THE REDISCOVERY OF ANCIENT CHINESE HERBAL FORMULAS 681

Copyright © 2004 John Wiley & Sons, Ltd. Phytother. Res. 18, 681–686 (2004)

Copyright © 2004 John Wiley & Sons, Ltd.

Received 12 September 2003Accepted 16 March 2004

PHYTOTHERAPY RESEARCHPhytother. Res. 18, 681–686 (2004)Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ptr.1506

LETTER TO THE EDITORThe Rediscovery of Ancient Chinese HerbalFormulas

Wei Jia1*, Wen-yuan Gao2, Yong-qing Yan3, Jie Wang4, Zhao-hui Xu1, Wen-jie Zheng1 andPei-gen Xiao5

1School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China2College of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China3China Pharmaceutical University, Nanjing, China4Xi-yuan Hospital, The Institute of Traditional Chinese Medicine, Beijing, China5Institute of Medicinal Plant, Chinese Academy of Medical Science and Peking Union Medical University, Beijing, China

This review presents some recent discoveries of ancient Chinese herbal formulas evolved through thousandsof years of clinical practice. It appears that many of the ancient combination formulas have sound scientificbasis through modern pharmacological evaluation. Significant chemical changes occurred during the prepara-tion (decoction) process of a prescribed herbal formula. For example, some toxic ingredients were significantlyreduced and new active compounds generated due to the chemical interactions among the ingredients. Manycombination formulas showed significantly better pharmacological results than individual herbal medicinesparticipated in the formula. These findings suggest that the current drug screening and regulatory methodologywill not be appropriate for the development of a botanical drug containing a group of phytochemicals, inwhich a synergistic interaction from chemical ingredients plays a fundamental role in the treatment of disease.If we view a diseased state in a holistic and dynamic way, i.e. it involves interactions among many biologicalsystems in human body and these interactions change as the disease improves or worsens, the treatment ofsuch disease with a single chemical entity may not be logical or technically feasible. Combination formulasmay hold the potential to become the therapeutics of choice in the future due to the synergistic effect anddynamic adjustment achieved by the multiple ingredients that will restore the balance of an imbalanced ordiseased human body. Copyright © 2004 John Wiley & Sons, Ltd.

Keywords: traditional Chinese medicine; combination herbal formulas; phytochemicals; herbal medicine.

INTRODUCTION

The formation of prescriptions with combination herbalformulas has undergone a considerably long history.Through long clinical practice, Chinese ancestors rec-ognized that a recipe composed of two or more drugsproved more advantageous for disease treatment. Theoldest extant medical formulary books are The Pre-scriptions for 52 Kinds of Diseases and Huangdi’s Classicon Medicine, dated over 2000 years ago (Fan, 2002).The former was discovered in 1973 during the excava-tion of the Ma Wang Dui tomb (dated 168 BC) atChangsha of Hunan Province. The Prescriptions listed52 diseases, with 283 known prescriptions for their treat-ment, over two-thirds of which were combination for-mulas containing two or more components (Jia, 2002).

With the inception, growth and development oftraditional Chinese medicine (TCM), the science of com-bination herbal formulas has experienced a long devel-opment process and has become a main therapeuticconcept in today’s traditional medicine in China andmany Asian countries. One of the most famous ancientformulary books is The Synopsis of Golden Cabinet

written by Zhang Zhong-jing about 1800 years ago, inwhich 210 herbal formulas were collected. Based onthese 210 ancient formulas, traditional Japanese medi-cine, also known as ‘kampo’, has developed 147 drugproducts, which constitute the main body of today’sherbal medicine industry in Japan. The word kampo inJapanese is a generic term for Chinese medicine. Theliteral meaning of kampo is the treatment system of theHans (Chinese) (Sasaki, 2001; Jia, 2002).

TCM assumes synergy to be taking place in a com-bination herbal formula and it has become an intrinsicpart of its philosophy. Speculation as to the reason forthis, whether it involves synergy, reduced toxicity, en-hanced bioavailability, cumulative effects or simply theadditive properties of the constituents requires researchwith modern scientific means as well as a thoroughunderstanding of the TCM theory. This paper outlinesand discusses some of the issues involved in the researchof Chinese ancient herbal formulas.

