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Original Research |

Oseltamivir Compared With the Chinese Traditional Therapy Maxingshigan–Yinqiaosan in the Treatment of H1N1 Influenza: A Randomized Trial

Chen Wang, MD, PhD; Bin Cao, MD; Qing-Quan Liu, MD; Zhi-Qiang Zou, MD; Zong-An Liang, MD; Li Gu, MD; Jian-Ping Dong, MD; Li-Rong Liang, MD; Xing-Wang Li, MD; Ke Hu, MD; Xue-Song He, MD; Yan-Hua Sun, MD; Yu An, MD; Ting Yang, MD; Zhi-Xin Cao, MD; Yan-Mei Guo, MD; Xian-Min Wen, MD; Yu-Guang Wang, MD; Ya-Ling Liu, MD; and Liang-Duo Jiang, MD
[+] Article and Author Information

From Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine, Capital Medical University, and Beijing Hospital, Ministry of Health, Beijing; Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing; Yantai Infectious Disease Hospital, Shandong; Chengdu Infectious Disease Hospital, Sichuan; Beijing Haidian Hospital, Beijing; Beijing Ditan Hospital, Institute of Infectious Diseases, Capital Medical University, Beijing; Renmin Hospital of Wuhan University; Changxindian Hospital of Fengtai District of Beijing, Beijing; Second Hospital of Chaoyang District of Beijing, Beijing; Second Hospital of Beijing, Beijing; and West China Medical School, West China Hospital, Sichuan University, Sichuan, China.

Note: Drs. C. Wang, B. Cao, Q.Q. Liu, Z.Q. Zou, Z.A. Liang, L. Gu, J.P. Dong, and L.R. Liang contributed equally to this article.

Acknowledgment: The authors thank Drs. Jing Zhao, Lai-Ying Fang, Zhi-Tao Tu, Chun Huang, Xiao-Hui Zhai, Xiao-Li Li, Wei Wu, Ran Li, Yi-Qun Guo, Jing-Ya He, Yong Guo, Yu-Dong Yin, Shufan Song, Na Cui, Lu Bai, and Ling-Ling Su, who participated in collection of clinical data, and Drs. Getu Zhaori, Weili Zhang, and Yiqing Song for assistance in careful editing of the manuscript. They also thank Drs. Hua-Xia Chen, Chun-Jiang Zhao, Xiao-Min Yu, Ran Miao, Ying-Mei Liu, and Li-Li Ren, and Mr. Xiang-Yang Ding for technical support.

Grant Support: By the Beijing Science and Technology Project (grants Z08050700020801and Z09000700090903) and the Beijing Nova Program (grant 2007A037).

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2829.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. B. Cao (e-mail, caobin1999@gmail.com).

Requests for Single Reprints: Bin Cao, MD, Department of Infectious Diseases and Clinical Microbiology, Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine, Capital Medical University, Gongti South Road, No. 8, Beijing, 100020 China (e-mail, caobin1999@gmail.com), or Chen Wang, MD, Department of Respiratory Medicine, Capital Medical University; Beijing Institute of Respiratory Medicine; Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders; Beijing Hospital, Ministry of Health, Beijing, 100020 China (e-mail, cyh-birm@263.net).

Current Author Addresses: Dr. C. Wang: Department of Respiratory Medicine, Capital Medical University; Beijing Institute of Respiratory Medicine; Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders; Beijing Hospital, Ministry of Health, Beijing, 100020 China.

Drs. B. Cao and Gu: Department of Infectious Diseases and Clinical Microbiology, Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine, Capital Medical University, Gongti South Road, No. 8, Beijing, 100020 China.

Drs. Q.Q. Liu and Jiang: Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Hai Yuncang Road, No. 5, Beijing, 100700 China.

Drs. Zou and Guo: Yantai Infectious Disease Hospital, Huan Shan Road, No. 62, Yantai, Shandong Province, 341000 China.

Dr. Z.A Liang: West China Medical School, West China Hospital, Sichuan University, Wainan Guoxue Road, No. 37, Chengdu, Sichuan Province, 610041 China.

Dr. Dong: Beijing Haidian Hospital, Haidian Road, Beijing, 100080 China.

Drs. L.R. Liang, Yang, and Z.X. Cao: Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine, Capital Medical University, Gongti South Road, No. 8, Beijing, 100020 China.

Drs. Li and Y.G. Wang: Beijing Ditan Hospital, Institute of Infectious Diseases, Capital Medical University, Jingshun East Road, Beijing, 100018 China.

Dr. Hu: Renmin Hospital of Wuhan University, Ziyang Road No. 99, Wuhan, Hubei Province, 430060 China.

Dr. He: Changxindian Hospital of Fengtai District of Beijing, Beijing, 100072 China.

