Toxicological aspects of Kampo medicines in clinical use

Toxicological aspects of Kampo medicines in clinical use

Chemico-Biological Interactions 145 (2003) 235 /250 www.elsevier.com/locate/chembioint Minireview Toxicological aspects of Kampo medicines in clini...
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Chemico-Biological Interactions 145 (2003) 235 /250 www.elsevier.com/locate/chembioint

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Toxicological aspects of Kampo medicines in clinical use Fumio Ikegami a,*, Yuichi Fujii b, Kazuhisa Ishihara b, Tetsuo Satoh c a

Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan b Tsumura & Co., Niban-cho 12-7, Chiyoda-ku, Tokyo 102-8422, Japan c Biomedical Research Institute, Hiratsuka 2802-1, Shiroi 270-1402, Japan Received 31 October 2002; received in revised form 29 December 2002; accepted 7 January 2003

Abstract Among 210 medicinal prescriptions used in present-day Japan, the clinical uses and the acute, chronic and mutagenic toxicity study of 16 Kampo (Japanese herbal) medicines are summarized. These Kampo medicines are classified into two categories; eight prescriptions containing Bupleurum root (Bupleurum falcatum L.) such as Sho-saiko-to and Saikokeishi-to, and eight prescriptions not containing Bupleurum root such as Juzen-taiho-to and Ninjin-yoei-to. Studies of some potential interaction between herbal medicine and western drugs are also described. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Kampo medicine; Japanese herbal medicine; Crude drug; Clinical use; Toxicity; Interaction

1. Introduction The unique role played in modern Japanese medicine by Kampo (Japanese herbal) medicine is gradually attracting world-wide attention. Although Kampo has much to offer to modern medicine, researchers and clinicians need to be aware of the fact that Kampo has its own distinctive philosophy and methodology, and it is not appropriate simply to take Kampo formulas and indiscriminately introduce them into modern medical practice.

* Corresponding author. Tel./fax: /81-43-290-2942. E-mail address: [email protected] (F. Ikegami).

Kampo is a general term for the unique system of traditional medicine developed in Japan from Chinese origins, and came to be used widely. There are many kinds of medicinal plants commonly used in traditional Japanese medicine, and now 120 kinds of crude drugs (almost all of plant origin, with some of animal or mineral origin) are listed in the Japanese Pharmacopoeia (JP XIV) (Table 1) [1], and are used or recommended as the source of Kampo medicine or traditional medicine (Table 2) [2]. One third of the crude herbal drugs listed in JP XIV are also listed in WHO monographs [3] and are used mainly in Kampo medicine in Japan. Not only has the usefulness of Kampo been recognized by the scientific medical system in present-day Japan, its usage has also steadily

0009-2797/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0009-2797(03)00004-8

236

Table 1 List of crude drugs using in Kampo medicine and numbers of the Japanese prescriptions in the Japanese Pharmacopoeia XIV Name of crude drug

No. Name of crude drug

No. Name of crude drug

5

Lotus seed: Nelumbo nucifera Gaertner

Clematis root: Clematis chinensis Osbeck

2

Gardenia fruit: Gardenia jasminoides Ellis

Artemisia Capillaris spike: Artemisia capillaris Thunb. Fennel: Foeniculum vulgare Miller

2

Cornus fruit: Cornus officinalis Sieb. et Zucc.

4

1

Zanthoxylum fruit: Zanthoxylum piperitum DC.

2

1

Jujube seed: Zizyphus jujuba Miller

3

4

Corydalis tuber: Corydalis turtshaninovii Bess. f. yanhusuo Y.H. Chou et C.C. Hsu

2 15

Astragalus root: Astragalus membranaceus Bunge, A. mongholicus Bunge

14

Dioscorea rhizome: Dioscorea japonica Thunb., D. batatas Decaisne

Scutellaria root: Scutellaria baicalensis Georgi

27

Rehmannia root: Rehmannia glutinosa Lib. var. 22 purpurea Makino Lycium bark: Lycium chinense Miller 2

Phellodendron bark: Phellodendron amurense Ruprecht, P. chinense Schneider Coptis rhizome: Coptis japonica Makino, C. chinensis Franchet Polygala root: Polygala tenuifolia Willd. Artemisia herb: Artemisia princeps Pamp., A. montana Pamp. Polygonum root: Polygonum multiflorum Thunb.

8 11 3 1

Lithospermum root: Lithospermum erythrorhizon Sieb. et Zucc. Tribulus fruit: Tribulus terrestris L. Peony root: Paeonia lactiflora Pallas

1

Plantago seed: Plantago asiatica L.

4

Pueraria root: Pueraria lobata Ohwi

4

Amomum seed: Amomum xanthioides Wallich

1

Talc

6

Ginger root: Zingiber officinale Roscoe

Trichosanthes root: Trichosanthes kirilowii Maxim., 2 T. kirilowii Maxim. var. japonicum Kitamura Trichosanthes seed: Trichosanthes kirilowii Maxim., 1 T. kirilowii Maxim. var. japonicum Kitamura Dried Ginger root: Zingiber officinale Rosc. 11 Licorice root: Glycyrrhiza uralensis Fisher, G. glabra L. Platycodon root: Platycodon grandiflorum A. DC.

Wheat seed: Triticum aestivum L.

1 1 44

52 1

94

Cimicifuga rhizome: Cimicifuga simplex 5 Wormsk., C. dahurica Maxim. Magnolia floral bud: Magnolia saliciflora Max- 2 im., M. kobus DC. Gypsum 10

12

Cnidium rhizome: Cnidium officinale Makino

25

Citrus Unshiu peel: Citrus unshiu Markv., C. reticulata Blanco Arisaema tuber: Arisaema japonicum Bl., A. heterophyllum Bl. Gastrodia tuber: Gastrodia elata Bl.

24 1 1

Chinese Asparagus root: Asparagus cochinchi2 nensis Merr. Benincasa seed: Benincasa cerifera Savi, B. 1 cerifera Savi f. emarginata K. Kimura et Sugiyama 38 Japanese Angelica root: Angelica acutiloba Kitagawa, A. acutiloba Kitag. var. sugiyamae Hikino Peach kernel: Prunus persica Batsch, P. persica 6 Batsch var. davidiana Maxim. Eucommia bark: Eucommia ulmoides Oliv. 1 Ginseng: Panax ginseng C.A. Meyer

37

Honeysuckle herb: Lonicera japonica Thunb. 1 Fritillary bulb: Fritillaria verticillata Willd. var. 2 thunbergii Bak. Malt: Hordeum vulgare L. var. hexastion 1 Aschers. Ophiopogon tuber: Ophiopogon japonicus Ker- 11 Gawler Mentha herb: Mentha arvensis L. var. piper7 ascens Malinvaud Glehnia root: Glehnia littoralis Fr. Schmidt ex 1 Miquel Pinellia tuber: Pinellia ternata Breit. 27 Lily bulb: Lilium lancifolium Thunb., L. brownii F.E. Brown var. colchesteri Wilson Angelica Dahurica root: Angelica dahurica Bentham et Hooker Atractylodes rhizome: Atractylodes japonica Koidz. ex kitam., A. ovata DC.

1 5 8

F. Ikegami et al. / Chemico-Biological Interactions 145 (2003) 235 /250

Gelatin

No.

Table 1 (Continued ) Name of crude drug

No. Name of crude drug

Schizonepeta spike: Schizonepeta tenuifolia Briquet 8 Cinnamom bark: Cinnamomum cassia Blume 39 Safflower: Carthamus tinctorius L.

2

Cyperus rhizome: Cyperus rotundus L.

6

Oryza seed: Oryza sativa L. Magnolia bark: Magnolia obovata Thunb., M. officinalis Rehder et Wilson Achyranthes root: Achyranthes fauriei Lev. et Vaniot, A. bidentata Blume Evodia fruit: Evodia rutaecarpa Benth., E. officinalis Dode Arctium fruit: Arctium lappa L. Sesame seed: Sesamum indicum L. Schisandra fruit: Schisandra chinensis Baillon Bupleurum root: Bupleurum falcatum L. Asiasarum root: Asiasarum sieboldii F. Maek., A. heterotropoides F. Maek. var. mandshuricum F. Maek. Alpinia Officinarum rhizome: Alpinia officinarum Hance

2 12

3 3 2 2 5 22 3

1

No.

Peucedanum root: Peucedanum praeruptorum Dunn. Nuphar rhizome: Nuphar japonicum DC.

1

Eriobotrya leaf: Eriobotrya japonica Lindley

1

1

Areca seed: Areca catechu L.

1

Cicada: Cryptotympana pustulata Fabr.

