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Roquinimex

Description of roquinimex: Roquinimex is a quinoline-3-carboxamide with potential antineoplastic activity. Roquinimex inhibits endothelial cell proliferation, migration, and basement membrane invasion; reduces the secretion of the angiogenic factor tumor necrosis factor alpha by tumor-associated macrophages (TAMs); and inhibits angiogenesis. This agent is also an immune modulator that appears to alter cytokine profiles and enhance the activity of T cells, natural killer cells, and macrophages. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:     Pfizer Inc.

Roquinimex (Linomide) is a quinoline derivative immunostimulant which increases NK cell activity and macrophage cytotoxicity. It also inhibits angiogenesis and reduces the secretion of TNF alpha. Roquinimex has been investigated as a treatment for some cancers (including as adjuvant therapy after bone marrow transplantation in acute leukemia) and autoimmune diseases, such as multiple sclerosis and recent-onset type I diabetes. Several trials have been terminated due to serious cardiovascular toxicity. (source: http://en.wikipedia.org/wiki/Roquinimex).

  1: Xiao ZY, Zhou WX, Zhang YX, Cheng JP, He JF, Yang RF, Yun LH. Inhibitory effect of linomide on lipopolysaccharide-induced proinflammatory cytokine tumor necrosis factor-alpha production in RAW264.7 macrophages through suppression of NF-kappaB, p38, and JNK activation. Immunol Lett. 2007 Dec 15;114(2):81-5. Epub 2007 Oct 1. PubMed PMID: 17964662.

2: Xiao ZY, Zhou WX, Zhang YX, Cheng JP, He JF, Yang RF, Yun LH. Roquinimex-mediated protection effect on the development of chronic graft-versus-host disease in mice is associated with induction of Th1 cytokine production and inhibition of proinflammatory cytokine production. Life Sci. 2007 Oct 27;81(19-20):1403-10. Epub 2007 Sep 29. PubMed PMID: 17950363.

3: Isaacs JT, Pili R, Qian DZ, Dalrymple SL, Garrison JB, Kyprianou N, Björk A, Olsson A, Leanderson T. Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer. Prostate. 2006 Dec 1;66(16):1768-78. PubMed PMID: 16955399.

4: Peltoniemi J, Broberg EK, Nygårdas M, Erälinna JP, Waris M, Hukkanen V. Enhancement of Th2 responses to replicative herpes simplex virus type 1 vectors by immunomodulative chemotherapy. Int Immunopharmacol. 2006 May;6(5):817-29. Epub 2006 Jan 4. PubMed PMID: 16546713.

5: He JF, Yun LH, Yang RF, Xiao ZY, Cheng JP, Zhou WX, Zhang YX. Design, synthesis, and biological evaluation of novel 4-hydro-quinoline-3-carboxamide derivatives as an immunomodulator. Bioorg Med Chem Lett. 2005 Jun 15;15(12):2980-5. PubMed PMID: 15908212.

6: Abdul-Hai A, Hershkoviz R, Weiss L, Lider O, Slavin S. Effect of Linomide on adhesion molecules, TNF-alpha, nitrogen oxide, and cell adhesion. Int Immunopharmacol. 2005 Feb;5(2):231-9. PubMed PMID: 15652754.

7: Li X, Klintman D, Sato T, Hedlund G, Schramm R, Jeppsson B, Thorlacius H. Interleukin-10 mediates the protective effect of Linomide by reducing CXC chemokine production in endotoxin-induced liver injury. Br J Pharmacol. 2004 Dec;143(7):865-71. Epub 2004 Oct 18. PubMed PMID: 15492015; PubMed Central PMCID: PMC1575945.

8: Yang JS, Xu LY, Xiao BG, Hedlund G, Link H. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol. 2004 Nov;156(1-2):3-9. PubMed PMID: 15465591.

9: Peltoniemi J, Broberg EK, Halenius A, Setala N, Eralinna JP, Salmi AA, Roytta M, Hukkanen V. Immunomodulation by roquinimex decreases the expression of IL-23 (p19) mRNA in the brains of herpes simplex virus type 1 infected BALB/c mice. Clin Exp Immunol. 2004 Aug;137(2):305-12. PubMed PMID: 15270847; PubMed Central PMCID: PMC1809122.

