TOXICOLOGYand

CLINICALPHARMACOLOGY

HERBALPRODUCTS

Edited by

Melanie Johns Cupp, PHARMD, BCPS

West Virginia UniversityMorgantown, WV

Humana Press 3w£ Totowa, New Jersey

Contents

Foreword by Steven B. Karch vPreface ixContributors xxvProduct Identification Guide following p. 134

PART I LEGAL/REGULATORY ASPECTS OF HERBAL PRODUCTS

Chapter 1: Legal/Regulatory Aspects of Herbal Products 3Melanie Johns Cupp

PART II MONOGRAPHS

Chapter 1: Ma Huang and the Ephedra Alkaloids 11Steven B. Karch

1.1 Sources 111.2 History and Traditional Uses 111.3 Current Promoted Uses 121.4 Available Products 131.5 Pharmacology 15

1.5.1 Introduction 151.5.2 Pharmacologic Effects 161.5.3 Metabolism and Elimination 161.5.4 Workplace and Sports Drug Testing 17

1.6 Drug Interactions 171.7 Toxicology 18

1.7.1 Neurologic Disorders 181.7.2 Renal Disorders 191.7.3 Cardiovascular Diseases 211.7.4 Other Medical Problems and Effects 22

XI

xii Contents

1.8 Postmortem Toxicology 231.9 Analytic Considerations 241.10 Methamphetamine Manufacture 241.11 Commission E Recommendations 24

Chapter 2: Kava 31Shawn Reeder and Melanie Johns Cupp

2.1 History and Traditional Uses 312.2 Current Promoted Uses 322.3 Products Available 322.4 Pharmacologic/Toxicologic Effects 32

2.4.1 Neurologic Effects 322.4.2 Dermatological Effects 352.4.3 Musculoskeletal Effects 362.4.4 Antimicrobial Activity 362.4.5 Hepatotoxicity 362.4.6 Antiplatelet Effects 36

2.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 36

2.6 Toxicity Associated with Traditional Use by Native Populations 372.7 Drug Interactions 382.8 Pharmacokinetics/Toxicokinetics 38

2.8.1 Absorption 382.8.2 Metabolism/Elimination 38

2.9 Analysis of Biofluids 382.10 Chemical Analysis 392.11 Regulatory Status 39

Chapter 3: Ginkgo biloba 43Forouzandeh Mahdavi and Melanie Johns Cupp

3.1 History and Traditional Use 433.2 Current Promoted Use 433.3 Products Available 433.4 Pharmacologic/Toxicologic Effects 44

3.4.1 Nervous System Effects 443.4.2 Cardiovascular Effects 463.4.3 Carcinogenicity/Mutagenicity/Teratogenicity 463.4.4 Endocrine Effects 47

3.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 47

3.6 Drug Interactions 483.7 Pharmacokinetics/Toxicokinetics 48

Contents xiii

3.7.1 Absorption 483.7.2 Distribution 493.7.3 Metabolism/Elimination 49

3.8 Chemical Analysis 493.9 Analysis of Biofluids 503.10 Regulatory Status 50

Chapter 4: Valerian 53Marlea Givens and Melanie Johns Cupp

4.1 History and/Traditional Uses 534.2 Current Promoted Uses 534.3 Products Available 544.4 Pharmacologic/Toxicologic Effects 54

4.4.1 Central Nervous System Effects 544.4.2 Musculoskeletal Effects 594.4.3 Reproduction 594.4.4 Cardiovascular Effects 604.4.5 Cytotoxicity 60

4.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 61

4.6 Drug Interactions 634.7 Chemical Analysis 644.8 Regulatory Status 64

Chapter 5: St. John's Wort 67John T. Schwarz and Melanie Johns Cupp

5.1 History and Traditional Uses 675.2 Current Promoted Uses 675.3 Products Available 685.4 Pharmacologic/Toxicologic Effects 68