Dr. Sun: Second Hospital of Chaoyang District of Beijing, Jintai Road, No. 13, Beijing, 100026 China.

Dr. An: Second Hospital of Beijing, Xi Rongxian Road, No. 9, Beijing, 100031 China.

Drs. Wen and Y.L. Liu: Chengdu Infectious Disease Hospital, Jingjusi South Road, Chengdu, Sichuan Province, 610061 China.

Author Contributions: Conception and design: C. Wang, B. Cao, Q.Q. Liu, L. Gu, J.P. Dong, Z.X. Cao, L.D. Jiang.

Analysis and interpretation of the data: B. Cao, L. Gu, L.R. Liang, X.W. Li.

Drafting of the article: B. Cao, L.R. Liang.

Critical revision of the article for important intellectual content: C. Wang, B. Cao, Q.Q. Liu.

Final approval of the article: C. Wang, B. Cao.

Provision of study materials or patients: J.P. Dong, X.W. Li, K. Hu, Y.H. Sun, X.M. Wen, Y.G. Wang, Y.L. Liu.

Statistical expertise: L.R. Liang.

Obtaining of funding: C. Wang.

Administrative, technical, or logistic support: B. Cao, Z.A. Liang, J.P. Dong, X.W. Li.

Collection and assembly of data: B. Cao, Z.Q. Zou, Z.A. Liang, L. Gu, J.P. Dong, L.R. Liang, X.W. Li, K. Hu, X.S. He, Y.H. Sun, Y. An, T. Yang, Y.M. Guo, Y.G. Wang.


Ann Intern Med. 2011;155(4):217-225. doi:10.7326/0003-4819-155-4-201108160-00005
Text Size: A A A

This article has been corrected. The original version (PDF) is appended to this article as a supplement.

Background: Observational studies from Asia suggest that maxingshigan–yinqiaosan may be effective in the treatment of acute H1N1 influenza.

Objective: To compare the efficacy and safety of oseltamivir and maxingshigan–yinqiaosan in treating uncomplicated H1N1 influenza.

Design: Prospective, nonblinded, randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00935194)

Setting: Eleven hospitals from 4 provinces in China.

Patients: 410 persons aged 15 to 69 years with laboratory-confirmed H1N1 influenza.

Intervention: Oseltamivir, 75 mg twice daily; maxingshigan–yinqiaosan decoction (composed of 12 Chinese herbal medicines, including honey-fried Herba Ephedrae), 200 mL 4 times daily; oseltamivir plus maxingshigan–yinqiaosan; or no intervention (control). Interventions and control were given for 5 days.

Measurements: Primary outcome was time to fever resolution. Secondary outcomes included symptom scores and viral shedding determined by using real-time reverse transcriptase polymerase chain reaction.

Results: Significant reductions in the estimated median time to fever resolution compared with the control group (26.0 hours [95% CI, 24.0 to 33.0 hours]) were seen with oseltamivir (34% [95% CI, 20% to 46%]; P < 0.001), maxingshigan–yinqiaosan (37% [CI, 23% to 49%]; P < 0.001), and oseltamivir plus maxingshigan–yinqiaosan (47% [CI, 35% to 56%]; P < 0.001). Time to fever resolution was reduced by 19% (CI, 0.3% to 34%; P = 0.05) with oseltamivir plus maxingshigan–yinqiaosan compared with oseltamivir. The interventions and control did not differ in terms of decrease in symptom scores (P = 0.38). Two patients who received maxingshigan–yinqiaosan reported nausea and vomiting.

Limitations: Participants were young and had mild H1N1 influenza virus infection. Missing viral data precluded definitive conclusions about viral shedding.

Conclusion: Oseltamivir and maxingshigan–yinqiaosan, alone and in combination, reduced time to fever resolution in patients with H1N1 influenza virus infection. These data suggest that maxingshigan–yinqiaosan may be used as an alternative treatment of H1N1 influenza virus infection.

Primary Funding Source: Beijing Science and Technology Project and Beijing Nova Program.

Figures

Grahic Jump Location
Figure.

Study flow diagram.

MY = maxingshigan–yinqiaosan.

* These patients were discharged early and declined to return.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 1.

Fitted curves from accelerated failure time models for median time to fever resolution.

MY = maxingshigan–yinqiaosan.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.

Mean viral titer among 148 participants for whom results were available.

MY = maxingshigan–yinqiaosan.

Grahic Jump Location

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Standardization of Herbal Medicine: Significance and Strategy
Posted on August 26, 2011
Chong-Zhi Wang
Tang Center for Herbal Medicine Research, University of Chicago
Conflict of Interest: None Declared
TO THE EDITOR: Upon reading Wang's article (1) about using a Chinese medicine formulation Maxingshigan-Yinqiaosan, we are very encouraged that the formula showed comparable efficacy with oseltamivir in treating human H1N1 influenza. However, we believe that the formulation named in the article is somewhat misleading. Furthermore, without standardization, the use of Chinese herbal formulations in the West may be limited.

