Drugs

, Volume 60, Issue 2, pp 273–292

Potential Novel Uses of Thalidomide

Focus on Palliative Care
Review Article
  • 91 Downloads

Abstract

Thalidomide, after being banned from the market in the early 1960s because of the worldwide teratogenesis disaster, is currently being rediscovered because of its multiple therapeutic effects in various serious diseases and symptoms. Original studies examined the anxiolytic, mild hypnotic, anti-emetic and adjuvant analgesic properties of this drug. Subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy (erythema nodosum leprosum) and even to be superior to aspirin (acetylsalicylic acid) in controlling leprosy-associated fever. Recent research shows promising results with thalidomide in patients with progressive bodyweight loss related to advanced cancer and HIV infection. Thalidomide therapy of diseases such as tuberculosis, sarcoidosis, aphthous ulcers in HIV syndrome and Behcet’s disease, rheumatoid arthritis, multiple myeloma, graft-versus-host disease, pyoderma gangrenosum, inflammatory bowel disease, Sjögren’s syndrome, lupus erythematosus and a variety of solid tumours is currently being explored.

Furthermore, in preliminary studies, thalidomide has been found to be effective in several syndromes related to advanced cancer, such as the cancer cachexia syndrome, chronic nausea, insomnia, profuse sweating and pain. Whether thalidomide has a therapeutic effect on neoplastic fever has yet to be elucidated. These intriguing features make the use of the drug potentially attractive for palliative care. In addition, by a distinct mechanism of action compared with most other drugs, thalidomide offers the possibility of combined treatment with other agents with non-overlapping toxicities.

The mechanism of action of thalidomide is probably based on the suppression of tumour necrosis factor-α and the modulation of interleukins. However, it is not possible to identify a single dominant mechanism, since the action of cytokines and the effect of thalidomide appear to be complex. This review article discusses the original uses and teratogenic effects of thalidomide within its historical context and, linking recent research at the molecular level with clinical findings, aims to provide the reader with insight into the current understanding of its biological actions, toxicities and potential benefits.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Martindale W. The extra pharmacapoeia. London: Pharmaceutical Press, 1977Google Scholar
  2. 2.
    McBride WG. Thalidomide and congenital abnormalities [editorial]. Lancet 1961; II: 1358CrossRefGoogle Scholar
  3. 3.
    Lenz W. Thalidomide and congenital abnormalities [editorial]. Lancet 1962; I: 45CrossRefGoogle Scholar
  4. 4.
    Woodcock J. Supervisory review of NDA 20-785. Washington (DC): Food and Drug Administration, 1998Google Scholar
  5. 5.
    Thalidomide: potential benefits and risks: open public scientific workshop. Washington (DC): National Institutes of Health, 1997Google Scholar
  6. 6.
    Alstead S, MacArthur JG, Thomson TJ, et al. Clinical pharmacology. London: Baillire Tindall & Cassell, 1969Google Scholar
  7. 7.
    Wolstenholme G, Porter R, editors. Drug responses in man. Symposium on drug responses in man. London: Churchill, 1966Google Scholar
  8. 8.
    Link to Thalidomide’s approved label: THALODMID (thalidomide) capsules. Washington (DC): US Food and Drug Administration/CTEP, 1998Google Scholar
  9. 9.
    Raje N, Anderson K. Thalidomide: a revival story. N Engl J Med 1999; 341: 1606–8PubMedCrossRefGoogle Scholar
  10. 10.
    Celgene Corporation. Thalomid (thalidomide) STEPS (System for Thalidomide Education and Prescribing Safety) folder. Warren (NJ): Celgene Corporation, 1998Google Scholar
  11. 11.
    Lutwak-Mann C, Schmid K, Keberle H. Thalidomide in rabbit semen. Nature 1967; 214: 1018–20PubMedCrossRefGoogle Scholar
  12. 12.
