Farmacoriflessioni
La talidomide
THALIDOMIDE
FEDERICO MARCHETTI, ALESSANDRO LENHARDT, MARZIA LAZZERINI, MARIO LIUBICH1,ALESSANDRO VENTURA
Clinica Pediatrica, 1Servizio di Farmacia, IRCCS “Burlo Garofolo”, Università di Trieste
Ottobre 2003 - pagg. 517 -523
Abstract
The Authors provide an overview of thalidomide: mechanism of action, pharmacokinetics,
efficacy and safety profile, with particular reference to experiences reported with pediatric
patients. The review was carried out using the MEDLINE database for the studies, particularly
RCTs, published from 1966 to February 2003. The exact mechanism of action of thalidomide
has not yet been understood. Thalidomide is an immunomodulating drug with antiinflammatory
properties. It also inhibits angiogenesis and has a sedative and hypnotic effect.
A total of 47 randomized controlled trials (RCT) have been published regarding adult
and pediatric patients, 4 of which studied patients aged from 0-18 years. Indications for
use of thalidomide in pediatric patients is not based on RCTs, but on non-controlled observational
studies of a limited number of cases. In pediatric patients thalidomide has been
used in the following conditions: chronic graft-versus host disease (GVHD), aphthous ulcers
in patients with HIV, Behçet’s syndrome, systemic lupus erythematosus, and Crohn’s disease.
In the adult patient, thalidomide has been also used in the treatment of certain cancers
and particularly of multiple myeloma. The most frequent side effects sonnolence, peripheral
neuropathy, constipation, headaches, a maculopapular, pruritic rash. In conclusion, little is
known about the efficacy of the drug when compared to conventional treatments, and
about dosage, duration of treatment and safety profile. Large multi-centre studies are needed
to define the use of the drug in pediatric patients.
Parole chiave
Classificazione MeSH
Bibliografia
1. Bonati M. Tra drammatiche certezze e potenziali
prospettive terapeutiche si ritorna a
parlare di talidomide. Ricerca & Pratica 1994;
57:86-90.
2. Annas GJ, Elias S. Thalidomide and the Titanic: reconstructing the technology tragedies of the twentieth century. Am J Publ Health 1999;89:98-101.
3. Seskin J. Thalidomide in the treatment of lepra reaction. Clin Pharmacol Ther 1965; 6:303- 6.
4. Teo SK, Resztak KE, Scheffler MA, Kook KA, Zeldis JB, et al. Thalidomide in the treatment of leprosy. Microbes and Infection 2002; 4:1193-202.
5. Jacobson RR, Krahenbuhl JL. Leprosy. Lancet 1999;353:655-60.
6. Calabrese L, Fleischer AB. Thalidomide: current and potential clinical applications. Am J Med 2000;108(6):487-95.
7. American Hospital Formulary Service 2001 (AHFS Drug). Thalidomide. 92:00 page 3655- 65.
8. Eriksson T, Bjorkman S, Hoglund P. Clinical pharmacology of thalidomide. Eur J Clin Pharmacol 2001;57:365-76.
9. Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering thalidomide: a review of ist mechanism of action, side effects, and potential uses. J Am Acad Dermatol 1996;35:969-79.
10. Heney D, Norfolk DR, Wheeldon J, Bailey CC, Lewis IJ, et al. Thalidomide treatment for chronic graft-versus-host disease. Br J Dermatol 1991;78:23-7.
11. Eriksson T, Bjorkman S, Roth B, Bjork H, Hoglund P. Hydroxylated metabolites of thalidomide: formation in vitro and in vivo in man. J Pharm Pharmacol 1998;50:1-8.
12. Eriksson T, Bjorkman S, Roth B, Hoglund P. Intravenous formulations of the enantiomers of thalidomide: pharmacokinetic and initial pharmacodynamic characterization in humans. J Pharm Pharmacol 2000;52:807-17.
13. Bessemertny O, Pham T. Thalidomide use in pediatric patients. Ann Pharmacother 2002; 36:521-5.
14. Vogelsang GB, Hess AD, Santos GW. Thalidomide for the treatment of chronic graft-versus- host disease. N Engl J Med 1992; 326: 1055-8.
15. Koc S, Leisenring W, Flowers ME. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood 2000;96:3995- 6.
16. Arora M, Wagner JE, Davies SM. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graftversus- host disease. Biol Blood Marrow Transplant 2001;7:265-73.
17. Chao NJ, Parker PM, Niland JC. Paradoxical effect of thalidomide prophylaxis on chronic graft-vs-host disease. Biol Blood Marrow Transplant 1996;2:86-92.
18. Cole CH, Rogers PC, Pritchard S, Phillips G, Chan KW. Thalidomide in the management of chronic graft-versus-host disease in children following bone marrow transplantation. Bone Marrow Transplant 1994;14:937-42.
19. Metha P, Kedar A, Graham-Pole J, et al. Thalidomide in children undergoing bone marrow transplantation: series at a single institution and review of the literature. Pediatrics 1999;103:806-10.
