The Toxicity and Attenuation Methods of Toxic Chinese Materia Medica for its Reasonable Application: A Review.

Over a millennia, traditional Chinese medicine (TCM) has been used to treat various diseases in China. In recent years, more and more Chinese materia medica (CMM) have been studied in scientific research projects, applied in clinical practice, and their extracts have even appeared in some health products. However, the toxicity of some CMM is often overlooked, including hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, etc. In this review, the toxic components and their toxicological mechanisms of some toxic CMM were listed according to the chemical structure classification of toxic components. Afterwards, the traditional methods (processing and compatibility) and modern methods (structural modification, biotransformation, etc.) of attenuation of CMM were discussed. Since ancient times, it has been said that "fight fire with fire, fight poison with poison," and toxic CMM are of great significance in the treatment of difficult and severe diseases. The rational application of toxic CMM and their components in clinical practice was also exemplified in this review. While the pharmacological effects of TCMs have been emphasized, the scientific attenuation and rational application of toxic components should be concerned. We hope this review can provide a reference for future related research.

Toxicological evaluation of Oviductus ranae: Acute, sub-acute and genotoxicity studies in mice and rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Oviductus ranae (OR) is a traditional animal-based Chinese medicine, which has been listed in the Chinese Pharmacopoeia since 1985 edition. Although its medicinal application has been widely acknowledged, there is little available information on its potential toxicity. AIM OF THE STUDY: The aim of this study was to investigate the acute, sub-acute, and genetic toxicities of OR. MATERIALS AND METHODS: In acute toxicity evaluation, OR was administered orally to mice at doses of 2.5, 5.0, 10.0, and 20.0g/kg BW for one time. Mortality, clinical signs, and body weight were observed for 14 days after treatment. In sub-acute toxicity evaluation, OR was administered orally to rats once a day for 28 consecutive days at doses of 1.75, 3.50, and 7.00g/kg BW. Animals were observed for general behaviors, mortality, food intake, and body weight changes. At the end of treatment, relative organ weight, pathology, hematological and biochemical parameters were monitored. In genotoxicity evaluation, bacterial reverse mutation assay (Ames test) was performed by treating OR with four different Salmonella typhimurium strains at doses of 8, 40, 200, 1000, and 5000µg/plate without or with S-9 mix, respectively. The genotoxicity of OR was also evaluated by micronucleus and sperm malformation assays in mice at doses of 2.5, 5.0, and 10.0g/kg BW, respectively. RESULTS: The results of acute toxicity study showed that the LD50 value of OR is higher than 20.0g/kg BW in mice. Death and abnormal clinical symptoms were not found during the period of experiment. In sub-acute toxicity, we found that the no-observed-adverse-effect levels (NOAEL) of OR in rats is up to 7.00g/kg BW. No statistically significant or toxicologically relevant defferences in body weight, food intake, relative organ weight, pathology, hematological and biochemical parameters were observed, when compared with control group. Results of Ames test, micronucleus and sperm malformation assays indicated that OR has no mutagenicity in vitro at a limited dose of 5000µg/plate, and dose not induce micronuclei and sperm malformation in mice at the dose of up to 10.0g/kg BW in mice. CONCLUSIONS: In conclusion, OR is a tranditional Chinese medicine with high safety.

The classification and application of toxic Chinese materia medica.

Many important drugs in the Chinese materia medica (CMM) are known to be toxic, and it has long been recognized in classical Chinese medical theory that toxicity can arise directly from the components of a single CMM or may be induced by an interaction between combined CMM. Traditional Chinese Medicine presents a unique set of pharmaceutical theories that include particular methods for processing, combining and decocting, and these techniques contribute to reducing toxicity as well as enhancing efficacy. The current classification of toxic CMM drugs, traditional methods for processing toxic CMM and the prohibited use of certain combinations, is based on traditional experience and ancient texts and monographs, but accumulating evidence increasingly supports their use to eliminate or reduce toxicity. Modern methods are now being used to evaluate the safety of CMM; however, a new system for describing the toxicity of Chinese herbal medicines may need to be established to take into account those herbs whose toxicity is delayed or otherwise hidden, and which have not been incorporated into the traditional classification. This review explains the existing classification and justifies it where appropriate, using experimental results often originally published in Chinese and previously not available outside China.

