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Page i

Toxicology and Clinical Pharmacology of Herbal Products

Page ii

Forensic Science and Medicine
Steven B
...
Trestrail, III, 2000
A PHYSICIAN'S GUIDE TO CLINICAL FORENSIC M EDICINE,
edited by Margaret M
...

999 Riverview Drive, Suite 208
Totowa, New Jersey 07512
All rights reserved
...

The content and opinions expressed in this book are the sole work of the authors and editors, who have
warranted due diligence in the creation and issuance of their work
...

Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy
of the information published and to describe generally accepted practices
...
Notwithstanding, as new research,
changes in government regulations, and knowledge from clinical experience relating to drug therapy
and drug reactions constantly occurs, the reader is advised to check the product information provided by
the manufacturer of each drug for any change in dosages or for additional warnings and
contraindications
...
It is the responsibility of the treating physician to determine dosages and
treatment strategies for individual patients
...

The publisher, editors, and authors are not responsible for errors or omissions or for any consequences
from the application of the information presented in this book and make no warranty, express or
implied, with respect to the contents in this publication
...

ANSI Z39
...

Cover design by Patricia F
...

For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact
Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-2568341;
E-mail: humana@humanapr
...
humanapress
...
, provided that the base fee of US $10
...
25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers,
MA 01923
...
The fee code for
users of the Transactional Reporting Service is: [0-89603-791-6/00 $10
...
25]
...
10 9 8 7 6 5 4 3 2 1

Library of Congress Cataloging in Publication Data
Toxicology and clinical pharmacology of herbal products / edited by Melanie Johns Cupp
...
; cm
...

ISBN 0-89603-791-6 (alk
...
Herbs—Toxicology
...
Materia medica, Vegetable—Toxicology
...
Title:Herbal
products
...
Cupp, Melanie Johns
...
Series
...
Herbs--adverse effects
...
Plants, Medicinal--adverse effects
...

Pharmacology
...
T68 2000
615
...
Trade group estimates suggest that total
sales exceeded $4 billion dollars in 1999
...
Along with the proliferation in sales has
come a proliferation of information sources
...
Traditional herbalists classify thistle and mugwort as "cholagogues," substances used to
make the gallbladder contract and release bile
...

Heroin and cocaine may not be the only drugs to come from plants, but a practicing physician or
toxicologist might be forgiven for thinking so
...
Unfortunately, the
majority of the papers about kava kava were published in journals not found in ordinary hospital
libraries
...
It is very badly needed
...
Of course many of the drugs first used in modern medicine are extracted from plants
...

Traditional physicians and scientists generally believe that, if a plant has any medicinal value at all, it is
because it con-

Page vi

tains one "active" ingredient that must be isolated and purified
...

There are risks and benefits to both approaches
...
This means that the effects, both therapeutic and toxic, will be
exaggerated
...
The low concentration of active
ingredients may explain why, given the enormous numbers of people taking herbal products, relatively
few toxic reactions have been reported
...
Indians who chew the leaves never
achieve blood cocaine concentrations high enough to produce serious toxicity
...

Herbalists also believe that combining herbs improves efficacy and reduces adverse effects
...
The combination of
Devil's claw, white willow, and tumeric, all agents with antiinflammatory effects, is rational, and quite
probably effective
...
John's Wort, which contains a selective serotonin reuptake
inhibitor, with Ephedra, which causes increased catecholamine release, is both dangerous and ill
advised
...
Under current US laws, anyone is free to market any combination of ingredients, no
matter how misguided the underlying science
...
So
do patients
...
Occassionally, this leads to dire
results
...
Fatal brain
hemorrhages have occurred in anticoagulated patients who self-medicated with gingko
...
For example, tetracycline and
penicillin would never be given at the same time, because the former slows bacterial growth, while the
later exerts its bactericidal effects only in growing bacteria
...
Comfrey may be an
effective treatment for bruises and sprains, but it also contains pyrrazolidine alkaloids which can cause
severe liver damage
...
Yet neither the alkaloid content, the country of
origin, nor the portion of the plant used is likely to be indicated on the product label
...
Cupp and her coauthors are to be congratulated for having done an excellent job in combing the
scientific literature for reliable, peer-reviewed, information about the most widely used herbal products
...
The
28 subsections of this book deal with the herbs that are most often encountered
...
As more is learned, it will be
incorporated into future editions
...
KARCH, MD
BERKELEY, CA

Page ix

PREFACE
Sales of herbal products have increased dramatically over the past five years
...
Data of questionable accuracy, often designed to sell products rather than to provide
objective information, can be found in the print and electronic media, most notably on the Internet
...

Toxicology and Clinical Pharmacology of Herbal Products is designed to provide medical examiners,
toxicologists, and health care providers with an objective review of the available information on the
pharmacology and toxicology of commonly used herbs
...
Sections on the relevant pharmacokinetics,
chemical analysis, and analysis of biofluids are unique to this volume, and will be of use to pathologists
and forensic scientists, as well as to clinicians
...
A good deal of pharmacology and therapeutics information is included in
this section, not only because toxicology is an extension of pharmacology, but also to make the book
useful for a wide variety of applications by professionals with various interests
...
At the end of the book, a summary table lists herbal
toxicities by affected organ, provides a list of herbs involved in drug interactions, and indicates the type
of data supporting the reported toxicities
...
This information, in conjuction with color photographs1 of some of the most popular
products, can be of assistance in those situations where the identity of an herbal product is in question
...
In addition, each herbal monograph reviews the herb's status
internationally, including approved uses
...
Without a foundation of knowledge upon which to inquire whether an herbal product
might be the cause of a given finding, further exploration of the possibility of an herb-induced toxicity
might not be undertaken
...
Toxicology and Clinical
Pharmacology of Herbal Products is designed to provide the necessary knowledge base upon which
such investigations may efficaciously proceed
...


Page xi

CONTENTS
Foreword
by Steven B
...

134

Part I
Legal/Regulatory Aspects of Herbal Products
Chapter 1: Legal/Regulatory Aspects of Herbal Products
Melanie Johns Cupp

3

Part II
Monographs
Chapter 1: Ma Huang and the Ephedra Alkaloids
Steven B
...
1
Sources

11

1
...
3
Current Promoted Uses

12

1
...
5
Pharmacology

15

1
...
1
Introduction

15

1
...
2
Pharmacologic Effects

16

1
...
3
Metabolism and Elimination

16

1
...
4
Workplace and Sports Drug Testing

17

1
...
7
Toxicology

18

1
...
1
Neurologic Disorders

18

1
...
2
Renal Disorders

19

1
...
3
Cardiovascular Diseases

21

1
...
4
Other Medical Problems and Effects

22

Page xii

1
...
9
Analytic Considerations

24

1
...
11
Commission E Recommendations

24

Chapter 2: Kava
Shawn Reeder and Melanie Johns Cupp

31

2
...
2
Current Promoted Uses

32

2
...
4
Pharmacologic/Toxicologic Effects

32

2
...
1
Neurologic Effects

32

2
...
2
Dermatological Effects

35

2
...
3
Musculoskeletal Effects

36

2
...
4
Antimicrobial Activity

36

2
...
5
Hepatotoxicity

36

2
...
6
Antiplatelet Effects

36

2
...
6
Toxicity Associated with Traditional Use by Native Populations

37

2
...
8
Pharmacokinetics/Toxicokinetics

38

2
...
1
Absorption

38

2
...
2
Metabolism/Elimination

38

2
...
10
Chemical Analysis

39

2
...
1
History and Traditional Use

43

3
...
3
Products Available

43

3
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

47

3
...
7
Pharmacokinetics/Toxicokinetics

48

Page xiii

3
...
1
Absorption

48

3
...
2
Distribution

49

3
...
3
Metabolism/Elimination

49

3
...
9
Analysis of Biofluids

50

3
...
1
History and/Traditional Uses

53

4
...
3
Products Available

54

4
...
4
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

61

4
...
7
Chemical Analysis

64

4
...
John's Wort
John T
...
1
History and Traditional Uses

67

5
...
3
Products Available

68

5
...
4
...
4
...
4
...
4
...
5
Adverse Effects and Toxicity

70

5
...
7
Pharmacokinetics/Toxicokinetics

74

5
...
1
Absorption

74

5
...
2
Distribution

75

5
...
3
Metabolism/Elimination

75

5
...
9
Analysis of Biofluids

76

5
...
1
History and Traditional Uses

79

6
...
3
Products Available

79

6
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

80

6
...
7
Analysis of Biofluids

82

6
...
1
History and Traditional Uses

85

7
...
3
Products Available

86

7
...
4
...
4
...
4
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

90

7
...
7
Regulatory Status

91

Chapter 8: Feverfew
Brian Schuller and Melanie Johns Cupp

95

8
...
2
Current Promoted Uses

95

8
...
4
Pharmacology/Toxicology

97

8
...
1
Neurologic Effects

97

8
...
2
Anti-Inflammatory Effects

100

8
...
3
Mutagenicity/Carcinogenicity/Teratogenicity

101

Page xv

8
...
6
Drug Interactions

102

8
...
8
Regulation

103

Chapter 9: Garlic
James Allman and Melanie Johns Cupp

107

9
...
2
Current Promoted Uses

107

9
...
4
Pharmacologic/Toxicologic Effects

109

9
...
1
Cardiovascular Effects

109

9
...
2
Gastrointestinal Effects

112

9
...
3
Antimicrobial Activity

112

9
...
4
Antineoplastic Effects

113

9
...
5
Immunostimulant Effects

114

9
...
6
Drug Interactions

118

9
...
7
...
7
...
7
...
8
Analysis of Biofluids

120

9
...
1
History and Traditional Uses

123

10
...
3
Products Available

124

10
...
4
...
4
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

128

10
...
7
Chemical Analysis

129

10
...
1
History and Traditional Uses

133

11
...
3
Products Available

134

11
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

136

11
...
6
...
6
...
6
...
7
Analysis of Biofluids

137

11
...
9
Regulatory Status
Chapter 12: Panax Ginseng
Angela Morgan and Melanie Johns Cupp

138

141

12
...
2
Current Promoted Uses

142

12
...
4
Pharmacologic/Toxicologic Effects

143

12
...
1
Endocrine Effects

143

12
...
2
Neurologic Effects

144

12
...
3
Cardiovascular Effects

144

12
...
4
Hematologic Effects

144

12
...
5
Immunologic Effects

145

12
...
6
Antineoplastic Effects

145

12
...
6
Drug Interactions

147

12
...
7
...
7
...
7
...
8
Analysis of Biofluids

149

12
...
10
Regulatory Status

150

Page xvii

Chapter 13: Cranberry
Angela J
...
1
History and Traditional Uses

155

13
...
3
Products Available

155

13
...
4
...
4
...
4
...
5
Chemical Analysis

159

13
...
1
History and Traditional Uses

161

14
...
3
Products Available

162

14
...
4
...
4
...
4
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity

167

14
...
7
Chemical Analysis

167

14
...
1
History and Traditional Uses

171

15
...
3
Products Available

172

15
...
4
...
4
...
4
...
4
...
4
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity

174

15
...
7
Regulatory Status

174

Chapter 16: Chaparral
Kim Melgarejo and Melanie Johns Cupp

177

16
...
2
Current Promoted Uses

178

16
...
4
Pharmacologic/Toxicologic Effects

178

16
...
1
Antineoplastic Activity

178

16
...
2
Hepatotoxicity

180

16
...
3
Effects on the Arachidonic Acid Cascade

180

16
...
4
Nephrotoxicity

181

16
...
5
Carcinogenicity

182

16
...
6
Dermatologic Effects

182

16
...
7
Antihyperglycemic Effects

182

16
...
6
Drug Interactions

187

16
...
8
Chemical Analysis/Analysis of Biofluids

188

16
...
1
History and Traditional Uses

191

17
...
3
Products Available

192

17
...
4
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

195

17
...
7
Pharmacokinetics/Toxicokinetics

198

Page xix

17
...
1
Absorption

198

17
...
2
Distribution

198

17
...
3
Metabolism/Elimination

198

17
...
9
Regulatory Status

200

Chapter 18: Comfrey
David Burch and Melanie Johns Cupp

203

18
...
2
Current Promoted Uses

204

18
...
4
Pharmacologic/Toxicologic Effects

204

18
...
1
Gastrointestinal Effects

205

18
...
2
Hepatotoxicity

205

18
...
3
Carcinogenicity/Mutagenicity

206

18
...
4
LD50

207

18
...
6
Drug Interactions

210

18
...
7
...
7
...
7
...
8
Analysis of Biofluids

211

18
...
10
Regulatory Status

212

Chapter 19: Scullcap
Jennifer Schumacher and Melanie Johns Cupp

215

19
...
2
Current Promoted Uses

216

19
...
4
Pharmacologic/Toxicologic Effects

216

19
...
1
Antispasmodic Effects

216

19
...
2
Hepatotoxicity

216

19
...
3
Cardiovascular Effects

216

19
...
4
Antimicrobial Activity

217

19
...
5
Anti-Inflammatory Activity

217

19
...
6
Chemotherapeutic Activity

218

19
...
6
Chemical Analysis

220

19
...
1
History and Traditional Uses

223

20
...
3
Products Available

224

20
...
4
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

227

20
...
6
...
6
...
6
...
6
...
7
Regulatory Status
Chapter 21: Pokeweed
A
...
1
History and Traditional Uses

237

21
...
3
Pharmacologic/Toxicologic Effects

238

21
...
1
Antimicrobial Activity and Antineoplastic Activity

238

21
...
2
Anti-Inflammatory Activity

238

21
...
3
Cardiovascular Effects

238

21
...
4
Musculoskeletal Effects

239

21
...
5
Gastrointestinal Effects

239

21
...
6
Respiratory Effects

239

21
...
7
Neurologic Effects

239

21
...
8
Hematologic Effects

239

21
...
5
Pharmacokinetics/Toxicokinetics

242

21
...
7
Regulatory Status

242

Chapter 22: Sassafras
David Hutson and Melanie Johns Cupp

245

22
...
2
Current Uses

246

22
...
3
...
3
...
3
...
3
...
4
Case Reports of Toxicity

248

22
...
5
...
5
...
5
...
6
Drug and Food Interactions

250

22
...
8
Regulatory Status

251

Chapter 23: Hawthorn
Jennifer Annon and Melanie Johns Cupp

253

23
...
2
Current Promoted Uses

254

23
...
4
Pharmacologic/Toxicologic Effects

254

23
...
1
Cardiovascular Effects

254

23
...
2
Neurologic Effects

256

23
...
3
LD50

256

23
...
4
Teratogenicity/Mutagenicity/Carcinogenicity

256

23
...
6
Pharmacokinetics/Toxicokinetics

257

23
...
8
Drug Interactions

257

23
...
1
History and Traditional Uses

259

24
...
3
Products Available

260

24
...
4
...
4
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

266

Page xxii

24
...
7
Pharmacokinetics/Toxicokinetics

267

24
...
1
Absorption

267

24
...
2
Distribution

268

24
...
3
Metabolism/Elimination

268

24
...
9
Regulatory Status

269

Chapter 25: Senna
Melanie Johns Cupp

273

25
...
2
Current Promoted Uses

274

25
...
4
Pharmacologic/Toxicologic Effects

274

25
...
1
Carcinogenicity/Mutagenicity/Genotoxicity

274

25
...
2
Gastrointestinal Effects

276

25
...
3
Laxative Abuse

278

25
...
5
...
5
...
5
...
6
Chemical Analysis

279

25
...
8
Regulatory Status

280

Chapter 26: Cascara Sagrada
Amy Renner and Melanie Johns Cupp

283

26
...
2
Current Promoted Uses

283

26
...
4
Pharmacologic/Toxicologic Effects

284

26
...
1
Gastrointestinal Effects

284

26
...
2
Nutritional and Metabolic Effects

284

26
...
3
Carcinogenicity/Mutagenicity/Genotoxicity

284

26
...
6
Drug Interactions

285

26
...
8
Analysis of Biofluids

286

26
...
10
Regulatory Status

286

Page xxiii

Chapter 27: Dong Quai
Rayna De Rosa and Melanie Johns Cupp

289

27
...
2
Current Promoted Uses

289

27
...
4
Pharmacologic/Toxicologic Effects

290

27
...
1
Cardiovascular Effects

290

27
...
2
Neurologic Effects

290

27
...
3
Musculoskeletal Effects

290

27
...
4
Immunologic Effects/Antineoplastic Activity/Antimicrobial
Activity

291

27
...
5
Anti-Inflammatory Activity

291

27
...
6
Dermatological Effects

291

27
...
7
Carcinogenicity

291

27
...
8
Estrogenic Effect

292

27
...
9
Gastrointestinal Effects

292

27
...
6
Chemical Analysis

293

27
...
1
History and Traditional Uses

295

28
...
3
Products Available

296

28
...
4
...
4
...
4
...
4
...
5
Case Reports of Toxicity Due to Commercially Available Products

297

28
...
Byrd Health Sciences, West Virginia
University School of Pharmacy, Morgantown, WV
AMANDA DAILEY • West Virginia University School of Pharmacy, Morgantown, WV
TARA DALTON • West Virginia University School of Pharmacy, Morgantown, WV
JULIE DAVIS • Beckley Appalachian Regional Hospital, Beckley, WV
RAYNA DE ROSA • West Virginia University School of Pharmacy, Morgantown, WV
MARLEA GIVENS • West Virginia University School of Pharmacy, Morgantown, WV
DAVID HUTSON • West Virginia University School of Pharmacy, Morgantown, WV
STEVEN B
...
HEATHER KNIGHT-TRENT • West Virginia University School of Pharmacy, Morgantown, WV
ANGELA J
...
S CHWARZ • West Virginia University School of Pharmacy, Morgantown, WV

Page 1

PART I—
LEGAL/REGULATORY ASPECTS OF HERBAL PRODUCTS

Page 3

Chapter 1—
Legal/Regulatory Aspects of Herbal Products
Melanie Johns Cupp
The US Food, Drug, and Cosmetic Act mandates that drugs be proven safe and effective for their
labeled use before marketing
...
Thus, herbal products do not have to be proven safe or effective
before marketing (Kurtzweil, 1999)
...
The passage of this act was a response to the
Food and Drug Administration's (FDA's) intent to remove some herbal products from the market in the
early 1990s
...
Obviously, the American
public is very interested in self-medication using herbal products (Vance, 1997)
...
Because the cost of drug development may be more than $200 million per drug and usually
takes longer than 10 yr, pharmaceutical manufacturers are unlikely to make the financial commitment
necessary to amass safety and efficacy data for an herb that cannot be patented (Vance, 1997)
...
It has been suggested that the dollar value provided by the
pharmaceutical manufacturers regarding the expense of developing a
From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...

Despite the controversy over whether these products should be held to the same safety and efficacy
standards as ''conventional medicines," the DSHEA currently allows herbal labeling to carry claims
about the product's ability to affect the structure or function of the human body or to promote general
wellbeing (Kurtzweil, 1999)
...
John's wort label may state, "Helps enhance general
mental well-being," but it cannot state, "Cures depression
...
For consumers, some structure/function claims may be difficult to
distinguish from claims of disease treatment/prevention
...

The FDA uses the "significant scientific agreement" standard to evaluate herbal product claims
...

They also concluded that the FDA's decision to deny four specific dietary supplement health claims was
a violation of the First Amendment (Anonymous, 1999c)
...
This product is not intended to diagnose, treat, cure, or prevent any
disease
...
In the future, more federal court rulings may lead to changes in the type of information seen on
herbal labels
...
The FDA
now requires an information panel titled "Supplement Facts" to appear on the label of dietary
supplements
...
g
...
If the
product contains nutrients (e
...
, iron, calcium, vitamins), these must appear on the panel just as they
would on a "Nutrition Facts" label on a food, with the percentage of the recommended daily value
listed
...
Products labeled prior
to March 23, 1999 may remain on shelves until stocks are depleted (Anonymous, 1999b)
...
The United States Pharmacopeia (USP) was first published in
1820, and has always included standards for botanicals; however, with the advent of modern medicinal
chemistry, many of the botanical drugs were replaced by monographs for synthetic chemicals
...
Herbs
are complex because they are not uniform by nature and contain many different chemicals that can vary
depending on soil, climate, season, and part of the plant used
...
In the absence of better data, "marker compounds" are
designated that are used to standardize the product
...
The USP has played an important role in designating marker
compounds for various herbs (Anonymous, 1999a)
...
The USP and NF are designated as the official
compendia by the Food, Drug, and Cosmetic Act as well as by state pharmacy practice acts (Valentino,
1983)
...
The USP and NF are now published in the same book
...
'' The USP published nine National Formulary botanical monographs in the Ninth
Supplement to the USP23-NF18, including feverfew, powdered feverfew, ginger, ginkgo, oriental
ginseng, powdered oriental ginseng, St
...
John's wort, and saw palmetto
...
In developing the
botanical monographs, US and international information is evaluated, including chemical information,
historical literature, expert opinion, anecdotal writings, case reports, and clinical trials
...
The USP
Committee of Revision and its advisory panels make the final decision on the information included in
each monograph (Anonymous, 1999a)
...
"Standard-

Page 6

ized" simply means that the manufacturer is claiming that a certain concentration of one or more
ingredients is consistent among batches
...
It does not mean that the
product meets a safety or efficacy standard (Anonymous, 1999e)
...
Problems with herbal products,
other dietary supplements, or drugs can be reported to this free service by calling 1-800-638-6725
...
Health care professionals may also contact the
FDA's MedWatch program at 1-800-FDA-1088 with reports of serious adverse effects involving herbal
products, other dietary supplements, or drugs
...

Several reviews pertaining to herbal medicine have been completed, including St
...
Included in the analysis are randomized controlled trials indexed on Medline as well
as trials published in journals not indexed on Medline
...
Publication bias, including whether "complementary medicine"
journals tend to publish studies favoring the safety and efficacy of "complementary medicine" while
"conventional medicine" journals tend to do the converse; whether non-English language studies are of
the same quality as those published in English; whether the publication language influences publication
of favorable vs unfavorable results; and whether "complementary medicine'' trials are published most
often in non English language journals is being investigated (Ezzo et al
...

Herbal products are regulated differently in countries other than the United States
...
Canada is moving toward a system resembling that in the U
...
(Allen,
1999)
...
In Germany, herbal monographs called the German Commission E monographs are
prepared by an interdisciplinary committee using historical information; chemical data; experimental,
pharmacological, clinical, and toxicological studies; epidemiological data; case reports; and
unpublished manufacturers' data
...
References
are not published in the monographs
...
In other Western European countries, herbal products are treated as drugs,
and are generally sold in pharmacies as licensed prescription and nonprescription drugs, with
registrations based on quality, safety, and efficacy
...
Like the German Commission E
monographs, the ESCP monographs address therapeutics, and do not set product quality standards
...

The German monograph system is not without precedent in the United States
...
g
...
Such products can be marketed
if they meet the standards set forth in monographs developed by FDA advisory committees in the 1970s
and 1980s
...
A general section applies to all nonprescription drugs, and sets forth acceptable
inactive ingredients, manufacturing processes, drug registration, container specifications, and labeling
requirements for all nonprescription drugs (e
...
, "Keep this and all drugs out of reach of children")
(Gilbertson, 1986)
...
Drugs deemed unsafe or ineffective are called category II drugs,
and category III drugs are those for which data are insufficient to make a determination
...
Clearly, there are drawbacks to such
a monograph system
...
Properly designed clinical trials using adequate numbers of patients and sound statisti-

Page 8

cal methods, funded by government or the private sector, would add to the knowledge base being
compiled by the Cochrane Collaboration
...

References
Allen D
...
Natural Pharm 1999;3(10):1
...

Anonymous
...
USP
quality review 1999a; April (65)
...
Dietary supplements now labeled with more information
...
March 23, 1999
...
fda
...
html
...

Anonymous
...
F-D-C
Reports
...

Anonymous
...
F-D-C
Reports
...

Anonymous
...
Pharmacist's letter 1999e;15
...

Blumenthal M
...
Therapeutic guide to herbal
medicines
...

Ezzo J, Berman BM, Vickers AJ, Linde K
...

JAMA 1998;280:1628-30
...
The FDA's OTC drug review
...

Washington, DC: American Pharmaceutical Association, 1986, pp
...

Kurtzweil P
...
U
...
Food and Drug
Administration Publication No
...
Available from: URL: http://
vm
...
fda
...
html
...

Marwick C
...
JAMA
1995;273:607-9
...
Herbs of choice
...

Valentino JG
...
Presentation to the National Council of
State Pharmaceutical Association Executives
...

Vance DA
...
Int J Pharmaceut Compound 1997;1(1):22-4
...
Karch, MD
1
...
It rarely grows to more than a foot in height, and at first glance, the plant looks
very much like a small broom
...
Some of the better known species include
Ephedra sinica and E
...

geriardiana, E
...
major which grow in India and Pakistan, and countless other
members of the family Ephedraceae that grow in Europe and the United States (E
...

vulgaris)
...
, 1976)
...
One of the most common Chinese
cultivars, known as "China 3," contains 1
...
361% pseudoephedrine, and 0
...
, 1983)
...

Noncommercial varieties of ephedra may contain no ephedrine at all (Zhang et al
...

1
...
Many thousands of years later, Pliny
accurately described the medicinal
From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
Fifteenth-century Chinese texts recommended ephedra as an
antipyretic and antitussive
...
, 1995)
...
That idea might also have had some
merit, as the latest studies show that ephedra contains a novel antibiotic called transtorine (Al-Khalil et
al
...
Settlers in the American West brewed ephedra teas, referred to by a variety of names
including teamsters' tea, Mormon tea, and chaparral tea (Max, 1991)
...

Forty years later, Nagi's original observations were confirmed by Merck chemists (Holmstedt, 1991)
...
During the 1920s and 1930s, epinephrine was the only effective oral
agent for treating asthma
...
Ephedrine was nearly as effective, and it
could be taken orally
...

Unlike the other alkaloids contained in ephedra, ephedrine is also a potent central nervous system
(CNS) stimulant (Martin et al
...
Injections of ephedrine, called philopon (which means "love of
work") were given to Japanese kamikaze pilots during World War II
...
Abusers in Tokyo, and other large Japanese cities, injected themselves
with ephedrine (then referred to as hirapon), in much the same way that methamphetamine is injected
today (Deverall, 1954; Suwanwela and Poshyachinda, 1986)
...
In the late 1980s,shabu
smoking gave way to the practice of smoking methamphetamine ("ice")
...

1
...
, 1998), par-

Page 13

ticularly during caesarean section
...
(The current PDR lists Quadrinal™,
Broncholate™, Mudrane™, Marax™, and Rynatuss™
...
Recent studies continue to confirm the effectiveness of ephedra formulations when they
are used in the short term as nasal decongestants (Jawad and Eccles, 1998)
...
Over the years ephedrine has been replaced by other, more effective agents (Pomerantz
and O'Rourke, 1969), and the advent of highly selective β-agonists has mostly eliminated the need to
use ephedrine in treating asthma
...
, 1998)
...
Generally, it is compounded with other
ingredients such as vitamins, minerals, and amino acids in products designed to increase muscle mass
and enhance endurance (Clarkson and Thompson, 1997)
...
, 1993; Hurlbut et al
...
, 1998),
and its principal metabolite norephedrine, in the urine
...
John's wort and/or caffeine, as herbal
supplement products designed to help build muscle
...
Except in the case of weight loss (Liu et al
...
After several well-publicized
accidental deaths, products clearly intended for abuse, such as "herbal ecstasy," and other "look-alike
drugs" (products usually containing ephedrine or phenylpropanolamine designed to look like illicit
methamphetamine) have recently been withdrawn from the market
...
4 Available Products
No one government agency is tasked with tracking production of ephedrine-containing products
...
Ephedrine-containing products are mostly purchased at health
food stores or over the Internet
...
The large supplement makers, of course, have Web
pages, many of which contain, or have links to, the most recent peer review studies, but in addition to
the established names, hundreds of other smaller manufacturers also advertise and sell over the Internet
...

A partial alphabetical listing of companies found in a cursory web search disclosed numerous sites
providing ephedra (or ephedrine) on the Web, many of which are located outside of the United States,
but clearly are attempting to reach a U
...
market
...
alterstatesherbs
...
dietnutrition
...
d-n-e
...
Gold Leaf Herbal Products (Canadian) Metabomax
(www
...
netcom
...
herbandvitaminshopl
...
mmainlablinc
...
natures-pantry
...
Global @PlanetaryHerbs
...
smartbomb
...
stimline
...
vrp
...
roncaskey
...

In addition to selling their own proprietary mixture, many of these same Web sites also carry the same
popular products sold in herbal and general retail outlets such as Twin Labs bestseller "Ripped Fuel,"
which contain ephedrine in the form of ma huang, combined with guarana, l-carnitine, and chromium
picolinate
...
metabolife
...
Another popular
product, sold in stores, and at a discount by many of the Web sites, is AST Research's "EPH 833,"
which is composed mainly ofephedrine-derived from ma huang
...
Ever since ephedrine became the precursor of choice for making methamphetamine,
federal regulators have severely restricted bulk sales of ephedrine, but these restrictions can be bypassed
by illegally ordering from a foreign Web site
...
Unless the product has been fortified, the expected
ephedrine content of ma huang capsules is generally <10%
...
Absent any laws controlling
production or sale of these food supplements, the ephedrine content (and the content of other added
ingredients) may vary from batch to batch, and month to month
...

1
...
5
...
These include (-)-ephedrine, (+)pseudoephedrine, (-)-norephedrine, (+)-norpseudo-ephedrine (also called cathine because it is a major
alkaloid of Catha edulis or khat, a plant used as a stimulant in North Africa), (-)-N-methylephedrine and
(+)-N-methylpseudoephedrine, (+)-pseudoephedrine, and (+/-)-norephedrine (phenylpropanolamine)
...
All of these alkaloids have important effects on the cardiovascular
and respiratory systems, but not to the same degree
...
, 1997; Waluga et al
...
, 1999)
...
Methamphetamine is a prime example
...
The l-isomer is merely a decongestant
...
" Doing so is both foolish and misleading, as it implies that the toxicity of all the enantiomers
is equivalent, which is clearly not the case
...
, 1983; Garriott et al
...
, 1985;
Glick et al
...
, 1989; Strand et al
...
, 1998) while no cases of
documented ephedrine cardiotoxicity have ever been reported in individuals taking recommended doses
(<50 mg two or three times a day)
...
Similar
considerations apply to pseudoephedrine which, unless it is consumed in massive quantities, generally
induces only modest blood pressure increases (Mariani, 1986; Waluga et al
...
, 1999)
...
5
...
It is for just those reasons that ephedrine is so widely used as a treatment for the
type of hypotensive episodes that often occur during caesarean section under spinal anesthesia (Webb
and Shipton, 1998)
...

Ephedrine is a potent CNS stimulant
...

1
...
3 Metabolism and Elimination
Phenylpropanolamine is readily and completely absorbed, but pseudoephedrine, with a bioavailability
of only approx 38%, is subject to gut wall metabolism, and absorption may be erratic (Kanfer et al
...
Pure ephedrine is well absorbed from the stomach, but absorption is much slower when it is
given as a component of ma huang, rather than in its pure form (White et al
...
Ephedrine ingested
in the form of ma huang has a tmax of nearly 4 h, compared to only 2 h when pure ephedrine is given
...

Peak concentrations for the other enantiomers, specifically phenylpropanolamine and pseudoephedrine,
occur earlier (0
...
6 and 5
...
No
proteinbinding data in humans are available
...
, 1997)
...
The results are comparable to those obtained in
studies done nearly 30 yr earlier (Wilkinson and Beckett, 1968)
...
Concentrations of methylephedrine <0
...
,

Page 17

1998), appear to be nontoxic and devoid of measurable effects
...
, 1989; Ishigooka et al
...
, 1993; Nakahara and Kikura, 1997)
...
, 1998)
...
, 1998)
...
Urinary
excretion of all three enantiomers is pH dependent
...
Patients with renal
impairment are at special risk for toxicity
...
5
...
Healthy
volunteers, given realistic doses of ephedrine-containing nasal spray (roughly 14 mg), were found to
have urine levels ranging from 0
...
65 mg/mL (Lefebvre et al
...
In addition, depending on
which screening test is used, the presence of ephedrine, or one of its enantiomers, could prove to be a
problem for individuals subject to workplace drug testing as well
...
, 1997; ElSohly and
Jones, 1995; Taylor et al
...
Of course, the true nature of the drug would be revealed by
confirmatory testing with gas chromatography and mass spectrometry, but such tests will occur only in
programs where confirmatory testing is in fact done
...
6 Drug Interactions
Phenylpropanolamine also increases caffeine plasma levels
...
, 1990; Upton, 1991)
...
Reduced metabolism of pseudoephedrine is

Page 18

seen with concurrent administration of monoamine oxidase inhibitors (MAO) (Dawson et al
...
In
extreme cases, combinations of ephedrine with MAO inhibitors can mimic symptoms of
pheochromocytoma
...
Whether this effect has any clinical significance is not known (Takahashi, 1997)
...
Such an interaction might explain the increasingly common practice of ''speedballing"—
injecting cocaine or amphetamine along with heroin (Karch et al
...
Although such
synergy has not been demonstrated with cocaine and methamphetamine, there are enough similarities
between these molecules to strongly suggest such a possibility
...
7 Toxicology
1
...
1 Neurologic Disorders
Reports of ephedra-related stroke on file with the FDA have not yet been published in the peer reviewed
literature
...
In other cases,
toxicology testing was not performed, and it is not known with any certainty whether ephedrine was
even taken
...
, 1982;
Stoessl et al
...
, 1983; Glick et al
...
,
1990; Thomas et al
...
, 1998), and even
methylephedrine (Ishigooka et al
...

In the only large study ever done to assess risk factors for stroke in young people (age 20–49) over a 1yr period (in Poland, a country where ephedra based products are widely used), nearly half the stroke
cases were associated with preexisting hypertension, another 15% had hyperlipidemia, and 6% were
diabetic (Jovanovic, 1996)
...

Sometimes, especially in Japan and the Philippines, ephedrine is taken specifically as a
psychostimulant
...
, 1989; Ishigooka et al
...
, 1993)
...
, 1994; Doyle and

Page 19

Kargin, 1996) and stroke (Stoessl et al
...
, 1993;Anonymous, 1996a,b;
Waluga et al
...

More often than not, psychosis occurs in individuals taking ephedrinebased products for asthma and
other respiratory conditions
...
As the medication becomes less and less
effective, patients tend to increase the dose
...
Of course,
ephedrine, and products containing ephedrine enantiomers, can also be taken specifically with the intent
of becoming intoxicated
...
4 mg/mL of caffeine,
and 0
...
Half of the group were also smoking marijuana and/or
abusing organic solvents
...
The FDA did not specify just why psychotic behavior in this group of individuals
should be attributed to massive ingestion of methylephedrine, rather than massive ingestion of caffeine,
chlorpheniramine, or codeine (Ishigooka et al
...
Why the FDA assumes that ephedrine in standard
clinical doses will produce the same toxicity as methylephedrine in particularly massive doses is
anyone's guess
...

Typically, patients with ephedrine psychosis will have ingested more than 1000 mg/d
...
, 1994)
...

1
...
2 Renal Disorders
Reports, particularly in the European literature, have described the occurrence of renal calculi in
chronic ephedrine users (Bories, 1976; Schweisheimer, 1976; Blau, 1998; Powell et al
...
A
review of cases from a large commer-

Page 20

cial laboratory that analyzes kidney stones found that 200 out of 166,466, or 0
...
Unfortunately, the analytic technique
used could not distinguish ephedrine from pseudoephedrine, and because pseudoephedrine is used so
much more widely than ephedrine, it seems that the risk of renal calculus associated with ephedrine use
must be quite small
...
Urinary retention, occurring as a consequence of drug overdose, has rarely been reported
(Glidden and DiBona, 1977;
Lindberg, 1988)
...

Ephedrine and most of its enantiomers are excreted unchanged in the urine (although small amounts are
oxidized in the liver to norephedrine and norpseudoephedrine, both CNS stimulants)
...
None of the
enantiomers are easily removed by dialysis, and treatment remains supportive, using pharmacologic
antagonists to counter the α- and β-adrenergic effects of these drugs (Lyon and Tuney, 1996)
...
, 1980)
...
No such cases have appeared in the peer reviewed literature, and review of the reports
published by the FDA shows that all of the affected individuals were taking multiple remedies
...

For example, a cluster of more than 100 cases of interstitial nephritis was reported from Belgium in
1992
...
Renal biopsies from these women disclosed acellular, interstitial fibrosis, often with precancerous
transformation of the urinary tract epithelia
...
Epidemiologic investigation disclosed that the renal injury was a result of the inadvertent
substitution of Stephnania tetrandra with Aristolochia fangji, an herb known to contain aristilochic
acid, a potent carcinogen
...
It seems extremely unlikely that ephedrine was
in any way associated with the hematuria reported in the FDA ADRs
...
7
...
Chronic
exposure to abnormally high levels of circulating catecholamines can damage the heart
...
, 1995; Karch, 1999), but ephedrine-related
cardiomyopathy is an extremely rare occurrence, occurring only in individuals who take massive
amounts of drug for prolonged periods of time
...

Another involved a woman who had been abusing ephedrine (300–600 mg/d) for 10 yr, and a third
case, involving a 28-yr-old, cigarette smoking, 321-pound woman taking 2000 mg of ephedrine every
day for 8 yr (To et al
...
, 1998)
...

Similar considerations apply to the relationship (if any) between myocardial infarction and ephedrine
use
...
, 1990), cardiomyopathy (To et al
...
,
1982; Wooten et al
...
, 1985; Bruno et al
...
More often than not, toxicology results were not even recorded, and the
victims were known to have long-term histories of polydrug use (Bruno et al
...
There are no case
reports in the peer review literature linking ephedrine, phenylpropanolamine (although case reports
linking phenylpropanolamine and stroke were once common), or pseudoephedrine to myocardial
infarction
...

Cardiac arrhythmia is known as a complication of catecholamine excess (Lermann et al
...
The literature contains
one case report (Weesner et al
...
The report described arrhythmias occur-

Page 22

ring in a 14-yr-old who overdosed on cold medications, taking a total of 3300 mg of caffeine, 825 mg
of phenylpropanolamine, and 412 mg of ephedrine
...

The problem in relating ephedrine to heart disease is that with so many people taking ephedrine-based
products, it is inevitable that some ephedrine users will become ill; some may even have preexisting
cardiac malformations
...
When
toxicology testing was done, no ephedrine was detected, but the heart, when finally examined, was
found to be diseased (Bland-White-Garland syndrome, with anomalous origin one of the coronary
arteries, a congenital disorder)
...
A body
building college student who died suddenly was found to have areas of myocardial necrosis and cellular
infiltration
...
The pattern,
at least as described in the journal article, could have been the result of many other disorders, including
steroid or stimulant abuse
...
7
...
However, the latest
studies suggest that there may be other reasons for treating respiratory infections with ephedra; it
contains a compound that, in the test tube at least, has antibiotic properties
...
It inhibits growth of common bacteria, such as Enterobacter
cloacae, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus (A1-Khalil et al
...
Unfortunately, there have been no clinical trials
...
, 1995)
...
One
problem in establishing efficacy is that traditional herbalists usually combine ephedra with other herbs
...
Magnolia obovata, Citrus unshiu, Glycyrrhiza uvalensis, and Bupleurum falcatan,
inhibits immunoglobulin E (IgE) mediated leukotriene

Page 23

synthesis, another action that could prove to be effective in the treatment of arthritis (Hamasaki et al
...

An area of very major interest is weight loss
...
Many obese people have a lower than expected resting metabolic
rate, a deficiency that may be genetically controlled
...
In most of the trials, the combination has
been shown to induce weight loss (Astrup and Lundsgaard, 1998)
...
The most exciting
new work in this area suggests that stimulation of some β-receptors may lead to the production of a
group of proteins (called uncoupling protein, or UCP1,2, and 3) that can uncouple ATP production from
mitochondrial respiration, resulting in the dissipation of energy as heat
...
,
1999)
...

1
...
A 1997 case report described a 28-yr-old woman with two prior suicide
attempts, who died after ingesting amitriptyline and ephedrine
...
9 mg/kg)
...
33 mg/kg in blood and 7
...
, 1997)
...
, 1993)
...
1 g of ephedrine combined with 7
...
Her blood ephedrine level was 5 mg/L, while the concentration in the liver was 15
mg/kg (Baselt and Cravey, 1989)
...
In 15 children diagnosed with sudden infant
death syndrome, the mean blood pseudoephedrine concentration was 3
...
3 mg/L,
with a range of 0
...
0 mg/L (SD = 3
...
The authors of the study take pains to point out that
"The data do not allow definitive statements about the toxicity of pseudoephedrine at a given
concentration" (Hanzlick, 1995)
...
9 Analytic Considerations
Reliable techniques exist for liquid-liquid extraction of ephedrine from alkaline tissue samples
...

Blood and tissue measurements have been reported in several ephedrine-related deaths, and in clinical
trials with therapeutic doses of the drug (Backer et al
...
More recently capillary electrophoresis
has been used to separate and identify all 10 stereoisomers of the ephedrine family found in nutritional
supplements
...
,
1995)
...
10 Methamphetamine Manufacture
In Japan, in the remote past, ephedrine abuse was a real and considerable public health problem
...
" Such products are no longer on the
market and are really not an issue
...
Either (-)-ephedrine or (+)pseudoephedrine can be used to make
methamphetamine by reductive dehalogenation using red phosphorus as a catalyst (Irvine and Chen,
1991)
...

If pseudoephedrine is used, the result will be dextromethamphetamine
...

1
...
Commission E Recommendations
Commission E recommends ephedra for "diseases of the respiratory tract with mild bronchospasms in
adults and children over the age of six
...
" "Anxiety and restlessness" are also considered
contraindications (Blumenthal, 1998)
...

The FDA has proposed a dosage limit of 8 mg every 6 h, and a daily maximum dose of 24 mg
(Anonymous 1997)
...
Transtorine, a new quinoline alkaloid from Ephedra transitoria
...

Anonymous
...
MMWR Morb Mortal Wkly Rep 1996a;45:689-93
...
Dietary supplements containing ephedrine alkaloids; proposed rule
...
Fed
Register 1997;62(107): 30677—724
...
From the Centers for Disease Control and Prevention
...
JAMA 1996b;276:1711-2
...
What do pharmacological approaches to obesity management offer? Linking
pharmacological mechanisms of obesity management agents to clinical practice
...

Backer R, Tautman D, et al
...
J Forensic Sci 1997;42:157-9
...
Disposition of toxic drugs and chemicals in man
...
, Chicago,London: Year
Book Medical Publishers, 1989
...
Ephedrine nephrolithiasis associated with chronic ephedrine abuse
...

Blumenthal M
...
) Complete German Commission E monographs, therapeutic guide to herbal
medicines
...

Bories H
...
Infirm Fr 1976; 179:13-8
...
Renal excretion of pseudoephedrine
...

Bruno A, Nolte KB, et al
...
Neurology 1993;43:1313-6
...
Ephedrine and related substances
...

Chicharro M, Zapardiel A, et al
...
J Chromatogr 1993;8,622:103-108
...
Intracerebral hemorrhage in a young woman with arterio-venous
malformation after taking diet control pills containing phenylpropanolamine:a case report
...


Clarkson P, Thompson H
...
Research findings and limitations
...

Dawson J, Eamshaw S, et al
...
J
...


Page 26

Deverall R
...
The story of opium, heroin, morphine, and philopon traffic, 3rd
edit
...

Doyle H, Kargin M
...
BrMedJ
1996;312:1441
...
Drug testing in the workplace: could a positive test for one of the mandated drugs
be for reasons other than illicit use of the drug? J Analyt Toxicol 1995;19:450-458
...
Determination of ephedrine compounds in nutritional supplements by
cyclodextrin-modified capillary electrophoresis
...

Forman HP, Levin S, et al
...
Pediatrics 1989;83:737-1
...
Five cases of fatal overdose from caffeine-containing "look-alike"
drugs
...

Gaultieri J
...
J Toxicol Clin Toxicol 1996;34:581-582
...
Phenylpropanolamine: an over-the-counter drug causing central nervous
system vasculitis and intracerebral hemorrhage
...
Neurosurgery 1987;20:969-74
...
Urinary retention associated with ephedrine
...

Grinspoon L, Hedblom P
...
Cambridge, MA,
and London, England: Harvard University Press, 1995
...
Ephedrine abuse among 36 female weight lifters
...

Hamasaki Y, Kobayashi I, et al
...
J Ethnopharmacol 1997;56:123-31
...
National Association of Medical Examiners Pediatric Toxicology (PedTox) Registry
Report 3
...
Am J Forensic Med Pathol
1995;16:270-7
...
Ephedrine psychosis
...

Holmstedt, B
...
J Ethnopharmacol 1991;32:724
...
Solid-phase extraction cleanup and liquid chromatography with ultraviolet
detection of ephedrine alkaloids in herbal products
...

Irvine G, Chen L
...
In NIDA Research Monograph 115, Miller, M
...
(eds
...

Ishigooka J, Yoshida Y, et al
...
Prog Neuropsychopharmacol
Biol Psychiatry 1991;15:513-21
...
Fatal intracranial hemorrhage associated with phenylpropano-lamine,
pentazocine, and tripelenamine overdose
...

Jawad SS, Eccles R
...
Rhinology 1998;36:73-6
...
Stroke and phenylpropanolamine use [letter]
...

Jovanovic Z
...
Srp Arh Celok Lek 1996;124:232-5
...
The pharmacology of psychoactive alkaloids from ephedra and catha
...

Kanfer I, Dowse R, et al
...
Pharmacotherapy 1993;13(6 Pt
2):116S-128S; discussion 143S-6S
...
The pathology of drug abuse, 2nd edit
...

Karch S
...
Theoharides
...

Karch S, Green G, et al
...
J
Forensic Sci 1995;40:591-595
...
Methylephedrine concentrations in blood and urine specimens
...

Lake C, Rosenberg D, et al
...
Clin Pharmacol
Ther 1990a;47:675-85
...
Adverse drug effects attributed to phenylpropanolamine: a review of 142
case reports
...

Lefebvre RA, Surmont F, Bouckaert J, Moerman E
...
J Pharm Pharmacol 1992;44:672-5
...
Catecholamine facilitated reentrant ventricular tachycardia: uncoupling of
adenosine's antiadreneregic effects
...

Levine B, Jones R, et al
...
J Analyt Toxicol
1993;17:381-3
...
Medicinal plants in a Middle Paleolithic grave Shanidar IV
...

Lindberg AW
...
Ugeskr Laeger 1988;150:2086-7
...
A component of the medicinal herb ephedra blocks activation in the
classical and alternative pathways of complement
...

Liu YL, Toubro S, et al
...
Int J Obes Relat Metab Disord 1995;19:678-85
...
Intracranial hemorrhage in association with pseudoephedrine overdose
...

Lyon CC, Tourney JH
...
Br J Clin Pract 1996;50:396-7
...
Pseudoephedrine-induced hypertensive emergency: treatment with labetalol
...


Page 28

Martin W, Sloan J, et al
...
Clin Pharmacol Ther
1971;12:245-8
...
This and that: the ethnopharmacology of simple phenethylamines, and the question of cocaine
and the human heart
...

Nadeau SE
...
Ann Neurol
1984;15:114-5
...
Hair analysis for drugs of abuse
...
Determination of ephedrine and its
homologs in rat hair and human hair
...

Namba T, Kubo M, et al
...
" Planta Med 1976;29:216-25
...
Effects of chronic administration of agonists and antagonists on the density of
beta-adrenergic receptors
...

Pomerantz B, O'Rourke R
...
Am J Med 1969;46:94160
...
Ma-huang strikes again: ephedrine nephrolithiasis
...

Ramsey JJ, Colman RJ, et al
...
Am J Clin Nutr 1998;68:42-51
...
Decongestant effects on hemodynamics at rest, exercise, and recovery
from exercise during 6 degrees of head down tilt
...

Roxanas MG, Spalding J
...
Med J Aust 1977;2:639-40
...
Ingestion of pseudoephedrine
...
Arch Otolaryngol 1963;77:145-6
...
Cerebral arteritis associated with oral use of phenylpropanolamine: report of a case
...

Sagara K, Oshima T, et al
...
Chem Pharmacol Bull (Tokyo) 1983;31:2359-65
...
Myocardial presynaptic and postsynaptic and postsynaptic autonomic
dysfunction in hypertrophic cardiomyopathy
...

Schrauwen P, Walder K, et al
...
Obes Res 1999;7:97-1105
...
[Kidney stones]
...

Shufman NE, Witztum E, et al
...
Harefuah 1994;127:166-8,215
...
The effects of ephedrine on the physiological and psychological responses to
submaximal and maximal exercise in man
...

Smith D, Perry P
...
Part II: Other performanceenhancing agents
...


Page 29

Stoessl AJ, Young GB, et al
...
Stroke 1985; 16:734-6
...
[Cerebral hemorrhage associated with phenylpro-panolamine]
...

Suwanwela C, Poshyachinda V
...
Bull Narc 1986;38:41-53
...
Amphetamines in hair by enzyme-linked immunosorbent assay
...
1998;22:418-24
...
Hyperamylasemia in response to ritodrine or ephedrine administered
to pregnant women
...

Takayasu T, Ohshima T, et al
...
Nippon Hoigaku Zasshi 1997;51:235-40
...
[Cerebral hemorrhage associated with the use ofphenylpropanolamine
...
Rev
Med Chil 1996;124:1499-503
...
Accuracy of five on-site immunoassay drugs-of-abuse testing devices
...

