AIM　To investigate the poteintation of vincristine-induecd apoptosis by tetrandrine, neferine and dauricine isolated from Chinese medicinal plants in the human mammary MCF-7 multidrug resistant cells. METHODS　The apoptotic cells were detected by fluorescent staining of a combination of Hoechst 33342 and propidium iodide (PI), flow cytometry and agarose electrophoresis. RESULTS　The apoptotic cells induced by vincristine alone accounted for about 10% of all the cancer cells, while the percentage of apoptotic cells induced by a combination of vincristine with tetrandrine, neferine, or dauricine was found to be significantly higher than that by vincristine alone, and their reversal effects were positively correlated with the drug concentration and the exposure time. In addition, tetrandrine was shown to be the most potent in the reversal efficacy among the three compounds to be tested for apoptosis in vitro. CONCLUSION　Tetrandrine, neferine and dauricine showed obvious potenitiation of vincristine-induced apoptosis in the human mammary MCF-7 multidrug-resistant cells.

OBJECTIVETo investigate hepatoxicity and nephrotoxicity of cinnabar to provide the scientific basis for safe uses in clinic.

METHODMaximally tolerated dose of cinnabar (MTD) was tested by single oral administration. Chronic toxicity of cinnabar at different dose level (0.025, 0.05, 0.1, 0.4, 0.8 g x kg(-1) x d(-1)) corresponding to 1/2, 1, 2, 8, 16 times of clinic doses of cinnabar was investigated. The rats were treated with the cinnabar through oral administration once a day for successive 90 days. Urinary qualitative test, blood routine examination, serum chemistry measurement and histomorphologic observation were conducted at day 30, 60 and 90. Toxic changes related to the treatment of cinnabar and no-observed adverse effect level (NOAEL) were evaluated.

RESULTFor the content of 98.1% total Hg and 21.5 microg x g(-1) absoluble Hg, MTD of cinnabar with oral administration was 24 g x kg(-1) (corresponding to 516 microg x kg(-1) absoluble Hg), equivalent to 3,000 times of clinical daily dose for an adult, and no obvious adverse effect was showed at this dose. Cinnabar can cause kidney and liver pathological changes when it is repeatedly administrated for over 30 days. The kidney was more sensitive to cinnabar than liver. Based on repeated dose toxicity study, NOAELs were 0.1, 0.05 g x kg(-1) x d(-1)) respectively for 30 day and 90 day treatment, and those were approximately accumulative intake of absoluble Hg 64.5 microg x kg(-1) and 96.76 microg x kg(-1). Thus, for safe use of cinnabar, the acceptable daily intake (ADI) of cinnabar was 0.0009-0.0017 g x kg(-1) x d(-1), namely daily dose 0.05-0.1 g for an adult with body weight about 60 kg. Considering the difference of drug sensitivity and lifecircle between human and rats, we suggest that cinnabar which contains absoluble Hg < or = 21 microg x g(-1) should be used for no longer than 2 weeks at daily dose 0.05-0.1 g.

CONCLUSIONLong term use of cinnabar can cause kidney and liver pathological change, so the dose and administration duration should be limited. The suggestion is as follows: cinnabar which contains absoluble Hg < or = 21 microg x g(-1) should be used less than 2 weeks at the daily dose below 0.05-0.1 g.

Administration, Oral ; Animals ; Dose-Response Relationship, Drug ; Female ; Kidney ; drug effects ; metabolism ; Liver ; drug effects ; metabolism ; Male ; Mercury Compounds ; administration & dosage ; toxicity ; Mice ; Organ Size ; drug effects ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the anti-thrombosis effect and its mechanism of Qingkailing injection (QKL).

METHODSD rats were randomly divided into control group, model group and QKL 2.5, 5.0, 10 groups. QKL were given (i.p.) to rats once a day for successively 4 days. The rats in all groups but control were pretreated with carrageenin (Ca) i.p. at 16 h before the last dose of QKL and followed by intravenous injection of endotoxin ( LPS fom E. coli O111:B4) 50 microg x kg(-1) 30 min after the last dosing of QKL. Thrombosis in rat tails were observed at 24 h after injection of LPS. The number of white blood cells and platelets, serum TNF-alpha, IL-6 level, CD11b/CD18 expression of white blood cells and platelet aggregation were analysed.

RESULTQKL obviously inhibited the LPS/Ca-induced thrombosis as showed a reduced infarction range due to thrombosis in tails. The sera concentration of TNF-alpha and IL-6, expression of CD11b/CD18 in WBC and platelet coagulation rate were reduced after QKL treatment.

CONCLUSIONThe anti-thrombosis action of QKL is associated with inhibition of WBC activation and adherence, reduction of inflammatory factor release and abating of platelet coagulation rate. The anti-thrombosis mechanism of QKL is consistent with its function of clearing away heat-evil and toxic materials.

Animals ; CD11 Antigens ; genetics ; metabolism ; CD18 Antigens ; genetics ; metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Fibrinolytic Agents ; administration & dosage ; Gene Expression ; drug effects ; Humans ; Injections, Intraperitoneal ; Interleukin-6 ; blood ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Thrombosis ; drug therapy ; genetics ; metabolism ; Tumor Necrosis Factor-alpha ; blood

OBJECTIVETo explore arsenic accumulation and toxicity mechanism following long-term use of realgar and provide scientific basis for safety use of realgar in clinic.

