OBJECTIVETo determine whether and to what degree the activity of cholinesterase(ChE) is inhibited by dimehypo at different doses of dimehypo [scientific name: 2-dimethylamine-1,3-bi(sodium hyposulfit)].

METHODRats were dosed with dimehypo or methamidophos orally, and were randomly divided into four subgroups according to the pesticide doses, which were 1/16, 1/8, 1/4 and 1/2 of LD50 respectively(the LD50 of dimethypo and methamidophos is 342 mg/kg and 20 mg/kg respectively). The activity of ChE in blood was determined before and 30 min, 1, 2, 4 and 24 h after exposure. The modified Ellman Method was employed to measure the activity of ChE.

RESULT1/16 LD50 dose of dimehypo did not affect the activity of ChE. When the dose increased, the activity of ChE decreased accordingly. 1/2 LD50 dose of dimehypo inhibited the activity of ChE by 35.9% compared with that of control group(P < 0.01). In rats dosed with methamidophos, even 1/16 LD50 dose inhibited the activity of ChE by 42.4% compared with that of control group. When the dose of methamidophos increased, the activity of ChE decreased accordingly. 1/2 LD50 dose of methamidophos inhibited the activity of ChE by 52.9%. The activity of ChE in the rats dosed with dimehypo at various doses was significantly lower than that in the rats dosed with corresponding doses of methamidophos(P < 0.01).

CONCLUSIONHigher doses of dimehypo may inhibit the activity of ChE. However, as compared with methamidophos, dimehypo is a weaker inhibitor of ChE.

Animals ; Cholinesterase Inhibitors ; toxicity ; Cholinesterases ; blood ; Dose-Response Relationship, Drug ; Insecticides ; toxicity ; Lethal Dose 50 ; Organothiophosphorus Compounds ; toxicity ; Rats

OBJECTIVETo investigate the toxicity of methanol extract of various parts (Root, Stem, Leaf, Flower and Fruit) of Lantana camara (L. Camara) in Artemia salina.

METHODSThe methanol extracts of L. camara were tested for in vivo brine shrimp lethality assay.

RESULTSAll the tested extract exhibited very low toxicity on brine shrimp larva. The results showed that the root extract was the most toxic part of L. camara and may have potential as anticancer agent.

CONCLUSIONSMethanolic extract of L. camara is relatively safe on short-term exposure.

Animals ; Artemia ; drug effects ; Dose-Response Relationship, Drug ; Lantana ; chemistry ; Lethal Dose 50 ; Plant Components, Aerial ; chemistry ; Plant Extracts ; toxicity ; Plant Roots ; chemistry

OBJECTIVETo evaluate three alternative methods for LD50 test-Fixed Dose Procedure (FDP), the Acute Toxic Class Method (ATC) and Up and Down Procedure (UDP).

METHODSFemale SD rats (8-12 weeks of age, 160-200 g) were used. Three alternative methods from OECD were applied to assess 22 chemicals (10 cosmetic raw materials and 12 raw materials of personal and home care products). The toxicity ranking for tested chemicals was established according to Globally Harmonized System (GSH). The results LD50 test were compared for the consistency and correlation between alternative methods and traditional test.

RESULTSFor cosmetic raw materials, the concordance rate of the three alternative methods was 80% (8/10); for raw material of personal and home care products, the concordance rates of FDP, ATC and UDP was 91.7% (11/12), 75.0% (9/12) and 83.0% (10/12), respectively. The number of animals required in three alternative methods was significantly lower than that in traditional test (P < 0.05), but the time required in three alternative methods was significantly higher than that in traditional test (P < 0.05).

CONCLUSIONSHigh consistency and correlation were found between each alternative method and LD50 test. FDP may be more potential when applied to assess acute oral toxicity of cosmetic raw materials.

Administration, Oral ; Animals ; Cosmetics ; toxicity ; Dose-Response Relationship, Drug ; Female ; Hazardous Substances ; toxicity ; Lethal Dose 50 ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests, Acute ; methods

OBJECTIVE: To investigate the lethal blood level, the target organs and tissues, the toxicant storage depots and the postmortem redistribution in mice died of emamectin benzoate poisoning. METHODS: The mice model of emamectin benzoate poisoning was established via intragastric injection. The main poisoning symptoms and the clinical death times of mice were observed and recorded dynamically in the acute poisoning group as well as the sub-acute poisoning death group. The pathological and histomorphological changes of organs and tissues were observed after poisoning death. The biodistribution and postmortem redistribution of emamectin benzoate in the organs and tissues of mice were assayed by the enzyme-linked immunosorbent assay (ELISA) at 0h, 24h, 48h and 72h after death. The lethal blood concentrations and the concentrations of emamectin benzoate were detected by high performance liquid chromatography (HPLC) at different time points after death. RESULTS: The symptoms of nervous and respiratory system were observed within 15-30 min after intragastric injection. The average time of death was (45.8 ± 7.9) min in the acute poisoning group and (8.0 ± 1.4) d in the sub-acute poisoning group, respectively. The range of acute lethal blood level was 447.164 0-524.463 5 mg/L. The pathological changes of the organs and tissues were observed via light microscope and immunofluorescence microscope. The changes of emamectin benzoate content in the blood, heart, liver, spleen, lung, kidney and brain of poisoning mice showed regularity within 72 h after death (P < 0.05). CONCLUSION The target organs of emamectin benzoate poisoning include heart, liver, kidney, lung, brain and contact position (stomach). The toxicant storage depots are kidney and liver. There is emamectin benzoate postmortem redistribution in mice.
Animals ; Autopsy ; Chromatography, High Pressure Liquid ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Ivermectin/toxicity* ; Lethal Dose 50 ; Mice ; Postmortem Changes ; Tissue Distribution

