Study designs of randomized controlled trials not based on Chinese medicine theory are improper
© Yan et al; licensee BioMed Central Ltd. 2009
Received: 07 July 2006
Accepted: 25 February 2009
Published: 25 February 2009
Current biomedical research methods to evaluate the efficacy of Chinese medicine interventions are often conceptually incompatible with the theory and clinical practice of Chinese medicine. In this commentary, we (1) highlight the theory and principles underlying Chinese medicine clinical practice; (2) use ginseng as an example to describe clinical indications in Chinese medicine; (3) propose a framework guided by Chinese medicine theory for the evaluation of study designs in Chinese medicine research; and (4) evaluate 19 randomized, double-blind, placebo-controlled trials of ginseng. Our analysis indicates that all 19 trials with both positive and negative results confirm the specific effects of ginseng indicated by Chinese medicine theory. Study designs guided by Chinese medicine theory are necessary to validate and improve future randomized controlled clinical trials in Chinese medicine.
Chinese medicine remains popular in China where traditional herbal preparations are estimated to account for 30–50% of the total medicinal consumption . Chinese medicine has also been gaining popularity in the West [1–3]. However, Chinese medicine lacks funding and leading scientists to conduct scientific research (e.g. randomized controlled trials) .
The study of ginseng provides an example of the research challenges in Chinese medicine. Highly valued in the Chinese medicine classics and widely used in China for more than two thousand years, ginseng has yet to prove its safety and efficacy through clinical trials [5, 6], which, many investigators believe, may be attributed to a paradigm conflict and the poor quality of some clinical trials [7, 8].
We found that this paradigm conflict may be resolved by using study designs guided by Chinese medicine theory.
Chinese medicine theory
Chinese medicine is a syndrome-oriented holistic medical system that is conceptually distinct from its Western counterpart. According to Chinese medicine theory, a syndrome is a group of associated signs and symptoms described in terms of Yin and Yang, Qi, and Xue (blood) . All illnesses fall into eight principal categories used to guide the prevention and treatment of illnesses . These categories are Yin and Yang, Biao (exterior) and Li (interior), Han (coldness) and Re (heat), and Xu (deficiency) and Shi (excess). Western medicine, however, views a disease or syndrome as pathological changes of specific biological processes . As a result, the syndromes in Chinese medicine do not always correspond with Western classifications of diseases and syndromes. For instance, hypertension may be related to syndromes of Gan (liver) Yang ascending, Yin deficiency of liver and kidney, flaming liver fire, stagnation of phlegm, Xue stasis and/or dual Yin/Yang deficiency . Conversely, Qi-deficiency syndrome is related to chronic obstructive pulmonary disease , lung cancer , coronary heart disease  and persistent allergic rhinitis .
In Chinese medicine, medicinal herbs are categorized according to the concepts of Yin, Yang, Qi, Xue, Jing (essence) and Jin (body fluid) . In general, 'tonics' are used to treat deficiency and 'clear-ups' are used to treat excess .
Impalpable pulse caused by severe Qi-deficiency;
Shortness of breath, feeble voice, spontaneous sweating and a weak pulse caused by Fei (lung) Qi-deficiency;
Fatigue, anorexia and loose bowels caused by Pi (spleen) Qi-deficiency;
Fever and strong thirst caused by Qi-deficiency;
Palpitation, insomnia and forgetfulness caused by dual deficiency of Qi and Xue.
Study design compatible with Chinese medicine theory
Instead of evaluating the efficacy of ginseng in all patients suffering from a single disease, researchers should focus on those patients with Qi-deficiency syndrome. Qi-deficiency causes decreased visceral functions and lowered immune resistance, leading to various diseases. The manifestations of Qi-deficiency include lassitude, shortness of breath, feeble voice, dizziness, spontaneous perspiration, susceptibility to cold, pale tongue and weak pulse .
Chinese medicine practitioners prescribe herbal medications to rectify disharmony in a patient's system . Healthy individuals should not participate in treatment groups in Chinese medicine studies. This explains the negative results from the ginseng studies in which healthy individuals participated [17–21].
