benzofurans and dictamnine

This study aims to characterize the pharmacokinetic (PK) profiles and identify important bioavailability barriers and pharmacological pathways of the key active components (KACs) of Antitumor B (ATB), a chemopreventive agent. KACs (matrine, dictamine, fraxinellone, and maackiain) of ATB were confirmed using the antiproliferative assay and COX-2 inhibition activities in oral cancer cells. The observed

Topics: Alkaloids; Animals; Benzofurans; Biological Availability; Chemoprevention; Drugs, Chinese Herbal; Matrines; Mice; Mice, Inbred C57BL; Molecular Structure; Mouth Neoplasms; Network Pharmacology; Pterocarpans; Quinolines; Quinolizines

Cortex Dictamni is a commonly-used traditional Chinese herbal medicine for the treatment of skin inflammation, tinea, and eczema. Recently, some studies reported that Cortex Dictamni might induce liver injury, suggesting more attention to its safety. The current study was designed to investigate subchronic toxicity of Cortex Dictamni aqueous extract (CDAE) and ethanol extract (CDEE) in mice and the potential hepatotoxicity mechanisms in vitro. Firstly, CDAE or CDEE groups were administrated with varying dosages (2.3, 4.6, or 9.2 g/kg/day, p.o.) in mice for 28 days in subchronic toxicity studies. General clinical signs and biochemical parameters were examined, and morphological analyses were conducted. Secondly, we identified the different constituents of CDAE and CDEE using HPLC-MS/MS and chose major components for further study. In order to determine the toxic components, we investigated the cytotoxicity of extracts and chosen components using CCK-8 assay in HepG2 cells. Furthermore, we explored the possible hepatotoxicity mechanisms of Cortex Dictamni using a high content analysis (HCA). The results showed that no significant differences of general clinical signs were observed in mice. Aspartate alanine aminotransferase (ALT) and aminotransferase (AST) were significantly increased in the high-dose CDAE and CDEE groups compared to the control group. Meanwhile, the absolute and relative liver weights and liver/brain ratio were significantly elevated, and histological examination of liver demonstrated cellular enlargement or nuclear shrinkage. In UPLC analysis, we compared the chemical constituents between CDAE and CDEE, and chose dictamnine, obakunone, and fraxinellone for hepatotoxicity evaluation in the in vitro studies. In the CCK-8 assay, CDAE, CDEE, dictamnine, obakunone, and fraxinellone decreased the cell viability in a dose-dependent manner after treatment for 48 h. Furthermore, the cell number decreased, while the nuclear intensity, cell membrane permeability, and concentration of reactive oxygen species were shown to increase, meanwhile, mitochondrial membrane potential was also changed in HepG2 cells following 48 h of compounds treatment using HCA. Our studies suggested that CDAE and CDEE have potential hepatotoxicity, and that the alcohol extraction process could increase toxicity. Dictamnine, obakunone, and fraxinellone may be the possible toxic components in Cortex Dictamni with dictamnine as the most potentially hepatotoxic component, whose

Topics: Animals; Apoptosis; Benzofurans; Benzoxepins; Cell Count; Cell Survival; Chemical and Drug Induced Liver Injury; Dictamnus; Drugs, Chinese Herbal; Ethanol; Female; Hep G2 Cells; Humans; Limonins; Liver; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred ICR; Quinolines; Toxicity Tests, Subchronic; Water

Zeng-Sheng-Ping (ZSP), also called antitumor B, is a marketed Chinese traditional medicine used for cancer prevention.. Currently, for the quality control of Chinese traditional medicines, marker compounds are not selected based on bioactivities and pharmaceutical behaviors in most of the cases. Therefore, even if the "quality" of the medicine is controlled, the pharmacological effect could still be inconsistent. The aim of this study is to establish an activity and absorption-based platform to select marker compound(s) for the quality control of Chinese traditional medicines.. We used ZSP as a reference Chinese traditional medicine to establish the platform. Activity guided fractionation approach was used to purify the major components from ZSP. NMR and MS spectra were used to elucidate the structure of the isolated compounds. MTT assay against oral carcinoma cell line (SCC2095) was performed to evaluate the activities. UPLC-MS/MS was used to quantify the pure compounds in ZSP and the active fraction. The permeabilities of the identified compounds were evaluated in the Caco-2 cell culture model. The intracellular accumulation of the isolated compounds was evaluated in the SCC2095 cells.. The major compounds were identified from ZSP. The contents, anti-proliferation activities, permeabilities, and intracellular accumulations of these compounds were also evaluated. The structure of these purified compounds were identified by comparing the NMR and MS data with those of references as rutaevine (1), limonin (2), evodol (3), obacunone (4), fraxinellone (5), dictamnine (6), maackiain (7), trifolirhizin (8), and matrine (9). The IC50 of compounds 5, 6, and 7 against SCC2095 cells were significantly lower than that of ZSP. The uptake permeability of compounds 5, 6, and 7 were 2.58 ± 0.3 × 10(-5), 4.33 ± 0.5 × 10(-5), and 4.27 ± 0.8 × 10(-5) respectively in the Caco-2 cell culture model. The intracellular concentrations of these compounds showed that compounds 5, 6, and 7 were significantly accumulated inside the cells.. Based on the activity against oral carcinoma cell line as well as the absorption permeability, compound 5, 6, and 7 are selected as quality control markers for ZSP. An activity and absorption-based platform was established and successfully used for the quality control of ZSP.