10: Jönsson S, Andersson G, Fex T, Fristedt T, Hedlund G, Jansson K, Abramo L, Fritzson I, Pekarski O, Runström A, Sandin H, Thuvesson I, Björk A. Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship. J Med Chem. 2004 Apr 8;47(8):2075-88. PubMed PMID: 15056005.

11: Lindberg P, Billström A, Kinnby B. Reduced gingival fluid flow: a peripheral marker of the pharmacological effect of roquinimex. Inflammopharmacology. 2003;11(3):267-76. PubMed PMID: 15035809.

12: Liu Q, Klintman D, Corbascio M, Ekberg H, Hedlund G, Forsberg G, Thorlacius H. Linomide and antibody-targeted superantigen therapy abolishes formation of liver metastases in mice. Eur Surg Res. 2003 Nov-Dec;35(6):457-63. PubMed PMID: 14593228.

13: Ivarsson K, Sturesson C, Stenram U, Tranberg KG. Linomide improves the effect of interstitial laser thermotherapy in a rat liver tumour model. Anticancer Res. 2003 Mar-Apr;23(2B):1257-63. PubMed PMID: 12820380.

14: Liu Q, Wang Y, Wan MX, Zhang XW, Andersson G, Hedlund G, Thorlacius H. Roquinimex inhibits dextran sodium sulfate-induced murine colitis. Inflamm Res. 2003 Feb;52(2):64-8. PubMed PMID: 12665123.

15: Shi J, Xiao Z, Ihnat MA, Kamat C, Pandit B, Hu Z, Li PK. Structure-activity relationships studies of the anti-angiogenic activities of linomide. Bioorg Med Chem Lett. 2003 Mar 24;13(6):1187-9. PubMed PMID: 12643940.

16: Dahlén E, Dawe K, Ohlsson L, Hall H, Hedse K, Annersten K, Aström M, Gross DJ, Hedlund G. Linomide inhibits insulitis and modulates cytokine production in pancreatic islets in the nonobese diabetic mouse. Int Immunopharmacol. 2003 Jan;3(1):17-30. PubMed PMID: 12538031.

17: Weiss L, Abdul-Hai A, Shufaro Y, Reich S, Slavin S. Linomide administration following bone marrow transplantation in mice. Cancer Immunol Immunother. 2002 Dec;51(11-12):596-602. Epub 2002 Sep 27. PubMed PMID: 12439604.

18: Peltoniemi J, Setälä N, Broberg E, Röyttä M, Hukkanen V, Salmi AA, Erälinna JP. Semliki Forest virus infection is enhanced in Th1-prone SJL mice but not in Th2-prone BALB/c mice during Linomide-induced immunomodulation. J Neuroimmunol. 2002 Nov;132(1-2):83-92. PubMed PMID: 12417437.

19: Osterberg J, Haglund U. Effect of linomide on gut immune cell distribution and on TNF-alpha in plasma and ascites: an experimental study in the septic rat. Shock. 2002 Nov;18(5):471-5. PubMed PMID: 12412629.

20: Brunmark C, Runström A, Ohlsson L, Sparre B, Brodin T, Aström M, Hedlund G. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2002 Sep;130(1-2):163-72. PubMed PMID: 12225898.

21: Weiss L, Barak V, Zeira M, Abdul-Hai A, Raibstein I, Reich S, Hirschfeld E, Gross D, Slavin S. Cytokine production in Linomide-treated nod mice and the potential role of a Th (1)/Th(2) shift on autoimmune and anti-inflammatory processes. Cytokine. 2002 Jul 21;19(2):85-93. PubMed PMID: 12182843.

22: Wiendl H, Hohlfeld R. Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials. BioDrugs. 2002;16(3):183-200. Review. PubMed PMID: 12102646.

23: Zou LP, Abbas N, Volkmann I, Nennesmo I, Levi M, Wahren B, Winblad B, Hedlund G, Zhu J. Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue. Neuropharmacology. 2002 Apr;42(5):731-9. PubMed PMID: 11985832.

24: Baxter AG, Smyth MJ. The role of NK cells in autoimmune disease. Autoimmunity. 2002 Feb;35(1):1-14. Review. PubMed PMID: 11908701.

25: Klintman D, Hedlund G, Thorlacius H. Protective effect of Linomide on TNF-alpha-induced hepatic injury. J Hepatol. 2002 Feb;36(2):226-32. PubMed PMID: 11830334.