Ginseng is a Qi-tonifying herb to treat five major syndromes  caused by Qi-deficiency. Therefore, we argue that only studies in which participants are diagnosed with Qi-deficiency are valid to evaluate ginseng's efficacy [22–25].
While at least eight species of ginseng are commercially available , only two major species, namely Panax ginseng (Chinese or Korean ginseng) and Panax quinquefolius (American ginseng), are used as medicinal herbs worldwide. According to Chinese medicine theory, the properties and functions of these two species are quite different . While P. ginseng enhances Yang, P. quinquefolius nourishes Yin. A search for randomized controlled trials of ginseng in PubMed (7 September 2008) found that about one-third of the studies did not mention the ginseng species used and that very few studies addressed the species issue.
Herbal quality may affect research results. Different batches of P. ginseng [27, 28] or P. quinquefolius  produced opposing study results respectively on acute postprandial glycemia. The primary active ingredients in ginseng are ginsenosides. G115, a ginsenoside-based standardized extract of P. ginseng, may help assess the efficacy and safety of ginseng. In fact, G115 was used in most P. ginseng (single herb) trials reviewed in this paper.
In Chinese medicine, herbs are often formulated to achieve increased therapeutic effects and reduced toxicity or side effects . Results from clinical trials on herbal formulae confirm this practice. A Japanese trial found that a 7-herb formula was effective in preventing liver cancer in cirrhosis patients . Two British trials showed that a 10-herb formula was effective in treating a severe atopic eczema [31, 32]. No single herbal ingredient explains the efficacy in these studies . Furthermore, ginseng herbal formulae were shown to be effective in treating chronic pulmonary disease [22, 34], congenital heart disease [35, 36], mild cognitive impairment , coronary heart disease  and nasopharyngeal carcinoma .
Certain Chinese medicine herbs are toxic and others may have adverse effects when used improperly . A condition known as the ginseng abuse syndrome is characterized by heart palpitations, heaviness in the chest, high blood pressure, dizziness, insomnia, agitation, restlessness, nausea, vomiting, abdominal pain and/or bloating, diarrhea, possible upper digestive tract bleeding, edema, and red skin rash . Most of these reported adverse effects are common manifestations of Qi-excess and Qi-stasis. While all clinical trials should document adverse effects, only one trial did do so .
Re-examination of equivocal ginseng trial results
Summary of results from single herb ginseng clinical trials
Chinese medicine theory
Allen JD et al. (1998)
Healthy young (28)
Cardinal BJ et al. (2001)
Healthy young adults (83)
Caron MF et al. (2002)
Healthy adults (30)
Dowling EA et al. (1996)
Highly trained distance runners (20)
Engels HJ et al. (1997)
Physiologic and psychological responses
Healthy adults (36)
Engels HJ et al. (2001)
Exercise & short-term recovery
Healthy active women (24)
Engels HJ et al. (2003)
Physical performance heart rate recovery
Active healthy adults (38)
Stavro PM et al. (2006)
Blood pressure and renal function
Inappropriate herb species
Wiklund IK et al. (1999)
Quality of life & physiological parameters
Symptomatic postmenopausal women (384)
Inappropriate herb species
Cicero AF et al. (2004)
Quality of life
Elderly hypertensive and digitalized (20)
Appropriate herb species
de Andrade E et al. (2007)
Erectile dysfunction (60)
Ellis JM et al. (2002)
Quality of life
Healthy young (30)
Gross D et al. (2002)
Chronic Obstructive Pulmonary Disease (COPD) (92)
Hong B et al. (2002)
Erectile dysfunction (45)
Kim JH et al. (2006)
Quality of life
Liang MT et al. (2005)
Untrained adults (29)
Appropriate herb species
McElhaney JE et al. (2004)
Acute respiratory illness
Sub healthy seniors(198)
McElhaney JE et al. (2006)
Acute respiratory illness
Sub healthy adults and seniors (43)
Predy GN et al. (2005)
Sub healthy adults (323)
Out of the 19 trials, nine had negative results, ten had positive results, and none targeted ginseng's efficacy on Qi-deficiency syndromes.