Tekol Y, Tercan E, et al
...
Acta Anaesthesiol Scand
1994;38:396-7
...
Reply to Comments by Dr
...
J Clin Psychol Pharmacol 1999;19:198-9
...
A comparison of the cardiovascular effects of phenylpro-panolamine and
phenylephrine containing proprietary cold remedies
...

To L, Sangster J, et al
...
Med J Aust 1980;2:35-6
...
Electroencephalographical analysis of acute drug intoxication—SS Bron
solution-W
...

Upton R
...
Clin
Pharmacokinet 1991;20:66-80
...
Heat exposure and drugs
...
Clin Pharmacokinet 1998;34:311-22
...
Cardiovascular effects of ephedrine, caffeine, and yohimbine measured by
thoracic electrical bioimpedance in obese women
...

Webb AA, Shipton EA
...
m
...
Can J Anaesth 1998;45:367-9
...
Cardiac arrhythmias in an adolescent following ingestion of an over-thecounter stimulant
...

Weiner I, Tilkian A, et al
...
Cath Cardiovas Diag
1990;20:51-3
...
Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra
sinica) in normotensive adults
...

Whitehouse AM, Duncan JM
...
Br J Psychiatry 1987;50:258-61
...
Absorption, metabolism, and excretion of the ephedrines in man
...

Pharmacokinetics
...

Wooten MR, Khangure MS, et al
...

Ann Neurol 1983;13:337-40
...
A comparison of three fluid-vasopressor regimens used to prevent
hypotension during subarachnoid anaesthesia in the elderly
...

Yin PA
...
Stroke
1990;21:1641
...
[Quality evaluation of twelve species of Chinese Ephedra]
...


Page 31

Chapter 2—
Kava
Shawn Reeder and Melanie Johns Cupp
Piper methysticum, kava-kava, awa, kew, tonga (Anonymous, 1996), kawa, yaqona, sakau (Norton and
Ruze, 1994), ava, ava pepper, intoxicating pepper (Heiligenstein and Guenther, 1998)
2
...
This South Pacific plant is a robust, branching, perennial shrub
with heart-shaped, green, pointed leaves (Singh, 1992) that grow up to 28 cm long and flower spikes
that grow up to 9 cm long (Anonymous, 1996)
...
Kava reproduces vegetatively, without fruit or seeds, usually under
cultivation (Norton and Ruze, 1994)
...
Kava has been described in the European
literature since the early 1600s when it was taken there by the Dutch explorers LeMaire and Schouten,
who had acquired it while seeking new passages across the Pacific (Norton and Ruze, 1994)
...
Thus, kava is used for
the purposes that Western society uses alcohol,
From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
Events typically accompanied by kava ceremonies included weddings, funerals, births,
religious occasions, seasonal feasts, reconciliations, welcoming of royalty or other guests, and the
exchange of gifts (Norton and Ruze, 1994)
...
The beverage was traditionally
made by mixing grated, crushed, or chewed fresh or dried root with cool water or coconut milk and then
straining the mixture through plant fibers to isolate the liquid, which was consumed (Norton and Ruze,
1994)
...
Other folk uses of kava have included treatment of headaches, colds, rheumatism, sexually
transmitted diseases, and inflammation of the uterus (Anonymous, 1996)
...
Several substances extracted from the roots were also used
briefly in Europe as diuretics (Norton and Ruze, 1994)
...
2 Current Promoted Uses
Kava is currently promoted for relief of anxiety and stress
...
3 Products Available
Kava is available from a variety of manufacturers in most health food stores under a variety of names
...
Kava is marketed in Europe
under a variety of names including Laitan ® or Kavasporal ® in Germany, Potter's antigian tablets in the
United Kingdom, Viocava® in Switzerland, and Mosaro ® in Austria (Schelosky et al
...

2
...
4
...
The main bioactive constituents include yangonin, desmethoxyyangonin,
11-methoxyyangonin, kavain (kawain), dihydrokavain, methysticin, dihydromethysticin, and 5,6 6
dehydromethysticin (Keller and Klohs, 1963)
...
, 1989)
...

A randomized 25-wk placebo-controlled study by Volz and Kieser showed a significant benefit from
the use of kava-kava extract WS 1490 over placebo in treating anxiety disorders of nonpsychotic origin
...
The main outcome criterion, the patients' score on the
Hamilton Anxiety Scale (HAMA), was significantly better (p<0
...
Few adverse effects were judged to be related or possibly related to kava
administration
...
These results support use of kava as an
alternative to antidepressants and benzodiazepines (Volz and Kieser, 1997)
...
, 1994)
...
Nevertheless, kava is purported to promote relaxation and sleep
without dampening alertness, causing heavy sedation, or causing a "hangover" effect the morning after
consumption (Anonymous, 1998)
...
,
1994)
...
Studies of kava's effects in vitro, in vivo, and
ex vivo show conflicting results in regard to kava's effects on benzodiazepine or γ-aminobutyric acid
(GABA) receptors (Davies et al
...
, 1994; Heiligenstein and Guenther, 1998)
...
, 1994)
...
, 1994)
...
, 1997)
...
Both forms of kavain inhibited [3H]noradrenaline uptake more than methysticin, but the
concentrations necessary to achieve this effect were about 10 times higher than those in mouse brains
after a dose of kavain high enough to cause significant sedation
...
No effects were seen on
the uptake of [ 3H]serotonin
...
, 1998) in rats showed that (+)-kavain and
other kavapyrones affect serotonin levels in the mesolimbic area
...
Dopamine levels in the nucleus accumbens were decreased by
yangonin and low-dose (+)-kavain, but were increased by higher doses of (+)-kavain and
desmethoxyyangonin
...

A study conducted in Germany indicates that kava may have neuroprotective properties primarily due
to its constituents methysticum and dihydromethysticum (Backhau β and Krieglstein, 1992)
...

The extract as well as the individual pyrones methysticin and dihydromethysticin showed significant
reductions in infarct area similar to those produced by memantine, an anticonvulsive agent known to
have neuroprotective qualities (Backhauβ and Krieglstein, 1992)
...
, 1981)
...
compared the antagonistic effects of kavain, dihydrokavain, methysticin, and
dihydromethysticin to those of mephenesin and phenobarbital in preventing convulsions and death
caused by strychnine
...
, 1970)
...

Kava also produces analgesic effects that appear to be mediated through a nonopiate pathway
...
Both the aqueous and lipid
extracts were effective analgesics, as were four of the eight purified pyrones (lactones):methysticin,
dihydromethysticin, kavain, and dihydrokavain (Jamieson and Duffield 1990a)
...
Naloxone failed to inhibit kava's effects at doses high enough
to inhibit the action of morphine, indicating that kava works through a nonopiate pathway to produce
analgesia
...
It has also been reported to cause
visual changes such as reduced near-point accommodation and convergence, increase in pupil diameter,
and oculomotor balance disturbances (Garner and Klinger, 1985)
...
, 1981)
...
Its effects on the peripheral nervous system are limited to a local anesthetic effect,
resulting in numbness in the mouth if kava is chewed (Anonymous, 1996)
...
, 1989)
...
4
...
Chronic ingestion of kava may cause a temporary yellowing of
the skin, hair, and nails (Blumenthal, 1997)
...
Chronic ingestion may also lead to a temporary condition known as kava
dermopathy (Norton and Ruze, 1994) or kawaism, characterized by dry, flaking, discolored skin and
reddened eyes which is reversible with discontinuation (Jappe et al
...
In the early 19th century,
Peter Corney, a lieutenant on a fur-trading vessel, described this phenomenon in great detail as it
applied to the use of this side effect in treating other skin disturbances
...
At this
time the body is covered all over with white scruff, or scale, resembling the dry scurvy
...
The exact mechanism
for this dermopathy is unknown but it has been speculated that kava may interfere with cholesterol
metabolism, leading to a reversible, acquired ichthyosis similar to that seen with the use of lipid
lowering agents such as triparanol (Norton and Ruze, 1996)
...
5) (Jappe et al
...
Yet another theory
involves interference with B vitamin metabolism or action (Mathews et al
...

2
...
3 Musculoskeletal Effects
As mentioned in Section 2
...
1, kava is a centrally acting skeletal muscle relaxant
...
, 1970)
...
4
...
, 1995); however, no clinical trials have established that it is truly effective
...
coli, Streptococcus pyogenes, or Staphylococcus
aureus (Locher et al
...

2
...
5 Hepatotoxicity
See Section 2
...

2
...
6 Antiplatelet Effects
Racemic kavain, a component of kava, has been shown to have antiplatelet effects, presumably due to
inhibition of cyclooxygenase, and thus inhibition of thromboxane synthesis (Gleitz et al
...

Antiplatelet effects have not been observed in vivo
...
5 Case Reports of Toxicity Due to Commercially Available Products
Kava dermatopathy in association with traditional use of kava is well described in the literature (Norton
and Ruze, 1994)
...
, 1998)
...
Skin biopsy revealed CD8 lymphocytic
infiltration with destruction of the sebaceous glands and lower infundibula
...
Skin biopsy revealed an infiltrate in the reticular dermis with disruption and necrosis of the
sebaceous gland lobules
...


Page 37

There have also been four cases of extrapyramidal effects associated with kava use (Schelosky et al
...
A 28-yr-old man with a history of antipsychotic-induced extrapyramidal effects experienced
torticollis and oculogyric crisis 90 min after a single 100-mg dose of Laitan ® (kava extract)
...
A 22-yr-old woman experienced oral and lingual
dyskinesia, painful twisting movements of the trunk, and torticollis 4 h after a 100 mg dose of the same
product taken by the previously described male
...
5 mg intravenous dose of beperiden was given, with immediate relief
...
A single 5 mg intravenous dose of beperiden was immediately
effective
...
Improvement was noted 2 d after discontinuation of the product
...

2
...
A study
(Mathews et al
...
Red blood cell volume increased in proportion to kava use, while bilirubin,
plasma protein, platelet volume, B-lymphocyte count, and plasma urea were inversely proportional to
kava consumption
...
Other findings
included hematuria and difficulty acidifying and concentrating the urine, suggesting an effect on the
renal tubules; and increased serum transaminases and increased highdensity lipoprotein (HDL)
cholesterol, suggesting some effect on the liver
...

This suggests that kava might be more hepatotoxic than alcohol
...
It was also noted by the authors of this
observational study that sudden death in relatively young

Page 38

men is more common in kava-using Aboriginal communities than in non-using communities
...
7 Drug Interactions
Alcohol appears to at least add to the hypnotic effect of kava in mice, and was also observed to increase
the lethality of kava (Jamieson and Duffield, 1990b)
...
Concomitant use
of barbiturates, melatonin, and other psychopharmacological agents might potentiate the effects of kava
as well (Thorndyke and Rhyne, 1998)
...
, 1988) also
raises concerns about concomitant alcohol use
...

The combination of kava and alprazolam was believed to be responsible for hospitalizing a 54-yr-old
man
...
He had
been taking an undisclosed brand of kava purchased in a health food store in combination with
alprazolam for 3 d
...

2
...
8
...
, 1989)
...
8
...
, 1989)
...
Demethylation of the
12-methoxy substituent in yangonin and hydroxylation at carbon 12 of desmethoxyyangonin have also
been observed
...

2
...
, 1989)
...

2
...
Similar
results were obtained from all samples with the major components kavain, dihydrokavain,
dihydromethysticin, yangonin, and desmethoxyyangonin being easily identifiable (Duffield et al
...
Several trace components were also identified
...
Additional information pertaining to GC -MS analysis of kava is available
(Duve, 1981; Duffield and Lidgard 1986; Duffield et al
...
, 1988)
...
11 Regulatory Status
Kava is currently sold as a dietary supplement in the United States (Blumenthal, 1997)
...

References
Almedia JC, Grimsley EW
...

Ann Intern Med 1996;125:940-1
...
Kava-kava
...
St
...

Anonymous
...
Available from: URL: www
...
com/Topic
...
Accessed
1998 Oct
...

Backhau β C, Krieglstein J
...
Eur J Pharmacol 1992;215:265-9
...
Effect of kava extract and individual kavapyrones on
neurotransmitter levels in the nucleus accumbens of rats
...

Blumenthal M
...
S
...
Kava-kava rhizome
...

Austin, TX, 1997
...
Identification by methane chemical
ionization gas chromatography/ mass spectrometry of the products obtained by steam distillation and
aqueous acid extraction of commercial Piper methysticum
...

Davies LP, Drew CA, Duffield P, Johnston GAR, Jamieson DD
...
Pharmacol Toxicol 1992;71:120-6
...
Identification of some human
urinary metabolites of the intoxicating beverage kava
...

Duffield PH, Jamieson D
...
Clin Exp Pharmacol Physiol
1991;18:571-78
...
Analysis of kava resin by gas chromatography and electron impact and
methane negative ion chemical ionization mass spectrometry
...

Duffield AM, Lidgard RO, Low GKC
...
Biomed Environ Mass Spectrometry
1986;13:305-13
...
Gas-liquid chromatographic determination of major contituents of Piper methysticum
...

Garner LF, Klinger JD
...
J Ethnopharamacol
1985;13:307-11
...
Antithrombotic action of kava pyrone (+)-kavain
prepared from Piper methysticum on human platelets
...

Heiligenstein E, Guenther G
...
John's wort,
valerian, and kava-kava
...

Heinze HJ, Munthe TF, Steitz J, Matzke M
...
Pharmacopsychiatry
1994;27:224-30
...
The antinociceptive actions of kava components in mice
...

Jamieson DD, Duffield PH
...
Clin Exp Pharmacol
Physiol 1990b;17:509-14
...
Comparison of the central nervous system activity
of the aqueous and lipid extract of kava (Piper methysticum)
...

Jappe U, Franke I, Reinhold D, Gollnick HPM
...

Jussofie A, Schmiz A, Hiemke C
...
Psychopharmacology 1994;116:469-74
...
A review of the chemistry and pharmacology of the constituents of Piper
methysticum
...

Kretzschmar R, Meyer HJ, Teschendorf HJ
...
Experientia 1970;26:283-4
...
Antimicrobial activity
and anti-complement activity of extracts obtained from selected Hawaiian medicinal plants
...

Mathews JD, Riley MD, Fejo L, Munoz E, Milns NR, Gardner ID, et al
...
Med J Aust
1988;148:548-55
...
Kava dermopathy
...

Schelosky L, Raffauf C, Jendroska K, Poewe W
...
J Neurol Nerosurg
Psychiatry 1995;58:639-40
...
[3H]-Monoamine uptake inhibition properties of kava pyrones
...

Singh YN
...
J Ethnopharmacol 1992;37:13-45
...
Effects of kava on neuromuscular transmission and muscle contractility
...

Thorndyke A, Rhyne H
...
Available from: URL: www
...
edu/˜cebradsh/kava
...
Accessed
1998 Oct
...

Tyler VE, Brady LR, Robbers JE
...
, Philadelphia: Lea and Febiger, 1981
...
Kava-kava extract WS 1490 versus placebo in anxiety disorders-arandomized
placebo-controlled 25-week outpatient trial
...


Page 43

Chapter 3—
Ginkgo Biloba
Forouzandeh Mahdavi and Melanie Johns Cupp
3
...
), is the last remaining member of the Ginkgoaceae family, which
once included many species (Tyler, 1993)
...
Since then it has become a
popular ornamental tree worldwide
...
Ginkgo fruits and seeds have been used in China for their
medicinal properties since 2800 BC (Tyler, 1993)
...
The ancient Chinese and Japanese ate roasted ginkgo seeds as a digestive aid and to prevent
drunkenness (Anonymous, 1998)
...

3
...
It is purported to improve
blood flow to the brain and to improve peripheral circulation
...
Other conditions for which it is
currently used are diabetes-related circulatory disorders, impotence, and vertigo
...
3 Products Available
An acetone-water mixture is used to extract the dried and milled leaves (Tyler, 1993)
...
J
...
, Totowa, New Jersey

Page 44

ized
...
, 1996;
Nemecz and Combest, 1997)
...
On average, the
brands were within 2% of meeting this standard, but within individual bottles, the content often varied
...
3% and 23
...
Nature
Made® by Pharmavite and Ginkgold®by Nature's Way were closest to the designated amounts of
terpene lactones, with 6
...
9%, respectively (Anonymous, 1999)
...
The usual dosage recommended is 120 mg of standardized
extract per day for treatment periods of up to 6 wk (Nemecz and Combest, 1997)
...
4 Pharmacologic/Toxicologic Effects
The effects of GB are attributed to several chemical constituents of the whole plant rather than to any
one individual component
...
,
1990; Houghton, 1994; Nemecz and Combest, 1997; Anonymous, 1998)
...
4
...
One study (Ramassamy et al
...
MPTP, which has caused Parkinsonism in young drug abusers, is thought
to damage these neurons through formation of free radicals
...
Whether
chronic GBE ingestion could prevent development of idiopathic Parkinson's disease in humans remains
to be seen
...
In one study (Le Bars et al
...
, Revised (DSM-III-R) and International Statistical Classification of Diseases, 10th
Revision (ICD-10) criteria
...
Thus, participants' cognitive impairment, daily living and
social behavior, and general psychopathology were objectively evaluated
...
Adverse effects did not differ from those of placebo
...
In addition, a meta-analysis of four double-blind, placebo-controlled studies including a total of
424 Alzheimer's patients found a small (3%) but clinically significant improvement on the ADAS -Cog
with 120–240 mg of Ginkgo biloba administered for 3–6 mo (Oken et al
...
Given such small
benefits in light of ginkgo's association with spontaneous bleeding (See Section 3
...

The cognitive effects of ginkgo have also been assessed in nonAlzheimer's patients
...
, 1993)
...
The effect of Zingicomb®(Mattern et
Partner, Starnberg, Germany), a combination product containing 24% ginkgo flavonoids and 23
...
5–100 mg/kg was compared to the effects of placebo and diazepam
administered intraperitoneally at a dose of 1 mg/kg on anxiety-associated behaviors (Hasenöhrl et al
...
The rats were subjected to an elevated plus-maze consisting of enclosed and open arms
...
5
mg/kg dose of Zingicomb®was associated with rats spending more time in the open arms and with
more excursions toward the ends of the open arms as compared to placebo
...
These results were interpreted to mean that the preparation exhibited
anxiolytic effects at a dose of 0
...
Both the herbal product
at a 0
...
These effects of the herbal preparation were
attributed to blockade of 5-hydroxytryptamine 3(5-HT3; serotonin) receptors, which has been shown in
previous studies to produce similar results in the elevated plus-maze
...

Vertigo and tinnitus have been successfully relieved with ginkgo at doses of 16–160 mg/d for 3 mo
(Kleijnen and Knipschild, 1992)
...
4
...

Another GB extract, LI 1730, increased blood flow in nailfold capillaries and decreased erythrocyte
aggregation compared to placebo in 10 volunteers at a dose of 112
...
, 1990)
...

Many studies have demonstrated that ginkgolides are capable of inhibiting platelet activating factor
(PAF), which is involved in platelet aggregation and inflammatory processes such as are seen in
asthma, ulcerative colitis, and allergies
...

3
...
3 Carcinogenicity/Mutagenicity/Teratogenicity
No mutagenic, carcinogenic, or teratogenic effects have been noted in studies performed using
commercially available ginkgo products containing 22–27% flavone glycosides and 5–7% terpene
lactones (Blumenthal, 1998)
...
4
...
, 1996) of GB extract 761 in rats demonstrated that high doses (10–100 mg/kg) of
the extract, as well as isolated ginkgolides A and B at doses of 2 mg/kg, decreased corticosteroid
synthesis by up to 50% and 60%, respectively
...

3
...

Bilateral subdural hematomas were discovered in a 33-yr-old woman who had been taking 60 mg of GB
twice daily for 2 yr, acetaminophen, and occasionally an ergotamine/caffeine preparation (Rowin and
Lewis, 1996)
...

In a similar case, a 61-yr-old man presented with a subarachnoid hemorrhage after taking 40 mg GB
tablets three or four times daily for >6 mo (Vale, 1998)
...

A 78-yr-old woman suffered a left parietal hemorrhage after taking a ginkgo preparation for 2 mo
(Matthews, 1998)
...
Prothrombin time was unchanged
...
Other medications included
325 mg of aspirin daily for 3 yr post-coronary bypass
...

''Gin-nan" food poisoning, a toxic syndrome associated with ingestion of 50 or more ginkgo seeds, can
result in loss of consciousness, tonic/clonic seizures, and/or death (Anonymous, 1998)
...
Infants were at greatest risk
...
, 1996)
...
, 1996)
...

Adverse effects listed in the German Commission E Ginkgo biloba leaf extract monograph include
gastrointestinal upset, headache, and rash (Blumenthal, 1998)
...
6 Drug Interactions
In two of the five spontaneous bleeding episodes described in Section 3
...
e
...
Because ginkgo is
known to be an inhibitor of PAF (Chung et al
...
g
...
g
...
In fact, EGb 761 was shown
to potentiate the antiplatelet effect of ticlopidine in rats (Kim et al
...
The dosages of both drugs
used were higher on a milligram per kilogram basis compared to the usual human dose
...
, 1989)
...
7 Pharmacokinetics/Toxicokinetics
3
...
1 Absorption
In humans, absolute bioavailability is 98–100% for ginkgolide A, 79–93% for ginkgolide B, and at least
70% for bilobalide (Blumenthal, 1998)
...
Additional data from
human experiments from the manufacturer of 80mg EGb 761 solution show that the absolute
bioavailabilities of ginkgolides A and B were >80%, while that of ginkgolide C was very low
...
Corroborating these
results was a later pharmacokinetic study (Fourtillan et al
...
Food intake did
increase the time to peak concentration, but did not affect bioavailability
...
Peak blood concentrations occurred at 1
...
At 3 h, the highest radioactivity was
measured in the stomach and small intestine, indicating that these are the sites of absorption
...
7
...
The radiolabeled extract was distributed into
glandular and neuronal tissues, as well as the eyes
...

3
...
3 Metabolism/Elimination
The half-life of the flavonol glycosides administered as the product LI 1370 is 2–4 h (Kleijnen and
Knipschild, 1992)
...
The half-life of bilobalide was 3 h after
administration of 120 mg of this extract
...
,
1995) using this same product; mean halflives of ginkgolide A, ginkgolide B, and bilobalide were 4
...
57 h, and 3
...

A study in rats using radiolabeled EGb 761 reveled a half-life of 4
...

Approximately 70% of ginkgolide A, 50% of ginkgolide B, and 30% of bilobalide is excreted
unchanged in the urine (Kleijnen and Knipschild, 1992)
...
, 1997)
...
Metabolites were not detectable in
blood samples
...
8 Chemical Analysis
Identification and chemical analysis can be found in the National Formulary (USP, 1998)
...
9 Analysis of Biofluids
Urine and blood samples were analyzed for EGb metabolites after administration to healthy volunteers
(Pietta et al
...
Urine was collected for 3 d, and blood samples were collected every 30 min for 5 h
...

Twelve healthy volunteers were administered 0
...
36 mg EGb 761 intravenously or orally on three
separate occasions (Fourtillan et al
...
Blood and urine samples were collected for up to 36 h and
48 h, respectively
...
Measurement of plasma concentrations as low as 0
...

3
...
It is regulated as a dietary supplement in the U
...

References
Allain H, Raoul P, Lieury A, LeCoz F, Gandon J
...
Clin Ther 1993; 15:549-57
...
In vivo regulation of peripheral-type
benzodiazepine receptor and glucocorticoid synthesis by Ginkgo biloba extract EGb 761 and isolated
ginkgolides
...

Anonymous
...
In: The review of natural products
...
Louis, Missouri: Facts and Comparisons,
1998
...
Ginkgo biloba active ingredients meet proper levels —Consumer Reports
...

"The Tan Sheet
...
8
...
Occurrence of neurotoxic 4O-mehtylpyridoxine in Ginkgo biloba leaves, Ginkgo medications, and Japanese ginkgo food
...

Blumenthal M
...
The complete German commission E monographs
...

Chavez ML, Chavez PI
...
Hosp Pharm
1998;33:658-72
...
Effect of ginkgolide mixture (BN
52063) in antagonizing skin and platelet responses to platelet activating factor in man
...


Page 51

Duche JC, Barre J Guinot P, Duchier J, Cournot A, Tillement JP
...
Int J Clin Pharmacol Res 1989;9:165-8
...
Pharmaco-kinetic properties
of bilobalide and ginkgolides A and B in healthy subjects after intravenous and oral administration of
Ginkgo biloba extract (EGb 761)
...

Gilbert GJ
...
Neurology 1997;48:1137
...
Huston JP, Mattern CM, Hacker R
...

Pharmacol Biochem Behav 1996;53:271-5
...
Ginkgo
...

Kim YS, Pyo MK, Park PH, Hahn BS, Wu SJ, Yun-Choi HS
...
Thrombos Res 1998;91:33-8
...
Ginkgo biloba
...

Jung F, Mroweitz C, Kiesewetter H, Wenzel E
...
Arzneim Forsch 1990;40:589-93
...
A placebo controlled,
double-blind, randomized trial of an extract of Ginkgo biloba for dementia
...

Matthews MK
...
Neurology
1998;50:1933-4
...
Ginkgo biloba
...

Oken BS, Storzbach DM, Kaye JA
...
Arch Neurol 1998;55:1409-15
...
Identification of Ginkgo flavonol metabolites after oral administration
to humans
...

Ramassamy C, Clostre F, Christen Y, Costentin J
...
J Pharm Pharmacol 1990;42:785-9
...
Spontaneous hyphema associated with ingestion of Ginkgo biloba extract
[letter]
...

Rowin J, Lewis SL
...
Neurology 1996;46:1775-76
...
The honest herbal
...
, Binghamton, NY: Pharmaceutical Products Press, 1993
...
National Formulary
...
, Suppl 9
...

Vale S
...
Lancet 1998;352:36
...
), V
...
(Indian valerian), V
...
sambucifolia Mik,
radix valerianae, red valerian (Centranthus ruber [L
...
1 History and Traditional Uses
Valerian is a perennial herb comprised of grooved hollow stems and sawtoothed green leaves
...
Valerian grows to heights of 3–5 ft in the
temperate climates of North America, western Asia, and Europe, often in moist soil along riverbanks
...
Although the fresh drug has no distinctive odor, over
time hydrolysis of compounds present in the volatile oil produces isovaleric acid, which has an
offensive, somewhat putrid odor (Anonymous, 1991)
...
Even though valerian has a
disagreeable odor, people in the 16th century considered it a fragrant perfume (Anonymous, 1991)
...
It
has also been applied externally on cuts, sores, and acne
...

4
...

From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp, ed
...
, Totowa, New Jersey

Page 54

4
...

Valerian is available as a capsule, tablet, oral solution, or tea (USP, 1998)
...
The following are a few examples of valerian products
found in retail outlets:
• Yourlife® valerian is standardized to 0
...
The recommended dose is two 100-mg soft gels at
bedtime with a full glass of water
...
15% valerenic acid
...
15
mg/mL liquid extract 30–60 min before going to sleep
...

• Twinlab TruHerbs® timed release valerian is standardized to 0
...
Each capsule contains 450 mg
of valerian (300 mg of valerenic acid and 150 mg of valerian root)
...
The recommended dose is one capsule daily
...
The recommended dose is
one or two capsules 1 h prior to bedtime
...
The recommended dose is two capsules up to four times daily as needed
...
Consumers are instructed to take 2–3 tablets
one-half hour to one hour before bedtime
...


4
...
4
...
, 1982; Leathwood and
Chauffard, 1985; Balderer and Borbely, 1985; Lindahl and Lindwall, 1989; Schulz et al
...

Leathwood and colleagues demonstrated valerian's effect on sleep quality
...
]) 400 mg was compared to two Hova®
(valerian 60 mg and hop flower extract 30 mg per tablet) tablets and placebo (finely ground brown
sugar) in this crossover study involving 128 volunteers
...
This was repeated on
nonconsecutive nights, such that each of the three treatments, identified only by a code number, was
administered in random order three times to each patient
...
The selfreported improvement in sleep quality was especially notable in smokers, those patients who considered
themselves poor or irregular sleepers, and those who reported having dif-

Page 55

ficulty falling asleep on a prestudy questionnaire
...
Because subjective sleep questionnaires
may not correlate with sleep EEG results, a parallel EEG sleep study was performed comparing valerian
to placebo in 10 young men
...
The authors hypothesized that the results of this experiment might have
differed from the questionnaire assessed study because of small sample size and differences in study
populations
...
Rather than
place more credence on the objective study, the investigators concluded that the questionnaire provides
a more sensitive means of detecting mild sedative effects
...
" Sleep latency was measured using an activity
monitor and questionnaire
...
No further
improvement was demonstrated with a 900-mg valerian dose; however, patients receiving the higher
dose were more likely to feel sleepy the next morning
...
However, the appropriateness of the
statistical analysis used to interpret the results of the subjective portion of the study is questionable
...
]) on two
groups of healthy, young (21–44 yr of age) volunteers at home and in a laboratory setting
...
The effects of valerian on the volunteers in the sleep laboratory were also measured using
polysomnography and spectral analysis of the sleep EEG
...
No difference in efficacy between the lower and higher valerian dose was appreciated, as in
the study by Leathwood and Chaffaurd
...
The
authors attributed these results to the unfamiliar, artificial conditions of the laboratory, or to the young
age of the study subjects
...
], on subjective sleep quality assessed using a three-point rating scale
...
Statistically significant improvement in
sleep in quality was noted with the valerian preparation
...
No adverse effects were
reported
...

The effects of repeated doses (three tablets thrice daily) for eight days of Valdispert Forte® (135 mg of
dried extract of Valeriana officinalis [L
...
, 1994)
...
Subjects could not
have medical, psychological, or weight-related causes of sleep difficulty, and had to have normal health
status for their age
...
Results showed an increase in slow-wavesleep (SWS), and a decrease in sleep stage 1
...

In aggregate, the results of these clinical studies suggest that at doses of approx 450 mg of the aqueous
extract, valerian has mild hypnotic effects, possibly by affecting non-REM sleep in patients with
reduced SWS
...
Further well-designed studies are needed to
objectively evaluate valerian
...
Sedative properties of Valdispert® (dried aqueous
extract of Valeriana officinalis [L
...
No significant anticonvulsant effect was observed
(Leuschner et al
...

Hendriks and colleagues tested several components of the volatile oil, obtained by steam distillation of
Valeriana officinalis [L
...
The essential oil, its hydrocarbon fraction, its oxygen fraction,
valeranone, valerenal,

Page 57

valerenic acid, and isoeugenyl-isovalerate were injected intraperitoneally at various doses ranging from
50 to 1600 mg/kg, with three mice receiving each dose
...
It was concluded that
components of the essential oil, particularly valerenic acid and valerenal, which are present in the
oxygen fraction, have a sedative and/or muscle relaxant effect
...
, 1985) tested the effect of intraperitoneal valerenic
acid compared to diazepam, chlorpromazine, and pentobarbital on ability to walk on a rotating rod and
grip strength in mice
...
Diazepam, a muscle relaxant, affected the grip test but not the
rotarod test, while chlorpromazine, a neuroleptic, affected the rotarod test but not the grip test
...
The authors
concluded that valerenic acid, like pentobarbital, has general CNS depressant activity
...
Doseresponse effects of valerenic acid were also observed by the investigators
...
At 100 mg/kg, mice exhibited ataxia, then remained
motionless
...

Sedation is mediated predominantly through the inhibitory neurotransmitter γ-aminobutyric acid
(GABA)
...
8% valerenic
acid; a lipid extract; an aqueous extract of the hydroalcoholic extract, and another aqueous extract of
Valeriana officinalis (L
...
, 1993)
...
Because hydroxyvalerenic acid (a volatile oil
sesquiterpene) and dihydrovaltrate (a valepotriate) did not show any notable activity, the investigators
could not identify the specific constituents responsible for this activity
...

Other in vitro studies have also yielded results that suggest GABA-mediated activity; however, the
active constituent was unidentified
...
1 mmol/L)
was not able to displace

Page 58

[3H] muscinol from the GABAA receptor, although both an aqueous and a hydroalcoholic extract were
able to do so
...
Both glutamate and glutamine, amino acids present in the aqueous extract,
had little inhibitory effect on [3H] muscinol binding
...

Thus, glutamine could be responsible for the sedative effect of the aqueous extract, but not the
hydroalcoholic extract, in which it is not present
...
, 1995)
...
, 1994b)
...
, 1994a) suggests a different
mechanism of action involving inhibition of neuronal GABA uptake and stimulation of GABA release
from synaptosomes
...

The CNS depressant component of valerian is still unknown
...

Valepotriates are unstable compounds and are easily hydrolyzed by heat and moisture (Wagner et al
...
In addition, valepotriates are not water soluble, and aqueous extracts contain small amounts
(Wagner et al
...
For example, the aqueous extract used in the study by Balderer and Borbely,
described previously, was analyzed using thin-layer chromatography (TLC), and no valepotriates were
detectable
...
Therefore, the
likelihood that valepotriates are a major contributor to valerian's effects is questionable
...
It is postulated that a combination of volatile oils, valepotriates, and possibly certain watersoluble constituents that have not yet been identified are responsible for valerian's sedative effects
(Tyler, 1993)
...
, 1995)
...
One active component isolated was α-kessyl alcohol, a volatile
oil component
...
Kessanol and

Page 59

cyclokessyl acetate, guaiane-type sesquiterpenoids, also exhibited antidepressant activity
...

A 30% ethanol extract of the Japanese valerian root (''Hokkai-Kisso") extract (4
...
7 g/kg)
and imipramine (20 mg/kg) also demonstrated statistically significant antidepressant effects compared
to placebo as measured by the forced swimming test in rats (Sakamoto et al
...
As in the Oshima
study, kessyl glycol diacetate exhibited no antidepressant activity in the forced swimming test
...
Both
valerian (11
...

4
...
2 Musculoskeletal Effects
(See also Section 4
...
1 for a discussion of the possible mechanisms of musculoskeletal effects
...
procera Meyer (Valeriana "mexicana") caused suppression of rhythmic
contractions in guinea pig ileum in vivo at a dose of 20 mg/kg administered intravenously via the
jugular vein
...
They concluded that these compounds have a musculotropic action in
concentrations from 10-5
...
, 1982)
...
4
...
, 1997)
...
, 1988)
...
) was tested on rats and their offspring
...
Ten rats received each dose, and 10
received placebo
...
Forty pregnant rats were also administered the
valepotriate mixture or placebo in the manner described previously from the first through the 19th day
of pregnancy
...
However,
internal examination revealed a significant increase in the number of fetuses with retarded ossification
with the 12 mg/kg and 24 mg/kg doses
...
, 1994)
...
4
...
) have shown antiarrhythmic activity and ability to dilate coronary
arteries in experimental animals
...
Vpt2 contains valtratum (50%), valeridine (25%), and valechlorin (3%), with trace
amounts of acevaltrate, dihydrovaltratum, and epi-7-desacetyl-isovaltrate (Petkov, 1979)
...
) root (labeled V103 and V115) demonstrated hypotensive
effects in rats, cats, and dogs
...
The first two fractions demonstrated hypotensive
effects in rats, with the first fraction showing a hypotensive effect at 30 mg/kg
...
The authors noted that apparently, with each
succeeding extraction, less of the hypotensive principle was extracted
...
, 1961)
...
4
...
The valepotriates tested were cytotoxic to granulocyte/macrophage
colony forming units (GM-CFCUs), lymphocytes, and erythrocyte colony forming units (E-CFCUs)
...
7 X 10-6 M vs ~ 1
...
8 X 10 -6 M vs ~ 3 X 10 -5 M) than dihydrovaltrate
...
3 X 10-8 vs ~ 4
...

Because pharmaceutical products containing valepotriates are orally administered, their cytotoxicity to
gastrointestinal mucosal cells is of concern (Tortarolo et al
...

The effects of valtrate, dihydrovaltrate, and deoxido-dihydrovaltrate, valepotriates extracted from
Valeriana wallichii (DC
...
Valtrate killed 50% of the
cell population at a concentration of 5 µ M, Deoxido-dihydrovaltrate and dihydrovaltae demonstrated
this same toxicity at double the dose
...
, 1983)
...

4
...
, 1989)
...
In addition, valerian was used by a patient who exhibited hepatotoxicity attributed to
Chaparral (see Chaparral chapter)
...
25 mg of hyoscine hydrobromide 2 mg of cyproheptadine
hydrochloride) between 1988 and 1991
...
8 yr (range 15–37 yr)
were treated
...

The mean number of Sleep-Qik® tablets taken per patient history was 33 (range 6–166), for an average
of 2
...
5–12 g) of valerian
...
The other 19 patients reported
drowsiness (n = 11), dilated pupils (n = 11), tachycardia (n = 6), nausea ( n = 4), confusion (n = 3),
urinary retention (n = 3), visual hallucination (n = 2), flushing (n = 2), dry mouth (n = 1), and dizziness
(n = 1)
...
One patient who
was drowsy had also taken Panseden®, and one who was confused had ingested alcohol
...
The patient who took 60 tablets of
Sleep-Qik® required ventillary support
...
Drowsiness and confusion

Page 62

resolved within 24 h
...
7 d
(range 1–6 d)
...
They had all remained well after discharge and none continued taking Sleep-Qik®
...
, 1995)
...
25 mg, and cyproheptadine hydrochloride 2 mg
...
Co-ingestants included alcohol (n = 10), cold
products (n = 3), hypnotics (n = 2), unknown drugs (n = 2), and gasoline (n = 1)
...
One patient required
ventilatory support
...
Over the next 22–
48 mo postingestion, none of the patients returned to the hospital or clinic for any reason, suggesting
that serious hepatotoxicity did not occur
...
Other adverse effects attributed to overdose or chronic use of
valerian include headaches, excitability, restlessness, uneasiness, blurred vision, and cardiac
disturbances (USP, 1998)
...
8–23
...
Thirty
minutes after ingestion, the patient complained of fatigue, crampy abdominal pain, chest tightness,
tremor of the hands and feet, and lightheadedness
...
Her vital signs were blood pressure 111/64 mm Hg, pulse 72 beats/min, respiratory rate 14
breaths/min, and temperature 37
...
Physical exam was unremarkable except for mydriasis (6 mm
bilaterally)
...
Toxicology screen was positive for marijuana, which she admitted using 2 wk previously
...
After two doses of activated charcoal, her symptoms resolved
within 24 h (Willey et al
...

Subsequently, Chan reported on twenty-four cases of overdose of a product containing valerian dry
extract 75 mg, hyoscine hydrobromide 0
...
Six patients
developed vomiting, and fifteen underwent gastric lavage
...
Symptoms were
mainly central nervous system depression and anticholin-

Page 63

ergic symptoms
...
Liver function tests performed in seventeen,
and all were normal
...
The author points out that
gastric lavage and spontaneous vomiting may have limited the amount of valerian absorbed in these
patients, thus decreasing the risk of any delayed adverse effects (Chan, 1998)
...
Withdrawal symptoms included sinus tachycardia of up to 150 beats/min, tremulousness, and
delirium after recovery from general anesthesia (propofol, nitrous oxide, isoflurane, and thiopental) for
open biopsy of a lung nodule
...
Medications included isosorbide dinitrate,
digoxin, furosemide, benazepril, aspirin, lovastatin, ibuprofen, potassium, zinc supplement, and
vitamins
...
Naloxone
was administered, with worsening of symptoms
...
At this time, interview with family members revealed the patient's long-standing valerian use
...
Signs and symptoms improved, and stabilized by the third postoperative day
...
He was discharged on postoperative day 7, and was stable at 5-mo follow-up
...
, 1998)
...

4
...
, 1961), and Valdispert®, an aqueous extract prepared from Valeriana officinalis (L
...
, 1993)
...

Also see Chapter 5, St
...
6 Drug Interactions
...
7 Chemical Analysis
Isolation and identification of the essential oil components valeranone, valerenal, valerenic acid and
isoeugenyl-isovalerate (Hazelhoff et al
...
, 1981) and the valepotriates valtrate,
isovaltrate, and didrovaltrate (Hazelhoff et al
...
, 1978)
...
8 Regulatory Status
Valerian was included as an official drug in the US Pharmacopeia until 1936 and in the National
Formulary until 1946
...
They encourage further research
(USP, 1998)
...
The German Commission E has approved valerian as a sleep-promoting and
calmative agent to be used in the treatment of unrest and sleep disturbances caused by anxiety
(Blumenthal, 1998)
...
In Belgium, subterranean parts, powder extract, and
tincture are allowed for use as traditional tranquilizers
...
In the
United Kingdom, valerian is included on the General Sale List of the Medicines Control Agency and is
allowed in "traditional herbal remedies" as a sedative to promote natural sleep (USP, 1998)
...
Effect of valepotriates on the behavior of rats in the elevated plusmaze during
diazepam withdrawal
...

Anonymous
...
Lawrence Review of Natural Products
...
Louis, MO: Facts and Comparisons,
1991
...
Effect of valerian on human sleep
...

Blumenthal M
...
The complete German Commission E monographs
...

Bounthanh C, Richert L, Beck JP, Haag-Berrurier M, Anton R
...
Planta Med 1983;49:138-142
...
In vitro study on the
interaction of Valeriana officinalis L
...

Arzneim Forsch 1995;45:753-5
...
An assessment of the delayed effects associated with valerian overdose [letter]
...

Chan TYK, Tang CH, Critchley J
...
Postgrad Med J 1995;71:227-8
...
Valerian
...

Czeizel A, Szentesi I, Szekeres H, Molnar G, Glauber A, Bucski P
...
Ach Toxicol 1988;62:1-7
...
Teratologic evaluation of 178 infants born to mothers who attempted
suicide by drugs during pregnancy
...

Garges HP, Varia I, Doraiswamy PM
...
JAMA 1998;280:1566-7
...
Antispasmodic effects of valeriana compounds: an in-vivo and
in-vitro study on the guinea-pig ileum
...

HazelhoffB, Smith D
...
The essential oil of Valeriana officinalis L
...
l
...
Hazelhoff B, Weert B, Denee R, Malingre TM
...
Pharm Wkbl 1979;114:140-8
...
Over-the counter psychotropics: a review of melatonin, St
...
J Am Col Health 1998;46:271-6
...
Pharmacological screening of valerenal
and some other components of essential oil of Valeriana officinalis
...

Hendriks H, Bos R, Woerdenbag HJ, Koster AS
...
Planta Medica 1985;1:28-31
...
The biological activity of valerian and related plants
...

Houghton P
...
Pharm J 1994;253:95-96
...
Aqueous extract of valerian reduces latency to fall asleep in man
...

Leathwood PD, Chauffard F, Heck E, Munoz-Box R
...
) improves sleep quality in man
...

Leuschner J, Muller J, Rudmann M
...
Arzneim Forsch 1993;43:638-41
...
Double blind study of a valerian preparation
...

MacGregor FB, Abernethy VE, Dahabra S, Cobden I, Hayes PC
...
Br
Med J 1989;299:1156-7
...
In vitro study on the interaction of extracts and
pure compounds from Valeriana officinalis roots with GABA, benzo-diazepine and barbiturate
receptors in rat brain
...

Oshima Y, Matsuoka S, Ohizumi Y
...
Chem
Pharmacol Bull 1995;43:169-70
...
Plants with hypotensive, antiatheromatous and coronarodilatating action
...

Rosecrans JA, Defeo JJ, Youngken HW
...
extracts
...

Sakamoto T, Mitani Y, Nakajima K
...
Chem
Pharmacol Bull 1992;40:758-61
...
An aqueous extract of valerian influences
the transport of GABA in synaptosomes
...

Santos MS, Ferreira F, Faro C, Pires E, Carvalho AP, Cunha AP, Macedo T
...

Planta Med 1994b;60:475-6
...
The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot
study
...

Tittel G, Chari VN, Wagner H
...
Planta Med
1978;34:305-10
...
[High-performance liquid chromatographic separation and quantitative
determination of valepotriates in valeriana drugs and preparations]
...

Tortarolo M, Braun R, Hubner GE, Maurer HR
...
Arch Toxicol 1982;51:37-42
...
Effects of a prolonged administration of valepotriates in
rats on the mothers and their offspring
...

Tyler VE
...
, Binghamton, NY: Pharmaceutical Products Press, 1993
...
Beyond benzodiazepines: alternative pharmacologic agents for
the treatment of insomnia
...

Willey LB, Mady SP, Cobaugh DG, Wax PM
...
Vet Hum Toxicol
1995;37:364-5
...
Valerian
...
Rockville, MD:
United States Pharmacopeial Convention, 1998
...
John's Wort
John T
...
1998); blutdkraut, Johnswort, qian ceng lou, Sankt Hans urt, St
...

Johnswort, toutsaine, tupfelhartheu, walpurgiskraut, zweiroboij, amber, chassediable, corazoncillo,
hardhay, hartheu, herbe de millepertuis, herrgottsblut, hexenkraut, hierba de San Juan, hipericon,
hypericum, iperico, Johannesort, pelatro, perforata, Johannisblut, Johanniskraut (USP, 1998a)
5
...
The flowers are said to be at their brightest and most abundant around
June 24th, the day traditionally believed to be the birthday of John the Baptist
...
It grows in the dry ground of fields,
roadsides, and woods
...
John's wort has been used to treat neurologic and psychiatric disturbances (anxiety,
insomnia, bed-wetting, irritability, migraine, excitability, exhaustion, fibrositis, hysteria, neuralgia, and
sciatica), gastritis, gout, hemorrhage, pulmonary disorders, and rheumatism, and has been used as a
diuretic (USP, 1998a)
...

5
...
John's wort is promoted for treatment of mood disorders, particularly depression, and promotion of
emotional well being
...
J
...
, Totowa, New Jersey

Page 68

in combination with ma huang (ephedra) for weight loss, but use of such products has been discouraged
by the FDA (USP, 1998a)
...
3 Products Available
Most commercially available preparations of hypericum in the United States are dried alcoholic extracts
in a solid oral dosage form
...
The following
is a list of a few of the available formulations:
Movana ®—tablet containing 0
...
3% hypericin extract (300 mg)
Dr
...
3% hypericin extract (300 mg) with
Siberian ginseng, vitamins B6, B 3, B12, zinc, and folic acid
One A Day®—tablet with 225 mg of hypericin and 100 mg of kava kava
Harmonex®—450 mg of hypericin from a flower extract and 90 mg ginseng
Sundown®Herbals—300 mg of hypericin with ginkgo biloba, ginseng, and ginger

5
...
4
...
John's wort to placebo or to tricyclic antidepressants
(Linde et al
...
However, problems with inclusion criteria, diagnostic criteria, antidepressant
dosing, and study duration do not permit definitive conclusions about the safety and efficacy of St
...

Studies indicate that St
...
, 1996)
...
St
...
These include naphthodianthrones
(hypericin, pseudohypericin, protopseudohypericin, cyclopseudohypericin), flavonoids (quercetin,
hyperosid, quercitrin, isoquercitrin, campherol, rutin, luteolin, and 13-II8-biapigenin), ethereal oil,
phenol carbonic acids (e
...
, chlorogenic acid), procyanidins, 1,3,6,7-tetrahydroxyxanthone, and
hyperforin
...

John's wort, while the other constituents are found in many plants (Wagner and Bladt, 1994)
...
John's wort flower
and leaf at concentrations of 4
...
75 µg/g, respectively (Murch et al
...
John's wort have yet to be investigated
...
John's wort has focused on the hypericins
(Wagner and Bladt, 1994)
...
In one study, the effects of
hypericum total extract, hypericum fractions, and hypericin on MAO and COMT activity were
examined in vitro (Thiede and Walper, 1994)
...
In addition, COMT
inhibition appeared to be associated with flavonols and xanthones rather than hypericins
...

Raffa found that hypericin had no significant affinity for dopamine D1, γ-aminobutyric acid (GABA),
opioid, benzodiazepine, 5-hydroxytryptamine1B (5-HT1B; serotonin), or norepinephrine receptors
...
However, binding
affinity at muscarinic cholinergic receptors (mAChRs) and σ-receptors was relatively good, and
hypericin displayed some affinity for 5-HT1A receptors and minor inhibition of dopamine reuptake
...
John's wort has different mechanisms of action than traditional
antidepressants
...
John's wort that has been hypothesized to be involved in its
central nervous system effects is amentoflavone
...

flower extracts correlates with the extracts' abilities to inhibit binding of radiolabeled flumazenil to
benzodiazepine receptors, while hypericin concentration does not correlate (Baureithel et al
...

St
...
In a study of 12 volunteers, hypericum extract
LI 160 (Jarsin®) 300 mg, three times daily, did not improve sleep onset, intermittent wakenings, or
total sleep duration
...
Human and animal studies suggest
these EEG effects may be due to hyperforin (Schellenberg et al
...
These effects on sleep are not
consistent with the effects observed with the use of traditional antidepressants, and are striking because
a deficit in slow-wave sleep has been associated with affective disorders (Schulz and Jobert, 1994)
...
4
...
25 mg/kg or 0
...
25 mg/kg intravenously thrice weekly, or 0
...
No regimen displayed antiretroviral activity based on CD4 lymphocyte counts, p24 antigen, or HIV
RNA titers (Gulick et al
...
In vitro studies suggest that St
...
, 1999)
...
4
...
John's wort and several other medicinal plants, has been
implicated as a mutagen
...
John's Wort aqueous ethanolic extract showed no mutagenic
effects in mammalian cells
...
, 1990)
...
4
...
John's wort at a dose of 900 mg/d
...
One patient discontinued her prescribed fluoxetine
and methylphenidate and began taking St
...
The gestational week during which this change was made and pregnancy
outcome were not reported
...
John's wort at gestational wk 24
...
The woman discontinued the St
...
Behavioral
assessment of the neonate, who was being breastfed, was normal at 4 and 33 d of age (Grush et al
...
The authors note that although animal studies suggest that St
...