Traditional Chinese medicine is governed by the sameprinciples of balance and harmony that run throughoutthe traditional Chinese arts and sciences. TraditionalChinese science was based on the ‘Theory of Birth-to-Death’ and characterized by the ‘Cycle-Production’model (Wang et al., 2001). Influenced by the thinkingmodel of traditional culture, the TCM takes Qi as itscore conception to describe and summarize the liveactivities of human body, and uses Yin-yang and the

* Correspondence to: Dr W. Jia, School of Pharmacy, Shanghai Jiao TongUniversity, Shanghai 200030, China.E-mail: weijia@mail:sjtu.edu.cn

682 W. JIA ET AL.

Copyright © 2004 John Wiley & Sons, Ltd. Phytother. Res. 18, 681–686 (2004)

not designed specifically for either constipation ordiarrhea. In the formula, Ginseng is used for invigorat-ing Qi, as the Monarch drug to strengthen the spleen;Atractylodis is used for invigorating the spleen andeliminating ‘dampness’, as the Minister drug; Poriaserves as the Adjuvant drug to eliminate ‘dampness’and strengthen the spleen; and Glycyrrhizae is used tomediate the therapeutic actions of the other three, andtherefore, as the Guiding drug. Pharmacological re-search revealed that such a decoction agent was able tosignificantly inhibit the spontaneous contraction of theisolated segments from the rabbit jejunum. This agentantagonized the contractions of isolated rabbit ileumand guinea pig ileum induced with acetylcholine andhistamine, respectively. It also antagonized the adrena-line induced inhibitory effect on the isolated rabbitileum. These results indicated that such a herbal decoc-tion can effect a two-way regulation on the gastro-intestinal activities, and therefore, explained its abilityto regulate constipation and diarrhea (Wang and Zhang,2002).

We have previously reviewed all of the herbal drugsapproved for diabetes mellitus available in the Chinesemarket, most of which were derived from ancient com-bination formulas (Jia et al., 2003). It was believed,through pharmacological research, that herbal medi-cines were meticulously organized in these formulassuch that polysaccharides-containing herbs restore thefunctions of pancreatic tissues and caused an increasein insulin output by the functional beta cells while otheringredients inhibit the intestinal absorption of glucose,increase availability of insulin, enhance the microcircula-tion and facilitate metabolization in insulin-dependentprocesses. For a specific disease, the combination for-mulas achieve an overall therapeutic effect with manydifferent components and different mechanisms of ac-tion, like a ‘cocktail therapy’ of the HIV treatment.

INTERACTIONS WITHIN HERBAL MEDICINES

A combination herbal formula does not mean a quan-titative addition of different herbs but more complexinteraction and interrelationship among herbs withdifferent therapeutic functions. The study on the inter-relationship of each herb in a well-organized formulashowed that there are different interrelationships be-tween herbal drugs in a formula such as synergism (twodrugs with similar effect reinforcing each other), assist-ing (strengthening effect of another drug), detoxication,antagonism (reducing curative effects), and rejection(increasing toxicity). The research with ‘Sini Decoc-tion’, an ancient combination formula, showed thatthis compounding agent could significantly strengthenmyocardium (Chen and Wu, 2001). The main com-ponent in this formula, Radix aconiti Praeparata, has amild effect of strengthening the heart. However, whencombined with dried ginger (Rhizoma Zingiberis), theknown pharmacological effect of which is almost irrel-evant to heart in the formula, the two herbs can readilyincrease the contraction of myocardium and dilatethe coronary artery. This is strong evidence of the rela-tionship of drug reinforcement. Additionally, duringthe decoction of this formula, Liquorice root (Radixglycyrrhizae praeparatae) was able to greatly reduce

Five Elements as its basic model to establish a systemof physiology, pathology, diagnosis and therapy of dis-eases (Xu, 1996; Fan, 2002). While Western medicineis, to a great extent, based on anatomy and quantitativeanalysis, TCM describes the life regulation with differ-ent perspectives including society, culture, physiologyand psychology. The human body is understood as an‘energetic composition’, through which energy flows.The unobstructed flow of energy through the meridians(pathways of energy) is considered a prerequisite forboth a healthy body and mind. If these energy streamsare interrupted, it will result in either physical or emo-tional disturbances, or possibly both. In this regard,ancient TCM views a disease in a holistic and dynamicway, which is rather foresighted even in the light oftoday’s medical science.

