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1.
Bioanalysis ; 15(18): 1147-1156, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37650495

ABSTRACT

Aim: This study aimed to establish a method to determine tigecycline (TGC) in the cerebrospinal fluid (CSF) and serum of 12 patients with multidrug-resistant Acinetobacter baumannii (MDRAB) central nervous system infection (CNSI) and evaluate the correlation of TGC in CSF and serum samples. Materials & methods: TGC in CSF and serum was detected by high-performance liquid chromatography with tandem mass spectrometry. Results: In all 12 patients, the CSF-to-serum ratio of TGC at a steady-state trough concentration ranged from 21.46 to 44.46%, and the mean value was 31.61 ± 8.13%. The correlation of TGC in CSF and serum was 0.5065. Conclusion: CNSI might have no potential to increase the penetration ability of TGC into the CSF. The correlation between the concentrations of TGC in CSF and serum at steady state was demonstrated to be positive.


Subject(s)
Acinetobacter baumannii , Central Nervous System Infections , Humans , Tigecycline , Chromatography, High Pressure Liquid , Tandem Mass Spectrometry
2.
Int J Antimicrob Agents ; 60(5-6): 106692, 2022.
Article in English | MEDLINE | ID: mdl-36372345

ABSTRACT

OBJECTIVES: To characterize trough concentrations (Cmin) of voriconazole and associated hepatotoxicity, and to determine predictors of hepatotoxicity and identify high-risk groups in critically ill patients. METHODS: This was a nationwide, multi-centre, retrospective study. Cmin and hepatotoxicity were studied from 2015 to 2020 in 363 critically ill patients who received voriconazole treatment. Logistic regression and classification and regression tree (CART) models were used to identify high-risk patients. RESULTS: Large interindividual variability was observed in initial voriconazole Cmin and concentrations ranged from 0.1 mg/L to 18.72 mg/L. Voriconazole-related grade ≥2 hepatotoxicity developed in 101 patients, including 48 patients with grade ≥3 hepatotoxicity. The median time to hepatotoxicity was 3 days (range 1-24 days), and 83.2% of cases of hepatotoxicity occurred within 7 days of voriconazole initiation. Voriconazole Cmin was significantly associated with hepatotoxicity. The CART model showed that significant predictors of grade ≥2 hepatotoxicity were Cmin >3.42 mg/L, concomitant use of trimethoprim-sulfamethoxazole or tigecycline, and septic shock. The model predicted that the incidence of grade ≥2 hepatotoxicity among these high-risk patients was 48.3-63.4%. Significant predictors of grade ≥3 hepatotoxicity were Cmin >6.87 mg/L, concomitant use of at least three hepatotoxic drugs, and septic shock; the predictive incidence among these high-risk patients was 22.7-36.8%. CONCLUSION: Higher voriconazole Cmin, septic shock and concomitant use of hepatotoxic drugs were the strongest predictors of hepatotoxicity. Plasma concentrations of voriconazole should be monitored early (as soon as steady state is achieved) to avoid hepatotoxicity.


Subject(s)
Drug Monitoring , Shock, Septic , Humans , Voriconazole/adverse effects , Retrospective Studies , Shock, Septic/drug therapy , Antifungal Agents/adverse effects , Critical Illness
3.
Biomed Chromatogr ; 36(7): e5370, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35297066

ABSTRACT

Ribavirin is a synthetic, broad-spectrum antiviral drug. Ribavirin is recommended as an antiviral drug in the Interim Guidance for Diagnosis and Treatment (the seventh edition) of COVID-19. The ribavirin levels in red blood cells may be closely related to both its efficacy and adverse drug reactions. In this study, a simple and fast HPLC-UV method was established to determine the concentrations of total ribavirin in the red blood cells of 13 patients with COVID-19. Phosphorylated ribavirin was dephosphorylated by phosphatase incubation to obtain the total amount of ribavirin in red blood cells. The chromatographic column was an Atlantis C18 . The recoveries were 85.45-89.05% at three levels. A good linear response was from 1 to 200 µg/ml, with a correlation coefficient of r2 = 0.9991. The concentration of total ribavirin in the red blood cells of the patients ranged from 30.83 to 133.34 µg/ml. The same samples without phosphatase incubation ranged from 4.07 to 20.84 µg/ml. About 85% of ribavirin was phosphorylated in red blood cells. In addition, we observed changes in these patients' hematological parameters and found that the erythrocyte, hemoglobin and hematocrit declined to the lowest levels on the fifth day after discontinuation of ribavirin (p < 0.05).


