Joseph G. Lombardino

Piroxicam, a potent inhibitor of prostaglandin production in cell culture. Structure-activity study☆

The new non-steroidal antiinflammatory (NSAI)2 agent, piroxicam [4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide], is a highly active inhibitor of prostaglandin (PG) synthesis by methylcholanthrene transformed mouse fibroblasts (MC5-5) and rabbit synovial cells in culture. Comparison of the PG biosynthesis inhibitory activity of piroxicam with other NSAI drugs in these experiments ranks piroxicam as among the most potent agents of this type now known. Some specific modifications of piroxicams structure result in significant loss in PG synthesis blocking activity.

Piroxicam, a structurally novel anti-inflammatory compound. Mode of prostaglandin synthesis inhibition

Piroxicam is a potent inhibitor of prostaglandin biosynthesis. Experiments utilizing cell culture and microsomes derived from various sources have demonstrated that piroxicam is a selective inhibitor of the cyclooxygenase step of arachidonic acid metabolism. Little blocking activity is observed at the phospholipase, thromboxane or prostacyclin synthetase, and arachidonic acid lipoxygenase steps.

1,2- and 2,1-Benzothiazines and Related Compounds

Publisher Summary The chapter focuses primarily on the two ring systems 1 and 2 and their oxidized derivatives. A few related ring systems, such as dibenzo- and hetero ring-fused 1,2-thiazines are included where it appears appropriate because of similar chemistry or analogous utility to the benzothiazine compounds. This chapter brings together all of the literature references to the title compounds, discusses the routes employed for their synthesis, and describes their reported chemical transformations. Special data and their utility are also discussed. The chapter discusses naptho- and dibenzo-1,2-thiazines, heterocyclic ring fused 1,2-thiazines, ring fused 1,2-benzothiazine derivatives, and 2,1-benzothiazines.

An analysis of piroxicam in rodent models of arthritis.

Piroxicam, a potent, long acting non-steroidal anti-inflammatory drug, was tested in several rodent models of arthritis to assess further the possible mechanisms underlying its anti-inflammatory action. Piroxicam inhibited rat adjuvant disease and its associated manifestations, which include erosion of bone and cartilage (as evidenced by X-ray examination), soft tissue swelling and disease-induced weight loss. Piroxicam also inhibited the edema, the total leukocyte infiltration and the mononuclear cell infiltration into the carrageenan-injected pleural cavity of the rat. The possible relationship of these effects to the clinical activity of piroxicam is discussed.

The topical anti-inflammatory effects of piroxicam in rodents.

Piroxicam is a structurally novel, long-acting anti-inflammatory drug with potent activity following oral administration in animal models of inflammation and in human inflammatory diseases. The present studies, performed in rats, demonstrate that topically applied piroxicam is a potent inhibitor of inflammation induced by either carrageenin or complete Freunds adjuvant. Comparable potencies (ED50 approximately 1–5 mg/kg) were obtained for topically and orally administered piroxicam in these models of inflammation. The potency of topical piroxicam exceeds that of topically applied bufexamac or phenylbutazone in the rat adjuvant arthritis model.

Chapter 18. Newer Agents for the Treatment of Arthritis

Publisher Summary Among the various anti-arthritic agents, the non-steroidal anti-inflammatory (NSAI) drugs are by far the largest and most important class. Some new insights have been gained concerning the mechanisms, by which NSAI agents control inflammation. The basic mode of action of these drugs is the ability of these agents to influence the biosynthesis of prostaglandins (PG). NSAI agents are of definite benefit to arthritic patients in aiding them to maintain a reasonably normal life by controlling the symptoms of inflammation. Although such drugs at high doses are considered as an effective anti-inflammatory drug, toxic side-effects can limit its use. Several of the newer NSAI drugs are more potent than Aspirin on a dose basis and the offer needed improved toleration. A longer half life of some of the newer agents offers the convenience of less frequent dosing and provides more constant plasma drug levels with more uniform control of the symptoms of inflammation. The immunoregulatory agents are at an earlier stage of development and those in clinical trials generally exhibit limiting side-effects. However, this class of compounds, rather than primarily alleviating symptoms, as the NSAI drugs do, offer the possibility of arresting the arthritic disease process and, thereby halting progressive joint destruction. The trend in current drug research is toward the development of well-tolerated and safe drugs that will arrest or reverse the arthritic disease process.

Chapter 18. New Agents for the Treatment of Inflammation and Arthritis

Publisher Summary This chapter reviews highly potent new non-steroidal anti-inflammatory (NSAI) agents as well as the immunoregulatory agents of potential use in arthritis. Recent clinical reports have established a number of compounds from both immunoregulatory and NSAI classes as being effective in treating inflammatory diseases. Immunoregulatory agents are increasingly being investigated for their effect on immunologically-mediated forms of arthritis, such as rheumatoid arthritis (RA). New compounds in both these classes continue to be discovered in animal models of inflammation. The chapter discusses of compounds that are reported to be potent in animals or man by the oral route, because high doses by other routes are known to produce false positive results because of toxicity or local irritating effects. Four areas of NSAI currently receive particular attention: the effect of NSAIs on arachidonic acid metabolism; highly active oxygen species; inflammatory cell movement; and preferential distribution of acidic NSAIs into inflamed tissues. With the NSAIs availability to control pain and inflammation, drug therapy for arthritis requires agents that will arrest the progressive joint destruction of this disease. Despite the many NSAI agents already available for treating arthritis and inflammation, newer drugs continue to appear. The new drugs are often used to treat patients not adequately controlled by existing agents. Some of the new agents require much lower daily doses than existing drugs to achieve effective control of inflammation. Clinical trials in RA now support the efficacy of one immunoregulatory agent (levamisole), although the mechanism of action of this compound is not yet understood.