Nature is a macroscopic system in which lives andsubstances are interrelated. The human body, as anelement of nature, is an open and complex system com-posed of various physiological and pathological factorswhich are interrelated. A traditional formula containingnatural ingredients extracted from plants, minerals andanimals is actually inseparable from the human bodyand its life cycle, and therefore, it becomes possiblethat such a formula could restore the balance of animbalanced or diseased human body.

THE ORGANIZATION OF A COMBINATIONFORMULA

A combination formula is not simply a pile up ofmedicinal herbs, the selection of individual herbs in theformula is strictly guided by TCM theory and followsthe rule of drug compatibility and combination. Gener-ally, different herbal compositions in TCM formulasare organized by certain rules following the TCM theoryof treating a specific disease. A typical rule, known asthe Four Responsible Roles, is often used to select herbsbased on the role each herb plays in the drug formula(Fan, 2002). The Four Roles are called Monarch,Minister, Adjuvant, and Guide. The Monarch drug isthe principal active herb in the formula, selected for itsknown therapeutic benefits for specific ailments. TheMinister’s role is to strengthen the curative effect ofthe Monarch drug, while the Adjuvant drug is usuallyadded to neutralize any side effects of the Monarchand Minister herbs. The role of the Guiding drug is toharmonize the action of all the other ingredients andto enhance their absorption or uptake into a specificorgan, or target tissues.

An interesting example is the clinical use of ‘Decoc-tion of Four Noble Ingredients’ for the treatment ofdeficiency syndrome of the spleen and stomach. One ofthe clinical findings was that this ancient formula wasable to treat both constipation and diarrhea (Wang andZhang, 2002). According to TCM theory, the spleen,one of the Five Elements, is responsible for ‘food trans-portation and transformation’, the Qi deficiency ofspleen may lead to disorder of food absorption, trans-portation, and clearance, which may involve constipationor diarrhea. This combination formula, governed bythe rule of drug interaction and compatibility in TCM,containing Radix ginseng, Rhizoma atractylodis macro-cephalae, Poria, and Radix glycyrrhizae praeparatae, is

THE REDISCOVERY OF ANCIENT CHINESE HERBAL FORMULAS 683

Copyright © 2004 John Wiley & Sons, Ltd. Phytother. Res. 18, 681–686 (2004)

the content of aconite alkaloids, a group of relativelytoxic compounds from Aconite root (Pei et al., 1996).So the relationships between Aconite root and Driedginger in the formula is ‘synergism’ while Liquoriceroot acts as a detoxifier.

Further investigation with Liquorice root has dis-covered that liquorice potentiates compounds such aspaeoniflorin as a neuromuscular blocking agent, whileaffecting intestinal absorption of toxic substances suchas the aconite alkaloids (Pei and Jing, 1996). Liquoriceis used in many combination formulas in Chinesemedicine as a synergistic agent, as a potentiator and/ordetoxifier. It has been shown that the crude extract ofliquorice inhibits angiogenesis, granuloma formation andfluid exudation in an inflammation model in mouse,whereas glycyrrhizin and glycyrrhetinic acid tend topromote angiogenesis (Kimura, 1992). These are ap-posing actions within the herb itself, indicating that theinteractions within herbal medicine can be extremelycomplicated, and also beneficial to treatment if a viablecombination formula is organized for the synergisticand dynamic treatment of diseases. Research with adifferent combination drug, ‘Hua-tuo Pill’, discoveredthat borneol in the formula facilitated the penetrationof one of the alkaloids (namely, tetramethylpyrazine)of Rhizoma ligustici chuanxiong across blood–brainbarrier, and significantly increased the concentration ofthe alkaloids in brain, which is a clear example of ‘chan-nel tropism’ in TCM (Sun, 1993).

