Back to products

Browse products

Approved anticancer agents

Anticancer agents in trials

Anticancer molecular libraries

MedKoo product information:

  Semapimod hydrochloride

Description of semapimod:  Semapimod (INN), formerly known as CNI-1493, is an investigational new drug which has anti-inflammatory, anti-cytokine, immunomodulatory, antiviral and antimalarial properties. According to wikipedia.com, Semapimod was developed at the former Picower Institute for Medical Research, and is now licensed to Cytokine PharmaSciences. In 2000, Cytokine PharmaSciences licensed anti-infective applications of semapimod to Axxima Pharmaceuticals, but Axxima became insolvent in Dec. 2004 and its assets were acquired by GPC Biotech, which has recently merged into Agennix AG. Although the disposition of Axxima's partial rights to semapimod was not specified in these merger announcements, Cytokine PharmaSciences does not currently list any licensees for semapimod on its website.

Current developer:  Picower Institute for Medical Research and Cytokine PharmaSciences Inc

In a preclinical study in rats, semapimod was found to suppress cytokine-storm induction by the anticancer cytokine interleukin-2 (IL-2) without decreasing its anticancer properties, allow larger doses of IL-2 to be administered. A subsequent phase I trial in humans failed to show an increase in the tolerated dose of IL-2, although indications of pharmacological activity as an inhibitor of tumor necrosis factor production were observed. In the clinical trials above, semapimod tetrahydrochloride was administered by intravenous injection. This route has drawbacks such as dose-limiting phlebitis. Recently Cytokine PharmaSciences has announced the development of novel salt forms of semapimod which are said to be orally absorbable; a phase I clinical trial of one of these salt forms, CPSI-2364, has been completed, and a phase II trial is planned for 2010. The above information was from: http://en.wikipedia.org/wiki/Semapimod

Semapimod was first developed to inhibit nitric oxide synthesis by inflammatory macrophages, via inhibition of the uptake of arginine which macrophages require for nitric oxide synthesis. Subsequently it was found that suppression of nitric oxide synthesis occurred even at semapimod concentrations 10-fold less than required for inhibition of arginine uptake, suggesting that this molecule was a more general inhibitor of inflammatory responses. Further work revealed that semapimod suppressed the translation efficiency of tumor necrosis factor production. Specifically, semapimod was found to be an inhibitor of p38 MAP kinase activation. Surprisingly, however, the primary mode of action in vivo is now thought to be via stimulation of the vagus nerve, thereby down-regulating inflammatory pathways via the recently discovered cholinergic anti-inflammatory pathway.

 1: Dotan I, Rachmilewitz D, Schreiber S, Eliakim R, van der Woude CJ, Kornbluth A, Buchman AL, Bar-Meir S, Bokemeyer B, Goldin E, Maaser C, Mahadevan U, Seidler U, Hoffman JC, Homoky D, Plasse T, Powers B, Rutgeerts P, Hommes D; Semapimod-CD04/CD05 Investigators. A randomised placebo-controlled multicentre trial of intravenous semapimod HCl for moderate to severe Crohn's disease. Gut. 2010 Jun;59(6):760-6. PubMed PMID: 20551461.

2: Oettinger CW, D'Souza MJ. Synergism in survival to endotoxic shock in rats given microencapsulated CNI-1493 and antisense oligomers to NF-kappaB. J Microencapsul. 2010;27(4):372-6. PubMed PMID: 20515262.

3: Wilms H, Rosenstiel P, Romero-Ramos M, Arlt A, Schäfer H, Seegert D, Kahle PJ, Odoy S, Claasen JH, Holzknecht C, Brandenburg LO, Deuschl G, Schreiber S, Kirik D, Lucius R. Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils. Int J Immunopathol Pharmacol. 2009 Oct-Dec;22(4):897-909. PubMed PMID: 20074453.

4: Arata S, Takada T, Hirata K, Yoshida M, Mayumi T, Hirota M, Yokoe M, Hirota M, Kiriyama S, Sekimoto M, Amano H, Wada K, Kimura Y, Gabata T, Takeda K, Kataoka K, Ito T, Tanaka M. Post-ERCP pancreatitis. J Hepatobiliary Pancreat Sci. 2010 Jan;17(1):70-8. Epub 2009 Dec 11. PubMed PMID: 20012323.