As the authors indicated, their Maxingshigan-Yinqiaosan formulation was composed of two traditional Chinese herbal formulas, Maxinshigan and Yinqiaosan. Maxinshigan contains four Chinese herbs, all of which were used. However, there are several recorded traditional Yinqiaosan formulations; but, compared to each formula, approximately half of the herbs were substituted for different herbs. Thus, it is not accurate to include the name Yinqiaosan for the Maxingshigan-Yinqiaosan formulation. More important than the terminology is how to identify the herbs being tested and to standardize herbal medicine formulations.

The authors stated that the quality of the herbs used was "in accordance with the 2005 Chinese pharmacopoeia." Regarding the identification of herbal species, the formulation contains gancao (Radix et Rhizoma Glycyrrhizae). In the Chinese pharmacopoeia (Volume 1, 2005 edition), there are three Glycyrrhiza species in gancao, but their chemical compositions vary. The content of glycyrrhizin, a major marker compound, showed a twofold difference when the three species were compared (2). Similarly, there are three Ephedra species listed as mahuang (Herba Ephedrae) in the pharmacopoeia.

The composition of an herb also is affected by variable growing conditions, differences in harvesting procedures, and processing of herbal extracts and other preparations (3). Thus, chromatographic fingerprints of the herbal decoction used in the trial should be reported.

For the safe and effective use of herbal medicines, standardizing herbal formulations is essential for consistency in composition and comparable clinical effectiveness. In addition, the potency of herbal medications may vary from manufacturer to manufacturer and from lot to lot within a manufacturer (4). The latest FDA's Draft Guidance for Industry: Dietary Supplements (5) requires tests and controls, which include raw material and process controls, chromatographic fingerprints, and chemical assays including, but not limited to, characteristic markers.

Herbal medicines have been used for thousands of years in different cultures and their widespread use is a potential addition to Western medicine. Establishing a valid herbal quality control system is an urgent issue that must to be resolved with diverse analytical methods and active management.

Chong-Zhi Wang, PhD Chun-Su Yuan, MD, PhD Tang Center for Herbal Medicine Research University of Chicago Chicago, IL 60637

Ping Li, PhD State Key Laboratory of Natural Medicines China Pharmaceutical University Nanjing 210009, China

References

1. Wang C, Cao B, Liu QQ, Zou ZQ, Liang ZA, Gu L, et al. Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: A randomized trial. Ann Intern Med. 2011;155:217-25.

2. Rauchensteiner F, Matsumura Y, Yamamoto Y, Yamaji S, Tani T. Analysis and comparison of Radix Glycyrrhizae (licorice) from Europe and China by capillary-zone electrophoresis (CZE). J Pharm Biomed Anal. 2005;38:594-600.

3. Marcus DM, Grollman AP. Botanical medicines--the need for new regulations. N Engl J Med. 2002;347:2073-6.

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

5. U.S. Food and Drug Administration. Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues. 2011. Accessed at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm257563.htm on August 24, 2011.

Conflict of Interest:

None declared

Role of Chinese medicine and health food for influenza infection
Posted on September 10, 2011
Hiroshi Yamada
University of Shizuoka
Conflict of Interest: None Declared

TO THE EDITOR: Wang et al. (1) reported that the use of oseltamivir and maxingshigan-yinqiaosan--alone and in combination--reduced the time to fever resolution in patients with H1N1 influenza virus infection, and suggested that maxingshigan-yinqiaosan may be used as an alternative treatment for H1N1 influenza virus infection when oseltamivir is not available.

Recent studies have reported that Chinese medicine and health food not only mitigate the symptoms of influenza and facilitate recovery but are also effective in preventing influenza. We have previously performed a small prospective cohort study on the topical effect of gargling with extracts of tea catechin, a major component of tea polyphenols, with respect to preventing influenza infection in elderly nursing home residents (2). Furthermore, we performed an epidemiological study involving schoolchildren and reported that consuming 1-5 cups of green tea daily was inversely associated with the incidence of influenza infection among schoolchildren in a tea plantation area in Japan (3). In another epidemiological study, we compared the results obtained for rural and urban regions on performing an anonymous questionnaire survey on the incidence of and strategies for preventing influenza infection. The study was performed from October 2007 to February 2008 and included a total of 2,653 children from all the elementary schools in Kikugawa City (rural tea plantation area) and 2,387 children from 3 elementary schools selected from the downtown area of Shizuoka City (prefectural government city). The incidence rate of influenza infection was 13.1% (293 children) in Kikugawa City and 17.7% (386) in Shizuoka City; the rate of green tea gargling in Kikugawa City (40.7%) was higher than that in Shizuoka City (20.6%).

