The novel phospho-non-steroidal anti-inflammatory drugs, OXT-328, MDC-22 and MDC-917, inhibit adjuvant-induced arthritis in rats

L. Huang, Gerardo Mackenzie, N. Ouyang, Y. Sun, G. Xie, F. Johnson, D. Komninou, B. Rigas

Research output: Contribution to journalArticle

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Abstract

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.

Original languageEnglish (US)
Pages (from-to)1521-1533
Number of pages13
JournalBritish Journal of Pharmacology
Volume162
Issue number7
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

Fingerprint

Experimental Arthritis
Aspirin
Anti-Inflammatory Agents
Pharmaceutical Preparations
Sulindac
Rheumatoid Arthritis
Safety
Cultured Cells
Joints
Cytokines
Inflammation
2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester
OXT-328
Jurkat Cells
Bone Resorption
Prostaglandins E
Plasma Cells
Interleukin-1
Interleukin-10
Interleukin-6

Keywords

  • anti-inflammation
  • arthritis
  • NSAIDs
  • phospho-aspirin
  • phospho-ibuprofen
  • phospho-sulindac
  • rheumatoid arthritis

ASJC Scopus subject areas

  • Pharmacology

Cite this

The novel phospho-non-steroidal anti-inflammatory drugs, OXT-328, MDC-22 and MDC-917, inhibit adjuvant-induced arthritis in rats. / Huang, L.; Mackenzie, Gerardo; Ouyang, N.; Sun, Y.; Xie, G.; Johnson, F.; Komninou, D.; Rigas, B.

In: British Journal of Pharmacology, Vol. 162, No. 7, 01.04.2011, p. 1521-1533.

Research output: Contribution to journalArticle

Huang, L. ; Mackenzie, Gerardo ; Ouyang, N. ; Sun, Y. ; Xie, G. ; Johnson, F. ; Komninou, D. ; Rigas, B. / The novel phospho-non-steroidal anti-inflammatory drugs, OXT-328, MDC-22 and MDC-917, inhibit adjuvant-induced arthritis in rats. In: British Journal of Pharmacology. 2011 ; Vol. 162, No. 7. pp. 1521-1533.
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AU - Mackenzie, Gerardo

AU - Ouyang, N.

AU - Sun, Y.

AU - Xie, G.

AU - Johnson, F.

AU - Komninou, D.

AU - Rigas, B.

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AB - BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.

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