5: de Jonge WJ, The FO, Löwenberg M, Boeckxstaens GE. P38 MAPK inhibitor semapimod reduces postoperative ileus via peripheral and central mechanisms. Gastroenterology. 2009 May;136(5):1841-2; author reply 1842. Epub 2009 Mar 18. PubMed PMID: 19303016.

6: Wehner S, Straesser S, Vilz TO, Pantelis D, Sielecki T, de la Cruz VF, Hirner A, Kalff JC. Inhibition of p38 mitogen-activated protein kinase pathway as prophylaxis of postoperative ileus in mice. Gastroenterology. 2009 Feb;136(2):619-29. Epub 2008 Oct 9. PubMed PMID: 19014943.

7: Nishimatsu H, Suzuki E, Takeda R, Takahashi M, Oba S, Kimura K, Nagano T, Hirata Y. Blockade of endogenous proinflammatory cytokines ameliorates endothelial dysfunction in obese Zucker rats. Hypertens Res. 2008 Apr;31(4):737-43. PubMed PMID: 18633186.

8: Bacher M, Dodel R, Aljabari B, Keyvani K, Marambaud P, Kayed R, Glabe C, Goertz N, Hoppmann A, Sachser N, Klotsche J, Schnell S, Lewejohann L, Al-Abed Y. CNI-1493 inhibits Abeta production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease. J Exp Med. 2008 Jul 7;205(7):1593-9. Epub 2008 Jun 23. PubMed PMID: 18573905; PubMed Central PMCID: PMC2442637.

9: van Westerloo DJ, Rauws EA, Hommes D, de Vos AF, van der Poll T, Powers BL, Fockens P, Dijkgraaf MG, Bruno MJ. Pre-ERCP infusion of semapimod, a mitogen-activated protein kinases inhibitor, lowers post-ERCP hyperamylasemia but not pancreatitis incidence. Gastrointest Endosc. 2008 Aug;68(2):246-54. Epub 2008 May 2. PubMed PMID: 18455169.

10: Specht S, Sarite SR, Hauber I, Hauber J, Görbig UF, Meier C, Bevec D, Hoerauf A, Kaiser A. The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria-inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase. Parasitol Res. 2008 May;102(6):1177-84. Epub 2008 Feb 7. PubMed PMID: 18256853.

11: Oke SL, Tracey KJ. From CNI-1493 to the immunological homunculus: physiology of the inflammatory reflex. J Leukoc Biol. 2008 Mar;83(3):512-7. Epub 2007 Dec 7. Review. PubMed PMID: 18065685.

12: Chen P, Zhang Y, Qiao M, Yuan Y. Activated protein C, an anticoagulant polypeptide, ameliorates severe acute pancreatitis via regulation of mitogen-activated protein kinases. J Gastroenterol. 2007 Nov;42(11):887-96. Epub 2007 Nov 22. PubMed PMID: 18008033.

13: Löwenberg M. Proximal signaling molecules as potential targets for anti-inflammatory therapy. Curr Opin Drug Discov Devel. 2007 Sep;10(5):560-4. Review. PubMed PMID: 17786854.

14: Osterman MT, Lichtenstein GR. Current and Future Anti-TNF Therapy for Inflammatory Bowel Disease. Curr Treat Options Gastroenterol. 2007 Jun;10(3):195-207. PubMed PMID: 17547858.

15: Dewil M, dela Cruz VF, Van Den Bosch L, Robberecht W. Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death. Neurobiol Dis. 2007 May;26(2):332-41. Epub 2007 Feb 6. PubMed PMID: 17346981.

16: Bowman G, Bonneau RH, Chinchilli VM, Tracey KJ, Cockroft KM. A novel inhibitor of inflammatory cytokine production (CNI-1493) reduces rodent post-hemorrhagic vasospasm. Neurocrit Care. 2006;5(3):222-9. PubMed PMID: 17290094.

17: Danese S, Semeraro S, Armuzzi A, Papa A, Gasbarrini A. Biological therapies for inflammatory bowel disease: research drives clinics. Mini Rev Med Chem. 2006 Jul;6(7):771-84. Review. PubMed PMID: 16842127.

18: Singer AJ, McClain SA, Hacht G, Batchkina G, Simon M. Semapimod reduces the depth of injury resulting in enhanced re-epithelialization of partial-thickness burns in swine. J Burn Care Res. 2006 Jan-Feb;27(1):40-9. PubMed PMID: 16566536.

