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10.1093/jac/dkv231 http://scihub22266oqcxt.onion/10.1093/jac/dkv231 C4677261!4677261 !26286574     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26286574 &cmd=llinks): Failed to open stream: HTTP request failed! 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Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection |pdf=|usr=}}{{26286574 }} gab.com Text Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection JO: J Antimicrob Chemother http://www.kidney.de/pget.php?&tw=1&pmid=26286574 #FOAvip OBJECTIVES: Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes. METHODS: A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action. RESULTS: Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P?<?0.05) than metronidazole in C. difficile-infected animals. Improved efficacy was not due to an alternative mode of action, as the leads retained the mode of action of metronidazole. CONCLUSIONS: This study provides the clearest empirical evidence that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role for the tetramic acid motif for colon-specific drug delivery. This approach also has the potential to lower systemic toxicity and drug interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases. Twit Text FOAVip Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection ????J Antimicrob Chemother http://www.kidney.de/pget.php?&tw=1&pmid=26286574 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26286574 #FOAvip English Wikipedia <ref>{{Cite pmid|26286574 }}</ref> Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection #MMPMID26286574 Cherian PT ; Wu X ; Yang L ; Scarborough JS ; Singh AP ; Alam ZA ; Lee RE ; Hurdle JG J Antimicrob Chemother 2015[Nov]; 70 (11 ): 3061-9 PMID26286574 show ga OBJECTIVES: Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes. METHODS: A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action. RESULTS: Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P? |Animals [MESH] |Anti-Bacterial Agents/administration & dosage/chemistry/*pharmacokinetics [MESH] |Clostridioides difficile/*drug effects [MESH] |Clostridium Infections/*drug therapy [MESH] |Colon/*chemistry [MESH] |Disease Models, Animal [MESH] |Male [MESH] |Mesocricetus [MESH] |Metronidazole/administration & dosage/chemistry/*pharmacokinetics [MESH] |Pyrrolidinones/chemistry/*pharmacokinetics [MESH] |Tenuazonic Acid/*analogs & derivatives/chemistry/pharmacokinetics [MESH]Gastrointestinal localization of metronidazole by a lactobacilli-inspi(epmc).pdf DeepDyve Pubget Overpricing