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This study was aimed to determine the pharmacokinetics of antisecretory‐acting racecadotril, used in the treatment of diarrhea in humans and dogs, following oral administration in both neonatal calves with healthy and neonatal calves with infectious diarrhea. The study was carried out on a total of 24 Holstein calves (2–20 days), of which 6 were healthy and 18 were infectious diarrhea. Calves with infectious diarrhea were divided into 3 groups according to the infectious agent (Escherichia coli, Cryptosporidium parvum, and rotavirus/coronavirus). Racecadotril was administered orally at 2.5 mg/kg dose to calves. The plasma concentrations of racecadotril and its main active metabolite (thiorphan) were determined using HPLC‐UV. The pharmacokinetic parameters were analyzed using the non‐compartmental method. In healthy calves, the t1/2ʎz, Cmax, Tmax, and AUC0‐12 of racecadotril were determined 4.70 h, 377 ng/ml, 0.75 h, and 1674 h × ng/ml, respectively. In the plasma of calves with infectious diarrhea, racecadotril and thiorphan were only detected at the sampling time from 0.25 to 1.5 h. As in calves with infectious diarrhea, thiorphan in plasma was only detected in healthy calves from 0.25 to 1.5 h. Racecadotril showed a large distribution volume, rapid elimination, and low metabolism to thiorphan in healthy calves. [ABSTRACT FROM AUTHOR]

The peptidase neprilysin modulates glucose homeostasis by cleaving and inactivating insulinotropic peptides, including some produced in the intestine such as glucagon-like peptide-1 (GLP-1). Under diabetic conditions, systemic or islet-selective inhibition of neprilysin enhances beta-cell function through GLP-1 receptor (GLP-1R) signaling. While neprilysin is expressed in intestine, its local contribution to modulation of beta-cell function remains unknown. We sought to determine whether acute selective pharmacological inhibition of intestinal neprilysin enhanced glucose-stimulated insulin secretion under physiological conditions, and whether this effect was mediated through GLP-1R. Lean chow-fed Glp1r+/+ and Glp1r-/- mice received a single oral low dose of the neprilysin inhibitor thiorphan or vehicle. To confirm selective intestinal neprilysin inhibition, neprilysin activity in plasma and intestine (ileum and colon) was assessed 40 minutes after thiorphan or vehicle administration. In a separate cohort of mice, an oral glucose tolerance test was performed 30 minutes after thiorphan or vehicle administration to assess glucose-stimulated insulin secretion. Systemic active GLP-1 levels were measured in plasma collected 10 minutes after glucose administration. In both Glp1r+/+ and Glp1r-/- mice, thiorphan inhibited neprilysin activity in ileum and colon without altering plasma neprilysin activity or active GLP-1 levels. Further, thiorphan significantly increased insulin secretion in Glp1r+/+ mice, whereas it did not change insulin secretion in Glp1r-/- mice. In conclusion, under physiological conditions, acute pharmacological inhibition of intestinal neprilysin increases glucose-stimulated insulin secretion in a GLP-1R-dependent manner. Since intestinal neprilysin modulates beta-cell function, strategies to inhibit its activity specifically in the intestine may improve beta-cell dysfunction in type 2 diabetes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Antibiotic resistance has been becoming more and more critical due to bacteria's evolving hydrolysis enzymes. The NDM-1 enzyme could hydrolyze not only carbapenems but also most of β-lactam's antibiotics and inhibitors. In fact, variant strains could impose a high impact on the resistance of bacteria producing NDM-1. Although previous studies showed the effect of some variants toward antibiotics and inhibitors binding, there has been no research systematically evaluating the effects of alternative one-point mutations on the hydrolysis capacity of NDM-1. This study aims to identify which mutants could increase or decrease the effectiveness of antibiotics and β-lactamase inhibitors toward bacteria. Firstly, 35 different variants with a high probability of emergence based on the PAM-1 matrix were constructed and then docked with 5 ligands, namely d-captopril, l-captopril, thiorphan, imipenem, and meropenem. The selected complexes underwent molecular dynamics simulation and free energy binding estimation, with the results showing that the substitutions at residues 122 and 124 most influenced the binding ability of NDM-1 toward inhibitors and antibiotics. The H122R mutant decreases the binding ability between d-captopril and NDM-1 and diminishes the effectiveness of this antibiotic toward Enterobacteriaceae. However, the H122R mutant has a contrary impact on thiorphan, which should be tested in vitro and in vivo in further experiments.