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@#To investigate the influential mechanism of total flavonoids from Abelmoschus Manihot (HKZ) on cytochrome P450 (CYP450) isoforms in human liver microsomes and to verify its effect on the most significantly inhibited subtype CYP2C9 in rats.The inhibitory effects of HKZ on human CYP3A4, CYP2C9, CYP2C19, CYP2E1, CYP1A2 and CYP2D6 were evaluated through the cocktail method using ultra-performance liquid chromatography tandem mass spectrometry, then its inhibitory mechanism was investigated and kinetic parameters of enzyme inhibition were calculated By comparing the pharmacokinetic behaviors of tolbutamide after single or multiple administration of 200 mg/kg HKZ and equal dose of CMC-Na in rats, the effects of HKZ on CYP2C11 enzyme (CYP2C9 isoenzyme) was estimated.The results indicated the significant inhibitory effect of HKZ on CYP2C9 and CYP2E1 with IC50 of 3.22 and 8.64 μg/mL, respectively. Also, it showed certain inhibitory ability on other isoforms with IC50 of 20-30 μg/mL.As demonstrated, HKZ may not be a time-dependent inhibitor which competitively inhibited CYP2E1 and CYP2C9 with Ki of 3.84 and 6.33 μg/mL.In contrast, it showed noncompetitive inhibition on CYP3A4 mediated testosterone-6β-hydroxylation and midazolam-4-hydroxylation reaction with Ki of 7.37 and 3.32 μg/mL.It was also a noncompetitive inhibitor of CYP1A2, CYP2D6 and CYPC219 with Ki values of 8.66, 11.49 and 21.94 μg/mL. HKZ did not change the pharmacokinetic parameters of CYP2C11 probe substrate tolbutamide in rat, but it affected the AUC0-t, cmax of 4-hydroxytolubutamide (P < 0.05). Therefore, drug-drug interaction mediated by CYP450 should be considered in clinical study.
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Diabetes mellitus is a common metabolic disorder of carbohydrate, fat, and protein, which results in high levels of glucose in the body after a meal or fasting. This disease is caused by the absence or reduction of insulin secretion. Accordingly, diabetes is usually classified into two types, Type 1(IDDM) and Type II (NIDDM). The aim of the present study is to carry the phytochemical analysis and antidiabetic activity of Salvia aegyptiaca Lethanolic leaves extract. Phytochemical study was carried out by standard methods, shows the presence of various phytochemical constituents such as, phenols, flavonoids, steroids, proteins, glycosides, carbohydrates, lipids, alkaloids, tannins and terpenoids, while saponins shown to be absent. Antidiabetic activity of Salvia aegyptiaca Lwere carried out in both normoglycemic and diabetic induced rats. Normoglycemic animal group were fed with ethanolic leaves extract of Salvia aegyptiaca Lat a dose of 250mg/kg and 500mg/kg alone for 14days, showed decrease in blood glucose level. In diabetic animal group the rats were made diabetic by intraperitoneal(i.p) injection of 100 mg/kg alloxan monohydrate, then followed by administration of ethanolic leaves extract of Salvia aegyptiaca(250mg/kg and 500mg/kg) and standard Tolbutamide (50mg/kg,p.o) for14 days. The results of the diabetic induced group also showed decrease in glucose levels. The results of thecurrent investigation demonstrate that various phytochemical present in Salvia aegyptiaca Lethanolic leaves extracts, might be responsible for antidiabetic effect, due to its known antioxidant property
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Objective To investigate the efficacy of sulforubicin combined with olanzapine in the treatment of adolescents with schizophrenia and to observe its effect on cognitive function.MethodsFrom August 2013 to August 2016, 124 adolescents diagnosed with schizophrenia were randomly divided into control group and observation group,each of 62 cases.The control group was given olanzapine treatment, the observation group was given olanzapine combined with amisulpride treatment.Positive and negative symptom scale (PANSS), Wisconsin Card Sorting Test (WCST) and Wechsler Memory Scale (WMS) were used to evaluate the patient and clinical symptoms and cognitive function after 8 weeks of treatment The clinical effect and adverse changes of two groups were compared.ResultsThe PANSS score, WCST score and WMS score of the two groups were not statistically significant.After 8 weeks of treatment, the PANSS score, WCST score and WMS score of the two groups were significantly higher than those before treatment (P<0.05), and the improvement of the above scores in observation group was better than that of the control group (P<0.05).The total effective rate was 93.55% in the observation group, which was significantly higher than that in the control group (67.74%, χ2=14.49, P<0.05).There was no serious adverse reaction between the two groups.ConclusionThe combination of sulforubicin and olanzapine for the first episode of schizophrenia is very effective in improving the clinical symptoms and cognitive function of patients, and has better safety.