20. Rovelli A, Arrigo C, Nesi F. The role of thalidomide in the treatment of refractory chronic graft-versus-host disease following bone marrow transplantation in children. Bone Marrow Transplant 1998;21:577-81.
21. Jacobson JM, Greenspan JS, Spritzler J, et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997;336:1487-93.
22. Revuz J, Guillaume JC, Janier M, et al. Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis. Arch Dermatol 1990;126:923-7.
23. Ordi-Ros J, Cortes F, Cucurull E, et al. Thalidomide in the treatment of cutaneous lupus refractory to conventional therapy. J Rheumatol 2000;27:1429-33.
24. Knop J, Bonsmann G, Happle R, et al. Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol 1983;108:461-6.
25. Atra E, Sato EI. Treatment of the cutaneous lesions of systemic lupus erythematosus with thalidomide. Clin Exp Rheumatol 1993;11:487- 93.
26. Kone-Paut I, Yurdakul S, Sultan AB, et al. Clinical features of Behçet’s disease in children: international collaborative study of 86 cases. J Pediatr 1998;132:721-5.
27. Tabata M, Tomomasa T, Kaneko H, Morikawa A. Intestinal Behçet’s disease: a case report and review of Japanese reports in children. JPGN 1999;29:477-81.
28. Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:443-50.
29. Kari JA, Shah V, Dillon MJ. Behçet’s disease in UK children: clinical features and treatment including thalidomide. Rheumatology 2001;40:933-8.
30. Terrin G, Borrelli O, Di Nardo G, et al. A child with aphthae and diarrhoea. Lancet 2002;359:316.
31. Marchetti F, Trevisiol C, Ventura A. Intestinal involvement in children with Behçet’s disease. Lancet 2002;359:2115.
32. Bariol C, Meagher AP, Vickers CR, et al. Early studies on the safety and efficacy of thalidomide for symptomatic inflammatory bowel disease. J Gastroenterol Hepatol 2002;17:135-9.
33. Bauditz J, Wedel S, Lochs H. Thalidomide reduces tumor necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn’s disease. Gut 2002;50:196-200.
34. Vasiliauskas EA, Kam LY, Abreu-Martin MT. An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn’s disease. Gastroenterology 1999; 117:1278-87.
35. Ehrenpreis ED, Kane SV, Cohen LB, et al. Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology 1999;117:1271-7.
36. Sabate JM, Villarejo J, Lemann M. An openlabel study of thalidomide for maintenance therapy in responders to infliximab in chronically active and fistulizing refractory Crohn’s disease. Aliment Pharmacol Ther 2002;16:1117-24.
37. Kane S, Stone LJ, Ehrenpreis E. Thalidomide as “salvage” therapy for patients with delayed hypersensitivity response to infliximab: a case series. J Clin Gastroenterol 2002; 35:149- 50.
38. Facchini S, Candusso M, Martelossi S, et al. Efficacy of long-term treatment with thalidomide in children and young adults with Crohn disease: preliminary results. JPGN 2001;32:178-81.
39. Marchetti F, Barbi E, Martelossi S, Ventura A. Use of thalidomide in patients with Crohn’s disease. BMJ 2002. Rapid response 18 december 2002.
40. Marchetti F, Martelossi S, Ventura A. Inflammatory bowel disease. N Engl J Med 2002;347:1982-4.
41. Gutierrez-Rodriguez O, Starusta-Bacal P, Gutierrez-Montes O. Treatment of refractory rheumatoid arthritis: the thalidomide experience. J Rheumatol 1989;16:158-63.
42. Stambe C, Wicks IP. TNF-alpha and response of treatment-resistant adult-onset Still’s disease to thalidomide. Lancet 1998;352: 544-5.
43. Lehman TJ, Striegel KH, Onel KB. Thalidomide therapy for recalcitrant systemic onset juvenile rheumatoid arthritis. J Pediatr 2002;140:125-7.
44. Huang F, Gu J, Zhao W. One-year open-label trial of thalidomide in ankylosing spondylitis. Arthritis Rheum 2002;47:249-54.
45. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187-93.
46. Asli B, Wechsler B, Lemaitre C. Inhibition of tumor necrosis factor alpha and ankylosing spondylitis. N Engl J Med 2003;348:359-61.
47. Drenth JP, Vonk AG, Simon A, et al. Limited efficacy of thalidomide in the treatment of febrile attacks of the hyper-IgD and periodic fever syndrome: a randomized, double-blind, placebo-controlled trial. J Pharmacol Exp Ther 2001;298:1221-6.
48. Wolkenstein P, Latarjet J, Roujeau JC, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 1998;352:1586-9.
49. Bastuji-Garin S, Ochonisky S, Bouche P, et al. Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients. J Invest Dermatol 2002; 119:1020-6.
50. Ochonisky S, Verroust J, Bastuji-Garin S, et al. Thalidomide neuropathy incidence and clinico-electrophysiologic findings in 42 patients. Arch Dermatol 1994;130:66-9.