    Schumacher H, Smith RL, Williams RT. The metabolism of thalidomide: the fate of thalidomide and some of its hydrolysis products in various species. Br J Pharmacol 1965; 25: 324–37Google Scholar
  13. 13.
    Shannon EJ, Sandoval F, Krahenbuhl JL. Hydrolysis of thalidomide abrogates its ability to enhance mononuclear cell synthesis of IL-2 as well as its ability to suppress the synthesis of TNF-alpha. Immunopharmacology 1997; 36: 9–15PubMedCrossRefGoogle Scholar
  14. 14.
    Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol 1998; 55: 1827–34PubMedCrossRefGoogle Scholar
  15. 15.
    Zwingenberger K, Wendt S. Immunomodulation by thalidomide: systematic review of the literature and of unpublished observations. J Inflamm 1995; 46: 177–211PubMedGoogle Scholar
  16. 16.
    Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173: 699–703PubMedCrossRefGoogle Scholar
  17. 17.
    Moreira AL, Sampaio EP, Zmuidzinas A, et al. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 1993; 177: 1675–80PubMedCrossRefGoogle Scholar
  18. 18.
    Rowland TL, McHugh SM, Deighton J, et al. Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells. Immunopharmacology 1998; 40: 11–20PubMedCrossRefGoogle Scholar
  19. 19.
    Huizinga TW, Dijkmans BA, van der Velde EA, et al. An open study of pentoxyfylline and thalidomide as adjuvant therapy in the treatment of rheumatoid arthritis. Ann Rheum Dis 1996; 55: 833–6PubMedCrossRefGoogle Scholar
  20. 20.
    Moreira AL, Tsenova-Berkova L, Wang J, et al. Effect of cytokine modulation by thalidomide on the granulomatous response in murine tuberculosis. Tuber Lung Dis 1997; 78: 47–55PubMedCrossRefGoogle Scholar
  21. 21.
    Sampaio EP, Kaplan G, Miranda A, et al. The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis 1993; 168: 408–14PubMedCrossRefGoogle Scholar
  22. 22.
    Moller DR, Wysocka M, Greenlee BM, et al. Inhibition of IL-12 production by thalidomide. J Immunol 1997; 159: 5157–61PubMedGoogle Scholar
  23. 23.
    Haslett PA, Corral LG, Albert M, et al. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med 1998; 187: 1885–92PubMedCrossRefGoogle Scholar
  24. 24.
    Zhu J, Deng GM, Diab A, et al. Thalidomide prolongs experimental autoimmune neuritis in Lewis rats. Scand J Immunol 1998; 48: 397–402PubMedCrossRefGoogle Scholar
  25. 25.
    Nogueira AC, Neubert R, Helge H, et al. Thalidomide and the immune system. 3. Simultaneous up-and down-regulation of different integrin receptors on human white blood cells. Life Sci 1994; 55: 77–92PubMedCrossRefGoogle Scholar
  26. 26.
    Neubert R, Nogueira AC, Neubert D. Thalidomide and the immune system. 2. Changes in receptors on blood cells of a healthy volunteer. Life Sci 1992; 51: 2107–16PubMedCrossRefGoogle Scholar
  27. 27.
    Haslett P, Hempstead M, Seidman C, et al. The metabolic and immunologic effects of short-term thalidomide treatment of patients infected with the human immunodeficiency virus. AIDS Res Hum Retroviruses 1997; 13: 1047–54PubMedCrossRefGoogle Scholar
  28. 28.
    Jacobson JM, Greenspan JS, Spritzler J, et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group [see comments]. N Engl J Med 1997; 336: 1487–93Google Scholar
  29. 29.
    Sampaio EP, Moraes MO, Nery JA, et al. Pentoxifylline decreases in vivo and in vitro tumour necrosis factor-alpha (TNF-alpha) production in lepromatous leprosy patients with erythema nodosum leprosum (ENL). Clin Exp Immunol 1998; 111: 300–8PubMedCrossRefGoogle Scholar
  30. 30.