Topics: Alkaloids; Benzofurans; Benzoxepins; Cell Line, Tumor; Cell Proliferation; Drugs, Chinese Herbal; Glucosides; Heterocyclic Compounds, 4 or More Rings; Humans; Limonins; Matrines; Medicine, Chinese Traditional; Permeability; Pterocarpans; Quality Control; Quinolines; Quinolizines; Triterpenes

A rapid and selective ultra high performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of four major ingredients in Cortex Dictamni extract, including limonin, dictamnine, obacunone and fraxinellone in rats plasma. Nimodipine was used as the internal standard. Following extraction by methyl tert-butyl ether, the analytes were separated on a Thermo Syncronis C18 column by a gradient elution within a runtime of 9min. The mobile phase consisted of A (methanol) and B (2mmol/L ammonium acetate in water). The detection was accomplished by using positive ion electrospray ionization in multiple reaction monitoring mode. The method was linear for all analytes over investigated range with all correlation coefficients greater than 0.998. The lower limits of quantification were 9.18ng/mL for limonin, 12.0ng/mL for dictamnine, 16.05ng/mL for obacunone and 4.59ng/mL for fraxinellone. The intra- and inter-day precision (RSD%) was within 10% and the accuracy (RE%) ranged from -12.9% to 9.7%. This rapid and sensitive method was fully validated and successfully applied to the pharmacokinetic study of limonin, dictamnine, obacunone and fraxinellone in the rat plasma after oral administration of Cortex Dictamni extract.

Topics: Administration, Oral; Animals; Benzofurans; Benzoxepins; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Limonins; Male; Quinolines; Rats; Rats, Sprague-Dawley; Rutaceae; Sensitivity and Specificity; Tandem Mass Spectrometry

To study the relationship between deposition content and time of the active ingredients in rat skin, and investigate the dermatopharmacokinetics of Liangfu Cream.. The contents of paeonol, dictamnine, fraxinellone and glycyrrhetinic acid in rat skin were determined by HPLC. The dermatopharmacokinetics parameters were calculated by DAS software.. The dermatopharmacokinetics of paeonol and glycyrrhetinic acid were two compartment model, while that of dictamnine and fraxinellone were one compartment model: T(1/2Ka) of four active ingredients were 0.307, 0.112, 0.146, 0.216 h, respectively; T(lag) of them were 0.006, 0.123, 0.136, 0.109 h, respectively; all the Tmax of them was 0.5 h; the Cmax, were 40.163, 1.607, 6.725, 100.553 microg x cm(-3), respectively; the t(1/2beta), were 14.719, 1.262, 0.838, 234.807 h, respectively; the AUC(0-infinity), were 16.987, 2.713, 9.345, 697.000 microg x cm(-3) x h(-1), respectively; and the MRT(0-infinity) were 3.662, 1.67, 1.585, 10.897, respectively.. The skin pharmacokinetics characteristic of four ingredients in Liangfu cream is lined with the cataplasm long time.