5
...
John's wort appears to be better than that of standard
prescription antidepressants, side effects have been

Page 71

reported
...

A study found that hypericin inhibits bovine choroidal endothelial cell proliferation in vitro (Kimura et
al
...
The effect was found to be dose dependent
...

Phototoxicity manifested as elevated, itching, erythematous lesions has been described (Golsch et al
...
Phototoxicty may also present as neuropathy, presumably caused by demyelination of cutaneous
axons by photoactivated hypericins (Bove, 1998)
...
John's wort extract for 4 wk,
a 35-yr-old woman complained of stinging pain on sun-exposed areas, worsened by cold, minimal
mechanical stimuli, and sun exposure
...

In a study (Gulick et al
...
4
...
Other adverse effects reported in this study included
fever, diarrhea, decreased hemoglobin < 8 mg/dL, and glucose > 250 mg/dL (one patient each)
...
Although the patients in this study were HIV
infected, those taking antiretrovial, phototoxic, or hepatotoxic drugs were excluded
...
1% St
...
These
symptoms resolved 2 d after she discontinued using St
...
She had discontinued 50 mg of
sertraline 1 wk prior to taking the St
...
Prior to taking
50 mg of sertraline, she had taken 75 mg of sertraline for several months, but required dosage reduction
after experiencing irritability and insomnia, demonstrating a vulnerability to activation
...
John's wort, rather than an interaction between sertraline
and St
...

An additional report describes two cases of hypomania occurring after 6 wk and after 3 mo of St
...
Hypomania was characterized by irritability, disinhibition, agitation, anger, insomnia, and
difficulty concentrating and required treatment with antimanic drugs (O'Breasail and Argouarch, 1998)
...
6 Drug Interactions
A 50-yr-old woman with a history of chronic depression experienced central nervous system symptoms
after taking a single dose of 20 mg of paroxetine in addition to her usual daily dose of 600 mg of St
...
Ten days earlier she discontinued paroxetine (40 mg/d), which she had been taking for 8
mo for treatment of depression, and initiated self-therapy with 600 mg of St
...
No
side effects were noticed at that time
...
John's wort therapy, she took a single 20 mg dose
of paroxetine because she was experiencing difficulty sleeping
...
She complained of fatigue, nausea, and weakness
...
Mental, neurologic, and physical exams
were normal the following day (Gordon, 1998)
...
John's wort therapy, but had not experienced adverse effects when
discontinuing paroxetine and starting St
...
Because it takes up to 2 wk for MAO to
regenerate after inhibition, the time course of this patient's symptoms suggests that some component of
St
...

Other authors have also reported evidence that St
...
In this case report, disorientation, agitation, and confusion in
association with use of St
...
On physical exam, pupils were unreactive and dilated at 6 mm
...
Abnormal blood chemistry results included mildly elevated glucose (139 mg/dL), and low
serum potassium (2
...
Toxicology screen was positive for opiods
...
Empiric treatment included thiamine 100 mg to prevent neurotoxicity due to thiamine
deficiency, naltrexone 2 mg for possible opioid intoxication, ceftriaxone 1 gram for possible infection,
and lorazepam 8 mg as a sedative
...
The patient recovered from her
delerium 2 d later
...
John's wort and valerian for the past 6 mo, with the
recent addition of loperamide to treat diarrhea, possibly caused by St
...
The authors did not
report doses
...
Operating under the assumption that St
...
, 1999)
...
John's wort
extract LI 160 on digoxin concentrations
...
25 mg twice daily for 2
d, then daily for 5 d, followed by 10 d of concomitant placebo (n = 12) or LI 160 900 mg (n = 13) daily
...
0023), and peak concentrations had decreased by a mean of 26% (p
= 0
...
The LI 160 group experienced a mean
decrease in trough concentration of 37% (p = 0
...
0013) between d 5 and 15
...
, 1999)
...
, 1999) describes an interaction between St
...
A
patient taking 300 mg of theophylline (TheoDur) twice daily required a dosage increase to 800 mg
twice daily to maintain a theophylline level of 9
...
John's wort
preparation standardized to 0
...
Other medications included furosemide, potassium,
morphine, zolpidem, valproic acid, ibuprofen, amitriptyline, albuterol, prednisone, zafirlukast, and
inhaled triamcinolone acetonide
...
Other than the
addition of St
...
St
...
6 mg/L
...
Using an in vitro model of
hepatic enzyme induction, hypericin at a concentration of 12
...
Other drugs that are metabolized by CYP1A2 and thus might interact with St
...

Concerns that St
...


Page 74

Some authors caution that tannins in St
...
Study is needed to determine if this is a
concern
...
7 Pharmacokinetics/Toxicokinetics
Two pharmacokinetic studies have examined the pharmacokinetics of hypericin and pseudohypericin
(Staffeldt et al
...
, 1996)
...
In Part I of the studies, subjects in both trials were
administered a single dose of either 300 mg, 900 mg, or 1800 mg of the extract (one, three, or six
coated tablets) at 10-14-d intervals
...
The doses were administered on an
empty stomach in the morning after a 12-h fast
...
Multiple plasma levels of hypericin and pseudohypericin were measured for up to 120 h
after administration
...
After a 4-wk washout from Part I, subjects were given one coated tablet containing 300 mg
of hypericum extract three times a day (8 am, 1 pm, and 6 pm) before meals for 14 d
...

5
...
1 Absorption
For single doses of 300 mg, 900 mg, or 1800 mg of dried hypericum extract in humans, the median time
that elapsed from taking the dose and detectable plasma concentration (tlag) in hours is as follows:
Hypericin: 2
...
0, and 2
...
, 1994)
2
...
9, and 1
...
, 1996)
Pseudohypericin: 0
...
4, and 0
...
, 1994)
0
...
4, and 0
...
, 1996)

A difference is observed between the tlag of hypericin compared to pseudohypericin
...
Pseudohypericin may be released from the dosage form
more quickly than hypericin
...
Another explanation may be that hypericin may undergo first-pass
hepatic metabolism (Staffeldt et al
...

The median maximum plasma concentrations (Cmax) in (g/L for the respective doses are as follows:
Hypericin: 1
...
5, and 14
...
, 1994)
1
...
2, and 16
...
, 1996)

Page 75
Pseudohypericin: 2
...
7, and 30
...
, 1994)
3
...
1, and 29
...
, 1996)

The maximum plasma concentrations increased in a nonlinear fashion (Staffeldt et al
...
,
1996)
...
2, 4
...
9 (Staffeldt et al
...
5, 6
...
7 (Kerb et al
...
7, 3
...
2 (Staffeldt et al
...
0, 3
...
0 (Kerb et al
...
However, hypericin takes longer to reach
maximum plasma concentration
...
, 1994)
...
5 µ g/L (Staffeldt et al
...
8 µg/L (Kerb et al
...
3 µ g/L ∗ (Staffeldt et al
...
9 µ g/L (Kerb et al
...
8 mg/L (Staffeldt et al
...
5 mg/L (Kerb et al
...
7 mg/L∗ (Staffeldt et al
...
8 mg/L (Kerb et al
...


5
...
2 Distribution
For oral doses, the volume of distribution appears to be approx 162 L for hypericin and 63 L for
pseudohypericum (Kerb et al
...

5
...
3 Metabolism/Elimination
The median half-lives in hours for single 300-mg, 900-mg, and 1800-mg oral doses are as follows:
Hypericin: 24
...
0, and 26
...
, 1994)
24
...
1, and 48
...
, 1996)
Pseudohypericin: 16
...
0, and 22
...
, 1994)
18
...
8, 19
...
, 1996)

After multiple doses of hypericum extract 300 mg three times daily, median half-lives in hours were:

Page 76
Hypericin: 28
...
, 1994)
41
...
, 1996)
Pseudohypericin: 23
...
, 1994)
18
...
, 1996)
∗ mean
...
It is difficult to
ascertain whether half-life for either hypericin or pseudohypericin is dose related
...
, 1996)
...
, 1996)
...
8 Chemical Analysis
Identification and chemical analysis of St
...

5
...
, 1996; Liebes et al
...
HPLC with a UV photometric
detector has also been used to analyze plasma (Staffeldt et al
...

5
...
John's wort for internal consumption for psychogenic
disturbances, depressive states, sleep disorders, anxiety and/or nervous excitement, particularly that
associated with menopause
...
Oily Hypericum preparations are also approved by the Commission E
for external use for the treatment of incised and contused wounds, muscle aches, and first degree burns
(Blumenthal, 1998)
...
John's wort has a long history of use
...

The National Institutes of Health (NIH) is conducting the first clinical trial of St
...
NIH's Office of Alternative Medi-

Page 77

cine (OAM) is performing the study
...
John's wort, placebo, or a selective serotonin re-uptake inhibitor (SSRI)
...

References
Baureithel KH, Buter KB, Engesser A, Burkard W, Schaffner W
...
Pharm Acta Helv
1997;72:153-7
...
St
...
The complete German Commission E monographs
...

Bove GM
...
John's wort [letter]
...

Bradshaw C, Nguyen A, Surles J
...
unc
...
html
...

Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots I
...
John's wort (Hypericum perforatum)
...

Cott JM
...

Pharmacopsychiatry 1997;30(Suppl 2): 108-12
...
Reversible increase in photosensitivity to UV-B
caused by St
...
Hautarzt 1997;48:249-52
...
SSRI's and St
...

Grush LR, Nierenberg A, Keefe B, Cohen LS
...
John's wort during pregnancy [letter]
...

Gulick RM, McAuliffe V, Holden-Wiltse J, Crumpacker C, Liebes L, Stein DS for the AIDS Clinical
Trials Group 150 and 258 Protocol Teams
...

John's wort, as an antiretroviral agent in HIV-infected adults
...

Kerb R, Brockmoller J, Staffeldt B, Ploch M, Roots I
...
Antimicrob Agents Chemother 1996;40:2087-193
...
Herbal medicines as a factor in delirium [letter]
...

Kimura H, Harris MS, Sakamoto T, Gopalakrishna R, Gundimeda U, Cui JZ, et al
...
Curr Eye Res 1997;16:967-72
...
A method for the quantification of hypericin, an antiviral agent, in biological fluids by
high-performance liquid chromatography
...


Page 78

Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D
...
John's wort for
depression - an overview and meta-analysis of randomized clinical trials
...

Murch SJ, Simmons CB, Saxena PK
...
Lancet
1997;350:158-9
...
Available from URL: http://www
...
gov/events/prsjw
...

Accessed Oct 26 1998
...
Potential metabolic interaction between St
...
Ann Pharmacother 1999;33:502
...
Hypomania and St
...
Can J Psychiatry 1998;43:746-7
...
Genotoxicity of a standardized hypericum
extract
...
Pharmacological profile of hypericum extract
...
Arzneim Forsch 1995;451145-8
...
Screen of receptor and uptake-site activity of hypericin component of St
...
Life Sci 1998;62:PL265-70
...
Pharmacodynamic effects of two different hypericum extracts in
healthy volunteers measured by quantitative EEG
...

Schempp CM, Pelz K, Wittmer A, Schopf E, Simon JC
...

John's wort, against multiresistant Staphylococcus aureus and gram-positive bacteria
...

Schneck C
...
John's wort and hypomania
...

Schulz H, Jobert M
...
J Geriatr
Psychiatry and Neurol 1994;7(Suppl 1):S39-43
...
Pharmacokinetics of hypericin and
pseudohypericin after oral intake of Hypericum perforatum extract LI 160 in healthy volunteers
...

Thiede HM, Walper A
...
J Geriatr
Psychiatry Neurol 1994;7(Suppl 1):S54-6
...
Hypericum (St
...
Botanical monograph
series
...

United States Pharmacopoeia (USP)
...
18th edit
...
9
...

Wagner H and Bladt S
...
J Geriatr Psychiatry Neurol
1994:7(Suppl 1):S65-8
...
St
...
US Pharmacist
1997;22:88-97
...
) (German chamomile, Hungarian chamomile, genuine chamomile), Anthemis
nobilis (English chamomile, Roman chamomile, common chamomile); sometimes called
Chamaemelum nobile (L
...
1 History and Traditional Uses
Chamomile has been used medicinally since ancient Rome for its purported sedative, antispasmodic,
and antirheumatic effects (Anonymous, 1991)
...
2 Current Promoted Uses
Chamomile is used topically to treat a variety of inflammatory conditions involving the mouth, skin,
respiratory tract (via inhalation), and gastrointestinal tract
...
Chamomile is purported to have sedative,
hypnotic, analgesic, and immunostimulant effects (Yamada et al
...

6
...
chamomile and A
...

Chamomile oil is used in aromatherapy (Yamada et al
...

6
...
4
...
, 1996)
...
j
...
, Totowa, New Jersey

Page 80

Inhalation of chamomile vapor attenuated restriction stress-induced adrenocorticotropic hormone
(ACTH) secretion, and was superior to diazepam in this regard
...
The investigators concluded that
chamomile might act via the γ-aminobutyric acid-ergic (GABAergic) system in a manner similar to the
benzodiazepines; however, properly designed studies of chamomile's sedative effects in humans are
lacking
...
4
...
Inhibition of protein kinase C, and thus protooncogene expression, by competing with ATP is the proposed mechanism of action (Huang et al
...
Apigenin has also been noted to cause reversible G2 /M arrest (Lepley et al
...

Apigenin at a 5µM concentration applied topically reduces the number of UVB-induced squamous cell
carcinomas in mice and may prove to be a useful sunscreen ingredient (Lepley et al
...

6
...
3 Anti-Inflammatory Activity
Chamomile is purported to have antiinflammatory effects, but studies of chamomile cream have not
proven its efficacy
...
These results prompted a double-blind, placebocontrolled trial for the prevention of 5-fluorouracil-induced stomatitis (Fidler et al
...
One hundred
and sixty-five patients were randomized to receive chamomile or placebo mouthwash
...
Stomatitis severity
was rated on a scale of 0 to 4 by the attending physician and by the patient
...
Subset analysis revealed that men tended to benefit, while the chamomile tended
to have a detrimental effect in women
...

Chamomile mouthwash was without toxicity
...
5 Case Reports of Toxicity Due to Commercially Available Products
A 35-yr-old pregnant woman was administered an enema containing glycerol and Kamillosan®, an oily
chamomile flower extract, during labor
...
Twenty-five
minutes after administration,

Page 81

she developed urticaria, laryngeal edema, tachycardia, and hypotension
...
Fortyfour minutes after enema administration, a
cesarean delivery was performed
...
The newborn had an Apgar
score of 0, and a pH of 6
...
Although initially responding to sodium bicarbonate, the newborn died the
next day after suffering a tonic-clonic seizure
...
Skin prick tests were negative for latex, glycerol, and common airborne allergens
...
Although the extraction of dried chamomile plants for
the production of Kamillosan® yields a low amount of protein in the product, it is apparently enough to
trigger anaphylaxis when the product is applied to a large area of the colonic mucosa
...
, 1998)
...
A 35yr-old woman experienced abdominal cramps, tongue ''thickness," a tight sensation in her throat,
angioedema of the lips and eyes, diffuse itching, and a full sensation in her ears after a few sips of
chamomile tea
...
A scratch test with chamomile produced a large wheal-and-flare with pseudopod
formation
...
Five of 15 additional patients with a history of positive reactions to ragweed developed positive
skin test reactions to chamomile tea
...

In another case report (Casterline, 1980), a 54-yr-old woman experienced generalized hives, upper
airway obstruction, and pharyngeal edema 20 min after drinking a cup of chamomile tea and taking two
aspirin tablets
...
The patient had no history of aspirin allergy, but reported mild seasonal
allergic rhinitis
...
Graded oral aspirin challenges
produced no immediate or delayed reaction
...
Seven patients ages 21–51 suffered conjunctivitis after eye washing with
chamomile tea
...
One
required emergency treatment with epinephrine
...
One patient reported allergy to honey (lip swelling and itching of mouth),
and one to sunflower seeds (scratchy feeling in the throat)
...
All patients had positive prick tests to
chamomile tea extract, but all tolerated oral chamomile tea (Subiza et al
...

One hundred additional patients with hay fever were challenged with chamomile tea extract as a skin
test and as a conjuctival provocation test to determine the prevalence of this type of reaction
...
Only two of the 100 patients had a positive reaction to ocular
chamomile tea extract
...
Twenty-eight patients had specific IgE to antigens contained in the chamomile
tea extract (Subiza et al
...

6
...
7
...
7 Analysis of Blofluids
Blood and urinary concentrations of the flavonoids apigenin, apigenin-7-glucoside, and herniarin were
measured in one patient after a single oral dose of 40 mL of a aqueous/ethanolic chamomile extract
(Tschiersch and Holzl J, 1993)
...
, 1997) and HPLC -scintillation analysis (Li and Birt, 1996) have been used to
determine apigenin content of mouse skin after topical application of apigenin
...
8 Regulatory Status
Chamomile is regulated as a dietary supplement in the United States
...
Internally, it is approved for use in treating gastrointestinal spasms and
inflammation (Blumenthal, 1998)
...
Chamomile
...
St
...


Page 83

Benner MH, Lee HJ
...
J Allergy Clin Immunol 1973;52:307-8
...
The complete German Commission E monographs
...
Austin, TX: American Botanical Council; 1998
...
Management of oral musositis during local radiation and systemic chemotherapy: a
study of 98 patients
...

Casterline CL
...
JAMA 1980;244:330-1
...
Prospective evaluation of a
chamomile mouthwash for prevention of 5-FU-induced oral mucositis
...

Huang Y, Kuo M, Liu J, Huang S, Lin J
...
Eur J Cancer 1996;32A:146-51
...
Fatal outcome of anaphylaxis to chamomilecontaining enema during labor
...

Lepley D, Li B, Birt DF
...
Carcinogenesis 1996; 17:2367-75
...
In vivo and in vitro percutaneus absorption of cancer preventive flavonoid apigenin in
different vehicles in mouse skin
...

Li B, Robinson DH, Birt DF
...
J Pharmacol Sci 1997;86:721-5
...
Allergic conjuctivitis to
chamomile tea
...

Tschiersch K, Holzl J
...
) (syn
...
)
Rauschert)
...

Yamada K, Miura T, Mimaki Y, Sashida Y
...
Biol Pharmacol Bull 1996;19:1244-6
...
purpurea (L
...
pallida (Nutt
...
1 History and Traditonal Uses
Echinacea, a genus including nine species that grow in the United States, is a member of the daisy
(Asteraceae; Compositae) family
...
angustifolia, the narrow-leaved echinacea;E
...
purpurea, the cultivated variety
...

Echinacea was originally utilized by Native Americans for a variety of conditions
...
, 1981)
...
Meyer informed the pharmaceutical manufacturer
Lloyd Brothers of Cincinnati about the purported benefits of echinacea in 1885
...
The company
marketed echinacea as an antiinfective, and by 1920, echinacea was their best-selling plant product
...
J
...
, Totowa, New Jersey

Page 86

modern antiinfectives such as the sulfa drugs led the product to fall out of favor (Tyler, 1993)
...
2 Current Promoted Uses
In the United States echinacea is promoted primarily in oral dosage forms as an immune stimulant that
helps increase resistance to colds, influenza, and other infections, although topical products for wounds
and inflammatory skin conditions are also available
...
3 Products Available
Fresh herb, freeze-dried or dried herb, and alcoholic extracts are available in the United States in the
form of tablets, capsules, lozenges, liquid, tea, and salves
...

Some echinacea-containing products have been found to be contaminated with Parthenium
integrifolium, a plant of the same family that has no known pharmacologic activity (Anonymous, 1996)
...
Although the standard some manufacturers use is 4% phenolic compounds (caffeoy1-tartaric
acid, chlorogenic acid, cichoric acid, and echinacoside), only three products, Vita-Smart® by American
Fare®, One-A-Day® Cold Season by Bayer, and Echinex® by Sunsource approached this standard at
4
...
9%, respectively
...

7
...
4
...
In many in vitro studies, echinacea extracts have been shown to stimulate
phagocytosis, increase leukocyte mobility, and increase cellular respiration
...

One constituent of echinacea, the polysaccharide arabinogalactan, has been identified as a macrophage
activator in vitro, causing macrophages to attack tumor cells and microorganisms
...
Macrophage production of
tumor necrosis factor-α (TNF -α), interleukin-1 (IL -1), and interferon-B2 was increased in vitro, and
production of oxygen free radicals was increased both in vitro and in vivo (Luettig et al
...
An
earlier study

Page 87

also showed that a crude polysaccharide extract of E
...
, 1984)
...
, 1989; Stimpel et al
...

7
...
2 Antimicrobial/Antiviral Effects
A study assessed ability of an echinacea extract to enhance natural killer cell activity against K562 cells
and antibody-dependent cellular cytotoxicity (ADCC) against human herpesvirus infected H9 cells (See
et al
...
Dried, ground preparations of fresh echinacea were homogenized and filtered to produce
an extract that was added in increasing concentrations to peripheral blood mononuclear cells from
patients with AIDS, chronic fatigue syndrome (CFS), and healthy volunteers
...
Echinacea extract enhanced the cytotoxicity of
natural killer cells, and increased activity against cells infected with human herpesvirus 6 (HH6) in all
three groups at concentrations of at least 0
...

The ability of an oral echinacea preparation to prolong the time to onset of an upper respiratory
infection was compared to that of placebo in 302 volunteers from an industrial plant and several
military institutions (Melchart et al
...
Volunteers were administered either placebo or 50 drops (2
mL) twice daily of 30% ethanol in water extract of E
...
purpurea providing approx 200
mg of echinacea daily for 12 wk
...
04),
there was no difference among the three groups in regard to time to the first upper respiratory infection,
the main outcome measure
...

Another study (Grimm and Muller, 1999) also examined the efficacy of echinacea in preventing colds
and upper respiratory infections, but used a different preparation
...
purpurea (without the
roots) in a 22% alcohol solution
...
This study was unique because patients were enrolled only if they had a history of more than
three colds or respiratory infections in the preceding year
...
The primary
outcome measures were the incidence and severity of colds during the study period
...
Patients were also
instructed to see the investigator if he or she experienced burning or tearing eyes, ear pain, loss of
hearing with pressure in the ear, stuffy or runny nose, sore throat, difficulty swallowing, hoarseness,
coughing, sputum production, headache, joint pain, myalgia, fever, rigors, sweating, or general
weakness/tiredness
...
Severity was graded on a scale of 1–3
...
33), duration of
infection (p = 0
...
15)
...
Reasons for withdrawal in the echinacea
group included nausea, constipation, and "awful taste
...
The incidence of adverse
effects was not significantly different (p = 0
...

The investigators in this study (Grimm and Muller, 1999) mention that echinacea has also been used to
treat colds and upper respiratory infections in adults, but the majority of these studies were
uncontrolled, retrospective studies that in some cases used other herbs as well as echinacea; however, in
two placebo-controlled trials, 900 mg/d of expressed juice of E
...
, 1992)
and ethanolic extract of E
...
, 1992; Brauning and Knick, 1993), clinical findings (Brauning et al
...
A more recent randomized, double blind, placebo-controlled study of treatment of the
common cold with Echinacea recruited 559 volunteers, 246 of whom caught a cold
...
Two tablets were taken three
times daily for 7 d or until symptoms resolved, whichever came first
...

Adverse effects were comparable to placebo (Brinkeborn et al
...
A review of all blinded placebocontrolled randomized trials of Echinacea for prevention or treatment of upper respiratory infection
concluded that Echinacea may be effective for early treatment of upper respiratory infec-

Page 89

tions, but evidence supporting efficacy for prevention is sparse (Barrett et al
...
Clearly, more
study is needed to identify the echinacea dose and preparation that is effective for the treatment or
prevention of colds and other upper respiratory infections
...
4
...
4
...
An investigation details the isolation of (Z)-1,8-pentadecadiene
from E
...
and E
...
) Britton
...

A clinical study was conducted to determine the toxicity and immunostimulating effect of echinacin, an
extract of E
...
, 1992)
...
Subsequently, the thymostimulin and echinacin were repeated
twice weekly
...
Because these patients had advanced cancer, tumor response rate was not an
outcome measure; however, after 2 mo of therapy, one patient experienced a 50% regression in tumor
size and in six patients tumor size stabilized
...
Immunological monitoring was performed on days 0, 1, 7, 14, and 21
...
All were increased
except CD8+ count and B-cell count
...
No adverse
effects were noted, but details about echinacin were not provided, limiting the applicability of these
results
...

7
...
4 Wound-Healing
The wound-healing actions of Echinacea stem from two effects: inhibition of hyaluronidase, an enzyme
produced by bacteria that enables them to spread throughout a wound, and stimulation of fibroblasts to
produce granulation tis-

Page 90

sue (Bauer 1996)
...
, 1993)
...
4
...
, 1994)
...
, 1988)
...
4
...

Hamster embryo cell carcinogenicity studies revealed no malignant transformation (Mengs et al
...

7
...
7 Reproduction
Preliminary results of a prospective cohort study suggest that echinacea does not appear to pose a
teratogenic risk
...
Forty-five
pregnancies in which echinacea was used have been followed thus far, with two spontaneous abortions,
no stillbirths, and no malformations
...
,
1998)
...
5 Case Report of Toxicity Due to Commercially Available Products
A 37-yr-old woman had been taking various dietary supplements, including echinacea, for 2–3 yr
...
Fifteen minutes later, she ingested one teaspoon (twice the amount recommended by the
manufacturer) of a 40% ethanol in water solution of echinacea, which she diluted in apple and black
currant juice, as directed by the label
...
angustifolia and 150 mg of dried root of E
...
Immediately, she experienced burning of
the mouth and throat, which she had not previously experienced
...
She self-administered 75 mg of promethazine orally, and was taken to the hospital by
ambulance
...
Past medical history was significant for mild wheezing precipitated
by respiratory infection, allergic rhinitis, and oral pruritis ("oral allergy syndrome") caused by various
raw (not cooked) fruits and vegetables, although apple and black currant juice were tolerated by the
patient
...
She had taken echinacea from the same
bottle a few weeks prior to this episode with no problems, but declined rechallenge with any of the
dietary supplements she had been taking
...

Radioallergosorbent (RAST) testing of the patient's serum revealed immunoglobulin E (IgE) against
echinacea
...
Skin prick testing with aqueous or glycerinated echinacea extracts was positive in 19%
(16) of 84 subsequent patients with asthma or allergic rhinitis, although only two had ever taken
echinacea
...

The Australian Adverse Drug Reactions Advisory Committee received 11 reports of adverse reactions
associated with echinacea use between July 1996 and September 1997
...
Echinacea was
the only reported ingestant in five of the eight reports, resembling hypersensitivity
...
There are two additional published case reports of echinaceaassociated contact dermatitis and anaphylaxis (Mullins, 1998)
...

7
...

7
...
German Commission E has
approved E
...
purpurea herb (above-

Page 92

ground parts)
...
purpurea root and E
...
This
decision was based on the realization that some pharmacologic studies done before 1988 using E
...
pallida
...
angustifolia
root and the above-ground (aerial) parts of E
...
pallida (Blumenthal, 1998)
...
Echinacea
...
St
...

Anonymous
...
F-D-C Reports
...
" March 8,1999
...
Echinacea for upper respiratory infection
...

Bauer R
...
Z Arztl Fortbild (Jena)
...

Bisset NG
...
London: CRC Press, 1994;182-4
...
The complete German Commission E monographs: therapeutic guide to herbal
medicines
...

Brauning B, Knick E
...

Naturheilpraxis 1993;1:72-5
...
[Echinacea purpurea radix: Zur starkung der korpereigenen abwehr bei
grippaken infekten]
...

Brinkeborn RM, Shah DV, Degenring FH
...
A randomized, placebo-controlled, double-blind clinical trial
...

Facino RM, Carini M, Aldini G, Marinello C, Arlandini E
...
Direct characterization of
caffeoyl esters with a trihyaluronidase activity in crude extracts fromEchinacea angustiflia roots by fast
atom bombardment tandem mass spectrometry
...

Gallo M, Au W, Koren G
...
Teratology 1998;57:283
...
A randomized controlled trial of the effect of fluid extract of Echinacea purpurea
on the incidence and severity of colds and respiratory infections Am J Med 1999;106:138-43
...
Nonspecific immunostimulation
with low doses of cyclophosphamide (LDCY), thymostimulin, and echinacea purpurea extracts
(echinacin) in patients with far advanced colorectal cancers: preliminary results
...

Leuttig B, Steinmuller C, Gifford GE, Wagner H, Lohmann-Matthes ML
...
J Natl Cancer
Inst 1989;81:669-75
...
Echinacea root extracts for the prevention of
upper respiratory tract infections
...
Arch Fam Med
1998;7:541-5
...
Toxicity of Echinacea purpurea
...
Arzneimittelforschung 1991;41:1076-81
...
In vitro inhibition of cyclooxygenase
and 5-lipoxygenase by alkamides from Echinacea and Achillea species
...

Mullins RJ
...
Med J Aust 1998;168:170-1
...
In vitro effects of echinacea and ginseng on natural killer and
antibody-dependent cell cytotoxicty in healthy subjects and chronic fatigue sysndrome or acquired
immunodeficiency syndrome patients
...

Stimpel M, Proksch A, Wagner H, lohmann-Matthes ML
...

Infect Immun 1984;46:845-9
...
Anti-inflammatory activity of Echinacea
angustifolia fractions separated on the basis of molecular weight
...

Tyler VE, Brady LR, Robbers JE
...
, Philadelphia: Lea and Febiger, 1981
...
The honest herbal
...
3rd edit
...

Voaden DJ, Jacobson M
...
3
...
J Med Chem 1972;15:619-23
...
) Bernh, Leucanthemum
parthenium (L
...
) Sm; also described as a member of the
genus Matricaria (Anonymous, 1994; USP, 1998a); featherfew, altamisa, bachelor's button, featherfoil,
febrifuge plant, midsummer daisy, nosebleed, Santa Maria, wild chamomile, wild quinine (Anonymous,
1994), amargosa, flirtwort, manzanilla, mutterkraut, varadika (USP, 1998a)
8
...
It reaches heights of 15–60
cm
...
The flowers bloom from July to October (Anonymous, 1994)
...
The common name is in fact a corruption of the Latin word febrifugia (Tyler,
1993)
...
It was also used to aid in expulsion of
the placenta and stillbirths (Knight, 1995), and in difficult labor (USP, 1998a)
...

8
...
J
...
, Totowa, New Jersey

Page 96

1993)
...

8
...
Brand names include Migracare (600 µg of
parthenolide per capsule), Migracin (feverfew extract 1:4 and white willow bark), MigraSpray,
MygraFew, Lomigran, 125-mg Migrelief (light green round tablet containing 600 µg of parthenolide),
Partenelle, Phytofeverfew, and 125-mg Tanacet (not <0
...
Feverfew contains flavonoid
glycosides and sesquiterpene lactones
...
Parthenolide is concentrated in
the flowers and leaves, as opposed to stems and roots, and parthenolide content of the leaves may
decrease during storage (Heptinstall et al
...
The vegetative cycle also influences
parthenolide content (USP, 1998a)
...

Most tablet and capsule formulations contain 300 mg of feverfew, and the recommended dose is usually
two to six tablets or capsules per day
...
2% parthnolide is considered the acceptable minimum parthenolide concentration;
therefore, the manufacturer's recommended dose is probably in excess of what is considered therapeutic
(Tyler, 1994)
...
, 1985; Palevitch et al
...
, 1988) (60 mg of
dried feverfew leaves = 2½ leaves) (USP, 1998a)
...
, 1992), and may be lower than stated on the label (Groenewegen and Heptinstall,
1986) or even absent from some preparations (Groenewegen and Hepinstall, 1986; Heptinstall et al
...
For example, no parthenolide could be detected in two-thirds of feverfew products purchased in
Louisiana health food stores (Tyler, 1994)
...
, 1992)
...
(See
discussion of melatonin content of feverfew products in Section 8
...
1
...
4 Pharmacology/Toxicology
8
...
1 Neurologic Effects
Feverfew's mechanism of action in the prevention of migraine headaches is not known
...
Results of in vitro studies suggest that rather than
acting as a cyclooxygenase inhibitor, feverfew inhibits phospholipase A2, thus inhibiting release of
arachidonic acid from the cell membrane phospholipid bilayer (Collier et al
...

Drugs that are serotonin antagonists are used in migraine prevention (e
...
, methysergide) (Murphy et
al
...
During a migraine, serotonin is released from platelets (Murphy et al
...
, 1992)
...
The effect of these substances on platelet aggregation due to a variety of chemicals
was tested, and was similar except that inhibition of platelet aggregation induced by the calcium
ionophore A23187 by chloroform extract leveled off at a relatively low concentration and was not
complete, while parthenolide inhibited aggregation in a dose-dependent manner, suggesting a different
mechanism of action
...
, 1993b)
...
In contrast, the extract from dried powdered feverfew leaves was
spasmogenic, causing a slow, maintained, reversible contraction
...
The specific functional group responsible for inhibition of smooth muscle contraction has
been identified as the α -methylene moiety present on parthenolide and other sesquiterpene lactones
(Hay et al
...
It

Page 98

has been hypothesized that the irreversible inhibition of platelet aggregation and inhibition of smooth
muscle contraction are caused by covalent binding of parthenolide and other lactones to sulfhydryl (SH) groups on proteins (Barsby et al
...

Another study using chloroform extract of fresh feverfew leaves demonstrated reversible blockade of
open voltage-dependent potassium channels, but not of calcium-dependent potassium channels, in
smooth muscle cells in vitro (Barsby et al
...
Inhibition of potassium channels would be expected
to increase the excitability of smooth muscle cells, potentiate the effects of depolarizing stimuli, and
open voltage-dependent calcium channels, thus leading to muscle contraction
...
, 1993a), the extract of dried, powdered feverfew had this very effect, which
could be explained by potassium channel blockade; however, the fresh extract had the opposite effect
(i
...
, it irreversibly inhibited contractility)
...
The substances in feverfew that cause
potassium channel blockade and muscle contraction have not been identified, but because voltagedependent potassium channels present in smooth muscle cells are similar to those present in neurons, it
is possible that feverfew interferes with the neurogenic response in migraine (Barsby, 1993a)
...
44 leaves [60 mg]) daily for at least 3 mo (Johnson et al
...

Patients were randomized to receive either 50 mg of freeze-dried feverfew powder or placebo for 6 mo
...
Efficacy was assessed using patient
diaries in which patients recorded the duration and severity of headache pain, severity and duration of
nausea and vomiting, and analgesic use on an ordinal scale
...
02) lower in the feverfew group, but analgesic use was similar
...
Patients taking
feverfew reported a similar number of migraine attacks during the study compared to before the study
when they were self-medicating with feverfew
...
At the end of the study, the patients assessed the
overall efficacy of the treatment; feverfew had a more favorable rating than placebo (p < 0
...
Because
there was underreporting of headache

Page 99

in the placebo group, the difference between feverfew and placebo may have been even greater
...

A potential problem with this study was blinding; most patients guessed correctly which treatment they
were receiving
...
Such a selection
process limits the extent to which these study results can be extrapolated to the general population
...
, 1988)
...
All subjects had migraine of at least 2 yr duration, and suffered at least one attack per month
...

Females of childbearing potential were excluded unless they were using adequate contraception
...
Patients were then randomized to placebo or feverfew for 4 mo each
...

In addition, every 2 mo, the patient's overall impression of migraine control was assessed using a 10-cm
visual analog scale
...
05) between placebo and feverfew in
number of attacks only after month 4, but there was a significant difference between the two groups in
overall impression after month 4 (p < 0
...
01) when assessed via the visual
analog scale
...
05), but the effect on the number of common migraine attacks was not statistically significant (p =
0
...
When assessing the responses of patients who had never used feverfew before study enrollment
(n = 42/59) the number of attacks was reduced by 23% (95% CI 10–33%, p = 0
...
This nonsignificant
result gives credence to the concerns about selection bias in the study by Johnson and colleagues
...
01)
...
Duration of attacks was unchanged
...

Another randomized, double-blind, crossover study assessed the efficacy of 100 mg of feverfew (0
...
, 1997)
...
Feverfew was superior to placebo in reducing intensity of migraine pain and
other symptoms
...
5 mg of parthenolide daily for 4
mo was not superior to placebo in the number of migraine attacks in a randomized, double-blind,
crossover study in 44 evaluable patients (DeWeerdt et al
...

Surprisingly, melatonin, a human pineal hormone, has been identified in fresh green feverfew leaves at
a concentration of 2
...
, Toronto, Canada) at a concentration of 0
...
Each Tanacet® tablet contains 70–
80 ng of melatonin, and the recommended dose is one or two tablets daily
...
19 µ g/g of melatonin, fresh golden feverfew leaf contains 1
...
69 µ g/g, freeze-dried golden leaf contains 1
...
37 µg/g
...
This finding underscores the need to fully characterize the ingredients in herbs and medicinal
preparations made from them (Murch et al
...

Larger studies are needed to definitively determine the efficacy of feverfew in the prevention of
migraine, and to identify the component or components responsible for its pharmacologic effects
...
4
...
, 1987)
...
Both
parthenolide and the extracts were cytotoxic to the PBMCs and synovial cells; thus, the
antiinflammatory effects of feverfew may be secondary to cytotoxicity
...
, 1971)
...
, 1989)
...
Fortyone
female RA patients from a rheumatology clinic participated
...
If a patient
deteriorated acutely during the study, a single intraarticular dose of 20 mg of triamcinolone
hexacetonide was allowed at week 3
...
Patients were also questioned
about adverse effects
...
At week 6, a global impression from both the patient and the clinician were
recorded as better, same, or worse
...
One patient
receiving feverfew reported minor ulceration and soreness of the tongue
...
By week 3, urea
levels had significantly increased (p = 0
...
At
6 wk, grip strength and IgG were increased in the feverfew group compared with baseline (p = 0
...
025, respectively)
...

8
...
3 Mutagenicity/Carcinogenicity/Teratogenicity
In 30 migraine patients who had been taking feverfew leaves, tablets, or capsules for at least 11 mo,
there was no increase in chromosomal aberrations or sister chromatid exchange in circulating
lymphocytes compared to migraine patients not taking feverfew matched for age and sex
...
, 1988)
...


Page 102

8
...
Feverfew
belongs to the Compositae family (Anonymous, 1994), and persons allergic to other members of this
family, such as chamomile, ragweed, asters, chrysanthemums (Benner and Lee, 1973) and echinacea,
could also be allergic to feverfew
...
3% (Johnson et al
...
Feverfew-induced mouth
ulceration is not a manifestation of contact dermatitis; it is a systemic reaction
...

In the study by Johnson and colleagues, in which 10 patients who had been taking fresh feverfew leaves
were switched to placebo, patients experienced recurrence of migraine, tension headaches, joint pain
and stiffness, nervousness, insomnia and disrupted sleep, and tiredness
...
" Dr
...
, 1985)
...
6 Drug Interactions
In vitro studies suggest that feverfew may inhibit platelet aggregation, leading to recommendations that
patients avoid use of feverfew with anticoagulants and medications with antiplatelet activity (USP,
1998a)
...
In patients who had been taking feverfew for at least 4 yr,
the threshold for platelet aggregation in response to 11α,9A-epoxymethanoprostaglandin H2 (U46619)
and serotonin was elevated (Biggs et al
...
Whether these results translate into the potential for
drug interactions and bleeding diatheses remains to be documented
...
7 Chemical Analysis
Thin-layer chromatography (TLC) has been used to identify parthenolide and other sesquiterpene
lactones (Pickman et al
...
The high-performance liquid chromatography (HPLC) elution profile of
parthenolide has also been illustrated (Barsby et al
...
, 1994)
...
, 1991; Dolman et al
...
, 1992) and other sesquiterpene
lactones (Dolman et al
...
, 1991)
...

8
...

A USP advisory panel, although recognizing that feverfew has a long history of use and lack of
documented adverse effects, does not recommend its use owing to the paucity of scientific evidence of
safety and efficacy
...

In Canada, the Health Protection branch allows sale of tablets and capsules made from feverfew crude
dried leaves for decreasing the frequency and severity of migraine headaches
...
2% parthenolide
...

References
Anderson D, Jenkinson PC, Dewdney RS, Blowere SD, Johnson ES, Kadam NP
...
Hum Toxicol 1988;7:145-52
...
Feverfew
...
St
...

Awang DVC
...
A headache for the consumer
...

Awang DVC, Dawson BA, Kindack DG, Heptinstall S
...
) Schultz-Bip
...
J Nat Prod 1991;54:151621
...
A chloroform extract of the herb feverfew blocks voltagedependent potassium currents recorded from single smooth muscle cells
...

Barsby RWJ, Salan U, Knight DW, Hoult JRS
...
Planta Med 1993b;59:20-5
...
Anaphylactic reaction to chamomile tea
...

Biggs MJ, Johnson ES, Persaud NP, Ratcliffe DM
...
Lancet 1982;ii:776
...
Extract of feverfew inhibits prostaglandin
biosynthesis
...

DeWeerdt CJ, Bootsma HPR, Hendriks H
...
Phytomed 1996;3:225-30
...
A quantitiative method for the estimation of parthenolide
and other sesquiterpene lactones containing alphamethylenebutyrolactone functions present in
feverfew, Tanacetum parthenium
...

Groenewegen WA, Heptinstall S
...
Lancet
1986;i:44-5
...
A comparison of the effects of an extract of feverfew and
parthenolide, a component of feverfew, on human platelet activity in vitro
...

Hay AJB, Hamburger M, Hostettmann K, Hoult JRS
...
Br J Pharmacol 1994;112:9-12
...
Parthenolide content and
bioactivity of feverfew (Tanacetum parthenium [L
...
Estimation of commercial and
authenticated feverfew products
...

Johnson ES, Kadam NP, Hylands DM, Hylands PJ
...
Br Med J 1985;291:569-73
...
Feverfew: chemistry and biological activity
...

Lee K, Huang E, Piantadosi C, Pagano JS, Geissman TA
...

Cancer Res 1971;31:1649-54
...
The active principle in feverfew
...

Marles RJ, Kaminski J, Arnason JT
...
J Nat Prod 1992;55:1044-56
...
Melatonin in feverfew and other medicinal plants
...

Murphy JJ, Heptinstall S, Mitchell JRA
...
Lancet 1988;ii: 189-92
...
Extracts of feverfew inhibit mitogen-induced human peripheral
blood mononuclear cell proliferation and cytokine mediated responses: a cytotoxic effect
...

Palevitch D, Earon G, Carasso R
...
Phytother Res1997;11:508-11
...
Feverfew in rheumatoid arthritis: a double blind,placebo
controlled study
...

Pickman AK, Huang ES, Piantidosi C, Pagano JS, Geissman TA
...
J Chromatogr 1980;189:187-98
...
The honest herbal
...
, Binghamton, NY: Pharmaceutical Products Press, 1993
...
Herbs of choice: the therapeutic use of phytomedicinals
...

United States Pharmacopeial Convention (USP)
...
Botanical monograph series
...

United States Pharmacopoeia (USP)
...
18th edit
...
Rockville,MD: United
States Pharmacopeial Convention, 1998b
...
1 History and Traditional Uses
Over the centuries, garlic has been used to ward off vampires, demons, witches, and evil beings; as an
aphrodisiac to improve performance and desire; and as a cure-all for everything from athlete's foot to
hemorrhoids and cancer (Tyler, 1993)
...
2 Current Promoted Uses
Garlic is promoted to lower cholesterol and blood pressure, delay atherosclerotic processes, prevent
heart attack and stroke, improve circulation, and prevent cancer
...
3 Products Available
Centrum® Herbals ''Garlic" capsules, 300 mg
Herbscience ® Garlic, 600 mg caplets
Kwai®, 600 µg of allicin/100 mg of dried garlic, 100 mg tablets (see detailed description below)
Kyolic® Aged Garlic Extract™, 600-mg caplets
Nature Made® Extra Strength Odor -controlled garlic, 500 mg
Nature Made® Garlic Oil, 500 -mg softgel
Nature Made® Odorless Garlic, 500-mg tablets
Nature Made® High Potency Garlic Oil, 1500-mg softgels
Nature's Resource® Garlic Powder, 180-mg enteric coated tablets
From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
Allicin then produces diallyl sulfide, diallyl disulfide, diallyl trisulfide, ajoenes, methyl
allyl trisulfides, vinyl dithiins, and other sulfur compounds, depending on how the garlic is prepared
...
Cooking whole or coarsely
chopped garlic destroys allinase, the enzyme necessary for production of allicin, ajoene, diallyl sulfide,
diallyl disulfide, and vinyl dithiins; only cysteine sulfoxides such as alliin remain
...
Steam distillation produces an oily mass of
active compounds including diallyl, methyl allyl, dimethyl, and allyl 1-propenyl oligosulfides that
originate from the thiosulfinates
...
This latter method is the one used to prepare
commercially available garlic capsules
...

Kwai® brand coated garlic powder tablets contain dried garlic powder prepared by freeze-drying fresh
garlic (Isaacsohn et al
...
The tablets are odorless because they contain alliin, but not allicin, the
source of garlic's characteristic odor
...


Page 109

9
...
4
...
(1993) completed a meta-analysis using Medline (1966–1991) to collect all
randomized, placebo-controlled trials that tested the effectiveness of oral garlic preparations in lowering
cholesterol in humans
...
17 mmol/L (200 mg/dL)
...
Of the 28 studies found, all but five were excluded
...
All five used parallel group design
...
One study used 1000 mg (4 mL) of
Kyolic® aqueous extract per day and the other study used 700 mg of spray-dried powder per day
...
The authors concluded that total
cholesterol levels decreased by a statistically significant (p < 0
...
Several more recent studies have
confirmed the results of this meta-analysis
...
(1998) performed a double-blind, randomized, placebocontrolled, crossover trial to
examine the effects of garlic oil on serum lipoproteins, cholesterol absorption, or cholesterol synthesis
...
The daily dosage corresponded to 4–5 g of fresh garlic cloves, or
4000 U of allicin equivalents per day
...
Twenty-six patients with moderately high cholesterol (240–338
mg/dL) and triglyceride (<265 mg/dL) were recruited through the local newspaper
...
Subjects were
allowed to eat their "normal" diets throughout the study, but could not eat any additional garlic
...
Garlic oil did not affect any of the parameters studied
...
Isaacsohn et al
...
3) for 12 wk was ineffective in lowering cholesterol
...
Dietary compliance was measured using the Food
Record Rating (FRR) Score
...
No
significant changes in blood pressure were noted
...
Baseline
measurements were taken to compare against readings at 6 and 12 wk of treatment
...
01)
...
No significant changes were noted for triglycerides, high-density lipoprotein (HDL)
cholesterol, serum glucose, blood pressure, and body weight
...

This latter side effect may be explained by platelet inhibition by various garlic components
...
Aggregation and platelet shape
changes were induced with 5-hydroxytryptamine and ADP
...
The author attributed the platelet inhibition to methyl
allyl trisulfide (MATS), which had been shown by other investigators (Ariga et al
...

The effects of ajoene, an allicin metabolite, on platelet aggregation have also been described (Srivastava
and Tyagi, 1993)
...
Blood was donated by from
healthy donors who had not taken aspirin or any other drug affecting platelets for 2 wk prior to giving
blood
...
5 min at room temperature before substances to induce aggregation (arachidonate, calcium,
collagen, epinephrine, ADP) were added
...
The inhibition of platelet aggregation was found to be dose dependent and irreversible
...

Other investigators have shown that oily garlic extracts, which contain ajoene, are able to inhibit
enzymes necessary for arachidonic acid conversion to thromboxane (Srivastava anad Tyagi, 1993)
...
(1979) demonstrated the effect of garlic oil on platelet thromboxane synthesis
...
These investigators also measured oxygen consumption to
confirm that platelet cyclooxygenase was also inhibited, but activity of lipoxygenase did not appear to
be decreased
...
This finding suggests that inhibition of
thromboxane synthesis is not the only mechanism by which garlic inhibits platelet aggregation
...
Investigators have demonstrated that
adenosine does not affect thromboxane production by affecting incorporation of arachidonic acid into
the platelet membrane, by inhibiting cyclooxygenase or lipoxygenase enzymes, or by inhibiting release
of arachidonic acid from the platelet membrane when stimulated
...
Thus, garlic's ability to inhibit platelet
aggregation may be the result of multiple mechanisms effected by multiple garlic components present
in varying amounts in aqueous vs oily garlic extracts
...
(1998) conducted a study to determine the effects of garlic on lipids, glucose, fibrinogen,
and fibrinolytic activity in patients with past myocardial infarction (> 6 mo)
...
Sixty patients
were administered either two capsules twice daily of garlic oil (30 subjects) or placebo (30 patients)
...
In addition,
the investigators studied the in vitro effects of garlic oil, diallyl disulfide, and diallyl trisulfide on
platelet aggregation and arachidonic acid metabolite formation
...
8% (p < 0
...
2% (p < 0
...
3% (p < 0
...
1% (p < 0
...
Blood glucose and fibrinogen did not change compared to baseline
...
In vitro, garlic oil and
the two garlic components tested inhibited both platelet aggregation and thromboxane synthesis
...


