Bear bile has been used in Traditional Chinese Medicine (TCM) for thousands of years. Modern investigations showed that it has a wide range of pharmacological actions with little toxicological side effect and the pure compounds have been used for curing hepatic and biliary disorders for decades. However, extensive consumption of bear bile made bears endangered species. In the 1980's, bear farming was established in China to extract bear bile from living bears with "Free-dripping Fistula Technique". Bear farming is extremely inhumane and many bears died of illness such as chronic infections and liver cancer. Efforts are now given by non-governmental organizations, mass media and Chinese government to end bear farming ultimately. At the same time, systematic research has to be done to find an alternative for bear bile. In this review, we focused on the literature, laboratory and clinical results related to bear bile and its substitutes or alternative in English and Chinese databases. We examined the substitutes or alternative of bear bile from three aspects: pure compounds derived from bear bile, biles from other animals and herbs from TCM. We then discussed the strategy for stopping the trading of bear bile and issues of bear bile related to potential alternative candidates, existing problems in alternative research and work to be done in the future.
Bears live in all the continents except Africa, Antarctica, and Australia, and they are classified into eight species including giant panda (Ailuropoda melanoleuca). The largest among all is polar bear (Thalarctos maritimus), followed by brown bear (Ursus arctos), American black bear (Ursus americanus), Asiatic black bear (Selenarctos thibetanus), spectacled bear (Tremarctos ornatus), sloth bear (Melursus ursinus), and sun bear (Helarctos malayanus). All of these species are endangered – five are listed in Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) Appendix I, whilst the remaining three are listed in Appendix II  .
China was the first country utilizing bear bile and its gall bladder in traditional medicinal products and this usage was adopted by Korea and Japan [2,3] centuries ago. Today the use of Traditional Chinese Medicine (TCM) was widespread not only in Asia but also throughout Asian communities in other areas of the world, including Europe and America. Many of these consumers bought bear bile products, either because they believed it was a traditional medicine, or because the products were marketed well by local TCM pharmacies.
Bear bile and bile extraction in TCM were under the category of animal drugs. Its medicinal functions were well documented in ancient Chinese medicinal and modern Chinese medicine publications [4,5] . Some recent textbooks and books of TCM still recommend formulae containing various animal tissues such as tiger bones, antelope, buffalo or rhino horns, deer antlers, testicles and penis of the dog, bear or snake bile. Some of them have drawn attention from international[6,7] . Usually, animal tissues were combined with medical herbs to form Chinese Medicine preparations and in most of the cases, the medical use of these preparations was justified in terms of the rules of TCM. However, only a few researches have been done to prove the claimed clinical efficacy of TCM animal products. Still, J. (2003)  has published a review paper in discussing some related ecological, ethico-legal and health concerns about hunting, breeding and trading with endangered species, risks of transmission of zoonoses, quality of the products, and alternatives to the preparations from endangered species.
Bear bile used in traditional chinese medicine
Traditional properties and actions
Bear bile (Xiongdan in Chinese) is the dried gallbladder with bile of selenarctos thibetanus curvier or Ursus arctos L. The dried gallbladder with bile from other species of Ursidae can be also used as Bear bile. Bear bile was first recorded in <Tang Ban Cao> (Newly Revised Materia Medica, Tang Dynasty, 659 A.D.), the first official book compiled and issued by the government and considered to be the first pharmacopoeia in China. From the point of view of TCM, bear bile was considered as a cold medicine, bitter in flavor, cool in nature and attributive to liver, gallbladder and heart, so it could clear heat to relieve toxin, stop endogenous wind to arrest convulsion and clear away liver fire to improve eyesight [5,9,10] .
In traditional clinical practice, bear bile was used in fever fighting, detoxification, inflammation, swelling and pain reduction. It was also used in the cure of carbuncle of heat type, pyocutaneous diseases, hemorrhoid, overabundance of liver-fire, convulsion caused by the overabundance of heat, epilepsy, tic, and redness of eyes due to liver heat etc .