Topics: Acetophenones; Administration, Cutaneous; Animals; Benzofurans; Drugs, Chinese Herbal; Glycyrrhetinic Acid; Male; Mice; Quinolines; Skin

To study the effects of different penetration enhancers on the in vitro percutaneous absorption and amount retained in skin of active ingredients in Liangfu cream and to screen out the effective accelerator.. Using improved Franz-type difusion cell and excised small mouse skin in vitro as transdermal barrier, the amount retained in skin and kinetics parameters of active ingredients such as cumulative permeation quantity, permeation rate and permeation lagged time were determined by HPLC. The enhancement ability of four different enhancers such as azone, oleic acid, transcutol P and isopropyl myristate were investigated.. 3% IPM enhanced the cumulative permeation quantity better than other penetration enhancers. The enhancive permeation multiples of paeonol, dictamnine, fraxinellone and glycyrrhetinic acid were 1.52, 1.24, 1.73 and 3.21 times (P < 0.05). The enhancive amount retained in skin multiple of glycyrrhetinic acid was 1.96 times (P < 0.05), but for other components there were no significant impacts.. The effects of penetration enhancers on the in vitro percutaneous absorption and amount retained in skin of components in Liangfu cream are different. 3% IPM which can enhance the cumulative permeation quantity of four components and amount retained in skin of glycyrrhetinic acid is the most suitable penetration enhancer for Liangfu cream.

Topics: Acetophenones; Administration, Cutaneous; Animals; Benzofurans; Drug Carriers; Drugs, Chinese Herbal; Glycyrrhetinic Acid; Male; Mice; Quinolines; Skin; Skin Absorption

The screening for insecticidal principles from several Chinese medicinal herbs showed that the root bark of Dictamnus dasycarpus possessed significant feeding deterrence against two stored-product insects (Tribolium castaneum and Sitophilus zeamais). From the methanol extract, two feeding deterrents were isolated by bioassay-guided fractionation. The compounds were identified as fraxinellone and dictamnine from their spectroscopic data. Fraxinellone was demonstrated to possess feeding deterrent activity against adults and larvae of T. castaneum as well as S. zeamais adults with EC50 values of 36.4, 29.1, and 71.2 ppm, respectively. Dictamnine was shown to have feeding deterrent activity against adults and larvae of T. castaneum as well as S. zeamais adults with EC50 values of 57.6, 47.9, and 91.7 ppm, respectively.

Topics: Alkaloids; Animals; Benzofurans; Chemical Fractionation; Eating; Food Contamination; Insecta; Larva; Plant Extracts; Plant Roots; Quinolines; Tribolium

The components of Dictamnus dasycarpus Turcz were tested for their vasorelaxing effect on the rat aorta, and fraxinellone and dictamine were shown to be effective vasorelaxants. In high K+ (60 mmol/l) medium, Ca2+ (0.03 to 3 mmol/l)-induced vasoconstriction was inhibited concentration-dependently by both agents. The IC50 for fraxinellone and dictamine were calculated to be about 25 mumol/l and 15 mumol/l (for Ca2+ concentration of 1 mmol/l), respectively. Cromakalim (0.2-10 mumol/l) relaxed aortic rings precontracted with 15 but not 60 mmol/l of K+. Fraxinellone and verapamil were more potent and effective in producing relaxation in 60 mmol/l than in 15 mmol/l K(+)-induced contraction. However, dictamine was more potent in producing relaxation in 15 mmol/l K(+)-induced contraction. Nifedipine (1 mumol/l), dictamine (100 mumol/l) and fraxinellone (100 mumol/l) relaxed the aortic contraction caused by KCl or Bay K 8644. The tonic contraction elicited by noradrenaline (NA, 3 mumol/l) was also relaxed by dictamine (500 mumol/l), but not by fraxinellone (500 mumol/l) in the nifedipine (1 mumol/l)-treated aorta. This relaxing effect of dictamine persisted in endothelium-denuded aorta. Glibenclamide (10 mumol/l) shifted the concentration-relaxation curve of cromakalim, but not that of dictamine, to the right in rat aortic rings precontracted with NA. Dictamine (500 mumol/l) did not affect tonic contraction of NA which are reduced by H-7 (1 mumol/l) in Ca(2+)-depleted medium. In conclusion, fraxinellone is a selective blocker of voltage-dependent Ca2+ channel, while dictamine relaxed the rat aorta by suppressing the Ca2+ influx through both voltage-dependent and receptor-operated Ca2+ channels.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Alkaloids; Animals; Aorta, Thoracic; Benzofurans; Benzopyrans; Calcium; Calcium Channel Blockers; Cromakalim; Cyclic AMP; Cyclic GMP; Drugs, Chinese Herbal; Female; Glyburide; In Vitro Techniques; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Potassium Channels; Potassium Chloride; Pyrroles; Quinolines; Rats; Rats, Inbred Strains; Verapamil