Page 112

9
...
2
...

Small doses of garlic are purported to increase the tone of smooth muscle in the gastrointestinal tract,
while large doses decrease such actions (Tyler, 1993)
...
002 mg/mL; however, an ethanol extract of fresh garlic bulb caused rat fundus
smooth muscle stimulation at a concentration of 0
...

The gastrointestinal side effects of garlic extracts and commercially available products are described in
Section 9
...
1
...
4
...
Garlic has also been claimed to suppress oropharyugeal or vaginal candidia
colonization, clear Candida cystistis in diabetics or patients with Foley catheters, cure dermatophytic
infections, and treat systemic aspergillosis
...

The contents of a 1500 mg garlic extract capsule distributed by the Windmill Natural Vitamin Co
...
Several yeasts (Candida sp
...
) and mycelial fungi species (Aspergillus sp
...
) were tested
...
glabrata and R
...
Similar results were obtained with urine samples from the
volunteers
...
The commercial
preparation did not exhibit antifungal activity
...
Clinical use of oral garlic extracts for purposes of treating fungal infections appears to
be limited because the gastrointestinal tolerance of the amount of garlic extract used in this study was

Page 113

poor, and larger amounts cause severe burning sensations in the esophagus and stomach, and vomiting
...
, 1983)
...
Freshly cut garlic
applied topically acted more quickly than tolnaftate against Microsporum crisis lesions on the arm of a
young woman (Rich, 1982); ajoene 0
...
, 1996); and culture-confirmed
sporotichosis was successfully treated using garlic juice (Tutakne et al
...
Well-designed studies
are needed to confirm the safety and efficacy of topical application of garlic, especially in light of case
reports of garlic burns (See 9
...

9
...
4 Antineoplastic Effects
Hu and colleagues completed a study (Hu et al
...
BP is believed to be a risk factor in human chemical
carcinogenesis
...

BP's carcinogenic metabolites can be inactivated in vivo by conjugation with glutathione by the enzyme
glutathione S-transferase (GST)
...
The investigators found that the garlic organosulfides diallyl
sulfide, diallyl disulfide, dipropyl sulfide, dipropyl disulfide, and diallyl trisulfide were capable of
inducing GST expression in murine liver and forestomach, as well as of preventing forestomach
neoplasia
...

Like BP, nitrosamines are ubiquitous environmental carcinogens
...
One hundred fifty rats were divided into 12
groups to evaluate the effects of these organosulfur compounds
...
After 2 wk on a basal
diet, they received DAS (100 mg/kg; group 1), DDS (25 mg/kg; group 2), AMS (150 mg/kg; group 3)
DPS (150 mg/kg; group 4), and DPD (150 mg/kg; group 5)
...
Group 6 received DEN and underwent PH but were not given any organosul-

Page 114

fides
...
Group 12 animals received placebos only and underwent PH
...
At wk 8, the rats were killed
...
The authors proposed that this was a result of organosulfide administration
during the promotion phase rather than prior to nitrosourea administration
...
01 µg/mL of selenium, selenium-methylselenocysteine (a seleno-amino acid found in
selenium-garlic), and sodium selenite (used for fertilizing selenium-garlic) on murine tumors (Lu et al
...
In vitro, both the extract of seleniumenriched garlic and selenium-methylselenocysteine resulted
in growth inhibition, G1, phase arrest, and DNA double-strand breaks in neoplastic murine mammary
cells
...
In addition, dietary supplementation with selenium-enriched garlic extract
provided protection against methylnitrosourea-induced mammary tumors
...

The authors concluded that the beneficial effects observed could be attributed to seleniummethylselenocysteine
...
4
...
(Hisoshima,
Japan), the protein fraction isolated from this same extract, and three additional extracts obtained from
health food stores in Loma Linda, CA for ability to stimulate murine T-lymphocyte function and
macrophage activity in vitro
...
Of the three extracts sold in American health
food stores, only one stimulated macrophage activity
...
Although not addressed by the authors, the
in vivo antifungal activity of garlic might also

Page 115

be explained by immunostimulation, especially in light of the in vitro study by Caporaso and colleagues
discussed in Section 9
...
3 that did not support the clinical antifungal activity of garlic extract
...
5 Case Reports of Toxicity
Chopped garlic and oil mixes left at room temperature can result in fatal botulism food poisoning,
according to the FDA (Lecos, 1998)
...
Clostridium botulinum bacteria are
dispersed throughout the environment, but are not dangerous in the presence of oxygen
...
The garlic oil in mixture provides the
environment for the spores to produce their toxin, leading to botulism
...

Garlic allergy can manifest as occupational asthma, contact dermatitis, urticaria, angioedema, rhinitis,
and diarrhea
...
Touching garlic also resulted in urticaria
...
The patient's symptoms were immunoglobulin E (IgE) mediated, but she also produced
specific IgG, which confounded the results of IgE testing (Asero et al
...

Twelve garlic workers with respiratory symptoms associated with garlic exposure underwent skin prick
tests (SPTs) using garlic powder in saline, commercial garlic extract, and various other possible
allergens; bronchial provocation tests with garlic powder; oral challenge with garlic dust; and specific
IgE testing using the CAP (CAP System; Pharmacia, Uppsala, Sweden) methodology
...
Seven patients
had positive responses (rhinitis or asthma) to the inhalation challenge test, and were designated as
Group 1
...
In addition, six
patients had specific IgE to onion, three to leeks, and four to asparagus
...
None had garlic or onion IgE
...
Two of these patients were administered garlic orally in increasing doses up to 1600
mg
...
Using immunoblot and IgE immunoblot inhibition analysis, the
investigators also attempted to elucidate the specific garlic component to which the patients reacted
...
, 1997)
...
, 1981); a 30-yr-old electrician working in a spice processing plant (Lybarger et al
...
Symptoms described included wheezing (Falleroni et al
...
, 1982); rhinitis (Falleroni et al
...
Garlic allergy was confirmed
using a wide variety of tests including scratch testing (Couturier and Bousquet, 1982); SPT (Falleroni et
al
...
, 1982; Armentia, 1996); IgE to garlic using radioallegosorbent test (RAST)
(Lybarger et al
...
, 1981), CAP system (Armentia, 1996);oral challenge (Lybarger et al
...
, 1981; Couturier and Bousquet, 1982; Lybarger, 1982; Arementia, 1996);
and basophil degranulation (Couturier and Bousquet, 1982)
...
Patients with occupational garlic allergy are often allergic to other foods as well as to
airborne allergens, including peanuts, onion, ragweed pollen (Falleroni et al
...
, 1982)
...
A 17-mo-old
infant suffered partial thickness burns when a plaster made of garlic in petroleum jelly was applied to
the skin for 8 h (Parish et al
...
Another infant, age 6 mo, suffered garlic burns when his father,
disappointed that no antibiotics had been prescribed for a treatment of suspected aseptic meningitis,
applied crushed garlic cloves by adhesive band to the wrists for 6 h (Garty, 1993)
...
A similar, more superficial lesion was also seen on the right wrist
...
The author of this case report described this reaction as a second-degree chemical burn
...
A patch test was not
done for ethical reasons
...
For example, a 6-yr-old child developed
a necrotic ulcer on her foot after her grandmother applied crushed garlic under a bandage as a remedy
for a minor sore (Canduela et al
...

A 38-yr-old woman developed a garlic burn after applying a poultice made from fresh, uncooked garlic
to her breast for treatment of a self-diagnosed Candida infection secondary to breastfeeding her 6-moold son (Roberge et al
...
Despite a burning sensation upon application, she left the poultice in
place for 2 d
...
Two days after removal of
the poultice, she presented to the emergency room
...
The area was
tender
...

Another adult suffered garlic burns after applying a compress of crushed garlic wrapped in cotton to her
chest and abdomen for 18 h (Farrell and Staughton, 1996)
...
She reported that the pain had been present for a
week and had a stabbing quality
...
Biopsy revealed full
thickness necrosis, many pyknotic nuclei, and focal separation of the necrotic epidermis from the
dermis
...
The patient refused patch testing, and specific IgE RAST
testing to garlic was negative
...
Three soldiers applied fresh ground
garlic to their lower legs and antecubital fossa to produce an erythematous, vesicular rash in an effort to
avoid military duty (Kaplan et al
...

Eight patients who developed contact dermatitis after rubbing cut fresh garlic cloves on fungal skin
infections responded to a topical fluorinated steroid but had negative garlic patch tests, suggesting
irritation rather than allergy (Lee and Lam, 1991)
...

See Sections 9
...
1 and 9
...
3 for additional adverse effects
...
6 Drug Interactions
There are no documented drug interactions, but garlic's antiplatelet effect might be dangerous in
patients taking warfarin or antiplatelet agents such as aspirin, clopidogrel, ticlopidine, or dipyridamole
...
7 Pharmacokinetics/Toxicokinetics
9
...
1 Absorption
The bioavailability of the garlic component S-allyl-L-cysteine (SAC) was 64
...
6%, and 98
...
5 mg/kg, 25 mg/kg, and 50 mg/kg, respectively
...
2% in dogs
...
25 h in dogs, 0
...
5 mg/kg and 25 mg/kg in rats,
and at 1 h in rats administered 50 mg/kg (Nagae et al
...

9
...
2 Distribution
Egen-Schwind and colleagues (1992) found that 1,2-vinyl dithiin, a component of oily preparations of
garlic, accumulates in fatty tissues, while 1,3vinyl dithiin is more hydrophilic and is rapidly eliminated
from serum, kidney, and fat tissue
...
Both 1,3-vinyl dithiin and 1,2-vinyl dithiin were
detected in the serum, kidney, and fat
...
, 1994)
...

Garlic apparently distributes into human amniotic fluid and breast milk
...
Four of the five amniotic fluid
samples from the women who had ingested garlic were judged by a blinded panel to have a stronger and
more garlic-like odor than a paired amniotic fluid sample from a woman in the placebo group
(Mennella et al
...
Ingestion of garlic for 3 d by nursing women decreased the infants' feeding time
compared to infants of mothers who had taken placebo (Mennella and Beauchamp, 1993)
...
7
...
(1996) conducted a study to evaluate the urinary excretion ofM-acetyl-S-allyl-L-cysteine
(allylmercapturic acid, ALMA)
...
Six human volunteers were administered 200 mg of garlic extract in
tablet form (Kwai®)
...
Urine samples were collected prior to administration of the garlic and up to 24 h postadministration
...

γ-glutamyl-S-allyl-L-cysteine (GAC) is ALMA's most likely precursor
...
This compound then undergoes
acetylation via N-acetyl transferase to form ALMA
...
By
assuming that GAC represents 1% of the dry weight of garlic bulbs, and that the tablets represented
100% dry garlic, the researchers approximated that 10% of GAC is excreted as ALMA within the first
24 h of garlic ingestion
...
0 ± 1
...
,
1996)
...
It is important to note that the study participants' urine contained N-acetyl-S(2carboxypropyl)-cysteine at baseline in minute amounts, even before garlic ingestion, but increased
after ingestion of garlic or onions
...

Elimination of other garlic components has also been studied
...
As
discussed in Section 9
...
2 Distribution, 1,2-vinyldithiin is lipophilic and tends to accumulate in fat,
while 1,3-vinyldithiin is less lipophilic and more quickly eliminated from the serum, fat, and kidney
...
, 1992)
...
SAC is likely
metabolized to N-acetylSAC (ALMA) by acetyltransferase in the liver and kidney
...
Thirty to fifty percent of the SAC dose is

Page 120

excreted in the urine in rats as N-acetyl-SAC, and <1% of the dose is excreted as unchanged SAC in the
urine and bile
...
5%) and the N-acetylated metabolite (7
...
The halflife of SAC in rats ranges from 1
...
5 mg/kg to 2
...
In mice, the half-life of SAC is 0
...
43 h for intravenous
administration, and in dogs approx 10 h after either oral or intravenous administration (Nagae et al
...

9
...
N-acetyl-S-(2-carboxypropyl) cysteine, N-acetyl-S-allyl-L-cysteine (ALMA,
allylmercapturic acid), and hexahydrohippuric acid were identified
...
Gas chromatographic sulfur selective analysis
with a flame photometric detector as well as mass selective analysis was performed
...
The
vinyl dithiins, found in oily garlic preparations, were detected in rat serum, kidney, fat, and liver using
GC-MS (Egen-Schwind et al, 1992)
...

9
...
The oil, extract, and oleo resin have been
deemed generally recognized as safe (GRAS) as food substances by the FDA, and garlic is also
regulated as a dietary supplement in the United States
...

References
Anibarro B, Fontela JL, De La Hoz F
...
J Allergy Clin
Immunol 1997;100:734-8
...
Platelet aggregation inhibitor in garlic
...

Armentia A
...

Asero R, Mistrello G, Roncarolo D, Antoniotti PL, Falagiani P
...
J Allergy Clin
Immunol 1998;101:427-8
...
Isolation, purification, identification, synthesis, and kinetics of activity of the
anticandidal component of Allium sativum and a hypothesis for its mode of action
...

Berthold HK, Sudhop T, von Bergmann K
...
A randomized controlled trial
...

Blumenthal, M
...
Therapeutic guide to herbal
medicines
...
Austin Texas: American Botanical Council, 1998
...
Popular herbs in the U
...
market
...
American Botanical Council, Austin
Texas, 1997
...
Effect of garlic (Allium sativum) on blood lipids, blood sugar,
fibrinogen and fibrinolytic activity in patients with coronary artery disease
...

Boullin DJ
...
Lancet 1981;i:776-7
...
Garlic: always good for the health [letter]?
Br J Dermatol 1995;132:161-2
...
Antifungal activity in human urine and serum after ingestion of
garlic (Allium sativum)
...

Couturier P, Bousquet J
...
J Allergy Clin
Immunol 1982;70:145
...
Garlic dermatitis
...

De Rooij BM, Boogaard PJ, Rijksen DA, Commandeur JNM, and Vermeulen NPE
...
Arch Toxicol
...

Egen-Schwind C, Eckard R, Jekat FW, Winterhoff H
...
Planta Med 1992;58:8-13
...
Occupational asthma secondary to inhalation of garlic dust
...

Farrell AM, Staughton RCD
...
Lancet 1996;317:1195
...
Garlic burns
...

Hu X, Benson PJ, Srivastava SK, Xia H, Bleicher RJ, Zaren HA, et al
...
Int J Cancer 1997;73:897-901
...
Garlic powder and
plasma lipids and lipoproteins
...
Arch Intern Med
1998;158:1189-94
...
Can garlic reduce levels of serum lipids? A
controlled clinical study
...

Jandke J, Spiteller G
...
J Chromatogr 1987;421:1-8
...
Facial dermatitis induced by application of garlic
...

Lau BHS, Yamasaki T, Gridley DS
...
Mol Biother 1991;3:103-7
...
Chopped garlic in oil mixes
...
fda
...
Accessed 1998 October 27
...
Jain MK, ApitzCastro R
...
Mycoses 1996;39:393-5
...
Contact dermatitis due to topical treatment with garlic in Hong Kong
...

Lu J, Pei H, Ip C, et al
...
Carcinogenesis 1996;9:1903-7
...
Occupational asthma
induced by inhalation and ingestion of garlic
...

Makheja AN, Vanderhoek JY, Bailey JM
...
Lancet 1979;i:781
...
The effects of repeated exposure to garlic-flavored milk on the
nursling's behavior
...

Mennella JA, Johnson A, Beauchamp GK
...
Chem Senses 1995;20:207-9
...
Pharmacokinetics of the garlic
compound S-allylcysteine
...

Parish RA, McIntyre S, Heimbach DM
...
Pediatr Emerg
Care 1987;3:258-60
...
Garlic an antibiotic? Med J Aust 1982;1:60
...
Garlic burns of the breast
...

Ross IA
...
Chemical constituents, traditional and modern medicinal uses
...
Totowa, NJ: Humana Press, 1998
...
Effects of aqueous extracts of onion, garlic, and ginger on platelet aggregation and
metabolism of arachidonic adin in the blood vascular system: in vitro study
...

Srivastava KC, Tyagi OD
...
Prostagland Leukotr Essent Fatty Acids 1993;49:587-95
...
al
...
Cancer
Res 1994;54:2895-9
...
Sporotrichosis treated with garlic juice
...
Indian J Dermatol 1983;28:41-5
...
Garlic
...
A sensible guide to the use of herbs and related remedies, 3rd
edit
...

Warshafsky S, Kamer, RS, Sivak SL
...
Ann Intern Med
1993;119:599-605
...
1 History and Traditional Uses
Ginger is a perennial plant with thick tuberous rhizomes from which an above ground stem rises about
3 ft (Leung, 1980)
...
Ginger is cultivated in areas of abundant rainfall (at
least 80 in
...
Native to southern Asia, ginger is cultivated in tropical areas such as
Jamaica, China, Nigeria, and Haiti (Leung, 1980)
...
, 1981)
...
Marco Polo documented its use in India in the late
13th century (Tyler, 1981)
...
The Chinese utilized
ginger for stomach aches, diarrhea, nausea, cholera, bleeding (Leung, 1980), asthma, heart conditions,
respiratory disorders (USP, 1998a), toothache, and rheumatic complaints (Awang, 1992)
...

From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
It has also been used to treat migraines, fever, flu, amenorrhea (USP, 1998a), snake bites,
and baldness (Leung, 1980)
...
2 Current Promoted Uses
In the United States, ginger is promoted to relieve and prevent nausea caused by motion sickness,
morning sickness, and other etiologies
...
3 Products Available
The best quality ginger comes from Jamaica and consists of whole ginger with the epidermis
completely peeled from the rhizomes and dried in the sun for 5–6 d, although high-quality, partially
scraped ginger used pharmaceutically also comes from Bengal and Australia (USP, 1998a)
...

Ginger is commercially available in the United States as the dried powdered root, syrup, tincture,
capsules, tablets, tea, oral solution, powder for oral solution, as a spice, and in candy, ice cream, and
beer (USP, 1998a)
...
Examples include:
Alvita® Teas Ginger Root tea bag
Breezy Morning Teas Jamaican Ginger tea bag
Celestial Seasonings® Ginger Ease™ Herb tea bag
Aura Cacia Essential Oil Ginger
Abunda Life Chinese Ginger powder
Frontier Ginger—Hawaiian Root capsule
Nature's Herbs® Ginger Root, 535-mg capsule
Nature's Way® Ginger Root, 550-mg capsule
Nature's Plus® Liquid Ginger Extract, 4% volatile oils
Health Plus Ginger Root extract, 50-mg capsule
Nature's Answer® Ginger Root Low Alcohol (Liquid)Nature's Answer® Ginger Root Alcohol Free (Liquid)
Nature's Herb® Ginger Root Extract (Liquid)
Nature's Way® Ginger Extract (Liquid)
Quanterra™ Stomach Relief, 250 mg dried ginger root powder (Zintona®) capsule

Page 125

10
...
4
...
, 1989)
...
Thirty-eight subjects, 20 women and 18 men between the ages of 22
and 34, were given 1 g of ginger (Zintona®), 100 mg dimenhydrinate, or placebo in a double-blind,
crossover fashion 90 min prior to each test
...

Therefore, a central nervous system (CNS) effect was ruled out as ginger's antiemetic mechanism of
action, and a direct gastrointestinal effect was proposed
...
The subjects were given either two
ginger capsules (940 mg), one dimenhydrinate capsule (100 mg), or two placebo capsules (powdered
chickweed herb [Stellaria media])
...
None of the dimenhydrinate or
placebo subjects were able to remain in the chair a full 6 min, and three patients in the placebo group
vomited
...
It was concluded that 940 mg of ginger was
superior to 100 mg of dimenhydrinate in preventing motion sickness
...
" Although the study subjects were blinded not only to the treatments used, but also to the
purpose of the study, it is unclear if the investigator was also blinded
...
, 1995)
...
The number of subjects provided 80% power to detect a reduction
in the incidence of nausea from 30% to 20%
...
Nausea, when present, was rated on a scale of 1 to
3 (mild,

Page 126

moderate, severe)
...
36)
...
Blinding may have been problematic in this study
because of the characteristic taste and smell of ginger, which was noted by one of the patients
...
One patient in the placebo group complained of "feeling
windy and having the urge to burp
...
, 1993)
...
The subjects were given either 1 g of ginger, 100 mg of
metoclopramide, or a placebo (1 g of lactose) 1 h prior to surgery
...
Ginger was similar
in effectiveness to metoclopramide in preventing postoperative nausea and vomiting (p = 0
...
006)
...
Thirty pregnant women at <20 wk gestation
previously admitted to the hospital for hyperemesis gravidarum participated in the study
...
After a 2-d
wash-out period, the subjects received the alternate treatment for 4 d
...
035)
...
4
...
, 1982)
...
In an additional
study of ginger's ability to affect arachidonic acid metabolism in human platelets and rat aorta, an
aqueous extract of ginger was able to inhibit production of thromboxane and prostaglandins in a dosedependent manner (Srivastava, 1984)
...
, 1994)
...
05mL suspension of heat-killed Mycobacterium tuberculosis bacilli in liquid paraffin (5 mg/mL) was
injected into the knees

Page 127

and paws to induce arthritis in treatment rats
...
Compared to normal saline, both treatments were effective in
decreasing both knee and paw swelling
...
4
...
A 42yr-old woman suffered migraine with aura for 10 yr once or twice every 2 or 3 mo
...
The patient reported some
relief within 30 min of the first dose
...
In a 13-mo
period, she reported only six migraines
...

10
...
4 Cardiovascular Effects
In vitro studies of gingerol using canine cardiac tissue and rabbit skeletal muscle demonstrated Ca2+ATPase activation in the cardiac and skeletal sarcoplasmic reticulum (SR) (Kobayashi et al
...

Gingerol (3–30 µM) increased Ca2+-ATPase pumping rate in a dose-dependent manner
...
The
investigators concluded that gingerol may be a useful phaarmacologic tool in the study of regulatory
mechanisms of the SR Ca2+ pumping systems, and their effect on muscle contractility
...
, 1982)
...

Thus, 8-gingerol was the most potent gingerol in regard to cardiotonic activity
...
However, this may not be clinically significant; inhibition of platelet aggregation
has been demonstrated in humans only after consumption of 5 g of raw ginger daily for 1 wk
(Srivastava, 1989)
...


Page 128

10
...
5 Mutagenicity
A study showed that 6-gingerol and 6-shogaol isolated from Zingiber officinale using column
chromatography were mutagenic at 700 µM in the Hs30 strain of Escherichia coli (Nakamura and
Yamamoto, 1983)
...
Another study documented the antimutagenicity of zingerone, another ginger component, in
addition to the mutagenicity of gingerol and shogaol in Samonella typhimurium strains TA 100, TA
1535, TA 1538, and TA 98 (Nagabhushan et al
...
Gingerol and shogaol activated by rat liver
enzymes at doses of 5–200 mcg/plate mutated strains TA 100 and TA 1535 while zingerone was nonmutagenic in all four strains
...
Although all three compounds are similar in chemical structure, zingerone has
a shorter side chain than the mutagenic compounds; thus the side chains may be responsible for the
mutagenic activity of gingerol and shogaol
...
4
...

Commission E contraindicates ginger's use during pregnancy for morning sickness, although this
contraindication has been disputed by some owing to the lack of reported problems despite its long
history of use in pregnancy in traditional Chinese medicine (Blumenthal, 1998)
...
5 Case Reports of Toxicity Due to Commercially Available Products
Consumption of Jamaica ginger, an alcoholic ginger extract that was popular as a beverage in the rural
southern United States during prohibition, resulted in a peripheral polyneuritis (Harris 1930)
...
After the soreness disappeared,
walking became notably difficult for the case subjects
...
Bilateral weakness of the upper and lower extremities and foot drop,
without sensory disturbance or pain, was a common physical finding
...
Deep tendon reflexes were inconsistent among patients; ankle jerks
were not present in any subject, but some had normal knee reflexes
...
Although the beverage contained 60–90% alcohol, alcoholic neuropathy was ruled out as an
etiology of the syndrome because of the sporadic nature of Jamaica ginger consumption
...
This chemical had been
added to the beverage presumably as a tasteless substitute for the oleo resin of ginger so that the product
would be more palatable
...
S
...
ginger fluid extract failed to
produce paralysis
...

10
...

10
...
Gas chromatographymass spectroscopy (GC -MS) has also been used to
confirm the purity and identity of gingerol, shogaol, and zingerone (Connell and Sutherland, 1969)
...
8 Regulatory Status
In Austria and Switzerland, ginger is registered as an over-the-counter (OTC) drug indicated for the
prevention of motion sickness, nausea, and in Austria, for vomiting in febrile pediatric patients
...
Likewise, in the United Kingdom ginger is on the General Sale List of the
Medicines Control Agency
...
Ginger is listed as an official monograph in the United States PharmacopoeiaNational Formulary (USP, 1998b)
...
It is
also considered "generally recognized as safe (GRAS) as a food substance" by the FDA (Tyler, 1994)
...
The Lawrence review of natural products
...
Louis, MO: Facts and Comparisons, 1991
...
A double-blind
randomized controlled trial of ginger for the prevention of postoperative nausea and vomiting
...


Page 130

Awang DVC
...
CPJ RPC 1992; (July): 309-11
...
Ginger in preventing nausea and vomiting of pregnancy: a caveat due to its thromboxane
synthetase activity and effect on testosterone binding [letter]
...

Blumenthal M
...
Austin, TX: American Botanical Council, 1998
...
A reexamination of gingerol, shogaol and zingerone, the pungent
principles of ginger
...

Fisher-Rasmussen W, Kjaer SK, Dahl C, Asping U
...
Eur J
Obstet Gynecol Reprod Biol 1990;38:19-24
...
Jamaica ginger paralysis (a peripheral polyneuritis)
...

Holtmann S, Clarke AH, Scherer H, Hohn M
...
A
comparative study with placebo and dimenhydrinate
...

Kiuchi F, Shibuya M, Sankawa U
...
Chem
Pharmacol Bull 1982;30:754-7
...
Gingerol, a novel cardiotonic agent, activates Ca 2+pumping ATPase
in skeletal and cardiac sarcoplasmic reticulum
...

Lumb AB
...
Thromb Haemost 1994;71:110-1
...
Ginger
...
New York, John Wiley and Sons, 1980; pp
...

Mowrey DB, Clayson DE
...
Lancet 1982;i:6557
...
Ginger (Zingiber officinale) in migraine headache
...

Nagabhushan M, Amonkar AJ, Bhide SV
...
Cancer Lett 1987;36:221-33
...
The active part of the [6]-gingerol molecule in mutagenesis
...

Phillips S, Ruggier R, Hutchinson SE
...

Anaesthesia 1993;48:715-7
...
Cardiotonic principles of ginger (Zingiber officinale Roscoe)
...

Srivastava KC
...
Prostagland Leukotr Med
1984;13:227-35
...
Effect of onion and ginger consumption on platelet thromboxane production in humans
...

Sharma JN, Srivastava KC, Gan EK
...

Pharmacology 1994;49:314-8
...
Digestive system problems
...

Tyler VE, Brady LR, Robbers JE
...
, Philadelphia, PA: Lea and Febiger;1981,
p
...

United States Pharmacopeial Convention (USP)
...
Botanical monograph series
...

United States Pharmacopoeia (USP)
...
18th edit
...
Rockville,MD: United
States Pharmacopoeia Convention, 1998b
...
The examination of cresyl-bearing extracts of ginger
...


Page 133

Chapter 11—
Saw Palmetto
Amy Meadows and Melanie Johns Cupp
Serenoa repens (Bartram) Small, Sabal serrulata (Michaux) Nichols, Serenoa serrulatum Schultes
(USP, 1998)
11
...
The tree grows up to 6 ft tall and has wide leaves divided into fan-shaped lobes that are
gray to blue-green in color
...

The earliest known use of saw palmetto was in the 15th century BC in Egypt to treat urethral
obstruction (Nemecz, 1998)
...
In the early 20th century it was used in conventional medicine as a mild
diuretic and as a treatment for benign prostatic hypertrophy (BPH) and chronic cystitis (Tyler, 1993)
...
Early settlers in the United States observed that animals
which ate the berries grew fat and healthy, and by the 1870s saw palmetto was purported to improve
general health, reproductive health, disposition, and body weight, and to stimulate appetite (Nemecz,
1998)
...
2 Current Promoted Uses
Saw palmetto is promoted as a treatment for BPH, to improve prostate health and urinary flow, and to
improve reproductive and sexual functioning
...
J
...
, Totowa, New Jersey

Page 134

11
...

Nature's Way® Standardized Saw Palmetto Extract contains 160 mg of saw palmetto in a soft gelcap
...

Nature's Fingerprint® Saw Palmetto contains 500 mg of saw palmetto in a capsule
...

Centrum® Saw Palmetto contains 160 mg of saw palmetto per soft gelcap
...

Celestial Seasonings® Saw Palmetto contains 160 mg of saw palmetto in a brown soft gelcap
...

Sundown® Saw Palmetto Complex contains 450 mg of saw palmetto, zinc, pygeum, and nettles in a gelcap
...

Spring Valley Saw Palmetto Extract contains 80 mg of saw palmetto and pumpkin seed oil in a soft gelcap
...

Prostata® is a preparation containing saw palmetto, zinc picolinate, pyridoxine, L-alanine, glutamic acid, Apis
mellifica pollen, silica, hydrangea extract, panax ginseng, and Pygeum africanum
...
4 Pharmacologic/Toxicologic Effects
11
...
1 Immunologic Effects
Saw palmetto is purported to stimulate immune function (Blumenthal and Riggins, 1997)
...
4
...
Genitourinary/Endocrine Effects
Saw palmetto's benefits in treatment of BPH are hypothesized to be due in part to antiandrogen effects
(Wilt et al
...
Saw palmetto is a multisite inhibitor of androgen action
...
, 1983), a liposterolic saw palmetto extract called Permixon® was shown to compete with

Page 135

a radiolabeled synthetic androgen for the cytosolic androgenic receptor of rat prostate tissue
...
, 1984)
...
, 1998)
...
, 1992)
...

Clinically, 160 mg of Permixon® twice daily was superior to placebo in a double-blind trial in 110 men
with BPH (Champault et al
...
A statistically significant (p < 0
...
Compared
to baseline, both placebo and saw palmetto were beneficial in improving nocturia (p < 0
...
001)
...

A double-blind study (Carraro et al
...
Both finasteride and
saw palmetto improved International Prostate Symptom Score and quality of life compared to baseline,
with no statistical difference between the two treatments
...
035), and residual volume was decreased more with finasteride than with
saw palmetto (p = 0
...
Finasteride decreased prostate volume more than saw palmetto (p < 0
...
001)
...
01)
...
Hypertension was the most common adverse effect, occurring in 3
...
2% of the finasteride patients
...
A drawback of this study is that no placebo group was included;
more data on the efficacy of these two drugs compared to placebo are needed
...

These results were confirmed by an in vitro study in which Permixon® 10 mcg/mL (calculated plasma
concentration achieved with therapeutic doses), did not interfere with secretion of PSA (Bayne et al
...
These results imply that PSA can continue to be used for prostate cancer screening in men taking
saw palmetto
...
, 1998) of randomized trials comparing saw palmetto to placebo or other
therapy was recently published
...

In regard to other endocrine effects, one Web site (www
...
com/Doc/Herbs/Sawpalm
...
"
11
...
3 Anti-Inflammatory Effects
Anti-inflammatory effects have been hypothesized to improve BPH symptoms (Wilt et al
...
An
acidic, lipophilic saw palmetto extract (Talso®) was shown in vitro to inhibit both the cyclooxygenase
and 5-lipoxygenase pathways, preventing the formation of inflammatory producing prostaglandins and
leukotrienes (Breu et al
...

11
...
, 1997)
...
The man
stopped taking the product after 2 wk of use because he developed jaundice and severe pruritus
...
Lab
results were as follows: bilirubin 8
...
3 × 103/mm 3, platelet count 153,000 cells/mm 3, serum protein 6
...
6 g/dL, carcinoembryonic antigen (CEA) <2 mg/µL
...
The patient was negative for antinuclear antibodies and antismooth

Page 137

muscle antibodies, but positive for antimitochondrial antibodies
...
Liver biopsy was done after 2 mo and showed parenchymal infiltrate of
neutrophils and lymphocytes that involved the portal tracts, early bridging, and mild periportal fibrosis
...
The authors postulated that the
patient's cholestasis was an extension of saw palmetto's estrogenic or antiandrogen effect
...
6 Pharmacokinetics/Toxicokinetics
Limited pharmacokinetic data are available because saw palmetto is a mixture of various compounds
(Plosker and Brogden, 1996)
...
6
...
6 mg/L of the "second component" with a highperformance liquid chromatography (HPLC) retention time of 26
...
The time to peak concentration occurred
1
...
, 1994)
...
6 µg/mL occurring 3 h after the dose (De Bernardi Di Valserra and
Tripodi, 1994)
...
6
...

11
...
3 Metabolism/Excretion
The elimination half-life of the "second component" discussed previously was 1
...
2 mg/L × h after a single oral dose of 320 mg (De
Bernardi Di Valserra et al
...
The AUC of the "second component" produced by a 640-mg rectal
dose of saw palmetto extract was 10 mg/L × h, and plasma levels were detectable up to 8 h post-dose
(De Bernardi Di Valserra and Tripodi, 1994)
...
7 Analysis of Biofluids
HPLC has been used to interpret plasma levels of the "second component" of saw palmetto (De
Bernardi Di Valserra and Tripodi, 1994; De Bernardi Di Valserra et al
...


Page 138

11
...

11
...
The berry is the only part of the
plant approved for use
...
This evaluation is based on reasonable
proof of safety and efficacy (Blumenthal, 1998)
...
Saw palmetto was
previously included in the NF (National Formulary) and the USP (United States Pharmacopeia), but
was deleted in 1950 and 1916, respectively
...
Saw palmetto was again included in the NF as an
official monograph in 1998 (Anonymous, 1998)
...
Saw palmetto
...
St
...

Bayne CW, Donnelly F, Ross M, Habib FK
...
Prostate 1999;40:232-41
...
The complete German Commission E monographs
...
Austin, TX: American Botanical Council, 1998
...
Popular herbs in the US market
...
Saw palmetto
berry
...

Breu W, Hagenlocher M, Redl K, Tittel G, Stadler F, Wagner H
...
In-vitro inhibition of
cyclooxygenase and 5-lipoxygenase metabolism
...

Briley M, Carilla E
...
Permixon, a new treatment for benign prostatic hyperplasia, acts directly
at the cytosolic androgen receptor in rat prostate [abstract]
...

Carraro J, Raynaud J, Koch G, Chisholm GD, Di Silverio F, Teillac P, et al
...
Prostate 1996;29:231-40
...
A double-blind trial of an extract of the plant Serenoa repens in
benign prostatic hyperplasia
...


Page 139

Chavez ML
...
Hosp Pharmacy 1998;33:1335-61
...
Serenoa repens capsules: a
bioequivalence study
...

De Bernardi di Valserra M, Tripodi AS
...
Arch Med Intern 1994;46:77-86
Di Silverio F, D'Eramo G, Lubrano C, Flammia GP, Sciarra A, Palma E, et al
...
Eur Urol 1992;21:309-14
...
Protracted cholestatic hepatitis after the use of Prostata
...

Nemecz G
...
US Pharm 1998 (Jan);23:97-8,100-2
...
Serenoa repens (Permixon®)
...
Drug Aging 1996;9:379-95
...
Inhibition of androgen
metabolism and binding by a liposterolic extract of "Serenoa repens B" in human foreskin fibroblasts
...

Tyler VE
...
, Binghamton, NY: Pharmaceutical Products Press, 1993
...
National Formulary, 18th edit
...

Wilt TJ, Ishani A, Stark G, MacDonald R, Lau J, Mulrow C
...
JAMA 1998;280:1604-9
...
Unless otherwise noted, the information in
this monograph refers specifically to species of the genus Panax
...
In this chapter, the term "panax ginseng"
will be used to refer to these species, and ''Siberian ginseng" will be used to refer to Eleutherococcus
senticosus
...

12
...
It grows in the
United States, Canada, and the mountainous forests of eastern Asia (Tyler et al
...
The translucent,
yellowish-brown roots are harvested when plants reach between 3 and 6 yr of age (Tyler et al
...

This herb has been used in the Orient for 5000 yr as a tonic (Chong and Oberholzer, 1988)
...
) is
a "cool" or "yin" tonic
From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products
Edited by: M
...
Cupp © Humana Press Inc
...
) is "hot" or "yang'' and is used to treat "cold" diseases (Awang, 1998)
...
This stems from the "Doctrine of Signatures" because the root is said
to resemble a man's appearance and is therefore useful to treat all of man's ailments (Anonymous,
1990)
...
Ginseng is also widely believed to be an aphrodisiac (Tyler, 1993)
...
2 Current Promoted Uses
Ginseng is promoted as a tonic capable of invigorating the user physically, mentally, and sexually
...
" Claims that ginseng can improve
athletic performance, enhance longevity, or treat toxic hepatitis are not supported by human trials
...
3 Products Available
Two commercial forms of the herb are available
...
Many
different formulations of the herb are available including capsules, gelcaps, powders, tinctures, teas,
slices to eat in salads, and whole root to chew
...
Prices vary widely based on the quantity and quality of
the ginseng root used (Kennedy, 1995)
...
Powder
capsules are cheaper but have a shelf-life of only 1 yr (Schiedermayer, 1998)
...
One of the
problems in the manufacture of ginseng is the lack of quality control and standardization (Muller and
Clauson, 1998)
...
(See Section 12
...
) The manufacturer (Pharmaton, Ridgefield, CT) claims that each Ginsana® capsule contains
100 mg of standardized, concentrated ginseng (Janetzky and Morreale, 1997)
...
, 1996)
of the Swedish Ginsana® product revealed consistency in ginsenoside content between batches
...
The capsules are
green because chlorophyll is added
...
Dosage strengths normally range between 50 mg and 300 mg of
panax ginseng extract per capsule or tablet
...
For
example, Ginkogin® is a combination of panax ginseng, ginkgo biloba, and garlic
...
These are not of the
genus Panax and do not contain ginsenosides (Tyler, 1997)
...
4 Pharmacologic/Toxicologic Effects
12
...
1 Endocrine Effects
Panax ginseng may exert hypoglycemic effects possibly by accelerating hepatic lipogenesis and
increasing glycogen storage (Yokozawa et al
...
, 1985; Sotaniemi et al
...
In a
study of 36 newly diagnosed type II diabetics, ginseng at a dose of 200 mg daily exerted a statistically
significant benefit on glycosylated hemoglobin (HbA1c) compared to 100 mg of ginseng daily or
placebo after 8 wk of therapy, and patients receiving 100 mg of ginseng had smaller mean fasting blood
glucose levels than patients taking 200 mg of ginseng or placebo (Sotaniemi et al
...
The actual
difference among the mean HbA1c in the three groups was small; the 200-mg ginseng group had a mean
glycosylated hemoglobin of 6% vs 6
...
Likewise, the
actual difference among mean fasting blood glucose in the three groups was small; the mean fasting
blood glucose was 7
...
4 mmol/L for the 200-mg ginseng
group, and 8
...
The observed differences might be
attributed to differences in body weight among the three groups
...

All the ginsenosids (saponins) so tested have shown anti-fatigue actions in mice (Kaku et al
...

This may reflect the purported "adaptogenic" action of ginseng, which can be defined as an increase in
resistance to stresses and is thought to be secondary to normalization of body processes through
regulation of the production of various hormones (Awang, 1998)
...
, 1979; Fulder, 1981), perhaps accounting for improvement in 11 quality of life
measurements in a large double-blind study using ginseng extract G115 (Caso Marasco et al
...


Page 144

Although many products containing ginseng are marketed specifically for postmenopausal women, a
recent review concluded that there is insufficient evidence that ginseng is effective for treatment of
menopausal symptoms (Schiedermayer, 1998)
...
Both extracts have affinity for progestin, glucocorticoid, and
mineralocorticoid receptors (Pearce et al
...

12
...
2 Neurologic Effects
Commercially available panax ginseng products have been reported to have stimulant effects on the
central nervous system in humans (Seigel, 1979) (See section 12
...
In animal models, ginseng extracts
have been shown to have CNS stimulant effects (Takagi et al
...
Ginsenoside Rg1 inhibits
neuronal apoptosis in vitro (Li et al
...
It has been suggested that ginseng may hold promise for the treatment of dementia
in humans (Awang, 1998; Li et al
...

12
...
3 Cardiovascular Effects
In animal studies, ginsenoside Rb1 decreases blood pressure, perhaps due to relaxation of smooth
muscle (Kaku et al
...
In humans, small studies suggest ginseng may decrease systolic blood
pressure at a dose of 4
...
, 1998), and enhance the efficacy of digoxin in class IV heart
failure (Ding et al
...
In contrast, ginsenoside Rg1 has been purported to have hypertensive effects
(Awang, 1998)
...
, 1998)
...
, 1995)
...
, 1983)
...
, 1975), but a study in
diabetic patients showed no effect on total cholesterol, low-density lipoprotein (LDL), HDL, or
triglyceride levels (Sotaniemi et al
...

12
...
4 Hematologic Effects
Panax ginseng may inhibit platelet aggregation by regulating the levels of cGMP and thromboxane A2
(Park et al
...


Page 145

12
...
5 Immunologic Effects
Red ginseng stimulates accumulation of neutrophils in a dose-dependent manner following
intraperitoneal injections in mice (Toda et al
...
Data show panax ginseng extracts are also able to
stimulate an immune response in humans
...
Both the phagocytosis index and fraction were enhanced in the ginseng groups
and intracellular killing was increased compared to the placebo group
...
, 1990)
...
, 1984)
...
4
...
These studies have been reviewed in detail elsewhere
(Xiaoguang et al
...
Prospective, placebo-controlled studies of ginseng's
ability to prevent or treat cancer are lacking
...
5 Case Reports of Toxicity Due to Commercially Available Products
In 1979 the term "ginseng abuse syndrome" (GAS) was coined as the result of a study (Siegel, 1979) of
133 people who had been using a variety of ginseng preparations for at least 1 mo
...
Fourteen patients experienced GAS, defined as hypertension,
nervousness, sleeplessness, skin eruptions, and morning diarrhea
...
The effects of ginseng on mood appeared to be dose dependent; four patients experienced
depersonalization and confusion at doses of 15 g, and depression was reported following doses >15 g
...
All of the patients experiencing GAS or
hypertension were also using caffeinated beverages
...
One subject experienced anaphylaxis
followed by confusion and hallucinations after injection of 2 mL of ginseng extract
...
One subject experienced hypotension, weakness, and tremor
when ginseng use was abruptly discontinued
...
GAS seemed

Page 146

to be found predominantly during the first year of use, possibly because by the 18-mo follow-up visit,
ginseng use had declined to an average of 1
...
Eight subjects
were still experiencing diarrhea and nervousness at 2 yr follow-up
...

Hypertension, shortness of breath, dizziness, inability to concentrate, a loud palpable fourth heart
sound, "thrusting" apical pulse, and hypertensive changes on fundal examination were reported in a 39yr-old man who had taken various ginseng products for 3 yr (Hammond and Whitworth, 1981)
...
He was advised to discontinue the ginseng
products, and 5 d later was normotensive at 140/85 mm Hg
...
No attempt was made to confirm the identity or
composition of the ginseng products
...
Infiltration of the dermis by mononuclear cells was noted
...
, 1996)
...
A 70-yr-old woman developed
swollen, tender breasts with diffuse nodularity after using a panax ginseng powder (Gin Seng) for 3 wk
...
Prolactin levels were within normal limits (Palmer et al
...

A 72-yr-old woman experienced vaginal bleeding after taking 200 mg daily of a Swiss-Austrian
geriatric formulation of ginseng (Geriatric Pharmaton, Bernardgrass, Austria) for an unspecified time
(Greenspan, 1983)
...
The patient derived a marked estrogenic effect from the product based
on microscopy of vaginal smears as well as the gross appearance of the vaginal and cervical epithelium
...
Estrone, estradiol, and estriol levels were essentially unchanged
over this time period, but the estrogenic effects on the vaginal smear coincided with ginseng use
...
They
did discover that a crude methanolic extract of the ginseng product competed with estradiol for the
estrogen and progesterone binding sites in human myometrial cytosol
...
Interestingly, these episodes of
bleeding were associated with a decrease in follicle-stimulating hormone (FSH) levels and a disordered
proliferative pattern on endometrial biopsy
...
, 1988)
...
Whether panax or Siberian
ginseng causes estrogenic effects requires further study
...
, 1990)
...
During pregnancy, the mother noted increased and thicker
hair growth on her head, face, and pubic area, and had experienced repeated premature uterine
contractions during late pregnancy
...
3 kg, had thick black pubic
hair, hair over the entire forehead, and swollen red nipples
...
She was advised to
discontinue the product when the baby was 2 wk old, and his pubic and forehead hair began to fall out
...
Weight gain was 1
...
4 kg during the next 3½ wk
...
8 kg), length (60
...
5 cm) were at or above the 97th percentile
...
Subsequent information did not confirm the
product's androgenic effects
...
No
androgenic effects were noted in rats administered the manufacturer's sample (Waller et al
...

Periploca sepium ("jia-pi") was reported previously to be mislabeled as Siberian ginseng ("wu-jia-pi"),
perhaps due to similarities in the Chinese terms for these herbs (Awang, 1991b)
...
6 Drug Interactions
A probable interaction between warfarin and a panax ginseng product has been reported (Janetzky and
Morreale, 1997)
...
Judetype mechanical aortic valve had been controlled on
warfarin with an international normalized ratio (INR) of 3
...
5–3
...
He experienced a
subtherapeutic INR of 1
...

Other medications included 30 mg of diltiazem three times

Page 148

daily, nitroglycerin as needed, and 500 mg of salsalate three times daily as needed
...
Discontinuation of ginseng
resulted in an increase in INR to 3
...

Manic-like symptoms were reported in a patient treated with phenelzine and ginseng
...
Users should also exercise
caution if ginseng is taken in combination with caffeinated beverages; as discussed in Section 12
...

Although Siberian ginseng is not of the same genus as panax ginseng, it may be confused with and
substituted for panax ginseng, and thus a discussion of drug interactions with Siberian ginseng is
warranted
...
, 1984)
...
9 and 2
...
6–2
...
He was asymptomatic for digoxin toxicity despite a level of 5
...
EKG,
potassium level, and serum creatinine level were normal
...
The product was analyzed for digoxin or digitoxin contamination, but none
was found
...
It was
hypothesized that some component of Siberian ginseng might impair digoxin elimination or interfere
with the digoxin assay
...

12
...
See also, Section 12
...

12
...
1 Absorption
β-Sitosterol is a steroid sapogenin that has been isolated from ginseng
...

After oral administration of radiolabeled ginsenoside Rg1, blood radioactivity peaked at 2
...

Bioavailability was 49% (Liu and Xiao, 1992)
...
7
...
Tissue radioactiv-

Page 149

ity was greatest in the kidney, followed by the adrenal gland, liver, lungs, spleen, pancreas, heart, testes,
and brain
...

12
...
3 Metabolism/Elimination
The blood radioactivity decreased in a triphasic manner after intravenous injection of [ 3H]ginsenoside
Rg1 to mice (Liu and Xiao, 1992)
...
Its metabolism is
complex and involves multiple hydrolysis reactions in the gastrointestinal tract
...
Details of the biotransformation of 20(S)-Rg2 and
chemical structures of the ginsenosides are available in the cited reference (Liu and Xiao, 1992)
...
, 1983a,b) suggesting that only trace amounts of ginsenosides
are excreted in the urine, low levels of ginsenoside aglycones were identified using gas
chromatography-mass spectroscopy (GC-MS) to analyze urine samples of 65 athletes claiming to have
ingested ginseng within the 10 d prior to urine collection (Cui et al
...
An aglycone (molecule
from which the sugar moiety has been removed) of ginsenosides, 20(S)-protopanaxatriol, was found at
concentrations between 2 and 35 ng/mL in approx 90% of the urine samples studied
...
This indicates that these two ginsenosides have different
pharmacokinetics
...

12
...
, 1982)
...
, 1982)
...
, 1996)
...
9 Chemical Analysis
There are over 30 ginsenosides found in Panax sp
...
The
ginsenoside content of American and Asian ginseng differs
...

American ginseng lacks Rf and Rg 2, and is low in Rb 2 and Rg 1
...
Rb1 concentrations are commonly ten times those of Rg1, and may
exceed twenty (Awang, 1998)
...

Panax ginseng identification using TLC, and determination of ginsenside Rb1 and Rg1 content using
liquid chromatography has been described in the National Formulary (USP, 1998)
...
,
1982; Sollorz, 1985; Ma et al
...
This method may be more reliable than mixed melting point
determination, elemental analysis, and TLC owing to the high molecular weight of the compounds
(Wagner et al
...
GC and GC-MS have also been used to analyze ginsenoside content of Swedish
ginseng preparations (Cui et al
...

12
...
In the United States, ginseng
is regulated as a dietary supplement
...
Diet and stomach cancer in Korea
...

Anonymous
...
Lawrence review of natural products
...
Louis, MO: Facts and Comparisons;
1990
...
Ginsana: Tonic or dud? Consumer Reports on Health 1998;10(7):2
...
The anti-stress potential of North American ginseng
...
Maternal use of ginseng and neonatal androgenization [letter]
...

Awang DVS
...
JAMA 1991b/266:363
...
Popular herbs in the U
...
market
...


Page 151

Blumenthal M
...
The complete German Commission E monographs
...