1

Poria sclerotium: Poria cocos Wolf

Atractylodes Lancea rhizome: Atractylodes lan- 34 cea DC., A. chinensis Koidz. Mulberry bark: Morus alba L. 2 Caesalpinia wood: Caesalpinia sappan L. 1 Perilla herb: Perilla frutescens Britton var. acuta 6 Kudo, P. frutescens Britton var. crispa Decaisne Rhubarb: Rheum palmatum L., R. tanguticum 14 Maxim., R. officinale Baillon Jujube fruit: Zizyphus jujuba Miller var. inermis 37 Rehder Alisma rhizome: Alisma orientale Juzepc. 14 Bamboo: Phyllostachys nigra Munro var. heno- 2 nis Stapf ex Rendle, P. bambusoides Sieb. et Zucc. Anemarrhena rhizome: Anemarrhena asphode6 loides Bunge Tea leaf: Thea sinensis L. 1 Clove: Syzygium aromaticum Merr. et Perry Uncaria thorn: Uncaria rhynchopylla Miq., U. sinensis Oliv. Polyporus sclerotium: Polyporus umbellatus Fries Forsythia fruit: Forsythia suspensa Vahl, F. viridissima Lindl. Aralia root: Aralia cordata Thunb.

Japanese Gentian: Gentiana scabra Bunge, G. manshurica Kitagawa

Aconite tuber: Aconitum carmichaeli Debx.

46 6

Sinomenium stem: Sinomenium acutum Rehder 3 et Wilson Mirabilitum 4 Saposhnikovia root: Saposhnikovia divaricata 11 Schischkin Quercus bark: Quercus acutissima Carruthers 2 Moutan bark: Paeonia suffruticosa Andrews

8

Oyster shell: Ostrea gigas Thunb. Ephedra herb: Ephedra sinica Stapf, E. intermedia Schrenk et C.A. Meyer, E. equisetina Bunge Hemp seed: Cannabis sativa L.

4 13

5

6

Akebia stem: Akebia quinata Decaisne, A. trifoliata Koidz. Saussurea rot: Saussurea lappa Clarke Coix seed: Coix lacryma-jobi L. var. mayuen Stapf Longan fruit: Euphoria longana Lamarck

2

5

Fossilized bone

2

1

Ipecac: Cephaelis ipecacuanha A. Richard, C. acuminata Karsten

1

2 4

3

3 3

F. Ikegami et al. / Chemico-Biological Interactions 145 (2003) 235 /250

Immature Orange: Citrus aurantium L. var. daidai 14 Makino, C. natsudaidai Hayata Chrysanthemum flower: Chrysanthemum indicum 1 L., C. morifolium Ramat. Notopterigum rhizome: Notopterygium incisum 3 Ting ex H.T. Chang, N. forbesii Boissieu Apricot kernel: Prunus armeniaca L., P. armeniaca 9 L. var. ansu Maxim Sophora root: Sophora flavescens Aiton 2

No. Name of crude drug

3

237

238

Table 2 Composition of crude drugs in the Japanese prescriptions studied for toxicity No Japanese prescription name Otsuji-to

2 3 4 5 6

17

Hatimi-jio-gan Dai-saiko-to Sho-saiko-to Saiko-keishi-to Saiko-ka-ryukotsuborei-to Hange-shashin-to Oren-gedoku-to Sho-seiryu-to Sho-hange-ka-bukuryo-to Toki-shakuyakusan Kami-shoyo-san Keishi-bukuryo-gan Mao-to Bakumondo-to Byakko-ka-ninjinto Shigyaku-san

18 19 20 21 22

Hochu-ekki-to Rikkunshi-to Choto-san Juzen-taiho-to Sokei-kakketsu-to

23

26 27 28 29 30

Keishi-ka-shakuyaku-to Shakuyaku-kanzoto Yokukan-san-kachimpi-hange Daio-kanzo-to Saiboku-to Unkei-to Gosha-jinki-gan Ninjin-yoei-to

31

Sairei-to

7 8 9 10 11 12 13 14 15 16

24 25

Jpn Angelica Rehmannia Bupleurum Bupleurum Bupleurum Bupleurum

Bupleurum

Scutellaria

Licorice

Cimicifuga

Rhubarb

Cornus Pinellia Pinellia Pinellia Pinellia

Dioscorea Scutellaria Scutellaria Scutellaria Scutellaria

Alisma Peony Licorice Licorice Poria

Poria Jujube Jujube Jujube Jujube

Moutan Citrus Unshiu Ginseng Ginseng Ginseng

Cinnamomum Ginger Ginger Ginger Ginger

Coptis Coptis Pinellia Pinellia

Pinellia Gardenia Poria Poria

Scutellaria Scutellaria Magnolia Ginger

Licorice Jujube Phellodendron Perilla Ginger

Ginseng

Ginger

Peony

Poria

Atractylodes

Alisma

Cnidium

Jpn Angelica

Peony Peony Armeniaca Ophiopogon Gypsum

Poria Poria Ephedra Pinellia Anemarrhena

Atractylodes Cinnamom Cinnamom Jujube Licorice

Bupleurum Peach Licorice Licorice Ginseng

Gardenia Moutan

Jpn Angelica

Ginseng Oryza

Oryza

Bupleurum

Peony

Jujube Jujube Ophiopogon Atractylodes Peach

Aconite Rhubarb Cinnamomum Peony Cinnamomum Oyster

Fossilized bone

Moutan

Licorice

Ginger

Mentha

Citrus Unshiu Licorice Licorice Jpn Angelica Poria

Licorice Ginger Ginger Ginseng Achyranthes

Ginger

Cimicifuga

Licorice

Astragalus Pinellia Gypsum Astragalus Peony

Citrus Unshiu Atractylodes Ginseng Atractylodes Ginseng Citrus Unshiu Ginseng Cinnamomum Cnidium Rehmannia Cnidium

Jpn Angelica Poria Poria Peony Atractylodes

Bupleurum Aurantium Pinellia Rehmannia Jpn Angelica

Peony

Cinnamomum Jujube

Licorice

Ginger

Peony

Licorice

Pinellia

Atractylodes

Poria

Cnidium

Citrus Unshiu

Jpn Angelica

Bupleurum

Licorice

Uncaria

Rhubarb Bupleurum Ophiopogon Rehmannia Rehmannia

Licorice Pinellia Pinellia Evodia Jpn Angelica

Poria Licorice Cornus Atractylodes

Licorice Jpn Angelica Dioscorea Poria

Jujube Cinnamomum Plantago Ginseng

Ginseng Peony Alisma Cinnamomum

Ginger Cnidium Poria Polygala

Scutellaria Ginseng Cinnamomum Peony

Bupleurum

Alisma

Pinellia

Scutellaria

Atractylodes

Jujube

Polyporus

Ginseng

Perilla Moutan Moutan Citrus Unshiu Poria

Licorice

Uncaria Poria Citrus Unshiu Angelica Dahurica

Chrysanthemum Licorice Sinomenium

Saposhnikovia

Jpn Gentian

Ginger

Notopterigum

Clematis

Magnolia Evodia Aconite Astragalus

Ginger

Gelatin

Licorice

Schisandra

Licorice

Ginger

Cinnamomum

F. Ikegami et al. / Chemico-Biological Interactions 145 (2003) 235 /250

1

F. Ikegami et al. / Chemico-Biological Interactions 145 (2003) 235 /250

spread. The most important aspect contributing to the widespread use of Kampo is that it is effective in the treatment of certain disorders and disease states. It is currently still serving many of the health needs of the Japanese people, and is enjoying their confidence when it is practiced in Japan in parallel with modern western medical treatment. However, it has been well demonstrated that several potential side effects such as allergic reactions, cramps, diarrhea, fever, gastrointestinal disturbances, headaches, hematuria, intestinal sluggishness associated with stimulant laxatives, nausea, photosensitization, and vomiting may be experienced when administering the herbal medicine or Kampo medicine [4]. In addition, it has been reported that herbal medicine or Kampo medicine may have antagonistic or synergistic interactions with western drugs or with some foods such as grapefruit juice. Since herbal medicine or Kampo medicine results from the combination of many substances and their effect is a combination of the various interactions of the constituent substances, and their toxicological effects in animals are naturally moderate. Until now, the mechanisms of toxicity of only three Kampo medicinal prescriptions, Sho-saiko-to, Shigyakusan and Keishi-bukuryo-gan, have been studied. Because of the complexity of composition of Kampo medicines, it might be difficult to demonstrate the mechanism or mode of action of Kampo medicines. Data available were obtained from only part of the constituent crude drugs that have been studied for their toxicity and for their pharmacokinetic interaction with other clinically used drugs. This paper presents the clinical uses and toxicity studies of 16 Kampo medicines based on herbal crude drugs in WHO monographs. These Kampo medicines are classified into two categories; eight prescriptions containing Bupleurum root (Bupleurum falcatum L.) and eight prescriptions not containing Bupleurum root. Toxicity in clinical uses for Bupleurum root-containing prescriptions have been most studied. Possible mechanism of interactions between herbal medicine and western drugs in terms of the inhibition and induction in drug metabolism are also considered.