    Goldberg RM, Loprinzi CL, Mailliard JA, et al. Pentoxifylline for treatment of cancer anorexia and cachexia? Arandomized, double-blind, placebo-controlled trial. J Clin Oncol 1995; 13: 2856–9PubMedGoogle Scholar
  31. 31.
    B ruera ED, Roca E, Cedaro L, et al. Improved control of chemotherapy-induced emesis by the addition of dexamethasone to metoclopramide in patients resistantto metoclopramide. Cancer Treat Rep 1983; 67: 381–3Google Scholar
  32. 32.
    Moertel CG, Schutt AJ, Reitemeier RJ, et al. Corticosteroid therapy of preterminal gastrointestinal cancer. Cancer 1974; 33: 1607–9PubMedCrossRefGoogle Scholar
  33. 33.
    Shannon EJ, Sandoval F. Thalidomide increases the synthesis of IL-2 in cultures of human mononuclear cells stimulated with Concanavalin-A, Staphylococcal enterotoxin A, and purified protein derivative. Immunopharmacology 1995; 31: 109–16PubMedCrossRefGoogle Scholar
  34. 34.
    Ostraat O, Riesbeck K, Qi Z, et al. Thalidomide prolonged graft survival in a rat cardiac transplant model but had no inhibitory effect on lymphocyte function in vitro. Transplant Immunol 1996; 4: 117–25CrossRefGoogle Scholar
  35. 35.
    Fernandez LP, Schlegal PG, Baker J, et al. Does thalidomide affect IL-2 response and production? Exp Hematol 1995; 23(9): 978–85PubMedGoogle Scholar
  36. 36.
    McHugh SM, Rifkin IR, Deighton J, et al. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen-and antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 1995; 99(2): 160–7PubMedCrossRefGoogle Scholar
  37. 37.
    Malaviya R, Ikeda T, Ross E, et al. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature 1996; 381: 77–80PubMedCrossRefGoogle Scholar
  38. 38.
    Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature 1990; 346: 274–6PubMedCrossRefGoogle Scholar
  39. 39.
    Dunzendorfer S, Schratzberger P, Reinisch N, et al. Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and transmigration of cytokine-and endotoxin-activated endothelium. Naunyn Schmiedebergs Arch Pharmacol 1997; 356: 529–35PubMedCrossRefGoogle Scholar
  40. 40.
    D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994; 91: 4082–5PubMedCrossRefGoogle Scholar
  41. 41.
    Kruse FE, Joussen AM, Rohrschneider K, et al. Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor. Graefes Arch Clin Exp Ophthalmol 1998; 236: 461–6PubMedCrossRefGoogle Scholar
  42. 42.
    Gutman M, Szold A, Ravid A, et al. Failure of thalidomide to inhibit tumor growth and angiogenesis in vivo. Anticancer Res 1996; 16: 3673–7PubMedGoogle Scholar
  43. 43.
    Lewis JJ. An introduction to pharmacology. Edinburgh: E. & S. Livingstone, 1960Google Scholar
  44. 44.
    Barr Brown, RW, Hamilton-Hislop HG, Pritchard JG. A comparative clinical trial in the elderly of Distaval, Doriden, and Welldorm, three non-barbiturate hypnotics. Br J Clin Pract 1962; 16: 342–7Google Scholar
  45. 45.
    Hoffman W, Grospietsch G, Kuhn W. Genital malformations in thalidomide-damaged girls. Gerburtsch u Frauenheilk 1976; 36: 1066–70Google Scholar
  46. 46.
    Eddy NB, Friebel H, Hahn KJ, et al. Codeine and its alternates for pain and cough relief. 2. Alternates for pain relief. Bull World Health Organ 1969; 40: 1–53PubMedGoogle Scholar
  47. 47.
    Paulus W, Keymer R. Detection of contergan and doriden, especially in cadavers. Arch Toxicol 1963; 20: 38–43CrossRefGoogle Scholar
  48. 48.