Caso Maraso A, Vargas Ruiz R, Salas Villagomez A, Begona Infante C
...
Drugs Exp Clin Res 1996;22:323-9
...
Clinical efficacy of Korean red ginseng for erectile dysfunction
...

Chong S, Oberholzer V
...

Cui J, Garle M, Bjorkhem I, Eneroth P
...
Scand J Clin Lab Invest
1996;56:151-60
...
Ginseng as a cause for Stevens-Johnson
syndrome? Lancet 1996;347:1344
...
[Effects of red ginseng on the congestive heart failure and its mechanism]
...

Fulder S
...
Am J Chin Med 1981;9:112-18
...
Ginseng and vaginal bleeding
...

Hammond TG, Whitworth JA
...
Med J Aust 1981;1:492
...
Effect of red ginseng on blood
pressure in patients with essential hypertension and white coat hypertension
...

Hiai S, Yokoyama H, Oura H
...

Endocrinol Japon 1979;26:737-40
...
Ginseng face cream and unexplained vaginal bleeding
...

Janetzky K, Morreale A
...
Am J Health Syst Pharm
1997;54:692-93
...
Interaction of ginseng with phenelzine
...

Kaku T, Miyata T, Uruno, T, Sako, I, Kinoshita A
...
Arzneim Forsch 1975;25:539-47
...
Herb of the month: ginseng
...

Kim HJ, Woo DS, Lee G, Kim JJ
...

Koren G, Randor S, Martin S, Danneman D
...
JAMA 1990;264:2866
...
Encyclopedia of common natural ingredients used in food, drugs, and cosmetics
...

Li J, Zhang X, Zhang J
...

Acta Pharmaceut Sinica 1997;32:406-10
...
Recent advances on ginseng research in China
...


Page 152

Ma YC, Zhu J, Sun L, Sain S, Kont K, Plaut-Carcasson YY
...
J Herbs Spices Med Plants
1995;3(4):41-50
...
Elevated serum digoxin levels in a pateint taking digoxin and siberian ginseng
...

Mendon PJ, Ferguson PW, Watson CF
...
J Ethnopharmacol 1984; 10:235-41
...
Top herbal products encountered in drug information requests (part 1)
...

Odani T, Tanizawa H, Takino Y
...
II
...
Chem
Pharamcol Bull 1983a;31:292-8
...
Studies on the absorption, distribution, excretion, and metabolism of
ginseng saponins
...
The absorption, distribution, excretion of ginsenoside-Rb1 in the rat
...

Oshima Y, Konno C, Hikino H
...
J Ethnopharmacol 1985;14:255-9
...
Gin Seng and mastalgia
...

Park H, Rheem M, Park K, Nam K, Park KH
...
J Ethnopharmacol 1995;49:157-62
...
Panax ginseng and Eleutherococcus senticosus extracts—in
vitro studies on binding to steroid receptors
...

Phillipson JD, Anderson LA
...

Punnonen R, Lukola A
...
Br Med J 1980;281:1110
...
Effects of drying on chemical and physical characteristics of American ginseng (Panax
quinquefolius L
...

Reynolds LB
...
) J Herbs Spices Med Plants 1998;6(2):63-9
...
Radioimmunoassay for the determination of
ginseng saponin, ginsenoside RG1
...

Scaglione F, Ferra F, Dugnan S, Falchi M, Santoro G, Fraschi F
...
Drugs Exp Clin Res 1990;16:537-42
...
Little evidence for ginseng as treatment for menopausal symptoms
...


Schon N, Engelhardt P
...

Arzneim Forsch 1960;10:491-6
...
Ginseng abuse syndrome
...
JAMA 1979;241:1614-5
...
Immunomodulatory activity of panax ginseng extract
...


Page 153

Soldati F, Sticher O
...
Planta Med 1980;38:348-57
...
Quality evaluation of ginseng roots
...

Deutch Apoth Ztg 1985;125:2052-55
...
Ginseng therapy in non-insulin-dependent diabetic patients
...

Takagi K, Saito H, Nabata H
...
Jpn J Pharmacol 1972;22:245-59
...
Induction of neutrophil accumulation by red ginseng
...

Tyler V
...

Tyler V
...
3rd edit
...

Tyler VE, Brady LR, Robbers JE
...
, Philadelphia: Lea and Febiger, 1981
...
National Formulary, 18th edit
...
9
...

Wagner H, Hikino H, Fansworth N
...
1
...

Waller DP, Martin AM, Fansworth NR, Awang DVC
...

JAMA 1992;267:692-3
...
Cancer chemopreventive and
therapeutic activities of red ginseng
...

Yamamoto M, Uemura T, Nakama S, Uemiya M, Kumagai A
...
Am J Chin Med 1983;11:96-101
...
Effect of ginseng extract on lipid and sugar metabolism
...

Yun TK
...
A
...
Nutr Rev 1996;54(11 Pt 2):S71-81
...
Lawson and Melanie Johns Cupp
13
...
Native Americans introduced the Europeans to cranberry as a
food, dye, and medicine (Tyler, 1993)
...
Cranberry has been used to prevent and treat
urinary tract infections since the 19th century (Siciliano, 1996)
...
2 Current Promoted Uses
Cranberry juice has been widely used for the prevention, treatment, and symptomatic relief of urinary
tract infections (Sobota, 1984)
...
Another
potential benefit of the use of cranberry is a decrease in the rates formation of kidney stones (Sternlieb,
1963; Zinsser et al
...
, 1973)
...
3 Products Available
Cranberry is available in a variety of forms such as fresh or frozen cranberries, cranberry juice cocktail,
other cranberry drinks, cranberry sauce, and powder in hard or soft gelatin capsules (Hughes and
Lawson, 1989; Siciliano, 1996)
...
J
...
, Totowa, New Jersey

Page 156

glucuronic acid, quinic acid, benzoic acid, ellagic acid, and vitamin C (Siciliano, 1996)
...
Pure
cranberry juice is tart like lemon juice because of the high citric and quinic acid content (Siciliano,
1996)
...
These sweetened beverages are relatively high in calories (approx
140 kcal per 8 oz serving) (Siciliano, 1996) and could cause weight gain in a patient consuming the
juice for medicinal purposes (Hughes and Lawson, 1989)
...

Cranberry sauce consisting of sweetened or gelled berries at a concentration half that of cranberry juice
cocktail is also readily available to consumers (Siciliano, 1996)
...
Hard gelatin capsules contain more crude fiber and organic acids than cranberry
juice cocktail, while the soft gelatin capsules contain soybean oil and contain only 8% of the total
organic acids found in fresh cranberries (Hughes and Lawson, 1989)
...
oz of cranberry juice cocktail (Hughes and Lawson, 1989)
...

Dosages used or recommended in clinical studies and case reports:
Prevention of urinary tract infection: 8 oz
...
cranberry juice of daily for 21 d (Papas
et al
...
twice daily (Moen, 1962)
Reduction of urinary odors: 16 oz
...

of cranberry juice daily, then increased by 1 oz
...

daily (DuGan and Cardaciotto, 1966)
Prevention of urinary stones: 1 quart of cranberry juice cocktail daily (Zinsser et al
...
of cranberry juice
four times a day for several days, then 8 oz
...
daily as a cocktail (Tyler, 1993)
Treatment of urinary tract infection: 12–32 oz
...
The recommended
dose is two to four capsules three times a day with water at meals
...
of liquids per day
...
The recommended dose is two to four capsules
three times a day preferably with meals
...
The recommended is two to
four capsules up to three times a day as needed
...
The recommended dose is one capsule every day as needed with a full
glass of water
...
It contains filtered water, high fructose corn syrup,
cranberry juice concentrate, and ascorbic acid
...
4 Pharmacologic/Toxicologic Effects
13
...
1 Antimicrobial Activity
Controversy exists on the pharmacologic mechanism of cranberry
...
From
the 1920s through the 1970s, many researchers thought that hippuric acid produced a bacteriostatic
effect by acidifying the urine (Blatherwick and Long 1923; Bodel et al
...
, 1994)
...
, 1968; Walsh, 1992)
...
, 1959)
...
, 1959)
...
0 to produce the minimum bacteriostatic hippuric acid concentration
...

More recently, however, studies have shown that the mechanism of action of cranberry is the inhibition
of bacterial adherence to mucosal surfaces (Sobota, 1984; Schmidt and Sobota, 1988; Zafriri et al
...
, 1991; Avorn et al
...
One study proposed that there are two substances in
cranberry juice cocktail, fructose and a glycoprotein, responsible for inhibiting adherence of
Escherichia coli to mucosal cells (Zafriri et al
...


Page 158

Escherichia coli is responsible for 85% of urinary tract infections (Schultz, 1984)
...
coli
express type 1 fimbrae, and most uropathogenic E
...
, 1989)
...
coli while a polymeric compound
inhibits P fimbriated E
...
, 1989)
...
coli to attach to
isolated uroepithelial cells at concentrations of 10–50 µg/mL
...

Epidemiologic data (Foxman et al
...
, 1994) support the use of cranberry juice to prevent urinary tract infections, although in the latter
study differences in baseline characteristics between study groups may have influenced the results
...
, 1997)
...
One study (Konowalchuk and
Speirs, 1978) evaluated the ability of various commercial juices and beverages to inactivate poliovirus
type I (Sabin) in vitro
...
The antiviral effect of commercial juices is thought to be due to
polyphenols, including tannins, which form complexes with viruses (Konowalchuk and Speirs, 1978)
...
4
...

13
...
3 Renal Effects
Ammoniacal fermentation, or alkalinization and decomposition of urine, is responsible for the foul odor
of urine (Kraemer, 1964)
...
The urine pH of five of six men free of urinary tract infections was also
lowered with this dose
...
Other subjective

Page 159

comments by nursing home personnel included a decrease in complaints among patients who had
experienced burning upon urination, and more frequent voiding
...
,
1968; Light et al
...
A specially prepared sweetened cranberry juice consisting of
80% juice was administered to 41 people who were randomly assigned to ingest 150, 180, 210, or 240
mL of the juice with each meal for 1 wk (Kinney and Blount, 1979)
...
Urine pH was measured by the subjects at each voiding, and a urine sample was collected
daily after the evening meal
...
The decrease was not dose related
...
The
effect of cranberry juice on urine pH persisted throughout the experimental period (i
...
, the kidney did
not compensate for changes in pH)
...

In another study of cranberry's effect on urinary pH (Schultz, 1984), two 6-oz servings of cranberry
juice daily for 20 d were able to lower urinary pH more than orange juice in eight multiple sclerosis
patients, but were unable to lower pH consistently to below 5
...

13
...

13
...

References
Anonymous
...
Lawrence review of natural products
...
Louis, MO: Facts and Comparisons,
1994
...
Reduction of bacteriuria and
pyruia after ngestion of cranberry juice
...

Blatherwick NR, Long ML
...
II
...
J Biol Chem 1923;57:815–8
...
Popular herbs in the U
...
market
...

Bodel PT, Cotran R, Kass EH
...
J Lab Clin
Med 1959;54:881–8
...
Reduction of ammoniacal urinary odors by the sustained feeding of
cranberry juice
...

Foxman B, Geiger AM, Palin K, Gillespie B, and Koopman JS
...
Epidemiology 1995;6:162–8
...
Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell
surfaces by proanthocyanidin extracts from cranberries
...

Hughes BG, Lawson LD
...
Am J Hosp Pharm
1989;46:1129
...
Effect of cranberry juice on urinary pH
...

Konowalchuk J, Speirs JI
...
Appl Environ Microbiol
1978;35:1219–20
...
Cranberry juice and the reduction of ammoniacal odor of urine
...

Light I, Gursel E, Zinnser HH
...
Effect of cranberry juice
...

Moen DV
...
Wise Med J
1962;61:282–3
...
Anti-Escherichia coli adhesion activity of
cranberry and blueberry juices [letter]
...

Papas PN, Brusch CA, Ceresia GC
...

Southwest Med J 1966;47:17–20
...
An examination of the anti-adherence activity of cranberry juice on urinary
and nonurinary bacterial isolates
...

Schultz A
...
J Comm Health Nurs 1984;1:159–69
...
Cranberry
...

Sobota AE
...
J Urol 1984;131:1013–6
...
Cranberry juice in renal disease
...

Tyler, VE
...
, Binghamton, NY: Pharmaceutical Products Press, 1993
...
Cranberry concentrate: UTI
prophylaxis [letter]
...

Walsh B
...
J ET Nurs 1992;9:110–3
...
Inhibitory activity of cranberry juice on adherence of
type I and type P fimbriated Escherichia coli toeucaryotic cells
...

Zinsser HH, Seneca H, Light I, Mayer G, Karp F, McGeoy G, Tarrasoli H
...
NY State J Med 1968;68:3001–9
...
), common borage, bee bread, common bugloss, starflower, ox's tongue, cool
tankard (Anonymous, 1992)
14
...
The plant reaches a height of 2 ft, and is
covered with coarse hairs
...

Borage has a salty flavor and smells like cucumbers
...
It has also been used in salads (Anonymous, 1992)
...

Writers from the first century AD noted that borage leaves and flowers steeped in wine dispelled
melancholy (Tyler, 1993)
...
As early as the second century
AD, borage was used to treat sore throat when mixed with honey, and is still recommended by
herbalists for this purpose (Tyler, 1993)
...
, 1981)
...
It is also purported to increase breast milk production
(Anonymous, 1992)
...
, 1981)
...
J
...
, Totowa, New Jersey

Page 162

14
...
Marketers claim deficiency of essential fatty
acids triggers fluctuations in blood glucose that lead to hunger and weight gain
...

14
...
Borage seed oil softgel, 1000 mg (240 mg
of γ-linolenic acid plus linoleic acid and 10 IU of vitamin E [d-α-tocopherol]), 1300-mg borage oil
capsules (300 mg of γ-linolenic acid, 494 mg of linoleic acid, 221 mg of oleic acid), borage oil hard
gelatin capsules (67 mg of γ-linolenic acid and 170 mg of linoleic acid), and 500-mg borage oil capsules
are available
...

14
...
,
1993; Tyler, 1993)
...

14
...
1 Anti-Inflammatory Effects
Arachidonic acid (AA), present in cell membrane phospholipids, is the precursor to eicosanoids such as
leukotrienes and prostaglandins that cause inflammation
...
, 1997); thus, GLA is hypothesized to decrease formation of inflammatory AA eicosanoid
metabolites (Leventhal et al
...
GLA is converted in vivo to dihomo-γ-linolenic acid (DGLA), the
immediate precursor to prostaglandin E1 (PGE 1), which has antiinflammatory and immunoregulatory
activity
...
, 1993)
...
, 1996)
...
, 1993)
...
, 1997)
...
, 1991)
after dietary borage oil supplementation
...
Borage oil increased the
percentage of n - 6 polyunsaturated fatty acids, decreased the percentage of n - 3 polyunsaturated fatty
acids, and increased fatty acid desaturation and elongation (Tocher et al
...
Similar results were
noted in a study using another type of fish (turbot), with a concomitant increase in PGE1 (Tocher et al
...
Turbot heart phospholipids demonstrated an increase in GLA and DGLA, and a decrease in
AA, while PGE1 content was increased in heart, kidney, and gill (Bell et al
...
These changes in
phospholipid fatty acid composition have also been demonstrated in humans
...
05) increased DGLA in polymorphonuclear neutrophil (PMN)
phospholipids and decreased PMN production of leukotriene B4 (Ziboh and Fletcher, 1992)
...
A diet
enriched with borage seed oil (23% GLA) was compared to one with safflower oil (<1% GLA) with
regard to effects on acute inflammation induced by monosodium urate crystals, subacute or chronic
inflammation caused by Freund's adjuvant in a subcutaneous air pouch, or adjuvant-induced arthritis
(Tate et al
...
Borage seed oil, but not safflower oil, decreased inflammation in all models
...

In humans, T-lymphocyte proliferation, which is involved in the pathophysiology of rheumatoid
arthritis (RA), was reduced with the administration of 2
...
, 1997)
...
, 1990), nine borage seed oil capsules daily were
administered for 12 wk to seven patients with active RA, and to seven ''normal" patients
...
In addition, the DGLA content of
the phospholipid bilayer of plasma cells, mononuclear cells, and platelets increased
...

A larger controlled study has also demonstrated the benefits of borage seed oil in RA
...
, 1993) compared four borage seed oil capsules three
times daily with cotton-

Page 164

seed oil capsule placebo RA patients (Leventhal et al
...
Each capsule contained 0
...
6 IU of vitamin E
...
4 g GLA (Boracelle capsules with oil of borage, Bio Oil
Research Ltd
...
The cottonseed oil placebo capsules contained 54%
linoleic acid, 18% oleic acid, 24% palmitic acid, and 4% other fatty acids (Bio Oil Research Ltd)
...
Patients had been taking stable doses of
nonsteroidal antiinflammatory drugs (NSAIDs) and/or 10 mg of prednisone or equivalent for at least a
month, and were maintained on these doses throughout the study
...
Patients were permitted to take
medications for other medical conditions
...
Complete blood count, including differential and platelet count, blood chemistries, urinalysis,
and rheumatoid factor were checked at wk 0 and 24, and erythrocyte sedimentation rate (SED rate) was
measured at wk 12 and 24
...
Meaningful improvement was defined
as important improvement of at least four of the following: tender joint count or score, swollen joint
count or score, physician global assessment, patient global assessment, morning stiffness, or SED rate
...
Patients treated with GLA showed significant
improvement from baseline in the joint tenderness score, joint swelling score, and platelet count, while
the placebo group did not improve
...
If only those patients who completed the study are considered
(five patients in each group dropped out), baseline data between the placebo and GLA groups did not
differ except that GLA patients had more morning stiffness and higher joint tenderness scores
...
The GLA patients who completed
the study showed significant improvement from

Page 165

baseline in number of tender joints, joint tenderness score, number of swollen joints, swollen joint
score, global assessment by physician, visual analog pain assessment, morning stiffness, and platelet
count
...
05) better than placebo in improving tender
joint count, joint tenderness score, number of swollen joints, joint swelling score, global assessment by
physician, and pain assessed by visual analog and by scaled assessment
...
No GLA patient showed deterioration
...
Adverse effects included soft stools (two GLA and one placebo patient), flatulence (one
GLA patient), belching (one GLA patient), and rash (one placebo patient)
...
4 g of GLA per day is a moderately effective adjunctive
therapy in the treatment of RA
...

14
...
2 Dermatologic Effects
Seborrheic dermatitis is associated with aberrant serum levels of essential fatty acids and the presence
of Malassezia furfur
...
, 1997)
...
Guinea pigs fed borage
oil as part of their diet had elevated levels of DGLA and its metabolite 15-HETrE in epidermal
phospholipids
...
, 1990)
...

Compared to 3% safflower oil cream or placebo cream, cream containing 3% borage oil significantly
decreased skin roughness and transepidermal water loss, and increased skin moisture in volunteers with
dry skin or surfactant-induced scaly skin (Nissen et al
...
In another study, topical borage oil had
no effect on visible signs of irritation, cutaneous blood flow, or transepidermal water loss in either
normal or surfactant (sodium lauryl sulfate)-irritated skin (Loden and Andersson, 1996)
...
, 1997)
...
4
...
, 1994) in patients with cystic fibrosis demonstrated an increase
in vital capacity after 4 wk of supplementation with 1500 mg of borage oil (330 mg of GLA) daily
...
AA, DGLA, and linoleic acid content of cholesterol esters also increased
...
4
...

14
...
5 Hematologic Effects
GLA at a dose of 5
...
, 1997)
...
4
...
, 1996)
...
4
...
Cholesterol levels and activity of β-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase were increased (Engler et al
...

A diet supplemented with GLA and eicosapentaenoic acids improved oxygen delivery by decreasing
vascular resistance and increasing cardiac index in endotoxin-induced lung injury in pigs
...
, 1995)
...
, 1997) in endotoxic rats demonstrated that in addition to
attenuation of thromboxane B2 production, production of leukotriene B4, leukotriene C 4/D 4 , and PGF 1α ,
as well as neutrophil accumulation, was attenuated
...

Cardiovascular effects have also been demonstrated in humans
...
5 mL/d for 4
wk in nine normotensive volunteers augmented

Page 167

arterial baroreflex control of vascular resistance as measured by plasma norepinephrine levels and
vasoconstrictor response to a 40 mm Hg drop in lower body pressure (Mills et al
...

Borage oil administered to male volunteers for 28 d attenuated the blood pressure, heart rate, and skin
temperature response to the Stroop color-word conflict test, and improved task performance (Mills et
al
...

14
...
Blood pressure was 120/75 mm Hg, and heart
rate was irregular at 52 beats/min
...
EKG revealed atrial fibrillation
with a slow ventricular rate with pauses of up to 1
...
Other aspects of the physical exam and laboratory investigations were
unremarkable, except a digoxin level of 3
...
5 ng/mL
...
The patient
improved with symptomatic treatment
...

14
...
DGLA is metabolized to
15-hydroxyeicosatrienoic acid (Chilton-Lopez et al
...
, 1990)
...
7 Chemical Analysis
Capillary gas chromatography has been used to analyze GLA content of evening primrose oil (Gibson
et al
...
GLA in borage seed oil has been separated using silver-ion high-performance liquid
chromatography (HPLC) with on-line atmospheric pressure chemical ionization-mass spectrometric
(APCI-MS) detection (Laasko and Voutilainen, 1996)
...
8 Regulatory Status
Borage oil is regulated as a dietary supplement in the United States
...


Page 168

References
Anonymous
...
The Lawrence review of natural products
...
Louis, MO: Facts and Comparisons,
1992
...
[Treatment of atopic dermatitis with borage seed oil (Glandol)—a time series
analytic study]
...

Bard JM, Luc G, Jude B, Bordet JC, Lacroix B, Bonte JP, et al
...
Fundam Clin Pharmacol
1997;11:143–4
...
The effect of borage oil consumption on the composition of individual
phospholipids in human platelets
...

Bell JG, Tocher DR, MacDonald FM, Sargent JR
...
Prostagland
Leukotr Essent Fatty Acids 1995;53:279–86
...
The complete German Commission E monographs
...
Austin, TX: American Botanical Council, 1998
...
[Gamma-linolenic-acid-rich borage seed oil capsules in children
with atopic dermatitis
...
Klin Padiatr 1997;209:100–4
...
[Bradycardiac atrial fibrillation after drinking herbal tea]
...

Chapkin RS, Carmichael SL
...
Lipids 1990;25:827–34
...
Metabolism of gamma
linolenic acid in human neutrophils
...

Christophe A, Robberecht E, Franckx H, DeBsets F, van de Pas M
...
Ann Nutr Metab 1994;38:40–7
...
Effectiveness of natural oils as sources of gamma-linolenic acid to
correct peripheral nerve conduction velocity abnormalities in diabetic rats: modulation by thromboxane
A2 inhibition
...

Engler MM, Karanian JW, Salem N Jr
...
Alcohol Clin Exp Res 1991;15:483–8
...
Dietary gamma-linolenic acid lowers blood pressure
and alters aortic reactivity and cholesterol metabolism in hypertension
...

Gibson RA, Lines DR, Neumann MA
...
Lipids 1992;27:82–4
...
Analysis of triacylglycerols by silver-ion high-performance liquid
chromatography-atmospheric pressure chemical ionization spectrometry
...


Page 169

Leventhal LJ, Boyce EG, Zurier RB
...
Ann
Intern Med 1993;119:867–73
...
Effect of topically applied lipids on surfactant-irritated skin
...

Mancuso P, Whelan J, DeMichele SJ, Snider CC, Guszcza JA, Karlstad MD
...
Clin Care Med 1997;25:1198–206
...
Dietary supplementation with oils rich in (n-3) and (n-6)
fatty acids influences in vivo levels of epidermal lipoxygenase products in guinea pigs
...

Mills DE, Mah M, Ward RP, Morris BL, Floras JS
...
Am J Physiol 1990;259 (6 Pt 2): R116–71
...
Select dietary fatty acids
attenuate cardiopulmonary dysfunction during acute lung injury in pigs
...

Nissen HP, Biltz H, Muggli R
...
Cosmet Toiletr 1995;110:71–3, 76
...
Cyclic vs continuous enteral feeding with omega-3
and gamma-linolenic fatty acids: effects on modulation of phospholipid fatty acids in rat lung and liver
immune cells
...

Pullman-Moar S, Laposata M, Lem D, Holman RT, Leventhal LJ, DeMarcoD, Zurier RB
...
Arthrit Rheum 1990;33:1526–33
...
Oral administration of unsaturated fatty
acids: effects on human peripheral blood T lymphocyte proliferation
...

Tate G, Mandell BF, Laposata M, Ohlinger D, Baker DG, Schumacher HR, Zurier RB
...
J Rheumatol 1989;16:729–34
...
Fatty acyl desaturation in isolated hepatocytes form Atlantic
salmon (Salmo salar): stimulation of dietary borage oil containing gamma-linolenic acid
...

Tocher DR, Bell JG, Ferndale BM, Sargent JR
...
Prostagland Leukotr Essent Fatty Acids 1997b;57:125–34
...
Lalassezia furfur in infantile seborrheic dermatitis
...

Tyler VE
...


Tyler VE, Brady LR, Robbers JE
...
, Philadelphia: Lea and Febiger, 1981
...
Dose-response effects of dietary gamma-linolenic acid-enriched oils on human
polymorphonuclear-neutrophil biosynthesis of leukotriene B4
...


Page 171

Chapter 15—
Calamus
Melanie Johns Cupp
Acorus calamus, rat root, sweet flag, sweet myrtle, sweet root, sweet sedge (Anonymous, 1996),
vekhand (Samudralwar and Garg 1996), sweet cane, sweet grass, sweet segg, cinnamon-sedge, beewort,
myrtle-flag, myrtle-grass, myrtle-sedge, sweet rush (Harding, 1972)
15
...
Calamus
is described in the Indian Ayurvedic literature (Samudralwar and Garg, 1996) and has been known
since biblical times (Tyler, 1993)
...
A rhizome infusion is
used to treat fevers and dyspepsia, while chewing the rhizome is recommended to clear the voice
(Tyler, 1993), relieve dyspepsia, aid digestion (Harding, 1972), and remove tobacco odor from the
breath (Anonymous, 1996)
...
, 1991; Sivaswamy et al
...
In the United
States, calamus was once used to flavor tooth powders, beer, bitters, and various tonics (Tyler, 1993),
while in rural Pakistan it is commonly used even today as a medicine in children (Riazuddin et al
...

From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
2 Current Promoted Uses
Calamus is not promoted commercially in the United States
...
3 Products Available
Calamus products are not widely available in the United States
...
4 Pharmacologic/Toxicologic Effects
15
...
1 Carcinogenicity
There are four varieties of Acorus calamus based on content of isoasarone ( β-asarone; cis-isoasarone),
which has been shown to cause duodenal tumors in rats (Tyler, 1993)
...
Type II is found in Europe and the oil
contains <10% isoasarone, while the oils of types III and IV contain up to 96% isoasarone
...
4
...
, 1991),
but had exhibited no mutagenic activity in a previous study (Riazuddin et al
...

Calamus oil in a dose of 0
...
, 1991)
...

15
...
3 Antimicrobial Activity
In vitro, both isomers of asarone were shown to inhibit motility of Toxocara canis larvae and to have
larvicidal activity, depending on duration of exposure (Sugimoto, 1995)
...
4
...
Cisisoasarone is thought to be the component of calamus responsible for these sedative properties
...
Motor activity decreased by 95% at the
highest dose compared to controls, and the animals became docile
...
No deaths occurred at any dose
...
Repeated vomiting occurred in dogs, cats, and monkeys during the first 4 h after
administration
...
Monoamine oxidase inhibition occurs in vitro, but at doses exceeding those
necessary for sedation in animal models (Dhalla and Bhattacharya, 1968)
...
,
1989)
...

15
...
5 Musculoskeletal Effects
(See also Section 15
...
4)
A water-soluble dried powder of an alcohol extract of the roots and rhizomes of Ascora calamus was
shown to inhibit caffeine citrate-induced contractions of frog rectus muscle, but was unable to inhibit
muscle contractions induced by acetylcholine (Panchal et al
...
Such spasmolytic effects have also
been demonstrated with the volatile oil in smooth muscle in other animal models, including isolated rat
intestine and uterus, isolated rabbit intestine and aorta, and isolated cat trachea (Maj et al
...

Calamus oil was also shown to protect guinea pigs from death due to histamine inhalation, and to
improve perfusion in rat hind legs (Maj et al
...
In contrast to the sedative effects of calamus,
isoasarone is not thought to be the component responsible for spasmolytic activity; isoasarone-free oil
from the type I plant had a pronounced spasmolytic effect, while oil from the type IV plant (isoasaronerich) has no spasmolytic effect (Anonymous, 1996)
...
4
...
, 1989)
...
4
...
6 mg/kg given enterally, and 310 mg/kg given intraperitoneally
(Belova et al
...

15
...
8 Reproductive Effects
Calamus oil vapor was able to induce sterility in male houseflies (Mathur and Saxena, 1975)
...

15
...
9 Local Anesthetic Effects
Calamus extract at concentrations of 0
...
, 1989)
...
5 Case Reports of Toxicity
Other than contact dermatitis (Mitchell and Rook, 1979), human toxicity has not been reported
...
6 Chemical Analysis
Gas chromatographic (GC) analysis of asarone has been described (Sugimoto et al
...

15
...
Despite this
ban, calamus can still be found in some herb shops in the United States
...
Calamus
...
St
...

Balachandran B, Sivaswamy SN, Sivaramakrishnan VM
...
Indian J Med Res 1991;94:378–83
...
Asarone and its biological
properties
...
A multidisciplinary overview of intoxicating snuff rituals in the western hemisphere
...
Further studies on neuropharmacological actions of acorus oil
...


Page 175

Harding AR
...
Columbus, OH: AR Harding, 1972
...
pharamcological properties of the native calamus (Acorus calamus L)
...
Spasmolytic
effect of etheric oil
...

Mathur AC, Saxena BP
...
oil
...

Menon MK, Dandiya PC
...
J Pharm Pharmacol 1967;19:170–5
...
Botanical dematology
...

Panchal GM, Venkatakrishna-Bhatt H, Doctor RB, Vajpayee S
...

Indian J Exp Biol 1989;27:561–7
...
Mutagenicity testing of some medicinal herbs
...

Samudralwar DL, Garg AN
...
Biol Trace Elem Res 1996;54:113–21
...
Morphological changes in Thermobia domestica uunder the influence of
Acorus calamus oil vapors
...

Sivaswamy SN, Balachandran B, Balanehru S, Sivaramakrishnan VM
...
Indian J Exp Biol 1991;29:730–7
...
Mobility inhibition and nematocidal
activity of asarone and related phenylpropanoids on second-stage larvae of Toxocara
...

Tyler VE
...
, Binghamton, NY: Pharmaceutical Products Press, 1993
...
divaricata Cav
...
mexicana Moric (Tyler, 1993), L
...
nitida, L
...
cuneifolia (Leonforte, 1986)
16
...
Chaparral is able to survive
the arid deserts of the United States and Mexico
...
Its bilobed leaves have a resinous feel and strong smell (Anonymous, 1993)
...
Chaparral purportedly possesses analgesic,
expectorant, emetic, diuretic, and antiinflammatory properties, and has been used in the treatment of
arthritis, colds, tuberculosis, and cancer
...
Tea made from boiled leaves has been used to treat sexually transmitted
diseases and intestinal cramps, and to stimulate urination
...
The dried powdered leaves were used as a
dusting powder for sores, and were mixed with badger oil to make an ointment used on burns to aid
new skin formation (Waller and Gisvold, 1945)
...
NDGA was used as a food antioxidant from 1945 to 1967, in
products such as lards, oils, candies, baking mixes, frozen foods, vitamins, and pharmaceuticals at
levels of 0
...
02% (Smart et al
...

From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
2 Current Promoted Uses
Based on the finding that NDGA is an antioxidant, chaparral has been promoted as an anticancer agent
(Tyler, 1993)
...

16
...
Products
available include leaves, stems, and bark in bulk to be used in brewing tea
...
Approximately 7–8 g of leaves are used per quart of water
(Smart et al
...
Capsules and tablets have also been formulated in various dosages
...
Dosages
used by patients in a case series detailing chaparral-associated hepatotoxicity and other adverse effects
(Sheikh, 1997) included 100-mg, 400-mg, 450-mg, and 480-mg capsules and 64
...

There are several on-line sources for chaparral and chaparral-containing products advertising chaparral
capsules, cut herb, herb powder, tincture, concentrated liquid for compresses, and various combination
products for colds, flu, arthritis, detoxification, immune system enhancement, and adrenal protection
...
4 Pharmacologic/Toxicologic Effects
16
...
1 Antineoplastic Activity
Antineoplastic activity was first noted in 1959 when the National Cancer Institute (NCI) received
correspondence from laypersons claiming that cancer patients were benefiting from the consumption of
chaparral tea
...
It was theorized that the antieoplastic activity of NDGA
was dependent upon the difference between the primary method of production of energy in cancer cells
vs normal cells; cancer cells were thought to more frequently utilize anaerobic glycolysis (Smart et al
...
Specifically, NDGA is a reducing substance that
maintains NAD in its reduced state (i
...
, NADH)
...
e
...
NDGA does not irreversibly inhibit the reaction, and NDGA's effect can be

Page 179

reversed in vitro by addition of NAD or pyruvate (Burk and Woods, 1963)
...
, 1968)
...
, 1969)
...
,
1994)
...
An elderly male had a
3–4 mm brown, slightly raised mole on his right cheek near the nasolabial fold that darkened and
enlarged over 1–2 yr
...
He was told that it was malignant, but that it had been
completely removed
...
It recurred a fourth time, but the patient did not seek medical care until the lesion
reached a size of 3×4 cm with small satellite lesions and a tender 5×7 cm mass in the right
submandibular area
...
A wedge biopsy of the facial lesion and a needle biopsy of the
neck mass revealed malignant melanoma and necrotic debris, respectively
...
One
month later, the patient began drinking chaparral tea prepared by steeping 7–8 g of dried leaves and
stems per quart of hot water
...
He rarely missed a dose, and
took no other medications
...
Eleven months after his initial diagnosis, he returned to the clinic
...
He
had gained approx 25 Ibs and looked healthier
...
The leaves and stems were analyzed by the College of Pharmacy and found to contain
7–8% NDGA dry weight
...
, 1969)
...
Of the melanoma patients, one experienced 95% regression

Page 180

with excision of the remaining tumor, but the other developed a new lesion after a 4-mo remission
...
The choriocarcinoma patient responded to the tea for 2 mo despite poor
response to other therapies, then relapsed (Anonymous, 1993)
...

16
...
2 Hepatotoxicity
Several cases of hepatotoxicity associated with chaparral use have been described (see Section 16
...

The mechanism of chaparral-associated hepatotoxicity is unknown
...
e
...
e
...
Proposed mechanisms of chaparral-associated hepatotoxicity include (1) inhibition of
cyclooxygenase or cytochrome P-450, (2) an immune-mediated reaction, (3) formation of a toxic
metabolite, (4) impairment of liver function by phytoestrogens found in chaparral, and (5) cholestatic
mechanisms causing impairment of bile formation or excretion
...
In addition, toxicity may be influenced by age, weight,
nutritional status, exposure to other drugs and chemicals, cumulative dose, and preparation (i
...
, tea,
dried plant parts, etc
...
, 1997)
...

Chaparral contains lignans that are similar to known estrogenic substances
...
, 1995)
...
,
1997)
...

16
...
3 Effects on the Arachidonic Acid Cascade
In a study by Salari and colleagues (1984), NDGA proved to be a potent and selective inhibitor of 5lipoxygenase (ID50 < 3×10-7 M)
...
, 1987)
...
, 1990)
...
4
...
, 1968; Goodman et al
...
, 1979) and humans (Smith et al
...
5)
...
, 1979)
...

NDGA is converted to this metabolite in the rat ileum and cecum, absorbed into the bloodstream, and
excreted by the kidney, where it is reabsorbed by the epithelial cells of the proximal convoluted tubules
...
e
...
, 1968)
...
Accumulation of the oquinone metabolite is hypothesized to increase the fragility of lysosomal membranes by lipid
peroxidation, causing autolysis, desquamation of necrotic proximal tubular epithelial cells, and
accumulation of cellular debris leading to blockage of the tubules
...
, 1979)
...
On cut section, the cysts were seen to extend to the inner
medulla
...
They
were lined with flattened or cuboidal tubular epithelial cells that were sometimes distended with
granular material
...
The
presence of a basement membrane and the structure of the cells lining the cysts supports the contention
that the cysts are of tubular origin
...
The cysts contained casts which in turn contained cells in varying stages
of degeneration
...
This acellular material stained yellow-brown with hematoxylin-phloxin-saffron
(HPS), blue-green with toluidine blue, blue-green to dark blue with Schmorl's method, and pale blue or
bright orange-red with Alcian blue-safranin
...
Cellular components were (PAS)negative, stained purple-blue with Alcian blue, blue-green with Schmorl's, and positive with the
Fontana-Masson method for argentaffin (Goodman et al
...

Focal necrosis of the proximal tubules was evident, with pale (i
...
, lighter staining) cells that contained
greatly enlarged lysosomes containing granular material and remnants of other cell organelles on
electron microscopy
...
The nucleus and other

Page 182

organelles of these pale cells were similar to those of adjacent normal proximal tubular cells, indicating
that they were probably proximal tubular cells that had lost their brush borders
...
An inflammatory interstitial reaction
was also evident, with infiltration of lymphoid cells, fibroblast proliferation, and histiocytes (Goodman
et al
...

Ether-extracted freeze-dried kidney tissue contained the o-quinone metabolite of NDGA, seen as redbrown granules
...
No free NDGA was found in the rat kidneys (Goodman et al
...

16
...
5 Carcinogenicity
Chaparral tea has been associated with cystic renal cell carcinoma
...
5
...
4
...
5
...
4
...
Insulin levels
were unchanged
...
, 1998)
...
5 Case Reports of Toxicity Due to Commercially Available Products
Several reports of chaparral-associated hepatitis have been published
...
A patient with asymptomatic elevation of liver function tests (LFTs) was mentioned in
this report, but the product taken by the patient contained pyrrolozidine alkaloids, which are known
hepatotoxins, so this patient was considered separately from the other 13
...
One had a history of drug abuse, two had a history of alcohol use, one was taking conjugated
estrogen, one was taking both diltiazem and occasional acetaminophen, and one had a history of
lovastatin use, all of which have been associated with hepatotoxicity
...
One patient also had a remote history of hepatitis C, but her
LFTs were normal until

Page 183

after she began taking chaparral
...
Chief complaints in most patients
included fatigue, right upper quadrant pain, dark urine, light stools, nausea, and diarrhea
...
Most patients had acute hepatitis characterized
by jaundice, increases in serum levels of alkaline phosphatase, alanine aminotransferase, aspartate
aminotransferase, total bilirubin, γ-glutamyltransferase, and lactate dehydrogenase
...
Five of seven patients
who underwent abdominal ultrasound had evidence of a thickened gallbladder
...
An exploratory laparotomy
was performed in one patient, revealing ascites and a nodular liver
...
Endoscopic retrograde
cholangiopancreatography (ERCP) revealed narrowed intrahepatic bile ducts in one of the two patients
in whom it was performed
...
In addition, they state that
hepatotoxic drugs or viruses might predispose patients to chaparral-associated hepatotoxicity
...
, 1994; Gordon et al
...

Two of the cases included in the review by Sheikh and colleagues were first reported by the Centers for
Disease Control (CDC) in 1992 (Anonymous, 1992)
...
Past
medical history included no unusual dietary practices, no alcohol for the past 3 yr, and no exposure to
hepatotoxins
...
Upper
abdominal ultrasound was normal
...
Serum chemistry revealed total bilirubin of
16
...
3 mg/dL), alkaline phosphatase of 133 U/L (normal is is 0–135 U/L), γglutamyltranspeptidase (GGT) of 158 U/L (normal is 0–32 U/L), aspartate aminotransferase (AST) of
1077 U/L (normal is 0–48 U/L), and lactate dehydrogenase (LDH) of 405 U/L (normal is 0–225 U/L)
...
Twenty-six days
after discontinuing the herb, his LFTs had returned to normal (Anonymous, 1992)
...
This 41-yr-old woman had con-

Page 184

sumed 150 tablets (64
...
, 1997)
...
Abdominal ultrasound and barium enema were normal
...
Liver function tests revealed normal alkaline phosphatase, total bilirubin of 30
mg/dL, AST of 3560 U/L, alanine aminotransferase (ALT) of 2790 U/L (normal is 0–53 U/L), GGT of
138 U/L, and LDH of 868 U/L
...

In a similar case also included in the Sheikh et al
...
, 1994; Sheikh et al
...
Past medical history included alcohol abuse for 4 yr
...
The patient denied a history of intravenous drug use, exposure to blood
products, use of oral contraceptives, or infectious contact
...
2
mg/d of clonidine; a multivitamin containing 400 IU of vitamin E, 1000 mg of vitamin C, 25 mg of
magnesium, and 10,000 IU of vitamin A; lecithin 15 g/d; and three capsules daily containing 150 mg of
passionflower, 100 mg of hops, and 25 mg of valerian
...
The only other potential hepatotoxin she had taken was lovastatin,
which was discontinued 2½ mo before beginning chaparral
...
Despite being normal approx 1 mo prior, LFTs were markedly elevated:
ALT was 1611 IU (normal is 0–65 IU), AST was 957 IU (normal is 0–50 IU), alkaline phosphatase
(ALP) was 265 IU (normal is 35–130 U/L), GGT was 993 IU (normal is 0–65 IU), and total bilirubin
was 11
...
4 mg/dL)
...
Hepatitis B and C, CMV, and EBV were ruled out, and autoantibody titers were
normal
...
6 g/dL, and prothrombin time (PT) and partial thromboplastin time
(PTT) increased to 13
...
2 s (normal is 20–30 s)
...
The cause of duct narrowing
could not be determined, but could be due to epithelial injury or intrahepatic cholestasis
...
Liver biopsy revealed acute inflammation with neutrophil and lymphoplasmocytic
infiltration, diffuse hepatic disarray and necrosis, focal acute pericholangitis, some ductal dilatation, and
proliferation of the bile ductules in portal and periportal areas
...
Mallory bodies were not seen on either
biopsy, ruling out alcoholic hepatitis
...
A steroid
taper was initiated, with almost complete resolution on biopsy 1 mo later
...
, 1994)
...
His symptoms began with a flulike
illness, followed by ascites and jaundice 2 wk later
...
Pertinent laboratory results included
AST of 404 IU/L (normal is < 40 IU/L), ALT of 385 U/L (normal is < 40 IU/L), ALP of 149 U/L
(normal is < 110 IU/L), bilirubin of 304 µ mol/L (normal is < 20 µmol/L), and PT of 13 s
...
His symptoms and laboratory test abnormalities resolved over the next 2 mo
after he discontinued using chaparral and alcohol, but recurred later with chaparral rechallenge
...
Physical exam also revealed icteric sclera and full abdominal flanks
...
Infectious hepatitis was ruled out based on serology results
...

Transjugular liver biopsy showed diffuse mild to moderate hepatocellular necrosis with inflammation,
portal tract expansion, mild cholestasis, and mild fibrous septation
...
Liver biopsy revealed
mild fibrous septation with some resolution of necrosis and inflammation
...
, 1995)
...
Six weeks after beginning chaparral for relief of chronic
tension headaches, she developed nausea and a flulike illness, followed by jaundice 2 wk later
...
Aspirin was her only medication
...

Laboratory results included AST of 1612 U/L, ALP of 129 U/L, and bilirubin of 166 µ mol/L, PT of 11
s, and albumin of 3
...
Hepatitis serology results were negative
...
,
1995)
...
Three weeks prior to hospital admission she
developed a flulike syndrome and increased consumption to six capsules daily
...
Past medical history was negative for liver
disease, blood transfusions, and alcohol use
...
Laboratory results were bilirubin, 12
...
1–1
...
4 mg/dL (normal is 3
...
9 s (normal
is 10
...
7 s)
...
Ultrasound and
CT scan showed a contracted gallbladder with a thickened multilaminated wall
...

Liver biopsy revealed severe acute hepatitis with areas of lobular collapse and nodular regeneration,
mixed portal inflammation, and marked bile duct proliferation
...
After suffering aspiration pneumonia, sepsis, and renal failure necessitating dialysis,
her bilirubin increased to 35
...
Despite aggressive supportive therapy,
an orthotopic liver transplantation was required 5 wk after initial admission
...
1 kg
...
Eighteen months after transplantation liver
function tests were normal and the patient was doing well (Gordon et al
...

In addition to hepatotoxicity, chaparral-associated renal cell carcinoma and cystic renal disease have
also been reported in humans
...
5
mg/dL (normal is is 0
...
1 mg/dL) was found to have bilateral renal cystic disease on ultrasound
...
Peripheral calcification with an irregular cyst wall was noted
...
Left radical nephrectomy was performed
...
A residual cyst wall at the biopsy sites
contained collections of stratified epithelial cells with clear cystoplasm and mildly enlarged
hyperchromatic irregular nuclei
...
An 8-mm cyst had a fibrotic wall with one
or two layers of atypical clear cells, similar to those

Page 187

in the two largest cysts
...

Most were glomerular and at the same stage of development
...
On postsurgical follow-up of almost 2 yr, serum creatinine stabilized at 1
...
, 1994)
...
, 1997)
...
Clinical presentation included scales, erythema, pruritus,
edema, vesicles, and papules
...
Biopsy, performed in one patient, revealed suprabasal, multiloculated blisters containing a net
of fibrin, neutrophils, eosinophils, and mononuclear cells
...
Patch test to chaparral leaves was positive in the four
patients in whom it was performed
...

In one of the cases reviewed by Sheikh and colleagues, a patient developed a generalized urticarial rash,
nausea, and abdominal pain after ingestion of chaparral, but had been taking chaparral for 1 yr, had a
history of allergies, and was also taking naproxen and ketorolac
...
, 1997)
...
6 Drug Interactions
Although drug interactions with chaparral have not been reported, NDGA is an inhibitor of CYP450
microsomal enzymes in vitro (Capdevila et al
...
, 1991)
...

16
...
It
is absorbed into the bloodstream, is filtered by the glomeruli, then reabsorbed and retained by the
proximal tubule epithelial cells

Page 188

(Grice et al
...
, 1970)
...
Free NDGA is not found in the rat
kidney, but is found in the feces (Goodman et al
...

16
...
The o-quinone metabolite gives a strong oxidation product with Schiff reagent
...
This metabolite reacts with Alcian blue, and a strong dark blue color
develops with Schmorl's ferri-ferricyanide method
...
, 1970)
...
, 1968)
...
NDGA is not
detected in the kidney using TLC
...
NDGA cannot be detected in the feces using TLC owing to interference with bile
salts (Goodman et al
...

16
...
The FDA has warned the public
about the dangers of consuming chaparral (Stone, 1992)
...

References
Agarwal R, Wang ZY, Bik DP, Mukhtar H
...
Drug Metab Dispos 1991;19:620–4
...
Cholestatic hepatitis after ingestion of
chaparral leaf: confirmation by endoscopic retrograde cholangiopan-creatography and liver biopsy
...

Anonymous
...
Morbid Mortal Wkly Rep
1992;41:812–4
...
The Lawrence review of natural products
...
Louis, MO: Facts and Comparisons, 1993
...
Chaparral-induced hepatic injury
...


Page 189

Blumenthal M
...
Austin, TX: American Botanical
Council, 1998
...
Hydrogen peroxide, catalase, glutathione peroxidase, quinones,
nordihydroguaiaretic acid, and phosphopyridine nucleotides in relation to x-ray action on cancer cells
...

Capdevila J, Gil L, Orellana M, Marnett LJ, Mason JI, Yadagiri P, Falck JR
...
Arch Biochem Biophys 1988;261:257–63
...
Nephron obstruction in nordihydroguaiaretic acid-induced renal cystic disease
...

Goodman T, Grice HC, Becking GC, Salem FA
...
Light and electron microscopic investigations
...

Gordon, D, Rosenthal G, Hart J, Sirota R, Baker A
...
The broadening spectrum of
liver injury caused by herbal medications
...

Grice HC, Becking G, Goodman T
...
Food Cosmet
Toxicol 1968;6:155–61
...
Reductive inactivation of soybean
lipoxygenase 1 by catechols: a possible mechanismfor regulation of lipoxygenase activity
...

Leonforte J
...
J Am Acad Dermatol 1986;14:202–7
...
Masoprocol (nordihydroguaiaretic acid): a
new antihyperglycemic agent isolated from the creosote bush (Larrea tridentata)
...

Obermeyer WR, Musser SM, Betz JM, Casey RE, Pohland AE, Page SW
...
Proc Soc Exp Biol
Med 1995;208:6–12
...
Inhibition of tumoral cell
respiration and growth by nordihydroguaiaretic acid
...

Robison T, Sevanian A, Forman H
...
Toxicol
Appl Pharmacol 1990;105:113–22
...
Comparative effects of indomethacin, acetylenic acids, 15-HETE,
nordihydroguaiaretic acid and BW755C on the metabolism of arachidonic acid in human leukocytes
and platelets
...

Sheikh NM, Philen RM, Love LA
...
Arch Intern Med
1997;157:913–9
...
An interesting observation on

nordihydroguaiaretic acid (NSC-4291; NDGA) and a patient with malignant melanoma—a preliminary
report
...