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2. Clinical uses and toxicity study of 16 kinds of Kampo medicine The clinical uses and toxicity studies of 16 Kampo medicines consisting of multiple crude drugs are summarized in this section. These herbal medicines are classified into two categories; eight prescriptions containing Bupleurum root and eight prescriptions not containing Bupleurum root. The toxicity studies of Kampo medicines used in present-day Japan are listed in Table 3. Among eight prescriptions containing Bupleurum root, Sho-saiko-to, Saiko-keishi-to, Saiboku-to and Sairei-to consist of several common crude drugs including Bupleurum root (B. falcatum L.), Licorice root (Glycyrrhiza uralensis Fisher or G. glabra L.), Ginger root (Zingiber officinale Roscoe), Ginseng root (Panax ginseng C.A. Meyer), Pinellia tuber (Pinellia ternata Breit.) and Jujube fruit (Zizyphus jujuba Miller var. inermis Rehder) (Table 2). Among the prescriptions containing Bupleurum root, only Hochuekki-to does not contain Pinellia tuber. Otsuji-to, Shigyaku-san and Kami-shoyo-san are grouped into a third group among the prescriptions containing Bupleurum root. In this group, Otsuji-to and Shigyaku-san do not contain Ginger root, Ginseng root, Pinellia tuber and Jujube fruit, and Kami-shoyo-san does not contain Ginseng root, Pinellia tuber and Jujube fruit, respectively. 2.1. Sho-saiko-to Sho-saiko-to is an extract of a mixture of seven crude drugs, i.e. Bupleurum root, Pinellia tuber, Scutellaria root (Scutellaria baicalensis Georg.), Jujube fruit, Ginseng root, Licorice root and Ginger root. This preparation has various pharmacological applications, e.g. inducing/augmenting antibody response and DNA synthesis [5]. This Kampo medicine has been used clinically for the treatment of acute fever, pneumonia, bronchitis, influenza, lymphadenitis, chronic gastrointestinal disorder and liver injuries. The acute lethal dose of Sho-saiko-to is more than 6.4 g/kg body weight in rats and mice, while those of Saiko-keishi-to, Saiboku-to and Sairei-to are more than 8 g/kg [6 /8]. A 13-week subacute

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240

Table 3 List of the Japanese prescriptions investigated for toxicity No Prescription name

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Otsuji-to Hatimi-jio-gan Dai-saiko-to Sho-saiko-to Saiko-keishi-to Saiko-ka-ryukotsu-boreito Hange-shashin-to Oren-gedoku-to Sho-seiryu-to Sho-hange-ka-bukuryoto Toki-shakuyaku-san Kami-shoyo-san Keishi-bukuryo-gan Mao-to Bakumondo-to Byakko-ka-ninjin-to Shigyaku-san Hochu-ekki-to Rikkunshi-to Choto-san Juzen-taiho-to Sokei-kakketsu-to Keishi-ka-shakuyaku-to Shakuyaku-kanzo-to Yokukan-san-ka-chimpihange Daio-kanzo-to Saiboku-to Unkei-to Gosha-jinki-gan Ninjin-yoei-to Sairei-to

Acute toxicity

Subacute toxi- Chronic toxi- Teratology Reproductive toxi- Mutagenicity Others city city city

1

1

1

2

3

2

1

1

1 2 2 1 1 1

1 1 1

1 1 1

1 1

1

1

2

2

1 1 1 1

1 1 1

2

1 1

1 1 1

1

1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1

1

1

1

1 1 1

1

1

1 1 1 1

1 2 1 1 1 2

1 1 1 1

1

1

1 1

Note: Numbers in the columns represent the number of toxicity studies that have been conducted and reported in the literature for each endpoint.

toxicity study showed that Sho-saiko-to caused no deaths throughout the test period and that the maximum non-toxic dose of Sho-saiko-to in rats was 1 g/kg per day [9]. The results indicate that the acute and subacute toxicity of Sho-saiko-to is comparatively low in mice and rats. A 3-month oral toxicity study with a 4-week recovery period in the rat indicated that a daily dose of Sho-saikoto up to 2 g/kg produces no toxicologically significant effects [10]. A 13-week study of Shosaiko-to in rats following multiple dosing showed

that Sho-saiko-to caused no notable effects on hematology, blood chemistry, on gross or microscopic examination [11]. The maximum non-toxic daily dose was estimated to be more than 2 g/kg body weight. A 1-year chronic oral toxicity study of Sho-saiko-to in rats showed an increase of serum a-hydroxybutyrate dehydrogenase level and a higher triglyceride value, but a decrease of serum alkaline phosphatase level at a dose of 640 mg/kg [12]. The chronic toxicity of Sho-saiko-to was also studied by oral administration to rats at a dose of

F. Ikegami et al. / Chemico-Biological Interactions 145 (2003) 235 /250

2.5 g/kg per day for 1 year [13]. Based on the results that Sho-saiko-to exhibited the decrease in serum GOT and GTP levels and in urine chloride level, suggesting its pharmacological effects, the no-effect dose level of Sho-saiko-to was concluded to be 500 mg/kg. From these results, it is suggested that Sho-saiko-to has no notable toxicity and is a highly safe Kampo medicine. A teratogenicity study of orally administered Sho-saiko-to in rats suggested that the no-effect daily dose level is more than 2.5 g/kg body weight for general toxicity and reproductive ability in parent animals, for fetal and postnatal development of F1 offspring, and for fetal development of F2 offspring [14]. Based on the reproductive and developmental toxicity study of Sho-saiko-to in rats by oral administration, the non-toxic daily dose level of Sho-saiko-to for general toxicity and reproductivity of F0 parents was concluded to be above 2 g/kg body weight, and the non-toxic dose level for the second generation was also above 2 g/ kg [15,16]. Mutagenic potential of Sho-saiko-to was studied by reverse mutation, chromosomal aberration, micronucleus tests and unscheduled DNA synthesis (UDS) assay [17]. From these results, it was concluded that Sho-saiko-to has no mutagenic potential in intact animals though it induces the slight increase of reverse mutation in vitro. It has been demonstrated that Sho-saiko-to showed synergistic effects with interferons a/b (IFN a/b) in vivo inducing interstitial pneumonia and that it also caused pseudoaldosteronism or hepatitis increasing GOT and GTP levels as heavy side effects [18]. Therefore, the Japanese Ministry of Health, Labour and Welfare has cautioned against using Kampo medicines containing Bupleurum root and Licorice root, especially Shosaiko-to, in clinical use. The quality of manufactured Kampo medicines is controlled against definite standards specifically concerning variations in formulae and herbal substitutions. It is of course necessary to study the potential effects of Kampo medicine to confirm the efficacy or risk for side effects in clinical use, also the pharmacodynamic and pharmacokinetic interactions of many Kampo medicines with or without western drugs remain to be studied. More information on the

241

mechanism or mode of action of Kampo medicines in clinical use may be needed for demonstrating the safety, efficacy and any actual or theoretical interactions of Kampo medicine. 2.2. Saiko-keishi-to Saiko-keishi-to is an extract of a mixture of nine crude drugs, i.e. Bupleurum root, Pinellia tuber, Scutellaria root, Licorice root, Cinnamon bark (Cinnamomum cassia Blume), Peony root (Paeonia lactiflora Pallas), Jujube fruit, Ginseng root and Ginger root. This preparation has been used clinically for the treatment of gastritis often accompanying abdominal pain, and for the symptoms of the later stage of cold such as mild fever, chill, headache and nausea. A subchronic (3-month) toxicity study in the rat by oral administration with a 4-week recovery period indicated that a daily dose of Saiko-keishito up to 2 g/kg body weight produced no significant toxicological effect [6]. The mutagenic potential of Saiko-keishi-to was also studied following the same protocols as for Sho-saiko-to, and it was concluded that, like as Sho-saiko-to, Saiko-keishi-to has no mutagenic properties [19]. 2.3. Saiboku-to Saiboku-to is an extract of a mixture of ten crude drugs, i.e.: Bupleurum root, Pinellia tuber, Poria sclerotium (Poria cocos Wolf), Licorice root, Jujube fruit, Ginseng root, Ginger root, Scutellaria root, Perilla herb (Perilla frutescens Britt. var. acuta Kudo or P. frutescens Britt. var. crispa Decne) and Magnolia bark (Magnolia obovata Thunb. or M. officinalis Rehder et Wilson). This preparation has been used clinically for the treatment of infant asthma, bronchial asthma and cough. A single oral dose toxicity study and a 13-week repeated dose study with a 4-week recovery period of Saiboku-to in rats has been reported [7]. A 90day oral toxicity study in rats showed that Saiboku-to produces no toxicologically significant effects at a daily dose of more than 2 g/kg body weight but the non-toxic dose level was slightly different for males and females [20]. Reproductive