19: Abdalla H, Forslund T, Schön T, Stendahl O, Sundqvist T. Effects of CNI-1493 on human granulocyte functions. Immunobiology. 2006;211(3):191-7. Epub 2006 Feb 9. PubMed PMID: 16530086.

20: Jia YT, Wei D, Xia ZF, Tian JG. [Role of p38 mitogen-activated protein kinase in the pathogenesis of stress ulcer]. Zhonghua Wai Ke Za Zhi. 2005 Oct 1;43(19):1284-7. Chinese. PubMed PMID: 16271232.

21: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2005 May;27(4):265-84. PubMed PMID: 16082427.

22: Löwenberg M, Verhaar A, van den Blink B, ten Kate F, van Deventer S, Peppelenbosch M, Hommes D. Specific inhibition of c-Raf activity by semapimod induces clinical remission in severe Crohn's disease. J Immunol. 2005 Aug 15;175(4):2293-300. PubMed PMID: 16081798.

23: Zamora R, Grishin A, Wong C, Boyle P, Wang J, Hackam D, Upperman JS, Tracey KJ, Ford HR. High-mobility group box 1 protein is an inflammatory mediator in necrotizing enterocolitis: protective effect of the macrophage deactivator semapimod. Am J Physiol Gastrointest Liver Physiol. 2005 Oct;289(4):G643-52. Epub 2005 Jun 9. PubMed PMID: 15947118.

24: Takeda R, Suzuki E, Satonaka H, Oba S, Nishimatsu H, Omata M, Fujita T, Nagai R, Hirata Y. Blockade of endogenous cytokines mitigates neointimal formation in obese Zucker rats. Circulation. 2005 Mar 22;111(11):1398-406. PubMed PMID: 15781751.

25: Chen XL, Xia ZF, Wei D, Wang YJ, Wang CR. Involvement of the p38 mitogen-activated protein kinase signal transduction pathway in burns-induced lung injury. Chin Med J (Engl). 2005 Feb 20;118(4):329-32. PubMed PMID: 15740673.

26: Larsson E, Harris HE, Palmblad K, Månsson B, Saxne T, Klareskog L. CNI-1493, an inhibitor of proinflammatory cytokines, retards cartilage destruction in rats with collagen induced arthritis. Ann Rheum Dis. 2005 Mar;64(3):494-6. PubMed PMID: 15708902; PubMed Central PMCID: PMC1755383.

27: Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, Stitt AW. Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am J Pathol. 2005 Feb;166(2):637-44. PubMed PMID: 15681845; PubMed Central PMCID: PMC1602321.

28: Hauber I, Bevec D, Heukeshoven J, Krätzer F, Horn F, Choidas A, Harrer T, Hauber J. Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy. J Clin Invest. 2005 Jan;115(1):76-85. PubMed PMID: 15630446; PubMed Central PMCID: PMC539192.

29: Mullins GE, Sunden-Cullberg J, Johansson AS, Rouhiainen A, Erlandsson-Harris H, Yang H, Tracey KJ, Rauvala H, Palmblad J, Andersson J, Treutiger CJ. Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scand J Immunol. 2004 Dec;60(6):566-73. PubMed PMID: 15584967.

30: Kherani AR, Moss GW, Zhou H, Gu A, Zhang G, Schulman AR, Fal JM, Sorabella R, Plasse T, Rui L, Homma S, Burkhoff D, Oz MC, Wang J. Macrophage inhibitor, semapimod, reduces tumor necrosis factor-alpha in myocardium in a rat model of ischemic heart failure. J Cardiovasc Pharmacol. 2004 Dec;44(6):665-71. PubMed PMID: 15550785.

31: Zinser E, Turza N, Steinkasserer A. CNI-1493 mediated suppression of dendritic cell activation in vitro and in vivo. Immunobiology. 2004;209(1-2):89-97. PubMed PMID: 15481144.

32: Kurtovic J, Segal I. Recent advances in biological therapy for inflammatory bowel disease. Trop Gastroenterol. 2004 Jan-Mar;25(1):9-14. Review. PubMed PMID: 15303463.

33: Sommer MN, Bevec D, Klebl B, Flicke B, Hölscher K, Freudenreich T, Hauber I, Hauber J, Mett H. Screening assay for the identification of deoxyhypusine synthase inhibitors. J Biomol Screen. 2004 Aug;9(5):434-8. PubMed PMID: 15296643.

