title: The novel phospho-non-steroidal anti-inflammatory drugs, OXT-328, MDC-22 and MDC-917, inhibit adjuvant-induced arthritis in rats.
abstract: OBJECTIVE
  The use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatoid arthritis (RA) is limited by their toxicity. We evaluated the anti-inflammatory efficacy and safety of three novel modified NSAIDs, phospho-aspirin, phospho-ibuprofen and phospho-sulindac.
  
  
  METHODS
  We determined the anti-inflammatory effects and gastrointestinal safety of the phospho-NSAIDs in the rat adjuvant arthritis model and studied their mechanism of action in cultured cells, Cytokines were measured with elisa and activation of nuclear factor-κB (NF-κB) by immunohistochemistry.
  
  
  RESULTS
  All three phospho-NSAIDs showed less gastrointestinal toxicity than their parent compounds and demonstrated strong anti-inflammatory effects, essentially reversing joint inflammation and oedema. They have a broad but not uniform effect on the expression of relevant cytokines, in general decreasing IL-6 and IL-1β and increasing IL-10 levels in rat plasma and cultured cells. Phospho-sulindac and phospho-ibuprofen but not phospho-aspirin suppressed PGE(2) production in vitro, whereas phospho-aspirin (in contrast to aspirin) showed the same effect in vivo. In joint tissues, phospho-aspirin inhibited NF-κB activation, and suppressed inflammation and bone resorption. Phospho-aspirin also inhibited Jurkat T cell proliferation. In general, phospho-aspirin had greater efficacy but different effects upon inflammatory mediators compared with aspirin. The chemical modification of the parent NSAIDs seems crucial for their safety and efficacy.
  
  
  CONCLUSIONS
  Phospho-aspirin, phospho-ibuprofen and phospho-sulindac were safer than their parent NSAIDs, were highly effective in rat adjuvant arthritis and inhibited many key mediators in the pathophysiology of RA. These novel compounds are promising candidate drugs for the treatment of RA and merit further evaluation.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.forename: Gg
authors.initials: G
authors.lastname: Mackenzie
authors.forename: N
authors.initials: N
authors.lastname: Ouyang
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: G
authors.initials: G
authors.lastname: Xie
authors.forename: F
authors.initials: F
authors.lastname: Johnson
authors.forename: D
authors.initials: D
authors.lastname: Komninou
authors.forename: B
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000633:toxicity; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D019169:Jurkat Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D010755:Organophosphates / Q000494:pharmacology / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016328:NF-kappa B; C553002:OXT-328; D010755:Organophosphates; D009943:Organophosphorus Compounds; C527365:phosphoaspirin; D013467:Sulindac; D015232:Dinoprostone; D001241:Aspirin; D007052:Ibuprofen