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Clinical pharmacology and therapeutics: nonopioids
Published in Nigel Sykes, Michael I Bennett, Chun-Su Yuan, Clinical Pain Management, 2008
The vasodilator nitric oxide protects gastric mucosal blood flow and mucus and bicarbonate production, counteracting suppression by COX inhibitors.289 It also reduces neutrophil adherence to endothelial surfaces, enhancing its anti-inflammatory role.290 CINODs (COX inhibitors and NO donors) were developed in the 1990s by adding a nitric oxide-donating moiety to NSAID molecules (producing, for example, NO-naproxen, now called naproxcinod, NO-aspirin, NO-indometacin, and NO-ibuprofen).291 Despite a potency and range of activity equaling conventional NSAIDs,292 they have no deleterious effect on blood pressure.293 CINODs are antiinflammatory and antipyretic in animals294 but cause less gastric toxicity than conventional NSAIDs.295 Human volunteer trials confirmed limited gastropathy and showed no increase in intestinal permeability after 12 days use.296 Astra Zeneca bought rights to a number of CINODs from NiCOX, the originator company. However, phase II trial results did not meet Astra Zeneca’s targets,297 as gastroduodenal toxicity was no better than with naproxen,298[II] and this led it to resell rights to two NONSAIDs to NiCOX.299 A number of NO-NSAIDs are in phase III trials and there are hopes of submitting the drugs for approval by 2009.300
NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs
Published in Expert Review of Clinical Pharmacology, 2018
Guillermo García-Rayado, Mercedes Navarro, Angel Lanas
One of those compounds, naproxcinod, reached a significant clinical development, because it combined the NSAID with the best CV profile with NO, an agent shown to be beneficial for both the GI and CV systems. Unfortunately, in phase III studies, naproxcinod did not show sufficient advantage over the current drugs, and both the EMA and FDA raised safety concerns. Other compounds, like PC-associated NSAIDs or PC-aspirin, were also tested in humans with good results, but longer-term studies that assess clinically relevant GI events are lacking. No new studies or applications for marketing approval are on the horizon. Currently, the only of new compounds undergoing clinical testing are H2S-releasing NSAIDs. In a very recent phase 2B GI safety study, H2S-naproxen showed significantly lower gastric and duodenal ulceration rates than naproxen alone in a 14-day treatment [94]. We must await results from clinical studies to ascertain whether these new H2S-releasing NSAIDs will be given the green light to be marketed as a new drug for patients that need NSAIDs.