34: Rutgeerts P, Van Assche G, Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology. 2004 May;126(6):1593-610. Review. PubMed PMID: 15168370.

35: Toth LA, Hughes LF. Macrophage participation in influenza-induced sleep enhancement in C57BL/6J mice. Brain Behav Immun. 2004 Jul;18(4):375-89. PubMed PMID: 15157955.

36: Sitaraman SV, Hoteit M, Gewirtz AT. Semapimod. Cytokine. Curr Opin Investig Drugs. 2003 Nov;4(11):1363-8. Review. PubMed PMID: 14758776.

37: Milligan ED, O'Connor KA, Armstrong CB, Hansen MK, Martin D, Tracey KJ, Maier SF, Watkins LR. Systemic administration of CNI-1493, a p38 mitogen-activated protein kinase inhibitor, blocks intrathecal human immunodeficiency virus-1 gp120-induced enhanced pain states in rats. J Pain. 2001 Dec;2(6):326-33. PubMed PMID: 14622812.

38: Waetzig GH, Rosenstiel P, Nikolaus S, Seegert D, Schreiber S. Differential p38 mitogen-activated protein kinase target phosphorylation in responders and nonresponders to infliximab. Gastroenterology. 2003 Aug;125(2):633-4; author reply 635-6. PubMed PMID: 12891581.

39: Sandborn WJ. Strategies for targeting tumour necrosis factor in IBD. Best Pract Res Clin Gastroenterol. 2003 Feb;17(1):105-17. Review. PubMed PMID: 12617886.

40: Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci. 2003 Feb 1;23(3):1026-40. PubMed PMID: 12574433.

41: Giallourakis C. Lowering the stress of inflammatory bowel disease. Inflamm Bowel Dis. 2002 Sep;8(5):370-1. PubMed PMID: 12479654.

42: Bayes M, Rabasseda X, Prous JR. Gateways to Clinical Trials. Methods Find Exp Clin Pharmacol. 2002 Apr;24(3):159-84. Review. PubMed PMID: 12087878.

43: Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, Sudan S, Czura CJ, Ivanova SM, Tracey KJ. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med. 2002 Mar 18;195(6):781-8. PubMed PMID: 11901203; PubMed Central PMCID: PMC2193742.

44: Hommes D, van den Blink B, Plasse T, Bartelsman J, Xu C, Macpherson B, Tytgat G, Peppelenbosch M, Van Deventer S. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease. Gastroenterology. 2002 Jan;122(1):7-14. PubMed PMID: 11781274.

45: Atkins MB, Redman B, Mier J, Gollob J, Weber J, Sosman J, MacPherson BL, Plasse T. 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. Clin Cancer Res. 2001 Mar;7(3):486-92. PubMed PMID: 11297238.

46: Borovikova LV, Ivanova S, Nardi D, Zhang M, Yang H, Ombrellino M, Tracey KJ. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton Neurosci. 2000 Dec 20;85(1-3):141-7. PubMed PMID: 11189021.

47: Palmblad K, Erlandsson-Harris H, Tracey KJ, Andersson U. Dynamics of early synovial cytokine expression in rodent collagen-induced arthritis : a therapeutic study using a macrophage-deactivating compound. Am J Pathol. 2001 Feb;158(2):491-500. PubMed PMID: 11159186; PubMed Central PMCID: PMC1850288.

48: Rutkowski MD, Pahl JL, Sweitzer S, van Rooijen N, DeLeo JA. Limited role of macrophages in generation of nerve injury-induced mechanical allodynia. Physiol Behav. 2000 Nov 1-15;71(3-4):225-35. PubMed PMID: 11150554.

49: Granert C, Abdalla H, Lindquist L, Diab A, Bahkiet M, Tracey KJ, Andersson J. Suppression of macrophage activation with CNI-1493 increases survival in infant rats with systemic Haemophilus influenzae infection. Infect Immun. 2000 Sep;68(9):5329-34. Erratum in: Infect Immun 2002 Aug;70(8):4754. PubMed PMID: 10948162; PubMed Central PMCID: PMC101796.

50: Denham W, Yang J, Wang H, Botchkina G, Tracey KJ, Norman J. Inhibition of p38 mitogen activate kinase attenuates the severity of pancreatitis-induced adult respiratory distress syndrome. Crit Care Med. 2000 Jul;28(7):2567-72. PubMed PMID: 10921596.