During the decoction process of a prescribed herbalformula, many physical and chemical changes willoccur in herbal ingredients. For example, the change ofpH may alter contents of certain chemical ingredients,and therefore, may alter the clinical effectiveness ofthe formula. A number of investigators have conductedin-depth research on how to define the coherence andsynergistic interactions of chemical ingredients in thecombination formulas, how they function on each other,and whether there are new compounds generatedthrough such a decoction process. Yan and his groupinvestigated an ancient combination formula, ‘Pulse-activating Powder’, through years of extensive chemi-cal and pharmacological studies (Xia et al., 1998; Zhuet al., 1998; Zhu and Yan, 1998). Such a formula wasfirst published in ‘The Origin of Medicine’, dated 1186,containing Radix ginseng, Radix ophiopogonis, andFructus schisandrae. This famous ‘tri-herb’ formula hasbeen used at an optimized ratio of 1:3:1.5, mainly forcoronary heart disease and endocrinopathy, pertainingto deficiency of both Qi and Yin. Yan reported that thechemical ingredients were greatly altered when the threemedicinal herbs were decocted together, and duringthe preparation of decoction, a new compound, 5-hydroxymethyl-2-furaldehyde (5-HMF), was discovered,which was found later in pharmacological studies tohave a strong effect of anti-oxidation in vivo. Such acompound produced in significant quantity (approxi-mately 250 mg from a mixture of three herbal materialsat 1 g : 3 g : 1.5 g) is therapeutically beneficial formyocardial infarction. During the decoction process, amajority of ginseng saponins, Rb1, Rb2, Rc, Rd, Re, Rg1,disappeared while Rf, Rg2, Rg3, and Rh1 remained, dueto the drug interaction between ginseng and the othertwo herbs. Pharmacodynamic studies showed that thecombination drug readily increased the blood flow ofcoronary artery in an isolated myocardial ischemic

reperfusion model. The result was significantly betterthan the three individual herbal medicines respectively,suggesting a synergistic interaction in the formula (Yan,2001).

We believe that the chemical ingredients became dif-ferent, during the preparation and absorption, from thesum of all phytochemicals participated in the formula.Although progress has been made in understanding theinteractions within the herbal medicines, there are noconclusive evidences at this stage as to whether newcomponents, or altered chemical contents are respons-ible for the improved treatment efficacy and whetherthose so-called ‘non-active’ components could be de-fined as ‘non-active’ with the current pharmacologicalmeans (Yan, 2001).

TREATMENT OF DISEASES WITHCOMBINATION FORMULAS

Zhang Zhong-jing once said, about 1800 years ago, ‘adoctor who uses herbal medicine is like a soldier usinghis weapons’. Being familiar with all the herbs andknowing how they work together, the effect they haveon the patient, and how to organize a combination for-mula best suitable for the disease are all important tothe practitioner; just as the soldier needs to know howto use his arms in order to win his battle. For example,a common cold can be treated differently by a TCMpractitioner. There are two types of syndrome clini-cally, wind-cold and wind-heat, in catching a cold. Awind-cold type syndrome is characterized by chills,fever, anhidrosis, headache, thin and white tongue coat-ing, and floating and tight pulse. The treatment of suchcold should involve combination formulas includingdiaphoretic medicinal herbs pungent in taste and warmin nature to disperse wind-cold from superficies. Oneof the formulas used frequently for this syndrome isMa-huang Decoction which contains Herba ephedrae,Ramulus cinnamomi, Semen armeniaccae amarum, andRadix glycyrrhizae praeparatae. For the syndrome ofwind and heat attacking upwards manifested as severefever, headache, redness of eyes, swollen and sorethroat, thin and yellow tongue coating, and floatingand rapid pulse, medicinal herbs pungent and cool innature will be used in the formulas. A representativeone is Sang-ju Decoction which includes Folium mori,Flos chrysanthemi, Semen armeniacae amarum, Fructusforsythiae, Herba menthae, Radix platycodi, Radixglycyrrhizae, and Rhizoma phragmitis (Tang, 2003).