Preclinical toxicological evaluations of the sclerotium of Lignosus rhinocerus (Cooke), the Tiger Milk mushroom.

ETHNOPHARMACOLOGICAL RELEVANCE: Lignosus rhinocerus (Tiger Milk mushroom) is distributed in South China, Thailand, Malaysia, Indonesia, Philippines and Papua New Guinea. In Malaysia, it is the most popular medicinal mushroom used by the indigenous communities to relieve fever, cough, asthma, cancer, food poisoning and as a general tonic. In China, this mushroom is an expensive traditional medicine used to treat liver cancer, chronic hepatitis and gastric ulcers. The sclerotium of the mushroom is the part with medicinal value. This rare mushroom has recently been successfully cultivated making it possible to be fully exploited for its medicinal and functional benefits. The present study was carried out to evaluate the chronic toxicity of the sclerotial powder of Lignosus rhinocerus cultivar (termed TM02), its anti-fertility and teratogenic effects as well as genotoxicity. MATERIALS AND METHODS: Sprague Dawley rats (10 rats/group/sex) were fed orally with 250, 500 and 1000 mg/kg of sclerotial powder of TM02. The sclerotial powder was orally administered once daily and consecutively for 180 days. At the completion of the oral feeding period, analysis of hematological and clinical biochemical parameters, urine profiles, organ weight as well as histopathological analysis were carried out. The effect of the sclerotial powder on fertility and its possible teratogenicity were examined by feeding rats orally with 100 mg/kg sclerotial powder consecutively for 7-8 weeks. Genotoxicity was evaluated by Ames test using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and Escherichia coli WP2 uvrA. RESULTS: The results showed that oral administration of the sclerotial powder of the Lignosus rhinocerus cultivar at daily dose of up to 1000 mg/kg for 180 days had no adverse effect on the general clinical observations, body weight, hematology, clinical biochemistry, urinalysis, absolute organ weight as well as relative organ weight, nor induced histological changes in the organs. Oral administration of 100 mg/kg sclerotial powder of the Lignosus rhinocerus for 7-8 weeks did not affect the fertility of the rats nor induce teratogenic effect on their offspring. Lignosus rhinocerus sclerotial powder up to 5000 µg/plate in the presence and absence of metabolic activation did not cause gene mutations by base pair changes or frameshifts in the genome of the tester strains used. CONCLUSION: Our results showed that the no-observed-adverse-effect level (NOAEL) dose of the sclerotial powder of Lignosus rhinocerus in 180-day chronic toxicity study is more than 1000 mg/kg. Oral feeding of the sclerotial powder at 100mg/kg did not induce adverse effect on rats' fertility nor causing teratogenic effect on their offspring. In the reverse mutation Ames test, the sclerotial powder at all tested concentration did not show any genotoxicity.

[Current situation of toxicity classification of Chinese materia medica and its research thoughts].

Toxicity of Chinese materia medica (CMM) is an important part of Chinese herbal nature theory. In clinical application, the dosage, time limitation and compatibility of CMM is mainly determined by toxicity. At present, there is no uniform toxicity classification standard for the evaluation of Chinese herbal toxicity. Therefore, it is significant to research toxicity classification of CMM. The current situation of toxicity classification of CMM is reviewed in this paper, and proposed research thoughts are as follows: the measurement of toxicity parameters, the confirmation of poisoning target organs, the investigation on toxic mechanism by serum pharmacology and toxicokinetics, the comprehensive evaluation on toxicity based on quantitative theory.

[Application of zebrafish model organism in the research of Chinese materia medica].

Zebrafish has become an important model organism in many fields of biomedical studies and been increasingly used in Chinese materia medica studies in recent years. This article summarized the achievements and prospect for zebrafish as a pharmacological and toxicological tool in the study and development of Chinese materia medica.

[Effects of centipede extracts on normal mouse and S180, H22 bearing mouse].