Both healthy and unhealthy participants were evaluated for the effects of ginseng. Seven out of the nine trials with negative results involved healthy participants, whereas eight out of the ten studies with positive results had participants with Qi-deficiency manifested by cancer, impotence and pulmonary disease. Ellis et al.  investigated the time-dependent effects of P. ginseng on the quality of life in a healthy young adult population. In this case, the participants had marginal Qi-deficiency as young adults are at the stage of 'gradual filling of Qi and Xue'  according to Chinese medicine theory.
The species of ginseng may be a confounding factor in the interpretation of trial results, which is illustrated by four trials as follows (Table 1).
Stavro et al.  enrolled 52 hypertensive participants to evaluate the long-term effects of P. quinquefolius on blood pressure . Long-term use of ginseng was reported to be associated with the development of hypertension, which was refuted by Stavro et al. In Chinese medicine practice, however, P. quinquefolius, unlike its cousin P. ginseng, is in fact used to treat hypertension in some cases.
Wiklund et al.  reported a trial in which 384 symptomatic postmenopausal women were assessed for the effects of P. ginseng on the quality of life and physiological parameters. Postmenopausal symptoms such as hot flashes are often regarded as Shen (kidney) Yin-deficiency  and are treated with P. quinquefolius rather than P. ginseng. Moreover, the use of P. ginseng in this study was contraindicated and might have produced adverse effects.
Cicero et al.  studied 20 elderly hypertensive and digitalized patients treated with Acanthopanax senticosus (Siberian ginseng) which is a mild Qi-tonic for an unspecific feeling of fatigue, a sign of Qi-deficiency . Hypertension is manifested in five syndromes , of which Qi-deficiency is only a minor one. The positive results from this trial were due to the fact that A. senticosus, an alternative Qi-tonic, was used .
Liang et al.  found that P. notoginseng improved endurance time to exhaustion and lowered mean blood pressure in 29 untrained young adults during an endurance exercise. P. notoginseng is another important ginseng species classified as homeostatic medicine to arrest bleeding and removes stagnant Xue.
Our analysis of 19 randomized controlled clinical trials of single herb ginseng shows that all the trials with both negative and positive results confirm the specific effects of ginseng indicated by Chinese medicine theory. Therefore, study designs guided by Chinese medicine theory are necessary to validate and improve future randomized controlled clinical trials in Chinese medicine.
We are grateful to the anonymous reviewers for their critical comments on this manuscript.
- World Health Organization. [http://www.who.int/mediacentre/factsheets/fs134/en/]
- Hesketh T, Zhu WX: Health in China. Traditional Chinese medicine: one country, two systems. Bmj. 1997, 315: 115-117.PubMed CentralView ArticlePubMedGoogle Scholar
- Ernst E: The role of complementary and alternative medicine. Bmj. 2000, 321: 1133-1135. 10.1136/bmj.321.7269.1133.PubMed CentralView ArticlePubMedGoogle Scholar
- Normile D: Asian medicine. The new face of traditional Chinese medicine. Science. 2003, 299: 188-190. 10.1126/science.299.5604.188.View ArticlePubMedGoogle Scholar
- Xiang YZ, Shang HC, Gao XM, Zhang BL: A comparison of the ancient use of ginseng in traditional Chinese medicine with modern pharmacological experiments and clinical trials. Phytother Res. 2008, 22: 851-858. 10.1002/ptr.2384.View ArticlePubMedGoogle Scholar
