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.

Toxicity study of mineral medicine haematitum.

ETHNOPHARMACOLOGICAL RELEVANCE: Haematitum, a time-honored mineral-based Chinese medicine, has been used medicinally in China for over 2000 years. It is now included in the Chinese Pharmacopoeia and used clinically for treating digestive and respiratory diseases. The Chinese Materia Medica records that it is toxic and should not be taken for a long period, but there are few research reports on the toxicity of Haematitum and its potential toxicity mechanisms. AIM OF THE STUDY: This study aimed to evaluate the toxicity of Haematitum and calcined Haematitum, including organ toxicity, neurotoxicity, and reproductive toxicity. Further, it is also necessary to explore the mechanism of Haematitum toxicity and to provide a reference for the safe clinical use of the drug. MATERIALS AND METHODS: The samples of Haematitum and calcined Haematitum decoctions were prepared. KM mice were treated with samples by gavage for 10 days, and lung damage and apoptosis were assessed by HE staining and TUNEL staining of lung tissues respectively. Metabolomics analysis was performed by HPLC-MS. Metallomics analysis was performed by ICP-MS. In addition, C. elegans was used as a model for 48 h exposure to examine the neurotoxicity and reproductive toxicity-related indices of Haematitum, including locomotor behaviors, growth and development, reproductive behaviors, AChE activities, sensory behaviors, apoptosis, and ROS levels. RESULTS: The use of large doses of Haematitum decoction caused lung damage in mice. Neither calcined Haematitum decoction nor Haematitum decoction at clinically used doses showed organ damage. Metabolomics results showed that disorders in lipid metabolic pathways such as sphingolipid metabolism and glycerophospholipid metabolism may be important factors in Haematitum-induced pulmonary toxicity. High doses of Haematitum decoction caused neurological damage to C. elegans, while low doses of Haematitum decoction and calcined Haematitum decoction showed no significant neurotoxicity. Decoction of Haematitum and calcined Haematitum did not show reproductive toxicity to C. elegans. Toxicity was also not observed in the control group of iron (Ⅱ) and iron (Ⅲ) ions in equal amounts with high doses of Haematitum. CONCLUSIONS: Haematitum is relatively safe for routine doses and short-term use. Calcination can significantly reduce Haematitum toxicity, and this study provides a reference for safe clinical use.

[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.

[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.

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.

[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.

[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.

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.

[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.

[Pharmacological studies on the comparison between the drainage and certified Fel Ursi].

A comparison between the drainage and certified Fel Ursi was studied by pharmacological methods. The results demonstrated that the drainage Fel Ursi was similar to the certified products in anti-inflammatory, antipyretic, sedative, anticonvulsive, antispasmodic and bacteriostatic actions.

[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.

[Preparation of huichun zhibao oral liquid (HZOL)].

The formulation, preparing method, quality standards, pharmacodynamic experinents and toxicological experiments of HZOL are described. The content of icariin, which is and effective component of epimedium herb as well as one of the main ingredients in HZOL, was successfully determined through HPLC, with an average recovery of 98.98% and RSD = 1.53%.

[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.

[Pharmacological studies on Bombyx mori L].

The toxicity of the Bombyx mori extract is very low. It can promote the growth of under-aged male mice, and increase markedly the weight of the prostate glands, seminal vesicles and preputial glands in castrated rats of mice. The results of the experiments have shown that Bombyx mori has androgen-like action.

[Pharmacological action of various processed Mylabris phalerata Pallas].

We have compared the acute toxicity, sub-acute toxicity and in vitro and in vivo anti-tumor action of the rude drug, stir-fried with rice, and alkali-processed drugs of Mylabris phalerata before and after removing the head, feet and wings. The results indicate that the toxicity of the processed drugs is lower than that of the rude ones; the toxicity becomes higher without head, feet, and wings; and the alkali-processing method is better than stir-frying with rice recorded in the pharmacopeia.

[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.

[Anti-inflammatory and analgesic effects of scolopendra from different habitats].

The water extracts of several species of the Chinese drug scolopendra from different habitats can inhibit obviously the increased permeability of abdominal blood capillaries and ear inflammation in mice. They can also raise the pain thresholds in mice during hot-plate and writhing tests. Their toxicity is very low.