Heliyon
·
2024
·
IF 3.4
Ying Jin,Hongtu Ma,Lisha Fu,Xiaohui Qi,Mengyu Zhang,Xiangjie Di,Li Zheng,Cuiyao He,Zhenlei Wang
Meropenem is an ultrabroad-spectrum antimicrobial agent that is often recommended for the treatment of bacterial meningitis (BM) in children. However, a subtherapeutic phenomenon occurred in BM children complicated with augmented renal clearance (ARC) at the recommended dose of meropenem. To support its pharmacokinetics, a sensitive, fast and robust ultra-liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was developed to measure meropenem concentrations in serum and cerebrospinal fluid (CSF). The method involved protein precipitation, and samples were diluted with a large proportion of water to eliminate solvent effects. The separation of samples was performed on a Waters Acquity™ BEH C 18 column (2.1 × 50 mm i.d., 1.7 μm) with a gradient profile. The mobile phases were formic acid–water (1:1000, v/v) and acetonitrile. The linear range was good, with a concentration range of 0.100–100 μg/mL for serum and 0.0400–20.0 μg/mL for CSF. The intra-day and inter-day precisions were less than 8.0%, and the intra-day and inter-day accuracies varied −6.6% from 6.5% for the both serum and CSF. The selectivity, carry-over, dilution integrity, matrix effect, recovery and stability were validated according to international guidelines. The developed UPLC–MS/MS method successfully determined the meropenem concentrations in the serum and CSF of children with BM complicated with ARC. The results indicated that under the recommended dosing regimen (40 mg/kg every 8 h), the time to reach the effective treatment target of 50%T > MIC was only approximately 3 h and lower CSF concentrations of meropenem were observed in children with BM with ARC.
研究领域:
药代动力学
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临床药学
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分析化学
·
儿科
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2017
·
IF 3.255
Katerina Grigori,Yannis L. Loukas,Anđelija Malenović,Vicky Samara,Anastasia Kalaskani,Efi Dimovasili,Magda Kalovidouri,Yannis Dotsikas
A sensitive Liquid Chromatography tandem mass spectrometry (LC–MS/MS) method was developed and validated for the quantitative analysis of three potential genotoxic impurities (318BP, M9, S5) in meropenem Active Pharmaceutical Ingredient (API). Due to the requirement for LOD values in ppb range, a high concentration of meropenem API (30 mg/mL) had to be injected. Therefore, efficient determination of meropenem from its impurities became a critical aim of this study, in order to divert meropenem to waste, via a switching valve. After the selection of the important factors affecting analytes’ elution, a Box-Behnken design was utilized to set the plan of experiments conducted with UV detector. As responses, the separation factor s between the last eluting impurity and meropenem, as well as meropenem retention factor k were used. Grid point search methodology was implemented aiming to obtain the optimal conditions that simultaneously comply to the conflicted criteria. Optimal mobile phase consisted of ACN, methanol and 0.09% HCOOH at a ratio 71/3.5/15.5 v/v. All impurities and internal standard omeprazole were eluted before 7.5 min and at 8.0 min the eluents were directed to waste. The protocol was transferred to LC–MS/MS and validated according to ICH guidelines.
研究领域:
分析化学
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药物分析
·
药学
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DOI
PubMed
高影响因子
TALANTA
·
2023
·
IF 6.1
Xuan Ma,Yue Wang,Wenting Wang,Jake Heinlein,Lisa D. Pfefferle,Xuemeng Tian
In this study, a facile method has been developed to synthesize a novel type of porous magnetic molecularly imprinted polymers (Fe 3 O 4 -MER-MMIPs) for the selective adsorption and removal of meropenem. The Fe 3 O 4 -MER-MMIPs, with abundant functional groups and sufficient magnetism for easy separation, are prepared in aqueous solutions. The porous carriers reduce the overall mass of the MMIPs, greatly improving their adsorption capacity per unit mass and optimizing the overall value of the adsorbents. The green preparation conditions, adsorption performance, and physical and chemical properties of Fe 3 O 4 -MER-MMIPs have been carefully studied. The developed submicron materials exhibit a homogeneous morphology, satisfactory superparamagnetism (60 emu g −1 ), large adsorption capacity (11.49 mg g −1 ), quick adsorption kinetics (40 min), and good practical implementation in human serum and environmental water. Finally, the protocol developed in this work delivers a green and feasible method for synthesizing highly efficient adsorbents for the specific adsorption and removal of other antibiotics as well.
研究领域:
环境科学
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材料科学
·
药物化学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 6.514
Fangfang Chen,Mengmeng Bai,Wentian Liu,Hongtao Kong,Tingting Zhang,Hong Yao,En Zhang,Juan Du,Shangshang Qin
The emergence and dissemination of metallo-β-lactamases (MBLs) producing Enterobacterales is a great concern for public health due to the limited therapeutic options. No MBL inhibitors are currently available in clinical practice. Herein, we synthesized a series of H 2 dpa derivatives containing pentadentate-chelating ligands and evaluated their inhibitory activity against MBLs. Related compounds inhibited clinically relevant MBLs (Imipenemase, New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase) with IC 50 values of 1–4.9 μM. In vitro , the most promising compounds, 5b and 5c , which had a chiral methyl at the acid adjacent to 5a , demonstrated potent synergistic activity against engineered strains, with fractional inhibitory concentration index values as low as 0.07–0.18. The addition of 5b and 5c restored meropenem efficacy against 42 MBL-producing Enterobacterales and Pseudomonas aeruginosa to satisfactory clinical levels. In addition, safety tests revealed that 5b/5c showed no toxicity in red blood cells, cell lines or mouse model. Further studies demonstrated that compounds 5b and 5c were non-competitive MBL inhibitors. In vivo compounds 5b and 5c potentiated meropenem efficacy and increased the survival rate from 0 to at least 83% in mice with sepsis caused by an NDM-1-positive clinical strain. The activity of the compounds exhibited consistency at the molecular, cellular, and in vivo levels. These data indicated that H 2 dpa derivatives 5b and 5c containing pentadentate-chelating ligands may be worthy of further study.