- Vogler BK, Pittler MH, Ernst E: The efficacy of ginseng. A systematic review of randomised clinical trials. Eur J Clin Pharmacol. 1999, 55: 567-575. 10.1007/s002280050674.View ArticlePubMedGoogle Scholar
- Shea JL: Applying evidence-based medicine to traditional chinese medicine: debate and strategy. J Altern Complement Med. 2006, 12: 255-263. 10.1089/acm.2006.12.255.View ArticlePubMedGoogle Scholar
- De Smet PA: Herbal remedies. N Engl J Med. 2002, 347: 2046-2056. 10.1056/NEJMra020398.View ArticlePubMedGoogle Scholar
- Li D: Basic Theory of Traditional Chinese Medicine. 2006, Beijing: People's Medical Publishing House, 1Google Scholar
- Ji S, Cheng Z: Traditional Chinese Diagnostics. 2005, Beijing: People's Medical Publishing House, 1Google Scholar
- Zou ZD, Liu N, Guo P, Guo LY, Sun Y, Shi J, Wang L: [Analysis on clinical treatment in hypertension by traditional Chinese medicine for 10 years in Beijing]. Zhongguo Zhong Yao Za Zhi. 2007, 32: 1569-1572.PubMedGoogle Scholar
- Xu XY, Liu QR, Chen J: [Clinical observation of Qi deficiency syndrome in 72 patients with chronic obstructive pulmonary disease treated with yiqi mianyi granule]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1996, 16: 81-83.PubMedGoogle Scholar
- Wang XM, Yu RC, Wang YT: [Study on advanced non-small cell lung cancer patients with Qi deficiency and blood stasis syndrome]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1994, 14: 724-726.PubMedGoogle Scholar
- Li J, Zhang MZ, Chen BJ: [Effect of tongguan capsule on post-intervention patients of coronary heart disease with qi-deficiency and blood stasis syndrome]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2008, 28: 32-35.PubMedGoogle Scholar
- Liu Q, Liu J, Liu D: Clinical research into ke min yin for treatment of persistent allergic rhinitis in patients with qi deficiency and blood stasis. J Tradit Chin Med. 2003, 23: 106-108.PubMedGoogle Scholar
- Huang Z: Traditional Chinese Pharmacology. 2006, Beijing: People's Medical Publishing House, 1Google Scholar
- Allen JD, McLung J, Nelson AG, Welsch M: Ginseng supplementation does not enhance healthy young adults' peak aerobic exercise performance. J Am Coll Nutr. 1998, 17: 462-466.View ArticlePubMedGoogle Scholar
- Cardinal BJ, Engels HJ: Ginseng does not enhance psychological well-being in healthy, young adults: results of a double-blind, placebo-controlled, randomized clinical trial. J Am Diet Assoc. 2001, 101: 655-660. 10.1016/S0002-8223(01)00165-1.View ArticlePubMedGoogle Scholar
- Engels HJ, Fahlman MM, Wirth JC: Effects of ginseng on secretory IgA, performance, and recovery from interval exercise. Med Sci Sports Exerc. 2003, 35: 690-696. 10.1249/01.MSS.0000058363.23986.D2.View ArticlePubMedGoogle Scholar
- Engels HJ, Kolokouri I, Cieslak TJ, Wirth JC: Effects of ginseng supplementation on supramaximal exercise performance and short-term recovery. J Strength Cond Res. 2001, 15: 290-295. 10.1519/1533-4287(2001)015<0290:EOGSOS>2.0.CO;2.PubMedGoogle Scholar
- Engels HJ, Wirth JC: No ergogenic effects of ginseng (Panax ginseng C.A. Meyer) during graded maximal aerobic exercise. J Am Diet Assoc. 1997, 97: 1110-1115. 10.1016/S0002-8223(97)00271-X.View ArticlePubMedGoogle Scholar
- Gross D, Shenkman Z, Bleiberg B, Dayan M, Gittelson M, Efrat R: Ginseng improves pulmonary functions and exercise capacity in patients with COPD. Monaldi Arch Chest Dis. 2002, 57: 242-246.PubMedGoogle Scholar
- Kim JH, Park CY, Lee SJ: Effects of sun ginseng on subjective quality of life in cancer patients: a double-blind, placebo-controlled pilot trial. J Clin Pharm Ther. 2006, 31: 331-334. 10.1111/j.1365-2710.2006.00740.x.View ArticlePubMedGoogle Scholar
