Aminophenazone is a phenyl-pyrazolone derivative with potent analgesic and antipyretic properties. Aminophenazone has been used as salt or complexes, including topically as the salicylate. It was recommended for the treatment of a fever, neuralgia, myositis, acute rheumatism, arthritis, chorea. In 1999 the FDA suspended aminophenazone. The drug caused agranulocytosis. Some of the cases of agranulocytosis were fatal. Another reason for suspending this drug from the market was its ability to react with nitrite-containing food, thus forming carcinogenic nitrosamines. A breath test with 13C-labeled aminopyrine has been used as a non-invasive measure of cytochrome P-450 metabolic activity in liver function tests.

Butibufen is a non-steroidal anti-inflammatory cyclooxygenase inhibitor with analgesic and antipyretic properties. The drug was investigated for the treatment of osteoarthritis, rheumatoid artritis, and other arthroses. It was marketed under tradenames Mijal and Butilopan but now is withdrawn from the market.

N,N-Dimethylcarbamoylmethyl alpha,2-dimethyl-5H-[1]- benzopyrano[2,3-b]pyridine-7-acetate (Y-23023/ Tilnoprofen arbamel) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID), by Yoshitomi and Japan Tobacco for treatment pain in Rheumatoid arthritis, but was discontinued. Y-23023 is rapidly hydrolysed to an active metabolite, alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (TILNOPROFENIC ACID), cyclo-oxygenase inhibitor.

Indoprofen is one of several NSAIDs that have been withdrawn from the market due to causing severe gastrointestinal bleeding. The UK Licensing Authority suspended the product license on grounds of safety in 1983 and in 1984 the Italian manufacturers decided to withdraw it from the world market. The UK decision was taken because there was a high rate of adverse drug reactions in a voluntary postmarketing surveillance study and the spontaneous adverse reaction reporting system had noted 217 serious adverse effects, mainly gastrointestinal bleeding and perforation.

(S)-Sulindac is the (S)-enantiomer of nonsteroidal anti-inflammatory drug (NSAID) Sulindac, that is marketed in the U.S. by Merck as Clinoril. Sulindac is a prodrug, derived from sulfinyl-indene, that is converted in vivo to an active sulfide compound by liver methionine sulfoxide reductases (Msr). The (Msr) family of enzymes includes two major classes, MsrA and MsrB, that specifically reduce the S- and R-epimers of Sulindac. Reduction of (S)-Sulindac to Sulindac Sulfide catalyzed by methionine sulfoxide reductase (Msr)-A. The oxidation of both epimers to sulindac sulfone is catalyzed primarily by the microsomal cytochrome P450 (P450) system. (S)-Sulindac increases the activity of the P450 system better than (R)-sulindac, but both epimers increase primarily the enzymes that oxidize (R)-sulindac. Both epimers can protect normal lung cells against oxidative damage and enhance the killing of lung cancer cells exposed to oxidative stress.

Tiaprofenic acid is a non-steroidal, anti-inflammatory, analgesic compound, which nonselectively inhibits cyclooxygenase protein. Tiaprofenic acid was approved in Europe for the symptomatic relief of arthritis, ankylosing spondylitis and other inflammatory-rheumatic disorders as well as the painful conditions after injury.

(R)-Sulindac is the (R)-enantiomer of nonsteroidal anti-inflammatory drug (NSAID) Sulindac, that is marketed in the U.S. by Merck as Clinoril. Sulindac is a prodrug, derived from sulfinylindene, that is converted in vivo to an active sulfide compound by liver methionine sulfoxide reductases (Msr). The (Msr) family of enzymes includes two major classes, MsrA and MsrB, that specifically reduce the S- and R-epimers of Sulindac. Reduction of (R)-Sulindac to Sulindac Sulfide catalyzed by methionine sulfoxide reductase (Msr)-B. The oxidation of both epimers to sulindac sulfone is catalyzed primarily by the microsomal cytochrome P450 (P450) system. (S)-Sulindac increases the activity of the P450 system better than (R)-sulindac, but both epimers increase primarily the enzymes that oxidize (R)-sulindac. Both epimers can protect normal lung cells against oxidative damage and enhance the killing of lung cancer cells exposed to oxidative stress.

Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme thereby suppressing thromboxane synthesis. Indobufen under brand name ibustrin is used in Italy for the following conditions: cerebrovascular insufficiency, atherosclerosis of peripheral and cerebral vessels, thrombophlebitis, deep vein thrombosis, and diabetes mellitus. In addition, this drug has been investigated in the phase II clinical trial for the prevention of thromboembolic events in patients with nonrheumatic atrial fibrillation. After oral administration, it is quickly and completely absorbed.

Tenidap ([Z]-5-chloro-2,3-dihydro-3-[hydroxy-2-thienylmethylene]-2-oxo-1H-indole-1-carboxamide) is an oxindole derivative, a COX/5-LOX inhibitor and cytokine-modulating anti-inflammatory drug candidate that was under development by Pfizer as a promising potential treatment for rheumatoid arthritis. Tenidap shows potent inhibition of cyclooxygenase in vitro, that is of several magnitudes greater than 5-lipoxygenase inhibition. Lipoxygenase inhibition, however, has been difficult to document in vivo because Tenidap is highly protein bound and free drug concentrations are below those necessary for 5-lipoxygenase inhibition. However, several in-vitro activities distinguish Tenidap from conventional cyclooxygenase inhibitors. As shown with stimulated human neutrophils, tenidap inhibits activation of collagenase, lysosomal enzyme secretion, and superoxide generation, as well as aggregation and adhesion to endothelium. Furthermore, unlike Non-steroidal anti-inflammatory drugs (NSAIDs), it lowers circulating C-reactive protein (CRP) concentrations by a magnitude equivalent to hydroxychloroquine and auranofin. This result suggests an effect on the synthesis and/or release of the cytokines known to induce the acute-phase protein response-namely, IL-1, IL-6, and TNF-alpha. Tenidap, like existing second-line drugs, lowers serum IL-6 concentrations, a property not shared by NSAIDs The cytokine inhibitory effect also includes reduced in-vitro concentrations of TNF-alpha and IL-1 from both RA synovium and peripheral blood mononuclear cells. There is no immunosuppressive effect of Tenidap in either animal or clinical studies. In clinical studies. The comparisons between tenidap and other second-line agents show that Tenidap produced a faster reduction in CRP than Auranofin. The rate of withdrawal because of inefficacy was similar (18-20%) in Auranofin and Tenidap groups. The quality of life using the arthritis impact measurement scales has also been assessed Scores were better with tenidap than with NSAID monotherapy, but equivalent to the second line plus NSAID combinations. Tenidap is registered in the United States, Netherlands, and Italy but is not marketed because marketing approval was rejected by the FDA in 1996 due to liver and kidney toxicity, which was attributed to metabolites of the drug with a thiophene moiety that caused oxidative damage.