5.4.1 Neurological Effects 685.4.2 Antimicrobial Effects 705.4.3 Mutagenicity 705.4.4 Reproduction 70

5.5 Adverse Effects and Toxicity 705.6 Drug Interactions 725.7 Pharmacokinetics/Toxicokinetics 74

5.7.1 Absorption 745.7.2 Distribution 755.7.3 Metabolism/Elimination 75

5.8 Chemical Analysis 765.9 Analysis of Biofluids 765.10 Regulatory Status 76

xiv Contents

Chapter 6: Chamomile 79Melanie Johns Cupp

6.1 History and Traditional Uses 796.2 Current Promoted Uses 796.3 Products Available 796.4 Pharmacologic/Toxicologic Effects 79

6.4.1 Neurologic Effects 796.4.2 Antineoplastic Effects 806.4.3 Anti-Inflammatory Activity 80

6.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 80

6.6 Pharmacokinetics/Toxicokinetics 826.7 Analysis of Biofluids 826.8 Regulatory Status 82

Chapter 7: Echinacea 85Julie Davis and Melanie Johns Cupp

1.1 History and Traditional Uses 857.2 Current Promoted Uses 867.3 Products Available 867.4 Pharmacologic/Toxicologic Effects 86

7.4.1 Immunologic Effects 867.4.2 Antimicrobial/Antiviral Effects 877.4.3 Antineoplastic Activity 897.4.4 Wound-Healing 897.4.5 Anti-Inflammatory Effects 907.4.6 Mutagenicity/Carcinogenicity 907.4.7 Reproduction 90

7.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 90

7.6 Chemical Analysis 917.7 Regulatory Status 91

Chapter 8: Feverfew 95Brian Schuller and Melanie Johns Cupp

8.1 History and Traditional Uses 958.2 Current Promoted Uses 958.3 Products Available 968.4 Pharmacology/Toxicology 97

8.4.1 Neurologic Effects 978.4.2 Anti-Inflammatory Effects 1008.4.3 Mutagenicity/Carcinogenicity/Teratogenicity 101

Contents xv

8.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 102

8.6 Drug Interactions 1028.7 Chemical Analysis 1038.8 Regulation 103

Chapter 9: Garlic 107James Allman and Melanie Johns Cupp

9.1 History and Traditional Uses 1079.2 Current Promoted Uses 1079.3 Products Available 1079.4 Pharmacologic/Toxicologic Effects 109

9.4.1 Cardiovascular Effects 1099.4.2 Gastrointestinal Effects 1129.4.3 Antimicrobial Activity 1129.4.4 Antineoplastic Effects 1139.4.5 Immunostimulant Effects 114

9.5 Case Reports of Toxicity 1159.6 Drug Interactions 1189.7 Pharmacokinetics/Toxicokinetics 118

9.7.1 Absorption 1189.7.2 Distribution 1189.7.3 Metabolism/Elimination 118

9.8 Analysis of Biofluids 1209.9 Regulatory Status 120

Chapter 10: Ginger 123Charity Metz and Melanie Johns Cupp

10.1 History and Traditional Uses 12310.2 Current Promoted Uses 12410.3 Products Available 12410.4 Pharmacologic/Toxicologic Effects 125

10.4.1 Gastrointestinal Effects 12510.4.2 Anti-Inflammatory Activity 12610 4.3 Use in Migraine 12710.4.4 Cardiovascular Effects 12710.4.5 Mutagenicity 12810.4.6 Reproduction 128

10.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 128

10.6 Drug Interactions 12910.7 Chemical Analysis 12910.8 Regulatory Status 129

xvi Contents

Chapter 11: Saw Palmetto 133Amy Meadows and Melanie Johns Cupp

11.1 History and Traditional Uses 13311.2 Current Promoted Uses 13311.3 Products Available 13411.4 Pharmacologic/Toxicologic Effects 134

11.4.1 Immunologic Effects 13411.4.2 Genitourinary/Endocrine Effects 13411.4.3 Anti-Inflammatory Effects 136

11.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 136

11.6 Pharmacokinetics/Toxicokinetics 13711.6.1 Absorption 13711.6.2 Distribution 13711.6.3 Metabolism/Excretion 137

11.7 Analysis of Biofluids 13711.8 Chemical Analysis 13811.9 Regulatory Status 138

Chapter 12: Panax Ginseng 141Angela Morgan and Melanie Johns Cupp

12.1 History and Traditional Uses 14112.2 Current Promoted Uses 14212.3 Products Available 14212.4 Pharmacologic/Toxicologic Effects 143

