DICLOFENAC MISOPROSTOL - NOVEL FINDINGS AND THEIR CLINICAL POTENTIAL/

The new class of antiinflammatory and analgesic drugs, the selective c yclooxygenase (COX-2) inhibitors, which promise to be devoid of the ty pes of toxicity associated with nonsteroidal antiinflammatory drugs (N SAID), especially adverse gastrointestinal effects, are under clinical trial but are not yet available for use. All NSAID, including those m ost recently introduced, exhibit nonselectivity of action, producing t herapeutic blood levels that inhibit constitutive COX-1 and deplete ti ssue protective prostaglandins. Among NSAID, the diclofenac/misoprosto l combination (Arthrotec(R)) is unique in possessing an active compone nt, misoprostol, to help prevent NSAID induced gastrointestinal damage . Ulcer damage and associated serious complications probably represent only the tip of the iceberg in relation to clinically significant sid e effects associated with the use of NSAID. In this context, metaanaly sis of 8 large multicenter studies reported here has shown that patien ts taking NSAID show a mean decrease in hemoglobin over 4 - 12 weeks' assessment, with some 10 - 20% of patients exhibiting clinically signi ficant decreases (greater than or equal to 1 g/dl) early in treatment, Patients taking diclofenac/misoprostol showed significantly less of a decline in hemoglobin and up to 50% fewer clinically significant decr eases than patients receiving diclofenac alone. The misoprostol compon ent of diclofenac/misoprostol may also help to restore homeostasis in tissues other than the gut. Inhibition of the activity or release of v arious tissue damaging agents and inflammatory cytokines, e.g., thromb oxane and interleukin 1, are described, as are in vivo animal studies that have revealed synergistic or potentiating analgesic and antiinfla mmatory activities between misoprostol and NSAID, particularly diclofe nac. Clinical studies in postsurgical dental pain in more than 500 pat ients have now shown enhanced analgesia, with greater relief over a lo nger period, for the diclofenac/misoprostol combination compared with diclofenac alone. The relevance of these findings to pain and inflamma tion control in arthritis is discussed. Enhanced control of morning st iffness provided by diclofenac/misoprostol, possibly also the result o f misoprostol/diclofenac synergy, is also reported, and the developmen t of an objective system that measures 24 hour ambulatory activity is described. Using this Numact recorder, improved mobility in patients r eceiving diclofenac 75 mg/misoprostol 200 mu g was observed compared w ith patients treated with diclofenac 75 mg slow release. Further studi es are being performed employing magnetic resonance imaging both to as sess antiinflammatory effects in joint soft tissue architecture and to assess whether the synergistic stimulatory effects of diclofenac and misoprostol on human osteoarthritic cartilage that have been reported in vitro are clinically evident. A growing body of evidence supports t he view that the diclofenac/misoprostol combination provides an improv ed therapeutic ratio over diclofenac alone, not only by improving gast rointestinal safety but also by enhancing analgesic/antiinflammatory e ffects.