    Horstmann W. Reference to central nervous system damage within the context of thalidomide embryopathy: pathologic-anatomic, electroencephalographic and neurologic findings. Eur J Pediatr 1966; 96: 291–307Google Scholar
  49. 49.
    Iyer CG, Languillon J, Ramanujam K, et al. WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. Bull World Health Organ 1971; 45: 719–32PubMedGoogle Scholar
  50. 50.
    Sheskin J. Thalidomide in the treatment of lepra reactions. J Clin Pharmacol Ther 1965; 6: 303–6Google Scholar
  51. 51.
    Murphy PG, Borthwick LS, Johnston RS, et al. Nature of the retrograde signal from injured nerves that induces interleukin-6 mRNA in neurons. J Neuroscience 1999; 19: 3791–800Google Scholar
  52. 52.
    Marx GM, Levi JA, Bell DR, et al. A phase I/II trial of thalidomide as an anti-angiogenic agent in the treatment of advanced cancer [abstract 1751]. Proc Annu Meet Am Soc Clin Oncol 1999; 18: 454aGoogle Scholar
  53. 53.
    Eisen T, Boshoff C, Mak I, et al. Continous low dose thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 2000; 82(4): 812–7PubMedCrossRefGoogle Scholar
  54. 54.
    Long G, Vredenburgh J, Rizzieri DA, et al. Pilot trial of thalidomide post-autologous peripheral blood progenitor cell transplantation (PBPC) in patients with metastatic breast cancer [abstract 697]. Proc Annu Meet Am Soc Clin Oncol 1998; 17: 181aGoogle Scholar
  55. 55.
    Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71PubMedCrossRefGoogle Scholar
  56. 56.
    Olson KB, Hall TC, Horton J, et al. Thalidomide (N-phthaloylglutamimide) in the treatment of advanced cancer. Clin Pharmacol Ther 1965; 6: 292–7PubMedGoogle Scholar
  57. 57.
    Minchinton AI, Fryer KH, Wendt KR, et al. The effect of thalidomide on experimental tumors and metastases. Anticancer Drugs 1996; 7: 339–43PubMedCrossRefGoogle Scholar
  58. 58.
    Browne WL, Wilson WR, Baguley BC, et al. Suppression of serum tumour necrosis factor-alpha by thalidomide does not lead to reversal of tumour vascular collapse and anti-tumour activity of 5,6-dimethylxanthenone-4-acetic acid. Anticancer Res 1998; 18: 4409–13PubMedGoogle Scholar
  59. 59.
    DiPaolo JA. Effect of thalidomide on a variety of transplantable tumors. Cancer Chemother Rep 1963; 29: 99–102PubMedGoogle Scholar
  60. 60.
    Grabstald H, Golbey R. Clinical experiences with thalidomide in patients with cancer. Clin Pharmacol Ther 1965; 6: 298–302PubMedGoogle Scholar
  61. 61.
    Braera E, Neumann CM, Pituskin E, et al. Thalidomide in patients with cachexia due to terminal cancer: preliminary report. Ann Oncol 1999; 10: 857–9CrossRefGoogle Scholar
  62. 62.
    Gutierrez-Rodriguez, O. Thalidomide. A promising new treatment for rheumatoid arthritis. Arthritis Rheum 1984; 27: 1118–21Google Scholar
  63. 63.
    Waters MF. An internally-controlled double blind trial of thalidomide in severe erythema nodosum leprosum. Leprosy Rev 1971; 42: 26–42PubMedGoogle Scholar
  64. 64.
    Opromolla DV, Lima LS, Marques MB. Thalidomide in acute symptoms in leprosy (erythema nodosum or multiforme). Hospital (Rio J) 1966; 69: 827–44Google Scholar
  65. 65.
    Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995; 332: 1351–62PubMedCrossRefGoogle Scholar
  66. 66.