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Objective:To establish an ultra performance liquid chromatography-tandem quadruple mass spectrometry ( UPLC-MS/MS) method to determine CYP2C9 activity in vitro. Methods:An ACQUITY UPLC? BEH C18 (100 mm × 2. 1 mm, 1. 7 μm) column was used as the stationary phase at 30℃. The mobile phase consisted of acetonitrile-water ( containing 0. 1% formic acid and 0. 5%ammonia water) (40∶60, v/v). The flow rate was 0. 2 ml·min-1. Chlorpropamide was used as the internal standard. The MS condi-tions were as follows:ESI with positive ion detection mode. Self-prepared CYP2C9?1, ?2, ?3 and ?13 protein were incubated with tolbutamide at 37℃ and 800μl ethyl acetate was added to stop the reaction. After centrifuged at 10 000g, the organic layer was then dried using nitrogen, the residue was re-dissolved in 200μl mobile phase and determined by UPLC-MS/MS. Results: The reten-tion time of 4-hydroxytolbutamide was 1. 21 min. An excellent linear calibration curve of 4-hydroxytolbutamide was obtained within the concentration range of 0. 05-5 ng·μl-1(r=0. 999 8). The lower limit of quantification of 4-hydroxytolbutamide was 0. 01 ng·μl-1 with the average recovery of 99. 3%-100. 3%. The intra- and inter-day RSDs were all less than 5%. There was no interference from the endogenous substances existing in the incubation system. The catalytic activity of the variants CYP2C9?2,?3 and?13 after tol-butamide was incubated with CYP2C9?1,?2,?3 and?13 was 47. 3%, 11% and 0. 3% of wild type CYP2C9?1. Conclusion:The method is simple and stable, and suitable for the fast evaluation of cytochrome CYP2C9 activity in vitro and relevant studies on the inhibitors.
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Insulin, Glibenclamide and Tolbutamide are some of the frequently used drugs for the most common metabolic disorders, diabetes mellitus. Along with hypoglycaemic drugs diabetic patient is exposed to variety of drugs. NSAIDs are one of the commonly used drugs in this metabolic syndrome. When a patient on hypoglycaemic drugs receives NSAIDs there are chances of drug interactions. This study was undertaken in the department of Pharmacology, GSVM medical college, Kanpur (UP) after approval by the institutional animal ethics committee to find out the interaction if any between Diclofenac and three hypoglycaemic drugs i.e. insulin, glibenclamide and tolbutamide. Young healthy rabbits were divided into six groups: five rabbits in each group. First group received Insulin 1 u/kg subcutaneously; second Glibenclamide 0.05 mg/kg orally; third Tolbutamide 40 mg/kg orally; fourth Diclofenac 1mg/kg orally and insulin 1mg/kg s.c. simultaneously; fifth glibenclamide 0.05mg/kg orally at 0 hour and diclofenac 1mg/kg orally at 2 hours and sixth tolbutamide 40mg/kg orally at 0 hour and diclofenac 1mg/kg orally at 2 hours. Blood samples were taken at 0, 1, 2, 4 and 6 hours for blood sugar estimation. Mean blood sugar levels reduced significantly from their fasting levels when insulin, glibenclamide and tolbutamide were administered. However blood sugar levels did not showed any significant changes when diclofenac was administered along with insulin, glibenclamide and tolbutamide in comparison to when insulin, glibenclamide and tolbutamide were given alone. The results showed that diclofenac does not interact with insulin, glibenclamide and tolbutamide on blood sugar levels in rabbits.
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OBJECTIVE: To study the effect of capsaicin on the activities of CYP1A2, 2C11 and 3A in rats by cocktail probe drug method. METHODS: Male rats were randomly divided into six groups. Three groups of rats (group A, B and C) were orally given capsaicin 25 mg · kg-1 once daily for 1, 3, 7 d, respectively. The other three groups (group a, b and c) received orally 0.5% carboxymethylcellulose sodium (CMC-Na) once daily for 1, 3, 7 d, respectively, as the blank control groups. Plasma was collected at different time after drug administration. The concentrations of caffeine, tolbutamide and dapsone in plasma were determined by HPLC method. The plasma concentration-time data was analyzed with DAS2.1.1 software to obtain the pharmacokinetic parameters of the cocktail probe drugs. RESULTS: Compared with the blank control group, the AUC0-t AUC0-t and pmax of caffeine in group C significantly decreased, along with significant increase of CL/F. The AUC0-t and pmax of tolbutamide in group C both significantly decreased compared with the blank control group. Meanwhile, the AUC0-t and AUC0-t of dapsone in group C significantly decreased, along with significant increase of CL/F and V/F. CONCLUSION: Capsaicin may significantly induce the activities of CYP1A2, CYP2C11 and CYP3A in rats after consecutive administration for 7 d. Reduced therapeutic efficacy of the drugs metabolized by CYP1A2, CYP2C11 and CYP3A should be anticipated during long-term administration of capsaicin.