51: Mendez C, Jaffray C, Wong V, Salhab KF, Kramer AA, Carey LC, Norman JG. Involvement of p38 mitogen-activated protein kinase in the induction of tolerance to hemorrhagic and endotoxic shock. J Surg Res. 2000 Jun 15;91(2):165-70. PubMed PMID: 10839967.

52: Jaffray C, Yang J, Norman J. Elastase mimics pancreatitis-induced hepatic injury via inflammatory mediators. J Surg Res. 2000 May 15;90(2):95-101. PubMed PMID: 10792947.

53: Milligan ED, Mehmert KK, Hinde JL, Harvey LO, Martin D, Tracey KJ, Maier SF, Watkins LR. Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein, gp120. Brain Res. 2000 Apr 7;861(1):105-16. PubMed PMID: 10751570.

54: D'Souza MJ, Oettinger CW, Milton GV, Tracey KJ. Prevention of lethality and suppression of proinflammatory cytokines in experimental septic shock by microencapsulated CNI-1493. J Interferon Cytokine Res. 1999 Oct;19(10):1125-33. PubMed PMID: 10547152.

55: Mendez C, Kramer AA, Salhab KF, Valdes GA, Norman JG, Tracey KJ, Carey LC. Tolerance to shock: an exploration of mechanism. Ann Surg. 1999 Jun;229(6):843-9; discussion 849-50. PubMed PMID: 10363898; PubMed Central PMCID: PMC1420831.

56: Kramer AA, Postler G, Salhab KF, Mendez C, Carey LC, Rabb H. Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int. 1999 Jun;55(6):2362-7. PubMed PMID: 10354283.

57: Hunt AE, Lali FV, Lord JD, Nelson BH, Miyazaki T, Tracey KJ, Foxwell BM. Role of interleukin (IL)-2 receptor beta-chain subdomains and Shc in p38 mitogen-activated protein (MAP) kinase and p54 MAP kinase (stress-activated protein Kinase/c-Jun N-terminal kinase) activation. IL-2-driven proliferation is independent of p38 and p54 MAP kinase activation. J Biol Chem. 1999 Mar 12;274(11):7591-7. PubMed PMID: 10066828.

58: kerlund K, Erlandsson Harris H, Tracey KJ, Wang H, Fehniger T, Klareskog L, Andersson J, Andersson U. Anti-inflammatory effects of a new tumour necrosis factor-alpha (TNF-alpha) inhibitor (CNI-1493) in collagen-induced arthritis (CIA) in rats. Clin Exp Immunol. 1999 Jan;115(1):32-41. PubMed PMID: 9933418; PubMed Central PMCID: PMC1905187.

59: Molina PE, Qian L, Schuhlein D, Naukam R, Wang H, Tracey KJ, Abumrad NN. CNI-1493 attenuates hemodynamic and pro-inflammatory responses to LPS. Shock. 1998 Nov;10(5):329-34. PubMed PMID: 9840647.

60: Wang H, Zhang M, Bianchi M, Sherry B, Sama A, Tracey KJ. Fetuin (alpha2-HS-glycoprotein) opsonizes cationic macrophagedeactivating molecules. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14429-34. PubMed PMID: 9826717; PubMed Central PMCID: PMC24390.

61: Yang J, Denham W, Carter G, Tracey KJ, Norman J. Macrophage pacification reduces rodent pancreatitis-induced hepatocellular injury through down-regulation of hepatic tumor necrosis factor alpha and interleukin-1beta. Hepatology. 1998 Nov;28(5):1282-8. PubMed PMID: 9794913.

62: Yang J, Denham W, Tracey KJ, Wang H, Kramer AA, Salhab KF, Norman J. The physiologic consequences of macrophage pacification during severe acute pancreatitis. Shock. 1998 Sep;10(3):169-75. PubMed PMID: 9744644.

63: Yang X, Szabolcs M, Minanov O, Ma N, Sciacca RR, Bianchi M, Tracey KJ, Michler RE, Cannon PJ. CNI-1493 prolongs survival and reduces myocyte loss, apoptosis, and inflammation during rat cardiac allograft rejection. J Cardiovasc Pharmacol. 1998 Jul;32(1):146-55. PubMed PMID: 9676735.