    Shannon EJ, Miranda RO, Morales MJ, et al. Inhibition of de novo IgM antibody synthesis by thalidomide as a relevant mechanism of action in leprosy. Scand J Immunol 1981; 13: 553–62PubMedCrossRefGoogle Scholar
  67. 67.
    Gehanno P, Barry B, Depondt J, et al. Mouth and pharyngeal hyperalgesic syndromes in AIDS. Ann Otolaryngol Chir Cervicofac 1990; 107: 311–3PubMedGoogle Scholar
  68. 68.
    Torras H, Lecha M, Mascaro JM. Thalidomide in the treatment of aphthosis and Behcet’s disease. 4 years’ experience. Med Cutan Ibero Lat Am 1982; 10: 103–12Google Scholar
  69. 69.
    Genvo MF, Faure M, Thivolet J. Treatment of aphthosis with thalidomide and with colchicine. Dermatologica 1984; 168: 182–8PubMedCrossRefGoogle Scholar
  70. 70.
    Klausner JD, Makonkawkeyoon S, Akarasewi P, et al. The effect of thalidomide on the pathogenesis of human immunodeficiency virus type 1 and M. tuberculosis infection. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 11: 247–57CrossRefGoogle Scholar
  71. 71.
    Field EO, Gibbs JE, Tucker DF, et al. Effect of thalidomide on the graft versus host reaction. Nature 1966; 211: 1308–10PubMedCrossRefGoogle Scholar
  72. 72.
    Rovelli A, Arrigo C, Nesi F, et al. The role of thalidomide in the treatment of refractory chronic graft-versus-host disease following bone marrow transplantation in children. Bone Marrow Transplant 1998; 21: 577–81PubMedCrossRefGoogle Scholar
  73. 73.
    Vogelsang GB, Fanner ER, Hess AD, et al. Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med 1992; 326: 1055–8PubMedCrossRefGoogle Scholar
  74. 74.
    Chao NJ, Parker PM, Niland JC, et al. Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-host disease. Biol Blood Marrow Transplant 1996; 2: 86–92PubMedGoogle Scholar
  75. 75.
    Gutierrez-Rodriguez O, Starusta-Bacal P, Gutierrez-Montes O. Treatment of refractory rheumatoid arthritis: the thalidomide experience. J Rheum 1989; 16: 158–63PubMedGoogle Scholar
  76. 76.
    Wolkenstein P, Latarjet J, Roujeau JC, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 1998; 352: 1586–9PubMedCrossRefGoogle Scholar
  77. 77.
    Sateia MJ, Silberfarb PM. Sleep. In: Doyle D, Hanks GW, MacDonald N, editors. Oxford textbook of palliative medicine. Oxford: Oxford University Press, 1998Google Scholar
  78. 78.
    Bruera E, Fainsinger RL, Schoeller T, et al. Rapid discontinuation of hypnotics in terminal cancer patients: a prospective study. Ann Oncol 1996; 7: 855–6PubMedCrossRefGoogle Scholar
  79. 79.
    Politi P, Reboredo G, Losso M, et al. Phase I trial of thalidomide in AIDS-related kaposi sarcoma (ks) [abstract 161]. Proc Annu Meet Am Soc Clin Oncol 1998; 17: 41aGoogle Scholar
  80. 80.
    Neuenschwander H, Bruera E. Asthenia-cachexia. In: Bruera E, Higginson I, editors. Cachexia-anorexia in cancer patients. Oxford: Oxford University Press, 1996: 57–75Google Scholar
  81. 81.
    Billingsly KG, Alexander HR. The pathophysiology of cachexia in advanced cancer and AIDS. In: Bruera E, Higginson I, editors. Cachexia-anorexia in cancer patients. Oxford: Oxford University Press, 1996: 1–22Google Scholar
  82. 82.
    Gagnon B, Bruera E. Areview of the drug treatment of cachexia associated with cancer. Drugs 1998; 55: 675–88PubMedCrossRefGoogle Scholar
  83. 83.