242

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and developmental toxicity study of Saiboku-to in rats by oral administration suggested that the nontoxic daily dose level was more than 2 g/kg, similar to Sho-saiko-to [21]. 2.4. Sairei-to Sairei-to is an extract of a mixture of twelve crude drugs, i.e. Bupleurum root, Alisma rhizome (Alisma orientale Juzep.), Pinellia tuber, Scutellaria root, Atractylodes lancea rhizome (Atractylodes lancea DC. or A. chinensis Koidz.), Jujube fruit, Polyporus sclerotium (Polyporus umbellatus Fries), Ginseng root, Poria sclerotium, Licorice root, Ginger root and Cinnamon bark. This preparation has been used clinically for the treatment of diarrhea, acute gastroenteritis and edema. A single oral dose toxicity study and a 13-week repeated dose study with a 4-week recovery period of Sairei-to in rats have been reported [8]. A 90day and 12-month toxicity studies in rats, and reproductive and developmental toxicity study in rats by oral administration were also reported on Sairei-to [22 /24]. Teratological evaluation of oral administration in rats and mutagenicity study of Sairei-to were also reported [25,26]. These results indicated that Sairei-to has no significant toxicological effect at a dose of more than 2 g/kg per day. 2.5. Hochu-ekki-to Hochu-ekki-to is an extract of a mixture of ten crude drugs, i.e. Astragalus root (Astragalus membranaceus Bunge or A. mongholicus Bunge), Atractylodes lancea rhizome, Ginseng root, Japanese Angelica root (Angelica acutiloba Kitagawa or A. acutiloba Kitagawa var. sugiyamae Hikino), Bupleurum root, Jujube fruit, Citrus Unshiu peel (Citrus unshiu Markovich or C. reticulata Blanco), Licorice root, Ginger root and Cimicifuga rhizome (Cimicifuga simplex Wormsk., C. dahurica Maxim., C. foetida L. or C. heracleifolia Komarov). This preparation has been used clinically for reinforcement of physical strength after disease, and for the treatment of anorexia or bathygastry, common cold and impotence. A single oral dose toxicity study of Hochu-ekkito in rats indicated that a lethal dose of Hochu-

ekki-to was more than 10 g/kg, and a 13-week repeated dose study with a 4-week recovery period in rats showed that Hochu-ekki-to produces no toxicologically significant effect at a daily dose of more than 2.5 g/kg body weight [27]. A teratology study in rats reported that the no-effect dose level was more than 2.5 g/kg body weight, similar to Sho-saiko-to [28]. The mutagenic potential of Hochu-ekki-to was also studied by reverse mutation, chromosomal aberration and micronucleus tests, and it was suggested that Hochu-ekki-to has no mutagenic potential [29]. The above results show that Hochu-ekki-to is one of the safest Kampo medicines. 2.6. Otsuji-to Otsuji-to is an extract of a mixture of six crude drugs, i.e. Japanese Angelica root, Bupleurum root, Scutellaria root, Licorice root, Cimicifuga rhizome and Rhubarb rhizome (Rheum palmatum L., R. tanguticum Maxim., R. officinale Baillon or R. coreanum Nakai). This preparation has been used clinically for the relief of constipation, particularly as it may lead to hemorrhoids. Studies on the teratology [30] and on the mutagenicity [31] of Otsuji-to in rats were reported, with similar results as for Sho-saiko-to. These results indicated that Otsuji-to has no significant toxicological effect. 2.7. Shigyaku-san Shigyaku-san is an extract of a mixture of four crude drugs, i.e.: Bupleurum root, Peony root, Immature orange (Citrus aurantium L. var. daidai Makino, C. aurantium L. or C. natsudaidai Hayata) and Licorice root. This preparation has been used clinically for the treatment of cholecystitis or cholelithiasis, gastric ulcer or gastritis, hysteria, insomnia and uneasiness. A single oral dose toxicity study of Shigyakusan in rats indicated that a lethal dose of Shigyaku-san was more than 8 g/kg body weight. A 13-week repeated dose study with a 4-week recovery period in rats showed that Shigyaku-san caused a moderate toxicity such as the reduction of total red blood cell count (RBC) and the increase

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of total bilirubin in both sexes at a daily dose level of 2 g/kg body weight [32]. In this study, urinalysis revealed no notable inter group differences and spleen weight was slightly increased in males of 2 g/kg dose group, but there were no notable inter group differences in gross and histopathological examinations. From these results, the non-toxic dose level of Shigyaku-san was estimated to be 0.4 g/kg body weight. 2.8. Kami-shoyo-san Kami-shoyo-san is an extract of a mixture of ten crude drugs, i.e. Peony root, Poria sclerotium, Atractylodes rhizome (Atractylodes japonica Koidz. ex Kitamura or A. ovata DC.), Bupleurum root, Gardenia fruit (Gardenia jasminoides Ellis), Japanese Angelica root, Moutan bark (Paeonia suffruticosa Andrews), Licorice root, Ginger root and Mentha herb (Mentha arvensis L. var. piperascens Malin.). This preparation has been used clinically for the treatment of the following diseases in women with feeble constitution, suffering from stiff shoulders, fatigue and symptoms of anxiety with a tendency for occasional constipation. This Kampo medicine also has been used for the sensitivity to cold, weak constitution, menstrual disorder and menopausal symptoms. A single oral dose toxicity study and a 13-week repeated dose study with a 4-week recovery period of Kami-shoyo-san in rats was reported, with similar results as for Shigyaku-san [33]. Kamishoyo-san was also reported as not having mutagenic potential [34]. Among eight prescriptions not containing Bupleurum root, Juzen-taiho-to, Ninjin-yoei-to and Unkei-to consist of common crude drugs such as Licorice root, Cinnamon Bark, Peony root, Japanese Angelica root and Ginseng root (Table 2). Juzen-taiho-to and Ninjin-yoei-to are similar in containing also Poria sclerotium, Astragalus root and Rehmannia root (Rehmannia glutinosa Liboschitz var. purpurea Makino or R. glutinosa Liboschitz) as common crude drugs. Among the non-Bupleurum containing Kampo medicines, Keishi-ka-shakuyaku-to and Keishi-bukuryo-gan are the only preparations containing Cinnamon bark and Peony root. Hange-shashin-to and

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Shakuyaku-kanzo-to are grouped into third group among the non-Bupleurum medicines. Ipecac syrup is a newly prepared herbal medicine and contains only Ipecac (Cephaelis ipecacuanha A. Richard or C. acuminata Karsten). 2.9. Juzen-taiho-to Juzen-taiho-to is an extract of a mixture of ten crude drugs, i.e. Astragalus root, Cinnamon bark, Cnidium rhizome (Cnidium officinale Makino), Peony root, Rehmannia root, Atractylodes rhizome, Japanese Angelica root, Ginseng root, Poria sclerotium and Licorice root. This preparation has been used clinically for the treatment of poor physical condition after disease or operation, chills in limbs and anemia. An acute toxicity study of Juzen-taiho-to in mice and rats indicated that a lethal dose of Juzentaiho-to was more than 15 g/kg body weight, and a 13-week subacute toxicity study with a 4-week recovery period of Juzen-taiho-to in rats showed that the non-toxic daily dose level was more than 3 g/kg body weight [35]. No deaths and no abnormal symptoms occurred throughout the experimental period, and no significant difference in body weight gain or food consumption and no marked changes in urinalysis, hematological and blood chemical examinations were seen. The potential teratogenic effect of Juzen-taiho-to in ICR mice was also studied [36]. It was suggested that a low dose of Juzen-taiho-to is not harmuful in terms of transplacental malformation in humans, since no teratological effects were found in mice even with high dose of Juzen-taiho-to. 2.10. Ninjin-yoei-to Ninjin-yoei-to is an extract of a mixture of twelve crude drugs, i.e. Rehmannia root, Japanese Angelica root, Atractylodes rhizome, Poria sclerotium, Ginseng root, Cinnamon bark, Polygala root (Polygala tenuifolia Willd.), Peony root, Citrus Unshiu peel, Astragalus root, Licorice root and Schisandra fruit (Schisandra chinensis Baillon). This preparation has been used clinically for the treatment of anemia, chills and fatigue.

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A 3-month repeated dose oral toxicity study and a mutagenicity study of Ninjin-yoei-to in rats has shown that Ninjin-yoei-to has no significant toxicological effect at a dose of more than 2 g/kg per day [37] and has no mutagenic potential [31].

weight gain or food consumption and no marked changes in urinalysis, hematological and blood chemical examinations were seen.