26: Gross DJ, Weiss L, Reibstein I, Hedlund G, Dahlén E, Rapoport MJ, Slavin S. The immunomodulator Linomide: role in treatment and prevention of autoimmune diabetes mellitus. Int Immunopharmacol. 2001 Jun;1(6):1131-9. Review. PubMed PMID: 11407307.

27: Hedlund G, Link H, Zhu J, Xiao BG. Effects of Linomide on immune cells and cytokines inhibit autoimmune pathologies of the central and peripheral nervous system. Int Immunopharmacol. 2001 Jun;1(6):1123-30. Review. PubMed PMID: 11407306.

28: Vougioukas VI, Siebert H, Heinecke K, Brück W. Effects of the immunomodulator linomide on macrophage migration and myelin phagocytic activity in peripheral nerve trauma: an experimental study. J Neurotrauma. 2001 May;18(5):555-62. PubMed PMID: 11393258.

29: Collin X, Robert JM, Duflos M, Wielgosz G, Le Baut G, Bobin-Dubigeon C, Grimaud N, Lang F, Petit JY. Synthesis of N-pyridinyl(methyl)-1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides and analogues and their anti-inflammatory activity in mice and rats. J Pharm Pharmacol. 2001 Mar;53(3):417-23. Erratum in: J Pharm Pharmacol 2001 Dec;53(12):1729. Robin-Dubigeon C [corrected to Bobin-Dubigeon C]. PubMed PMID: 11291760.

30: Hartoft-Nielsen ML, Rasmussen AK, Kaas A, Bock T, Buschard K, Feldt-Rasmussen U. Linomide does not prevent spontaneous autoimmune thyroiditis in NOD mice. Autoimmunity. 2001;33(2):79-84. PubMed PMID: 11264786.

31: Khan SR, Mhaka A, Pili R, Isaacs JT. Modified synthesis and antiangiogenic activity of linomide. Bioorg Med Chem Lett. 2001 Feb 26;11(4):451-2. PubMed PMID: 11229745.

32: Whitaker JN, Wolinsky JS, Narayana PA, Bartolucci AA, Noseworthy JH, Lublin FD, Linde A, Gjörstrup P, Sullivan HC; North American Linomide Investigators. Relationship of urinary myelin basic protein-like material with cranial magnetic resonance imaging in advanced multiple sclerosis. Arch Neurol. 2001 Jan;58(1):49-54. PubMed PMID: 11176936.

33: Strandgården K, Höglund P, Grönquist L, Svensson L, Gunnarsson PO. Absorption and disposition including enterohepatic circulation of (14C) roquinimex after oral administration to healthy volunteers. Biopharm Drug Dispos. 2000 Mar;21(2):53-67. PubMed PMID: 11100907.

34: Dahlén E, Andersson M, Dawe K, Tellander AC, Brunmark C, Björk A, Hedlund G. Inhibition of autoimmune disease by the immunomodulator linomide correlates with the ability to activate macrophages. Autoimmunity. 2000 Oct;32(3):199-211. PubMed PMID: 11092700.

35: Zhang XW, Hedlund G, Borgström P, Arfors KE, Thorlacius H. Linomide abolishes leukocyte adhesion and extravascular recruitment induced by tumor necrosis factor alpha in vivo. J Leukoc Biol. 2000 Nov;68(5):621-6. PubMed PMID: 11073099.

36: Tuvesson H, Wienkers LC, Gunnarsson PO, Seidegård J, Persson R. Identification of cytochrome P4503A as the major subfamily responsible for the metabolism of roquinimex in man. Xenobiotica. 2000 Sep;30(9):905-14. PubMed PMID: 11055268.

37: Ohsuga Y, Rowe JM, Liesveld J, Burns RP, Gaspari AA. Dermatologic changes associated with roquinimex immunotherapy after autologous bone marrow transplant. J Am Acad Dermatol. 2000 Sep;43(3):437-41. PubMed PMID: 10954654.

38: Simonsson B, Tötterman T, Hokland P, Lauria F, Carella AM, Fernandez MN, Rozman C, Ferrant A, de Witte T, Zander AR, Meier K, Hansson F, Nilsson BI. Roquinimex (Linomide) vs placebo in AML after autologous bone marrow transplantation. Bone Marrow Transplant. 2000 Jun;25(11):1121-7. PubMed PMID: 10849523.