    Fong Y, Moldawer LL, Marano M, et al. Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol 1989; 256: R659–65PubMedGoogle Scholar
  84. 84.
    Plata-Salaman, CR, Borkoski JP. Interleukin-8 modulates feeding by direct action in the central nervous system. Am J Physiol 1993; 265: R877–82PubMedGoogle Scholar
  85. 85.
    Leon LR, White AA, Kluger MJ. Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol 1998; 275: R269–77PubMedGoogle Scholar
  86. 86.
    Tamura S, Ouchi KF, Mori K, et al. Involvement of human interleukin 6 in experimental cachexia induced by human uterine cervical carcinoma xenograft. Clin Cancer Res 1995; 11: 1353–8Google Scholar
  87. 87.
    Pereira J, Bruera E. Chronic nausea. In: Bruera E, Higginson I, editors. Cachexia-anorexia in cancer patients. Oxford: Oxford University Press, 1996: 112–19Google Scholar
  88. 88.
    Traldi A, Vaccari GL, Davoli G. Use of imide of N-phthalylglutamic acid (thalidomide) in the symptomatic therapy of vomiting of many patients with malignant neoplasms or caused by administration of mechlorethamine HCl. Cancro 1965; 18: 336–41PubMedGoogle Scholar
  89. 89.
    Bruera E, Ernst S, Hagen N, et al. Effectiveness of megestrol acetate in patients with advanced cancer: a randomized, double-blind, crossover study. Cancer Prev Control 1998; 2: 74–8PubMedGoogle Scholar
  90. 90.
    Tisdale MJ. Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia. Nutrition 1996; 12Suppl. 1: S31–3PubMedCrossRefGoogle Scholar
  91. 91.
    Maltin CA, Delday MI, Watson JS, et al. Clenbuterol, a beta-adrenoreceptor agonist, increases muscle strength in orthopaedic patients. Clin Sci 1993; 84: 651–4PubMedGoogle Scholar
  92. 92.
    Burman R, Chamberlain J. The assessment of nutritional status, caloric intake, and appetite in patients with advanced cancer. In: Bruera E, Higginson I, editors. Cachexia-anorexia in cancer patients. Oxford: Oxford University Press, 1996: 34–49Google Scholar
  93. 93.
    Dinarello CA, Wolff SM. Molecular basis of fever in humans. Am J Med 1982; 72: 799–819PubMedCrossRefGoogle Scholar
  94. 94.
    Brendzten KL, Baek D, Berild H, et al. Demonstration of circulating leukocytic pyrogen/interleukin 1 during fever [letter]. N Engl J Med 1984; 310: 596Google Scholar
  95. 95.
    Schroder JM, Gibbels E. Unmyelinated nerve fibers in senile nerves and in late thalidomide neuropathy: a quantitative electron microscopic study. Acta Neuropathologica 1977; 39: 271–80PubMedCrossRefGoogle Scholar
  96. 96.
    Deaner P. Thalidomide for distressing night sweats in advanced malignant disease [letter]. Palliat Med 1998; 12: 208–9PubMedCrossRefGoogle Scholar
  97. 97.
    Calder K, Bruera E. Thalidomide for night sweats in patients with advanced cancer [letter]. Palliat Med 2000; 14(1): 77–8PubMedCrossRefGoogle Scholar
  98. 98.
    Foley KM. The treatment of cancer pain. N Engl J Med 1985; 313: 84–95PubMedCrossRefGoogle Scholar
  99. 99.
    Bruera E, MacMillan K, Hanson J, et al. The Edmonton staging system for cancer pain: preliminary report. Pain 1989; 37: 203–9PubMedCrossRefGoogle Scholar
  100. 100.
    Ebadi M, Bashir RM, Heidrick ML, et al. Neurotrophins and their receptors in nerve injury and repair. Neurochem Int 1997; 30: 347–74PubMedCrossRefGoogle Scholar
  101. 101.