One of the most influential examples of herbal mis-use is the toxification of xiao-chai-hu-tang (Decoctionof Bupleuri for Regulating Shaoyang) recently observedin Japan. This ancient formula was used to treat febrilediseases in Shaoyang meridian, marked by alternateattacks of chills and fever, fullness in the chest, hypo-chondriac discomfort, dizziness, dry throat, vomiting,etc. (Fan, 2002). Based on modern pharmacologicalfindings, some TCM practitioners used such a formulato treat certain hepatitis specifically showing the abovesymptoms and obtained reasonably good results. How-ever, the formula was, at one time, widely prescribedin Japan for the long-term treatment of all types ofhepatitis, and unfortunately, resulted in severe adverseeffects including a number of deaths (Sasaki, 2001).

684 W. JIA ET AL.

Copyright © 2004 John Wiley & Sons, Ltd. Phytother. Res. 18, 681–686 (2004)

Medicine and pharmacy are inseparable. Certainmedical theory guides and supports the use of certainherbs. There will be consequences if we choose to keepthe drugs and discard the traditional medical theory.Japan is a country where Kampo medicine is main-tained for use but no longer with the support of a medi-cal theory behind it. This situation is also the case inmany countries using those tried-and-true herbal medi-cines and formulas as dietary supplements withouthaving a basic understanding of the Chinese medicaltheory or rationale. It was recently reported that aspecific type of nephropathy occurred due to ingestionof certain Chinese herbs such as Aristolochiae mans-huriensis. The case highlighted the role of aristolochicacid and its metabolite, aristololactam I, in causing thisnephropathy, which was first observed in a Belgiancohort (Lord et al., 2001). The phenomenon, nowcalled ‘Chinese herbal nephropathy’ led to a public mis-conception of the toxic nature of Chinese herbs. Whilefurther research with herbs containing aristolochic acidis being conducted in China (Ma et al., 2001), we wouldlike to make the following points here. In ancient times,the herbs, Mu-tong (Akebia quinata), San-ye-mu-tong(Akebia trifoliate), or Bai-mu-tong (Akebia quinatavar, australis) were used in the combination formulasrather than the herb, Guan-mu-tong (Aristolochiaemanshuriensis). The three herbs used in ancient formu-las have no aristolochic acid and were replaced now-adays with Guan-mu-tong due to the much decreasedresources. Such a replacement greatly altered the toxi-cology of these Mu-tong containing formulas and wasresponsible for many of the cases of toxification clini-cally. Therefore, when one intends to study or usemedicinal herbs in a formula, one should bear in mindthe nature of their source and the correct taxonomicorigin because they can produce widely different phar-macological effects. Secondly, the preparation of manyherbal medicines, nowadays, has been greatly modifiedfor convenience so that the drug decoction process isreplaced with ‘instant’ water-soluble granule form ofherbal extracts. This has minimized chemical interac-tions including ‘drug detoxication’ among herbal medi-cines during the decoction process. Additionally, theuse of a single herbal medicine, or refined fractions inlarge quantity may exhibit certain therapeutic activity,but are often more toxic and less efficacious than awell-designed combination formula. Any use of herbalproducts in high dosage, or for long-term medication isnot advisable unless patients see a practitioner for adiagnosis and holistic approach to their conditions andobtain a ‘tailor-made’ prescription taking into accountthe various manifestations of their symptoms andperceived causes. In fact, a carefully prepared com-bination formula works rather differently because theycontain synergistic and balanced elements that mayinteract in different ways and neutralize the negativeeffects of some toxic constituents the plants mightcontain.