Smith AY, Feddersen RM, Gardner KD, Davis CJ
...
J Urol 1994;152:2089–91
...
Chaparral consumption warning
...
Rockville, MD: Food and Drug
Administration, December 10, 1992
...
The honest herbal, 3rd edit
...

Waller C, Gisvold O
...
J Am Pharm Assoc
1945;34:78–81
...
), coughwort, feuilles de tussilage, horse-hoof, huflattichblatter, kuandong hua
(Anonymous, 1996), Petasites japonicus Maxim (''fuki-no-toh") (Hirono et al
...
1 History and Traditional Uses
Coltsfoot is a perennial yellow flower that reaches heights of 30 cm
...
Coltsfoot is native to Europe, but can also be found in the northeastern and north
central United States, southern Canada, and China (Anonymous, 1996;Berry, 1996)
...
In
addition to treatment of respiratory ailments, coltsfoot has also been used to treat diarrhea, to purify the
blood, to stimulate metabolism, to cause diuresis and sweating, and topically as a wound treatment
(Blumenthal, 1998)
...

17
...

Respiratory ailments such as cough and hoarseness,
From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...

Coltsfoot is also touted as nourishment for the endocrine system, providing rejuvenation of hormones,
the adrenal system, pancreas, pituitary, thyroid, and reproductive system
...

17
...
Coltsfoot leaves can be mail-ordered via the World Wide Web as a chelated extract, capsules,
powder, or cut and sifted
...

Bronchostad ® is an instant tea made from coltsfoot leaves, which can also be used to prepare liquid and
solid extracts
...
Syrups may be prepared
by adding boiling sugar water to a coltsfoot tincture, and an external ointment can also be prepared
...
Hormone Rejuvenator ® is a capsule containing bilberry
bark, cascara sagrada, chamomile, chickweed, coltsfoot, comfrey root, dandelion root, golden seal root,
hyssop, juniper berries, licorice root, and wild cherry bark
...
Alvita Teas, Herb Pharm, and Nature's Answer are all
manufacturers that provide coltsfoot products
...
4 Pharmacologic/Toxicologic Effects
17
...
1 Respiratory Effects
Mucilage is the sole ingredient responsible for coltsfoot's pharmacologic action as a demulcent
(Salvador, 1996)
...
As a
viscous solution, often in the form of tea, mucilage creates a protective barrier over the pharynx, larynx,
and trachea
...

Components of coltsfoot have also been noted to increase the activity of epithelial cilia in the frog
esophagus, possibly giving credence to use of coltsfoot as an expectorant (Anonymous, 1996)
...
Doses ranging from 0
...
03 mg/kg were administered via the femoral vein to
anesthetized dogs
...
The effects of
tussilagone were short in duration (approx 5 min) and appeared to be centrally mediated (Li and Wang,
1988)
...
Unlike tussilagone, L-652,469 is
orally active, as demonstrated by its ability to inhibit PAF -induced rat foot edema and carrageenaninduced rat paw edema (Hwang et al
...
By virtue of these effects, coltsfoot may elicit efficacy
against certain inflammatory respiratory diseases such as asthma
...
4
...
Tussilagone was injected into the femoral vein of
anesthetized cats (0
...
5 mg/kg), dogs (0
...
3 mg/kg), and rats (0
...
The pressor
response was immediate, and blood pressure returned to normal within 6 min
...
01–0
...
There was also a dose-related decrease in the heart rate of the anesthetized dogs
...

17
...
3 Antimicrobial Effects
In vitro antibacterial activity limited to Gram-negative bacteria has been demonstrated using aqueous
leaf extracts and phenolic components of coltsfoot (Anonymous, 1996)
...
4
...
Hepatic
venoocclusive disease is characteristic of PA intoxication
...
5, but generally include endothelial edema, sclerosis and occlusion of the small vessels,
necrosis, progressive fibrosis, and eventually cirrhosis (Roulet et al
...
PAs are not hepatotoxic
themselves, but are converted

Page 194

by the liver by dehydrogenation to highly reactive, electrophilic pyrrole-like compounds capable of
binding to tissues (Mattocks, 1968)
...
, 1992)
...
, 1982)
...

Tussiglione, discussed in Sections 17
...
1 and 17
...
2, does not have the molecular features that would
predict hepatotoxicity (Li and Wang, 1988)
...
, 1985)
...
, 1985)
...
4
...
, 1976)
...
The PA senkirkine has proved to be
carcinogenic, causing nonmalignant liver cell adenomas in rats (Hirono et al
...
Proliferation of
intrahepatic bile ducts and oval cells, blood lagoons, and cirrhosis was found, even in rats that did not
develop tumors
...
, 1985)
...
, 1973)
...
, 1977)
...
One rat had metastasis of hemangioendothelial sarcoma to the lung
...
, 1985) using radiolabeled senecionine and seneciphylline, the ability of
senecionine to bind to liver DNA in female rats was four times higher than that in males, suggesting
that females are more susceptible to the carcinogenic effects of these compounds
...
, 1992); thus, the two effects are closely related, as evidenced by the hepatotoxic changes
noted in the carcinogenicity studies, and the carcinogenicity noted in the hepatotoxicity studies
...
5 Case Reports of Toxicity Due to Commercially Available Products
Death attributed to hepatic venoocclusive disease was reported in the newborn infant of a woman who
drank herbal tea throughout her pregnancy (Roulet et al
...
The 5-d-old infant was admitted to the
hospital because of jaundice, massive hepatomegaly, and ascites
...
Physical exam upon admission revealed an icteric, apathetic infant with a
distended abdomen, hard liver palpated 5 cm below the right costal margin, and moderate ascites
...
Abnormal laboratory values included aspartate aminotransferase (AST) 3725 U/L, alanine
aminotransferase (ALT) 760 U/L, fibrinogen 0
...
8–4 g/L), prothrombin time 13%
(normal is 70–140 %), plasma ammonia 133 µmol/L (normal is <100 mmol/L), serum albumin 27
...
Sodium, potassium,
urea, glucose, and blood pH values were normal
...
An open liver biopsy done at age 27
d showed marked centrilobular fibrosis, neovascularization, and iron deposition, associated with
widespread circumferential connective tissue occlusion of small and medium size hepatic veins,
strongly suggested a diagnosis of hepatic venoocclusive disease
...

Postmortem examination revealed an icteric female infant with 500 mL of yellow ascitic fluid and a
firm, green 120-g liver
...
Calcium deposits were found in areas of centrilobular
fibrosis
...
Budd-Chiari syndrome was ruled out based on the absence of
thrombosis in the large hepatic veins
...
Chemical analysis by thin-layer chromatography (TLC) revealed a concentration of 0
...
According to the manufacturer,
the tea contained 9% Tussilago farfara plus nine other plants
...
, 1995)
...

The liver was palpated 3 cm below the costal margin
...
e
...
14 mg/dL (normal is 5
...
6 mg/dL), prothrombin time 55% (normal is 80–100%),
fibrinogen 55 mg/dL (normal is 150–500 mg/dL), and total bilirubin 2
...
3–1
...
Ultrasonography revealed severe ascites and hepatomegaly with slit-like hepatic veins and
compression of the vena cava
...
Liver biopsy revealed severe distortion of
the liver cell plates by massive hemorrhagic congestion affecting zones II and III of the acinus,
extending almost into zone I in some areas
...
The diagnosis of venoocclusive disease was made, which led to
investigation of the homemade herbal tea
...
Chemical analysis of a methonolic extract of the plant leaves
revealed the presence of 0
...
The plant was
determined to be Adenostyles alliariae (Aldendost), which, like coltsfoot, contains the PA
seneciphylline
...
Assuming a fixed concentration the
herbal tea, the exposure dose was calculated to be at least 60 µg/kg/d
...
Symptoms of hepatomegaly and ascites began 1945 d
after start of tea consumption
...
The third patient continued to take the tea for an additional 16 d, against
medical advice, and ultimately died of hepatic failure, gastrointestinal hemorrhage, and portal
hypertension despite treatment with diuretics and paracentesis
...
When evaluated 77 d later, she was found to have mild
hepatomegaly only
...
The patient who later died presented with an elevated bilirubin of 55 µmol/L
(normal is < 26 µ mol/L), which increased to 402 mmol/L after 12 d
...
AST and ALT were initially elevated (52–232 U/L) in all but the fourth
patient, and decreased over time in all but the patient who died, in which they increased slightly
...
2, which increased to 1
...
Ultrasonography revealed hepatomegaly with patent hepatic and portal veins,
even in the two patients who had portal hypertension, reflecting the short duration of the disease
...
The biopsy from the patient who eventually died showed areas of intense
centrilobular sinusoidal dilatation with hemorrhage, cell atrophy, and necrosis
...
Liver biopsies from two of
the three patients who survived were similar, but congestion and liver cell changes in the centrilobular
zone were not as severe
...
Postmortem examination of the patient who died revealed a slightly enlarged liver with
"nutmeg" appearance and reverse lobulation, extensive centrilobular hemorrhagic necrosis, and scarring
around severely narrowed, sclerotic sublobular and central veins
...

The tea consumed by these four women was analyzed using spectrophotometry after reaction with
Ehrlich's reagent revealed unsaturated PAs that were determined to be senecionine and the
corresponding N-oxide in concentrations of 0
...
4 mg/g, respectively
...
Cumulative doses of these alkaloids were
calculated to be 1350 mg over 45 d for one patient, 1380 mg over 46 d for the patient who died, 570 mg
over 19 d for another patient, and 630 mg over 21 d for the patient with the mildest symptoms
...


Page 198

17
...
9
mg/kg (Li and Wang, 1988)
...
, 1979)
...
7 Pharmacokinetics/Toxicokinetics
17
...
1 Absorption
Mucilage, the component of coltsfoot responsible for its soothing effect on the throat and oral mucosa,
is not absorbed; it produces a local effect only (Tyler, 1994)
...
7
...
, 1985)
...
At 6 h postdose, on average 60
...
4% in the lung, and 3% in the kidney
...
9%, 1%, and 4
...
Data on the same order of
magnitude were obtained for seneciphylline
...
, 1982)
...
6%
in the intestines with contents, 1
...
Average values for radioactivity measured 16 h after radiolabeled
seneciphylline administration were similar
...
04% of each PA was found in the milk of lactating
mice, suggesting this would be a minor route of exposure for neonates of women drinking herbal teas
...
Likewise, senecionine intravenously administered to
fetal rats crossed the placenta and caused liver damage in the mother (Sundareson 1942)
...
7
...
4
...
4
...
, 1982) and petasitenina (Hirono et

Page 199

al
...
Pyrrole metabolites possess
chemically reactive alkylating groups that can form covalent bonds with nucleophilic groups on tissue
...
Physical and chemical properties of
PAs that promote hepatotoxicity include lipophilicity, which makes hepatic enzymes more accessible, a
structural shape that promotes C-hydroxylation rather than N-oxidation, and resistance to ester
hydrolysis (Mattocks, 1981)
...
1 and 2 carbons in the
necine ring structure of the molecule is also necessary for metabolism to the toxic metabolite (Frei et
al
...
The N-oxide metabolites are less hepatotoxic and genotoxic than their parent compounds
when administered intraperitoneally, but N-oxides formed in vivo are excreted into the bile and
transformed back into the parent compound by intestinal microorganisms (Frei et al
...
Another
metabolite is excreted in the urine as an N-acetylcysteine conjugate (Estep et al
...

Radioactivity was measured in the bile, urine, and blood after intravenous administration of
radiolabeled senecionine to rats (Estep et al
...
Bile, urine, and blood samples were collected over
7 h
...
Total excretion over 7 h
resulted in 43% of the administered radioactivity appearing in urine and 44% in bile
...
Senecionine N-oxide
represented 52% of the radioactivity in the bile and 30% of the radioactivity in the urine, accounting for
>35% of the total administered radioactivity
...
3% (males) and 11
...
An average of 3
...
These
data suggest slow elimination of the compounds from the liver, reflecting the ability of the compounds
to covalently bind to liver DNA, especially in female rats
...
8 Analysis of Biofluids/Chemical Analysis
A simple check for the presence of PAs metabolites in urine and tissues using Ehrlich reagent has been
described (Mattocks, 1968)
...
Modification of the reagent with acid is required to overcome tissue buffering activity
...
Ehrlich reagent gives a mauve color in the presence of tissue samples containing PA
metabolites
...
Because PA metabolites are highly bound to tissues, Ehrlich
reagent works for fresh tissues that have been frozen, ethanol-fixed slices, ethanolic homogenates that
are 2 wk old, and perhaps even on older tissues
...
Quantification of PAs and metabolites can be done
using spectrophotometry (Mattocks, 1968; Kumana et al
...
PAs in herbal products can also be
quantified using this method (Kumana et al
...

TLC analysis of PAs (Sharma et al
...
Seneciphylline and its N-oxide metabolite have been detected in
herbs using TLC, fast atom bombardment mass spectrometry, NMR spectrometry, gas
chromatographymass spectroscopy (GC-MS), and co-chromatography (thin-layer and gas
chromatography) (Speri et al
...
Senkirkine was detected in dried, milled flowers using GC-MS
(Hirono et al
...
Alternatively, senkirkine can be extracted from the milled buds (Koekemoer and
Warren, 1951), then its melting point, TLC, and infrared (IR) spectrum can be compared to an authentic
sample (Hirono et al
...
Boiling point, melting point, retention time (RT) for gas chromatography,
and retention factor (RF ) for TLC have been published for senecionine, seneciphylline, and senkirkine,
along with procedural details of these analyses (Chalmers et al
...

High-performance liquid chromatography (HPLC) was used to measure seneciphylline and senecionine
in rat lung, liver, and kidney (Candrian et al
...
Details of HPLC detection of these compounds
using a reversed-phase styrene-divinylbenzene resin column and Schoeffel SF-770 detector set at 220
nm have been described (Ramsdell and Buhler, 1981)
...
, 1990a)
...
9 Regulatory Status
The German Commission E recommends limiting the use of coltsfoot leaf to 4–6 wk per year
...
The fact that the concentrations of PAs are not
standardized in available coltsfoot's products presents a safety problem with its use
...
The efficacy of coltsfoot flower, herb, and root for
any indication is undocumented, and in consideration of the toxicity of the PA component, are
unapproved for use (Blumenthal, 1998)
...

References
Anonymous
...
The Lawrence review of natural products
...
Louis, MO: Facts and
Comparisons, 1996
...
Herbal products
...
Phannaceut J 1996;256:234–5
...
The complete German Commission E monographs
...

Candrian URS, Luthy J, Schlatter C
...
Chem Biol Interact 1985;54:57–69
...
Characterization of pyrrolizidine alkaloids by gas, thin-layer
and paper chromatography
...

Eastman DF, Dimenna GP, Segall HJ
...
Drug Metab Dis 1982; 10:236–40
...
N-Acetylcysteine-conjugated pyrrolizidine alkaloids,
monocrotaline and senecionine
...

Estep JE, Lame MW, Segall HJ
...
Toxicology 1990b;64:179–89
...
Structure/activity relationships of the
genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutations
and recombination in wing cells of Drosophila mealnogaster
...

Hirono I, Shimizu M, Fushimi K, Mori H, Kato K
...
, a kind of coltsfoot
...

Hirono I, Mori H, Culvenor CCJ
...
Gann
1976;67:125–9
...
Carcinogenic activity of
petasitenine, a new pyrrolizidine alkaloid isolated from Petasites japonicus Maxim
...


Hirono I, Haga M, Fujii M, Matsuura S, Matsubara N, Nakayama M et al
...
J Nati Cancer Inst 1979;63:469–71
...
L-652,469—a dual receptor
antagonist of platelet activating factor and dihydropyridines from Tussilago farfara L
...

Koekemoer MJ, Warren FL
...
VIII
...
An improved method of extraction of the senecio alkaloids
...

Kumana CR, NG M, Lin HJ, Ko W, Wu P, Todd D
...
Gut 1985;26:101–4
...
Evaluation of tussilagone: a cardiovascular-respiratory stimulant isolated from Chinese
herbal medicine
...

Mattocks AR
...
J Chromatogr
1967;27:505–8
...
Toxicity of pyrrolizidine alkaloids
...

Mattocks AR
...
Chem Biol Interact 1981;35:301–10
...
Chemistry and toxicology of the pyrrolizidine alkaloids
...

Mori H, Sugie S, Yoshimi N, Asada Y, Furuya T, Williams GM
...
Cancer Res 1985;45:3125–9
...
High-performance liquid chromatrographic analysis of pyrrolizidine
(senecio) alkaloids using a reveresed-phase styrene-divinylbenzene resin column
...

Roulet M, Laurini R, Rivier L, Calame A
...
J Pediatr 1988; 112:433–6
...
Coltsfoot
...

Schoental R
...
Nature 1970;227:401–
2
...
Thin-layer chromatography of pyrrolizidine alkaloids
...

Sperl W, Stuppner H, Gassner I, Judmaier W, Dietze 0, Vogel W
...
Eur J Pediatr
1995;154:112–6
...
An experimental study on placental permeability to cirrhogenic poisons
...

Tyler, V
...
New York: Haworth Press, 1994
...
), S
...
officinale and S
...
1 History and Traditional Uses
Comfrey is a perennial herb that has a thick root and white, hairy, branching stems (Leung, 1980)
...
Over the past 2000 yr,
people from all over the world have been using comfrey to heal their ailments
...
Around 200 AD, the Greek physician
Dioscorides praised the therapeutic uses of comfrey in his book Materia Medico, and coined the genus
name Symphytum from the Greek word syuphuo, which means "to make to grow together
...
It was during this time that comfrey received nicknames such as boneset, knitbone, and
knitback
...
Comfrey
has been used to treat respiratory problems (bronchitis, catarrh, hemoptysis, pleurisy, whooping cough),
gastrointestinal diseases (cholecystitis, colitis, dysentery, diarrhea, ulcers, hematemesis), metorrhagia,
phlebitis, and tonsillitis (USP, 1998)
...

From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
, 1998)
...

18
...
Combination products
containing comfrey for internal use are promoted for nourishing and repairing bone and muscle
...

18
...

Comfrey can be bought in bulk as dried leaf or whole root to be used in preparing teas or poultices
(Awang, 1987)
...
Combination products containing pepsin in tablets
or capsules are promoted to aid digestion, and can contain as much as 2
...
In Europe, a company called Kytta makes preparations of comfrey including poultice
paste (Kytta-Plasma®) and ointment (Kytta-Salbe®) (Bisset, 1994)
...

Bone ™ is a capsule that contains a 310 mg net wt combination of oatstraw, horsetail, comfrey, and pan
pien lien
...
BM&C ™ is a capsule that contains a 380 mg net wt combination of white oak bark, marshmallow
root, mullein herb, wormwood herb, lobelia herb, scullcap herb, comfrey root, black walnut bark, and
gravel root
...
Simply Clean® Combination/Oily Skin is a cosmetic cream that contains five hydroxy
acids, chamomile, comfrey, and aloe
...

18
...


Page 205

18
...
1 Gastrointestinal Effects
In an in vitro study using rat gastric tissue, researchers showed that an extract of 10 mg of dried
comfrey leaves (S
...
As numerous
prostaglandins have been found to protect the gastric mucosa, there may be a biologic basis for use of
comfrey as a treatment for peptic ulcers
...
4
...
However, some products are derived from Symphytum x uplandicum Nyman
(Russian comfrey) or Symphytum asperum Lepech (prickly comfrey), which appear to be more toxic
than common comfrey (Anonymous, 1998)
...

Although common comfrey does not contain echimidine, it does contain other hepatotoxic PAs
...

These PAs can cause hepatic venoocclusive disease with zonal or focal hemorrhagic hepatic necrosis,
damage to the endothelium of the central and sublobular veins, hepatocyte swelling, biliary hyperplasia,
and marked fibrosis (Abbott, 1988)
...

Several studies in rats have shown liver damage caused by comfrey
...
, 1991),
three groups of mice received different doses of PAs derived from the fresh roots and leaves of
Symphytum x uplandicum Nyman (Russian comfrey)
...
All of the rats developed dose-dependent liver
damage evident by light and electron microscopy
...

Group I rats also developed noticeable extravasation of red blood cells
...
Loss of sinusoidal lining cells and disruption of hepatocyte
cellular margins was found in both group II and group III rats
...

Another study examined the activity of various hepatic drug-metabolizing enzymes in liver
homogenates of three groups of six male Long-Evans rats fed

Page 206

a 5%, 10%, or 30% comfrey diet ad libitum for 3 wk (Garrett et al
...
The activity of aminopyrine
N-demethylase was found to be increased, but the activity of glutathione S-transferase and epoxide
hydrolase was not affected by comfrey
...

Another study involved injecting eight adult rats (four male, four female) with 50 mg/kg of comfrey
(Symphytum × uplandicum Nymann leaves, roots, and stems) derived alkaloids per week for 6 wk
(Yeong et al
...
One week after the last dose was given, the rats were killed and their livers were
examined with light and electron microscopy
...

Ultrastructural damage such as endothelial sloughing and loss of hepatocyte microvilli was evident
...
Formation of blebs is an indicator of
impending irreversible liver damage
...
Some
of these blebs occluded the sinusoidal lumina
...
These findings were not found in the two control groups
...

Some have also questioned the safety of comfrey externally
...

An animal study supports Mattock's hypothesis
...
A Swiss experiment with rats showed that 0
...
4% of a dermal
dose of 194 mg of alkaloid N-oxides/kg (extracted from the roots of Polish S
...
, 1982)
...
Of the dermally absorbed alkaloids, only a small amount was converted to the toxic free
alkaloids
...

18
...
3 Carcinogenicity/Mutagenicity
Long-term studies in animals have shown that comfrey is carcinogenic (USP, 1998)
...
Several studies involving rats have
made this correlation
...
, 1978b)
...

officinale) or dried comfrey roots (S
...
Three groups of rats consisting of 19–22 rats were fed
comfrey leaves as 0
...
A control group was fed a normal diet
...
The results also showed that the highest incidence of liver tumors occurred in those rats being
fed comfrey roots
...
Twenty rats were injected with 13
mg/kg of symphytine (a PA common in comfrey) (10% of the LD50) extracted from dried comfrey roots,
while a control group received intraperitoneal injections of 0
...
, 1978a)
...
The rats in the control group developed no liver
tumors
...

Lasiocarpine is another carcinogenic PA
...
officinale roots by thinlayer chrommatography (TLC) at a concentration of 0
...
An experiment
conducted by Northwestern University Medical School involved feeding 20 male inbred strain F-344
rats lasiocarpine at a concentration of 50 ppm over 55 wk (Rao and Reddy, 1978)
...
At the end of 59 wk, necropsies were performed on all animals
(survivors were killed along with the control animals)
...
Of the 20 experimental rats, 17 developed malignancies
...

One rat developed malignant adnexal tumor of the skin and one developed lymphoma
...

Mutagenicity has been demonstrated by many PAs using several standard tests (Mattocks, 1986)
...
4
...
However, it is important to note that the LD50 varies among the alkaloids, and because the plant
contains

Page 208

multiple alkaloids, calculations based on administration of a single alkaloid might not apply clinically
(Mattocks, 1986)
...
As an
example, the LD50 of one alkaloid, retrosine, is 34 mg/kg in male rats, but 800 mg/kg in guinea pigs
...
5 Case Reports of Toxicity Due to Commercially Available Products
In 1994, Joseph Betz, an FDA pharmacognosist, analyzed the PA content of 11 products containing
comfrey that were bought throughout the Washington, DC area
...
, 1994)
...
It is
estimated that comfrey root tea can contain up to 26 mg of alkaloid per cup (Bach, 1989)
...
,
1994)
...

A 10-yr-old British boy was diagnosed with Crohn's disease and was treated with an herbal tea
containing comfrey leaf
...

Three years later, he presented with weight loss, diarrhea, fever, abdominal pain, ascites, tender
hepatomegaly, and fatigue
...

Ascitic fluid protein concentration was 27 g/L
...
He was treated with salt restriction and spironolactone, with good response
...
, 1987)
...
Four years later, her aminotransferase
levels were documented to be twice normal
...
Liver biopsy 1 mo after admission revealed a normal lobular
structure with thickening of the terminal hepatic venules and narrowing of their lumens confirmed by
trichrome stain
...
Portal tracts
were mildly fibrotic, and a few scattered glycogenated nuclei were seen
...
A repeat liver biopsy 20 mo later
showed dense fibrosis of portal tracts with proliferating bile ductules and minimal inflammatory cells
...
Thin, fibrous septa
compressed by regenerating nodules radiated from small, occluded terminal hepatic venules
...
The bile ducts were
unremarkable
...
, 1990), a 23-yr-old man was diagnosed with venoocclusive disease
...
He
presented with a 3-mo history of flulike symptoms followed by malaise and night sweats, and a 3-wk
history of abdominal distension and peripheral edema
...
The prothrombin time (PT) ratio was 1
...

Two tricut liver biopsies on two separate occasions showed centrilobular hemorrhagic necrosis and
platelet plugging of the central and sublobular veins
...
Cellular infiltrate in the necrotic areas consisted of fibroblasts, lymphocytes, and macrophages
...
Hepatic venous wedge pressure was elevated at 30
mm Hg
...
He later died of liver failure attributed to comfrey-induced hepatic
venoocclusive disease
...

In the first published case of venoocclusive disease associated with consumption of a comfreycontaining preparation, a 49-yr-old woman presented with swelling of the abdomen and extremities that
had begun 4 mo prior
...
During hepatic
venography, a wedge pressure of 23 mm Hg and a corrected sinusoidal pressure of 17 mm Hg were
recorded, suggesting moderate portal hypertension
...
The smaller hepatic venules were seen to be nearly obliterated on films taken
during bal-

Page 210

loon distention of one of the intrahepatic venous tributaries
...
During surgery, portal pressures and postshunt preportal pressure
confirmed postsinusoidal block
...
Other food supplements taken by the patient included
vitamins C, K, E, A, and B complex; calcium, magnesium, zinc, iron, lecithin, sterotrophic adrenal
bovine extract, and approx 3 cups of chamomile tea per week
...
1 µg/kg/d pyrrolizidines from the capsules, and 0
...
45 µg/kg/d from the tea
(Ridker et al
...

Comfrey tea from a particular distributor in Britain was found to be contaminated with the
anticholinergic Atropa belladonna (deadly nightshade) (Anonymous, 1983)
...
In these case reports, belladonna was
not definitively identified as the contaminant, but the tea consumed by one patient was found to contain
atropine at a concentration of 0
...

18
...
The USP recognizes this as a possible drug interaction
and also suggests that patients on any medications avoid taking comfrey (USP, 1998)
...
7 Pharmacokinetics/Toxicokinetics
18
...
1 Absorption
Comfrey is absorbed through the skin as well as the gastrointestinal tract (Abbott, 1988)
...
1–0
...
officinale) was absorbed and was recovered in urine
within 48 h (Brauchli et al
...


Page 211

18
...
2 Distribution
The pyrrole metabolites are distributed throughout the body (Abbott, 1988)
...
Rats suckled by mothers fed lasiocarpine, a PA found in
comfrey, developed liver damage (Schoental, 1959)
...

[tansy ragwort]—not comfrey) secreted milk that contained 9
...
7 µg of a PA called jacoline (which
is not found in comfrey) per 100 mL of milk (Dickinson et al
...
The investigators measured blood
leukocyte counts, serum protein levels, serum albumin levels, and globulin content in both the calves
and the cows
...
The four cows were shown to have marked sorbitol dehydrogenase (an
indicator of liver function) levels, leukocytosis, and decreased albumin levels
...

No abnormalities were found in the calves
...

18
...
3 Metabolism/Elimination
The PAs are not toxic until they are metabolized in the liver
...
These pyrrolic metabolites either undergo hydrolysis to pyrrolic
alcohols or destroy surrounding tissues
...

In animals, the PAs are rapidly metabolized and eliminated such that they are not detectable in biofluids
more than 24 h post-ingestion (Winship, 1991)
...
8 Analysis of Biofluids
In a study (Brauchli et al
...

Details are available in the cited reference
...
, 1976)
as described by a previous investigator (Mattocks, 1967)
...
9 Chemical Analysis
HPLC (Ramsdell and Buhler, 1981), GC-MS (Betz, 1994), and TLC analyses of the PAs has been
described (Sharma et al
...

18
...
It is recommended that external poultices be applied only to intact skin, and
pregnant women should not apply or take comfrey internally without consulting a physician
...
Also, it is recommended
that the duration of administration not to exceed 4–6 wk per year
...
The
Delaney Clause of the Food, Drug and Cosmetic Act establishes no tolerance for carcinogens in foods
...

In Australia, comfrey is classified as a poison, and its sale has been restricted in several states (USP,
1998)
...
A similar situation exists in
Sweden, where comfrey products must be registered
...
In Canada, the Health Protection Branch of Health does not accept
comfrey root as an ingredient in medicinal products, and it is listed as unacceptable as a food
...

References
Anonymous
...
Available from:
www
...
com/RainForest/Canopy/4809/whatiscomfrey
...
Accessed 1998 Oct 22
...
Comfrey
...
St
...

Anonymous
...
Pharm J 1983;230:173
...
Comfrey: assessing the low-dose health risk
...

Awang DVC
...
Can Pharmaceut J 1987;120:101–4
...
Comfrey herb tea-induced hepatic veno-occlusive disease
...

Betz J, Eppley R, Taylor W, Andrzejewski D
...
J Pharmaceut Sci 1994;83:649–52
...
Herbal drugs and phytopharmaceuticals
...

Blumenthal M
...
Austin, TX: American Botanical Council, 1998
...
Pyrrolizidine alkaloids from Symphytum officinale L
...
Experientia 1982;38:1085–7
...
Milk transfer of pyrrolizidine alkaloids in cattle
...

Galizia EJ
...
Br Med J 1983;287:979
...
Consumption of poisonous plants (Senecio
jacobaea, Symphytum officinale, Pteridium aquilinum, Hypericum perforatum) by rats: chronic toxicity,
mineral metabolism, and hepatic drug-metabolizing enzymes
...

Grieve, M
...
New York, NY: Dover, 1971
...
Induction of hepatic tumors in rats by senkirkine and symphytine
...

Hirono I, Mori H, Haga M
...
J Natl Cancer Inst
1978b;61:85–9
...
Human embryotoxicity of pyrrolizidine-containing drugs
...

Johnson AE
...
Am J Vet Res 1976;37:107–10
...
Hepatic metabolism and pulmonary toxicity of monocrotaline using
isolated perfused liver and lung
...

Leung A
...
New York: John Wiley & Sons, 1980
...
Spectrophotometric determination of unsaturated pyrrolizidine alkaloids
...

Mattocks A
...
Nature 1968;217:723–8
...
Toxic pyrrolizidine alkaloids in comfrey
...

Mattocks, AR
...
Orlando, FL: Academic Press,
1986
...
High-performance liquid chromatographic analysis of pyrrolizidine (Senecio)
alkaloids using a reversed-phase styrene-divinylbenzene resin column
...

Rao MS, Reddy JK
...
Br J Cancer 1978;37:289–92
...
Hepatic venocclusive disease associated

with the consumption of pyrrolizidine-containing dietary supplements
...

Routledge PA, Spriggs TLB
...
Lancet 1989;I:963–4
...
Liver lesions in young rats suckled by mothers treated with the pyrrolizidine (Senecio)
alkaloids, lasiocarpine and retrosine
...

Sharma RK, Khajuria GS, Atal CK
...
J
Chromatogr 1965;19:433–34
...
The effect of an aqueous extract on prostaglandin synthesis by rat isolated
stomach
...

Svoboda D, Reddy J
...
Cancer Res 1972;32:908–12
...

Alternative Field Crops Manual: Comfrey
...
hort
...
edu/newcrop/articles/comfrey
...
Accessed 1998 Oct 22
...
The honest herbal, 3rd edit
...

Tyler, V
...
The therapeutic use of phytomedicinals
...

United States Pharmacopeial Convention (USP)
...
Botanical monograph series
...

Weston CF, Cooper BT, Davies JD, Levine JD
...
Br Med J 1987;295:183
...
Pharmacists and Comfrey
...

Winship KA
...
Adverse Drug React Toxicol Rev 1991;10:47-59
...
The effects of comfrey derived pyrrolizidine alkaloids on rat liver
...

Yeong ML, Swinburn B, Kennedy M, Nicholson G
...
J Gastroenterol Hepatol 1990;5:211–4
...
Hepatocyte membrane injury and bleb formation following low dose
comfrey toxicity in rats
...


Page 215

Chapter 19—
Scullcap
Jennifer Schumacher and Melanie Johns Cupp
Virginian scullcap, mad-dog scullcap, madweed (Scutellaria laterifolia); common scullcap, greater
scullcap, helmet flower, toque, hoodwort (Scutellaria galericulata); lesser scullcap (Scutellaria minor)
(Grieve, 1971), mad-dog weed (Anonymous, 1993), monkey-flower (Crellin and Philpott, 1990),
Scutellaria baicalensis Georgi (Tyler, 1993)
...
1 History and Traditional Uses
Scullcap is a perennial that grows mainly in temperate regions and tropical mountains near rivers, lakes
(Grieve, 1971), and moist woods (Anonymous, 1993)
...
Reaching about 3 ft in height, the plant
blooms from July to September and has blue, pink, purple or red flowers (Grieve, 1971; Anonymous,
1993)
...
Lawrence Van Derveer who
used it to treat rabies (Tyler, 1993); hence the common name mad-dog weed (Anonymous, 1998b)
...
Scullcap later came to be recognized as a tonic, tranquilizer, and antispasmodic, and
was therefore used as an ingredient in many ''patent medicines" for "female weakness" (Tyler, 1993)
...
Other traditional uses include epilepsy,
headache, insomnia, various other neurologic and psychiatric disorders, hypertension, fever,
rheumatism, and stress (Anonymous, 1998a)
...
J
...
, Totowa, New Jersey

Page 216

19
...
Other purported uses include
headache (Grieve, 1971) and epilepsy (Anonymous, 1998b)
...
3 Products Available
Scullcap is currently commercially available in the United States as capsules, tea, liquid extract,
tincture, and bulk root
...
The liquid extract is available in a small brown bottle containing either 1 or 2 oz; instructions
are to put 10–12 drops in a glass of water per day and drink
...
The products are not sold under a specific brand name
and are labeled as "scullcap" or "skullcap
...
John's wort
...
4 Pharmacologic/Toxicologic Effects
19
...
1 Antispasmodic Effects
A study by Pitcher in 1916 found scullcap extract to have very weak ability to inhibit the contractility of
excised guinea pig uterus, and no effect on the uterus in living animals that received what was
considered to be a normal dose (Tyler, 1993)
...
galericulata and S
...

19
...
2 Hepatotoxicity
See Section 19
...

19
...
3 Cardiovascular Effects
Neither S
...
scordiifolia was found by Kurnakov to affect blood pressure in cats or
rabbits (Tyler, 1993)
...
baicalensis was reported by Ursow in 1958 to cause a decline in
blood pressure in dogs
...


Page 217

19
...
4 Antimicrobial Activity
Scullcap has in vitro antimicrobial activity
...
Sufficient quantities of this
solution were added to Mueller Hinton Medium to yield final concentrations of 100 µg/mL, 200 µg/
mL, 400 µg/mL, 800 µg/mL, and 1600 µg/mL
...

The minimum inhibitory concentration (MIC), defined as the lowest concentration resulting in complete
absence of growth at 36 h post-incubation, was 200 µg/mL, 200 µg/mL, 800 µg/mL, 400 µg/mL, and
1600 µg/mL for each organism, respectively (Franzblau and Cross, 1986)
...

19
...
5 Anti-Inflammatory Activity
Sialic acids, which are present in cell membranes and mucous secretions, are thought to allow viruses
and other substances to enter cells
...
Elevated serum sialic acid levels have also been found in men with coronary artery
disease and type II diabetes mellitus (Pickup et al
...
It has been hypothesized that inhibition of the
enzyme sialidase, which is involved in the formation of sialic acid, could be of therapeutic importance
(Anonymous, 1993)
...
baicalensis has been studied by Japanese
researchers (Anonymous, 1993)
...
, 1989a)
...
, 1989b) demonstrated that a hot water extract of the root of Scutellaria baicalensis had
potent mouse liver sialidase inhibition
...
The flavonoids wogonin, wogonin glucuronide, baicalein,
and baicalin all demonstrated similar inhibition at higher concentrations (50–125 µg/mL); inhibitory
activity of wogonin and baicalein was more potent than that of wogonin glucuronide or baicalin at
lower concentrations (10 µg/mL)
...
, 1989a)
...
, 1989a)
...
4
...
Scutellaria baicalensis Georgi was found to decrease
tumor cell viability and ameliorate myelosuppression when used with cyclophosphamide and 5fluorouracil in both mice and rats (Razina et al
...

19
...

One report from Scotland (MacGregor et al
...

Three were taking Kalms® tablets and one woman took Neurelax ® tablets
...
None of the women had a history of drug or alcohol
abuse, but one woman drank approximately the equivalent of 120 g of alcohol per week
...
All had been in good health previously, and none had traveled
abroad, received blood or blood products, or been in contact with persons with jaundice or hepatitis
...
Save for one woman who had mild
hepatomegaly on exam, none had signs of chronic liver disease on physical exam
...
Liver biopsy revealed severe acute hepatitis with centrilobar and bridging necrosis in
one case, moderately active acute hepatitis in another, and chronic aggressive hepatitis with advanced
fibrosis in a third case (this biopsy was performed 3 mo after presentation); biopsy was unsuccessful in
the fourth case
...
3 to 1
...
In one patient,
antinuclear antibody and rheumatoid factor were tested and found to be positive
...
The
rapid onset of liver damage after beginning the herbal therapy in three of the women (ranging from 3 d
in one case to 3 wk in two cases) may suggest a hypersensitivity type reaction
...
The authors
of this case study were uncertain if the Kalms® tablets taken by their patients were the reformulated
products or the older scullcap-containing formulation
...
Because of the presence of
coingestants and questions about the ingredients in the Kalms ® tablets ingested, it is not possible to
definitively implicate scullcap as the cause of hepatotoxicity in these four cases
...
A 49-yr-old woman presented with nausea,
malaise, and a dull ache in the lower right quadrant
...
Liver biopsy revealed light inflammatory infiltration of the portal tracts
with preservation of liver architecture
...
Liver function tests
returned to normal over 6 mo
...

It was then that it was discovered that she had been taking tablets containing motherwort, kelp, wild
lettuce, scullcap, and mistletoe for several weeks before this presentation as well as prior to the previous
admission
...
Liver biopsy revealed light
inflammatory infiltrate with occasional focal necrosis, but with preservation of architecture
...
Upon rechallenge with the same herbal medicine, nausea and malaise
appeared after 10 d, and after 14 d liver biopsy showed heavy infiltration of lymphocytes and plasma
cells, considerable focal necrosis, and distortion of liver architecture
...
An increase in
serum IgG with no increase in complement concentrations was also noted
...
The
hepatotoxicity experienced by this woman was attributed to the mistletoe component of the product
because no record of toxic reactions to kelp, motherwort, or scullcap were found
...

There is currently no experimental data that document liver toxicity of scullcap (Larrey, 1997)
...
The genus Teucrium is of the same family (Lamiaceae) as scullcap but is associated with
hepatotoxicity
...
, 1992)
...
It is difficult to attribute hepatotoxicity to scullcap because it has not been reported
with products containing only scullcap
...
For example, scullcap is often
formulated with valerian (Foster, 1998)
...

19
...
, 1989b)
...
09 µ g/g (Murch et al
...

19
...
Scutellaria baicalensis can be found in the Japanese Pharmacopoeia (Anonymous,
1998b)
...
In the United States, scullcap is regulated as a dietary
supplement, and has been classified as an "Herb of Undefined Safety" by the FDA (Duke, 1985)
...
Scullcap is not listed in the German Commission E monographs
...
Herbal review: an educational service of sequential healing health services
...
sequentialhealing
...
html
...

Anonymous
...
The Lawrence review of natural products
...
Louis, MO: Facts and
Comparisons, 1993
...
Scullcap substitution
...

Anonymous
...
Compiled from Reader's Digest
"Family guide to natural medicine
...
wampole
...
htm
...

Crellin JK, Philpott J
...
Vol
...
Durham, NC: Duke University Press,
1990
...
Handbook of medicinal herbs
...

Foster, S
...
Med Herbal 1994;6(1)
...
medherb
...
htm
...

Franzblau SG, Cross C
...

Grieve M
...
New York, NY: Dover, 1971
...
Mistletoe hepatitis
...

Israel D, Youngkin EQ
...

Pharmacotherapy 1997;17:970–84
...
Hepatotoxicity of herbal remedies
...
1):47–51
...
Hepatitis after germander
(Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity
...

MacGregor FB, Abernethy VE, Dahabra S, Cobden I, Hayes PC
...
Br
Med J 1989;299:1156–7
...
Melatonin in feverfew and other medicinal plants
...

Nagai T, Miyaichi Y, Tomimori T, Yamada H
...

Biochem Biophys Res Commun 1989a;163:25–31
...
Inhibition of mouse liver sialidase by the root of Scutellaria
baicalensis
...

Phillipson JD, Anderson LA
...

Pharmaceut J 1984;233:80–2
...
Serum siliac acid
concentration and coronary heart disease in NIDDM
...

Razina TG, Udintsev SN, Prishchep TP, Iaremenko KV
...
Vopr Onkol 1987;33:80–4
...
The honest herbal, 3rd edit
...


Page 223

Chapter 20—
Licorice
Michael Newton and Melanie Johns Cupp
Glycyrrhiza glabara (L
...
uralensis, G
...
1 History and Traditional Uses
Licorice is harvested from the roots of Glycyrrhiza glabara, a 4–5 ft shrub found in subtropical climates
with rich soil (Anonymous, 1998)
...
Its use dates back thousands of
years to ancient Egyptian rituals that enabled the spirits of pharaohs to prepare a sweet drink known as
mai sus in the afterlife
...

Theophrastus, an ancient Greek botanist, referred in his writings to the ability of licorice to treat asthma
and heal wounds
...

Western herbalists recognized licorice as a remedy for "dropsy," as did Pliny, and asserted that the root
had emollient, demulcent, expectorant, and diuretic effects
...

In traditional Chinese medicine licorice was considered to benefit all organs of the body
...
2 Current Promoted Uses
Today, licorice is employed in many capacities around the world
...
J
...
, Totowa, New Jersey

Page 224

disease (Davis and Morris, 1997), sore throats, carbuncles, diarrhea due to "spleen deficiency," thirst
due to "stomach deficiency," cough due to "dry lungs," and palpitations (Blumenthal, 1997)
...
Licorice contains the natural sweetener glycyrrhizic acid (Gunnarsdottir and
Johannesson, 1997), and is used to flavor soy sauce in China and Japan (Davis and Morris, 1991)
...
Most licorice-flavored candies
and other products in the United States today actually contain anethole from the aniseed plant as a
substitute for licorice (Davis and Morris, 1991); however, licorice may still be found in some imported
confections, gums, cough mixtures and lozenges, and Belgian beers (De Klerk et al
...

20
...
One product, for example, contains licorice root and several
other "natural" substances such as shark cartilage, and is promoted to meet the complex nutritional
needs of the musculoskeletal system
...

Licorice may also be found in herbal teas
...
" The tea manufacturer also claims that their product
helps with hormonal balance and relief of premenstrual syndrome
...
4 Pharmacologic/Toxicologic Effects
20
...
1 Respiratory Effects
Licorice has often been touted as an expectorant and cough suppressant
...
, 1997)
...

20
...
2 Anti-Inflammatory Effects
Some components of licorice may have anti-inflammatory effects
...
, 1989)
...
This inflammatory model has
been used to assess the antiinflammatory activity of other substances by other investigators as well
...
Glycyrrhetinic acid itself was a less potent
antiinflammatory than its derivatives topically, and produced no antiinflammatory effect when
administered orally
...
, 1993)
...
The dihemiphthalate compounds attenuated vascular permeability
caused by histamine, PAF, and bradykinin, while glycyrrhetinic acid had little effect on paw swelling
induced by these vasoactive substances
...
These findings suggest that glycyr rhetinic acid has a different mechanism
of antiinflammatory action than its derivatives, which apparently modulate vascular permeability
...
, 1991)
...
, 1997)
...

20
...
3 Adrenocorticotropic Effects
Licorice has a well-documented mineralocorticoid-like effect
...
, 1987)
...
, 1987)
...
, 1995)
...
977)
...
For example, there is a rise in free urinary cortisol,
and a decreased urinary ratio of cortisone to cortisol metabolites in both situations (Stewart et al
...

However, the elevated urinary ratio of 5β-tetrahydrocortisol to 5α-tetrahydrocortisol that occurs with
licorice ingestion is the opposite of the finding expected in children with the syndrome of apparent
mineralocorticoid excess (Stewart et al
...

Plasma atrial natriuretic peptide levels increased in healthy volunteers who ingested 100 g of licorice
daily for 8 wk (Forslund et al
...
This effect is thought to be a physiologic response to prevent
licorice-induced fluid retention and hypertension
...
4
...
The exact mechanism of action is unknown, but it is thought to
enhance mucus secretion, increase the life span of gastric epithelial cells, inhibit back-diffusion of
hydrogen ions induced by bile, and to inhibit peptic activity (Lewis, 1974)
...
Although these adverse
effects can be ameliorated with spironolactone, the therapeutic effects are also negated (Lewis, 1974)
...
Deglycyrrhizinated licorice (DGL;
licorice from wh ich glycyrrhizin has been removed) has also been investigated as an antiulcer agent,
but results have been inconclusive (Anonymous, 1998)
...
4
...
It has been shown to protect mice exposed to a lethal dose of
influenza virus (Utsunomiya et al
...
This effect may be produced through the stimulation of
interferon-γ production by T cells (Abe et al
...
, 1997)
...

In vivo and in vitro studies have shown glycyrrhizin to have an antiviral effect on the human
immunodeficiency virus (HIV)
...

Another study (Hattori et al
...
Researchers administered 400–1600 mg/d of glycyrrhizin intravenously for periods of
at least 1 mo, for a total of six treatment courses
...
The effect of glycyrrhizin treatment on CD4 count was equivocal
...

Preliminary studies suggest that glycyrrhizin may also be effective for the treatment of other viruses
...
, 1994)
...
, 1997)
of hepatitis C patients revealed that long-term treatment with an intravenous Japanese medicine called
Stronger Neo-Minophagen (0
...
1% cysteine, and 2% glycine) was associated with a
decreased incidence of hepatocellular carcinoma and stabilization of alanine aminotransferase (ALT)
levels
...
Glycyrrhizin may also be effective in altering the
course of hepatitis B (Eisenburg, 1992)
...

The antimicrobial effects of licorice may extend beyond antiviral activity
...
, 1993)
...

Licochalcone A and C have been shown to possess activity in vitro against Gram-positive bacteria
(Haraguchi et al
...
The mechanism of this effect is hypothesized to be inhibition of oxygen
consumption and NADH oxidation in susceptible bacterial cells through inhibition of mitochondrial
NADH-cytochrome c reductase
...
5 Case Reports of Toxicity Due to Commercially Available Products
Several reports of toxicity due to licorice ingestion exist in the medical literature
...
Rhabdomyolysis, acute renal failure, pseudoaldosteronism,
pulmonary edema, hypertension, and any combination thereof have also been reported
...
, 1997), a 21-yr-old woman presented to her primary care physician with a
headache
...
Examination was normal except for an
elevated blood pressure of 190/120 mm Hg
...
Her blood pressure remained elevated and did not return to normal even after
treatment with a combination of atenolol, lisinopril, hydrochlorothiazide, and amlodipine
...
Two weeks later her blood pressure was 180/110 mm Hg, and plasma
concentrations of sodium, potassium, and bicarbonate were 143 mmol/L (normal is 136–146 mmol/L),
2
...
8–5 mmol/L), and 35
...
Plasma renin
activity was 0
...
96–3
...
After a more thorough history, she was found to have been using two packets of Stimorol
Sugar Free ® (Warner Lambert Confectionery) chewing gum per day
...
Based on this information, her daily intake of
glycyrrhizinic acid was approx 120 mg
...
3 mmol/L
...
2 mmol/L
...
Other clinical findings included blood
pressure of 140/80 mm Hg, pitting edema, and plasma bicarbonate concentration of 30
...
One
week after stopping chlorothiazide and starting 600 mg of oral potassium chloride three times daily, her
sodium, potassium, and bicarbonate levels were still abnormal at 146 mmol/L, 2
...
One week later, the electrolyte abnormalities persisted, with a plasma potassium
level of 1
...
She was admitted to the
hospital for evaluation and intravenous potassium chloride replacement
...
036 ng/(L×s) (normal is 1
...
32 ng/[L ×s]), plasma aldosterone
level of 80 pmol/L, and daily sodium excretion of 57 mmol
...
It was found that she had been using three packets of BenBits Cool
Mint ® chewing gum daily, which contained 160 mg of licorice (10% glycyrrhizinic acid) in each 16-g
packet
...
Three weeks later, her blood pressure had fallen to 110/80 mm Hg,
her potassium concentration had risen to 4
...
, 1997)
...
, 1987)
...
A family member witnessed each episode
...
They were independent of posture, and did
not resemble seizures
...
On admission, her serum potassium level was 3
...
Serum chloride, bicarbonate, creatinine, and calcium were normal, and blood pressure was
140/90 mm Hg
...
Soon after electrocardiographic monitoring
leads were attached, she developed a characteristic torsades de pointes rhythm
...
She was treated with 75 mg of lidocaine, and she converted
to normal sinus rhythm
...
7 mmol/L with intravenous and oral supplementation
...
Because the Chinese remedy she had been taking
contained glycyrrhizic acid, it was implicated as the cause of her tongue discoloration, hypokalemia,
and subsequent torsades
...

