COX-2 Selective Drugs Research Articles

Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs (NSAIDs)

The popular view that all nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the production of prostaglandins has been challenged by the discovery that they also affect a wide variety of cellular processes that are important for their therapeutic actions and side effects. Although recognition of the differential activities of new and established NSAIDs on the activities of the cyclooxygenases (COXs) affecting production of inflammatory prostaglandins (from COX-2) and those that are physiologically important (from COX-1) may have significance for the prostaglandin components of the underlying inflammatory and physiologic processes, there are important features of their chemical structures that determine the various cellular and biochemical actions of these agents. Several established NSAIDs have low propensity to cause gastrointestinal (GI) ulceration and bleeding that may relate to these drugs having unique pharmacokinetic characteristics (pro-drugs, protein binding, etc). They also have weak effects on the production of GI mucosal prostaglandins and have specific physicochemical characteristics such that they cause minimal damage to mucosal membranes or effects on nonprostaglandin-related cellular mechanisms important in mucosal defenses. Some of the new COX-2–selective drugs with methyl or amino-sulfonyl moieties have relatively high pKa values and other properties that are similar to established NSAIDs with low GI ulcerogenicity. These physicochemical properties may contribute to the low irritancy of the new COX-2–selective drugs quite apart from their sparing of COX-1 in the GI mucosa. With concerns that some established NSAIDs may accelerate cartilage destruction in osteoarthritis (OA), interest is now focusing on whether the COX-2–selective drugs may have a lower potential for this adverse effect by avoiding the inhibitory effects on cartilage proteoglycan metabolism seen with such drugs as indomethacin and the salicylates. Meloxicam appears to be without inhibitory effects on proteoglycan metabolism, but it remains to be seen if this translates into any beneficial actions on the progression of joint changes in OA observed radiologically or from magnetic resonance imaging.

SELECTIVE CYCLOOXYGENASE-2 INHIBITORS

The identification of COX-2 less than a decade ago has been followed by an unprecedented period of discovery and drug development. An awareness of the existence of two COX isoforms has led to potential novel insights into disease pathogenesis (arthritis, Alzheimer's disease, cancer) and the regulation of normal physiology (brain, kidney). The preliminary in vivo experience with COX-2-selective inhibitors has provided evidence for proof of concept for the COX-1 and COX-2 hypothesis, namely that the selective inhibition of COX-2-derived prostaglandins is sufficient to inhibit inflammation and is nonulcerogenic. It may be that we have moved closer to the "better aspirin" envisioned by Sir John Vane for the treatment of degenerative and inflammatory arthritides; however, caution is still warranted. Some toxicities of current NSAIDs may result from COX-2 inhibition, as in the kidney and brain; such side effects may be shared by the selective compounds. In addition, unexpected toxicities may arise simply because new chemical compounds will be widely prescribed. Finally, since the efficacy of traditional NSAIDs derives largely from their capacity to inhibit COX-2, it may be that the COX-2 selective drugs will not prove to be therapeutically superior to available agents. Given the well-recognized toxicity of NSAIDs, however, the availability of COX-2-selective agents promises to provide significant advantage to patients with chronic diseases, such as RA and OA.

Differential effects of inhibitors of cyclooxygenase (cyclooxygenase 1 and cyclooxygenase 2) in acute inflammation

The anti-inflammatory activity of drugs more selective for cyclooxgenase isoform inhibition (cyclooxygenase 1, cyclooxygenase 2), were compared in rat carrageenin-induced pleurisy. Suppression of inflammation by cyclooxygenase 2-selective inhibitors, NS-398 ( N-[-2-cyclohexyloxy]-4-nitrophenyl methanesulphonamide) and nimesulide (4-nitro-2-phenoxy-methanesulfonanilide), and by piroxicam and aspirin, more selective for cyclooxygenase 1, was measured. Piroxicam and aspirin significantly inhibited inflammatory cell influx, exudate and prostaglandin E 2 formation, 6 h after carrageenin injection. Cyclooxygenase 2 inhibitors had little effect on these parameters with NS-398 alone reducing prostaglandin E 2 levels, but increasing levels of leukotriene B 4. In contrast, at 3 h after carrageenin injection, cyclooxygenase 2 inhibitors significantly inhibited all inflammatory parameters however suppression with piroxicam and aspirin was greater, and more pronounced than at 6 h. NS-398 and nimesulide dosing did not reduce thromboxane B 2 production from platelets isolated from rats with carrageenin-induced pleurisy, demonstrating that at the doses used, cyclooxygenase 2 inhibitors did not inhibit cyclooxygenase 1, as platelets contain only this isoform. Therefore, in the rat carrageenin-induced pleurisy, drugs more selective for the inhibition of cyclooxygenase 1 attenuate inflammation over a wider time frame than cyclooxygenase 2-selective drugs, suggesting a significant role for cyclooxygenase 1 in this model. Inhibition of cyclooxygenase 2 by NS-398 however, resulted in an increase in the potent chemoattractant leukotriene B 4.