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DOI
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2019
·
IF 2.983
Fábio de Souza Barbosa,Leonardo Capra Pezzi,Marisa Tsao,Sandra Manoela Dias Macedo,Tiago Franco de Oliveira,Elfrides E.S. Schapoval,Andreas S.L. Mendez
An ESI-MS/MS method through direct infusion was validated for quantitative analysis of meropenem powder for injection. The validation parameters were established in a rapid analysis of 30 s. Drug stability was studied through the submission to stress testing, resulting on four degradation products. Under hydrolytic conditions, in acid, neutral and alkaline media, the major degradation product was formed through the cleavage of the β-lactam ring. Oxidation of the drug using H 2 O 2 (3%) showed the formation of two degradation products from a decarboxylation reaction and N-oxide formation. Under high humidity conditions, there was detected a dimer product. The stability of meropenem after reconstitution was studied in conditions that simulate its clinical use. In samples reconstituted and diluted in infusion fluids, an extensive degradation was observed. At room temperature meropenem maintained its content > 90% for up to 4 h when prepared in 5% glucose and for up to 12 h when prepared in 0.9% NaCl. Through ESI-MS/MS analyzes it was observed a degradation product formed by β-lactam ring cleavage, detected in all conditions studied. It was also identified a degradation product formed only in 5% glucose, generated by the hydrolysis of β-lactam followed by the attachment of a glucose molecule to the nitrogen of the pyrrolidine ring. In general, all the results obtained in the stability studies contribute to the knowledge about this antibiotic and future candidates of this class.
研究领域:
药学
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分析化学
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药物代谢
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DOI
PubMed
高影响因子
Antibiotics-Basel
·
2022
·Vol. 11
·期 11
·1660
·
IF 5.222
Yan Wang,Lanyu Liu,Qiping Wu,Qiufen Yin,Feifan Xie
Background: The pharmacokinetic/pharmacodynamic (PK/PD) index of carbapenems that best correlates with in vivo antimicrobial activity is percent time of dosing interval in which free drug concentration remains above MIC (%fT > MIC), while the magnitudes of the PK/PD index of carbapenems remains undefined in critically ill sepsis patients.Methods: A sepsis rat model was first developed by comparing the survival outcomes after intraperitoneal injection of different inoculum size (1–10 × 107CFU) ofPseudomonas aeruginosaATCC9027 (MIC = 0.125 mg/L) in neutropenic rats. The PK characteristics of the model drug meropenem in the developed sepsis rat model was then evaluated, and PK modeling and simulation was applied to design meropenem dosing regimens attaining various PD targets (40%fT > MIC, 100%fT > MIC, and 100%fT > 4 × MIC). The microbiological response and survival outcomes for different meropenem treatment regimens were investigated in the rat sepsis model (n= 12 for each group).Results: The optimal inoculum for the rat sepsis model was 1 × 107CFU ofPseudomonas aeruginosaATCC9027. A one-compartment model with first-order absorption best described the PK of meropenem in sepsis rats. Pronounced survival prolongation and lower hazard risk were observed in the treatment groups of 50 or 75 mg/kg/q2.4h (100%fT > MIC) and 75 mg/kg/q2h (100%fT > 4 × MIC) compared to the 75 mg/kg/q6h (40%fT > MIC) group, while meropenem groups with PD targets of 100%fT > MIC and 100%fT > 4 × MIC showed comparable survival curves. Microbiological response for different PD targets is inconclusive due to irregular bacterial counts in blood samples.Conclusions: The PD target of 40%fT > MIC is suboptimal for sepsis rats, and the aggressive 100%fT > 4 × MIC target does not provide a survival benefit against the target of 100%fT > MIC.Keywords:pharmacokinetics;PK/PD;survival;meropenem;sepsis rat model
研究领域:
药理学
·
感染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2026
·
IF 3.4
XiangLong Chen,Jinhui Xu,Chengliang Wang,Lijuan Yang,Jinwei Fan,Tongtong Li,Qian Zhang,Yanxia Yu,Lian Tang,Shenjia Huang
Central nervous system (CNS) infections require adequate drug exposure at the site of action, yet antibiotic meropenem (MER) shows limited cerebrospinal fluid (CSF) penetration and easily undergoes non-enzymatic degradation to an inactive open-ring metabolite (ORM). In this study, we developed a simple, sensitive, and fast liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of MER and ORM in human serum and CSF. Chromatographic separation was accomplished on an Agela Venusil MP C18 column, with MER-d6 and ORM-d6 as internal standards. Methanol was found to promote methanolysis, yielding a characteristic product ( m/z 416.2). Therefore, acetonitrile was selected as both the organic phase and the protein-precipitation solvent. Method validation was conducted according to the ICH M10 guideline. Follow validation, the method was successfully applied to 57 serum and 16 CSF samples. ORM concentrations in human CSF were reported for the first time. This method provides a valuable tool to support MER monitoring in patients with CNS infections.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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