Another case report (Brayley and Jones, 1994) cites life-threatening hypokalemia due to excessive
licorice ingestion
...
This patient had
increased her licorice candy consumption over the past month from 300 g to 600 g/d in the month
before admission
...
She was dehydrated, had a
serum potassium level of 0
...
8–4
...
Vital signs included a pulse of 92 beats/min, blood pressure of 125/80
mm Hg, temperature 36°C, and respiratory rate 24 breaths/min
...
Her ECG showed marked S–T segment depression and a
prolonged Q–T interval consistent with hypokalemia
...
Muscle
weakness resolved, and she was discharged from the hospital
...
1
mmol/L after she stopped taking both licorice and furosemide
...
In one atypical case (Saito et al
...
The man
had been taking 280 mg of glycyrrhizin per day for the last 7 yr, and had a history of hypertension
...
9 mEq/L with metabolic alkalosis, and hyporeninemic hypoaldosteronism
...
During the hospital
course, blood urea nitrogen (BUN) rose from 20
...
3 mg/dL to 6
...
Lactic dehydrogenase (LDH) and creatine phosphokinase (CPK) were also
markedly elevated
...

In another case (Farese et al
...
He had had hypertension for
4 yr, and blood pressure had been difficult to control over the past year
...
Nine months prior to evaluation,
treatment of a thiazide diuretic had resulted in hypokalemia (plasma potassium, 1
...
He required 20 mmol of potassium chloride three times daily, 240 mg of verapamil
daily, and 25 mg of spironolactone four times daily for blood pressure control and normalization of
plasma potassium
...
History revealed that for the past 4–5 yr, he had been eating 60–100 g daily of a licorice candy
(Panda, Vaajakoski, Finland; 0
...
Upon admission, physical exam revealed a thin gentleman with a blood pressure of 124/63
mm Hg
...
7 mmol/L
...
During this time, his dietary sodium
and potassium were held constant, and verapamil was continued
...
Plama renin activity, plasma
aldosterone, and urinary aldosterone were elevated upon admission, but fell while he was taking
licorice
...
Urinary glycyrrhetinic acid was detected for the first 3 d after
licorice discontinuation, but was undetectable 15 d later
...
These findings are in agreement with those
of Stewart and colleagues, described in Section 20
...
3
...
6 Pharmacokinetics/Toxicokinetics
20
...
1 Absorption
Glycyrrhizin (glycyrrhizic acid) is biotransformed in the large intestine to the active glycyrrhetinic acid
(glycyrrhetic acid) by the glucuronidase activity of anaerobic bacteria in the large intestine (Hattori et
al
...
Absorption is independent of dose (Krahenbuhl et al
...
In one human
study, the mean Cmax of glycyrrhetic acid after ingestion of 200 mg of glycyrrhizic acid in licorice was
794 ng/mL (range 466–1636 mg/mL), occurring at a mean Tmax of 13 h (range 8–30 h) (Gunnarsdottir
and Johannesson, 1997)
...
6
...
, 1992)
...
After oral administration of 500 mg, 1000 mg, and 1500 mg of glycyrrhetinic acid,
volume of distribution was calculated to be 2300 mL/kg, 3100 mL/kg, and 3800 mL/kg, respectively
(Krahenbuhl et al
...

20
...
3 Metabolism/Elimination
The elimination half-life of glycyrrhizic acid after intravenous administration is 3
...
, 1992)
...
, 1983; Hattori et al
...
, 1994b)
...
5 h after a dose of 100 mg, and 38
...
The terminal half-life could not be calculated after a dose of 500 mg
...
, 1994b)
...
Human
studies suggest that enterohepatic recirculation occurs (Krahenbuhl et al
...
6
...
, 1963), enzyme immunoassay (Kanaoka et al
...
, 1988b), and gas chromatography-selected ion monitoring (Itoh et
al
...
Most pharmacokinetic studies have been performed using HPLC; thus, Krahenbuhl and
colleagues have written a review of HPLC methods of bioanalysis of glycyrrhizin and glycyrrhetinic
acid
...
These extracts can be used directly for
HPLC
...
Extraction using a combination of ion-pairing with organic solvent
extraction or with solid-phase extraction using C 18 columns is more time consuming than direct
solvent extraction, but recovery is in excess of 90% (Krahenbuhl et al
...
The latter technique has
been described for detection in plasma using commercially available 18-β-glycyrrhetinic acid as the
internal standard and the use of a Bond Elut C2 (ethy1) extraction column to minimize the amount of
organic solvent required (Russel et al
...

A micellar electrokinetic chromatographic technique for determining glycyrrhizin and glycyrrhetinic
acid in human plasma and urine has limits of detection of glycyrrhizin in urine and plasma of 1
...
8 µg/mL, respectively, and limits of 2 µg/mL and 1 µg/mL for glycyrrhetinic acid in urine
and plasma (Wang et al
...
In contrast, an HPLC technique has been described with a limit of
detection of both compounds in plasma of 0
...

20
...
They also recommend that treatment not exceed 6 wk because of
the known side effects of licorice
...
Patients prone to potassium deficiency are also advised
not use licorice
...
It is Generally
Recognized as Safe (GRAS) (Blumenthal, 1997), a designation that refers only to its use as a food
additive
...
Interferon induction by glycyrrhizin and glycyrrhetinic acid in mice
...

Akamatsu H, Komura J, Asada Y, Niwa Y
...
Planta Med 1991;57:119–
21
...
Licorice
...
St
...

Arase Y, Ikeda K, Murashima N, Chayama K, Tsubota A, Koida I, et al
...
Cancer 1987;79:1494–500
...
Antiviral activity of glycyrrhizin against varicella-zoster virus in vitro
...

Blumenthal, M
...
S
...
Licorice root
...

Blumenthal M
...
The complete German Commission E monographs
...

Brayley J, Jones J
...
Am J
Psychiatry 1994;151:617–8
...
Torsades de pointes precipitated by a Chinese herbal
remedy
...

Cantelli-Forti G, Maffei F, Hrelia F, Bugamelli F, Bernandi P, D'Intino P, et al
...
Environ Health Perspect 1994;102(Suppl 9):65–8
...
Licochalcone A, a novel
antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania
...

Davis EA, Morris DJ
...
Mol
Cell Endocrinol 1991;78:1–6
...
Improvement of selectivity and sensitivity by column switching in the
determination of glycyrrhizin and glycyrrhetic acid in human plasma by highperformance liquid
chromatography
...

De Klerk GJ, Nieuwenhuis MG, Beutler JJ
...
Br Med J 1997;314:731–2
...
Treatment of chronic hepatitis B
...
Fortschr Med 1992;110:395–8
...
Effect of eating liquorice on the reninangiotensin
aldosterone axis in normal subjects
...


Farese RV, Biglieri EG, Shackleton CHL, Irony I, Gomez-Fontes R
...
New Engl J Med 1991;325:1223–7
...
Effects of licorice on plasma atrial natriuretic peptide
in healthy volunteers
...

Gunnarsdottir S, Johannesson T
...
Pharmacol Toxicol 1997;81:300–2
...
Mode of antibacterial action of
tertrochalcones from Glycyrrhiza inflata
...

Hattori M, Sakamoto T, Kobas K, Namba T
...

Planta Med 1983;48:38–42
...
Preliminary evidence for
inhibitory effect of glycyrrhizin on HIV replication in patients with AIDS
...

Inoue H, Moir T, Shibata S, Koshihara Y
...
Br J Pharmacol 1989;96:204–10
...
Inhibition of rat acute inflammatory paw oedema
by dihemiphthalate of glycyrrhetinic acid derivatives: comparison with glycyrrhetinic acid
...

Itoh M, Asakawa N, Hashimoto Y, Ishibashi M, Miyazaki H
...
Yakugaku Zasshi 1985;105:1150–4
...
Studies on the enzyme immunoassay of bioactive constituents contained in oriental medicinal drugs
...
Enzyme immunoassay of glycyrretic acid
...

Kanaoka M, Yano S, Kato H
...
Chem Pharmaceut Bull 1985b;36:3264–
70
...
3-Monoglucuronyl-glycyrrhetinic acid is a major
metabolite that causes licorice-induced pseudoaldosteronism
...

Krahenbuhl S, Hasler F, Frey BM, Frey FJ, Brenneisen R, Krapf R
...
J Clin Endocrinol Metab 1994a;78:581–5
...
Analysis and pharmacokinetics of glycyrrhizic acid and
glycyrrhetinic acid in humans and experimental animals
...

Kroes BH, Beukelman CJ, Van den Berg AJJ, Wolbink GJ, Van Dijk H, Labadie RP
...
Immunology 1997;90:115–20
...
Carbenoxolone sodium in the treatment of peptic ulcer
...

Nakashima H, Matsui T
...
Jpn
J Cancer Res 1987;11:225–61
...
Effect of glycyrrhizin in children with liver dysfunction associated
with cytomegalovirus infection
...


Parke DV, Poilock S, Williams RT
...
J Pharm
Pharmacol 1963;15:500–6
...
Solid-phase extraction of I 8beta-glycyrretinic acid from
plasma and subsequent analysis by high-performance liquid chromatography
...

Saito T, Tsuboi Y, Fujisawa G, Sakuma N, Honda K, Okada K, et al
...
Nippon Jinzo
Gakkai Shi 1994;36:1308–14
...
Mineralocorticoid
acitivity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age
...

Utsunomiya T, Kobayashi M, Pollard RB, Suzuki F
...
Antimicrob
Agent Chemother 1997;41:551–5
...
Determination of glycyrrhizic acid and 18-beta-glycyrrhetinic acid in
biological fluids by micellar electrokinetic chromatography
...

Yamamura Y, Kawakami J, Santa T, Kotaki H, Uchino K, Sawada Y, et al
...
J
Pharmaceut Sci 1982;81:1042–1046
...
Heather Knight-Trent and Melanie Johns Cupp
Phytolacca americana, P
...
rigida, American night shade, coakum, crowberry, pokeberry,
inkberry, pigeonberry, garget, poke, red ink plant, cancer jalap, cancer root, chongras, and scoke
(Anonymous, 1991)
21
...
It is a large perennial herb reaching heights of up to 12 ft
(Macht, 1937)
...
Stems vary in color
from green to red or purple (Hardin and Arena, 1974) and can resemble that of horseradish, resulting in
accidental poisoning (Macht, 1937)
...
The purple
berries are round and about ½ in
...
Pokeweed has various traditional uses from medicinal to
industrial
...
Additional
medicinal uses included treatment of various skin diseases, conjunctivitis, syphilis, cancer, parasitic
infestations of the scalp, chronic rheumatism, ringworm (Macht, 1937), dyspepsia, swollen glands,
scabies, ulcers (Tyler, 1993), edema, dysmenorrhea, mumps, and tonsillitis (Anonymous, 1991)
...
The
berries have been cooked in pies without harm, and the Europeans used their juice as a dye for wine
(Macht, 1937)
...
J
...
, Totowa, New Jersey

Page 238

1979)
...

21
...
Pokeroot and pokeberries
are commercially available as powder, capsules, and cut pieces
...

21
...
3
...
Three lectins (PL-A, PL-B, and PL-C) were purified from the pokeweed root
...
PL-B's hemagglutinating and mitogenic performance are greater
than those of PL-A and PL-C (Kino et al
...
Investigators have also linked pokeweed antiviral
protein to murine monoclonal antibodies for the treatment of B-lineage acute lymphoblastic leukemia
(ALL) (Myers et al
...
The mechanism of action involves inactivation of ribosomes by enzymatic
cleavage of a single adenine from the 3' terminus of all large ribosomal RNAs
...

21
...
2 Anti-Inflammatory Activity (see also Section 21
...
, 1978)
...
3
...
,
1995)
...
, 1986)
...
, 1986; Hamilton et al
...
Of note, however, is the observation that pokeroot evaporated fluid extract administered
intravenously to cats produced circulatory depression at a dose of 1 mL, and at 4 mL "paralyzed … the
heart" (Macht, 1937)
...
3
...
4)
Musculoskeletal effects of pokeweed include muscle weakness and spasms (French, 1900; Hardin and
Arena, 1974; Jaeckle and Freeman, 1981)
...
3
...
4)
Nausea, vomiting, watery and bloody diarrhea, abdominal pain with cramping, and hematemesis were
associated with ingestion of pokeroot tea (Lewis and Smith, 1979)
...
These effects were attributed to a nonspecific irritant effect, rather than to a central
effect on the vomiting center
...
3
...
Intravenous administration of 4 mL of an evaporated fluid extract of the
root caused respiratory arrest in cats (Macht, 1937)
...
3
...

21
...
8 Hematologic Effects
Extracts of whole ripe and unripe berries, seed, pulp, root, leaf, and stem produce erythrocyte
agglutination and leukocyte mitosis (Farnes et al
...
A glycoprotein known as pokeweed mitogen
is responsible for leukocyte mitosis, and in pokeweed poisonings, plasmacytosis variable in onset and
lasting 2 mo or longer is seen (Barker et al
...
, 1986)
...
4 Case Reports of Toxicity
Clinical clues that a patient has ingested pokeweed include purple stains from pokeberry juice on the
hands and face, lymphocytosis caused by pokeweed mitogens (lectins), and foamy diarrhea caused by
glycoside (triterpenoid) saponins, or phytolaccosides, that cause a sudsing effect on the colon contents
(Roberge et al
...
The phytolaccosides are also the components responsible for emesis and diarrhea
associated with pokeweed ingestion (Anonymous, 1981; Roberge et al
...
Although all parts of the
pokeweed

Page 240

plant should be considered toxic, the root is generally thought to be the most toxic part
...
Ripe pokeberries are the least toxic part of the plant, but as few as 10 ripe berries can lead to
toxicity in children
...
The following case reports illustrate the
clinical course of pokeweed poisoning
...
Thirty minutes later she experienced nausea, vomiting, abdominal cramping and
pain, and watery diarrhea
...
She was hypotensive and tachycardiac
...
The condition stabilized within a day of presentation
...
, 1995)
...
Hematocrit and platelets were normal
...
Within 15 min of promethazine
administration vomiting stopped, and 1 h later, the Mobitz type I block had disappeared, and a first
degree AV block remained
...

Twenty (43%) of 46 campers who ate a salad prepared from young pokeweed leaves that had been
boiled, drained, and reboiled experienced nausea, stomach cramps, vomiting, headache, dizziness,
burning in the stomach or mouth, and diarrhea (Anonymous, 1981)
...
Symptoms began 30 min to 5 h (mean 3 h) after
ingestion of the salad, and lasted from 1 to 48 h (mean 24 h)
...

A 68-yr-old man drank pokeweed tea as a treatment for constipation
...
He became unconscious for 10 or 15 min
...
After arrival at the hospital his blood pressure increased from
74/54 mm Hg to 120/80 mm Hg over the course of an hour
...
Physical exam revealed generalized
weakness and a broad-based gait
...

A 65-yr-old Laotian woman arrived at the hospital with complaints of crampy abdominal pain,
vomiting, profuse watery diarrhea, and generalized weakness after chewing on pokeroot that she found
in her backyard (Roberge et al
...
Although she had used this remedy in the past for relief of sore
throat and cough, in this instance she failed to boil the root before consumption
...
Hematocrit was 54%, and WBC count was 15,400/mm 3 with 37 PMNs, 51 band forms, and
8 metamyelocytes
...
The patient was
admitted to the ICU with supplemental oxygen by nasal cannula and IV fluid challenge of 500 mL of
normal saline solution over 1 h
...
She was discharged in good condition after 7 d
...
Cecil French D
...
S
...
He consumed the pokeroot at 1:00 PM, at dinner, and promptly spit it out when he
experienced a burning sensation and bitter taste
...
" At 2:30 PM he experienced a dry, burning sensation in his throat, and inspection
of his pharynx with the aid of a mirror revealed erythema
...
He
then experienced a "warm" sensation in his stomach, followed by severe abdominal cramps and
retching, with six or seven occurrences of vomiting
...
By 3:15 PM vomiting and gastralgia had become
very severe, especially with movement, and he experienced vertigo and almost complete loss of vision
...
At 3:30 PM a doctor examined Dr
...
The physician
administered one half a grain of morphine sulfate and one-fiftieth of a grain of atropine subcutaneously
...
The physician
took Dr
...
He was sent home 2 h later where he experienced vomiting every hour
...
He experienced diarrhea and a bitter taste
for 48 h
...
5 Pharmacokinetics/Toxicokinetics
Pokeweed is absorbed in the gastrointestinal tract and through abrasions on the skin (Lewis and Smith,
1979)
...
6 Chemical Analysis
Pharmacologically/toxicologically important components of the plant include triterpenoid saponins
(phytolaccosides) (Woo et al
...
, 1995), and pokeweed antiviral
protein (PAP) (Myers et al
...
Isolation of lectins A, B, and C from pokeroot using Q-Sepharose
column chromatography followed by gel filtration on a Sephadex G-75 column, hydrophobic
chromatography using a Butyl-Toyopearl column, FPLC on a Mono-Q column, and sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS -PAGE) have been described (Kino et al
...

Phytolaccosides A, B, D, E, and G have also been isolated from pokeweed root using chromatographic
techniques (Woo et al
...
7 Regulatory Status
In 1979, the Herb Trade Association recommended that members should stop selling pokeroot as an
herbal food or beverage, and that except for the immature leaves, all pokeweed products should be
withdrawn from sale in the United States (Lewis and Smith, 1979)
...
Pokeweed
...

Anonymous
...
Mortal Morbid Wkly Rep 1981;30:65–7
...
Peripheral blood plasmacytosis following systemic exposure to
Phytolacca americana (pokeweed)
...

Farnes P, Barker BE, Brownhill LE, Fanger H
...
Lancet 1964;ii:1100–1
...
Pokeroot poisoning
...

Hamilton RJ, Shih RD, Hoffman RS
...
Vet Hum
Toxicol 1995;37:66–7
...
Human poisoning from native and cultivated plants
...

Jaeckle KA, Freemon FR
...
South Med J 1981;74:639–40
...
Purification and characterization of three mitogenic
lectins from the roots of pokeweed (Phytolacca americana)
...

Lewis WH, Smith PR
...
JAMA 1979;242:2759–60
...
A pharmacological study of Phytolacca
...

Myers DE, Yanishevski Y, Masson E, Irvin JD, Evans WE, Uckun FM
...

Leukem Lymphoma 1995;18:93–102
...
The root of
evil—pokeweed intoxication
...

Tyler VE
...
,Binghamton,NY: Pharmaceutical Products Press, 1993
...
Triterpenoid saponins from the roots of
Phytolacca americana
...


Page 245

Chapter 22—
Sassafras
David Hutson and Melanie Johns Cupp
Sassafras albidum (Nuttal) Nees (a
...
a
...
officinale Nees et Erbem and S
...
1 History and Traditional Uses
Sassafras is a small tree native to eastern North America and eastern Asia
...
According to the Spanish physician Monardes, sassafras could "comfort" the liver and stomach,
and dissolve obstructions in the body to "engender good humors" because it was capable of moving the
stools and urine
...
" Sassafras was used for stomach ache, vomiting, urinary retention, lameness,
gout, dropsy, syphilis, scurvy, and jaundice
...
Demand for sassafras was high and expeditions were sent to
New England in the early 1600s to scout for English entrepreneurs who envisioned selling the root bark
for £50 per ton (Estes, 1995)
...

Over the years, people have experimented with each part of the sassafras plant
...
After being dried and powdered, the
leaves and pith have been used as soup thickeners
...

From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
2 Current Uses
Sassafras oil, sassafras bark, and safrole (80% of the oil) are prohibited by the FDA as food additives
and flavorings because of their carcinogenic properties
...

Nevertheless, sassafras is touted in herbal home remedy books and continues to be available in health
food stores
...
Unfortunately, sassafras seems to be nothing more
than a folk medicine; for more than 200 yr it has been known to be without therapeutic utility (Tyler,
1994)
...
3 Pharmacologic/Toxicologic Effects
22
...
1 Anti-Inflammatory Activity
As part of a research program to develop therapeutically active compounds from raw materials in
nature, researchers have synthesized a potentially useful nonsteroidal anti-inflammatory drug (NSAID)
structurally similar to sulindac from safrole (Pereira et al
...
In addition,
sassafras itself has been used for relieving eye inflammation (Duke, 1989)
...
3
...
Over the years many different
preparations, including teas, salves, and fluid extracts have been utilized for breast, cervical, and other
types of cancer
...
In 1833 The American Practice of Medicine listed sassafras oil as a cure for
osteosarcomatous tumors (Hartwell, 1969)
...

22
...
3 Carcinogenicity
Based on studies conducted by the Food and Drug Administration (FDA) showing that safrole is a
hepatocarcinogen in rats, the sale of sassafras has been prohibited since 1960 (Segelman et al
...

Since this ruling by the FDA, more investigations have supported these earlier findings
...
, 1970) found a high incidence ofhepatomas in infant Swiss mice

Page 247

administered various subcutaneous doses of safrole weekly for the first 4 wk of life
...
66 mg of safrole, 50% had developed hepatomas by the time they were killed
at 1 yr of age
...
6 mg, 58% developed hepatomas
and 6% developed multiple pulmonary adenomas
...
Histologically, the pulmonary adenomas and hepatomas were well
differentiated, while the pulmonary adenocarcinomas were less well differentiated with atypical cells,
frequent mitotic figures, and local invasion
...
0 mg/kg of safrole (Segelman et al
...

Another study (Vesselinovitch et al
...
Seven percent of female
offspring, but none of the male offspring or controls, developed renal epithelial tumors due to exposure
in utero
...
One group of mice was administered safrole orally twice
weekly for 90 wk after weaning
...
This is in contrast to the sex difference favoring males in the study by
Epstein and colleagues
...

Despite these animal data, it is not entirely clear if safrole is carcinogenic in humans; documentation
that humans can metabolize safrole to its carcinogenic metabolite is lacking (Benedetti et al
...
See
Section 22
...

22
...
4 Antimicrobial Activity
Two antimicrobial neolignans, magnolol and isomagnolol, have been isolated from the roots of
Sassafras randaiense
...
, 1983)
...
, 1981) using magnolol
isolated from Magnolia grandiflora L
...
These
compounds have not been found to have activity against Gram-negative bacteria
...
4 Case Reports of Toxicity
A case of sassafras poisoning that occurred in 1888 was described in the U
...
The details
are scanty, but apparently a young adult male took 1 teaspoonful of sassafras oil, vomited, collapsed
with dilated pupils, lapsed into a stupor, and eventually died
...
Generally, symptoms were present within 10–90 min of ingesting the oil
...
One subject
responded dramatically to emesis, followed by an injection of nikethamide (a cardiovascular and
respiratory stimulant) at the hospital
...

A 47-yr-old woman called a regional poison center 1 h after accidentally ingesting 1 teaspoonful of
sassafras oil
...
She was instructed
to go to the emergency department
...
She was given activated charcoal
with sorbitol, intramuscular prochlorperazine, and intravenous electrolyte replacement
...
After overnight observation the patient was released with normal kidney and liver function
(Grande and Dannewitz, 1987)
...
She
denied chest pain, dyspnea, dizziness, syncope, palpitations, fever, chills, or night sweats
...
5 kg) and had hypertension, her blood pressure was controlled at 120/82 mm
Hg
...
She was taking furosemide, potassium chloride, and aspirin at the time, but
denied smoking, drinking, or using over-the-counter medications
...
" The patient was instructed to stop
drinking the herbal tea, and her symptoms promptly resolved (Haines, 1991)
...

Additional alleged symptoms of sassafras oil overdose include hypothermia, exhaustion, spasms,
hallucinations, and paralysis
...


Page 249

22
...
5
...
, 1977)
...
163-mg or 1
...
Doses in rats ranged from 0
...
In
both species, orally administered safrole was absorbed rapidly
...
655 mg dose
...
5
...
, 1977)
...
2
mg/kg dose, suggesting that accumulation in these tissues occurs
...
After
a 4
...
Unchanged safrole accounted for only a minor part of total plasma radioactivity, and its
levels decreased more rapidly than total radioactivity, suggesting the presence of metabolites with long
half-lives
...
The safrole-to-total plasma radioactivity ratio was 50%
between 1 and 24 h post-dose with the 750 mg/kg dose, but with the lower dose it was only 10% at 1 h
and 2% at 24 h
...
Repeated high doses of safrole would be expected to accumulate in
tissues, resulting in chronic toxicities such as cancer
...
5
...
,
1977)
...
Nearly complete recovery of the administered dose was obtained as
metabolites in the urine
...

No delay in elimination was detected with increasing dosage
...

In the rat, 20% of the radioactivity of a 0
...
, 1977)
...
In rats, elimination was
delayed as the dose was increased from 0
...
The total
radioactivity recovered in the urine in 4 d did not differ among the three doses
...
In humans, either such saturation does not occur, or the administered dose was not high enough
to saturate the pathway
...
, 1977)
...
The minor metabolite 1-methoxy-2hydroxy-4allylbenzene, is found in both rat and man
...
1'Hydroxysafrole, thought to be the carcinogenic metabolite of safrole, was found in the urine as the
glucuronide conjugate in rats but not in humans
...
Another metabolite unique to the rat is 3'-hydroxysafrole, a product of 1'-hydroxysafrole
hydrolysis and isomerization
...
6 Drug and Food Interactions
Safrole is potent inhibitor of liver microsomal hydroxylating enzymes, and thus could increase plasma
levels of certain drugs
...
, 1968)
...
, 1985)
...
7 Analysis of Biofluids
Oil of sassafras has been reported to interfere with serum phenytoin concentration determination
...
The child's mother had a seizure disorder and was taking phenytoin
and phenobarbital
...
According to the method of
Svensmark and Kristensen, the phenytoin level was 6
...
8 mg/L
...
Hand's teething
lotion and a multivitamin preparation
...
These findings were confirmed by
administering the teething lotion to a dog via gastric tube and measuring the resulting phenytoin
concentration
...
By using the more specific method of serum phenytoin determination
described by Dill, phenytoin could not be detected in the patient's serum
...
, 1967)
...
Plasma and tissue safrole concentrations in rats and
humans were measured by GC-MS
...
, 1977)
...
8 Regulatory Status
As a result of data showing safrole caused hepatocarcinomas in rats, a regulation published in the
Federal Register on December 3, 1960 prohibits the use of safrole in foods (Segelman et al
...

References
Anonymous
...
The review of natural products
...
Louis: Facts and Comparisons, 1997
...
The synthesis and antiinflammatory properties of a new sulindac analogue
synthesized from natural safrole
...

Benedetti MS, Malnoe A, Broillet AL
...
Toxicology 1997;7:69–83
...
Antimicrobial activity of phenolic constituents of Magnolia
grandiflora L
...

Craig JO
...
Arch Dis Child 1953;28:475–83
...
CRC Handbook of medical herbs
...

El-Feraly FS, Cheatham SF, Breedlove RL
...
J
Nat Prod 1983;46:493–8
...
Carcinogenicity testing of selected food additives by
parenteral administration to infant Swiss mice
...


Page 252

Estes JW
...
Pharm Hist1995;37(1):3–23
...
Thin-layer chromatography of rat bile and urine following
intravenous administration of safrole, isosafrole, and dihydrosafrole
...

Grande GA, Dannewitz SR
...
Vet Hum Toxicol 1987;29:447
...
Sassafras tea and diaphoresis
...

Hartwell JL
...
Lloydia 1969;32:247–96
...
Interactions of safrole and isosafrole and their metabolites with
cytochrome P-450
...

Jaffe H, Fujii K, Sengupta M, Guerin H, Epstein SS
...
Life
Sci 1968;7:1051–62
...
Metabolism of safrole in the rat
...

Pereira EFR, Pereira NA, Lima MEF, Coelho FAS, Barreiro EJ
...
Brazilian J Med
Biol Res 1989;22:1415–9
...
Sassafras and herb tea
...

JAMA 1976;236:477
...
The honest herbal, 3rd edit
...

Tyler VE
...

Tyler VE, Brady LR, Robbers JE
...
, Philadelphia: Lea and Febiger, 1981
...
Transplacental and lactational carcinogenesis by safrole
...


Page 253

Chapter 23—
Hawthorn
Jennifer Annon and Melanie Johns Cupp
Crataegus oxyacantha (L
...
laevigata, C
...
1 History and Traditional Uses
Hawthorn is a spiny, small tree or bush with white flowers and red berries (haws), each containing one
to three nuts, depending on the species (Anonymous, 1994)
...
Hawthorn is a member of the rose
family and is found in Europe, North Africa, and western Asia (Grieve, 1971)
...
, 1998)
...
The use of hawthorn can be dated back to Dioscorides in the first century AD
(Tyler, 1993)
...
Hawthorn is also purported to have
spasmolytic and sedative effects (Anonymous, 1994)
...
, 1998)
...

From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...
2 Current Promoted Uses
Hawthorn preparations are popular in Europe, and are gaining popularity in the United States (Tyler,
1993; Anonymous, 1994)
...

23
...
The French Pharmacopoeia requires
45% ethanol for the fluid extract and 60% ethanol for the tincture (Bahorun et al
...
It is
recommended that 0
...
The tea is made from 0
...
, 1998)
...
8% vitexin-4 rhamnoside, is 100–250 mg three times daily
...

23
...
4
...
Benefits have been
demonstrated in heart failure patients (Iwamoto et al
...
In patients with Stage II New York Heart
Association (NYHA) heart failure, doses of 160–900 mg/d of the aqueous-alcoholic extract for up to 56
d showed an increase in exercise tolerance, decrease in rate/pressure product, and increased ejection
fraction (Blumenthal, 1998)
...

Investigators attempted to elucidate the mechanism of action of the flavonoids hyperoside, luteolin-7glucoside, rutin, vitexin, vitexin-rhamnoside, and monoacetyl-vitexin-rhamnoside in spontaneous
beating Langenhoff preparations of guinea pig hearts (Schussler et al
...
Dose-dependent effects
on contractility, heart rate, and coronary blood flow similar to that of theophylline

Page 255

were exhibited by luteolin-7-glucoside, hyperoside, and rutin, while vitexin and its derivatives were less
potent
...
Vitexin-rhamnoside increased coronary blood flow,
heart rate, and contractility in the previous study
...
The investigators concluded that the mechanism behind the cardiac effects of
these flavonoids involved phosphodiesterase inhibition, causing an increase in cAMP concentration, as
well as inhibition of thromboxane synthesis and enhancement of prostacyclin (PGI2) synthesis, as
described by previous researchers
...

Because reactive oxygen species may play a role in the pathogenesis of atherosclerosis, angina, and
cerebral ischemia, the antioxidant activity of dried hawthorn flowers and flowering tops, fluid extract,
tincture, freeze-dried powder, and fresh plant extracts was investigated (Bahorun et al
...

Antioxidant activity, determined by the ability of the preparations to scavenge hydrogen peroxide,
superoxide anion, and hypochlorous acid (HOCL), was provided by all preparations, but was highest
with the fresh young leaf, fresh floral buds, and dried flowers
...

The effects of hawthorn extract LI 132 standardized to 2
...
, 1995)
...
The concentrations used in their
study were chosen for their physiologic plausibility based on the assumption that the volume of
distribution of both hawthorn extract and procyanidins in humans is 5 L, and that the daily dose is 900
mg and 5 mg, respectively
...
Hawthorn also prolonged the effective refractory period, indicating that it might be
an effective antiarrhythmic agent
...
1–30 µg/mL had no
detectable effect on contractility, suggesting that they are not responsible for the positive inotropic
effect of hawthorn
...
5 mL/100 g body wt for 6 wk
...
, 1996)
...
This
was due to an increased number of receptors, not an increase in receptor binding affinity
...
Despite LDL receptor up-regulation, the atherogenic diet fed to the rats offset the
beneficial effects; LDL levels increased 104% and liver cholesterol increased by 231%
...

23
...
2 Neurologic Effects
The flavonoids present in hawthorn purportedly have a sedative effect (Hamon, 1988; Tyler, 1993)
...
4
...
8 mL/kg in rats and 18
...
This particular extract was manufactured by Schwabe
and contained 2% or 10% oligomeric procyanidins
...
(Ammon and Handel, 1981)
...
4
...

No experimental data have been reported concerning toxicity in the embryo or fetus, or the effects on
fertility or postnatal development
...
Despite experiential data that hawthorn may be mutagenic, Commission E feels that the
amount of mutagenic substances ingested would not be sufficient to pose a risk to humans
...

23
...
, 1998), no substantiative case reports can be located
...
6 Pharmacokinetics/Toxicokinetics
Although the investigators of one study (Popping et al
...

23
...
High-performance liquid
chromatography (HPLC) analysis using a UV detector at 280 nm for proanthocyanidins and phenolic
acids, and 360 nm for flavonoids is also described (Bahorun et al
...

23
...
In addition, the flavonoid constituents have been shown to have
inhibitory and inducible effects on the cytochrome P-450 enzyme system, making other drug
interactions possible (Canivenc-Lavier et al
...

23
...
However, in 1993, the preparations were reevaluated and it was
concluded that sufficient scientific evidence was lacking to justify use of the flowers, leaves, and berries
as individual compounds
...
In addition, the Approved monograph has only one approved indication: treatment of
''decreasing cardiac output according to functional stage II of the NYHA (Blumenthal, 1998)
...
Hawthorn is not on the General Sales List in the United Kingdom
...
In Sweden, hawthorn is classified as a natural product, whereas in the United States, it is
considered a dietary supplement (Blumenthal, 1997)
...
Crataegus toxicology and pharmacology
...
Planta Med
1981;43:105–20
...
Hawthorn (Crataegus monogyna)
...

Anonymous
...
Louis, MO: Facts and Comparisons, 1994
...
Oxygen species scavenging activity of phenolic extracts from hawthorn fresh plant organs and
pharmaceutical preparations
...

Bigus A, Massengil D, Walker C
...
Available from: URL:
http://www
...
edu/~cebradsh/main
...
Accessed 1998 Oct 15
...
Popular herbs in the U
...
Market
...

Blumenthal M
...
Austin, TX: American Botanical
Council, 1998
...
Comparative effects of
flavonoids and model inducers on drug-metabolizing enzymes in rat liver
...

Grieve M
...
New York, NY: Dover, 1971
...
Hawthorns
...

Iwamoto M, Sato T, Ishizaki T
...
A multicenter double-blind study
...

Popping S, Rose H, Ionescu I, Fisher Y, Hammermeier H
...
Arzneim Forsch 1995;45:1157–60
...
Effect of tincture of Crataegus
on the LDL -receptor activity of hepatic plasma membrane of rats fed an atherogenic diet
...

Schussler M, Holzl J, Fricke U
...
Arzneim
Forsch 1995;45:842–5
...
The honest herbal, 3rd edit
...

Williamson JS, Wyandt CM
...
Drug Topics 1997; (Aug
4);141:78–85
...
vera Linne, aloe vera, A
...
vulgaris Lamark, Cape aloe, Zanzibar aloe, Socotrine aloe, A
...
perryi Baker, A
...
capensis, A
...
, 1991), A
...
) N
...
Burm (Blumenthal, 1998)
24
...
The word vera is derived from the Latin versus, which means
true
...
The species most widely used is Aloe baradensis Miller, also known as A
...
vulgaris Lamark, Curacao aloe, aloe vera (Swanson, 1995), A
...
) N
...
Burm
(Blumenthal, 1998), andA
...
) Webb et Berth non Miller (Wichtl, 1994)
...
ferox Miller, its
hybrids, and preparations made from them (Blumenthal, 1998)
...
It is
grown in the Caribbean, especially the West Indies, in Japan, and in coastal areas of Venezuela
(Anonymous, 1992; Wichtl, 1994)
...
J
...
, Totowa, New Jersey

Page 260

Oklahoma (Wichtl, 1994; Hennessee, 1998)
...
The flowers are yellow to orange-red in color (Swanson, 1995)
...
Mesopotamians were also aware of its medicinal properties by that
time (Swanson, 1995)
...
Aloe was first mentioned in Greek literature as a
laxative before the first century (Hennessee, 1998)
...
In the seventh
century, aloe was used in the Orient for eczema and sinusitis (Shelton, 1991)
...

24
...
It is an ingredient in dieters' teas used for their laxative effect (Kurtzweil, 1997)
...
It is used in areas around the world for wounds,
ringworm, hemorrhoids, joint inflammation, edema, burns, hair loss, and constipation (Morton, 1961)
...

24
...
The oral dosage forms range in strengths from 100 to 200 mg
...
It is also available as a
houseplant from which the fluid gel can be expressed and applied to minor burns and wounds (Briggs,
1995; Swanson, 1995)
...
It is a brown, round tablet with the logo "NR
...
Aloe gel, also called aloe vera gel,
mucilage, or (incorrectly) aloe juice, is the thin, clear jelly obtained by crushing the cells in the
parenchymal tissue found inside the leaves (Tyler, 1993; Swan son, 1995)
...
Although this gel does not contain laxative anthraquinones,
contamination can occur, so a cathartic effect might occur if the gel is used internally (Tyler, 1993)
...
Whether these substances are stable during storage is controversial (Tyler,
1993)
...
It is dried to yield a solid material called "aloe" that contains
anthraquinones (Leung, 1980)
...
The term "aloin" also refers to a crystalline,
concentrated form of the dried latex (aloe)
...
Two preparations that may contain only minimal amounts of aloe include
"aloe extract," which may be highly diluted, and "reconstituted aloe vera," which is prepared from a
powder or liquid concentrate (Tyler, 1993)
...
One author (Swanson,
1995) found a product labeled "100% pure aloe vera," with an asterisk referring to small print reading
"plus emollients, stabilizers, and preservatives to ensure potency and efficacy
...
4 Pharmacologic/Toxicologic Effects
24
...
1 Gastrointestinal Effects
See also Sections 25
...
2 and 25
...
3 for additional pertinent information
...
, 1963)
...
The proposed mechanism of action of aloe in treating
peptic ulcer disease is that aloe may inhibit the secretion of hydrochloric acid in the stomach and
prevent irritating substances from aggravating the ulcer
...
An earlier study showed aloin to be effective alone, and even more effective in
combination with phenolphthalein (Chapman and Pittelli, 1974)
...

See also Section 26
...
1 regarding mechanism of cathartic action
...
4
...
This will eventually disappear with discontinuation of the drug
...
, 1993b) of 1095 patients who underwent colorectal endoscopy revealed
a melanosis coli incidence of 6
...
3%, 9
...
8%, and 18
...
The authors calculated a relative risk of 3
...
This study also found that 28 of
the 30 patients with adenoma or carcinoma admitted abuse of anthranoid laxatives for >10 yr
...
, 1993b) of 3049 patients revealed lower incidences of melanosis coli
in patients with inflammatory diseases, diverticulosis, adenoma, and carcinoma, but these results may
be due to poor documentation
...
03% aloin for 20 wk support
these findings; alonin did not promote dimethylhydrazine-induced adenomas or carcinomas (Siegers et
al
...

See Section 25
...
1 for further discussion of the mutagenicity and genotoxicity of emodin, aloe-emodin,
and rhein, as well as a discussion of the association between colon cancer and laxative use
...
4
...

24
...
3 Hematopoietic Activity
The product CARN 750, an injectable form of acemannan derived from Aloe barbadensis Miller, was
administered for 18 d in subcutaneous doses of 0
...

Hematopoietic activity of CARN

Page 263

750 at a dose of 1–2 mg/d was superior to placebo and at least comparable to that of G-CSF 3 µg/d
(Egger et al
...

24
...
4 Antimicrobial Activity
Extracts of 28 species of aloe were tested against Mycobacterium tuberculosis, Staphylococcus aureus,
and Escherichia coli (Gottshall et al
...
Only A
...
A
...
tuberculosis
...
tuberculosis (minimum inhibitory concentration [MIC] = 0
...
25 mg/mL) (Gottshall et al
...
Diluted and undiluted homogenates
of the gelatinous material, the outer green vascular part of the leaves, and the entire leaf aloe did not
inhibit growth of S
...
coli in another study (Fly and Kiem, 1963)
...
aureus but quickly became unstable (Lorenzetti et al
...
Aloe juice that
was heated and then freeze dried was bacteriostatic against S
...
pyrogenes, Corynebacterium
xerose, and S
...
Individual components of the juice, aloe-emodin, emodin, and chrysophanic
acid, did not inhibit S
...
, 1964)
...
5% aloe extract) is effective at 70% concentration against Klebesilla sp
...
aeruginosa,
Enterobacter sp
...
aureus, S
...
marcescens(Robson et al
...
At concentrations
exceeding 90%, Dermaide® inhibited E
...
albicans, and S
...
It did not inhibit B
...
The aloe vera extract contained 3
...
Other components,
emodin, emolin, and barbaloin are converted to salicylic acid by the Kolbe reaction, perhaps explaining
in part the anti-inflammatory activity of the extract (Robson et al
...

Acemannan (Carrisyn®), a β-(1,4)-linked acetylated polymannan, derived from A
...
Another in vitro study showed
that 15
...
001 ng/mL of azidothymidine (AZT) inhibited
HIV-1 in a synergistic manner (Kahlon et al
...
The combination of 15
...
32 µ g/mL of AZT protected the cells from rapid HIV-1 replication, which causes premature cell
death
...
025 µg/mL and 40 µg/mL
also inhibited HSV-1 replication
...
, 1991)
...
(Montaner et al
...

24
...
5 Antineoplastic Activity
Aloctin A is a glycoprotein obtained from A
...
Aloctin A administered to six mice at a
dose of 10 mg/kg/d intraperitoneally for 5 d inhibited growth of methylcholanthrene-induced
fibrosarcoma in four of the mice vs zero of ten untreated mice
...
, 1981)
...
The National
Cancer Institute tested aloe as an antineoplastic, with negative results (Hecht, 1981)
...
4
...
barbadensis inhibited mustard-induced rat
paw edema compared to control (p < 0
...
The effectiveness increased with the use of RNA and
vitamin C (p < 0
...
Another study (Vazquez et al
...
It was also shown that aloe vera decreased prostaglandin E2 production
...
, 1987)
...
e
...
Rats injected with colorized aloe vera for 12 d also had a decrease in wound diameter
...

These observations might be explained by the bradykinase activity of A
...
,
1976)
...
, 1979)
...
As discussed in section 24
...
4, some aloe
constituents to salicylic acid (Robson et al
...

A case reported in 1935 involved a woman who developed dermatitis 14 mo after roentgen treatment
for depilatory purposes (Collins and Collins 1935)
...
The patient reported
severe itching and burning sensations in the area, and had to wear gloves to bed to prevent scratching
...
She was then treated with fresh whole aloe leaf which ceased the burning and
itching and resulted in complete skin healing over a period of 5 wk
...
One investigator demonstrated that 1 g of fresh aloe gel applied for 14 d promoted complete
healing in 10 of 28 rats that had received 4000 rads
...
Only 5 rats
treated with saline showed marked improvement (Rowe, 1940)
...
of x-ray radiation
in a single dose
...
Fresh rind was also used to treat a
patient with a chronic x-ray reaction of 7 mo duration, also with negative results (Rowe et al
...

Another animal study showed that acemannan wound dressing gel applied to mice that had received 30–
47
...
It was determined that the wound dressing gel was
most effective if treatment began immediately after radiation and was continued for at least 2 wk
...
In a phase III
study, aloe gel from A
...
, 1996)
...
Allergic reactions to aloe
were reported in three patients
...
, 1940)
...
, 1994)
...
Combination with systemic pentoxifylline showed 30% improvement
...
, 1990)
...
, 1988)
...
Only the aloe
vera gel extract was significantly (p < 0
...
A study found concentrated aloe
gel (98%) to be ineffective against experimental hydrofluoric acid burns on the hind legs of rats
(Bracken et al
...

Aloe vera extract 0
...
, 1996)
...
No adverse effects or hypersensitivity reactions were noted
...
Burning was reported with the aloe
dressing
...
025% sodium hypochlorite) (Schmidt and Greenspoon, 1991)
...
5 Case Reports of Toxicity Due to Commercially Available Products
A woman who had taken Carter's Little Pills®, which contained aloe and podophyllum, daily for 4 yr
presented with unexplained hypokalemic metabolic alkalosis (Ramirez and Marieb, 1970)
...

One retrospective study (Gold, 1980) reviewed cases of acute renal failure in 91 patients who had used
herbal remedies
...
Seventy-four of the patients required peritoneal dialysis, 16 had jaundice, eight had
neurologic impairment, and four died
...


Page 267

Dermatologic reactions to aloe have also been reported
...

She immediately experienced a burning sensation, and the area became red, swollen, and crusted
...
(Hunger and Frumkin, 1991)
...
After 3 yr of ingestion of aloe gel 1 teaspoonful three times
daily, a patient developed eczema that persisted for 3 mo (Morrow et al
...
This patient had also
been applying the gel daily, for the past year, after shaving and for the previous month had noticed
urticarial lesions in his beard area that lasted 5 min after each gel application
...
These teas contain laxatives such as senna, aloe, and
buckthorn
...
O[ther adverse effects include
chronic diarrhea, dependence on laxatives for normal bowel function, and abdominal pain, which occur
with long-term use
...

24
...

Thiazide diuretics, corticosteroids, and licorice could exacerbate hypokalemia
...

24
...
7
...
Based on renal excretion data from rats fed
radiolabeled aloe-emodin, at least 20–25% of a given dose is absorbed (Lang, 1993)
...
e
...
Because aloe-emodin is metabolized quickly, its bioavailability is
low—perhaps <10% (Lang, 1993)
...
7
...
Rhein, an active metabolite of aloe-emodin,
passes into breast milk, but a laxative effect has not been noted in nursing infants (Lang, 1993;
Blumenthal, 1998)
...
Concentrations in brown fat, muscle, eyes, perirenal fat, bones, bone
marrow, and gonads were low or unmeasurable
...
7
...
In humans, rhein was
recovered in the urine after consumption of 86 mg and 200 mg of aloe powder (Blumenthal, 1998)
...
The rest was excreted in
the feces mainly as aloe-emodin, with small amounts of rhein and an unknown metabolite
...
Not all of the radioactivity in the feces was analyzed, however,
owing to inability to extract all of the radioactivity with methanol
...
Whether biliary excretion is involved, or if radioactivity found in the feces
represented nonabsorbed drug is unknown
...
7 regarding biotransformation of aloe-emodin, barbaloin, and chrysophanol
...
8 Analysis of Biofluids
Note that aloe use can turn the urine a harmless red color during treatment (Blumenthal, 1998)
...

Concentrations of aloe-emodin, rhein, an unknown metabolite, and their conjugated metabolites were
determined in plasma, urine, feces, liver, and kidney using TLC (Lang, 1993)
...
5/13
...

Use of HPLC to detect rhein and aloin in the urine to screen for laxative abuse has been described
(Perkins and Livesey, 1993)
...

24
...
It should be used only after failure of
dietary modification or a bulk-forming laxative
...
perryi Baker, A
...
ferox Miller, and hybrids of A
...
africana
Miller, and A
...
For use as a
laxative aloe is regulated as a drug by the FDA but many aloe products are classified as dietary
supplements under the Dietary Supplement Health and Education Act of 1994 (Kurtzweil, 1997)
...
The FDA
Center for Drug Evaluation and Research proposed that aloe undergo genotoxicity and carcinogenicity
tests owing to its chemical similarity to phenolphthalein, which is possibly carcinogenic
...
Two FDA
advisory panels have shown no benefit with aloe as a treatment of minor burns and cuts and urge further
studies (Anonymous, 1992)
...

References
Anonymous
...
St
...

Anonymous
...
21 CFR Parts 310 and 334
...


Page 270

Blumenthal M
...
Austin, TX: American Botanical Council, 1998
...
Aloe vera in peptic ulcer: preliminary report
...

Bracken WM, Cuppage F, McLaury RL, Kirwin C, Klaassen CD
...
J Occup Med 1985;27:733–9
...
Herbal medicine: aloe
...

Chapman DD, Pittelli JJ
...

Curr Ther Res 1974;16:817–20
...
Roentgen dermatitis treated with fresh whole leaf of aloe vera
...

Cook C, Baisden D
...
South Med J 1986;79:1098–101
...
Aloe vera and wound healing
...

Egger SF, Brown GS, Kelsey LS, Yates KM, Rosenberg LJ, Talmadge JE
...
Cancer Immunol Immunother 1996;43:195–205
...
Tests of aloe vera for antibiotic activity
...

Fujita K, Teradaira R, Nagatsu T
...
Biochem Pharmacol
1976;25:205
...
Properties of carboxypeptidase from aloe
...

Fulton JE
...
J Dermatol Surg Oncol 1990;16:460–7
...
Acute renal failure from herbal and patent remedies in Blacks
...

Gottshall RY, Lucas EH, Lickfeldt A, Roberts JM
...
J
...

Gottshall RY, Jennings JC, Weller LE, Redemann CT, Lucas EH, Sell HM
...
Am Rev Tuberculosis 1950;62:475–80
...
The overselling of aloe vera
...

Hennessee OM
...
Available from: http://www
...
com/aloe1
...

Accessed 1998 Oct 31
...
Widespread dermatitis after topical treatment of chronic leg ulcers and stasis dermatitis
...


