Nabumetone, a new nonsteroidal anti-inflammatory drug: Criteria for therapeutic selection: Selective summary and conclusions

Abstract

T he papers presented have summarized the development of nabumetone from preclinical through clinical studies with emphasis on its possible use in rheumatoid and osteoarthritis. Basic consideration of the mechanisms of action of anti-inflammatory agents has been provided in the overview by Dr. Kantor, and the subsequent authors have evaluated the performance of nabumetone in animal models and human studies with special emphasis on gastrointestinal toxicity..Mangan, Flack, and Jackson have shown that in animal models nabumetone may diverge from the usual consistent correlation between the development of gastric lesions and the anti-inflammatory efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs). Increased gastric tolerance is further suggested in human studies measuring gastrointestinal blood loss or endoscopically observed gastric lesions. In a study using radioactive chromium-labeled cells, Lussier and LeBel demonstrated that nabumetone produces no more blood loss than placebo under conditions in which aspirin causes considerable bleeding. Using endoscopic examination, Roth found substantially less gastropathy with nabumetone than with naproxen. This difference from naproxen is corroborated by a second endoscopy study reported by Greb and associates. Subsequent presentations by Willkens and Altman outlined the basic considerations necessary for evaluating agents used in the treatment of rheumatoid arthritis and osteoarthritis, respectively. Dr. Michael Weisman has provided an excellent keynote discussion on the difficult problem of determining the proper use of x-rays in evaluating the efficacy of therapeutic agents for rheumatoid arthritis. In the double-blind efficacy trials reported in this issue, nabumetone was again compared with naproxen in patients with rheumatoid arthritis or osteoarthritis. In these studies, no differences in gastropathy were demonstrated. Since no ulcers were observed for either drug in the six months of double-blind comparison, it is apparent that longer treatment periods may be required in order for the differences in endoscopically observed lesions to manifest themselves clinically. Many of the patients from the double-blind studies were continued on or switched to nabumetone, with open treatment in increasing dosages continuing for extended periods. As discussed by Jackson, nearly 2,000 patients have been treated with nabumetone in the United States for a period of six months or longer. Almost 1,000 have been treated for more than a year, and significant numbers for two and even three years. These evaluations have included dosages up to 2,000 mg per day, with little increase in toxicity. During these studies, a total of Ii ulcers were detected. One of these was in a patient with viral encephalopathy, whereas another was in a patient who had had a single dose of nabumetone following six months of naproxen therapy. Deleting this last event, IO ulcers among approximately 2,000 patients yields an incidence of 0.5 percent, not substantially different from what might be expected in the general population. Since there is an asynchrony between symptoms and endoscopic findings with NSAID-associated gastropathy, more careful examination may have detected a somewhat higher incidence of gastric lesions in those patients treated with nabumetone. Nevertheless, these findings suggest that this agent might provide a reasonable improvement in gastrointestinal tolerance at no expense in decreased efficacy. In addition to the trend toward gastrointestinal safety, other interesting points have been raised by several of the authors. It is interesting that in patients with varying degrees of renal impairment who received single doses of nabumetone in the study reported by Boelaert et al, there