1. Low dose rifaximin combined with N-acetylcysteine is superior to rifaximin alone in a rat model of IBS-D: a randomized trial.
- Author
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Leite G, Rezaie A, Morales W, Weitsman S, de Freitas Germano J, Barlow GM, Parodi G, Pimentel ML, Villanueva-Millan MJ, Sanchez M, Ayyad S, Mathur R, and Pimentel M
- Subjects
- Animals, Rats, Male, Rats, Sprague-Dawley, Drug Therapy, Combination, Rifaximin pharmacology, Rifaximin therapeutic use, Acetylcysteine pharmacology, Acetylcysteine administration & dosage, Escherichia coli drug effects, Disease Models, Animal, Diarrhea drug therapy, Diarrhea microbiology, Irritable Bowel Syndrome drug therapy, Irritable Bowel Syndrome microbiology
- Abstract
Rifaximin is FDA-approved for treatment of irritable bowel syndrome with diarrhea (IBS-D), but poor solubility may limit its efficacy against microbes in the mucus layer, e.g. Escherichia coli. Here we evaluate adding the mucolytic N-acetylcysteine (NAC) to improve rifaximin efficacy. In a resazurin checkerboard assay, combining rifaximin with NAC had significant synergistic effects in reducing E. coli levels. The optimal rifaximin + NAC combination was then tested in a validated rat model of IBS-D (induced by cytolethal distending toxin [CdtB] inoculation). Rats were inoculated with vehicle and treated with placebo (Control-PBS) or rifaximin + NAC (Control-Rif + NAC, safety), or inoculated with CdtB and treated with placebo (CdtB-PBS), rifaximin (CdtB-Rifaximin), or rifaximin + NAC (CdtB-Rif + NAC) for 10 days. CdtB-inoculated rats (CdtB-PBS) developed wide variability in stool consistency (P = 0.0014) vs. controls (Control-PBS). Stool variability normalized in rats treated with rifaximin + NAC (CdtB-Rif + NAC) but not rifaximin alone (CdtB-Rifaximin). Small bowel bacterial levels were elevated in CdtB-PBS rats but normalized in CdtB-Rif + NAC but not CdtB-Rifaximin rats. E. coli and Desulfovibrio spp levels (each associated with different IBS-D microtypes) were also elevated in CdtB-inoculated (CdtB-PBS) but normalized in CdtB-Rif + NAC rats. Cytokine levels normalized only in CdtB-Rif + NAC rats, in a manner predicted to be associated with reduced diarrhea driven by reduced E. coli. These findings suggest that combining rifaximin with NAC may improve the percentage of IBS-D patients responding to treatment., (© 2024. The Author(s).)
- Published
- 2024
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