12.4.1 Endocrine Effects 14312.4.2 Neurologic Effects 14412.4.3 Cardiovascular Effects 14412.4.4 Hematologic Effects 14412.4.5 Immunologic Effects 14512.4.6 Antineoplastic Effects 145

12.5 CaseReports of Toxicity Due to CommerciallyAvailable Products 145

12.6 Drug Interactions 14712.7 Pharmacokinetics/Toxicokinetics 148

12.7.1 Absorption 14812.7.2 Distribution 14812.7.3 Metabolism/Elimination 149

12.8 Analysis of Biofluids 14912.9 Chemical Analysis 15012.10 Regulatory Status 150

Contents xvii

Chapter 13: Cranberry 155Angela J. Lawson and Melanie Johns Cupp

13.1 History and Traditional Uses 15513.2 Current Promoted Uses 15513.3 Products Available 15513.4 Pharmacologic/Toxicologic Effects 157

13.4.1 Antimicrobial Activity 15713.4.2 Gastrointestinal Effects 15813.4.3 Renal Effects 158

13.5 Chemical Analysis 15913.6 Regulatory Status 159

Chapter 14: Borage 161Melanie Johns Cupp

14.1 History and Traditional Uses 16114.2 Current Promoted Uses 16214.3 Products Available 16214.4 Pharmacologic/Toxicologic Effects 162

14.4.1 Anti-Inflammatory Effects 16214.4.2 Dermatologic Effects 16514.4.3 Respiratory Effects 16614.4.4 Carcinogenicity 16614.4.5 Hematologic Effects 16614.4.6 Effects in Diabetic Neuropathy 16614.4.7 Cardiovascular Effects 166

14.5 Case Reports of Toxicity 16714.6 Pharmacokinetics/Toxicokinetics 16714.7 Chemical Analysis 16714.8 Regulatory Status 167

Chapter 15: Calamus 171Melanie Johns Cupp

15.1 History and Traditional Uses 17115.2 Current Promoted Uses 17215.3 Products Available 17215.4 Pharmacologic/Toxicologic Effects 172

15.4.1 Carcinogenicity 17215.4.2 Mutagenicity/Genotoxicity 17215.4.3 Antimicrobial Activity 17215.4.4 Central Nervous System Effects 17215.4.5 Musculoskeletal Effects 173

xviii Contents

15.4.6 Cardiovascular Effects 17315.4.7 LD50 17415.4.8 Reproductive Effects 17415.4.9 Local Anesthetic Effects 174

15.5 Case Reports of Toxicity 17415.6 Chemical Analysis 17415.7 Regulatory Status 174

Chapter 16: Chaparral 177Kim Melgarejo and Melanie Johns Cupp

16.1 History and Traditional Uses 17716.2 Current Promoted Uses 17816.3 Products Available 17816.4 Pharmacologic/Toxicologic Effects 178

16.4.1 Antineoplastic Activity 17816.4.2 Hepatotoxicity 18016.4.3 Effects on the Arachidonic Acid Cascade 18016.4.4 Nephrotoxicity 18116.4.5 Carcinogenicity 18216.4.6 Dermatologic Effects 18216.4.7 Antihyperglycemic Effects 182

16.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 182

16.6 Drug Interactions 18716.7 Pharmacokinetics 18716.8 Chemical Analysis/Analysis of Biofluids 18816.9 Regulatory Status 188

Chapter 17: Coltsfoot 191Amanda Dailey and Melanie Johns Cupp

17.1 History and Traditional Uses 19117.2 Current Promoted Uses 19117.3 Products Available 19217.4 Pharmacologic/Toxicologic Effects 192

17.4.1 Respiratory Effects 19217.4.2 Cardiovascular Effects 19317.4.3 Antimicrobial Effects 19317.4.4 Hepatotoxicity 19317.4.5 Carcinogenicity/Genotoxicity 194

