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

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, histopa...

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Autores principales:	Federica Sodano, Bice Avallone, Monica Tizzano, Chiara Fogliano, Barbara Rolando, Elena Gazzano, Chiara Riganti, Salvatore Magliocca, Mariarosaria Cuozzo, Stefania Albrizio, Antonio Calignano, Claudia Cristiano, Roberto Russo, Maria Grazia Rimoli
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ketorolac ketogal histological evaluation colonic cytotoxicity mitochondrial oxidative stress Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/cfc1f4c4e463400faf7872078583b19b
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spelling	oai:doaj.org-article:cfc1f4c4e463400faf7872078583b19b2021-11-25T18:39:44ZKetogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice10.3390/ph141111491424-8247https://doaj.org/article/cfc1f4c4e463400faf7872078583b19b2021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1149https://doaj.org/toc/1424-8247In 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.Federica SodanoBice AvalloneMonica TizzanoChiara FoglianoBarbara RolandoElena GazzanoChiara RigantiSalvatore MaglioccaMariarosaria CuozzoStefania AlbrizioAntonio CalignanoClaudia CristianoRoberto RussoMaria Grazia RimoliMDPI AGarticleketorolacketogalhistological evaluationcolonic cytotoxicitymitochondrial oxidative stressMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1149, p 1149 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ketorolac ketogal histological evaluation colonic cytotoxicity mitochondrial oxidative stress Medicine R Pharmacy and materia medica RS1-441
spellingShingle	ketorolac ketogal histological evaluation colonic cytotoxicity mitochondrial oxidative stress Medicine R Pharmacy and materia medica RS1-441 Federica Sodano Bice Avallone Monica Tizzano Chiara Fogliano Barbara Rolando Elena Gazzano Chiara Riganti Salvatore Magliocca Mariarosaria Cuozzo Stefania Albrizio Antonio Calignano Claudia Cristiano Roberto Russo Maria Grazia Rimoli Ketogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice
description	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.
format	article
author	Federica Sodano Bice Avallone Monica Tizzano Chiara Fogliano Barbara Rolando Elena Gazzano Chiara Riganti Salvatore Magliocca Mariarosaria Cuozzo Stefania Albrizio Antonio Calignano Claudia Cristiano Roberto Russo Maria Grazia Rimoli
author_facet	Federica Sodano Bice Avallone Monica Tizzano Chiara Fogliano Barbara Rolando Elena Gazzano Chiara Riganti Salvatore Magliocca Mariarosaria Cuozzo Stefania Albrizio Antonio Calignano Claudia Cristiano Roberto Russo Maria Grazia Rimoli
author_sort	Federica Sodano
title	Ketogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice
title_short	Ketogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice
title_full	Ketogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice
title_fullStr	Ketogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice
title_full_unstemmed	Ketogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice
title_sort	ketogal safety profile in human primary colonic epithelial cells and in mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/cfc1f4c4e463400faf7872078583b19b
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Ketogal Safety Profile in Human Primary Colonic Epithelial Cells and in Mice

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