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Chemical Compound Review

AXD455     N,N'-bis[3,5-bis[N- (diaminomethylideneamin...

Synonyms:
 
 
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Disease relevance of AXD455

  • We recently synthesized a tetravalent guanylhydrazone compound (CNI-1493) that inhibits cytokine-inducible arginine transport and nitric oxide (NO) production in macrophages, and protects mice against lethal endotoxemia and carrageenan-induced inflammation [1].
  • Twelve patients with severe Crohn's disease (mean baseline, CDAI 380) were randomly assigned to receive either 8 or 25 mg/m(2) CNI-1493 daily for 12 days [2].
  • Taken together, these data showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor response to IL-2 therapy [3].
  • With the protection afforded by CNI-1493 treatment, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas [3].
  • Serum TNF- protein and nitrites correlated with gene induction in that both were increased following the onset of pancreatitis, and TNF- protein production was significantly attenuated in animals receiving CNI-1493 [4].
 

High impact information on AXD455

 

Chemical compound and disease context of AXD455

 

Biological context of AXD455

 

Anatomical context of AXD455

 

Associations of AXD455 with other chemical compounds

  • In combination with high-dose IL-2, CNI-1493 at > or = 25 mg/m2 seemed to exacerbate IL-2-induced nephrotoxicity: grade 3 or 4 creatinine increases developed in 3 of 6 patients at 25 or 32 mg/m2, as compared with 1 of 16 patients at doses < or = 16 mg/m2 [11].
  • Addition of TNF-alpha to CNI-1493-exposed LPS-stimulated cells partially restored the incidence of IL-1alpha-, IL-1beta-, and IL-8-producing cells [15].
  • TNF production by tolerant Mphi in response to LPS was significantly (P < 0.05, t test) decreased and p38 inhibition with CNI-1493 at the time of SLH reversed the inhibitory effects of tolerance on TNF production [17].
  • Bilateral cervical vagotomy or atropine blockade (1 mg/kg/h) abrogated the anti-inflammatory effects of CNI-1493 (1 microg/kg, i.c.v. or 5 mg/kg, i.v.), indicating that the intact vagus nerve is required for CNI-1493 activity [18].
 

Gene context of AXD455

 