39: Tuvesson H, Strandgården K, Nordle O, Gunnarsson PO, Seidegård J, Persson R. Metabolism of roquinimex in mouse and rat: an in vitro/in vivo comparison. Xenobiotica. 2000 Apr;30(4):371-80. PubMed PMID: 10821166.

40: Wolinsky JS, Narayana PA, Noseworthy JH, Lublin FD, Whitaker JN, Linde A, Gjörstrup P, Sullivan HC. Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators. Neurology. 2000 May 9;54(9):1734-41. PubMed PMID: 10802777.

41: Noseworthy JH, Wolinsky JS, Lublin FD, Whitaker JN, Linde A, Gjorstrup P, Sullivan HC. Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators. Neurology. 2000 May 9;54(9):1726-33. PubMed PMID: 10802775.

42: Schwid SR, Trotter JL. Lessons from linomide: a failed trial, but not a failure. Neurology. 2000 May 9;54(9):1716-7. PubMed PMID: 10802772.

43: Tan IL, Lycklama à Nijeholt GJ, Polman CH, Adèr HJ, Barkhof F. Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials. Mult Scler. 2000 Apr;6(2):99-104. PubMed PMID: 10773855.

44: Bex A, Luboldt H, Sudermann T, Rembrink K, Otto T, Rübben H. Influence of linomide on local tumor growth and metastasis of the human hormone-resistant prostate cancer cell line PC3 in an orthotopic model. Eur Urol. 2000 May;37(5):628-33. PubMed PMID: 10765105.

45: Strandgârden K, Höglund P, Nordle O, Polacek J, Wännman H, Gunnarsson PO. Dissolution rate-limited absorption and complete bioavailability of roquinimex in man. Biopharm Drug Dispos. 1999 Oct;20(7):347-54. PubMed PMID: 10760843.

46: Shalev M, Ko A, Gelderman MP, Fortin E, Reed G, Slavin S, Gery I. Multiformic modulation of endotoxin effects by linomide. Clin Immunol. 1999 Dec;93(3):250-5. PubMed PMID: 10600336.

47: Cazzato G, Antonello RM, Zorzon M, Torre P, Zivadinov R, Moretti R, Bragadin LM, De Masi R, Nasuelli D. [Treatment of multiple sclerosis. The present and the future. Study Group on Diagnosis and Therapy of Multiple Sclerosis]. Recenti Prog Med. 1999 Oct;90(10):538-44. Review. Italian. PubMed PMID: 10592740.

48: Gross DJ, Reibstein I, Weiss L, Slavin S, Stein I, Neeman M, Abramovitch R, Benjamin LE. The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice. Clin Cancer Res. 1999 Nov;5(11):3669-75. PubMed PMID: 10589785.

49: Rowe JM, Rapoport AP, Ryan DH, Nilsson BI, Duerst RE, Packman CH, Abboud CN, DiPersio JF, Linder T, Wang N, Simonsson B, Liesveld JL. Treatment of chronic myelogenous leukemia with autologous bone marrow transplantation followed by roquinimex. Bone Marrow Transplant. 1999 Nov;24(10):1057-63. PubMed PMID: 10578155.

50: Hokland M, Jørgensen H, Holm MS, Simonsson B, Nilsson B, Bengtsson M, Hokland P. Natural effector cells in patients with acute myeloid leukemia treated with the immunomodulator Linomide after autologous bone marrow transplantation. Eur J Haematol. 1999 Oct;63(4):251-8. PubMed PMID: 10530414.

51: Qi Z, Tufveson G, Ekberg H. Tolerance or rejection: A delicate balance as judged by exposure of heart-transplanted rats to the immunomodulator Linomide. Scand J Immunol. 1999 Oct;50(4):394-8. PubMed PMID: 10520179.

52: Kremer S, Breuer R, Lossos IS, Berkman N, Christensen TG, Connor MW, Goldstein RH, Or R. Effect of immunomodulators on bleomycin-induced lung injury. Respiration. 1999;66(5):455-62. PubMed PMID: 10516543.

53: Vroegop SM, Chapman DL, Galinet LA, Decker DE, Ready KA, Brideau RJ, Dunn CJ, Buxser SE. Pharmacology of the biological response modifier bropirimine (PNU-54461) on experimental autoimmune encephalomyelitis (EAE) in mice. Int J Immunopharmacol. 1999 Jun;21(6):391-409. PubMed PMID: 10405874.

