Glucosamine and Leukotriene Inhibitors

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Glucosamine and Leukotriene Inhibitors

• BEH.214 Presentation
• 24 February 2003

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Glucosamine as a building block

• In absence of inflammation, glucosamine
  (2-amino-2-deoxy-glucose) may be used as
• heparin building block (N-acetyl-glucosamine)
• GPI linkage unit
• hyaluronic acid building block
• signaling molecule-- O-NAcGln proteins (1)
• membrane and ECM protein glycosylation

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Glucosamine in Inflammation

• Evidence Gln may inhibit T-cells and NK cells and
  dendritic cells (NFkB modulation) (2)
• Gln modulates IL-1B affects by inhibiting NF-kB
  pathway (chondrocytes) (3)
• Gln inhibits NO, COX-2, IL-6 via a non-MAPK,
  non-JNK, non-ERK and non-p38 inhibition or NFkB
  activation (chondrocytes. M-phage) (4,5)

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Glucosamine in IBD treatment

• A pilot student of N-acetyl-glucosamine as a
  nutriceutical adjuvant therapy for pediatric
  chronic IBD showed some efficacy. (6)
• A few case/anecdotal reports suggest it works for
  IBD most in journal not easily obtainable.
• A number web-sites advertising and selling
  glucosamine suggest it works for IBD.

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Is Glucosamine an interesting lead?

• Probably not

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What about Leukotriene Inhibitors?

• Lets take a quick look

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Leukotrienes General

• Biologically active molecule produced from
  arachidonic acid by lipoxygenase enzymes (5-,
  12-, 15) often requires several cells
• aspirin acetylated COX-2 also produces H(P)ETEs
• LTC4, LTD4 are the slow-acting substances of
  anaphylaxs
• LTB4 induces neutrophil and eosinophil chemotaxis
• Some leukotrienes can be converted to lipoxins
  with further biological function

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Leukotriene Inhibitors

• -lukast (Monelukast, Zafirlukast)
• leukotriene receptor antagonist (LTD4)
• Zileuton
• 5-Lipoxygenase inhibitor
• Results show some efficacy in small Phase II
  trial as treatment for UC (7)
• Works on experimentally induced colitis in rats
  (12)

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Leukotrienes in IBD

• Some evidence for increased 5-LO activity and
  12-LO (at site of inflammation only) in Crohns
  disease. (8, 9)
• LTB4 main chemotactic signal in mucosa during IBD
  relapse. (10, 11)
• Equilibrium dialysate showed increased
  leukotriene production (LTB4) only in patients
  with ulcerations. (12)
• Leukotrienes production appears to be greater in
  UC the Crohns disease

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Leukotriene Inhibitors in IBD treatment?

• Possibly, but not a great candidate

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References Cited

• 1. Ma, L. et al. JBC, 277(42), 2002. pg 39343-9
• 2. Gouze, JN. FEBS Letters 510, 2002 166-70
• 3. Shikhman, RS., et al. Journal of Immunology,
  2001 pg 5155-60
• 4. Leach, K. personal communication
• 5. Salvatore, S. et al. Alimentary Pharmacology
  and Therapeutics, 2000, 14 1567-79
• 6. Collawn, C., American Journal of
  Gastroenterology, Mar 1992, 87(3) 342-6.
• 7. Shannon, VJ et al., American Journal of
  Physiology. 264(1 Pt 1) G104-11, 1993 Jan.
• 8. Hendel, J. et al. Inflammation Research, Aug
  2002 51(8) 423-6.
• 9. Hawkey, CJ. Et al., Agents and Actions. Spec
  No C22-6, 1992
• 10. Nielson, OH., et al. Clinical and
  Experimental Immunology. 65(2) 465-71, 1986.
• 11. Lauritsen, K. et al. Gastroenterology. 95(1)
  11-7, 1988
• 12. Zingarelli, B., et al. Agents and Actions.
  39(3-4)150-6, 1993