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Brief Communication: American Ginseng Reduces Warfarin's Effect in Healthy Patients: A Randomized, Controlled Trial

Chun-Su Yuan, MD, PhD; Gang Wei, MD, PhD; Lucy Dey, MD; Theodore Karrison, PhD; Linda Nahlik, RPh; Spring Maleckar, BA; Kristen Kasza, MS; Michael Ang-Lee, MD; and Jonathan Moss, MD, PhD
[+] Article and Author Information

From the Tang Center for Herbal Medicine Research, Committee on Clinical Pharmacology and Pharmacogenomics, Anticoagulation Consult Service, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois.


Acknowledgments: The authors thank Dorothy Sellers, Jacqueline Imperial, and Linda Trumbore for their technical assistance.

Grant Support: By the National Institutes of Health (NIH) (grants AT00563, CA79042, and CA14599); NIH Clinical Therapeutics Training grant (T32-GM07019); NIH General Clinical Research Center Program grant (M01 RR00055); and Tang Center for Herbal Medicine Research at the University of Chicago.

Potential Financial Conflicts of Interests: None disclosed.

Requests for Single Reprints: Chun-Su Yuan, MD, PhD, Tang Center for Herbal Medicine Research and Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637; e-mail, cyuan@uchicago.edu.

Current Author Addresses: Dr. Yuan: Tang Center for Herbal Medicine Research and Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637.

Dr. Wei: Akros Pharma, Inc., 302 Carnegie Center, Suite 300, Princeton, NJ 08540.

Drs. Dey, Ang-Lee, and Moss: Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637.

Dr. Karrison and Ms. Kasza: Department of Health Studies, University of Chicago, 5841 South Maryland Avenue, MC 2007, Chicago, IL 60637.

Ms. Nahlik: Anticoagulation Consult Service, University of Chicago Hospitals, 5841 South Maryland Avenue, Chicago, IL 60637.

Ms. Maleckar: Department of Surgery, University of Chicago, 5841 South Maryland Avenue, MC 7114, Chicago, IL 60637.

Author Contributions: Conception and design: C.-S. Yuan, G. Wei, L. Dey, T. Karrison, L. Nahlik, M. Ang-Lee, J. Moss.

Analysis and interpretation of the data: C.-S. Yuan, G. Wei, L. Dey, T. Karrison, L. Nahlik, K. Kasza, J. Moss.

Drafting of the article: C.-S. Yuan, G. Wei, L. Dey, T. Karrison, K. Kasza.

Critical revision of the article for important intellectual content: C.-S. Yuan, G. Wei, T. Karrison, K. Kasza.

Final approval of the article: C.-S. Yuan, T. Karrison, K. Kasza, J. Moss.

Provision of study materials or patients: C.-S. Yuan, G. Wei, S. Maleckar.

Statistical expertise: T. Karrison, K. Kasza.

Obtaining of funding: C.-S. Yuan.

Administrative, technical, or logistic support: C.-S. Yuan, S. Maleckar.

Collection and assembly of data: C.-S. Yuan, G. Wei, L. Dey, S. Maleckar.


Ann Intern Med. 2004;141(1):23-27. doi:10.7326/0003-4819-141-1-200407060-00011
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Data from all 20 patients (12 patients in the ginseng group and 8 patients in the placebo group) were used in the analysis. For the 6 men and 6 women in the ginseng group (7 patients were white, 3 patients were black, 1 patient was Hispanic, and 1 patient was Asian), the mean age and body weight (±SD) were 30.2 ± 7.2 years and 69.2 ± 20.6 kg, respectively. For the 3 men and 5 women in the placebo group (3 patients were white, 2 patients were black, 2 patients were Hispanic, and 1 patient was Asian), the mean age and body weight (±SD) were 24.3 ± 4.0 years and 62.0 ± 9.1 kg, respectively (Appendix Table).

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Figures

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Figure.
Changes in individual peak international normalized ratio (INR), INR area under the curve (AUC), peak plasma warfarin level, and warfarin AUC in weeks 1 and 4 in American ginseng or placebo groups.