Subject(s)
COVID-19 Drug Treatment , Ribavirin , Antiviral Agents , Chromatography, High Pressure Liquid/methods , Erythrocytes , Humans , Phosphoric Monoester Hydrolases/analysis , Ribavirin/analysis , Ribavirin/therapeutic use
4.
Toxicol Lett ; 347: 78-85, 2021 Sep 01.
Article in English | MEDLINE | ID: mdl-33865921

ABSTRACT

BACKGROUND: Arsenic trioxide (ATO) has been successfully applied in the treatment of acute promyelocytic leukemia (APL). Arsenic metabolites including inorganic arsenic and methylated arsenic could lead to different toxicity and curative effect. This study aims to establish a method to determine arsenic species in red blood cells (RBCs), clarify the distribution characteristics of arsenic species in RBCs. METHODS: Steady state blood samples were collected from 97 APL patients. H2O2 and HClO4 were used to release the hemoglobin bounding arsenic and precipitate protein. Arsenite (iAsIII), arsenate (iAsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in plasma and RBCs were detected by HPLC-HG-AFS. Free and bound arsenic species in RBCs were separated by 30 kDa molecular mass cutoff filters and determined to evaluate hemoglobin binding capacity of different arsenic species. RESULTS: The method was validated with accuracy ranged from 84.75% to 104.13%. Arsenic species in RBCs followed the trend iAs > MMA > DMA (p < 0.01), while the concentration of DMA was significantly higher than iAs and MMA in plasma (p < 0.01). The correlation between iAs concentration in plasma and corresponding RBCs arsenic level was weak. And the concentrations of DMA and MMA in plasma were moderately positive correlated with those in RBCs. Hemoglobin-binding ratios of iAs, MMA and DMA were all over 70 %. CONCLUSIONS: In this study, we provided a reliable method to determine arsenic species in RBCs of APL patients treated with ATO by HPLC-HG-AFS. It was confirmed that the concentration of DMA is the highest in plasma, while MMA is the most predominant methylated arsenic in RBCs. High affinity of MMA with human Hb was responsible for the accumulation of arsenic in RBCs of APL patients.


Subject(s)
Antineoplastic Agents/blood , Antineoplastic Agents/therapeutic use , Arsenic Trioxide/blood , Arsenic Trioxide/therapeutic use , Erythrocytes/metabolism , Leukemia, Promyelocytic, Acute/drug therapy , Adolescent , Adult , Arsenicals/blood , Biotransformation , Cacodylic Acid/blood , Child , Child, Preschool , Chromatography, High Pressure Liquid , Female , Hemoglobins/metabolism , Humans , Infant , Infant, Newborn , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/diagnosis , Male , Methylation , Middle Aged , Protein Binding , Spectrometry, Fluorescence , Spectrophotometry, Atomic , Young Adult
5.
Biomed Chromatogr ; 34(2): e4716, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31633824

ABSTRACT

Tizoxanide, the active metabolite of nitazoxanide, has recently been reported as an effective agent for the treatment of glioma. As there had been no report about the analysis of tizoxanide in brain tissue, we established extraction and UHPLC-MS/MS methods to quantify tizoxanide in rat brain and plasma to evaluate the brain-to-plasma ratio of tizoxanide. The biological samples were mainly prepared by acetonitrile and the separation was performed on a Waters XBridge® BEH C18 column. The mobile phase was composed of water mixed with 10 mm ammonium formate (pH 3.0) and acetonitrile according a gradient volume. Tizoxanide and topiramate (internal standard) were monitored utilizing negative electron spray ionization in multiple reaction monitoring mode. The methods were validated to be precise and accurate within the dynamic range of 5-1000 ng/mL and 0.2-50 ng/g for plasma and brain tissue samples, respectively. The lower limit of quantitation of the method was 0.2 ng/g, which was far more sensitive than all existing methods to quantify tizoxanide in biological samples. Application performed on rats exhibited that the brain-to-plasma ratio of tizoxanide ranged from 3.16 to 26.86% in 1 h after administration of 10 mg/kg nitazoxanide.


