-gedoku-to, which consists of four of the constituents of Unsei-in (Coptidis rhizoma, Scutellariae radix, Gardeniae fructus, and Angelicae radix), markedly reduced rat paw edema induced by injection of carrageenan, egg albumin, or bradykinin (Wang et al., 1997). These two formulae also reduced the increased serum IL-8 levels accompanying acetic acid-induced inflammation in rats (Wang et al., 1997).

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Table 3 Immunomodulatory effects of Kampo formulae and their possible mechanisms Compound

Effect

Possible mechanisms

Juzen-taiho-to

General immuno-stimulation

Keishi-bushi-to

Ameliorates CIA

Keishi-ni-eppiichi-to Shosaiko-to

Protects mice against influenza virus

Unsei-in

Used for treatment of eczema, allergic dermatitis, Behc¸et’s disease

Activates complement and stimulates mouse spleen cell proliferation in vitro; pectic polysaccharide fraction increases number of PFC ex vivo Decreases anti-collagen Abs, increases clearance of exogenous anti-collagen Abs Decreases viral titers, but also decreases anti-influenza Ab titers Has direct cytostatic effect on hepatocellular carcinoma cell lines; increases IFN production and NK activity; upregulates G-CSF, TNF-, IL-1, IL-10, downregulates Con A-stimulated IL-4 and IL-5 production by human PBMC; increases serum IFN and IL-6 activity of i.p. treated mice; increases serum TNF activity in orally treated mice Decreases rheological activity of activated human leukocytes; inhibits inflammation-induced IL-8 production in rats; inhibits type IV allergic and graft versus host reactions in mice

Protects against viral hepatitis and hepatocellular carcinoma

When administered orally to mice starting at the time of primary immunization, Unsei-in inhibited type IV allergic reactions to picryl chloride, SRBC, or tuberculin (Koda et al., 1987). However, Unseiin was ineffective when it was given at the time of the primary challenge, indicating that it could influence the induction, but not the effector phase of these reactions. Administered orally for 8 days beginning at the time of transplantation of spleen cells, Unsei-in inhibited significantly the graft versus host reaction as measured by the weight increase of popliteal lymph nodes. Unsei-in did not affect significantly the number of IgM-PFC after immunization with SRBC. Taken together, these results suggest that Unsei-in has modulatory effects mostly on cellular, not on humoral, immunity.

9. Conclusion Consumer interest in medicinal botanicals has increased greatly in recent years, particularly in the United States. However, there is little statistical data that quantitates the use of TCM in the United States. Nonetheless, there has been a rapid increase in the number of practitioners of Oriental medicine,

and Chinese herbal/Kampo formulae are now offered in specialty and health food stores. The usage of medicinal botanicals, though difficult to assess with precision, appears particularly high among patients with chronic diseases, including cancer (Ernst and Cassileth, 1998), autoimmune diseases (Pal, 1998; Rao et al., 1998), asthma (Andrews et al., 1998; Ernst, 1998), and acquired immunedeficiency syndrome (AIDS) (Ernst, 1997). This, along with the fact that echinacea and goldenseal, putative immune-enhancers, are among the top-selling herbal products in the United States (Scimone and Scimone, 1998), suggests that many consumers turn to botanicals in order to ‘boost’ their immune system, while others seek to downregulate certain immune responses. Yet available research demonstrates that individual herbal constituents of Kampo medicines often have different and even opposite effects on immune function than the whole formula, emphasizing the need for research on component interaction and quality control in manufacturing. The latter takes on particular importance in view of the well-known fact that botanical extracts vary considerably in their chemical composition depending on growing, harvesting, processing and storage conditions. Although the biological

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activities of some Kampo formulae, e.g. Shosaiko-to and Juzen-taiho-to, have been investigated extensively and systematically, for many other compounds only isolated research reports exist (Table 3). Because these herbal formulae have been used for centuries, both in China and in Japan, it has been assumed they are both safe and efficacious. Further, a limited number of adequately controlled and randomized clinical trials tends to confirm some beneficial effects of some Kampo formulae. However, as with other medicinal botanicals (Homma et al., 1993b; Matsuoka et al., 1997), there appear to be responders and non-responders among patients. Clearly, it would be desirable to obtain data on the pharmacokinetics of these plant extracts and differences in response due to sex and age. In view of their chemical complexity such an undertaking might be difficult, but some pharmacokinetic studies on specific marker compounds of the Kampo medicine, Saiboku-to, suggest that such an approach could be useful in identifying patients for whom a particular compound might be beneficial (Homma et al., 1992, 1993a,b). The occurrence of acute pneumonitis in hepatitis patients treated with Shosaiko-to either alone or in combination with interferon, provides an example of the adverse effects and drug interactions that can arise from the consumption of botanicals. There is a paucity of data on other interactions between Kampo formulae and Western pharmaceuticals. However, the data that exist suggest that certain Kampo medicines can enhance or inhibit both the absorption and elimination of Western drugs (Chan et al., 1995; Nishimura et al., 1998; Ohnishi et al., 1999). The growing number of case reports of adverse reactions to botanicals consumed either alone or in combination with other medications (Shaw et al., 1997; Cupp, 1999) underscores the urgent need for systematic research addressing not only direct toxicity and allergenicity, but also pharmacologic interactions with modern pharmaceuticals.

Acknowledgements Supported by National Institutes of Health

Grant U24 AI37627 and a grant from the Uehara Memorial Foundation, Japan.

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