OBJECTIVE: To study the effects of centipede extracts on H22 tumor-bearing mouse, sarcoma S180 mouse and normal mouse. METHODS: Normal and tumor-bearing mouse were orally administrated by centipede extracts. Rate of restraining tumor, index of thymus and spleen were calculated after 12 days treatment. Acute toxicity testing tried to figure out In LD50 of centipede extracts. RESULTS: The restraining tumor rates of centipede ethanol extracts at low and medium doses were 22.2% and 17. 88%. There was no tumor restraining effect by the high dose treatment. The tumor growth of the H22 model mouse was not restrained by the centipede water extracts. There were no significant differences among the treatments in their spleen weight and spleen index. In LD50 test, the administrating dosages of centipede extracts given to the mouse were 48 times those given to patients on clinic. The result showed no mouse dead in centipede group. CONCLUSION: Centipede water extracts had no anti-tumor effect on tumor-bearing mouse. There is certain toxicity in ethanol extracts of centipede, suggesting that centipede alone for treatment of cancer needs further study.

Under pressure: homeopathy UK and its detractors.

Though homeopathy has been in successful and continuous use for well over 200 years, in the United Kingdom it is under growing pressure, from scientific detractors and sections of the media. As such, homeopathy's free National Health Service provision is threatened because it is derided as 'unproven', 'unscientific', and even 'deadly'. While refuting these and other detractions, this paper considers possible reasons for the current plight of homeopathy UK. Thus, the current attacks against homeopathy should be viewed more in the context of the globalised pharmaceutical industry which is itself in crisis, and a succession of UK governments seemingly supine in the face of legislation originating from the European Union.

[Study of toxicity effect of different rate of Sargassum and Radix Glycyrrhizae on rats].

OBJECTIVE: Study the toxicity effect of different rate of Sargassum and Radix Glycyrrhizae on rats. METHOD: 32 Wistar rats [body weight (123 +/- 15.3) g] were random divided into 4 groups of 8: normal group (A) and compatibility medicine group (B, C, D). The normal group was oral administrated with the distilled water, B, C, D group were oral given the Sargassum and Radix Glycyrrhizae (1:1), Sargassum and Radix Glycyrrhizae (1:2), Sargassum and Radix Glycyrrhizae (1:3) for 35 days, the dose was 20 mg x g(-1) weight, in the meantime, general state of health was observed, then rats were slaughtered, and the body weight, internal organs coefficient, blood routine, serum biochemistry and liver drug enzyme were assaied. RESULT: The rats' general state of health, body weight, internal organs coefficient has not been affected, the hemoglobin, the red blood cell, the kidney function and liver function have been affected, and has some toxic effect on the rats' white blood cell and cardic muscle, the toxic effect on cardic muscle was increase along with the rate of Sargassum and Radix Glycyrrhizae; liver drug enzyme activity has been improved. CONCLUSION: The different rates of Sargassum and Radix Glycyrrhizae have some selective toxic effect on internal organs of rats.

[Study on anti-tumor effect of dry and fresh Gekko swinhonis freeze-dried powders on mice sarcoma S180 and acute toxicity testing of two powders].

OBJECTIVE: To investigate the anti-tumor activity of dry Gekko swinhonis freeze-dried powder (DGFP) and fresh G. swinhonis freeze-dried powder (FGFP) on mice sarcoma S180 and acute toxicity testing of the two powders. METHOD: Mice xenotransplant model of sarcoma S180 was established. Eighty mice were randomly divided into 8 groups. Control group were orally administrated by saline, another intraperitoneally injected with 5-Fu, the other six groups were orally administrated by DGFP and FGFP, each at three different doses (low, moderate and high). Rate of restraining tumor, index of thymus and spleen were calculated after 10 days' treatment. Acute toxicity testing tried to figure out LDs and LD, of DGFP and FGFP. RESULT: The restraining tumor rates of DGFP and FGFP each at three doses were 31.4%, 50.8%, 37.7% and 14.8%, 19.1%, 54.7%. DGFP and FGFP elevated the thymic weight and thymic index of the mice to different extent. There were no significant differences among the eight groups in their spleen weight and spleen index. Acute toxicity testing did not figure out LD50 of DGFP and FGFP. In LD0 test, the administrating dosages of DGFP and FGFP given to the mice were both more than 2000 times than those given to patients on clinic. The result showed nothing abnormal in DGFP group. Compared with the DGFP and control group there was only a significant body weight decrease (P < 0.01) in the FGFP group in the first three days. However, on the fifth day and the seventh day there was no significant difference. CONCLUSION: DGFP and FGFP have conspicuous anti-tumor effects in vivo. The mechanism may be related to the elevated cellular immune function. Acute toxicity testing reveals that DGFP and FGFP are quite safe for conventional oral use on clinic.

