Amyloid Neuropathies, Familial/drug therapy* ; Benzoxazoles ; Humans ; Prealbumin

The present study was aimed to investigate the effects of orexin-A and orexin-1 receptor (OX1R) antagonist injected into the fourth ventricle of rats on food-intake and spontaneous physical activity (SPA). Obese rat model was induced by high fat diet. Different doses of orexin-A or SB334867, an OX1R antagonist, were injected into the fourth ventricle of obese and normal rats respectively. SPA and food intake were monitored for 4 h after injection in both light and dark environment. In the light measurement cycle, different doses of orexin-A significantly stimulated feeding and SPA in all injected rats, and the animals' responses showed a dose-dependent manner (P < 0.05-0.01), and compared with those of normal rats, the orexin-A induced food intake and SPA were more pronounced in obese rats. In the dark measurement cycle, different doses of orexin-A had no obvious effect on food intake and SPA in both normal and obese rats (P > 0.05). In the light cycle, different doses of SB334867 significantly decreased food intake and SPA in all rats during 0-2 h and 2-4 h after injection (P < 0.05), but the food intake and SPA in obese rats were significantly greater than those of normal rats. In the dark cycle, different doses of SB334867 showed no obvious effect on food intake and SPA of normal and obese rats (P > 0.05). These results suggest that fourth cerebral ventricle nuclei may be one target for orexin-A and light condition may play an important role in orexin-A and OX1R physiological functional processes.
Animals ; Benzoxazoles ; pharmacology ; Diet, High-Fat ; Eating ; drug effects ; Fourth Ventricle ; Motor Activity ; drug effects ; Obesity ; Orexin Receptor Antagonists ; pharmacology ; Orexin Receptors ; Orexins ; pharmacology ; Rats ; Urea ; analogs & derivatives ; pharmacology

BACKGROUND/AIMS: The unique role of enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes makes it a therapeutic target for inflammatory bowel disease (IBD). The aim of this study was to evaluate the effects of B-98, a newly synthesized benzoxazole derivatives and a novel 5-LO inhibitor, in a mouse model of IBD induced by dextran sulfate sodium (DSS). METHODS: C57BL/6 mice were randomly assigned to four groups: normal control, DSS colitis (DSS+saline), low dose B-98 (DSS+B-98 20 mg/kg) and high dose B-98 (DSS+B-98 100 mg/kg). B-98 was administered with 3% DSS intraperitoneally. The severity of the colitis was assessed via the disease activity index (DAI), colon length, and histopathologic grading. The production of inflammatory cytokines interleukin (IL)-6 was determined by RT-PCR. Th cells were examined for the proportion of Th1 cell, Th2 cell, Th9 cell, Th17 cell and Treg cell using intracellular cytometry. RESULTS: The B-98 group showed lower DAI, less shortening of the colon length and lower histopathologic grading compared with the DSS colitis group (p<0.01). The expression of IL-6 in colonic tissue was significantly lower in the B-98 groups than the DSS colitis group (p<0.05). The cellular profiles revealed that the Th1, Th9 and Th17 cells were increased in the DSS colitis group compared to the B-98 group (p<0.05). CONCLUSIONS: Our results suggest that acute intestinal inflammation is reduced in the group treated with B-98 by Th1, Th9 and Th17 involved cellular immunity.
Acute Disease ; Animals ; Arachidonate 5-Lipoxygenase/chemistry/metabolism ; Benzoxazoles/chemistry/*pharmacology ; Colitis/chemically induced/pathology/*prevention & control ; Colon/drug effects/pathology/physiology ; Dextran Sulfate/toxicity ; Disease Models, Animal ; Forkhead Transcription Factors/metabolism ; Injections, Intraperitoneal ; Interleukin-6/genetics/metabolism ; Lipoxygenase Inhibitors/chemistry/*pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Severity of Illness Index ; T-Lymphocytes/classification/*drug effects/metabolism

Chlorzoxazone ; blood ; Chromatography, High Pressure Liquid ; methods ; Cytochrome P-450 CYP2E1 ; blood ; Humans

OBJECTIVETo investigate the effect of CYP450 enzyme inhibition of berberine in pooled human liver microsomes by cocktail probe drugs.