METHODThe realgar which was used in the study contains 90% insoluble asenic sulfide (As2S2) and 1.696 mg x kg(-1) soluble arsenic. Two separate experiments were performed: 1) Twenty-eight fasting SD rats were orally given a single dose of realgar at the dose of 0.8 g x kg(-1) and the other four rats were given ultra-filtrated water served as control group. Blood, hearts, livers, kidneys, lungs and brains of four rats were taken out at 0.5, 1, 2, 4, 8, 16, 36 h respectively after treatment. Asenic quantity of each organ or blood sample was measured. 2) Forty SD rats were randomly divided into four groups: control group and realgar 0.02, 0.08, 0.16 g x kg(-1) groups, each group containing 5 females and 5 males. The rats were intra-gastrically treated with realgar once a day for successively 90 days, while the control group was given ultra-filtrated water. Asenic amount in blood, liver, kidney and brain of each rat was measured in fasting rats at 16 h after last dosing.

RESULTAsenic amount of blood, liver, kidney, heart, lung and brain increased after single dosing of realgar at dose of 0.16 g x kg(-1), with the order from high to low blood > kidney > lung > liver > heart > brain. Asenic amount was much higher in blood than that in other organs. The feature of asenic distribution in blood following realgar administration may be the basis for its use for leukemia Ninety-day oral treatment of realgar led to significant accumulation of asenic in blood, kidney, liver and brain. The highest asenic accumulation times was found in kidney followed by liver, which was assumed to be associated with nephrotoxicity and hepatotoxicity of realgar. The highest amount of asenic was observed in blood after 90 day's administration of realgar, and the amount of asenic in organs was in the order of blood > kidney > liver > brain.

CONCLUSIONAsenic can be absorbed and extensively distributed in various organs or tissesses after realgar administration in rats. Long-term use of realgar caused high asenic accumulation in various tissueses, including blood, kidney, liver, and brain. The nephrotoxicity and hepatotoxicity of realgar could be associated with the asenic accumulation in relative organs. Blood is the target of the most highest distribution and accamulation of asenic after realgar treatment, that could be associated with the efficacy of realgar on the treatment of leakemia.

Animals ; Arsenic ; analysis ; chemistry ; pharmacokinetics ; toxicity ; Arsenicals ; administration & dosage ; adverse effects ; chemistry ; Female ; Male ; Rats ; Rats, Sprague-Dawley ; Solubility ; Sulfides ; administration & dosage ; adverse effects ; chemistry ; Time Factors

OBJECTIVETo investigate the toxicity of realgar and provide the scientific basis for safety use of realgar in clinic.

METHODAcute toxicity was tested by single oral administration. Chronic toxicity of realgar was tested at different dose levels (5, 10, 20, 80, 160 mg x kg(-1) x d(-1)) which correspond to 1/2, 1, 2, 8, 16 times of human dose levels. The rats were treated with the test substances through oral administration once daily for successively 90 days. Urinary qualitative test, blood routine examination, serum chemistry measurement, and histomorphologic observation were conducted at day 30, 60 and 90. Toxic changes related to the treatment of realgar and no-observed adverse effect level (NOAEL) was evaluated.

RESULTWith the content of 90% total arsenic and 1.696 mg x g(-1) soluble asenic, LD50 of Realgar with oral administration was 20.5 g x kg(-1) (corresponding to 34.8 mg x kg(-1) soluble arsenic), equivalent to 12 812 times of clinical daily dose for an adult. Realgar can cause kidney toxicity or/and liver toxicity after administration for over 30, 60 or 90 days respectively. The kidney was more sensitive to realgar than liver. Based on repeated dose toxicity study, NOAELs were 160 mg x kg(-1) x d(-1) for 30 day's administration, 20 mg x kg(-1) x d(-1) for 60 day's administration, 10 mg x kg(-1) x d(-1) mg x kg(-1) x d(-1) for 90 day's administration respectively. Thus, for safety use of realgar, it is recommended that the daily doses of realgar (with soluble arsenic < or = 1.7 mg x g(-1)) for an adult of the body weight about 60 kg could be 10-160 mg depending on the variation of the treatment duration.

CONCLUSIONLong term use of realgar can cause kidney and liver pathological change, so the doses and administration duration should be limited. The suggestion is as follows: realgar which contains soluble arsenic < or = 1.7 mg x g(-1) should be used less than 2 weeks at daily dose 160 mg, less than 4 weeks at the dose of 20 mg and less than 6 weeks at the dose of 10 mg.

Administration, Oral ; Animals ; Arsenicals ; administration & dosage ; chemistry ; Dose-Response Relationship, Drug ; Female ; Kidney ; drug effects ; Liver ; drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; Solubility ; Sulfides ; administration & dosage ; chemistry ; toxicity ; Time Factors ; Toxicity Tests, Acute ; methods ; Toxicity Tests, Chronic ; methods