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This superiority of diclofenac plus misoprostol was observed especially in patients with more severe OA, whereas patients with mild OA had similar improvements with both therapeutic options. Pincus and colleagues 14 found significantly higher levels of improvement for diclofenac plus misoprostol than for acetaminophen over 6 weeks. 16 Over 2 weeks, pain intensity, stiffness, and functional disability decreased significantly more in the ibuprofen than in the acetaminophen group. In the Ibuprofen, Paracetamol Study in Osteoarthritis (IPSO) study, the analgesic efficacy of ibuprofen 400 mg as a single dose and as multiple doses (1200 mg/day) was compared with that of acetaminophen either as a single dose of 1000 mg or as multiple doses (3000 mg/day) in patients with knee or hip OA. 13–16 All studies except one 13 have found nonselective NSAIDs to be superior to acetaminophen.
Several trials have compared nonselective NSAIDs with acetaminophen for hip and knee OA. Francis Berenbaum, in Targeted Treatment of the Rheumatic Diseases, 2010 Nonselective Nonsteroidal Anti-inflammatory Drugs Symptomatic Efficacy The lower rate of GI ulceration associated with these drugs is likely related to NO-associated vasodilation and the relatively lower concentration of the parent NSAID. 48 The NO moiety is slowly released by enzymatic activity in vivo, likely by esterases, resulting in slow accumulation of the parent NSAID. 47Ī different strategy is nitric oxide releasing NSAIDs (NO-NSAIDs), which are synthesized by the ester linkage of an NO-releasing moiety to conventional NSAIDs including aspirin, flurbiprofen, diclofenac, sulindac, and others. This agent was shown to reduce endoscopically detected gastric ulcers. 46 The combination of enteric-coated naproxen and the proton pump inhibitor (PPI) esomeprazole (Vimovo) into a single pill has been approved by the U.S. 45 In population-based studies, Arthrotec was more effective than diclofenac and misoprostol co-prescription in preventing hospitalization for peptic ulcer disease or GI hemorrhage. Combining diclofenac with the synthetic PGE 1 analogue misoprostol (Arthrotec) is shown to reduce risk of NSAID-related peptic ulcerations and mucosal injury, but utility of the combination is often limited by misoprostol-induced cramping and diarrhea. This strategy may increase compliance with effective protective agents, thereby reducing adverse effects in clinical practice.
NSAIDs have also been combined with agents having gastroprotective effects into “polypills” that are currently available on the market. Crofford, in Kelley's Textbook of Rheumatology (Ninth Edition), 2013 Combination Drugs Results from clinical trials with COX-2 selective inhibitors suggest that this may be the case for humans as well obviating the need for prescribing additional gastric cytoprotective agents in the future (30). Recently, a COX-2 selective inhibitor, L-745,337, has been shown to be effective in a carrageenan-induced hyperalgesia model in rats without causing any gastric ulceration at doses up to 100 times those required to illicit the antinociceptive effects (29). This would suggest that the EP 3 receptor plays an important role in gastric cytoprotection, however, it is unclear as to the role the EP 1 receptor plays vis-à-vis gastric acid secretion and diarrhea. Enprostil, while more potent at the EP 3 receptor with a Ki of 12 nM also shows activity at the EP, and FP receptors with Ki’s of 82 nM and 88 nM, respectively (28). The prodrug is selective for the EP 3 receptor with a Ki of 319 nM as measured by a radioligand binding assay using membranes prepared from HEK 293 EBNA cells stably expressing one of the eight prostanoid receptors (28).
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Misoprostol acts as a prodrug from which the α-methyl ester must be hydrolyzed to the free acid form by esterase activity (27). Activation of the EP 3 receptor has been proposed as the receptor responsible for the antisecretory and cytoprotective effects as well as the uterine contractions, while the EP, receptor has been postulated as the one responsible for causing diarrhea (26).
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