- McElhaney JE, Gravenstein S, Cole SK, Davidson E, O'Neill D, Petitjean S, Rumble B, Shan JJ: A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr Soc. 2004, 52: 13-19. 10.1111/j.1532-5415.2004.52004.x.View ArticlePubMedGoogle Scholar
- Predy GN, Goel V, Lovlin R, Donner A, Stitt L, Basu TK: Efficacy of an extract of North American ginseng containing poly-furanosyl-pyranosyl-saccharides for preventing upper respiratory tract infections: a randomized controlled trial. Cmaj. 2005, 173: 1043-1048.PubMed CentralView ArticlePubMedGoogle Scholar
- Sievenpiper JL, Arnason JT, Leiter LA, Vuksan V: Decreasing, null and increasing effects of eight popular types of ginseng on acute postprandial glycemic indices in healthy humans: the role of ginsenosides. J Am Coll Nutr. 2004, 23: 248-258.View ArticlePubMedGoogle Scholar
- Sievenpiper JL, Arnason JT, Leiter LA, Vuksan V: Null and opposing effects of Asian ginseng (Panax ginseng C.A. Meyer) on acute glycemia: results of two acute dose escalation studies. J Am Coll Nutr. 2003, 22: 524-532.View ArticlePubMedGoogle Scholar
- Sievenpiper JL, Sung MK, Di Buono M, Seung-Lee K, Nam KY, Arnason JT, Leiter LA, Vuksan V: Korean red ginseng rootlets decrease acute postprandial glycemia: results from sequential preparation- and dose-finding studies. J Am Coll Nutr. 2006, 25: 100-107.View ArticlePubMedGoogle Scholar
- Sievenpiper JL, Arnason JT, Leiter LA, Vuksan V: Variable effects of American ginseng: a batch of American ginseng (Panax quinquefolius L.) with a depressed ginsenoside profile does not affect postprandial glycemia. Eur J Clin Nutr. 2003, 57: 243-248. 10.1038/sj.ejcn.1601550.View ArticlePubMedGoogle Scholar
- Oka H, Yamamoto S, Kuroki T, Harihara S, Marumo T, Kim SR, Monna T, Kobayashi K, Tango T: Prospective study of chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9). Cancer. 1995, 76: 743-749. 10.1002/1097-0142(19950901)76:5<743::AID-CNCR2820760506>3.0.CO;2-V.View ArticlePubMedGoogle Scholar
- Sheehan MP, Atherton DJ: One-year follow up of children treated with Chinese medicinal herbs for atopic eczema. Br J Dermatol. 1994, 130: 488-493. 10.1111/j.1365-2133.1994.tb03383.x.View ArticlePubMedGoogle Scholar
- Sheehan MP, Atherton DJ: A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema. Br J Dermatol. 1992, 126: 179-184. 10.1111/j.1365-2133.1992.tb07817.x.View ArticlePubMedGoogle Scholar
- Xue T, Roy R: Studying traditional Chinese medicine. Science. 2003, 300: 740-741. 10.1126/science.300.5620.740.View ArticlePubMedGoogle Scholar
- Wang W, Niu RJ: [Effects of sheng mai injection on thoracoabdominal motion]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1993, 13: 91-93.PubMedGoogle Scholar
- Ding DZ, Shen TK, Cui YZ: [Effects of red ginseng on the congestive heart failure and its mechanism]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1995, 15: 325-327.PubMedGoogle Scholar
- Xia ZY, Liu XY, Zhan LY, He YH, Luo T, Xia Z: Ginsenosides compound (shen-fu) attenuates gastrointestinal injury and inhibits inflammatory response after cardiopulmonary bypass in patients with congenital heart disease. J Thorac Cardiovasc Surg. 2005, 130: 258-264. 10.1016/j.jtcvs.2005.02.046.View ArticlePubMedGoogle Scholar
- Tian JZ, Zhu AH, Zhong J: [A follow-up study on a randomized, single-blind control of King's Brain pills in treatment of memory disorder in elderly people with MCI in a Beijing community]. Zhongguo Zhong Yao Za Zhi. 2003, 28: 987-991.PubMedGoogle Scholar
- Hu JX, Jia GX, Yan ZR: [Clinical and experimental study of shenshao tongguan pian in treating angina pectoris of coronary heart disease]. Zhong Xi Yi Jie He Za Zhi. 1990, 10: 596-599.PubMedGoogle Scholar