    DeLeo JA, Colburn RW, Nichols M, et al. Interleukin-6 mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model. J Interferon Cytokine Res 1996; 16: 695–700PubMedCrossRefGoogle Scholar
  102. 102.
    Sommer C, Marziniak M, Myers RR. The effect of thalidomide treatment on vascular pathology and hyperalgesia caused by chronic constriction injury of rat nerve. Pain 1998; 74: 83–91PubMedCrossRefGoogle Scholar
  103. 103.
    Ringheim GE, Burgher KL, Heroux JA. Interleukin-6 mRNA expression by cortical neurons in culture: evidence for neuronal sources of interleukin-6 production in the brain. J Neuroimmunol 1997; 63: 113–23CrossRefGoogle Scholar
  104. 104.
    Bourde O, Kiefer R, Toyka KV, et al. Quantification of interleukin-6 mRNA in wallerian degeneration by competitive reverse transcription polymerase chain reaction. J Neuroimmunol 1999; 69: 135–40Google Scholar
  105. 105.
    Shin HC, Oh SJ, Jung SC, et al. Differential modulation of short and long latency sensory responses in the Si cortex by IL-6. Neuroreport 1997; 8: 2841–4PubMedCrossRefGoogle Scholar
  106. 106.
    Rauen HM. Are thalidomide and its biological metabolites vitamin antagonists. Arzneitmittelforschung 1963; 13: 1081–4Google Scholar
  107. 107.
    Felisati D. Teratogenic action of thalidomide. Lancet 1964; I: 724–5CrossRefGoogle Scholar
  108. 108.
    Evered DF, Randall HG. Thalidomide and the B vitamins [editorial]. Br Med J 1963; 5330: 610CrossRefGoogle Scholar
  109. 109.
    Rauen HM. Are thalidomide and its biological metabolites antagonists of glutamic acid. Arzneitmittelforschung 1964; 14: 111–5Google Scholar
  110. 110.
    McColl JD, Globus M, Robinson S. An attempted reversal of thalidomide embryopathy in the rat by glutamine. Can J Physiol Pharmacol 1965; 43: 69–73PubMedCrossRefGoogle Scholar
  111. 111.
    Furberg S. Structural relationship between thalidomide and nucleosides. Acta Chem Scand 1965; 19: 1266–7PubMedCrossRefGoogle Scholar
  112. 112.
    Papst W. Thalidomide and congenital abnormalities of the eye. Ber Deutsch Opth Ges 1964; 65: 209–15Google Scholar
  113. 113.
    Drugs and poisons in relation to the developing nervous system. Conference on drugs and poisons as etiological agents in mental retardation. Bethesda (MD): U.S. National Institute of Neurological Diseases and Blindness, 1967Google Scholar
  114. 114.
    Micks RH. The essentials of materia medica, pharmacology and therapeutics. London: J & A Churchill Ltd, 1965Google Scholar
  115. 115.
    Cant JS. Minor ocular abnormalities associated with thalidomide [letter]. Lancet 1966; I: 1134CrossRefGoogle Scholar
  116. 116.
    Hirsch M. Chromosomal studies on so-called thalidomide embryopathy. Med Klin 1963; 58: 397–400PubMedGoogle Scholar
  117. 117.
    Bohm R, Nitsch K. Another chance for thalidomide [editorial]? Lancet 1966; I: 92CrossRefGoogle Scholar
  118. 118.
    Jensen MK. Chromosome aberrations in human cells induced by thalidomide in vitro: preliminary report. Acta Med Scand 1965; 117: 783–4Google Scholar
  119. 119.
    Ashby J. Thalidomide is not a mutagen [letter]. Nature 1997; 389: 118PubMedCrossRefGoogle Scholar
  120. 120.
    Smithells D. Does thalidomide cause second generation birth defects? Drug Saf 1998; 19: 339–41PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of AlbertaEdmontonCanada
  2. 2.Department of Symptom Control and Palliative CareThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations