Gastrointestinal localization of metronidazole ~ the agency of a lactobacilli-inspired tetramic acid motif improves management outcomes in the hamster model of Clostridium difficile infection.
J Antimicrob Chemother. 2015 Aug 18;
Authors: Cherian PT, Wu X, Yang L, Scarborough JS, Singh AP, Alam ZA, Lee RE, Hurdle JG
OBJECTIVES: Metronidazole, a mainstay management for Clostridium difficile infection (CDI), is many times ineffective for severe CDI. Whilst this is view to arise from suboptimal levels of metronidazole in the colon becoming to rapid absorption, empirical validation is lacking. In striking difference, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal plot. In this study, we modified metronidazole by reutericyclin’s tetramic acid motif to achieve non-absorbed compounds, enabling assessment of the pack close of pharmacokinetics on treatment outcomes.
METHODS: A course of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in provisions of anti-C. difficile activities, of the stomach permeability, in vivo pharmacokinetics, efficacy in the hamster archetype of CDI and mode of series of events.
RESULTS: Most compounds were absorbed inferior than metronidazole in cell-based Caco-2 permeability assays. In hamsters, be in advance of compounds compartmentalized in the colon sooner than the bloodstream with negligible levels detected in the children, in direct contrast with metronidazole, which was rapidly absorbed into the noble extraction and was undetectable in caecum. Accordingly, four leads were in greater numbers efficacious (P < 0.05) than metronidazole in C. difficile-infected animals. Improved potency was not due to an choice mode of action, as the leads retained the quality of action of metronidazole.
CONCLUSIONS: This study provides the clearest empirical manifest that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role notwithstanding the tetramic acid motif for colon-particular drug delivery. This approach also has the possible to lower systemic toxicity and unsalable article interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases.
PMID: 26286574 [PubMed – as supplied by publisher]
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