Traditional toxicity documentation of Chinese Materia Medica--an overview.

Documentation of Chinese materia medica (CMM) dates back to around 1,100 BC when only dozens of drugs were first described. By the end of the 16th century, the number of drugs documented had reached close to 1,900. And by the end of the last century, published records of CMM have reached 12,800 drugs. The recorded traditional information includes toxicities, incompatibilities, cautions, precautions and contraindications. Thus, contrary to a general misconception, toxicity data on Chinese herbs exist and are not meager. If consulted properly before embarking on a study of CMM, it will save researchers much time and efforts and the frustration of not obtaining consistent or expected results. The history of documentation is reviewed with examples of major classic and contemporary works highlighting and emphasizing the manner in which CMM toxicities have traditionally been documented through clinical experience as opposed to most modern toxicity data that are based on animal experimentation.

[General situation of the study on the toxicity of Cinnabaris].

Traditional Chinese medicine (TCM) experienced a gradual course in recognition of the toxicity of Cinnabaris from "nontoxic" to "toxic". The ancient doctors of TCM understood both the toxic property and the regularity of increasing toxicity of Cinnabaris. In long-term clinical practice they developed the methods of detoxification guiding the safe use of Cinnabaris. The toxicity of Cinnabaris is produced by mercury existed in it. Improper administration leading to an acute absorption or chronic accumulation was the main cause of clinical adverse effects. Kidney was the main poisoning target organ. On the other hand, improperly combinative application of Cinnabaris with other drugs of TCM or western medicine could increase the toxicity. Therefore, the crucial approach to avoid the poisoning is to use Cinnabaris properly.

[Pharmacodynamic tests of wulong kangai on transplantable tumors in mice].

OBJECTIVE: To observe the pharmacodynamic and side effects of Wulong Kangai, a new drug of Chinese traditional herbal medicine, on 4 strains of mice transplantable tumors. METHOD: Mice transplantable tumors S180, H22, P388 and Lewis were used in the pharmacodynamic test on the granules of Wulong Kangai. The test on each tumor strain was repeated three times. In each test, 50 mice were used and divided into 5 groups. They were negative control group treated by physiological saline, cyclophosphamide control group and 3 test groups treated respectively with Wulong Kangai at deferent dosages of 10, 25, 40 g x kg(-1) x d(-1) in the treatment of Lewis and P388 and 15, 30, 50 g x kg(-1) x d(-1) in the treatment of S180 and H22. RESULT: The tumor weight were inhibited at the rates of 90.1%, 30.8%, 49.8% and 52. 3% in the mice with tumors of Lewis, P388, S180, and H22 by high dosage of Wulong Kangai as compared with negative control group. The inhibitory rates in cyclophosphamide groups were 90.6%, 77.2%, 79.6% and 60.3% respectively. The mice body weights grew slower in high dose groups treated by Wulong Kangai granule. CONCLUSION: Wulong Kangai was effective in treating mice transplantable tumors of Lewis, P388, S180 and H22 with a dose-dependent manner. The Lewis was the most sensitive strain to the drug among the 4 kinds of tested tumors. Side effects appeared during 9-11 days of uninterrupted treatment with high dose Wulong Kangai.

The effects of elk velvet antler consumption on the rat: development, behavior, toxicity and the activity of liver gamma-glutamyltranspeptidase.