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Objective To investigate the effect of diltiazem, one of calcium antagonists, on the function of rat beta cells and the re- lease of insulin induced by D860. Methods Intravenous glucose tolerance test (IVGTY) was conducted to assess beta-cell function of rats among control, dihiazem, D860, and dihiazem plus D860 groups, followed by treatment with dihiazem and D860 for 4 weeks respectively. Another IVGTT was carded out at the end of the study. Results The data showed that diltiazem could inhibit insulin released from normal SD rats. Moreover, it reduced the hypoglycemic effect promoted by D860. However, in long term, the rise of blood sugar in rats treated with D860 respectively was not found. Conclusion Diltiazem did not impair beta cells function and interfere the hypoglycemic effect of D860 in rats in long time.
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AIM: To establish the methods for assaying the activities of tolbutamide hydroxylase (CYP2C8/9) and chlorzoxazone 6-hydroxylase (CYP2E1) from adult human livers microsomes. METHODS: The microsomes was isolated from human adults liver and the contents of microsomal protein were determined. Using the tolbutamide and chlorzoxazone as substrates, the amount of hydroxytoblbutamide and hydroxychlorzoxazone formed during the incubation period was quantified by extroppolating from the standard curve and the specific activity of CYP2C8/9 and CYP2E1 were calculated. RESULTS: There was no siginificant influence on the activities of CYP2C8/9 and CYP2E1 in different times. CONCLUSIONS: The methods utilized to estimate the activity of CYP2C8/9 and CYP2E1 were simple, stable, and repeatable. These methods can be used in new drug screening, safety evaluation and reseasch on pathology and toxicology of liver.
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Polysaccharide sulphate (PSS) 1. 8, 5. 4 and 18mg ? kg-1 ig could remarkably reduce blood glucose of alloxan - induced diabetes in rabbits . The doses of PSS could decrease the high blood glucose caused by adrenaline . PSS 1. 8 and 5. 4mg ? kg-1 could not reduce blood glucose concentration in normal rabbits, but PSS 18mg ? kg-1 could do. The glucose to lerance test showed that PSS 5. 4 and 18mg ?kg-1 could reduce the increase of blood glucose level caused by glucose loading after administration of glucose in rats (5g ? kg-1, ig) and could also persistently decrease blood glucose of alloxan - induced diabetes in rats after the doses of PSS ig for 5d.
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AIM To establish the methods for assaying the activities of tolbutamide hydroxylase (CYP2C8/9) and chlorzoxazone 6-hydroxylase(CYP2E1) from adult human livers microsomes. METHODS The microsomes was isolated from human adults liver and the contents of microsomal protein were determined. Using the tolbutamide and chlorzoxazone as substrates, the amount of hydroxytoblbutamide and hydroxychlorzoxazone formed during the incubation period was quantified by extroppolating from the standard curve and the specific activity of CYP2C8/9 and CYP2E1 were calculated. RESULTS There was no siginificant influence on the activities of CYP2C8/9 and CYP2E1 in different times. CONCLUSIONS The methods utilized to estimate the activity of CYP2C8/9 and CYP2E1 were simple, stable, and repeatable. These methods can be used in new drug screening, safety evaluation and reseasch on pathology and toxicology of liver.
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Objective To investigate the effect of calcium antagonist verapamil on the function of rat?- cells and tolbutamide (D860)-induced insulin release.Methods Insulin released from isolated islets were measured in control,verapamil,D860,and verapamil+D860 groups.Furthermore,intravenous glucose tolerance test (IVGTT) was conducted in acute experiments treated with verapamil and D860 respectively to assess?-cell function in rats with the same allocation as in vitro.Another IVGTT was performed in the end of 4 weeks' treatment.The insulin contents in pancreas were assayed and pancreas islets morphology were observed with immunohistochemistry.Results Verapamil could inhibit insulin release from isolated islets.Verapamil group was [(1.244?0.082)ng?ml~(-1)?islet~(-1)]and control group (2.623?0.226) ng?ml~(-1)?islet~(-1)(P0.05).Also,similar results were obtained in normal rats during acute experiments and verapamil reduce the hypoglycemic effect promoted by D860. However,above results were not observed in the end of 4 weeks experiments,and no difference for insulin content and morphological change in islets was found among four groups.Conclusion Treatment of verapamil chronically does not impair islet function and interfere with the hypoglycemic effect of D860 in rats .