17.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 195

17.6 LD50 19817.7 Pharmacokinetics/Toxicokinetics 198

Contents xix

17.7.1 Absorption 19817.7.2 Distribution 19817.7.3 Metabolism/Elimination 198

17.8 Analysis of Biofluids/Chemical Analysis 19917.9 Regulatory Status 200

Chapter 18: Comfrey 203David Burch and Melanie Johns Cupp

18.1 History and Traditional Uses 20318.2 Current Promoted Uses 20418.3 Products Available 20418.4 Pharmacologic/Toxicologic Effects 204

18.4.1 Gastrointestinal Effects 20518.4.2 Hepatotoxicity 20518.4.3 Carcinogenicity/Mutagenicity 20618.4.4 LD50 207

18.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 208

18.6 Drug Interactions 21018.7 Pharmacokinetics/Toxicokinetics 210

18.7.1 Absorption 21018.7.2 Distribution 21118.7.3 Metabolism/Elimination 211

18.8 Analysis of Biofluids 21118.9 Chemical Analysis 21218.10 Regulatory Status 212

Chapter 19: Scullcap 215Jennifer Schumacher and Melanie Johns Cupp

19.1 History and Traditional Uses 21519.2 Current Promoted Uses 21619.3 Products Available 21619.4 Pharmacologic/Toxicologic Effects 216

19.4.1 Antispasmodic Effects 21619.4.2 Hepatotoxicity 21619.4.3 Cardiovascular Effects 21619.4.4 Antimicrobial Activity 21719.4.5 Anti-Inflammatory Activity 21719.4.6 Chemotherapeutic Activity 218

19.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 218

19.6 Chemical Analysis 22019.7 Regulatory Status 220

xx Contents

Chapter 20: Licorice 223Michael Newton and Melanie Johns Cupp

20.1 History and Traditional Uses 22320.2 Current and Promoted Uses 22320.3 Products Available 22420.4 Pharmacologic/Toxicologic Effects 224

20.4.1 Respiratory Effects 22420.4.2 Anti-Inflammatory Effects 22420.4.3 Adrenocorticotropic Effects 22520.4.4 Gastrointestinal Effects 22620.4.5 Antimicrobial Activity 226

20.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 227

20.6 Pharmacokinetics/Toxicokinetics 23120.6.1 Absorption 23120.6.2 Distribution 23120.6.3 Metabolism/Elimination 23120.6.4 Analysis of Biofluids 232

20.7 Regulatory Status 232

Chapter 21: Pokeweed 237A. Heather Knight-Trent and Melanie Johns Cupp

21.1 History and Traditional Uses 23721.2 Products Available 23821.3 Pharmacologic/Toxicologic Effects 238

21.3.1 Antimicrobial Activity and Antineoplastic Activity 23821.3.2 Anti-Inflammatory Activity 23821.3.3 Cardiovascular Effects 23821.3.4 Musculoskeletal Effects 23921.3.5 Gastrointestinal Effects 23921.3.6 Respiratory Effects 23921.3.7 Neurologic Effects 23921.3.8 Hematologic Effects 239

21.4 Case Reports of Toxicity 23921.5 Pharmacokinetics/Toxicokinetics 24221.6 Chemical Analysis 24221.7 Regulatory Status 242

Chapter 22: Sassafras 245David Hutson and Melanie Johns Cupp

22.1 History and Traditional Uses 24522.2 Current Uses 24622.3 Pharmacologic/Toxicologic Effects 246

Contents xxi

22.3.1 Anti-Inflammatory Activity 24622.3.2 Antineoplastic Activity 24622.3.3 Carcinogenicity 24622.3.4 Antimicrobial Activity 247

22.4 Case Reports of Toxicity 24822.5 Pharmacokinetics/Toxicokinetics 249

22.5.1 Absorption 24922.5.2 Distribution 24922.5.3 Metabolism/Elimination 249

22.6 Drug and Food Interactions 25022.7 Analysis of Biofluids 25022.8 Regulatory Status 251

Chapter 23: Hawthorn 253Jennifer Annon and Melanie Johns Cupp

23.1 History and Traditional Uses 25323.2 Current Promoted Uses 25423.3 Products Available 25423.4 Pharmacologic/Toxicologic Effects 254