Short horizontal bars represent median values. Values for patient 18, which are off scale, are not plotted. A. Peak INR values before and after 2 weeks of treatment with ginseng or placebo. The reduction in peak INR was significantly greater after ginseng administration than after placebo administration ( = 0.0012). B. The INR AUC in patients from days 1 to 7 before and after treatment with ginseng or placebo. The AUC was significantly decreased after 2 weeks of ginseng treatment compared with placebo treatment ( = 0.025). C. Peak plasma warfarin levels before and after 2 weeks of treatment with ginseng or placebo. The reduction in peak warfarin level was significantly greater after ginseng administration than after placebo administration (  = 0.026). D. Warfarin AUC in patients from days 1 to 7 before and after treatment with ginseng or placebo. The AUC was significantly decreased after 2 weeks of ginseng treatment compared with placebo treatment ( = 0.0069).

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Appendix Figure.
Study flow chart showing American ginseng and placebo dosing and blood sample collection.

Patients received warfarin, 5 mg daily; received ginseng, 1 g, or placebo, twice daily, on the basis of group assignment; and had blood samples taken to measure international normalized ratio and warfarin levels.

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Tables

References

Letters

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Herbal Medicine Precautions
Posted on July 21, 2004
Gregory A. Plotnikoff
University of Minnesota Medical School
Conflict of Interest: None Declared

To the Editor: Yuan et al's brief communication provides an important opportunity to recognize two caveats when interpreting the significance of botanical medicine research.

First, terms such as ginseng may actually represent many species. For example, North American Ginseng (Panax quinquefolius L.) is just one type of commercially available ginseng. From a scientific point of view, data from a study of P. quinquefolius are not applicable to other commercially available Panax species that may also go by the general name ginseng. These include P. ginseng CA Meyer (Asian Ginseng,) P. japonicus CA Meyer (Japanese Ginseng) P. pseudoginseng Wallich (Himalayan Ginseng) and P. notoginseng (Burk) F.H. Chen (Sanqui Ginseng, China). Additionally, data from a study of any Panax species cannot be applied to Siberian Ginseng (Eleutherococcus senticosus (Rupr. & Maxim.) Maximowicz)) which is a different genus in the same family as Ginseng (Araliaceae) but does not share any marker compounds with plants in the Panax genus.

Second, HPLC identification, quantification and comparison of marker compounds by validated methodologies are essential in order to understand the significance of the results. Significant variation exists in marker compounds based on plant age, part, source and processing. 2,3 For the genus Panax, the pharmacologically active marker compounds are saponic triterpene glycosides termed ginsensosides. Among the Panax species, significant variation exists in both the types of ginsensosides and the ratio of ginsensosides. For example, P. quinquefolius does not contain the ginsensoside Rf found in the more commercially popular P. ginseng. Likewise, 24(R)-pseudoginsenoside F11 is specific to American ginseng4 The most abundant ginsensosides in P. ginseng are Rb1 and Rg1 which generally occur in a ratio from 1 to 3. 4 For the P. quinqefolius used in this study, the Rb1/ Rg1 ratio was approximately 6 to 1. For P. quinquefolius, Rb1 and Rb2 ginsenosides have been well documented to be higher and lower in concentration than those in P. ginseng.5 Such variations in constituents may explain why warfarin interference has not been reported by physicians who routinely prescribe Panax ginseng in Japan.

Unfortunately, in the absence of comparative data from other P. quinquefolius species and other species in the genus Panax, the clinical implications this pioneering study cannot be generalized.

Gregory A. Plotnikoff, MD, MTS Dennis McKenna, PhD University of Minnesota Medical School Kenji Watanabe, MD, PhD Keio University Medical School Mark Blumenthal American Botanical Council

1Yuan CS, Wei G, Dey L et al. Brief Communication: American ginseng reduces warfarin's effect in healthy patients. Ann Int Med. 2004;141:23- 27. 2Assinewe VA, Baum BR, Gagnon D, Arnason JT. Phytochemistry of wild populations of Panax quinquefolius L. (North American Ginseng). J Ag Food Chem. 2003;51: 4549-53. 3 Shibata S, Tanaka O, Shoji I, Saito H. Chemistry and Pharmacology of Panax. In Economic and Medicinal Plant Research; Wagner H, Hikino H, Farnsworth NR, Eds; Academic Press: New York, 1985; vol 1, pp 217-284. 4 Awang DVC. The neglected ginsenosides of North American Ginseng. J Herbs Spices Med Plants.2000; 7: 103-109. 5Asaf-Adjaye EB, Wong SK. Determination of ginsenosides (ginseng saponins) in dry root powder from Panax ginseng, Panax quinquefolius and selected commercial products by liquid chromatography: interlaboratory study. J AOAC Int. 2003;86:1112-23.