For seasonal febrile disease with high fever in children and infantile convulsion, bear bile can be dissolved in milk or succus from Bambusae (Zhulishui in Chinese). For heat-toxin syndrome manifested by skin carbuncle, sore throat and hemorrhoids, bear bile can be used as oral administration or external use. In treating conjunctivitis and nebula, it is prepared to be a water solution as eyewash or used together with Borneolum (Bingpian in Chinese)  . Besides traditional use, the modern application of bear bile was extensive spread to many modern diseases based on traditional indications and pharmacological studies (also see Pharmacological study of bear bile and Scientific research).
Usage and dosage
0.25–2.5 g is taken as a dose in pill or powder. It is mainly single use and rarely used together with other herbs. Due to its fishy and bitter taste that may induce vomiting, it should be given as capsules. For external use, the fine powder can be applied to the local area or used with water  .
Being extremely bitter and cold, it is easy to injure yang-qi of the spleen and stomach and so, it is contraindicated for deficiency and cold of the spleen and stomach  .
Bear bile in the world
Trading of gall bladders from wild bears has been extensive over the past few decades. Tens of thousands of bears have been killed in the wilds to obtain their gall bladders and body parts, such as the paws (a delicacy in some Eastern countries), hide, claws, meat, fat and bones. Moreover, gall bladder has been the prize as it has the greatest commercial value. It was because prices of bear parts in China have dramatically risen. In 1970 one kilo of bear gall bladder cost around US $200, but by 1990 the price had risen to between US $3,000 and US $5,000 per kilo  . Recent market price with legal certification has risen to between US $30,000 and US $50,000 per kilo (our experience in legal market of Hong Kong). This has led to an increased threat to bears in the past few decades as price for bear gall bladder has increased making it a lucrative trade for hunters and middlemen alike.
Illegal products containing bear bile were on sale in Traditional Medicine shops in USA, Canada, Japan, Taiwan, Korea, Singapore, Australia and New Zealand according to the new findings from investigations led by the World Society for the Protection of Animals (WSPA)  . The report showed bear products offered by these shops were originated from China's bear farms.
With the great demand for bear bile products, fraudulent products were found in the markets. Two surveys reported that most of the bear bile products were indeed gall bladders or bile originated from domestic pigs, goats, and water buffalo or mixture with the true bear bile. Only minority of the specimens was found purely from bears [24,30] .
Coptis as a herbal alternative to bear bile
Among the possible alternatives for bear bile, Coptis ("Huanglian" in Chinese) was a possible choice since both of these materials were under the category of clearing heat. Apart from that, both bear bile and Coptis could detoxify, purify liver, improve eyesight, as well as treating eclampsia, epilepsy, tic caused by fire, carbuncle of heat type, pyocutaneous diseases. At present, prescriptions with Coptis (such as Huang Lian Jie Du Tang, Qing Ying Tang, and An Gong Niu Huang Wan) were widely used to treat symptoms such as coma, eclampsia, epilepsy, tic and we have also used it to treat liver diseases (Major active compound, UDCA derived from bear bile is mainly used for liver diseases) and cancer in TCM clinical practice . Now, we are doing comparative research between bear bile and Coptis in chemical analysis, pharmacological study and clinical efficacy to clarify what we concern.
To summarize, it was believed that the usage of bear bile is a problem of history, culture and economy and it may also become a political issue. Before stopping use of bear bile, it needs combined efforts from various routes of the society. As we reviewed in this paper, research on alternative for bear bile has been conducted in the past decade including comparative studies of various animal biles, the major effective components of bear bile, and substitutes of bear bile by artificial materials and herbal medicines. In this review, it showed that animal biles, such as those from pigs and rabbits, the synthetic compound of UDCA, and herbs, such as Coptis, were possible substitutes for bear bile. However, plant substitutes were only suggested in literature without solid evidence to support, while some animal substitutes were superficially studied. Thus, it is necessary for us to design systematic, serious and comparative research to get convincing data. It is important to note that animal substitutes will be found contradictory to the tenets of World Animal Protection sooner or later. The final choice will be using plant materials to substitute bear bile. Our previous study showed Coptis was a promising drug due to its similarity to bioactivity characteristics of bear bile, therefore comparative study for both Coptis and bear bile will be carried out. More persuasive research has to be done to explore their integrative functions and prove their similarities to bear bile in terms of medicinal use.