2.11. Unkei-to

Keishi-bukuryo-gan is an extract of a mixture of five crude drugs, i.e. Peony root, Poria sclerotium, Cinnamon bark, Peach kernel (Prunus persica Batsch or P. persica Batsch var. davidiana Maxim.) and Moutan bark. This preparation has been used clinically for the treatment of menstrual abnormalities, climacteric disorder, inflammation of uterus, menopausal symptoms, stiff shoulders or heavy feeling in the head. A single oral dose toxicity study of Keishibukuryo-gan in rats indicated that the lethal dose of Keishi-bukuryo-gan was more than 10 g/kg body weight. A 13-week repeated dose study with a 4-week recovery period in rats showed that Keishi-bukuryo-gan caused slight erythropenia and increased total bilirubin in both sexes at a daily dose level of 2.5 g/kg body weight [41]. A slight increase of spleen weight and an increased incidence of extramedullary haemopoesis were also found in males only. From these results, the non-toxic daily dose level of Keishi-bukuryo-gan was estimated to be 0.5 g/kg body weight. Based on the reproductive and developmental toxicity study of Keishi-bukuryo-gan in rats by oral administration, the non-toxic dose level of Keishi-bukuryo-gan for general toxicity and reproductivity of F0 parents was concluded to be above 2.5 g/kg per day, and the non-toxic dose level for the next generation was also above 2.5 g/ kg body weight [42]. A mutagenicity study of Keishi-bukuryo-gan has also been reported indicating no mutagenic potential [43].

Unkei-to is an extract of a mixture of 12 crude drugs, i.e. Ophiopogon tuber (Ophiopogon japonicus Ker-Gawler), Pinellia tuber, Licorice root, Japanese Angelica root, Cinnamon bark, Peony root, Cnidium rhizome, Ginseng root, Moutan bark, Evodia fruit (Evodia rutaecarpa Bentham or E. officinalis Dode), Ginger root and Gelatin. This preparation has been used clinically for the treatment of menoxenia, postmenopausal disease and anhypnosis. A single oral dose toxicity study of Unkei-to in rats indicated that a lethal dose of Unkei-to was more than 8 g/kg body weight, and a 13-week repeated dose study with a 4-week recovery period in rats showed a non-toxic dose level was more than 2 g/kg per day [38]. Based on the reproductive and developmental toxicity study of Unkei-to in rats by oral administration, the non-toxic dose level of Unkei-to for general toxicity and reproductivity of F0 parents was concluded to be above 2 g/kg per day, and the non-toxic dose level for the second generation was also above 2 g/kg body weight [39]. 2.12. Keishi-ka-shakuyaku-to Keishi-ka-shakuyaku-to is an extract of a mixture of five crude drugs, i.e. Peony root, Cinnamon bark, Jujube fruit, Licorice root and Ginger root. This preparation has been used clinically for the treatment of abdominal pain. A single oral dose toxicity study of Keishi-kashakuyaku-to in rats indicated that the lethal dose of Keishi-ka-shakuyaku-to was more than 10 g/kg body weight, and a 13-week repeated dose study with a 4-week recovery period showed a non-toxic dose level was more than 2 g/kg per day [40]. These results showed that no deaths and no abnormal symptoms occurred throughout the experimental period, and that no significant difference in body

2.13. Keishi-bukuryo-gan

2.14. Hange-shashin-to Hange-shashin-to is an extract of a mixture of seven crude drugs, i.e. Pinellia tuber, Scutellaria root, Licorice root, Jujube fruit, Ginseng root, Coptis rhizome (Coptis japonica Makino, C. chinensis Franchet, C. deltoidea C.Y. Cheng et Hsiao or C. teeta Wallich) and Dried Ginger root. This preparation has been used clinically for the

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treatment of acute and chronic enterogastric catarrh, indigestion and diarrhea, vomiting and nausea, heartburn and hangover. A single oral dose toxicity study of Hangeshashin-to in rats indicated that a lethal dose of Hange-shashin-to was more than 8 g/kg body weight, and one-month repeated oral dose toxicity study showed that a non-toxic dose level of Hange-shashin-to was more than 2 g/kg per day for both males and females [44]. 2.15. Shakuyaku-kanzo-to Shakuyaku-kanzo-to is an extract of a mixture of two crude drugs: Peony root and Licorice root. This preparation has been used clinically for the treatment of pain accompanying acute spasm muscles. This Kampo medicine has been investigated only for mutagenicity by reverse mutation, chromosomal aberration and micronucleus tests [45]. From the results, it was suggested that Shakuyakukanzo-to had no mutagenic potential. 2.16. Ipecac syrup Ipecac syrup is an herbal preparation: an extract of Ipecac (Cephaelis ipecacuanha A. Richard or C. acuminata Karsten) containing the nauseant alkaloids cephaeline and emetine. Ipecac syrup is used in western medicine as a common household emetic, in case of accidental domestic poisoning [46,47]. Many pharmacological studies on Ipecac have shown that emetine has higher expectorant activity but less emetic activity than cephaeline, suggesting that Ipecac syrup contains more cephaeline than emetine [48]. The mechanism of emetic action has been studied and it is suggested that the main alkaloids of Ipecac syrup may act at peripheral sites and that the emetic acts via 5-HT3 and 5-HT4 receptors [49,50]. Many toxicity studies of Ipecac or emetine in animals were reported [51 /53], however, these data have not confirmed safety for its clinical use. Therefore, we recently studied on the toxicity of Ipecac syrup. In a single oral dose toxicity study the lethal dose of Ipecac syrup was found to be 0.1

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ml/kg in young dogs. An oral administration study with a 4-week recovery period in rats indicated that a dose of Ipecac syrup up to 0.003 ml/kg per day produced no significant toxicological effects in young rats and that 0.025 ml/kg per day produced no significant toxicological effects in mature rats. A study including a 4-week recovery period in dogs also indicated that a dose of Ipecac syrup up to 0.01 ml/kg per day produce no significant toxicological effects in both young and mature dogs, showing no notable effects on hematology, blood chemistry, on gross or microscopic examination. However, when Ipecac syrup was administered in higher doses than the above ones in these animals, common toxic symptoms such as soft face, diarrhea, body weight loss and death were observed. Among histopathological finding, bleeding or/and congestion in gastrointestinal tract of these animals were also observed. Although cardiotoxicity and muscle toxicity of emetine in animals were reported [54,55], the mechanism of action of Ipecac syrup is considered to mainly activate the 5-HT3 receptor and directly affects gastrointestinal mucosa. The mutagenic potential of Ipecac syrup was studied by the reverse mutation test using four strains (TA100, 1535, 98 and 1573) of Salmonella typhimurium and one strain (WP2uvrA) of Escherichia coli . Chromosomal aberration and micronucleus tests for the mutagenic potential were also examined, and it was concluded that Ipecac syrup has no mutagenic potential in live animals. Our above results and the cardiotoxicity and muscle toxicity of emetine in animals suggested that Ipecac syrup should be used only as an emetic in therapy.

3. Interactions between herbal medicine and western drugs Recently, it has been demonstrated that herbal medicine may cause changes in the pharmacokinetics of other drugs, resulting in a reduction of efficacy and an enhancement of side effects. FughBerman studied the interaction between herbal medicine and western drugs in clinical use [56]. Among 21 herbal medicines having some interac-

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tions with western drugs, effects of Angelica root with warfarin, Licorice root with prednisolone, and Sho-saiko-to or Saiboku-to with prednisolone were reported for Kampo medicines. Kampo medicines are generally combinations of two or more crude drugs and may contain many ingredients that inhibit the activity of cytochrome P450, such as furanocoumarins and flavonoids [45,57]. Angelica root affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits [58,59]. Glycyrrhetinic acid in Licorice root and magnolol in Saiboku-to both inhibited 11b-hydroxysteroid dehydrogenase in herbal remedy for steroid-dependent bronchial asthma [60]. Licorice root and its major constituent, glycyrrhizin, are well-known to cause pseudoaldosteronism [61,62], and the Japanese Ministry of Health, Labour and Welfare has therefore cautioned against using more than 200 mg/day glycyrrhizin to sweeten/flavor Kampo medicines. Other interactions such as Shigyaku-san with nicardipine [63], Sho-saiko-to or Sairei-to with ofloxacin [64], Hochu-ekki-to or Juzen-taiho-to with levofloxacin [65], and Saiboku-to with theophylline [66] were also reported, while it was demonstrated that Juzen-taiho-to did not interact with cisplatin [67,68]. Sho-saiko-to delayed the half-life period of phenytoin in rabbits [69] and also showed synergistic effects with interferons a/b (IFN a/b) in vivo inducing of side effects such as interstitial pneumonia [18]. Scutellaria root extract inhibited the metabolic enzyme activity in rat liver [70] although the causative component has not been determined. It was demonstrated that the hotwater extract of eight kinds of crude drugs such as Angelica root and Bupleurum root belonging to the Umbelliferae family inhibited the rat liver microsomal aniline hydroxylase activity and aminopyrine N -demethylase activity [71]. Moreover, the hot-water extract of Angelica dahurica root (Angelica dahurica Benth. et Hook.) exhibited the potential to affect the metabolism of other drugs by liver cytochrome P450 [72]. The crude drugs belonging to this family contained furanocoumarins such as notopterol and paradisins, which were reported to inhibit a specific human drug metabolizing enzyme, cytochrome P450 3A (CYP3A) activity [73,74]. Furanocoumarins have also been