Subject(s)
Brain/metabolism , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Thiazoles/analysis , Animals , Limit of Detection , Linear Models , Male , Nitro Compounds , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Tissue Distribution
6.
Pharmazie ; 69(7): 537-41, 2014 Jul.
Article in English | MEDLINE | ID: mdl-25073400

ABSTRACT

OBJECTIVE: To investigate the influence of scutellarin on the activities of CYP1A2, CYP2C11, CYP2D1, and CYP3A1/2 in rats in vivo. METHODS: Scutellarin and saline were intravenously administered to male Wistar rats via the caudal vein for 7 days consecutively. On the 8th day, the rats were treated with probe drugs of caffeine (10 mg/kg), tolbutamide (10 mg/kg), metoprolol (20 mg/kg), dapsone (10 mg/kg) by intraperitoneal injection, and the blood samples were collected at different times. The probe drugs in the blood samples were measured by ultra performance liquid chromatography mass spectrometer (UPLC-MS/MS) and the changes of the pharmacokinetics parameters of the drugs were observed to evaluate the effects of scutellarin on the four CYP450 isoforms in rats. RESULTS: The activity of CYP1A2 in rats was inhibited significantly after treatment with scutellarin by increased caffeine t1/2 (21.76%, P < 0.05), T(max) (43.05%, P < 0.05), C(max) (43.92%, P < 0.01) and AUC(0-infinity) (50.88%, P < 0.01) in the scutellarin-treated group compared with those of the blank control. The activity of CYP2C11 in rats was inhibited significantly after treatment with scutellarin by increased tolbutamide t1/2 (16.74%, P < 0.01), T(max) (116.87%, P < 0.05), C(max) (63.78%, P < 0.01) and AUC(0-infinity) (70.61%, P < 0.01) in the scutellarin-treated group compared with those of the blank control. The activity of CYP3A1/2 in rats was inhibited significantly after treatment with scutellarin by increased dapsone t1/2 (45.28%, P < 0.05), T(max) (81.55%, P < 0.05), C(max) (155.58%, P < 0.01)and AUC(0-infinity) (176.35%, P < 0.01) in the scutellarin-treated group compared with those of the blank control. The pharmacokinetic parameters of metoprolol were not significantly changed in the scutellarin-treated group compared with those of the blank control. CONCLUSION: Scutellarin could significantly inhibit CYP1A2, CYP2C11 and CYP3A1/2 activities in rats in vivo, but had no effects on the activity of CYP2D1.


Subject(s)
Apigenin/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Glucuronates/pharmacology , Alcohol Oxidoreductases/antagonists & inhibitors , Alcohol Oxidoreductases/metabolism , Animals , Area Under Curve , Aryl Hydrocarbon Hydroxylases/metabolism , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP3A/metabolism , Cytochrome P450 Family 2 , Drug Combinations , Half-Life , Isoenzymes/metabolism , Mass Spectrometry , Rats , Rats, Wistar , Steroid 16-alpha-Hydroxylase/metabolism , Tandem Mass Spectrometry
7.
BMC Complement Altern Med ; 14: 1, 2014 Jan 02.
Article in English | MEDLINE | ID: mdl-24383621

ABSTRACT

BACKGROUND: Chemicals of herbal products may cause unexpected toxicity or adverse effect by the potential for alteration of the activity of CYP450 when co-administered with other drugs. Eleutherococcus senticosus (ES), has been widely used as a traditional herbal medicine and popular herbal dietary supplements, and often co-administered with many other drugs. The main bioactive constituents of ES were considered to be eleutherosides including eleutheroside B (EB) and eleutheroside E (EE). This study was to investigate the effects of EB and EE on CYP2C9, CYP2D6, CYP2E1 and CYP3A4 in rat liver microsomes in vitro. METHOD: Probe drugs of tolbutamide (TB), dextromethorphan (DM), chlorzoxazone (CLZ) and testosterone (TS) as well as eleutherosides of different concentrations were added to incubation systems of rat liver microsomes in vitro. After incubation, validated HPLC methods were used to quantify relevant metabolites. RESULTS: The results suggested that EB and EE exhibited weak inhibition against the activity of CYP2C9 and CYP2E1, but no effects on CYP2D6 and CYP3A4 activity. The IC50 values for EB and EE were calculated to be 193.20 µM and 188.36 µM for CYP2E1, 595.66 µM and 261.82 µM for CYP2C9, respectively. Kinetic analysis showed that inhibitions of CYP2E1 by EB and EE were best fit to mixed-type with Ki value of 183.95 µM and 171.63 µM, respectively. CONCLUSIONS: These results indicate that EB and EE may inhibit the metabolism of drugs metabolized via CYP2C9 and CYP2E1, and have the potential to increase the toxicity of the drugs.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Glucosides/pharmacology , Lignans/pharmacology , Microsomes, Liver/enzymology , Phenylpropionates/pharmacology , Animals , Chlorzoxazone/pharmacology , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 CYP2E1/metabolism , Dextromethorphan/pharmacology , Inhibitory Concentration 50 , Kinetics , Male , Phytotherapy , Rats , Rats, Wistar , Testosterone/pharmacology , Tolbutamide/pharmacology
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