Lafutidine prevents low-dose aspirin and loxoprofen induced gastric injury: A randomized, double-blinded, placebo controlled study

Abstract
Background and Aim: The concomitant use of non-steroidal anti-inflammatory drugs is a risk factor for low-dose aspirin (LDA)-associated upper gastrointestinal toxicity. Lafutidine is an H2-receptor antagonist with gastroprotective activity, produced by acting oncapsaicin-sensitive afferent neurons. To evaluate the preventive effect of lafutidine ongastric damage caused by LDA alone and by the combination of both LDA and loxoprofen,we conducted a clinical study using healthy volunteers.

Methods: A randomized, double-blinded, placebo-controlled, crossover study was carriedout. Sixteen healthy volunteers without Helicobacter pylori infection were randomlyassigned to two groups. Both groups received 81 mg of aspirin once daily for 14 days (ondays 1 to 14) and 60 mg of loxoprofen three times daily for the last 7 days (on days 8 to 14).Placebo or 10 mg of lafutidine was administered twice daily for 14 days in each group.After a 2-week washout period, placebo and lafutidine were crossed over. Endoscopicfindings of gastric mucosal damage were evaluated according to the modified Lanza score.Results: The mean modified Lanza score was 2.19 1.06 (SD) for aspirin plus placebo ascompared with 0.50 0.77 for aspirin plus lafutidine (P < 0.001), and 3.00 1.56 foraspirin plus loxoprofen and placebo as compared with 1.25 1.37 for aspirin plus loxoprofen and lafutidine (P < 0.01).Conclusions: The addition of loxoprofen to LDA increases gastric mucosal damage.Standard-dose lafutidine significantly prevents gastric mucosal damage induced by LDAalone or LDA plus loxoprofen in H. pylori-negative volunteers. Larger controlled studiesare needed to strengthen these findings.

Introduction
Low-dose aspirin is widely used to prevent cerebrovascular disease and ischemic heart disease because of its antiplatelet activity.1,2 Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for the management of chronic pain associated with diseases such as rheumatoid arthritis and osteoarthritis. Because the prevalence of these diseases is particularly high among elderly patients, a growing proportion of such patients are likely to receive lowdose aspirin in combination with other NSAIDs. Aspirin and other NSAIDs inhibit cyclooxygenase-1 (COX-1) and reduce the production of prostaglandins, which protect the gastrointestinal mucosa, leading to gastric mucosal damage.3,4 These drugs have also been reported to directly injure the gastric mucosa under acidic conditions.5,6 Proton-pump inhibitors (PPIs), high-dose histamine (H2)-receptor antagonists, and misoprostol have been shown to prevent NSAID-induced gastrointestinal ulcers.7–15 Lafutidine is an H2-receptor antagonist that continuously suppresses gastric-acid secretion and protects the gastric mucosa by acting on capsaicin-sensitive afferent neurons. Experimental studies have shown that lafutidine inhibits gastric mucosal damage induced by aspirin or other NSAIDs.16 Aspirin and NSAIDs have caused acute gastric mucosal lesions in gastric corpus in rats. Lafutidine dose-dependently and significantly has prevented the development of gastric lesions.16

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