suggested as candidates for causative agents of grapefruit-juice-mediated drug interaction [75] and a new CYP3A4 inhibitor, paradisin C, was recently isolated from grapefruit juice [76]. These results, therefore, raised the concern that the furanocoumarin cotaining Kampo medicines may alter pharmacokinetics of co-ingested drugs similar to the case with grapefruit juice. Elucidation of the interaction between CYP3A and inhibitors may be significant in the pharmacokinetics of clinically used drugs. It is well-known that metal ions and tannic acid present in herbal medicine form insoluble chelates or complexes with some western drugs such as antibiotics, isoniazid and levodopa, resulting in a reduction of drug absorption [4]. It is also reported that alkaloids or other flavonoids form precipitates with some western drugs containing aluminium, bismuth, calcium, ferrous and magnesium ions. Such interactions however do not necessarily produce adverse effects but may be beneficial or may mitigate side effects. For example, Kampo medicine Hange-shashin-to is effective for the prevention of chronic diarrheal symptoms induced by the administration of the anticancer agent, irinotecan hydrochloride (CPT-11) [77]. It was also suggested that the prophylactic use of Hange-shashin-to and Sairei-to may be of value against CPT-11-induced intestinal toxicity [78]. Moreover, it was shown that crude drugs of Kampo medicines containing glucuronides such as baicalin, wogonoside and glycyrrhizin could be used in vivo to decrease the enterohepatic circulation of SN-38, an active metabolite of CPT-11, and possibly that of other western drugs [79]. The effects of the interactions between the herbs and western drugs should also be in relation to absorption. The enhancing activity of dipotassium glycyrrhizinate (Grz) on the intestinal absorption of drugs has been demonstrated in an in vitro study using Caco-2 cell monolayers and in an in vivo absorption study in rats [80,81]. These results also indicated that the in vivo enhancing-activity of Grz on the absorption of drugs is dependent on glycyrrhetinic acid, a hydrolysis product of Grz resulting from the action of b-glucuronidase in intestinal flora.

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As more potential interactions between the herbs and western drugs are reported [82,83], further in depth studies are needed on the interactions between western drugs and herbal remedies to better understand the effects of herbal medicine in clinical use.

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Acknowledgements We are grateful to Professor F. Lambein and Dr Y.-H. Kuo, Faculty of Medicine and Health Sciences, Ghent University, Belgium, for their valuable advice and for reading the manuscript.

4. Concluding remarks and future prospects Kampo is a part of traditional Japanese culture, and is a therapeutic method that relies on the ingestion of Kampo medicines as the primary method of treatment. Kampo medicines have been produced by combining multiple crude drugs, almost all of plant origin but with some of animal or mineral origin and contain a great many substances. Since Kampo medicine results from the combination of many substances, their effect is a combination of the various interactions of the constituent substances, whether they are enhancing, synergistic, or suppressive. Kampo medicine has an overall effect different from the combined effects of individual crude drugs. Now more than 210 Kampo medicines are listed in Kampo treatment in Japan, and the role of Kampo in modern medicine is publicly acknowledged. In this paper, some useful information on the clinical uses, toxicity and interaction with western drugs of 16 Kampo medicines are described. With the increasing awareness of the value of natural products, and the growth in the use of herbal medicines, international trade in these products and their medicinal plants has grown substantially. Recently, the nature of disease has been changing, and there is an increase in disorders brought on by stress, cancer, intractable infections and circulatory dysfunction, where the cause is not readily apparent and fundamental treatment is not yet known. For these disorders, which are difficult to treat with western drugs, it is expected that Kampo medicines will play an important role in the treatment and the healing process. The usefulness of herbal medicines in medical treatment can further improve by integrating knowledge obtained through study of their pharmacological and toxicological properties when used alone or in combination with western drugs.

References [1] The Japanese Pharmacopoeia 14th Edition, Hirokawa Publishing Co., Tokyo, Japan, 2001. [2] F. Ikegami, Herbal drugs in Kampo medicine in presentday Japan, in: Emerging Drugs; Molecular Aspects of Asian Medicines, vol. 1, PJD Publication, New York, USA, 2001, pp. 489 /507. [3] World Health Organization (WHO), WHO monographs on selected medicinal plants, vol. 1, World Health Organization, Geneva, Switzerland, 1999. [4] K. Chan, L. Cheung, Examples of interactions between Chinese herbal medicinal products and orthodox drugs, in: Interactions between Chinese Herbal Medicinal Products and Orthodox Drugs, Harwood Academic Publishers, Amsterdam, The Netherlands, 2000, pp. 57 /97. [5] Y. Ikemoto, Y. Mizoguchi, T. Arai, S. Yamamoto, S. Morisawa, Effects of Syosaiko-to (Xiao-Chai-Hu-Tang) and Daisaiko-to (Da-Chai-Hu-Tang) on antibody response in vitro, J. Trad. Med. 1 (1984) 235 /242. [6] S. Minematsu, M. Taki, M. Watanabe, Y. Kobayashi, N. Tuchiya, Y. Harada, K. Izumi, S. Imamura, Y. Fujii, A single oral dose toxicity study and a 13-week repeated dose study with a 4-week recovery period of Tsumura Saikokeishi-to (TJ-10) in rats, Jpn. Pharmacol. Ther. 23 (1995) 33 /52. [7] S. Minematsu, S. Maemura, C.A. Perry, M. Mulhern, A single oral dose toxicity study and a 13-week repeated dose study with a 4-week recovery period of Tsumura Saibokuto (TJ-96) in rats, Jpn. Pharmacol. Ther. 23 (1995) 315 / 330. [8] M. Kanitani, S. Maemura, S. Yamada, S. Minematsu, H. Kuboniwa, N. Tsuchiya, Y. Fujii, A single oral dose toxicity study and a 13-week repeated dose study with a 4week recovery period of Tsumura Sairei-to (TJ-114) in rats, Jpn. Pharmacol. Ther. 23 (1995) 371 /387. [9] H. Sameshima, T. Unno, K. Hirakawa, F. Ogino, H. Takase, S. Nurimoto, Acute and subacute toxicity of Shosaiko-to, Pharmacometrics 33 (1987) 793 /808. [10] S. Minematsu, J.E. Atkinson, H.F. Bolte, H. Sakai, Y. Fujii, A subchronic (3-month) oral toxicity study of Tsumura Sho-saiko-to (TJ-9) in the rat via oral gavage administration with a 4-week recovery period, Pharmacometrics 43 (1992) 19 /42. [11] E. Yanagisawa, K. Ishihara, K. Imai, S. Maemura, Y. Fujii, M. Aburada, T. Oyama, Toxicokinetics of Sho-