The effect of exposure to, followed by consumption of, a diet containing 10% powdered elk velvet antler (EVA) from the 18th day of gestation to the 88th day after birth was examined in male and female Fischer 344 rats. There were no teratogenic effects of EVA exposure in utero or differences in birth outcomes between pups born to regular chow fed and EVA chow fed dams. Growth curves of the EVA fed rats were identical to those of regular chow fed rats, as were developmental milestones of pinna development and eye-opening. Acoustical startle and righting reflexes, developmental and behavioral indices, were identical. Blood glucose levels were comparable in EVA chow fed and regular chow fed rats, indicating that EVA is without effect on glucose balance. There were no signs of toxicity in the EVA chow fed compared to regular chow fed rats as judged from plasma enzyme markers of liver damage: plasma levels of alanine aminotransferase were 50% lower in EVA chow fed rats compared to regular chow fed rats; and plasma levels of gamma-glutamyltranspeptidase (gammaGT) were the same. The activity of gammaGT displayed a decrease in the livers of EVA chow fed rats, more so in the male (22%) than in the female (14%), suggestive of an androgenic effect. A possible hepatobeneficial effect of the EVA induced decrease in liver gammaGT is discussed. In summary, dietary10% EVA chow is without long term effect on growth, development and behavior is non-toxic and may be hepatobeneficial.

[Influence of oral administration of realgar on contents of copper, zinc and selenium in rat tissues].

OBJECTIVE: To investigate the changes of copper, zinc and selenium levels in rat tissues after long-term oral administration of Realgar. METHODS: Rats were given Realgar with dosage of 50, 150, 450 mg.kg-1.d-1 for 5 weeks, and the concentrations of copper, zinc and selenium in different rat tissues as well as the contents of metallothionein in rat liver and kidney were determined with atomic absorption and hydride generation-atomic fluorescent technique. The total amount of copper excreted from feces and urine of each rat 5 days before the rat was killed was also measured. RESULTS: No significant changes of levels of copper, zinc and selenium in rat tissues were found after administration of low and middle dosages of Realgar. But higher dosage (450 mg.kg-1.d-1) of Realgar administration could induce a small but significant decrease of zinc concentration in hearts and a increase of copper contents in spleen and tibia, as well as twice more copper concentration of kidney. CONCLUSION: Copper deposit in kidney was the most significant change found among the trace elements levels in rat tissues, and this might be one of the mechanisms for kidney toxicity of Realgar.

[Preliminary studies on process and ultramicro-pulverization on pharmacodynamics of Leech].

OBJECTIVE: To compare pharmacodynamics of decoction and powder of Leech; To identify effect of pharmacodynamics of Leech with new methods of process and ultrmicro-pulverization. METHOD: The size of ultramicor-powder of Leech and new method processed Leech is determined by BT-1500 size distributive instrument. It is compared that the pharmacodynamics of Leech decoction and powder as well as ultramicro-powder with new method processed of 1/2 decoction dose by anticoagulation and antithrombus action of mice. The safety of different samples is identified. RESULT: The pharmacodynamics of samples is as ultramicro-powder of Leech with new method processed > ultrmicro-powder of Leech > powder of Leech > decoction of Leech. CONCLUSION: The ultramicro-powder of Leech with new method processed has better pharmacodynamic effect and the smell of Leech is improved.

[Influence of alum on intestinal flora in mice].

OBJECTIVE: To observe the influence of alum on the intestinal microecological balance in normal microorganisms. METHOD: The mice were administered orally with alum of a small dosage(0.25/kg) and a large dosage(1 g/kg) for half a month, two months and three months, and a micro flora analysis of the mice was carried out at intervals of the above mentioned administrations. RESULT: The intestinal flora in the animals administered with alum was imbalanced. The counts of bifidobacteria and lactobacilli closely related to human physiological activities were decreased. The counts of pathogenic E. Coli significantly increased; and the longer the animals were treated with alum, the stronger the microecological balance was influenced. CONCLUSION: Alum could induce imbalance of the normal intestinal flora in mice.