- Xie FY, Zeng ZF, Huang HY: [Clinical observation on nasopharyngeal carcinoma treated with combined therapy of radiotherapy and ginseng polysaccharide injection]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2001, 21: 332-334.PubMedGoogle Scholar
- Siegel RK: Ginseng abuse syndrome. Problems with the panacea. Jama. 1979, 241: 1614-1615. 10.1001/jama.241.15.1614.View ArticlePubMedGoogle Scholar
- Scaglione F, Cattaneo G, Alessandria M, Cogo R: Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Exp Clin Res. 1996, 22: 65-72.PubMedGoogle Scholar
- Caron MF, Hotsko AL, Robertson S, Mandybur L, Kluger J, White CM: Electrocardiographic and hemodynamic effects of Panax ginseng. Ann Pharmacother. 2002, 36: 758-763. 10.1345/aph.1A411.View ArticlePubMedGoogle Scholar
- Dowling EA, Redondo DR, Branch JD, Jones S, McNabb G, Williams MH: Effect of Eleutherococcus senticosus on submaximal and maximal exercise performance. Med Sci Sports Exerc. 1996, 28: 482-489.View ArticlePubMedGoogle Scholar
- de Andrade E, de Mesquita AA, Claro Jde A, de Andrade PM, Ortiz V, Paranhos M, Srougi M: Study of the efficacy of Korean Red Ginseng in the treatment of erectile dysfunction. Asian J Androl. 2007, 9: 241-244. 10.1111/j.1745-7262.2007.00210.x.View ArticlePubMedGoogle Scholar
- Hong B, Ji YH, Hong JH, Nam KY, Ahn TY: A double-blind crossover study evaluating the efficacy of korean red ginseng in patients with erectile dysfunction: a preliminary report. J Urol. 2002, 168: 2070-2073. 10.1016/S0022-5347(05)64298-X.View ArticlePubMedGoogle Scholar
- McElhaney JE, Goel V, Toane B, Hooten J, Shan JJ: Efficacy of COLD-fX in the prevention of respiratory symptoms in community-dwelling adults: a randomized, double-blinded, placebo controlled trial. J Altern Complement Med. 2006, 12: 153-157. 10.1089/acm.2006.12.153.View ArticlePubMedGoogle Scholar
- Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ: Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996, 17: 1-12. 10.1016/0197-2456(95)00134-4.View ArticlePubMedGoogle Scholar
- Ellis JM, Reddy P: Effects of Panax ginseng on quality of life. Ann Pharmacother. 2002, 36: 375-379. 10.1345/aph.1A245.View ArticlePubMedGoogle Scholar
- Stavro PM, Woo M, Leiter LA, Heim TF, Sievenpiper JL, Vuksan V: Long-term intake of North American ginseng has no effect on 24-hour blood pressure and renal function. Hypertension. 2006, 47: 791-796. 10.1161/01.HYP.0000205150.43169.2c.View ArticlePubMedGoogle Scholar
- Wiklund IK, Mattsson LA, Lindgren R, Limoni C: Effects of a standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebo-controlled trial. Swedish Alternative Medicine Group. Int J Clin Pharmacol Res. 1999, 19: 89-99.PubMedGoogle Scholar
- Zell B, Hirata J, Marcus A, Ettinger B, Pressman A, Ettinger KM: Diagnosis of symptomatic postmenopausal women by traditional Chinese medicine practitioners. Menopause. 2000, 7: 129-134. 10.1097/00042192-200007020-00010.View ArticlePubMedGoogle Scholar
- Cicero AF, Derosa G, Brillante R, Bernardi R, Nascetti S, Gaddi A: Effects of Siberian ginseng (Eleutherococcus senticosus maxim.) on elderly quality of life: a randomized clinical trial. Arch Gerontol Geriatr Suppl. 2004, 69-73. 10.1016/j.archger.2004.04.012.Google Scholar
- Yin H: Basic Theory of Traditional Chinese Medicine. 1991, Shanghai: Shanghai Scientific and Technical Publishers, 1Google Scholar
- Liang MT, Podolka TD, Chuang WJ: Panax notoginseng supplementation enhances physical performance during endurance exercise. J Strength Cond Res. 2005, 19: 108-114.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.