Ketogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice

Abstract

In our previous studies, a ketorolac–galactose conjugate (ketogal) showed prolonged anti-inflammatory and analgesic activity, causing less gastric ulcerogenic effect and renal toxicity than its parent drug ketorolac. In order to demonstrate the safer profile of ketogal compared to ketorolac, histopathological changes in the small intestine and liver using three staining techniques before and after repeated oral administration in mice with ketorolac or an equimolecular dose of its galactosylated prodrug ketogal were assessed. Cytotoxicity and oxidative stress parameters were evaluated and compared in ketorolac- and ketogal-treated Human Primary Colonic Epithelial cells at different concentrations and incubation times. Evidence of mitochondrial oxidative stress was found after ketorolac treatment; this was attributable to altered mitochondrial membrane depolarization and oxidative stress parameters. No mitochondrial damage was observed after ketogal treatment. In ketorolac-treated mice, severe subepithelial vacuolation and erosion with inflammatory infiltrates and edematous area in the intestinal tissues were noted, as well as alterations in sinusoidal spaces and hepatocytes with foamy cytoplasm. In contrast, treatment with ketogal provided a significant improvement in the morphology of both organs. The prodrug clearly demonstrated a safer profile than its parent drug both in vitro and ex vivo, confirming that ketogal is a strategic alternative to ketorolac.

Galactosylated Prodrugs: A Strategy to Improve the Profile of Nonsteroidal Anti-Inflammatory Drugs

“…We applied the galactosylated prodrug strategy to a number of NSAIDs. The first successful example of this approach was Ketogal [ 25 ], with ACEgal and PARgal then following [ 26 , 27 ]. In each study, the galactosylated prodrug showed marked improvements, compared with its parent drug, in some or all of its physicochemical, pharmacokinetic, pharmacodynamic and toxicological parameters.…”

“…Promising results have been obtained with the prodrug approach when using D-galactose as a carrier for NSAIDs. In our previous studies, the conjugation of a galactose molecule with ketorolac (Ketogal) [ 25 ], paracetamol (PARgal) [ 26 ] and aceclofenac (ACEgal) [ 27 ] improved their physicochemical, toxicological, pharmacokinetic and pharmacodynamic profiles, resulting in remarkable safety profiles. In particular, the prolonged pharmacological action of the aforementioned prodrugs, in comparison with their parent drugs, would allow their daily intake to be reduced, while also decreasing side effects.…”

Galactose: A Versatile Vector Unveiling the Potentials in Drug Delivery, Diagnostics, and Theranostics

“…Significant advancements have also been made in the development of galactosylated prodrug derived from the potent NSAID ketorolac. Recent studies by Russo et al (2017) and Sodano et al (2021) have demonstrated that Ketogal, the galactosylated prodrug of ketorolac, exhibits lower toxicity in the stomach, kidney, small intestine, and liver compared to ketorolac [ 28 , 29 ]. In vivo and ex vivo experiments conducted on mice have consistently shown that repeated administration of Ketogal induces reduced toxicity in these organs, supporting its potential as a safer alternative to ketorolac.…”

Hepatocyte Aquaporins AQP8 and AQP9 Are Engaged in the Hepatic Lipid and Glucose Metabolism Modulating the Inflammatory and Redox State in Milk-Supplemented Rats

“…Each block was immediately fixed in 4% PFA for 24 h at 4 • C. Samples were then processed for wax embedding according to [68], and serial sections (5 µm) were cut. Hematoxylin-eosin staining was used to highlight the general morphology; periodic acid-Schiff (PAS) was used to underline mucin, glycogen and glycoproteins [69]; and the alternative PAS/diastase was performed to highlight all the PAS-positive substances except for the glycogen, that is, digested by diastase, while PAS/dimedone (5,5-dimethyl-1,3-cyclohexanodione) was used to specifically identify the glycogen. Dimedone, in fact, digests all the other PAS-positive substances.…”