Analytical, diagnostic and therapeutic context of AXD455

References

  1. Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone. Bianchi, M., Bloom, O., Raabe, T., Cohen, P.S., Chesney, J., Sherry, B., Schmidtmayerova, H., Calandra, T., Zhang, X., Bukrinsky, M., Ulrich, P., Cerami, A., Tracey, K.J. J. Exp. Med. (1996) [Pubmed]
  2. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease. Hommes, D., van den Blink, B., Plasse, T., Bartelsman, J., Xu, C., Macpherson, B., Tytgat, G., Peppelenbosch, M., Van Deventer, S. Gastroenterology (2002) [Pubmed]
  3. The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy. Kemeny, M.M., Botchkina, G.I., Ochani, M., Bianchi, M., Urmacher, C., Tracey, K.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Macrophage pacification reduces rodent pancreatitis-induced hepatocellular injury through down-regulation of hepatic tumor necrosis factor alpha and interleukin-1beta. Yang, J., Denham, W., Carter, G., Tracey, K.J., Norman, J. Hepatology (1998) [Pubmed]
  5. Pharmacological stimulation of the cholinergic antiinflammatory pathway. Bernik, T.R., Friedman, S.G., Ochani, M., DiRaimo, R., Ulloa, L., Yang, H., Sudan, S., Czura, C.J., Ivanova, S.M., Tracey, K.J. J. Exp. Med. (2002) [Pubmed]
  6. Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy. Hauber, I., Bevec, D., Heukeshoven, J., Krätzer, F., Horn, F., Choidas, A., Harrer, T., Hauber, J. J. Clin. Invest. (2005) [Pubmed]
  7. Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein, gp120. Milligan, E.D., Mehmert, K.K., Hinde, J.L., Harvey, L.O., Martin, D., Tracey, K.J., Maier, S.F., Watkins, L.R. Brain Res. (2000) [Pubmed]
  8. Semapimod. Cytokine. Sitaraman, S.V., Hoteit, M., Gewirtz, A.T. Current opinion in investigational drugs (London, England : 2000) (2003) [Pubmed]
  9. Strategies for targeting tumour necrosis factor in IBD. Sandborn, W.J. Best practice & research. Clinical gastroenterology. (2003) [Pubmed]
  10. CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency. Cohen, P.S., Nakshatri, H., Dennis, J., Caragine, T., Bianchi, M., Cerami, A., Tracey, K.J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  11. A phase I study of CNI-1493, an inhibitor of cytokine release, in combination with high-dose interleukin-2 in patients with renal cancer and melanoma. Atkins, M.B., Redman, B., Mier, J., Gollob, J., Weber, J., Sosman, J., MacPherson, B.L., Plasse, T. Clin. Cancer Res. (2001) [Pubmed]
  12. Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kramer, A.A., Postler, G., Salhab, K.F., Mendez, C., Carey, L.C., Rabb, H. Kidney Int. (1999) [Pubmed]
  13. High-mobility group box 1 protein is an inflammatory mediator in necrotizing enterocolitis: protective effect of the macrophage deactivator semapimod. Zamora, R., Grishin, A., Wong, C., Boyle, P., Wang, J., Hackam, D., Upperman, J.S., Tracey, K.J., Ford, H.R. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  14. Suppression of macrophage activation with CNI-1493 increases survival in infant rats with systemic Haemophilus influenzae infection. Granert, C., Abdalla, H., Lindquist, L., Diab, A., Bahkiet, M., Tracey, K.J., Andersson, J. Infect. Immun. (2000) [Pubmed]
  15. Targeted suppression of cytokine production in monocytes but not in T lymphocytes by a tetravalent guanylhydrazone (CNI-1493). Björk, L., Tracey, K.J., Ulrich, P., Bianchi, M., Cohen, P.S., Akerlund, K., Fehniger, T.E., Andersson, U., Andersson, J. J. Infect. Dis. (1997) [Pubmed]
  16. Prevention of lethality and suppression of proinflammatory cytokines in experimental septic shock by microencapsulated CNI-1493. D'Souza, M.J., Oettinger, C.W., Milton, G.V., Tracey, K.J. J. Interferon Cytokine Res. (1999) [Pubmed]
  17. Involvement of p38 mitogen-activated protein kinase in the induction of tolerance to hemorrhagic and endotoxic shock. Mendez, C., Jaffray, C., Wong, V., Salhab, K.F., Kramer, A.A., Carey, L.C., Norman, J.G. J. Surg. Res. (2000) [Pubmed]
  18. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Borovikova, L.V., Ivanova, S., Nardi, D., Zhang, M., Yang, H., Ombrellino, M., Tracey, K.J. Autonomic neuroscience : basic & clinical. (2000) [Pubmed]
  19. Specific inhibition of c-Raf activity by semapimod induces clinical remission in severe Crohn's disease. Löwenberg, M., Verhaar, A., van den Blink, B., ten Kate, F., van Deventer, S., Peppelenbosch, M., Hommes, D. J. Immunol. (2005) [Pubmed]
  20. Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Gardiner, T.A., Gibson, D.S., de Gooyer, T.E., de la Cruz, V.F., McDonald, D.M., Stitt, A.W. Am. J. Pathol. (2005) [Pubmed]
  21. Dynamics of early synovial cytokine expression in rodent collagen-induced arthritis : a therapeutic study using a macrophage-deactivating compound. Palmblad, K., Erlandsson-Harris, H., Tracey, K.J., Andersson, U. Am. J. Pathol. (2001) [Pubmed]
  22. An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality. Bianchi, M., Ulrich, P., Bloom, O., Meistrell, M., Zimmerman, G.A., Schmidtmayerova, H., Bukrinsky, M., Donnelley, T., Bucala, R., Sherry, B. Mol. Med. (1995) [Pubmed]
 
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