RECENT DEVELOPMENT OF ANCIENTCOMBINATION FORMULAS

Over the past several decades, the Chinese TCM in-dustry has made much progress in bringing traditional

medicines into a modern environment. While scrutiniz-ing traditional medicines with modern methods on theone hand, investigators continue to expand their tradi-tional uses on the other. Currently, there are over 600bases in China for the production of Chinese medicinalherbs. About 5 million mu (1 mu = 0.165 acre) of landproduce Chinese medicinal materials every year withan output at about 400 000 tons. In the year 2001,there were a total of 1175 herbal pharmaceutical facto-ries in China producing more than 5000 Chinese herbaldrug products, prepared medicinal herbs, and naturalhealth products in over 40 different kinds of pharma-ceutical dosage forms. Thus far, Chinese health regula-tory agencies have approved approximately 700 drugproducts of plant origin, which account for about $ 5billion USD as annual sales in the Chinese domesticmarket (Jia et al., 2003). These products were evalu-ated through a procedure which includes rationaliza-tion of herbal formula, chemistry, quality control,pharmaceutical, pharmacological, and clinical studies.A great number of modern drug products were devel-oped from the ancient formulas and became verysuccessful in the market. One of the most successfulproducts is Compound Danshen Pill (CDP), a com-bination herbal formula consisting of active ingredientsextracted from Danshen (Salvia miltiorrhiza), Sanqi(Radix notoginseng) and Borneol (Cinnamomumcamphora). This combination formula was developedinto a sublingual, fast-release form, by Xijun Yan usingcontemporary pharmaceutical technology, and becamea Chinese ‘blockbuster’ product (Zhu, 2002). It reachedan annual sales exceeding $ 120 million USD in theyear of 2002, occupying about 40% of market shares ofChinese herbal drugs used for preventing and treatingcoronary heart disease. In 1998, CDP received approvalfrom FDA (IND No: 56956) for phase II and III clini-cal trials. This formula was originally designed to pro-mote blood circulation and remove blood stasis, regulateQi and relieve pain associated with coronary heart dis-ease and oppressed chest. It appears that in controlledclinical studies, CDP displayed a significant therapeuticeffect for the relief of angina pectoris. The long-termadministration of CDP can increase pain-relief rate andECG improvement rate, and that the overall curativeeffect is superior to isosorbide dinitrate. Studies alsosuggested that the long-term use of CDP could resultin stable and sustainable curative effect with no ob-served drug tolerance. The CDP (10 pills, 25 mg each)was compared with nitroglycerin (0.5 mg) for relief ofangina pectoris. The results are listed in Table 1 (Zhu,2002). It appears that CDP performed similarly tonitroglycerin for quick relief of angina. The timeneeded to effect pain relief by CDP was found to besomewhat longer than nitroglycerine, however the dif-ference was not statistically significant (p > 0.05).

A number of ancient combination formulas areunder extensive pharmacological evaluation for treat-ment of medically challenging diseases such as HIVinfection, Alzheimers disease, various types of cancer,and many chronic and debilitating diseases such as dia-betes, rheumatoid arthritis, osteoporosis, and glomer-ulonephritis. However, the pharmacological study ofcombination formula appeared to be difficult usingthe existing animal models and clinical protocolsoriginally developed in Western medicine. It is unlikelyto demonstrate and elaborate the advantages and

THE REDISCOVERY OF ANCIENT CHINESE HERBAL FORMULAS 685

Copyright © 2004 John Wiley & Sons, Ltd. Phytother. Res. 18, 681–686 (2004)

Table 1. Comparison of CDP with nitroglycerin for fast relief of angina pectoris

Pain relief Pain relief Total efficacyGroup Cases <3 min (%) 3–8 min (%) %

CDP 102 41 (40.20) 49 (48.04) 88.24Nitroglycerin 30 16 (53.33) 12 (40.00) 93.33

characteristics of combination formulas during theevaluation. Presently, a number of animal models basedon TCM theory have been developed at many TCMresearch institutes for the evaluation of various herbalformulas.

The research of combination formulas is rather likea complex engineering system. The main function andcompatibility of all herbs in combination formulas arethe fundamental part of the study. The work involvingdifferentiation, optimization, and selection of combina-tion formulas, and use of appropriate pharmacologicalmodels and multidisciplinary technology would be themain avenue of establishing a modern platform of drugdevelopment from traditional medicine.