METHODCocktail probe drugs method has been established, an LC-MS/MS analytical method has been established to determine the five probes of midazolam, phenacetin, dextromethorphan, tolbutamide, chlorzoxazone and the internal standard was benzhydramine to evaluate the effect of CYP450 activity following administration of berberine in pooled human liver microsomes.

RESULTCompared with control group, the pharmacokinetics of midazolam, phenacetin and tolbutamide were no significant differences, but the pharmacokinetics of chlorzoxazone was significantly decreased. There were no significant differences for the pharmacokinetics of dextromethorphan when the concentration of berberine was 50 microg x L(-1). The pharmacokinetics of dextromethorphan was significantly decreased when the concentration of berberine was exceed 200 microg x L(-1).

CONCLUSIONBerberine has no influence on the activities of CYP3A4, CYP1A2 and CYP2C19 below 2 000 microg x L(-1), but can inhibit the activity of CYP2E1 and CYP2D6 in concentration-dependent.

Berberine ; pharmacology ; Chlorzoxazone ; pharmacokinetics ; Cytochrome P-450 Enzyme Inhibitors ; Dextromethorphan ; pharmacokinetics ; Dose-Response Relationship, Drug ; Humans ; Microsomes, Liver ; enzymology ; Midazolam ; pharmacokinetics ; Phenacetin ; pharmacokinetics ; Tolbutamide ; pharmacokinetics

Cytochrome P450 2E1 (CYP2E1) is involved in the toxicity and carcinogenicity of a number of solvents and xenobiotics. Like the various types of oxidation pharmacogenetics, the activity of the enzyme shows a discernible interindividual and interethnic variation. However, no pharmacogenetic information on CYP2E1 polymorphism has been available from a Korean population. The aim of this study was to explore the pharmacogenetics of CYP2E1 polymorphism in a native Koreans after an oral 400 mg dose of chlorzoxazone administered to 128 subjects. Urine samples were collected during the subsequent 8-hour period and urinary concentrations of chlorzoxazone and 6-hydroxychlorzoxazone were determined by a high performance liquid chromatography with an ultraviolet detector. The limit of detection in the samples was found to be 0.5 mug/ml. The mean value of the 6-hydroxychlorzoxazone excreted in 8 hr urine expressed as the percentage was 48.2 13.8%. The frequency distribution of percentage of the administered dose excreted as the 6-hydroxy metabolite was unimodally distributed in the subjects studied. However, the values showed wide (7-fold) interindividual difference, ranged from 11.6% to 79.8% of the dose of chlorzoxazone. Thus, it was considered that the pharmacogenetic characteristics of CYP2E1 in a Korean population did not-represent multimodal distribution in the 6-hydroxychlorzoxazone excreted in 8-hr urine expressed as the percentage. And the activity of the CYP2E1 in a Korean population seemed to be less compared with that of the Caucasian subjects.
Asian Continental Ancestry Group ; Chlorzoxazone ; Chromatography, Liquid ; Cytochrome P-450 CYP2E1* ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Humans ; Limit of Detection ; Pharmacogenetics ; Solvents ; Xenobiotics

OBJECTIVETo study the effect of ferment powder caterpillar fungus on cytochrome P450 isozymes CYP1A2, CYP3A4 and CYP2E1.

METHODThe methods of Cocktail probe drugs were used. The rats were randomly divided into two groups. One group were given ferment powder caterpillar fungus once daily orally for ten days. Another group received orally normal saline one daily as the blank control. After ten days of treatment, the rats were given probe drugs of coffine, dapsone and chlorzoxazone and the blood was taken out by femoral catheterization. The plasma concentration of probe drugs were determined by HPLC. Data of plasma drug level-time were disposed with DAS Ver 2.0.

RESULTThe metabolism of caffeine and dapsone speeded up after receiving ferment powder caterpillar fungus, but the metabolism of chlorzoxazone was hardly changed.

CONCLUSIONIt suggested that ferment powder caterpillar fungus tended to be the inducer of CYP1A2 and CYP3A4. But the CYP2E1 was hardly affected.