OBJECTIVE: To find out the pathological change and the toxic mechanism of Chloranthus serratus Roem. et Schalt in mice. METHODS: Mice were intoxicated by oral administration with extracts of Chloranthus serratus Roem. et Schalt followed by pathological, serum biochemical, and coagulation mechanism examination. RESULTS: The LD50 in mice was 41.12 g/kg; All poisoned mice serum BUN and ALT increased markedly; Thrombocyte decreased and coagulation time increased; The organ index of liver, spleen and kidneys increased significantly; The cells of liver, kidney and heart were degeneration and necrosis, There were extensive hyperemia and hemorrhage in many organs. CONCLUSION The experiment suggests that the target organs were liver, kidney, heart and blood vessels; The toxic mechanism was the damage on the mitochondrional, endoplasmic reticulum and coagulation system.
Animals ; Biomarkers/blood* ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/drug effects* ; Female ; Forensic Pathology ; Kidney/pathology* ; Lethal Dose 50 ; Liver/pathology* ; Magnoliopsida/chemistry* ; Male ; Mice ; Mitochondria, Heart/drug effects* ; Mitochondria, Liver/drug effects* ; Myocardium/pathology* ; Plant Extracts/toxicity* ; Random Allocation

Because of its officinal value, strychnos is widely used by clinic and individual. Since toxic dose and therapeutic dose are very close, strychnos poisoning cases are frequently reported. In this paper the chemical component, toxic dose, mechanisms of toxicity, poisoning symptom and pathological changes after strychnos poisoning are reviewed.
Alkalies/poisoning* ; Animals ; Central Nervous System/drug effects* ; Dose-Response Relationship, Drug ; Forensic Medicine ; Humans ; Immune System/drug effects* ; Lethal Dose 50 ; Plants, Medicinal/chemistry* ; Seeds/chemistry* ; Strychnine/poisoning* ; Strychnos/toxicity*

OBJECTIVETo investigate the effects of pre-treatment of alpha-ketoglutarate (alpha-KG) on cyanide-induced lethality and changes in various physiological parameters in rodents.

METHODSThe LD50 of potassium cyanide (KCN) given orally (po), intraperitoneally (ip), subcutaneously (sc) or intravenously (iv) was determined in male mice, in the presence or absence alpha-KG given po, ip or iv. alpha-KG was administered 10, 20 or 40 min prior to KCN at 0.50, 1.0 or 2.0 g/kg by po or ip route, and at 0.10, 0.20 or 0.40 g/kg by iv route. Protection index (PI) was calculated as the ratio of LD50 of KCN in the presence of alpha-KG (protected animals) and LD50 of KCN in the absence of alpha-KG (unprotected animals). In a separate experiment, several physiological variables viz. mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), neuromuscular transmission (NMT) and rectal temperature (RT) were measured in anesthetized female rats pre-treated (-10 min) with po (2.0 g/kg) or iv (0.125 g/kg) alpha-KG and then administered sub-lethal (0.75 LD50) or lethal (2.0, 4.0 or 8.0 LD50) doses of KCN (po).

RESULTSPI of 4.52, 6.40 and 7.60 at -10 min, 3.20, 5.40 and 6.40 at -20 min, and 1.40, 3.20 and 5.40 at -40 min of po administration with a-KG was observed for 0.50, 1.0 and 2.0 g/kg doses, respectively, against KCN given by po route. When KCN was given ip, a PI of 3.38, 4.79 and 5.70 was observed for 0.50, 1.0 and 2.0 g/kg alpha-KG given ip (-10 min), respectively. A lower PI of 3.37, 2.83 and 2.38 was observed when KCN given sc was challenged by 2.0 g/kg alpha-KG given ip at -10, -20 or -40 min, respectively. Similarly, a PI of 3.37, 2.83 and 2.0 was noted when KCN given sc was antagonized by 2.0 g/kg alpha-KG given po at -10, -20 or -40 min, respectively. No appreciable protection was observed when lower doses of alpha-KG (ip or po) challenged KCN given by sc route. Pre-treatment of iv or po administration of alpha-KG did not afford any protection against KCN given po or iv route. Oral treatment of 0.75 LD50 KCN caused significant decrease in MAP and HR after 15 min, RR after 30 min and NMT after 60 min. There was no effect on RT. No reduction in MAP, HR, RR and RT was observed when rats received 2.0 or 4.0 LD50 KCN after pre-treatment of alpha-KG (po; 2.0 g/kg). However, no protection was observed on NMT. Protective efficacy of alpha-KG was not observed on MAP, HR, RR, and NMT decreased by 8.0 LD50 KCN. Decrease in MAP and NMT caused by 2.0 LD50 KCN (po) was resolved by iv administration of alpha-KG.