WHAT WE LEARNED FROM ANCIENTCOMBINATION FORMULAS

The combination formulas of traditional medicineevolved through thousands of years of clinical practiceand are still routinely used today by medical practi-tioners in an attempt to improve therapeutic success andreduce side effects. These herbal formulas have beenvery extensively documented medical traditions that are,unfortunately, out of reach of most Western researchers.This is not due to a separation by physical distance, butrather by the language barrier. It appeared that theselection and organization of herbal ingredients in manyof the ancient formulas have been proven to have soundscientific basis through modern research and evalu-ation. The mechanism of action of most combinationformulas is still unknown although a multi-targetedapproach is generally assumed in the treatment. Thereare also instances of the use of ‘unusual’ formulas con-taining peculiar herbal ingredients or a large numberof herbs, i.e. more than 50 members, for which we haveno real rationale.

What we have learned from combination formulasis that traditional Chinese medicine pursues an overalltherapeutic effect with a multi-ingredient treatment,which differs from conventional medication using a well-characterized chemical compound with a known mecha-nism of action. The interaction between the ingredientsin a formula and the diseased state of the host may befar more complex than merely the result of a directinteraction exerted by a single chemical entity. If weview a diseased state as a whole and in a dynamic way,i.e. it involves interactions among many biologicalsystems in the human body and these interactionschange as the disease improves or worsens, the treat-ment of such disease with a single chemical entity maynot be logical or technically feasible. Combination for-mulas may hold the potential to become the therapeu-tics of choice in future due to the synergistic effect and

dynamic adjustment achieved by the multiple ingredi-ents that inhibit the causative agent at different stages,strengthen the impaired immune system, and improvethe overall symptoms and patients quality of life.

What we have also learned from combination formulasis that the current drug screening and regulatory meth-odology will not be appropriate for the development ofa botanical drug containing a group of phytochemicals,in which a synergistic interaction from chemical ingre-dients such as polysaccharides, polypeptides, proteins,and other molecules plays a fundamental role in thetreatment of disease. A botanical drug with combina-tion formula is far more difficult to characterize andevaluate if it is evaluated using the concept and stand-ards of chemical drugs.

During the course of drug development, investigatorstend to identify, extract, isolate and/or synthesize theactive compounds from natural sources. Thus far, millionsof compounds isolated from plants, animals, and marineorganisms have been characterized and screened fortherapeutic activities. However, few of them have adv-anced to controlled, double blinded, and multi-centeredclinical trials where high potency and low toxicity aregenerally required as a prerequisite. What we learnedfrom ancient combination formulas is that ‘fractionation’,i.e. bioactivity – guided isolation, may be a wrong direc-tion. There exists a different, perhaps more brightapproach of new drug development, that is, to developwell-organized combination drugs or multi-ingredientagents with established clinical-based therapeutic evid-ences as new treatment modality. Clinical efficacy is,and should be, the basis of the drug development. Andthe efficacy should also include patients’ improved com-fort level, increased life span, and quality of life.

THE FUTURE

Chinese philosophy draws its inspiration and insightdirectly from the perennial pattern of nature, which iswhy the Tao (Way) transcends all cultural boundariesand consistently withstands the tests of time. The veryfact that many ancient Chinese herbal formulas havebeen in continuous use by millions of people for thou-sands of years, with consistently positive results, is aclear testimony to their safety and reliability. This ex-tensive record of clinical experience is arguably a morereliable basis for human therapeutics than the relativelybrief and limited laboratory tests on which modernpharmaceutical standards are based. With the changeof the economy, culture and living style in various re-gions as well as the aging in the world population, thedisease spectrum has changed. And such a change haspaved the way for the new application of traditionalmedicine. Besides, the new requirements initiated by

686 W. JIA ET AL.

Copyright © 2004 John Wiley & Sons, Ltd. Phytother. Res. 18, 681–686 (2004)

the new diseases and the achievements and limitationsof modern medicine have also created challenges fortraditional medicine. As a healing art, the future ofTCM including those ancient combination formulas ispromising with its success in research and education,and very importantly, in commercialization in theinternational market. We believe that the developmentof TCM has been a process of integrating practicalexperience, philosophy, holism, Confucianism, Taoism,

astronomy and other thoughts over 5000 years. Thefurther development of TCM demands continuousabsorption of the multidisciplinary knowledge andtechnological achievements of modern science. Withthe emerging technology and research findings inmodern science, the traditional medicine based on thetheory of the Chinese ancestors should be supple-mented, revised and further developed as an importantpart of the modern drug industry and public health.

