Ketogal: A Derivative Ketorolac Molecule with Minor Ulcerogenic and Renal Toxicity

Abstract

Ketorolac is a powerful non-steroidal anti-inflammatory drug (NSAID), with a great analgesic activity, present on the Italian market since 1991. Despite the excellent therapeutic activity, the chronic use of ketorolac has long been limited owing to the high incidence of gastrointestinal and kidney side events. In our previous study, we demonstrated that ketorolac–galactose conjugate (ketogal), synthesized and tested in a single-dose study, was able to reduce ulcerogenicity, while preserving the high pharmacological efficacy of its parent drug. In this paper, in order to verify the suitability of this compound, for repeated administration, ex vivo experiments on naïve mice were performed. Mice were treated for 5 or 7 days with the highest doses of two drugs (ketorolac 10 mg/kg and ketogal 16.3 mg/kg), and the expression of both gastric COX-1 and PGsyn was evaluated. Results showed that oral ketorolac treatment significantly reduced both enzymes; surprisingly, oral treatment with ketogal did not produce significant variation in the expression of the two constitutive enzymes. Moreover, histological experiments on stomach and kidneys clearly indicated that repeated administration of ketogal induced lower toxicity than ketorolac. At same time, in vivo results clearly showed that both ketorolac and ketogal had a similar therapeutic activity in a model of inflammation and in pain perception. These effects were accompanied by the reduction of enzyme expression such as COX-2 and iNOS, and by the modulation of levels of nuclear NF-κB and cytosolic IκB-α in the inflamed paws. These very encouraging results demonstrate for the first time that ketogal could represent a valid and novel therapeutic alternative to the ketorolac and might pave the way for clinical studies.

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

“…Once it was established that ketogal did not induce oxidative stress in the lower GI tract, consistent with most clinical studies of NSAIDs, we demonstrated the safer profile of ketogal compared with ketorolac in the other organs as well, particularly in the upper GI tract [3,7] and in the liver [16,17]. Consistently, we examined histopathological changes after repeated oral treatment in mice with ketorolac and ketogal, under the conditions previously adopted for the stomach and kidneys in our past work [31].…”

“…The results obtained for the small intestine, liver, and, previously, for the stomach and kidneys [31], demonstrate that ketogal undoubtedly has the potential to overcome most of the side effects associated with repeated administration of ketorolac. Indeed, its toxicological profile has consistently exceeded expectations in in vivo and ex vivo models [31,32].…”

“…Chronic treatment with ketorolac causes multiple side events despite its outstanding pharmacological profile. We have previously shown that esterification of ketorolac with a simple and natural carrier, such as D-galactose, improves its safety profile [31,32]. In particular, repeated administration of ketogal exerted significant pharmacological activity that was similar to that of its parent drug, ketorolac, but was less ulcerogenic and caused less renal toxicity [31].…”

“…In order to predict the toxicity of ketogal in the colon, compared to ketorolac, human CoEpi cells were incubated at different times and at different concentrations of the parent drug and prodrug. The choice of three time points, 24, 48, and 72 h, was due to the remarkable and sustained anti-inflammatory activity of ketogal, as demonstrated in our past works [31,32]. The three concentrations were selected using a previous dose-response curve of CoEpi cells incubated with ketorolac and ketogal, where we observed no reduced viability in the range of 5-500 µM for either drug (data not shown).…”

“…In order to investigate whether similar alterations to those described occurring in the small intestine also occur in the lower GI tract, we evaluated the cytotoxicity of ketorolac and ketogal against Human Primary Colonic Epithelial (CoEpi) cells. Another aim of the present study was to perform histopathological and morphological evaluations on the small intestine and liver, under the same experimental conditions used for the stomach and kidneys and described in our recent work [31].…”