Determination of azide genotoxic impurity in linezolid API and glucose injection by UPLC-MS/MS / 中国药科大学学报

@#A UPLC-MS/MS method was established for the determination of the genotoxic impurity (R)-5-(azidomethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone in linezolid API and its glucose injection. Chromatographic separation was performed on a Waters Acquity UPLC HSS T3 column (100 mm × 2.1 mm, 1.8 μm) with 0.1% formic acid water-0.1% formic acid acetonitrile (60∶40) at a flow rate of 0.3 mL/min. The UPLC-MS/MS was equipped with electrospray ionization in positive ionization mode and multiple reaction monitoring mode. The results showed that the calibration curve was linear in the range of 4-12 ng/mL and the limit of quantification was 0.073 ng/mL.The average recoveries of the low, medium and high concentration (80%,100%,120% limit concentration) loading solutions were 101.14%, 100.59% and 101.47%, respectively (RSDs:0.73%, 1.10% and 0.91%, respectively).The sample solution was stable for 6 d.No genotoxic impurity of (R)-5-(Azidomethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinonewas not detected in the samples of linezolid API and its glucose injection.

Occurrence of linezolid induced thrombocytopenia and its association with the risk factors: a review article

Linezolid is the oxazolidinone group of antibiotic with wide range of activity against the gram positive bacteria including methicillin resistant staphylococcus aureus and penicillin resistant pneumococci and vancomycin resistant enterococci. Patients who are on linezolid were reported to have reversible myelosuppression especially thrombocytopenia and anaemia. Since there are less number of studies regarding the occurrence of thrombocytopenia and the risk factors associated with it, this study was undertaken to evaluate the occurrence of linezolid induced thrombocytopenia and its association with risk factors. It was a systematic review with synthesis of available literature in English language. Articles were retrieved using search terms included “linezolid”, “and”, “or”, “thrombocytopenia” from Clinical key and PubMed, published during 2000 - 2017. Out of 16 studies retrieved, only 7 studies were analysed based on inclusion and exclusion criteria; of them, 3 were found to be prospective and retrospective cohort each and only one was retrospective cross-sectional study. The occurrence of linezolid induced thrombocytopenia range from 18-50% with normal renal function and 57% of incidence associated with renal insufficiency patients. The risk factors were found to be dose of linezolid >18-27mg/kg, body weight of subjects <55kg, creatinine clearance <88.39 to 60ml/min/1.73m2 and baseline platelet count <200*103/mm3, serum albumin concentration, serum creatinine, concomitant caspofungin therapy and duration of linezolid therapy.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182) vs linezolid (N = 171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Application of Time-resolved Fluroimmunoassay for Determination of Furaltadone Metabolite 3-Amino-5-morpholinomethyl-2-oxazolidinone / 分析化学

To detect furaltadone metabolite 3-amino-5-morpholinomethyl-2-oxazolidinone ( AMOZ ) in fish sample, an Eu3+ labeling time-resolved fluoroimmunoassay ( TRFIA ) was developed. The effects of experimental conditions including AMOZA-OVA concentration, dilution of antibody, and reaction time on the sensitivity of TRFIA were explored. The results showed that the optimized assay conditions were as follows:the AMOZA-OVA concentration was 0. 25 μg/mL; the antibody was diluted 5í104 folds, and the competitive reaction time was 50 min. Under optimal conditions, the method showed a detection limit of 0. 01 ng/mL, an IC50 of 0. 26 ng/mL and a linear range (IC20-IC80) of 0. 025-2. 83 ng/mL. The recoveries of AMOZ in fish at three spiked levels ranged from 78 . 0% to 86 . 0%, and the relative standard deviations were less than 15%. Good correlation between the ic-TRFIA and high performance liquid chromatography-tandem mass spectrometry was obtained for spiked food samples. The proposed ic-TRFIA method was suited for the determination of AMOZ residue in food samples.

Development and validation of a rapid and robust LC-MS/MS method for quantifi-cation of a new oxazolidinone antibiotic MRX-I in human plasma and urine / 中国感染与化疗杂志

Objective To establish and validate an ultra performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS)method for quantification of MRX-I,a new oxazolidinone antibacterial agent,in human plasma and urine.Methods Chromatographic separation was performed on a Waters ACQUITY UPLC BEH C8 column using an isocratic elution.The mo-bile phase consisted of acetonitrile and water (40∶60,v/v).Quantitative analysis was conducted in the multiple reaction moni-toring mode.Linezolid was used as an internal standard.Liquid-liquid extraction with ethyl acetate was used to remove impuri-ties in the plasma and urine samples.The method was validated in terms of matrix effect,recovery,precision,accuracy and stability.Results The calibration curves were linear within the range of 0.005 00-1 .00 mg/L.The lower limit of quantification was 0.005 00 mg/L for both plasma and urine samples.Retention time was less than 1 .5 min for both MRX-I and internal standard in plasma and urine.The ma-trix effect factors of plasma and urine for MRX-I was 90.4%±8.2% and 82.7%±7.9%,respectively.The recovery of MRX-I was 112.8% ± 13.4% from plasma and 105.6% ± 13.4% from urine samples,respectively.The inter- and intra-day accuracy of MRX-I was 98.9%-105.0% and 96.5%-102.6% in plasma samples,and 92.7%-98.6% and 95.1 %-105.7% in urine samples.MRX-I was stable for 24 h at room tem-perature,48 h in automatic sampler after pretreatment,and stable after 3 freeze-thaw cycles in plasma and urine.MRX-I was also stable at-40℃for eight months in plasma and six months in urine,respectively.Conclusions The UPLC-MS/MS method established in this study shows high sensitivity and specificity for determination of MRX-I in human plasma and urine.The re-sults of validation are consistent with the requirement of bioanalytical method validation.

Preparation and Certification of Reference Materials for 3-Amino-2-oxazolidinone Residue in Eel Muscle Lyophilisates / 分析化学

A methodology for preparing and certifying the reference material of 3-amino-2-oxazolidinone(AOZ) in eel muscle lyophilisates was presented. Furazolidone was accessed to eel by dipping fish in pond with furazolidone solution at a dosage of ca 0.16 mg/L. With the metabolism of furazolidone in eel, the muscles contain a certain concentration of AOZ as furazolidone metabolite was obtained. Lyophilization of the muscles was performed in one batch and 400 bags of samples were obtained by the procedure of homogenation, cryodesiccation and irradiation. The homogeneity and stability of the sample was examined. The value of the chemical constituent of the sample was certified through the collaborative analysis program participated by 11 laboratories using isotope dilution liquid chromatography-tandem mass spectrometry, and the uncertainty assessment was performed. The reference materials have been approved as certified reference materials by AQSIQ, China (State General Administration of the People′s Republic of China for Quality Supervision and Inspection and Quarantine) in 2009 after one year of trial period. The serial numbers is GBW(E)100180.