54: Karussis D, Abramsky O, Rosenthal Y, Mizrachi-Koll R, Ovadia H. Linomide downregulates autoimmunity through induction of TH2 cytokine production by lymphocytes. Immunol Lett. 1999 Apr 15;67(3):203-8. PubMed PMID: 10369127.

55: Pollard M. Prevention of prostate-related cancers in Lobund-Wistar rats. Prostate. 1999 Jun 1;39(4):305-9. PubMed PMID: 10344221.

56: Dabrowska A, Golab J, Giermasz A, Marczak M, Jakóbisiak M. Re: Macrophage role in the anti-prostate cancer response to one class of antiangiogenic agents. J Natl Cancer Inst. 1999 May 5;91(9):804-6. PubMed PMID: 10328115.

57: Guttmann CR, Kikinis R, Anderson MC, Jakab M, Warfield SK, Killiany RJ, Weiner HL, Jolesz FA. Quantitative follow-up of patients with multiple sclerosis using MRI: reproducibility. J Magn Reson Imaging. 1999 Apr;9(4):509-18. PubMed PMID: 10232508.

58: Hutchings P, Hedlund G, Dawe K, Howlett S, Cooke A. Effect of the synthetic immunomodulator, linomide, on experimental models of thyroiditis. Immunology. 1999 Mar;96(3):340-7. PubMed PMID: 10233714; PubMed Central PMCID: PMC2326756.

59: Zbar B, Kaelin W, Maher E, Richard S. Third International Meeting on von Hippel-Lindau disease. Cancer Res. 1999 May 1;59(9):2251-3. PubMed PMID: 10232616.

60: Olausson M, Lukes D, Norrby J, Qi Z, Ekberg H, Gannedahl G, Tufveson G, Mjörnstedt L. Antithymocyte globulin and cyclosporin A are synergistic in an experimental transplantation tolerance model in the rat. Scand J Immunol. 1999 Jan;49(1):38-44. PubMed PMID: 10023855.

61: Zhu J, Bai XF, Hedlund G, Björk J, Bakhiet M, Van Der Meide PH, Link H. Linomide suppresses experimental autoimmune neuritis in Lewis rats by inhibiting myelin antigen-reactive T and B cell responses. Clin Exp Immunol. 1999 Jan;115(1):56-63. PubMed PMID: 9933420; PubMed Central PMCID: PMC1905200.

62: Pekarski O, Björk J, Hedlund G, Andersson G. The inhibitory effect in experimental autoimmune encephalomyelitis by the immunomodulatory drug Linomide (PNU-212616) is not mediated via release of endogenous glucocorticoids. Autoimmunity. 1998;28(4):235-41. PubMed PMID: 9892505.

63: Arbel I, Chezen E, Abramsky O, Karpati T, Ovadia H, Mizrachi-Koll R, Karussis D. Linomide induces apoptotic death of cortical CD4/CD8 double positive thymocytes and thymic atrophy by a corticosteroid-independent pathway. Clin Immunol. 1999 Jan;90(1):108-14. PubMed PMID: 9884358.

64: Mackean MJ, Kerr D, Lesko M, Svedberg A, Hansson F, Jodrell D, Cassidy J. A feasibility study of roquinimex (Linomide) and alpha interferon in patients with advanced malignant melanoma or renal carcinoma. Br J Cancer. 1998 Dec;78(12):1620-3. PubMed PMID: 9862573; PubMed Central PMCID: PMC2063243.

65: Zhu J, Diab A, Mustafa M, Levi M, Wahren B, Björk J, Hedlund G. Linomide suppresses chronic-relapsing experimental autoimmune encephalomyelitis in DA rats. J Neurol Sci. 1998 Oct 8;160(2):113-20. PubMed PMID: 9849793.

66: Karpati T, Karussis D, Abramsky O, Mizrahi-Koll R, Arbell I, Ovadia H. Inhibition of experimental autoimmune neuritis by the immunomodulator linomide. Immunol Lett. 1998 Oct;63(3):141-5. PubMed PMID: 9840682.

67: Joseph IB, Isaacs JT. Macrophage role in the anti-prostate cancer response to one class of antiangiogenic agents. J Natl Cancer Inst. 1998 Nov 4;90(21):1648-53. PubMed PMID: 9811314.