23.4.1 Cardiovascular Effects 25423.4.2 Neurologic Effects 25623.4.3 LDS0 25623.4.4 Teratogenicity/Mutagenicity/Carcinogenicity 256

23.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 256

23.6 Pharmacokinetics/Toxicokinetics 25723.7 Chemical Analysis 25723.8 Drug Interactions 25723.9 Regulatory Status 257

Chapter 24: Aloe 259Tara Dalton and Melanie Johns Cupp

24.1 History and Traditional Uses 25924.2 Current Promoted Uses 26024.3 Products Available 26024.4 Pharmacologic/Toxicologic Effects 261

24.4.1 Gastrointestinal Effects 26124.4.2 Carcinogenicity/Genotoxicity 26224.4.3 Hematopoietic Activity 26224.4.4 Antimicrobial Activity 26324.4.5 Antineoplastic Activity 26424.4.6 Anti-Inflammatory and Wound

Healing Activity 26424.5 Case Reports of Toxicity Due to Commercially

Available Products 266

xxii Contents

24.6 Potential Drug Interactions 26724.7 Pharmacokinetics/Toxicokinetics 267

24.7.1 Absorption 26724.7.2 Distribution 26824.7.3 Metabolism/Elimination 268

24.8 Analysis of Biofluids 26824.9 Regulatory Status 269

Chapter 25: Senna 273Melanie Johns Cupp

25.1 History and Chemistry 27325.2 Current Promoted Uses 27425.3 Products Available 27425.4 Pharmacologic/Toxicologic Effects 274

25.4.1 Carcinogenicity/Mutagenicity/Genotoxicity 27425.4.2 Gastrointestinal Effects 27625.4.3 Laxative Abuse 278

25.5 Pharmacokinetics/Toxicokinetics 27825.5.1 Absorption 27825.5.2 Distribution 27925.5.3 Metabolism/Elimination 279

25.6 Chemical Analysis 27925.7 Analysis of Biofluids 27925.8 Regulatory Status 280

Chapter 26: Cascara Sagrada 283Amy Renner and Melanie Johns Cupp

26.1 History and Traditional Uses 28326.2 Current Promoted Uses 28326.3 Products Available 28326.4 Pharmacologic/Toxicologic Effects 284

26.4.1 Gastrointestinal Effects 28426.4.2 Nutritional and Metabolic Effects 28426.4.3 Carcinogenicity/Mutagenicity/Genotoxicity 284

26.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 285

26.6 Drug Interactions 28526.7 Pharmacokinetics/Toxicokinetics 28526.8 Analysis of Biofluids 28626.9 Chemical Analysis 28626.10 Regulatory Status 286

Contents xxiii

Chapter 27: Dong Quai 289Rayna De Rosa and Melanie Johns Cupp

27.1 History and Traditional Uses 28927.2 Current Promoted Uses 28927.3 Products Available 28927.4 Pharmacologic/Toxicologic Effects 290

27.4.1 Cardiovascular Effects 29027.4.2 Neurologic Effects 29027.4.3 Musculoskeletal Effects 29027.4.4 Immunologic Effects/Antineoplastic

Activity/Antimicrobial Activity 29127.4.5 Anti-Inflammatory Activity 29127.4.6 Dermatological Effects 29127.4.7 Carcinogenicity 29127.4.8 Estrogenic Effect 29227.4.9 Gastrointestinal Effects 292

27.5 Drug Interactions 29227.6 Chemical Analysis 29327.7 Regulatory Status 293

Chapter 28: Cafs Claw 295Melissa Dawn Bostic and Melanie Johns Cupp

28.1 History and Traditional Uses 29528.2 Current Promoted Uses 29528.3 Products Available 29628.4 Pharmacologic/Toxicologic Effects 296

28.4.1 Antiviral Effects 29628.4.2 Antineoplastic Activity 29628.4.3 Antimutagenic Activity 29628.4.4 Cytotoxicity 297

28.5 Case Reports of Toxicity Due to CommerciallyAvailable Products 297

28.6 Regulatory Status 297

PART III SUMMARY OF TOXICITIES AND DRUG INTERACTIONS

Chapter 1: Summary of Toxicities and Drug Interactions 301Melanie Johns Cupp

Index 303