CONCLUSIONSCyanide antagonism by alpha-KG is best exhibited when both alpha-KG and KCN are given by po route. The protective effect of a-KG on cyanide-induced changes in several physiological parameters also indicates a promising role of alpha-KG as an alternative cyanide antidote.

Administration, Oral ; Animals ; Antidotes ; administration & dosage ; Dose-Response Relationship, Drug ; Female ; Injections, Intraperitoneal ; Injections, Intravenous ; Injections, Subcutaneous ; Ketoglutaric Acids ; administration & dosage ; Lethal Dose 50 ; Male ; Mice ; Potassium Cyanide ; poisoning ; Rats ; Rats, Wistar

It has been demonstrated by our previous research that 4-(2-acetoxybenzoylamino) butyramide derivatives exhibited good antiepileptic activities. In this paper, to explore the SAR and improve the antiepileptic activities of these derivatives, a series of novel 4-(2-acetoxybenzoylamino) butyramide heterocyclic compounds (5a-5n) were synthesized and biologically evaluated. Their structures were confirmed by 1H MNR, ESI-MS and elemental analysis. Pharmacological test in vivo showed that target compounds (5f, 5i-5n) displayed strong antiepileptic activities on 4-AP induced epilepsy in mice with ED50 values ranging from 0.3137 to 0.3604 mmol x kg(-1).
4-Aminopyridine ; Amides ; administration & dosage ; chemical synthesis ; chemistry ; therapeutic use ; Animals ; Anticonvulsants ; administration & dosage ; chemical synthesis ; chemistry ; therapeutic use ; Dose-Response Relationship, Drug ; Epilepsy ; chemically induced ; drug therapy ; Female ; Lethal Dose 50 ; Male ; Mice ; Molecular Structure ; Random Allocation ; Receptors, GABA ; metabolism ; Structure-Activity Relationship

OBJECTIVETo characterize the function of a new xanomeline-derived M1 agonist, 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6- tetrahydro-1-methylpyridine Oxalate (EUK1001), the acute toxicity and the effects on synaptic plasticity and cognition of EUK1001 were evaluated.

METHODSTo examine the median lethal dose (LD50) of EUK1001, a wide dose range of EUK1001 was administered by p.o. and i.p. in aged mice. Furthermore, novel object recognition task and in vitro electrophysiological technique were utilized to investigate the effects of EUK1001 on recognition memory and hippocampal synaptic plasticity in aged mice.

RESULTSEUK1001 exhibited lower toxicity than xanomeline, and improved the performance of aged mice in the novel object recognition test. In addition, bath application of 1 micromol/L EUK1001 directly induced long-term potentiation in the hippocampus slices.

CONCLUSIONWe conclude that EUK1001 can improve the age-related cognitive deficits.

Aging ; drug effects ; Animals ; Brain ; drug effects ; Dose-Response Relationship, Drug ; Excitatory Postsynaptic Potentials ; drug effects ; Lethal Dose 50 ; Long-Term Potentiation ; drug effects ; Memory ; drug effects ; Mice ; Muscarinic Agonists ; administration & dosage ; adverse effects ; Pyridines ; administration & dosage ; adverse effects ; chemistry ; Thiadiazoles ; administration & dosage ; adverse effects ; chemistry

OBJECTIVETo screen and evaluate the active constituents of Chinese medicinal herbs as potent inhibitors of Cdc25 phosphatase.

METHODSThe affinity chromatography purified glutashione-S-transferase/Cdc25A phosphatase fusion protein and Cdc2/cyclin B from the extracts of starfish M phase oocytes are used as the cell cycle-specific targets for screening the antimitotic constituents. We tested 9 extracts isolated from the Chinese medicinal herbs and vegetables including the agents currently used in cancer treatment by measuring the inhibition of Cdc25A phosphatase and Cdc2 kinase activity. The antitumor activity of the extracts was also evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry.

RESULTSCdc25A inhibitory activity and antitumor activity are detected in the extracts isolated from three Chinese medicinal herbs Agrimona pilosa; Herba solani lyrati; Galla chinesis.

CONCLUSIONWe found three extracts isolated from Chinese medicinal herbs have potential inhibitory activity of Cdc25 phosphatase using a highly specific mechanism-based screen assay for antimitotic drug discovery.

Apoptosis ; drug effects ; Cell Cycle Proteins ; antagonists & inhibitors ; metabolism ; Cell Line, Tumor ; Cyclin-Dependent Kinases ; metabolism ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; analysis ; chemistry ; pharmacology ; Humans ; Lethal Dose 50 ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; enzymology ; pathology ; Medicine, Chinese Traditional ; methods ; Mitosis ; drug effects ; Phytotherapy ; methods ; Plants, Medicinal ; chemistry ; cdc25 Phosphatases ; antagonists & inhibitors ; metabolism