Plasma metabolites changes in male heroin addicts during acute and protracted withdrawal.

BACKGROUND: Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. However, the changes of metabolites in heroin addicts during withdrawal remain largely unknown. METHODS: A total of 50 participants including 20 heroin addicts with acute abstinence stage, 15 with protracted abstinence stage and 15 healthy controls, were recruited. We performed metabolic profiling of plasma samples based on ultraperformance liquid chromatography coupled to tandem mass spectrometry to explore the potential biomarkers and mechanisms of heroin withdrawal. RESULTS: Among the metabolites analyzed, omega-6 polyunsaturated fatty acids (linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid, n-6 docosapentaenoic acid), omega-3 polyunsaturated fatty acids (docosahexaenoic acid, docosapentaenoic acid), aromatic amino acids (phenylalanine, tyrosine, tryptophan), and intermediates of the tricarboxylic acid cycle (oxoglutaric acid, isocitric acid) were significantly reduced during acute heroin withdrawal. Although majority of the metabolite changes could recover after months of withdrawal, the levels of alpha-aminobutyric acid, alloisoleucine, ketoleucine, and oxalic acid do not recover. CONCLUSIONS: In conclusion, the plasma metabolites undergo tremendous changes during heroin withdrawal. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and withdrawal stages in heroin addicts.

N-(Sulfamoylbenzoyl)-L-proline Derivatives as Potential Non-ß-lactam ESBL Inhibitors: Structure-Based Lead Identification, Medicinal Chemistry and Synergistic Antibacterial Activities.

BACKGROUND: There is an urgent need to develop novel inhibitors against clinically widespread extended-spectrum ß-lactamases (ESBLs) to meet the challenges of the ever-evolving threat of antibiotic resistances. Most existing ESBL inhibitors sharing a common chemical feature of ß-lactam ring in their molecule, this structural characteristic makes them intrinsically susceptible to enzymatic breakdown by the resistance mechanisms employed by the bacteria. OBJECTIVE: The aim of this study was to screen and discover novel lead compounds by using Lproline as initial scaffold to create a "non-sulfur, non-ß-lactam" new chemotypes for potential ESBL inhibitors. METHODS: Structure-based molecular docking and virtual screening were employed in the novel inhibitor generation process for lead compound screening and SAR analysis. Evaluation of the ESBL inhibitory activity of the lead compounds was performed in combination with three of the most susceptible antibiotics: ceftazidime, meropenem and ampicillin, against thirteen ESBL enzymes including four new CTX-M harboring strains and four KPC-2 producing species. RESULTS: L-proline derived (S)-1-(2-sulfamoylbenzoyl)pyrrolidine-2-carboxylic acid (compound 6) as a "non-sulfur, non-ß-lactam" and the most potential ESBL inhibitor was identified. Compound 6 possesses ideal anti-resistance activities by reducing MICs of ceftazidime, meropenem and ampicillin by 16-133, 32-133 and 67-267 fold respectiveily. The inhibitory mechanism of 6 with CTX-M, KPC-2 and penicillinase were proposed and probed with molecular docking analysis. CONCLUSION: Given that the simple proline derivative but promising synergistic antibacterial properties of compound 6 augers well for further investigations into its in vivo efficacy.