Hunter D, Frumkin A
...
Cutis 1991;47:193–6
...
Pharmacological studies of plant lectin, Aloctin A
...
Growth
inhibition of mouse methylcholanthrene-induced fibrosarcoma (Meth A) in ascites form by Aloctin A
...

Kahlon JB, Kemp MC, Yawei N, Carpenter RH, Shannon WM, McAnalley BH
...
Mol
Biother 1991;3:214–23
...
Tumor inhibitors in aloe emodin: antileukemic principle isolated from
Rhamnus frangula L
...

Kurtzweil P
...
FDA Consumer 1997;31:6–11
...
Pharmokinetic-metabolic studies with 14C-aloe emodin after oral adminstration to male and
female rats
...

Leung AY
...
New
York: John Wiley & Sons, 1980
...
Bacteriostatic property of aloe vera
...

McCauley RL, Heggers JP, Robson MC
...
Postgrad Med
1990;88:67–77
...
Treatment of experimental frostbite with pentoxifylline and aloe vera cream
...

Montaner JS, Gill J, Singer J, Raboud J, Arseneau R, McLean BD, et al
...
J Acquired
Immune Def Synd Hum Retrovirol 1996;12:153–7
...
Hypersensitivity to aloe
...

Morton JF
...
Econ Bot 1961;15:311–9
...
Aloe vera, fiction or fact
...

Odes HS, Madar Z
...
Digestion 1991;49:65–71
...
Inhibition of arachidonic acid oxidation in vitro by vehicle components Acta
Dermatovener 1982;62:59–61
...
A rapid high-performance thin-layer chromatographic urine screen for laxative
abuse
...

Ramirez B, Marieb NJ
...
Conn Med
1970;34:169–70
...
Acemannan-containing wound dressing gel reduces radiation-induced skin
reactions in C3H mice
...

Robson MC, Heggers JP, Hagstrom WJ
...
J Burn
Care Rehab 1982;3:157–63
...
Comparative evaluation of aloe vera in the management of
burn wounds in guinea pigs
...

Rowe TD
...


J Am Pharm Assoc 1940;29:348–50
...
Further observations on the use of aloe vera leaf in the treatment of
third degree x-ray reactions
...

Schmidt JM, Greenspoon JS
...

Obstet Gynecol 1991;78:115–7
...
Aloe vera: its chemical and therapeutic properties
...

Siegers CP, Siemers J, Baretton G
...
Pharmacology 1993a;47(Suppl l):205–8
...
Anthranoid laxative abuse—a risk for
colorectal cancer? Gut 1993b;34:1099–101
...
Prevention of ultraviolet radiation-induced suppression of
contact and delayed hypersensitivity by Aloe barbadensis gel extract
...

Swanson, LN
...
US Pharm 1995;20:26–35
Syed TA, Ahmad SA, Holt AH, Ahmad SA, Ahmad SH, Afzal M
...
Trop Med Int Health
1996;1:505–9
...
Pharmacognosy, 8th edit
...

Tyler VE
...
, Binghamton, NY: Pharmaceutical Products Press, 1993
...
Antiinflammatory activity of extracts from aloe vera gel
...

Wichtl M
...
Stuttgart: MedPharm, 1994
...
Phase III double-blind
evaluation of an aloe vera gel as a prophylactic agent for radiationinduced skin toxicity
...

Womble D, Helderman JH
...
Immunopharmacol Immunotoxicol 1992;14:63–77
...
) (C
...

angustifolia Vahl, known as Indian senna, Tinnevelly senna, and Meca senna (Franz, 1993)
25
...
Its medicinal use was introduced by Arabian
physicians who used both the leaves and the pods
...
senna (L
...
angustifolia Vahl, from
India
...
Both are annual shrubs that approach heights of 3 ft
...
The flowers are yellow and produce the fruits, or seed
pods
...
The
anthraquinones chrysophanol, emodin, and rhein are monoanthraquinones that combine with each other
and with sugar molecules to form other senna constituents
...
e
...
This rhein dimer
is called sennidin, and sennosides A and B are the two optical isomers of the β-glucosides of sennidin
(De Witte, 1993)
...
Hydrocolloids found in senna are also
important for its therapeutic (i
...
, laxative) effect because they influence the rheology of the
From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...

Cupp©Humana Press Inc
...
Other senna constituents include the monoanthrones rhein anthrone-8monoglucoside, and rhein-8-monoglucoside (Anonymous, 1998)
...
2 Current Promoted Uses
Senna is used in the United States and other industrialized countries as a laxative (Nusko et al
...

25
...
Sennosides A and B
are available as a tablet (Ex-Lax Gentle Nature®, 20 mg)
...
Senna concentrate is available
as tablets (Senexon®, Senolax®, Senokot®, 187 mg [8
...
Caldwell Senna Laxative® or Fletcher's Castoria®, 33
...
3 mg/mL), and syrup (Senokot® and Senokot Children's®, 8
...

Senna concentrate, 187 mg (8
...
Herb-Lax® is a tablet
containing 175 mg of senna leaf powder, and Innerclean Herbal® is a tablet containing the cut plant,
psyllium seed husks, buckthorn bark, anise seed, and fennel seed
...
25 g/tsp
...
4 Pharmacologic/Toxicologic Effects
25
...
1 Carcinogenicity/Mutagenicity/Genotoxicity
Senna constituents have been tested for mutagenicity in several in vitro test systems with varying
results
...
Aloe-emodin was also positive in three of the four tests; with the HGPRT test, no clear
reproducible results could be obtained
...
Senna

Page 275

extract gave weak to strong positive results depending on the S
...
, 1993)
...
, 1993)
...
Although acidic
mucin content and cytokeratin AE1 expression were increased, these changes were not thought to be
precancerous (Yang et al
...
A sennoside-enriched diet (0
...
,
1993)
...
, 1993)
...

It has been speculated that the increase in colon cancer in Western society is associated with use of
cathartics
...
This is much higher than in
agricultural regions of Africa and South America
...
, 1993)
...
Eleven
of these studies contained information about the use of cathartics prior to cancer diagnosis
...
Most studies found a higher incidence of colorectal
cancer in patients with a history of cathartic use, but this was statistically significant in a minority of
studies
...
46 (1
...
61 for 95% CI)
...
48 (1
...
66 for 95% CI), the
investigators hypothesized that constipation and cathartic use reflect a diet high in fat, meat, and alcohol
and low in vegetables
...

A cohort study also aimed to clarify whether laxative use and melanosis coli (a blackish-brown
discoloration of the colonic mucosa caused by longterm use of anthranoid-containing laxatives) are risk
factors for colorectal can-

Page 276

cer (Nusko et al
...
A cohort of 2277 patients who had undergone a total of 4474 colonoscopies
was identified
...
g
...
Data
were analyzed in regard to family history of colorectal cancer, bowel habits, laxative use, and other
medications
...
72 (1
...
01 for 95% CI, p < 0
...
For patients
who had used laxatives but had not developed melanosis coli, there was a relative risk of 1
...
19–
1
...
0064)
...
19 (1
...
67 for 95% CI)
...
This is despite aloe-emodin blood levels produced in rodents that approximate the
concentrations that produced genotoxicity in in vitro test systems (Heidemann et al
...
Aloeemodin is not detectable in human plasma after repeated administration of commercially available
senna products (Krumbiegel and Schulz, 1993)
...
5 ng/mL) is
well below the concentrations that were mutagenic in in vitro test systems, the risk of genotoxicity
would appear low (Heidemann et al
...

25
...
2 Gastrointestinal Effects
Chronic laxative use in general leads to a change in shape and rarefaction of the intestinal microvilli,
mitochondrial damage, an increase in the number of colonocyte lysosomes, plication of the lateral cell
membrane with widening of the intracellular space, and granular inclusions within the colonocytes
...
Sennosides also lead to colonocyte apoptosis in guinea pigs, characterized by chromatin at the
periphery of the cell, and migration of cells to the intercryptal region (Muller-Lissner, 1993)
...
A causal relationship between
melanosis coli and use of anthraquinone laxatives has been shown in animals and humans
...
Melanosis coli begins abruptly at the ileocolonic junction and may extend to the dentate line
...
The pigment has not been definitively
identified, but it is probably lipofuscin
...
The terminal ileum may contain pigmented
macrophages, even if the melanosis is not visible to the naked eye
...
Over time, the macrophages migrate to the mesenteric lymph nodes, thus dispersing the
pigment
...

''Cathartic colon" is a term used to describe certain radiologic findings in patients using laxatives
chronically
...
Macroscopic and microscopic observations include muscle
atrophy, superficial ulceration, submucosal infiltrates of monocytes and eosinophils, fibrosis of the
muscularis mucosa and submucosa, and an increase in submucosal fat
...

Animal and human studies suggest that senna laxative use might result in damage to the colonic nerve
plexus
...
Studies in which mice were administered 10 mg/kg/d of sennosides for 4 mo, and rats were
administered 25–100 mg/kg/d of sennosides revealed no intestinal changes on electron microscopy
...
It
has been hypothesized that the dissimilar results in these animal studies were due to high levels of free
anthraquinones in the senna syrup administered intraperitoneally, resulting in greater systemic
absorption and toxicity
...

It would be expected that pathologic findings involving the autonomic nervous system would result in
functional impairment of the intestine
...
"Tolerance" to laxatives has not been documented, but some

Page 278

patients report having to increase the dose of laxatives with long-term use (Muller-Lissner, 1993)
...
Products containing
crystalline glycosides of senna are more stable, more reliable, and cause less cramping than products
made from the crude drug (Curry, 1986)
...
4
...

25
...
3 Laxative Abuse
Although when taken at recommended doses, senna laxatives do not cause changes in electrolytes,
hypokalemia and resultant muscle weakness can occur when laxatives are abused for purposes of
weight loss, such as in patients with anorexia nervosa or bulimia, and in Munchhausen syndrome
...
Hypokalemia
leads to metabolic alkalosis, reduction in renal tubular concentrating ability, and reduction in creatinine
clearance
...
The dose of senna
or other laxatives required to produce hypokalemia is unknown because laxative abusing patients are
often unreliable historians
...
Use of high-performance liquid chromatography (HPLC) to detect rhein and aloin in the urine to
screen for laxative abuse has been described (Perkins and Livesey, 1993)
...
5 Pharmacokinetics/Toxicokinetics
Additional information on rhein and aloe-emodin pharmacokinetics can be found in Section 24
...

25
...
1 Absorption
Chemically, sennosides, having sugar moieties attached, are extremely hydrophilic and have a relatively
high molecular weight, resulting in poor oral absorption
...
However, rhein, a sennoside component
released in the intestine, is lipophilic and has a low molecular weight, characteristics that favor
absorption (De Witte, 1993)
...
After repeated

Page 279

administration of Agiolax® containing 378 µg of "potential" aloe-emodin (free aloe-emodin plus aloeemodin in the form of dianthrone sennosides and monoanthrone glucosides) and Sennatin® containing
400 µg of "potential" aloeemodin, plasma levels of aloe-emodin were below the limit of detection (0
...
The average rhein Cmax was 43
...
6 ng/mL after
the fourth dose, with Tmax occurring 11
...
7 h after the first and fourth doses, respectively
...
An additional small peak in plasma
concentration was noted 1–3 h after administration, corresponding to absorption of free rhein in the
formulation
...
1 ng/mL after the first dose, and 81
...
These peak plasma concentrations occurred 3
...
9 h after the first and fourth
doses
...

25
...
2 Distribution
Although lactating mothers have reported milk discoloration and laxative effect in breast-fed infants
while taking senna (Curry, 1986), 15 mg of sennosides administered to 20 lactating women for 3 d
resulted in rhein concentrations of < 10 ng/mL in the breast milk in 94% of the women (Faber, 1988)
...
Data in monkeys reflect these findings
(Cameron et al
...

25
...
3 Metabolism/Elimination
Intestinal flora metabolizes the sennosides, releasing free rhein that is subsequently absorbed
...
Chrysophanic acid is excreted in urine and
colors acidic urine yellowish-brown and alkaline urine reddish-violet (Curry, 1986)
...
6 Chemical Analysis
Determination of sennoside content can be achieved spectrophotometrically, or via HPLC (Christ et al,
1978; Lainonen et al
...
There is also a USP monograph (USP, 1999) that details the chemical
analysis of senna
...
7 Analysis of Biofluids
Determination of human plasma levels of aloe-emodin and rhein using HPLC with a fluorometric
detector has been described (Krumbiegel and Schulz, 1993)
...
8
...
8 Regulatory Status
Although the component or components responsible for senna's effect have not been definitively
identified, most pharmacopoeias standardize senna based on its sennoside B content
...
5% for the leaves, 3
...
2% in
the Indian pods (Franz, 1993)
...

Senna has been available in many nonprescription laxative products in the United States for many
years
...
This decision was based on the positive genotoxicity
data for the senna constituents aloe-emodin, emodin, and chrysophanol, as well as the need for
additional carcinogenicity information
...
Further study should also include chemical analysis
to determine quantitatively the components of the senna preparation used in the study, as well as doseranging studies (Anonymous, 1998)
...
Laxative drug products for over-the-counter human use; proposed amendment to the
tentative final monograph
...
Fed Register 1998;63:33592–5
...
The complete German Commission E monographs
...
Austin, TX: American Botanical Council, 1998
...
Milk transfer of rhein in the rhesus monkey
...

Christ B, Poppinghaus T, Wirtz-Peitz H
...
Arzneim Forsch 1978;28:225–31
...
Laxative products
...
8th ed Washington, DC:
American Pharmaceutical Association, 1986
...
Metabolism and pharmacokinetics of anthranoids
...

Faber P
...
Pharmacology 1988;36(Suppl l):212–20
...
The senna drug and its chemistry
...


Page 281

Geboes K, Nijs G, Mengs U, Geboes KPS, Van Damme A, de Witte P
...
Pharmacology 1993;47(Suppl 1):187–95
...
The genotoxicity status of senna
...

Krumbiegel G, Schulz HU
...
Pharmacology
1993;(Suppl 1):120–4
...
The effect of different storage conditions on the
chemical stability, laxative effect and acute toxicity of sennoside solutions
...

Lyden-Sokolowski A, Nilsson A, Sjoberg P
...
Pharmacology 1993;(Suppl 1):209–15
...
Adverse effects of laxatives: fact and fiction
...

Nusko G, Schneider B, Múiller G, Kusche J, Hahn EG
...
Pharmacology 1993;47(Suppl 1):234–41
...
A rapid high-performance thin-layer chromatographic urine screen for laxaive
abuse
...

Siegers C-P, Siemers J, Baretton G
...
Pharmacology 1993;47(Suppl 1):205–8
...
Constipation and cathartics as risk factors of colorectal cancer: a metaanalysis
...

United States Pharmacopoeial Convention (USP)
...
Rockville, MD: United States
Pharmacopeial Convention, Inc; 1999
...
Effects of sennosides and nonanthranoid laxative on
cytochemistry of epithelial cells in rat colon
...


Page 283

Chapter 26—
Cascara Sagrada
Amy Renner and Melanie Johns Cupp
Rhamnus purshiana (D
...
), synonymous with Frangula purshiana (D
...
) A
...
C
...
1 History and Traditional Uses
Cascara sagrada, the dried bark of Rhamnus purshiana, was first used in conventional American
medicine in 1877, after being introduced as a laxative by Mexican and Spanish priests in California
...
frangula) was described by the Anglo-Saxons, and the
berries were included in the 1650 London Pharmacopoeia (Anonymous, 1996)
...
2 Current Promoted Uses
Cascara sagrada is a nonprescription laxative
...

26
...
Fluid extracts are
more reliable than the solid dosage forms
...
Cascara tea is available, but has an extremely bitter taste (Tyler, 1994)
...
j
...
, Totowa, New Jersey

Page 284

Specific products containing cascara sagrada include concentrated milk of magnesia-cascara (cascara
sagrada equivalent to 1 mL of aromatic fluid extract per teaspoon of milk of magnesia), Kondremul®
with Cascara (220 mg per teaspoon of mineral oil)
...

26
...
4
...

The anthrone glucofrangulin is present in the cortex of the European species Rhamni frangula (De
Witte, 1993)
...
In addition, the anthrones inhibit absorption of
water and electrolytes from the large intestine
...

The use of fresh bark, which contains free anthrones, may cause severe vomiting, intestinal cramping,
and possibly spasms (Anonymous, 1996)
...

See also Section 25
...
2 for information on effects of chronic laxative use
...
4
...
4
...
4
...
, 1998)
...
4
...
4
...


Page 285

26
...
, 1997)
...
After working in the pharmacy in this capacity for 6 mo, he began experiencing sneezing;
coryza; nasal congestion, pruritus of the nose, eyes, ears, and oropharynx; and ocular tearing and
pruritus
...
Symptoms improved on Sundays and in the evenings after work, but worsened when he
entered the pharmacy in the morning and when he had contact with cascara sagada and passion flower
...
History revealed a
smoking habit with a 16-yr pack history, but no history of allergies
...
Peak flow rate (PFR) was 480 L/min, compared to the predicted 622 L/min
...
Forced vital
capacity was 71%, forced expiratory volume in one second (FEV1) was 68%, FEV/FCV was 97%,
FEV25 –75% was 47%, and PFR was 73% of predicted
...
Maxillary sinuses showed reduced transparency
bilaterally on X-ray film
...
01–10%)
...
Western blot revealed IgE and IgG to passion flower and cascara sagrada protein
...
The 6-mo latent period before symptom
onset supports an IgE-mediated allergy
...
6 Drug Interactions
Theoretically, given that cytochrome P-450 is involved in metabolism of emodin and chrysophanol to
genotoxic metabolites (Mueller et al
...

26
...
7
...
Enterococcus
faecalis and E
...
Human
fecal flora is able to metabolize barbaloin, but the bacteria responsible have not been identified (De
Witte, 1993)
...
The
metabolism of the former could not be induced, but the formation of 2-hydroxyemodin was inducible
...
Chrysophanol is metabolized by
CYP450 to aloe-emodin (Mueller et al
...

26
...
8 regarding aloe-emodin
...
9 Chemical Analysis
The USP monograph for cascara sagrada includes chemical analysis information (Tyler, 1994)
...
10 Regulatory Status
Cascara sagrada is available in nonprescription form pursuant to an approved monograph
...
However, the FDA is proposing that cascara sagrada be reclassified from a
category I drug (monograph; recognized as safe and effective) to category III (more data needed) based
on lack of mutagenicity, genotoxicity, or carcinogenicity data (Anonymous, 1998)
...
Dried bark of USP quality contains not <7%
total hydroxyanthracenes calculated as cascaroside A
...

Cascara sagrada bark is an approved German Commission E monograph (Blumenthal, 1998)
...
The Lawrence review of natural products
...
Louis, MO: Facts and Comparisons, 1996
...
Laxative drug products for over-the-counter human use; proposed amendment to the
tentative final monograph
...
Fed Register 1998;63:33592–5
...
The complete German Commission E monographs
...
Austin, TX: American Botanical Council, 1998
...
Laxative products
...
, Washington, DC:
American Pharmaceutical Association, 1986
...
Metabolism and pharmacokineticsofanthranoids
...

Giavina-Bianchi PF, Castro FFM, Machado MLS, Duarte AJS
...
Ann Allergy Asthma Immunol
1997;79:449–54
...
Biotransfbrmationofthe anthraquinones emodin and chrysophanol by
cytochrome P450 enzymes
...

Tyler VE
...


Page 289

Chapter 27—
Dong Quai
Rayna DeRosa and Melanie Johns Cupp
Angelica polymorpha Maxim
...
sinensis, A
...
dahurica, A
...
1 History and Traditional Uses
Dong quai root has been used for centuries throughout the East (Anonymous, 1997)
...
It has white to greenish-white flowers that bloom from May to
August (Johns, 1996)
...
Dong quai is
known historically as a female remedy and has been referred to as "empress of the herbs," "sovereign
herb for women," and "the female ginseng
...
It is also said to ensure healthy pregnancies and easy deliveries (Walker et al
...

27
...

27
...
Dong quai is
also available in combination with other herbs
From Forensic Science: Toxicology and Clinical Pharmacology of Herbal Products Edited by: M
...
Cupp ©
Humana Press Inc
...

27
...

27
...
1 Cardiovascular Effects
Researchers have isolated seven coumarin derivatives in dong quai that may have vasodilating and
antispasmodic effects that may improve circulation (Johns, 1996), lower blood pressure, and dilate
coronary arteries (Walker et al
...
, 1998)
...
Other reported cardiovascular effects include inhibition of
platelet aggregation via inhibition of platelet serotonin release; prolongation of the refractory period;
and reduction of atherosclerotic plaque formation
...
25–0
...
Cardiovascular side
effects include excessive bleeding (Huang, 1993)
...
4
...
, 1994) in murine neurocyte culture suggest Dong quai may
accelerate the growth of neurocyte processes and prevent decline in process branch number
...

The tranquilizing and sedative effects that have been attributed to dong quai may help alleviate of mood
swings and irritability in premenstrual syndrome (Johns, 1996)
...
, 1998)
...
4
...
, 1998)
...
This relaxation may help reduce the pain associated
with menstrual cramps (Johns, 1996)
...
A dong quai root
preparation administered intravenously was also shown to prolong prothrombin time in humans (Mei et
al
...

27
...
4 Immunologic Effects/Antineoplastic Activity/Antimicrobial Activity
Selective inhibition of experimentally induced immunoglobulin E (IgE) production has been
demonstrated with aqueous extracts of dong quai (Sung et al
...
Thus, the herb may prove useful
in the treatment and/or the prevention of allergic symptoms
...
, 1994)
...
The
coumarins found in dong quai purportedly stimulate macrophages, enhancing phagocytosis
...
, 1998), and interleukin-2 production (Chen, 1994)
...
, 1998)
...
4
...
The analgesic action is said to be 1
...
, 1998)
...
, 1982)
...
4
...
Psoralen and bergapten, two of the furocoumarins found in dong quai, are
photoreactive and have the potential to cause severe photodermatitis
...
The risk of phototoxicity in humans from ingestion of dong quai has not been
characterized
...
4
...
These
agents are also photocarcinogenic, and muta-

Page 292

genicity persists even in the absence of light (Ivie, 1981)
...
Safrole, a component of the essential
oil of dong quai (Anonymous, 1997), has also demonstrated carcinogenicity and its ingestion is not
recommended (see Sassafras monograph)
...
4
...
These phytoestrogens are reportedly lower in potency than animal estrogens
...
Use of dong quai is also recommended for
amenorrhea, dysmenorrhea, and menorrhagia (Walker et al
...
Dong quai has also been reported to
enhance regularity of menstrual cycles, control premenstrual symptoms, and alleviate some signs and
symptoms of menopause (Johns, 1996)
...
In a 24-wk, doubleblind, placebo-controlled trial (Hirata et al
...
5 g daily of dong quai dried aqueous extract standardized to 0
...
The
main outcome measures were endometrial thickness, vaginal cytology, Kupperman index, and patient
diary of vasomotor symptoms
...
Adverse effects included burping, gas, and
headache, which occurred with similar frequencies in both the placebo and dong quai groups
...
4
...
It has also been
used to treat dysentery (Huang, 1993)
...
5 Drug Interactions
A 46-yr-old black female experienced an increase in INR from 2–3 to 4
...
9 after taking 565 mg of
dong quai once or twice daily for 4 wk
...
Medications included 5 mg/d of warfarin, 0
...
Upon dechallenge from dong quai, her

Page 293

INR decreased to 3
...
48 2 wk later, with no change in warfarin dose (Page
and Lawrence, 1999)
...
, 1995), the authors
suspected a pharmacodynamic mechanism for the interaction
...

27
...
, 1981)
...
7 Regulatory Status
Dong quai is a dietary supplement in the United States
...

References
Anonymous
...
St
...

Anonymous
...
Available from: URL:http://www
...
com/herb/dongquai
...
Accessed
1998a Oct 28
...
Dong-quai or Dang gui
...
mothernature
...
stm
...

Blumenthal M
...
Therapeutic guide to herbal
medicine
...

Chen YH
...
Chung Kuo Chung Yao Tsa Chih 1994;19:739–41,763
...
Immunopharmacological studies of low
molecular weight polysaccharide from Angelica sinenses
...

Gao SW, Chen ZJ
...
Chung Hsi I Chieh Ho Tsa Chih 1988;8:263–5, 259
...
Does dong quai have estrogenic effects in
postmenopausal women? A double-blind placebo-controlled trial
...

Hoult JR, Paya M
...
Gen Pharmacol 1996;27:713–22
...
[Effects of Chinese herb drugs on aging-related
changes in neurocyte culture]
...

Huang KC
...
Boca Raton, FL: CRC Press, 1993
...
Natural toxicants in human foods: psoralens in raw and cooked parsnip
root
...

Johns J
...

Lo ACT, Chan K, Yeung JHK, Woo KS
...
Eur J Drug Metab Pharmacokinet 1995;20:55–60
...
Advances in the pharmacological studies of radix Angelica sinesis (Oliv) Diels
(Chinese Danggui)
...

Ozaki Y
...
Chem Pharmacol Bull
1992;40:954–6
...
Potentiation of warfarin by dong quai
...

Sung CP, Baker AP, Holden DA, Smith WJ, Charkin LW
...
J Nat Prod 1982;45:398–406
...
Dong quai
...
unc
...
htm
...


Page 295

Chapter 28—
Cat's Claw
Melissa Dawn Bostic and Melanie Johns Cupp
Uncaria tomentosa, Uncaria guianensis, Uncaria gambir, una de gato, life-giving vine of Peru,
samento (Anonymous, 1996)
28
...
These sharp
thorns resemble the claws on the paw of a cat, thus the origin of the plant's common name
...
It has a long history of use
in South America as an antiinflammatory, antirheumatic, and contraceptive
...
Native South Americans also use cat's claw to
"cleanse the kidneys" and treat bone pain
...
The stem, bark, roots, and leaves are all
used medicinally (Giesler and Jones, 1998)
...
2 Current Promoted Uses
A case report of a cancer patient in Austria who underwent a miraculous recovery helped bring
attention to cat's claw in the 1970s (Giesler and Jones, 1998)
...
J
...
, Totowa, New Jersey

Page 296

ness of cat's claw tea in the treatment of diverticulitis, hemorrhoids, peptic ulcer disease, colitis,
parasites, and "leaky bowel syndrome" have fueled demand for the bark in the United States
...
Although few clinical studies support its use for the treatment or
prevention of any disease, claims include benefit as an immunostimulant, antihypertensive, and
hypocholesterolemic agent
...
It is also promoted in the treatment of Crohn's disease, diabetes, lupus, chronic
fatigue syndrome, gastritis, and premenstrual syndrome, (Williamson and Wyandt, 1997)
...
3 Products Available
Cat's claw is available in 300-mg capsules to be taken three times daily; 1000-mg time-release capsules
to be taken once daily; liquid concentrate (8:1 in 20% alcohol) to be diluted in water and taken one to
three times daily; and bark to be used for tea
...
4 Pharmacologic/Toxicologic Effects
28
...
1 Antiviral Effects
An in vitro study examined the ability of six components of a a cat's claw bark extract to inhibit two
RNA viruses, vesicular stomatitis virus (VSV) and rhinovirus type 1B (HRV 1B) (Aquino et al
...

Three major glycosides and three other quinovic acid glycosides were studied
...
e
...

28
...
2 Antineoplastic Activity
Reportedly, scientific studies by the National Cancer Institute (NCI) verify that some constituents of
cat's claw may have anticancer properties (Anonymous, 1996)
...
4
...
In addition to
testing the extracts and fractions directly, the investigators also tested urine from two volunteers (a
smoker and a nonsmoker) who had ingested 6
...
The decoction was prepared
by boiling the dried bark in water for 3 h until the initial volume was reduced by one third
...
This effect persisted for 8 d
following discontinuation of cat's claw (Rizzi et al
...

28
...
4 Cytotoxicity
Aqueous extracts of cat's claw were tested for cytotoxicity in four in vitro bioassays using Chinese
hamster ovary cells and bacterial cells (Santa Maria et al
...
Concentrations of 10, 20, 30, 40, 50,
75, and 100 mg/mL were used
...

28
...
Renal biopsy revealed diffuse
membranoproliferative glomerulonephritis (WHO class IV)
...
0 mg/dL
...
In 1996, the patient presented with
a SCr of 2
...
0 mg/dL 1 mo earlier
...

The patient had no complaints
...
Serum complement levels were normal
...
The patient's medications included
prednisone, atenolol, metolazone, furosemide, and nifedipine
...
The diagnosis of acute allergic interstitial nephritis was made, and cat's
claw was discontinued
...
7 mg/dL, but there was no evidence of pyuria or
white blood cell casts on urinalysis (Hilepo et al
...

28
...
There is no
German Commission E monograph for cat's claw
...
Cat's claw (Una de gato)
...
St
...

Aquino R, DeSimone F, Pizza C
...
Structure and in vitro antiviral activity of quinovic
acid glycosides from Uncaria tomentosa and Guettarda platypoda
...

Giesler M, Jones K
...
Available from: URL: http://www
...
edu/˜cebradsh/catsclaw
...

Accessed 1998 Nov 2
...
Acute renal failure caused by "cat's claw" herbal remedy in a
patient with systemic lupus erythematosus
...

Rizzi R, Re F, Bianchi A, DeFeo V, deSimone F, Bianchi L, Stivala LA
...
J Ethnopharmacol 1993;38:63–77
...

Evaluation of the toxicity of Uncaria tomentosa by bioassays in vitro
...

Williamson JS, Wyandt CM
...
Drug Topics 1997;(Aug
4):7885
...
John's wort — C
Hematologic
Feverfew — V
Garlic — V, C
Ginkgo — C
Hepatic
Chaparral — C, A
Colt's foot — C, A
Comfrey — C, A
Sassafras — A
Scullcap — C
(coingestants involved)
Valerian — C
(coingestants involved)
Neurologic
Ephedra — C
Ginkgo — C
Kava — C
St
...
J
...
, Totowa, New Jersey

Page 302

Reproduction
Colt's foot — C
Valerian — T
Renal
Cat's claw — C
Chaparral — C, A
Ephedra — C
Licorice — C
Drug interactions
Aloe — T
Cascara sagrada — V
Chaparral — V
Comfrey — V
Dong quai — A, C
Ephedra — T
Feverfew — T
Garlic — T
Ginger — T
Ginkgo — C
Ginseng — C
Hawthorn — T, V
Kava — C
St
...
cardiovascular effects, 60
acevaltrate, pregnancy, 60
adaptogen, 142, 143
adenosine, platelet effects as garlic constituent, 111
thromboxane production, 111
African ginger, 123
ague tree (See Sassafras)
ajoene, garlic constituent, 108
platelet effects, 110, 111
thromboxane production, 111
all heal, 53
allicin, garlic constituent, 108
metabolism, 119
platelet effects, 111
thromboxane production, 111
alliin, garlic constituent, 108
allinase, garlic constituent, 108
allyl mercaptopuric acid (See ALMA)
allyl methyl sulfide, antineoplastic effect, 113, 114
allyl methyl trisulfide, antineoplastic effect, 113, 114

allyl 1-propenyl oligosulfides, garlic constituents, 108
ALMA, eliminiation, 118, 119
half-life, 119
metabolism, 119, 120
urinalysis, 120
aloctin A, 264
Aloe, absorption, 267, 268
adverse effects, 262, 265-267
allergic reactions, 265
analysis of biofluids, 268, 269
anti-inflammatory effects, 264, 265
antimicrobial activity, 263, 264
carcinogenicity, 262
chemical constituents, 261
dermatitis, 267
distribution into milk, 268
distribution into tissues, 268
elimination, 268
genotoxicity, 262
hypokalemia, 266, 267
lactation, 268
laxative effects, 262
melanosis coli, 262

Page 304

metabolic alkalosis, 266
metabolism, 268
peptic ulcer disease, 261, 262
pharmacokinetics, 267, 268
preparations, 260, 261
protein binding, 268
regulation, 269
renal effects, 266
urine discoloration, 268
wound healing, 264-266
aloe-emodin, absorption, 267, 279
aloe constituent, 261
analysis of biofluids, 268, 269, 279, 280
antimicrobial activity, 263
antineoplastic activity, 264
bioavailability, 268
cascara sagrada constituent, 284
Cmax (See peak concentration)
distribution into tissues, 268
elimination, 268
genotoxicity, 276, 284
half-life, 268
metabolism, 268
mutagenicity, 274, 276
peak plasma concentration, 279
plasma concentration determination, 268, 269, 279
protein binding, 268

senna constituent, 273
tissue concentration determination, 268, 269
Tmax 279
urinalysis 268, 269
aloin, absorption, 267
aloe constituent, 261
analysis of biofluids, 268
altamisa, 95
amantilla, 53
amargosa, 95
amber, 67
amber touch and heal, 67
amentoflavone, receptor affinity, 69
St
...
John's wort interaction, 73
Angelica spp
...
John's wort component, 68
bilobalide, bioavailability, 48
distribution into tissues, 49
ginkgo biloba component, 44
half-life, 49
plasma concentration determination, 50
seizures, 48
urinalysis, 50
volume of distribution, 49
Bioginkgo®, 44
black susan (See Echinacea)
blackwort (See comfrey)
blood pressure, ephedra, 15
bludtkraut, 67

BM&C‰, ingredients, 204
bodybuilders, ephedra use, 13
Bone‰, ingredients, 204
boneset (See comfrey)
borage, adverse effects, 165, 167
anti-inflammatory effects, 162-165
arthritis, 163-165
blood pressure, 166, 167
carcinogenicity, 166
cardiovascular effects, 166, 167
chemical analysis, 167
chemical constituents, 162
cholesterol, 166
cystic fibrosis, 166
dermatitis, 165
diabetic neuropathy, 166
metabolism, 167
pharmacologic effects, 162
regulation, 167
rheumatoid arthritis, 163, 165
Borago officinalis (L
...
John's wort component, 68
Canada, herbal product regulation, 6
Canada, valerian regulation, 64
cancer root (See pokeweed)
CARN, 750, 262-263
Carrisyn® 259, 263
cascara sagrada, adverse effects 284, 285
allergic reactions, 285
chemistry, 284
drug interactions, 285
metabolism, 286
prepartations, 283
products, 284
cascarosides, cascara sagrada constituents, 284
metabolism, 286
Cassia spp
...
) DC, 53
Chamaelum nobile (L
...
John's wort)
Chinese angelica (See dong quai)
Chinese silk vine, conamination of Siberian ginseng products, 177
Chittem bark (See cascara sagrada)

Page 307

chlorogenic acid, echinacea component, 86
St
...
John's wort, 70
chromium, 14
chrysaloin, 284
Chrysanthemum parthenium (L
...
John's wort, 68
consound (See comfrey)
consolida (See comfrey)
cool tankard (See borage)
corazoncillo, 67
coughwort (See coltsfoot)
coumrins, 291
cranberry, adverse effects, 158
antimicrobial activity, 157, 158
chemical constituents, 155, 156
products available, 155-157
urinary tract infection prevention 157, 158

Page 308

urine odor, 158
Crataegus spp
...
John's wort component, 68
cysteine sulfoxides, 108
D
daisy, 85
dang-gui (See dong quai)
5,6-dehydromethysticin, 32
deoxido-dihydrovaltrate, cytotoxicity, 60, 61
Dermaide®, 263
Desmethoxyyangonin, kava component, 32
metabolism, 38
neurotransmitters, 34
diallyl disulfide, antineoplastic effect, 113
garlic constituent, 108
platelet effects, 111
thromboxane production, 11
diallyl 1-propenyl oligosulfides, 108
diallyl sulfide, antineoplastic effect, 113
garlic constituent, 108
diallyl trisulfide, antineoplastic effect, 113
garlic constituent, 108
platelet effects, 111
thromboxane production, 111

Dietary Supplement Health and Education Act, 3
dietary supplements, 3
dihydrogingerdione, 126
dihydrokavain, kava component, 32
dihydromethysticin, kava component, 32
neuroprotective effect, 34
dihydropyrones, 32
dihydrovaltrate, cytotoxicity, 60, 61
pregnancy, 60
receptor binding, 57
dimeric bioflavones (See ginkgoflavone glycosides)
dimethyl 1-propenyl oligosulfides, 108
dipropyl disulfide, 113, 114
dipropyl sulfide, 113, 114
diterpenes (See terpenes)
dithiins, 108
dong quai, adverse effects, 290
anti-inflammatory activity, 291
antimicrobial effect, 291
antineoplastic activity, 291
carcinogenicity, 291, 292
cardiovascular effects, 290
chemical analysis, 293
dermatologic uses, 291
drug interactions, 292, 293
estrogenic effects, 292
gastrointestinal effects, 292

immunomodulation, 291
immunostimulant effects, 291
menopause, 292
muscle relaxation, 290
mutagenicity, 291, 292
neuroprotective effect, 290
phototoxicity, 291, 292
platelet effects, 290, 291
preparations, 289, 290
prothrombin time, 291
regulation, 293
sedation, 290
warfarin interaction, 292, 293

Page 309

DPPRP (See Drug Product Problem Reporting Program)
Drug Product Problem Reporting Program, 6
DSHEA (See Dietary Supplement Health and Education Act)
E
Echimidine, 205
Echinacea angustifolia DC, 85, 87, 89, 90, 92
Echinacea pallida (Nutt
...
) Moench, 85, 87, 88, 89, 90, 92
echinacoside, echinacea component, 86
Echinacea, adverse effects, 88, 90, 91
AIDS, 87
allergic reactions, 90, 91
analysis of product, 91
anaphylaxis, 90, 91
anti-inflammatory effects, 90
antimicrobial effect, 87-89
antineoplastic activity, 89
carcinogenicity, 90
chamomile cross-sensitivity, 91
chemical analysis of products, 91
chronic fatigue syndrome, 92
cold prevention, 87-89
cold treatment, 88, 89
cross-sensitivity, 91
cyclooxygenase inhibition, 90
feverfew cross-sensitivity, 91
fibroblast stimulation, 89, 90

hepatotoxicity, 91
herpesvirus, 87
hyaluronidase inhibition, 89
immunostimulation, 86, 87
5-lipoxygenase inhibition, 90
mutagenicity, 90
natural killer cell activity, 87
pale-flowered, 85
ragweed cross-sensitivity, 91
regulation, 91, 92
respiratory infection prevention, 87-89
respiratory infection treatment 88, 89
wound healing 89, 90
Echinaforce, 88
Echinex®, 86
EGb 761, Alzheimer's dementia, 45
Bioavailability, 49
biofluid analysis, 50
blood rheology, 46
cognitive effects, 45
corticosteroid synthesis, 47
distribution into tissues, 49
hepatic enzyme induction, 48
memory, 45
metabolites, 49, 50
neuroprotective effects, 45
pharmacokinetics, 49

Eleutherococcus senticosus, 141
emodin, antimicrobial activity, 263
cascara sagrada constiuent, 284
metabolism, 263, 284, 286
mutagenicity, 274
senna constituent, 273
emolin, 263
English chamomile, 79
Ephedra (also see ephedrine and other individual constituents), chemical constituents, 15
ephedrine content, 14
hematuria, 20, 21

Page 310

International Olympic Committee, 17
neurologic effects, 18, 19
phenylpropanoloamine content, 15, 18
methylephedrine content, 15, 17
stroke, 18
Ephedrine, absorption, 16
abuse, 12
analysis, chemical, 24
antimicrobial effects, 22
arthritis, 22, 23
beta receptor downregulation, 19
caffeine, 12, 13
cardiac effects, 15, 21, 22
cardiomyopathy, 21
Cmax (See peak levels)
Complement inhibition, 22
elimination, 16, 17, 20
extraction from tissue samples, 24
half-life, 16
intracranial hemorrhage, 21
lethal blood and tissue levels, 23, 24
ma huang component, 14
methamphetamine manufacture, 24
monoamine oxidase inhibitor interaction, 18
morphine interaction, 18
myocardial infarction, 21, 22
nasal spray, 17

pharmacologic effects, 21
psychosis, 19
sales restriction, 24
suicide, 23, 24
time to peak concentration (See Tmax)
Tmax,16
toxicologic analysis, 24
weight loss, 23
epi-7-desacetyl-isovaltrate, cardiovascular effects, 60
ESCP (See European Coopertative on Phytotherapy)
Ethereal oil, St
...
S
...
(See licorice)
glycyrrhetinic acid, absorption, 231
analysis of biofluids, 232
anti-inflammatory effects, 224, 225
bile concentration determination, 232
biofluids analysis, 232
elimination, 231
half-life, 231
metabolism, 225, 231
plasma concentration determination, 232
urinalysis, 232
glycyrrhizc acid (See glycyrrhizin)
glycyrrhizin, absorption, 231
analysis of biofluids, 232

anti-inflammatory effects, 225
antiviral effects, 226
bile concentration determination, 232
biofluids analysis, 232
metabolism, 224, 231
Tmax, 231
urinalysis, 232
volume of distribution, 231
goat weed, 67
greaseweed, 177
Great Britain (See United Kingdom)
guarana, 14
gum root, (See comfrey)
H
hagthorn (See hawthorn)
hardhay (See St
...
John's wort)
hawthorn, adverse effects, 256
carcinogenicity, 256
cardiovascular effects, 254
chemical analysis, 257
drug interactions, 257
lactation, 256
LD50, 256
mutagenicity, 256
pregnancy, 256

regulation, 257, 258
sedation, 256
volume of distribution, 257
hazels (See hawthorn)
hedgehog, 85
hediondilla, 177
helmet flower (See scullcap)
herbal ecstasy, 13, 18
herb de millepertuis (See St
...
John's wort)
hexahydrohippuric acid, elimination, 119
urinalysis, 120
hexenkraut (See St
...
John's wort)
hirapon, 12

Page 315

hoodwort (See scullcap)
Hormone Rejuvenator®, 192
horse-hoof (See coltsfoot)
Hova®, 54
huflattichblatter (See coltsfoot)
hydroxyemodin, 284
hydroxyvalerenic acid, 57
hyperforin, 68
hypericin, absorption, 74, 75
antimicrobial effect, 70
biofluids analysis, 76
catechol-O-methyltransferae inhibition, 68
Cmax (See peak concentration)
distribution into tissues, 75
elimination, 75, 76
half-life, 75, 76
metabolism, 76
molecular weight, 76
monoamine oxidase inhibition, 68
norepinephrine reuptake, 69
peak concentration, 75
plasma concentration analysis, 76
receptor binding, 69
serotonin reuptake, 69
St
...
(See St
...
John's wort, 71
I
Indian ginseng, 143
Indian head (See Echinacea)
ingwerwurzelstok, 123
inkberry (See pokeberry)
iperico (See St
...
John's wort)
Johannisblut (See St
...
John's wort)
Johnswort (See St
...
(See chaparral)
lasiocarpine, carcinogenicity, 207
Leucanthemum parthenium (See feverfew)

LI 132, 255
LI 160, absorption, 74, 75
distribution, 75
elimination, 75, 76
half-life, 75, 76
metabolism, 76
pharmacokinetics, 74-76
sleep, 69
LI 1370, blood rheology, 46
pharmacokinetics, 49
lichochalcone, antiprotozoal effects, 227
licorice, absorption, 231
adverse effects, 227-230
anti-inflammatory effects, 224
antimicrobial effects, 226, 227
antiviral effects, 226, 227
distribution into tissues, 231

Page 317

elimination, 231
gastrointestinal effects, 226
metabolism, 231
mineralocorticoid effects, 225, 227-230
regulation, 232
life-giving vine of Peru (See cat's claw)
Lomigran, 96
Luteolin, 68
M
Mad-dog weed (See scullcap)
madweed (See scullcap)
Ma huang (See Ephedra)
manzanilla, 95
MAO inhibitors, interaction with pseudoephedrine, 18
Marax‰, 13
Marker compounds, 5
Matricaria, 95
Matriarca chamomilla, 79, 95
may (See hawthorn)
mayblossom (See hawthorn)
maybush (See hawthorn)
Medicines Control Agency, 6, 64
MedWatch, 6
melanosis coli, 262, 275, 276
melatonin, 68, 100, 220
menopause, chamomile, 79
Metabolife™, 14

methamphetamine, 12
methyl allyl trisulfide, garlic constituent, 108
platelet effects, 110
methyl allyl 1-propenyl oligosulfides, 108
methylephedrine,
blood concentrations after BRON ingestion 17(?), 23
elimination, 17
ephedra constituent, 15, 17
metabolism, 17
pharmacologic effects, 17
urine drug screening, 17
methylpseudoephedrine, 15
methylpyridoxine (See ginkgotoxin)
11-methyoxyyangonin, 32
methysticin, effect on neurotransmitters, 33, 34
kava constituent, 32
methyl propyl disulfide, antineoplastic effects, 113, 114
muscle relaxant effects, 34
neuroprotective effects, 34
Meyer, 85
midsummer daisy, 95
Migrelief, 96
Migracare, 96
Migracin, 96
MigraFew, 96
Migraspray, 96
Monkey-flower (See scullcap)

monoamine oxidase inhibition, St
...
John's wort constituent, 72
partenelle, 96
Parthenium integrifolium, 86, 91
parthenolide, chemical analysis of feverfewer products, 103
content of feverfew products, 96, 103
dose, 96
factors affecting content of feverfew, 96
feverfew constituent, 96
pelatro, 67
(Z)-1, 8-pentadecadiene, 89
perforata (See St
...
John's wort constituents, 68
phenolic compounds, echinacea product standardization, 86
phenylalanine, 15
phenylpropanolamine, absorption, 16

caffeine interaction, 17

Page 319

cardiac effects, 15, 21
drug interactions, 17, 18
elimination, 17
ephedra constituent, 15, 18
myocardial infarction, 21
theophylline interaction, 17
Tmax, 16
stroke, 21
volume of distribution, 16
philopon, 12
phototoxicity, St
...
John's wort constituent, 68
Proscar® 135
protopseudohypericin, St
...
96
Phytolacca spp
...
John's wort constituent, 68
psoralens, chemical analysis, 293
dong quai constituents, 291
psychosis, ephedrine, 19
pulse (See heart rate)
purple cone flower, 85
Pyrethum parthenium (L
...
John's wort constituent, 68
quercetrin, 68
Quanterra‰ Prostate, 134
Quanterra‰ Sleep, 54
Quanterra‰ Stomach Relief, 124
R
radix valerianae, 53

rate rool (See calamus)
red ginseng, description, 142
hyperlipidemia, 144
red ink plant (See pokeweed)
renal calculi (See kidney stones)
renal impairment, ephedra, 20
Respiratory Rejuvenator® 192
Rhamnus purshiana (See cascara sagrada)
rhein, absorption, 278
analysis of biofluids 268, 269
Cmax (See peak concentration)
distribution into milk, 268
elimination, 268, 279
half-life, 279
peak plasma concentration, 279
mutagenicity, 274
senna constituent, 273
Ripped Fuel, 14
rosin rose (See St
...
John's wort)
salicylic acid, 263
S-allyl-L-cysteine (See SAC)
S-allyl-mercaptopurine, 108
saloop (See sassafras)
Sakau, 31
Samento (See cat's claw)

Page 321

Sankt Hans urt (See St
...
(See scullcap)
scurvy root, 85
6'-shogaol, mutagenicity, 128
snake root, 85
Selenium-enriched garlic, antineoplastic effect, 114
senecionine, carcinogenicity, 194
chemical analysis, 200

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distribution into tissues, 198
elimination, 199
genotoxicity, 194
hepatotoxicity, 194
metabolism, 198, 199
pregnancy, 198
tissue concentration determination, 200
urinalysis, 200
seneciphylline, carcinogenicity, 194
chemical analysis, 200
distribution into tissues, 198
hepatotoxicity, 194
metabolism, 198, 199
tissue concentration analysis, 200
senkirkine, carcinogenicity, 194
chemical analysis, 200
genotoxicity, 194
hepatotoxicity, 194
metabolism, 198, 199
senna, urine discoloration, 279
sesquiterpene lactones, feverfew constituent, 96
sesquiterpenes, antidepressant activity, 59
coltsfoot constituent, 193
receptor binding, 57
valerian constituent, 58
setwell, 53
shabu, 12

Siberian ginseng, andogenic effects, 147
barbiturate interaction, 148
description, 141
digoxin interaction, 148
estrogen receptor binding, 144, 146
glucocorticoid receptor binding, 144, 146
hexobarbital interaction, 148
mineralocorticoid receptor binding, 144, 146
pregnancy, 147
progesterone receptor binding, 144, 146
β-sitosterol, absorption, 148
Sleep-Qik®, ingredients, 61
overdose, 61
slippery root (See comfrey)
starflower (See borge)
Stephnania tetrandra, 20
St
...
John's wort)
St
...
(See comfrey)
T
Talso®, 136
Tanacet, 96
Tanacetum parthenium (See St
...
John's wort)
tonga (See kava)
toque (See scullcap)
toutsaine (See St
...
John's wort)
Tussilago farfara (See coltsfoot)
Tussilagone, cardiovascular effects, 93
LD50, 198
respiratory effects, 193
U
una de gato (See cat's claw)
Uncaria spp
...
sambucifolia Mik (See valerian)
Valeriana officinalis (L
...
John's wort)
whitethorn (See hawthorn)
wild quinine (See chamomile)
WS 1490, anxiolytic effect, 33

neuroprotective effect, 34
wu-jia-pi, 147
X
xanthones, 69
Y
yangonin, kava component, 32
neurotransmitter effect, 34
yaquona (See kava)

Page 325

Z
zenzero (See ginger)
zingerberis rhizoma (See ginger)
zingerone, antimutagenic effect, 128
Zingiber spp
...
John's wort)



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