Medicines such as oseltamivir may not be easily available depending on the area (e.g. rural area); therefore, we think that Chinese medicine or health food can be used as an alternative treatment or a preventive method for influenza infection. We agree with Wang et al. (4) that establishing a valid herbal quality control system for standardization is an urgent issue that must be resolved by using diverse analytical methods and active management. Sequentially, as well as Western medicine, the effectiveness and safety of Chinese medicine and health food should be scientifically confirmed by performing clinical trials such as randomized controlled trials (RCTs).

Mijong Park, Ph.D.

Hiroshi Yamada, M.D., Ph.D., F.A.C.P.

Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan

References:

1. Wang C, Cao B, Liu QQ, Zou ZQ, Liang ZA, Gu L, et al. Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: A randomized trial. Ann Intern Med. 2011;155:217-225. [PMID: 21844547]

2. Yamada H, Takuma N, Daimon T, Hara Y. Gargling with tea catechin extracts for the prevention of influenza infection in elderly nursing home residents: A prospective clinical study. J Altern Complement Med. 2006;12:669-672. [PMID: 16970537]

3. Park M, Yamada H, Matsushita K, Kaji S, Goto T, Okada Y, et al. Green tea consumption is inversely associated with the incidence of influenza infection among schoolchildren in a tea plantation area of Japan. J Nutr. Epub 2011 Aug 10. [PMID: 21832025]

4. Wang CZ, Yuan CS, Li P. Standardization of herbal medicine: Significance and strategy. Ann Intern Med [Internet]. 2011 August 26 [cited 2011 Aug 30]. Available from: http://www.annals.org/content/155/4/217.abstract/reply

Conflict of Interest:

None declared

Author's response
Posted on October 31, 2011
Bin, Cao, MD, Chen Wang. M.D. Ph.D. Department of Respiratory Medicine, Capital Medical University; Beijing Institute of Respiratory Medicine; Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders; Beijing Hospital, Ministry of Health, Beijing, Qing
Department of Infectious Diseases and Clinical Microbiology, Beijing Chao-Yang Hospital, Beijing Ins
Conflict of Interest: None Declared

TO THE EDITOR -- We appreciate the comments from Drs. Wang CZ, Yuan CS and Li P (1) to our article, "Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: A randomized trial" (2). We agree that standardization is essential for the use of Chinese herbal medicine not only in China, but also in the West.

Yinqiaosan was first reported in an ancient Chinese medicine book named "Wen Bing T ia o Bian" by Dr. Ju -T ong W u in 1789. After publication , the original composition of Yinqiaosan ha s been modified by many Chinese medicine practitioners according to different kind s of acute respiratory infections. In China, the termination of modifi ed formula of Yinqiaosan was not changed. We agreed that the Maxingshigan-Yinqiaosan formulation which composed of 12 kinds of Chinese herb medicine in our study was not exactly the same as recorded in "Wen B ing T iao B ian". For the reference of readers, we have detailed all the 12 herbs in our Appendix Table 1 (2).

We fully agreed with Drs. Wang CZ, Yuan CS and Li P that e stablishing a valid herbal quality control system is an urgent issue that must to be resolved with strict analytical methods. Though difficulties in quality control of herbs in production, processing, and marketing, it is possible to establish bioactive marker compounds for their effective application. High-performance liquid chromatography, gas chromatography, and capillary electrophoresis have been successfully applied to separation techniques for qualitative and quantitative analysis of Traditional Chinese Medicines ( TCMs ) (3 , 4 ). In our study, the quality of the herbs and decoction was in accordance with Chinese pharmacopoeia (2005). All the herbs were supplied by the same manufacturer (Beijing Tcmages Pharma ceutical Co., Ltd. ) with the same lots. We added the source of harvest and the analytical results of all the herbs we used in our study (Table 1).

Table 1 : S ource of harvest and the analytical results of all the herbs in our study

 

Source of Harvest

Bioactive marker compounds determined by Spectroscopic methods

Similarity with positive control

Report number by manufacturer

Zhimahuang

Nei Meng Province

EPHEDRINE HYDROCHLORIDE (C 10 H 15 NO.HCl)1.0%

0.9771

YD0903123

Zhimu

He Bei Province

sarsasapogenin ( C 27 H 44 O 3 ) 1.3%

0.9733

YD0906105

Qinghao 

He Bei Province

Ethyl alcohol extract 2.5%

0.9483

YD0906106

Shigao

He Bei Province

hydrated calcium sulphate ( CaSO 4 ? 2H 2 O ) 99.6%

0.9818

YD0906095

Yinhua

He Nan Province

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