Animals ; Caffeine ; metabolism ; Chlorzoxazone ; metabolism ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System ; metabolism ; Dapsone ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Fermentation ; Male ; Random Allocation ; Rats ; Rats, Wistar

This study aimed to explore the impact of depression caused by chronic unpredictable mild stress (CUMS) on in vivo activity of six kinds of CYP450 isoforms in rats. According to 'Katz' method, the model of CUMS was established. Tolbutamide, chlorzoxazone, theophylline, midazolam, omeprazole and dextromethorphan were chosen as probe substrates of CYP2C6, CYP2E1, CYP1A2, CYP3A2, CYP2D1 and CYP2D2 of rats. Plasma concentration of six kinds of CYP450 in control group and model group were determined by LC-MS/MS and computed pharmacokinetic parameters. Consequently, metabolism of theophylline and chlorzoxazone accelerated significantly (P < 0.01), but tolbutamide, dextromethorphan, omeprazole and midazolam had no significant difference. The present study proved that depression caused by CUMS had strong induction to CYP1A2 and medium induction to CYP2E1.
Animals ; Chlorzoxazone ; metabolism ; Chromatography, Liquid ; Cytochrome P-450 Enzyme System ; metabolism ; Depression ; Dextromethorphan ; metabolism ; Liver ; enzymology ; Midazolam ; metabolism ; Omeprazole ; metabolism ; Rats ; Stress, Physiological ; Tandem Mass Spectrometry ; Theophylline ; metabolism ; Tolbutamide ; metabolism

This study is to investigate the mechanism of inhibitory effect of imipramine on the calcium utilization in single cells isolated from canine detrusor. 2 mm thick smooth muscle chops were incubated in 0.12% collagenase solution at 36degreeC, and aerated with 95% O2/5% CO2, and then cell suspension was examined Acetylcholine (ACh) evoked a concentration-dependent contraction of the isolated detrusor cells in normal physiologic salt solution (PSS), and the ACh-induced contraction was significantly inhibited by imipramine. In Ca2+-free PSS, ACh-induced contraction was less than those in normal PSS and it was not affected by the pretreatment with imipramine. Ca2+-induced contraction in Ca2+-free PSS was supressed by imipramine, but addition of A 23187, a calcium ionophore, overcomed the inhibitory effect of imipramine. High potassium-depolarization (40 mM KCl) evoked cell contraction, which was inhibited by imipramine. Caffeine, a releasing agent of the stored Ca2+ from sarcoplasmic reticulum, evoked a contraction of the cells that was not blocked by the pretreatment with imipramine. These results suggest that imipramine inhibits the influx of calcium in the detrusor cells through both the receptor-operated- and voltage-gated-calcium channels, but does not affect the release of calcium from intracellular storage site.
Acetylcholine ; Caffeine ; Calcimycin ; Calcium* ; Collagenases ; Imipramine* ; Muscle, Smooth ; Sarcoplasmic Reticulum

It has been implicated that leukotrienes play roles in the pathogenesis of gastritis and gastric ulceration associated with Helicobacter pylori (H. pylori). Rebamipide is being used as an antiulcer drug but it's mechanism of action has not been understood well. One possible mechanism of action of this drug is to inhibit the cellular release of leukotrienes by various stimuli, particularly H. pylori. In the present study, attempts were made to test this possibility and the results are as follows. When Kato III cells (gastric adenoma cells) were stimulated by H. pylori, leukotriene D4 (LTD4) was released and rebamipide inhibited this release dose-dependently. Similar experiment was performed on neutrophils because the infilteration of neutrophils is a common phenomenon in H. pylori-infected gasrtric tissues. Neutrophils released LTD4 when these cells were stimulated by H. pylori and rebamipide also inhibited this release. Furthermore, rebamipide inhibited the release of LTD from neutrophils induced by calcium ionophore A23187 and arachidonic acid. The results suggest that rebamipide has the action to inhibit the release of LTD4 from various cells and this action may contribute in part to prevent the ulcerogenesis induced by H. pylori.
Adenoma ; Arachidonic Acid ; Calcimycin ; Calcium ; Gastritis ; Helicobacter pylori* ; Helicobacter* ; Leukotriene D4* ; Leukotrienes ; Neutrophils ; Stomach Ulcer