68: Wahl LM, Kleinman HK. Tumor-associated macrophages as targets for cancer therapy. J Natl Cancer Inst. 1998 Nov 4;90(21):1583-4. PubMed PMID: 9811301.

69: Coutant R, Landais P, Rosilio M, Johnsen C, Lahlou N, Chatelain P, Carel JC, Ludvigsson J, Boitard C, Bougnères PF. Low dose linomide in Type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial. Diabetologia. 1998 Sep;41(9):1040-6. PubMed PMID: 9754822.

70: Tian WZ, Navikas V, Matusevicius D, Söderström M, Fredrikson S, Hedlund G, Link H. Linomide (roquinimex) affects the balance between pro- and anti-inflammatory cytokines in vitro in multiple sclerosis. Acta Neurol Scand. 1998 Aug;98(2):94-101. PubMed PMID: 9724006.

71: Erälinna JP, Röyttä M, Hukkanen V, Zinhu D, Salmi AA, Salonen R. Selective downregulation of Th1 response by Linomide reduces autoimmunity but increases susceptibility to viral infection in BALB/c and SJL mice. J Neuroimmunol. 1998 Aug 1;88(1-2):165-76. PubMed PMID: 9688338.

72: Drescher KM, Rivera-Quinones C, Lucchinetti CF, Rodriguez M. Failure of treatment with Linomide or oral myelin tolerization to ameliorate demyelination in a viral model of multiple sclerosis. J Neuroimmunol. 1998 Aug 1;88(1-2):111-9. PubMed PMID: 9688332.

73: Xiao BG, Bail XF, Zhang GX, Hedlund G, Link H. Linomide-mediated protection of oligodendrocytes is associated with inhibition of nitric oxide production and IL-1beta expression in Lewis rat glial cells. Neurosci Lett. 1998 Jun 12;249(1):17-20. PubMed PMID: 9672378.

74: Zhang GX, Yu LY, Shi FD, Xiao BG, Björk J, Hedlund G, Link H. Cytokine profiles of experimental autoimmune myasthenia gravis after treatment by the synthetic immunomodulator linomide. Ann N Y Acad Sci. 1998 May 13;841:580-3. PubMed PMID: 9668300.

75: Nagler A, Feferman R, Shoshan S. Reduction in basic fibroblast growth factor mediated angiogenesis in vivo by linomide. Connect Tissue Res. 1998;37(1-2):61-8. PubMed PMID: 9643647.

76: Ekström PA, Hedlund G, Karlsson J, Andersson G. The immune modulator Linomide prevents neuronal death in injured peripheral nerves of the mouse. Neuroreport. 1998 May 11;9(7):1337-41. PubMed PMID: 9631425.

77: del Real G, Llorente M, Boscá L, Hortelano S, Serrano A, Lucas P, Gómez L, Torán JL, Redondo C, Martínez C. Suppression of HIV-1 infection in linomide-treated SCID-hu-PBL mice. AIDS. 1998 May 28;12(8):865-72. PubMed PMID: 9631139.

78: Diab A, Michael L, Wahren B, Deng GM, Björk J, Hedlund G, Zhu J. Linomide suppresses acute experimental autoimmune encephalomyelitis in Lewis rats by counter-acting the imbalance of pro-inflammatory versus anti-inflammatory cytokines. J Neuroimmunol. 1998 May 15;85(2):146-54. PubMed PMID: 9630163.

79: Shaw M, Ratanawong S, Chou P, Ray V, Mirochnik Y, Slobodskoy L, Rubenstein M, Guinan P. Paclitaxel, bropirimine and linomide: effect on growth inhibition in a murine prostate cancer model by different growth regulatory mechanisms. Methods Find Exp Clin Pharmacol. 1998 Mar;20(2):111-4. PubMed PMID: 9604852.

80: Gross DJ, Weiss L, Reibstein I, van den Brand J, Okamoto H, Clark A, Slavin S. Amelioration of diabetes in nonobese diabetic mice with advanced disease by linomide-induced immunoregulation combined with Reg protein treatment. Endocrinology. 1998 May;139(5):2369-74. PubMed PMID: 9564847.