64: Faist E, Kim C. Therapeutic immunomodulatory approaches for the control of systemic inflammatory response syndrome and the prevention of sepsis. New Horiz. 1998 May;6(2 Suppl):S97-102. Review. PubMed PMID: 9654318.

65: Martiney JA, Rajan AJ, Charles PC, Cerami A, Ulrich PC, Macphail S, Tracey KJ, Brosnan CF. Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent. J Immunol. 1998 Jun 1;160(11):5588-95. PubMed PMID: 9605164.

66: Kemeny MM, Botchkina GI, Ochani M, Bianchi M, Urmacher C, Tracey KJ. The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4561-6. PubMed PMID: 9539777; PubMed Central PMCID: PMC22529.

67: Tracey KJ. Suppression of TNF and other proinflammatory cytokines by the tetravalent guanylhydrazone CNI-1493. Prog Clin Biol Res. 1998;397:335-43. Review. PubMed PMID: 9575574.

68: Hyon SH, Tracey KJ, Kaufman DB. Specific inhibition of macrophage-derived proinflammatory cytokine synthesis with a tetravalent guanylhydrazone CNI-1493 accelerates early islet graft function posttransplant. Transplant Proc. 1998 Mar;30(2):409-10. PubMed PMID: 9532103.

69: Amiot F, Fitting C, Tracey KJ, Cavaillon JM, Dautry F. Lipopolysaccharide-induced cytokine cascade and lethality in LT alpha/TNF alpha-deficient mice. Mol Med. 1997 Dec;3(12):864-75. PubMed PMID: 9440119; PubMed Central PMCID: PMC2230288.

70: Denham W, Fink G, Yang J, Ulrich P, Tracey K, Norman J. Small molecule inhibition of tumor necrosis factor gene processing during acute pancreatitis prevents cytokine cascade progression and attenuates pancreatitis severity. Am Surg. 1997 Dec;63(12):1045-9; discussion 1049-50. PubMed PMID: 9393251.

71: Meistrell ME 3rd, Botchkina GI, Wang H, Di Santo E, Cockroft KM, Bloom O, Vishnubhakat JM, Ghezzi P, Tracey KJ. Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia. Shock. 1997 Nov;8(5):341-8. PubMed PMID: 9361344.

72: Björk L, Tracey KJ, Ulrich P, Bianchi M, Cohen PS, Akerlund K, Fehniger TE, Andersson U, Andersson J. Targeted suppression of cytokine production in monocytes but not in T lymphocytes by a tetravalent guanylhydrazone (CNI-1493). J Infect Dis. 1997 Nov;176(5):1303-12. PubMed PMID: 9359732.

73: Watkins LR, Martin D, Ulrich P, Tracey KJ, Maier SF. Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain. 1997 Jul;71(3):225-35. PubMed PMID: 9231865.

74: Cohen PS, Schmidtmayerova H, Dennis J, Dubrovsky L, Sherry B, Wang H, Bukrinsky M, Tracey KJ. The critical role of p38 MAP kinase in T cell HIV-1 replication. Mol Med. 1997 May;3(5):339-46. PubMed PMID: 9205949; PubMed Central PMCID: PMC2230081.

75: Cohen PS, Nakshatri H, Dennis J, Caragine T, Bianchi M, Cerami A, Tracey KJ. CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3967-71. PubMed PMID: 8632999; PubMed Central PMCID: PMC39469.

76: Bianchi M, Bloom O, Raabe T, Cohen PS, Chesney J, Sherry B, Schmidtmayerova H, Calandra T, Zhang X, Bukrinsky M, Ulrich P, Cerami A, Tracey KJ. Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone. J Exp Med. 1996 Mar 1;183(3):927-36. PubMed PMID: 8642296; PubMed Central PMCID: PMC2192362.

77: Cerami C, Zhang X, Ulrich P, Bianchi M, Tracey KJ, Berger BJ. High-performance liquid chromatographic method for guanylhydrazone compounds. J Chromatogr B Biomed Appl. 1996 Jan 12;675(1):71-5. PubMed PMID: 8634770.

78: Bianchi M, Ulrich P, Bloom O, Meistrell M 3rd, Zimmerman GA, Schmidtmayerova H, Bukrinsky M, Donnelley T, Bucala R, Sherry B, et al. An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality. Mol Med. 1995 Mar;1(3):254-66. PubMed PMID: 8529104; PubMed Central PMCID: PMC2229913.