REFERENCES

Chen JP, Wu WK. 2001. The Pharmacological Activity of SiniDecoction. In Progress in Pharmacological and Clinical Stud-ies, Wang JH, Zhang YX (ed.). Military Medical SciencePress: Beijing.

Fan QL. 2002. Science of Prescription. Shanghai TCM Univer-sity Press: Shanghai.

Jia DD. 2002. History of Chinese Medicine. Shanxi Science &Technology Press: Taiyuan.

Jia W, Gao WY, Tang LD. 2003. Antidiabetic herbal drugs offici-ally approved in China. Phytother Res 17: 1127–1134.

Jia W, Li XB, Guo ZX. 2004. The challenge and strategiesof TCM globalization. World Science and Technology –Modern Trad Chin Med 6: 43–47.

Kimura M, Kimura I, Guo X, et al. 1992. Combined effects ofJapanese-Sino medicine ‘Kakkon-to-ka-senkyu-shini’ and itsrelated combinations and component drugs on adjuvant-induced inflammation in mice. Phytother Res 6: 209–212.

Lord GM, Cook T, Arlt VM, et al. 2001. Urothelial malignantdisease and Chinese herbal nephropathy. Lancet 358: 1515–1516.

Ma HM, Zhang BL, Xu ZP, et al. 2001. Experimental studies onnephrotoxic mechanism of Caulis Aristolochiae Manshurien-sis. Clin Pharmacol Tradit Chin Med 12: 404–409.

Pei MR, Jing L. 1996. Pro 40th Anniversary Conference, BeijingUniversity of Chinese Medicine. Beijing University Press:Beijing.

Pei MR, Yan RH, Miao H, et al. 1996. Chemical and pharmacologicalstudy on Sini decoction. Chin J Pharmacol Clin 3: 10–13.

Sasaki H, 2001. Kampo medicine products in Japan. Inter-national Senior Forum of Traditional Chinese Medicines &Botanical Products. Speech Collection: 38–41, Hangzhou,China.

Sun QM. 1993. The pharmacology of borneol. Chin PatentedMed 15: 43–46.

Tang DC. 2003. Science of Chinese Materia Medica. ShanghaiTCM University Press: Shanghai.

Wang J, Zhang LG, Meng SH. 2001. Chemical, pharmacologicaland organizational considerations of combination Chinesemedicines. J Chin Materia Medica 26: 799–804.

Wang JH, Bian ZX. 2002. Basic Pharmacological Research ofTCM. In Progress in Pharmacological and Clinical Studiesof TCM, Wang JH, Zhang YX (ed.). Military Medical SciencePress: Beijing.

Wang JH, Zhang YX. 2002. Progress in Pharmacological andClinical Studies of TCM, Wang JH, Zhang YX (ed.). MilitaryMedical Science Press: Beijing.

Xia Y, Li ZM, Zhu DN, Yan YQ. 1998. Study of dynamic chemi-cal and pharmacological changes in the combination for-mula, ‘pulse activating powder’ (I). J Chin Materia Medica23: 230–231.

Xu G. 1996. Chinese Herbal Medicine. Vermilion: London.Yan YQ. 2001. Enhancement of active ingredients in Chinese

combination drug formulas. World Science and Technology– Modern Trad Chin Med 3: 17–20.

Zhu DN, Li ZM, Yan YQ, Zhu JG. 1998. Study of dynamic chem-ical and pharmacological changes in the combination for-mula, ‘pulse activating powder’ (II). J Chin Materia Medica23: 291–293.

Zhu DN, Yan YQ, Li ZM. 1998. Study of dynamic chemical andpharmacological changes in the combination formula,‘pulse activating powder’ (III). J Chin Materia Medica 23:483–485.

Zhu GG. 2002. Danshen Dripping Pills. China Medical Scienceand Technology Press: Beijing.