248

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

F. Ikegami et al. / Chemico-Biological Interactions 145 (2003) 235 /250 saiko-to (TJ-9) in rats following multiple dosing for 13 weeks, Pharmacometrics 44 (1992) 649 /657. T. Itoh, S. Murai, H. Yoshida, Y. Masuda, H. Saito, T. Hatakeyama, H. Yonekura, Chronic toxicity test of Shosaiko-to in rats, Pharmacometrics 23 (1982) 279 /285. K. Yamasaki, K. Shiraishi, N. Imatanaka, K. Nagai, Y. Tatsumi, O. Miura, A. Suzuki, One-year chronic oral toxicity study of Shosaiko-to in rats, Pharmacometrics 39 (1990) 405 /426. S. Aso, S. Horiwaki, C. Mashiba, Y. Tatsumi, A. Suzuki, Teratogenicity study of orally administered Sho-saiko-to in rats, Pharmacometrics 44 (1992) 659 /673. H. Shimazu, Y. Katsumata, T. Takamatsu, H. Matsumoto, S. Minematsu, S. Maemura, Reproductive and developmental toxicity study of Tsumura Sho-saiko-to (TJ-9) in rats by oral administration: single study design, Jpn. Pharmacol. Ther. 25 (1997) 29 /43. H. Konishi, Y. Yasuda, H. Abe, S. Arichi, T. Tanimura, Effects of Syo-saiko-to on pregnant rats and development of their fetuses, J. Trad. Med. 3 (1986) 111 /118. H. Kuboniwa, M. Katayama, S. Maemura, S. Minematsu, M. Onishi, Mutagenicity studies of Sho-saiko-to (TJ-9), Jpn. Pharmacol. Ther. 27 (1999) 13 /19. K. Fukuda, R. Suzuki, T. Kido, M. Yamamoto, Y. Komatsu, Synergistic effects of Sho-saiko-to and interferons in vivo, J. Trad. Med. 12 (1995) 414 /415. H. Kuboniwa, M. Katami, S. Maemura, S. Minematsu, M. Onishi, K. Saigou, F. Agura, Mutagenicity studies of Saiko-keishi-to (TJ-10), Jpn. Pharmacol. Ther. 27 (1999) 101 /107. S. Kiwaki, Y. Yamashita, H. Yamamae, T. Nakamura, Y. Oketani, Ninety-day toxicity study of a Chinese herb medicine Saiboku-to extract in rats, Pharmacometrics 38 (1989) 495 /509. H. Shimazu, Y. Katsumata, K. Yasuda, H. Matsumoto, S. Minematsu, S. Maemura, Reproductive and developmental toxicity study of Tsumura Saiboku-to (TJ-96) in rats by oral administration: single study design, Jpn. Pharmacol. Ther. 25 (1997) 89 /102. S. Kiwaki, C. Ono, K. Sakai, H. Tada, Y. Oketani, Ninetyday toxicity study of a Chinese herb medicine Sairei-to extract in rats, Pharmacometrics 38 (1989) 241 /254. H. Kimura, T. Koike, T. Fujimura, M. Inukai, T. Furuhashi, K. Iwahashi, Twelve-month toxicity study of a Chinese herb medicine Sairei-to extract in rats, Pharmacometrics 42 (1991) 539 /558. H. Shimazu, T. Takamatsu, Y. Katsumata, M. Makino, S. Minematsu, S. Maemura, Reproductive and developmental toxicity study of Tsumura Sairei-to (TJ-114) in rats by oral administration: single study design, Jpn. Pharmacol. Ther. 23 (1995) 55 /69. S. Kiwaki, C. Ono, K. Sakai, T. Nakamura, Y. Oketani, A teratological evaluation of orally administered Sairei-to extract in rats, Pharmacometrics 38 (1989) 255 /270. H. Kuboniwa, M. Katami, S. Maemura, S. Minematsu, M. Onishi, F. Aruga, Mutagenicity studies of Sairei-to (TJ114), Jpn. Pharmacol. Ther. 27 (1999) 29 /35.

[27] O. Iijima, S. Minematsu, S. Maemura, L.A. Waterson, C. Gopinath, A single oral dose toxicity study and a 13-week repeated dose study with a 4-week recovery period of TSUMURA Hochu-ekki-to (TJ-41) in rats, Jpn. Pharmacol. Ther. 23 (1995) 209 /224. [28] K. Fukunishi, M. Nagano, M. Teraoka, Y. Sakaguchi, N. Watanabe, N. Awata, Teratology study of Hochu-ekki-to in rats, Pharmacometrics 53 (1997) 293 /297. [29] H. Kuboniwa, S. Maemura, S. Mimematsu, M. Onishi, K. Saigou, F. Aruga, Y. Miwa, Mutagenicity studies of Hochu-ekki-to (TJ-41), Jpn. Pharmacol. Ther. 27 (1999) 37 /42. [30] Y. Sakaguchi, K. Fukunishi, I. Watanabe, M. Teraoka, S. Nurimoto, N. Awata, Teratology study of Otsuji-to in rats, Parmacometrics 53 (1997) 287 /292. [31] T. Maekawa, F. Irie, K. Fukunishi, T. Unno, S. Nurimoto, Mutagenicity tests of Ninjin-yoei-to, Kami-kihi-to, Hachimi-jio-gan ryo, Dai-saiko-to and Otsuji-to, Hennigennsei Siken 3 (1994) 115 /122. [32] Y. Kobayashi, S. Minematsu, S. Maemura, C.J. Perry, M. Mulhern, A single oral dose toxicity study and a 13-week repeated dose study with a 4-week recovery period of Tsumura Shigyaku-san (TJ-35) in rats, Jpn. Pharmacol. Ther. 23 (1995) 191 /207. [33] O. Iijima, K. Sudo, Y. Kobayashi, S. Minematsu, S. Maemura, Y. Fujii, A single oral dose toxicity study and a 13-week repeated dose study with a 4-week recovery period of Tsumura Kami-shoyo-san (TJ-24) in rats, Jpn. Pharmacol. Ther. 23 (1995) 127 /149. [34] H. Kuboniwa, S. Maemura, S. Minematsu, M. Onishi, F. Aruga, Y. Miwa, Mutagenicity studies of Kami-shoyo-san (TJ-24), Jpn. Phramacol. Ther. 27 (1999) 71 /76. [35] S. Minematsu, K. Sudo, W. Suzuki, O. Iijima, M. Taki, M. Kanitani, Y. Fujii, M. Aburada, E. Hosoya, Safety evaluation of Juzentaiho-to. Acute toxicity study in mice and rats and thirteen-week subacute toxicity study in rats with four-week recovery period, Pharmacometrics 38 (1989) 215 /229. [36] A. Ogata, Y. Kubo, H. Ando, I. Yasuda, M. Sasaki, Teratological tests of Juzen-taiho-to extract in ICR mice, Ann. Rep. Tokyo Metr. Res. Lab. P.H. 44 (1993) 268 /273. [37] I. Shimonishi, K. Hirakawa, H. Idogawa, N. Ugumori, T. Unno, N. Awata, S. Nurimoto, Three-month repeated oral dose toxicity study of Ninjin-yoei-to dried extract in rats, Pharmacometrics 51 (1996) 7 /16. [38] T. Yanagisawa, S. Minematsu, S. Maemura, C.A. Perry, M. Mulhern, A single oral dose toxicity study and a 13week repeated dose study with a 4-week recovery period of Tsumura Unkei-to (TJ-106) in rats, Jpn. Pharmacol. Ther. 23 (1995) 331 /349. [39] Y. Katsumata, H. Shimazu, M. Fujioka, H. Matsumoto, H. Takei, S. Maemura, Reproductive and developmental toxicity study of Tsumura Unkei-to (TJ-106) in rats by oral administration: single study design, Jpn. Pharmacol. Ther. 25 (1997) 105 /119. [40] S. Minematsu, M. Taki, M. Kanitani, A. Kasuya, M. Ito, T. Oyama, S. Amagaya, A single oral dose toxicity study

F. Ikegami et al. / Chemico-Biological Interactions 145 (2003) 235 /250

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51] [52]

[53]

[54]

[55]

and a 13-week repeated dose study with a 4-week recovery period of Tsumura Keishi-ka-shakuyaku-to (TJ-60) in rats, Jpn. Pharmacol. Ther. 23 (1995) 277 /297. Y. Kobayashi, S. Minematsu, S. Maemura, C. Atkinson, M. Mulhern, A single oral dose toxicity study and a 13week repeated dose study with a 4-week recovery period of Tsumura Keishi-bukuryo-gan (TJ-25) in rats, Jpn. Pharmacol. Ther. 23 (1995) 151 /168. Y. Katsumata, H. Shimazu, T. Takamatsu, H. Matsumoto, S. Minematsu, S. Maemura, Reproductive and developmental toxicity study of Tsumura Keishi-bukuryo-gan (TJ-25) in rats by oral administration: single study design, Jpn. Pharmacol. Ther. 25 (1997) 73 /87. H. Kuboniwa, S. Maemura, S. Mimematsu, M. Onishi, K. Saigou, F. Aruga, Y. Miwa, Mutagenicity studies of Keishi-bukuryo-gan (TJ-25), Jpn. Pharmacol. Ther. 27 (1999) 95 /100. S. Minematsu, M. Taki, M. Kanitani, A. Kasuya, S. Maemura, S. Amagaya, Single and 1-month repeated oral dose toxicity studies of Tsumura Hange-shashin-to (TJ-14) in rats, Shinyaku To Rinsyou 43 (1997) 137 /159. H. Kuboniwa, S. Maemura, S. Minematsu, K. Saigou, Y. Nagasawa, Y. Miwa, Mutagenicity studies of Shakuyakukanzo-to (TJ-68), Jpn. Pharmacol. Ther. 27 (1999) 57 /63. P. Letteron, V. Descatoire, D. Larrey, M. Tinel, J. Geneve, D. Pessayre, Interaction and induction of cytochrome P450 by various psoralen derivatives in rats, J. Pharmacol. Exp. Ther. 238 (1986) 685 /692. M.O. Keith, H.M. Frank, H.A. Bruce, E.S. Richard, Lowvolume whole bowel irrigation and salicylate absorption: a comparison with ipecac-charcoal, Pharmacotherapy 13 (1993) 229 /232. J.L. Radomski, E.C. Hegan, H.N. Fuyat, A.A. Nelson, The pharmacology of ipecac, J. Pharmacol. Exp. Ther. 104 (1952) 421 /426. T. Endo, M. Nemoto, T. Ogawa, M. Hasegawa, Y. Fujii, M. Minami, Pharmacological aspects of ipecac syrup (TJ119)-induced emesis in ferrets, Res. Commun. Mol. Pathol. Pharmacol. 108 (2000) 187 /200. M. Hasegawa, T. Sasaki, K. Sadakane, M. Kimura, Y. Fujii, Studies for the emetic mechanisms of ipecac syrup (TJ-119) and its active components in ferrets: involvement of 5-hydroxytryptamine receptors, Jpn. J. Pharmacol. 89 (2002) 113 /119. B.R. Manno, J.E. Manno, Toxicology of ipecac: a review, Clin. Toxicol. 10 (1977) 221 /242. A.D. Ray, A.K. Chatterjee, S.C. Datta, Effects of emetine on serum proteins of rats fed diets of various protein levels, Jpn. J. Pharmacol. 27 (1977) 165 /167. A.I. Gimble, C. Davison, P.K. Smith, Studies on the toxicity, distribution and excretion of emetine, J. Pharmacol. Exp. Ther. 94 (1948) 431 /438. S.J. Pan, A.B. Combs, Effects of pharmacological interventions on emetine cardiotoxicity in isolated perfused rat hearts, Toxicology 97 (1995) 93 /104. N.J. Hopf, H.H. Goebel, Experimental emetine myopathy: enzyme histochemical, electron microscopic, and immuno-