Conflict of Interest:

None declared

No Title
Posted on September 1, 2004
Chun-Su Yuan
University of Chicago
Conflict of Interest: None Declared

IN RESPONSE: We appreciate the comments of Dr. Plotnikoff and his colleagues. Their letter addresses important issues that warrant clarification and further discussion.

Our data showed that American ginseng (Panax quinquefolius L.), a most commonly used herb in this country, reduces the anti-coagulation effect of warfarin. Limitations on the length of our article prevented us from providing information about other types of ginseng, which were discussed in our previous publications (1,2). We did not extrapolate our data on American ginseng to other species of ginseng. Our study, however, provides an example of drug-herbal interaction. Herbal medicines, like American ginseng, have beneficial effects (1). But herbs contain pharmacologically active constituents that may also interact with drugs. This interaction is particularly important if the drug has a narrow therapeutic index, such as warfarin. A slight alteration to warfarin's effect may have clinical consequences. To prevent the possible clinical consequences of herbal therapies, more controlled trials of herbal-drug interaction are needed.

The major active constituents of ginseng are ginsenosides. Dr. Plotnikoff and his colleagues point out that the American ginseng in our study has an Rb1/Rg1 ratio of approximately 6 to 1, a ratio higher than usual. We believe, however, that this ratio falls within the range of 5.5 to 9.6, a range found in previous reports (3,4). Nonetheless, we acknowledge the variability of the chemical composition of botanicals. The composition of herbal products can vary from manufacturer to manufacturer and from lot to lot from the same manufacturer (4). Data from our laboratory found significant variation in ginsenoside content between measured samples (5). Cultivation conditions such as soil, temperature, moisture, period of cultivation, and harvest season can change total ginsenoside concentration, as well as the percentage of individual ginsenosides. Asian ginseng (Panax ginseng) has a different ginsenoside profile than American ginseng. Whether Asian ginseng interacts with warfarin remains to be tested.

Since animal studies and clinical trials performed in the past to test the effects of ginseng often used preparations with variable phytochemical content, results of these studies are difficult to compare. Lack of standardized processing methods contributes to the variations in a ginseng product. Some herbal manufacturers have tried to standardize products to fixed concentrations of selected chemical constituents. The benefit of this effort is uncertain, however, because herbs may achieve their effects through the combined or synergistic actions of different constituents. Thus, future investigation towards standardization of preparations is clearly needed.

Chun-Su Yuan, MD, PhD, Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60635

References

1. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol. 1999;58:1685 -93.

2. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001;286:208-16.

3. Assinewe VA, Baum BR, Gagnon D, Arnason JT. Phytochemistry of wild populations of Panax quinquefolius L. (North American Ginseng). J Agric Food Chem. 2003; 51:4549-53.

4. Harkey MR, Henderson GL, Gershwin ME, Stern JS, Hackman RM. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr. 2001;73:1101-6.

5. Yuan CS, Wu JA, Osinski J. Ginsenoside variability in American ginseng samples. Am J Clin Nutr. 2002;75:600-1.

Conflict of Interest:

None declared

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Summary for Patients

Ginseng Reduces the Effect of Warfarin in a Study of Healthy Volunteers

The summary below is from the full report titled “Brief Communication: American Ginseng Reduces Warfarin's Effect in Healthy Patients. A Randomized, Controlled Trial.” It is in the 6 July 2004 issue of Annals of Internal Medicine (volume 141, pages 23-27). The authors are C.-S. Yuan, G. Wei, L. Dey, T. Karrison, L. Nahlik, S. Maleckar, K. Kasza, M. Ang-Lee, and J. Moss.

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