81: Ziche M, Donnini S, Morbidelli L, Parenti A, Gasparini G, Ledda F. Linomide blocks angiogenesis by breast carcinoma vascular endothelial growth factor transfectants. Br J Cancer. 1998 Apr;77(7):1123-9. PubMed PMID: 9569049; PubMed Central PMCID: PMC2150124.

82: Pollard M. Effects of linomide on advanced prostate-seminal vesicle cancers in Lobund-Wistar rats. Prostate. 1998 Apr 1;35(1):43-9. PubMed PMID: 9537598.

83: Mavromoustakos T, Zervou M, Panagiotopoulos D, Theodoropoulou E, Matsoukas J, Karussis D. Structural elucidation and conformational properties of the immunomodulator linomide. J Pharm Biomed Anal. 1998 Jan;16(5):741-51. PubMed PMID: 9535185.

84: Xia Z, DePierre JW, Nässberger L. Modulation of apoptosis induced by tricyclic antidepressants in human peripheral lymphocytes. J Biochem Mol Toxicol. 1998;12(2):115-23. PubMed PMID: 9443068.

85: Amerini S, Filippi S, Parenti A, Ledda F, Ziche M. Vasorelaxant effects induced by the antiangiogenic drug linomide in aortic and saphenous vein preparations of the rabbit. Br J Pharmacol. 1997 Dec;122(8):1739-45. PubMed PMID: 9422822; PubMed Central PMCID: PMC1565121.

86: Qi Z, Riesbeck K, Ostraat O, Tufveson G, Ekberg H. Single dose anti-CD4 monoclonal antibody for induction of tolerance to cardiac allograft in high- and low-responder rat strain combinations. Transpl Immunol. 1997 Sep;5(3):204-11. PubMed PMID: 9402687.

87: Harring AC, Xu Z, Andersson G, Hedlund G. Linomide enhances apoptosis in CD4+CD8+ thymocytes. Scand J Immunol. 1997 Nov;46(5):488-94. PubMed PMID: 9393631.

88: Weidenfeld J, Karussis D, Abramsky O, Lehmann D, Arbell I, Ovadia H. Linomide activates the adrenocortical axis in the rat: inhibition of experimental autoimmune encephalomyelitis by linomide is not related to the increase of corticosterone. J Neuroimmunol. 1997 Oct;79(1):49-53. PubMed PMID: 9357446.

89: Lehmann D, Karussis D, Mizrachi-Koll R, Linde AS, Abramsky O. Inhibition of the progression of multiple sclerosis by linomide is associated with upregulation of CD4+/CD45RA+ cells and downregulation of CD4+/CD45RO+ cells. Clin Immunol Immunopathol. 1997 Nov;85(2):202-9. PubMed PMID: 9344704.

90: Antiangiogenesis strategies proving valuable against breast and prostate cancer. Oncology (Williston Park). 1997 Sep;11(9):1358. PubMed PMID: 9306424.

91: Hartley-Asp B, Vukanovic J, Joseph IB, Strandgården K, Polacek J, Isaacs JT. Anti-angiogenic treatment with linomide as adjuvant to surgical castration in experimental prostate cancer. J Urol. 1997 Sep;158(3 Pt 1):902-7. PubMed PMID: 9258116.

92: Bai XF, Shi FD, Zhu J, Xiao BG, Hedlund G, Link H. Linomide-induced suppression of experimental autoimmune neuritis is associated with down-regulated macrophage functions. J Neuroimmunol. 1997 Jun;76(1-2):177-84. PubMed PMID: 9184648.

93: Shirkey BL, Slavin S, Vistica BP, Podgor MJ, Gery I. Immunomodulatory effects of linomide in animals immunized with immunopathogenic retinal antigens: dissociation between different immune functions. Clin Exp Immunol. 1997 Jun;108(3):539-44. PubMed PMID: 9182904; PubMed Central PMCID: PMC1904689.

94: Rosenfeld CS, Zeigler ZR, Shadduck RK, Nilsson B. Phase II study of roquinimex in myelodysplastic syndrome. Am J Clin Oncol. 1997 Apr;20(2):189-92. PubMed PMID: 9124198.

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96: Ostraat O, Qi Z, Olausson M, Tufveson G, Ekberg H. Mycophenolate mofetil, azathioprine and cyclophosphamide enhanced efficacy combined with cyclosporine in rat cardiac transplantation. Scand J Immunol. 1997 Apr;45(4):343-8. PubMed PMID: 9105419.

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