l-745337 and Edema

Adjuvant arthritis, induced by Mycobacterium butyricum, is an experimental immunopathy that shares many features of human rheumatoid arthritis and, as such, is one of the most widely used models for studying the anti-inflammatory activity of compounds. In rats with adjuvant induced arthritis, IgG antibodies to M. butyricum have been detected and autoantigens that cross react with mycobacteria may be involved in the pathogenesis of adjuvant arthritis. In this study, the anti-inflammatory and immunosuppressive activities of two cyclooxygenase-2 selective inhibitors, flosulide and L-745,337, at doses of 0.1, 1 and 5 mg/kg/day, were examined in adjuvant arthritic rats. After 14 days of treatment, a clear dose-dependent inhibition of plantar edema was seen for both flosulide (ID50 lower than 0.1 mg/kg) and L-745,337 (ID50 = 0.4 mg/kg). Plasma levels of IgG anti-M. butyricum antibodies were also decreased by both drugs. In each case the maximal immunosuppressive effect was observed at doses lower than 5 mg/kg. The non-selective COX-2 inhibitor, indomethacin (1 mg/kg) decreased paw edema by 65% and the levels of IgG anti-M. butyricum by 45%. Neither cyclooxygenase selective inhibitors nor indomethacin decreased the delayed hypersensitivity reaction induced by M. butyricum. Thus, in vivo inhibition of COX-2 inhibited articular swelling and also the humoral immune response to Mycobacterium.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Bacterial; Arthritis, Experimental; Body Weight; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Foot; Immunoglobulin G; Immunosuppression Therapy; Indans; Indomethacin; Isoenzymes; Mycobacterium; Peroxidases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar

The anti-inflammatory activity of the cyclooxygenase-2 inhibitor, L-745,337, was assessed in adjuvant arthritic rats (AA). The relationship between PGE2 organ levels and drug activity or adverse effects was determined. Arthritic rats were orally treated for two weeks with L-745,337 (0.1, 1 and 5 mg/kg/day), indomethacin (1 mg/kg/day) or vehicle and paw swelling was determined. At the end of the study, samples from paw, stomach (wall and mucosa) and kidney were obtained from rats with or without treatment at high doses of L-745,337 or indomethacin and PGE2 levels were determined. The L-745,337 anti-inflammatory effective-dose-50 was 0.4 mg/kg. Maximal anti-inflammation was obtained with L-745,337 or indomethacin at doses of 5 and 1 mg/kg respectively. L-745,337 showed anti-arthritic activity. No stomach ulcers appeared in either untreated or treated arthritic and healthy control rats. In AA rats, PGE2 increased in paw, stomach wall, gastric mucosa and kidney. These levels were lower in all organs after both drugs but not below PGE2 control levels.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Edema; Female; Hindlimb; Indans; Indomethacin; Isoenzymes; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Severity of Illness Index; Stomach Ulcer

Alminoprofen is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylpropionic acid class. It has anti-inflammatory properties different from the classical NSAID. Using both in vitro systems of cells in culture and in vivo models of inflammation, we report here that alminoprofen possesses both antiphospholipase A2 (PLA2) activity and anti-cycloxygenase (COX) activity. The PLA2 targeted by alminoprofen is likely the secretory phospholipase A2 (sPLA2) while the COX targeted is the COX-2.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Edema; Flurbiprofen; Group II Phospholipases A2; Humans; Indans; Indomethacin; Isoenzymes; Melitten; Membrane Proteins; Phospholipases A; Phospholipases A2; Phospholipids; Propionates; Prostaglandin-Endoperoxide Synthases; Prostaglandins F; Rats; Rats, Wistar

A series of 1,2-diarylcyclopentene methyl sulfones and sulfonamides have been shown to be remarkably potent and selective cyclooxygenase-2 (COX-2) inhibitors. The methyl sulfone analogs 7 showed excellent COX-2 activity, with IC50s ranging from 0.003 (7f,n) to 0.87 (7o) microM. In addition, most analogs of 7 showed no activity (IC50 > 100 microM) against the COX-1 enzyme. Replacement of the methyl sulfone moiety with a sulfonamide group gave a slightly more potent (typically 2-5-fold) but less selective COX-2 inhibitor, mainly due to an increase (20- > 100-fold) in COX-1 activity. However, in vitro COX-1/COX-2 selectivity for the sulfonamides 8 could be increased in many cases by simply incorporating a substituent at the 3-position of the phenyl group. Furthermore, in vitro selectivity increased with the size and number of substituents, as demonstrated in the selectivity trend of 8k (8000) > 8j (1900) > 8i (500) > 8h (100). More importantly, the sulfonamide COX-2 inhibitors showed greatly enhanced oral activity in the rat model of established adjuvant-induced arthritis, with inhibition values of 79.0% (8a), 81.5% (8c), and 83.0% (8g) at 1 mg/kg. On the basis of its overall biological profile, sulfonamide 8c was evaluated as a potential clinical candidate, displaying an ED50 of 22 mpk in the rat carrageenan-induced paw edema model and an ED50 of 0.16 mpk in the rat established adjuvant-induced arthritis model with no indication of gastrointestinal toxicity in rats and mice at 200 mpk. In addition, a preparative-scale synthetic route to sulfonamide 8c has been developed.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cyclooxygenase Inhibitors; Cyclopentanes; Dose-Response Relationship, Drug; Edema; Indomethacin; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Structure; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sulfonamides; Sulfones

Recent studies have shown that there are two isoforms of cyclooxygenases. The constitutive form, cyclooxygenase 1 (COX-1), is believed to be involved in the maintenance of physiological functions. A second isoform, cyclooxygenase 2 (COX-2), has been shown to be induced in inflammation. In the present study, the pharmacology of a selective inhibitor of COX-2, L-745,337 (5-methanesulfonamido-6-(2,4-difluorothiophenyl)-1-indano ne), is described. L-745,337 has IC50 values of 23 +/- 8 nM and > 10 microM for the inhibition of prostaglandin E2 production in whole-cell assays for COX-2 and COX-1, respectively. This compound inhibited carrageenan-induced rat paw edema and rat paw hyperalgesia with ID50 values of 2.00 and 0.37 mg/kg, respectively. In an endotoxin-induced pyresis assay in the rat, L-745,337 significantly reversed the pyretic responses (ID50 = 3.75 mg/kg). L-745,337 did not cause visible gastric lesions in rats at up to 30 mg/kg (4 hr after dosing). In a fecal 51chromium (51Cr) excretion assay to detect gastrointestinal integrity in rats and primates, L-745,337 had no effect at doses up to 100 mg/kg (rat) or after chronic dosing at 20 mg/kg per day for 5 days (primates). In contrast, oral administration of indomethacin, diclofenac or flurbiprofen resulted in substantial increase in fecal 51Cr excretion and/or frank gastric ulceration (rats). L-745,337 significantly inhibited the prostaglandin E2 levels in the inflammatory exudates from the rat pleural cavity after injection with carrageenan but did not inhibit prostaglandin E2 levels in the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Carrageenan; Chromium Radioisotopes; Cyclooxygenase Inhibitors; Edema; Electron Transport Complex IV; Feces; Fever; Humans; Hyperalgesia; Indans; Isoenzymes; Male; Pleurisy; Rats; Rats, Sprague-Dawley; Saimiri; Stomach Ulcer; Tumor Cells, Cultured