[56] [57]

[58] [59]

[60]

[61] [62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

249

morphological studies, Acta Neuropathol. 85 (1993) 414 / 418. A. Fugh-Berman, Herb /drug interactions, Lancet 355 (2000) 134 /138. M.T. Obermeier, R.E. White, C.S. Yang, Effects of bioflavonoids on hepatic P450 activities, Xenobiotica 25 (1995) 575 /584. R.L. Page, II, J.D. Lawrence, Potentiation of warfarin by Dong Quai, Pharmacotherapy 19 (1999) 870 /876. A.C.T. Lo, K. Chan, J.H.K. Yeung, K.S. Woo, Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits, Eur. J. Drug Metab. Pharmacokinet. 20 (1995) 55 /60. M. Homma, K. Oka, T. Niitsuma, H. Itoh, A novel 11 beta-hydroxysteroid dehydrogenase inhibitor contained in Saiboku-to, a herbal remedy for steroid-dependent bronchial asthma, J. Pharm. Pharmacol. 46 (1994) 305 /309. J.J. Chamberlin, I.Z. Abolnik, Western J. Med. 167 (1997) 184 /185. G.J. de Klerk, M.G. Nieuwenhuis, J.J. Beutler, Hypokalaemia and hypertension associated with use of liquorice flavoured chewing gum, Br. Med. J. 314 (1997) 731 /732. T. Uno, T. Ohkubo, K. Sugawara, A. Higashiyama, S. Motomura, Effects of Shigyaku-san (TJ-35) on pharmacokinetics and pharmacodynamics of nicardipine, Res. Drug Actions Interact. 21 (1998) 139 /145. T. Hasegawa, K. Yamaki, M. Nadai, I. Muraoka, L. Wang, K. Takagi, T. Nabeshima, Lack of effect of Chinese medicines on bioavailability of ofloxacin in healthy volunteers, Int. J. Clin. Pharmacol. Ther. 32 (1994) 57 /61. T. Hasegawa, K. Yamaki, I. Muraoka, M. Nadai, K. Takagi, T. Nabeshima, Effect of traditional Chinese medicines on pharmacokinetics of levofloxacin, Antimicrob. Agents Chemother. 39 (1995) 2135 /2137. A. Iwai, Y. Sugiyama, A. Kawakami, K. Ueno, Effects of Saiboku-to on theophylline disposition and laboratory findings, Jpn. J. TDM 8 (1991) 57 /64. O. Iijima, Y. Fujii, M. Aburada, E. Hosoya, Protective effects of Juzentaiho-to (TJ-48) on the adverse effects of some antitumor agents, in: Recent Advances in the Pharmacology of Kampo Medicines, Excepta Medica, Tokyo, 1988, pp. 353 /358. S. Ebisuno, A. Hirano, I. Kyoku, T. Ohkawa, O. Iijima, Y. Fujii, E. Hosoya, Protective effects of Juzentaiho-to (TJ48) on the toxic side effects of CDDP and antitumor effects with CDDP on murine bladder tumor (MBT-2), J. Jpn. Soc. Cancer Ther. 24 (1989) 1305 /1312. J. Hosoya, H. Nagaoka, Y. Nakagawa, Effects of Shousaiko-to, Keishi-ka-shakuyaku-to and its simultaneous use on the pharmacokinetics of phenytoin in rabbit, Jpn. J. Hosp. Pharm. 19 (1993) 203 /208. K. Koizumi, H. Iijima, M. Nohmi, S. Nakayama, K. Oguchi, Effect of Byakushi and Ogon on the hepatic drug metabolizing enzymes in rats, Folia Pharmacol. Jpn. 104 (1994) 413 /419. M. Shinyanagi, S. Nakayama, K. Oguchi, Effects of SinoJapanese herbs in the family Umbelliferae on the hepatic

250

[72]

[73]

[74]

[75]

[76]

[77]

F. Ikegami et al. / Chemico-Biological Interactions 145 (2003) 235 /250 drug metabolizing enzymes and lipid peroxidation in rats, Folia Pharmacol. Jpn. 99 (2001) 115 /121. K. Ishihara, H. Kushida, M. Yuzurihara, Y. Wakui, M. Kitada, Interaction of drugs and Chinese herbs: pharmacokinetic changes of tolbutamide and diazepam caused by extract of Angelica dahurica, J. Pharm. Pharmacol. 52 (2000) 1023 /1029. J. Me¨enpa¨a¨, H. Sigusch, H. Raunio, T. Syngelma¨, P. Vuorela, O. Pelkonen, Differential inhibition of coumarin 7-hydroxylase activity in mouse and human liver microsomes, Biochem. Pharmacol. 45 (1993) 1035 /1042. L.-Q. Guo, M. Taniguchi, Y.-Q. Xiao, K. Baba, T. Ohta, Y. Yamazoe, Inhibitory effect of natural furanocoumarins on human microsomal cytochrome P450 3A activity, Jpn. J. Pharmacol. 82 (2000) 122 /129. K. Fukuda, T. Ohta, Y. Oshima, N. Ohashi, M. Yoshikawa, Y. Yamazoe, Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimmers as components of drug interaction, Pharmacogenetics 7 (1997) 391 /396. T. Ohta, T. Maruyama, M. Nagahashi, Y. Miyamoto, Y. Yamazoe, S. Tsukamoto, Paradisin C: a new CYP3A4 inhibitor from grapefruit juice, Tetrahedron 58 (2002) 6631 /6635. Y. Kase, T. Hayakawa, M. Aburada, Y. Komatsu, T. Kamataki, Preventive effects of Hange-shashin-to on irinotecan hydrochloride-caused diarrhea and its relevance to the colonic prostaglandin E2 and water absorption in the rat, Jpn. J. Pharmacol. 75 (1997) 407 /413.

[78] K. Takasuna, Y. Kasai, Y. Kitano, K. Mori, E. Nagai, T. Kamataki, Protective effects of Kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT11), in rats, Jpn. J. Cancer Res. 86 (1995) 978 /984. [79] M. Narita, E. Nagai, H. Hagiwara, M. Aburada, T. Yokoi, T. Kamataki, Inhibition of b-glucuronidase by natural glucuronides of Kampo medicines using glucuronide of SN-38 (7-ethyl-10-hydroxycamptothecin) as a substrate, Xenobiotica 23 (1993) 5 /10. [80] M. Sakai, T. Imai, H. Ohtake, H. Azuma, M. Otagiri, Simultaneous use of sodium deoxycholate and dipotassium glycyrrhizinate enhances the cellular transport of poorly absorbed compounds across Caco-2 cell monolayers, J. Pharm. Pharmacol. 51 (1999) 27 /33. [81] T. Imai, M. Sakai, H. Ohtake, H. Azuma, M. Otagiri, In vitro and in vivo evaluation of the enhancing activity of glycyrrhizin on the intestinal absorption of drugs, Pharm. Res. 16 (1999) 80 /86. [82] M. Zhu, K.W. Chan, L.S. Ng, Q. Chang, S. Chang, R.C. Li, Possible influences of Ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats, J. Pharm. Pharmacol. 51 (1999) 175 /180. [83] K. Sugimoto, M. Ohmori, S. Tsuruoka, K. Nishiki, I. Miyamori, A. Fujimura, Different effects of St John’s Wort on the pharmacokinetics of simvastatin and pravastatin, Clin. Pharmacol. Ther. 70 (2001) 518 /524.