51. Harland CC, Steventon GB, Marsden JR. Thalidomide-induced neuropathy and genetic differences in drug metabolism. Eur J Clin Pharmacol 1995;49:1-6
52. Chaudhry V, Cornblath DR, Corse A, et al. Thalidomide-induced neuropathy. Neurology 2002;59(12):1872-5.
2. Annas GJ, Elias S. Thalidomide and the Titanic: reconstructing the technology tragedies of the twentieth century. Am J Publ Health 1999;89:98-101.
3. Seskin J. Thalidomide in the treatment of lepra reaction. Clin Pharmacol Ther 1965; 6:303- 6.
4. Teo SK, Resztak KE, Scheffler MA, Kook KA, Zeldis JB, et al. Thalidomide in the treatment of leprosy. Microbes and Infection 2002; 4:1193-202.
5. Jacobson RR, Krahenbuhl JL. Leprosy. Lancet 1999;353:655-60.
6. Calabrese L, Fleischer AB. Thalidomide: current and potential clinical applications. Am J Med 2000;108(6):487-95.
7. American Hospital Formulary Service 2001 (AHFS Drug). Thalidomide. 92:00 page 3655- 65.
8. Eriksson T, Bjorkman S, Hoglund P. Clinical pharmacology of thalidomide. Eur J Clin Pharmacol 2001;57:365-76.
9. Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering thalidomide: a review of ist mechanism of action, side effects, and potential uses. J Am Acad Dermatol 1996;35:969-79.
10. Heney D, Norfolk DR, Wheeldon J, Bailey CC, Lewis IJ, et al. Thalidomide treatment for chronic graft-versus-host disease. Br J Dermatol 1991;78:23-7.
11. Eriksson T, Bjorkman S, Roth B, Bjork H, Hoglund P. Hydroxylated metabolites of thalidomide: formation in vitro and in vivo in man. J Pharm Pharmacol 1998;50:1-8.
12. Eriksson T, Bjorkman S, Roth B, Hoglund P. Intravenous formulations of the enantiomers of thalidomide: pharmacokinetic and initial pharmacodynamic characterization in humans. J Pharm Pharmacol 2000;52:807-17.
13. Bessemertny O, Pham T. Thalidomide use in pediatric patients. Ann Pharmacother 2002; 36:521-5.
14. Vogelsang GB, Hess AD, Santos GW. Thalidomide for the treatment of chronic graft-versus- host disease. N Engl J Med 1992; 326: 1055-8.
15. Koc S, Leisenring W, Flowers ME. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood 2000;96:3995- 6.
16. Arora M, Wagner JE, Davies SM. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graftversus- host disease. Biol Blood Marrow Transplant 2001;7:265-73.
17. Chao NJ, Parker PM, Niland JC. Paradoxical effect of thalidomide prophylaxis on chronic graft-vs-host disease. Biol Blood Marrow Transplant 1996;2:86-92.
18. Cole CH, Rogers PC, Pritchard S, Phillips G, Chan KW. Thalidomide in the management of chronic graft-versus-host disease in children following bone marrow transplantation. Bone Marrow Transplant 1994;14:937-42.
19. Metha P, Kedar A, Graham-Pole J, et al. Thalidomide in children undergoing bone marrow transplantation: series at a single institution and review of the literature. Pediatrics 1999;103:806-10.
20. Rovelli A, Arrigo C, Nesi F. The role of thalidomide in the treatment of refractory chronic graft-versus-host disease following bone marrow transplantation in children. Bone Marrow Transplant 1998;21:577-81.
21. Jacobson JM, Greenspan JS, Spritzler J, et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997;336:1487-93.
22. Revuz J, Guillaume JC, Janier M, et al. Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis. Arch Dermatol 1990;126:923-7.
23. Ordi-Ros J, Cortes F, Cucurull E, et al. Thalidomide in the treatment of cutaneous lupus refractory to conventional therapy. J Rheumatol 2000;27:1429-33.
24. Knop J, Bonsmann G, Happle R, et al. Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol 1983;108:461-6.
25. Atra E, Sato EI. Treatment of the cutaneous lesions of systemic lupus erythematosus with thalidomide. Clin Exp Rheumatol 1993;11:487- 93.
26. Kone-Paut I, Yurdakul S, Sultan AB, et al. Clinical features of Behçet’s disease in children: international collaborative study of 86 cases. J Pediatr 1998;132:721-5.
27. Tabata M, Tomomasa T, Kaneko H, Morikawa A. Intestinal Behçet’s disease: a case report and review of Japanese reports in children. JPGN 1999;29:477-81.
28. Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:443-50.
29. Kari JA, Shah V, Dillon MJ. Behçet’s disease in UK children: clinical features and treatment including thalidomide. Rheumatology 2001;40:933-8.
30. Terrin G, Borrelli O, Di Nardo G, et al. A child with aphthae and diarrhoea. Lancet 2002;359:316.
31. Marchetti F, Trevisiol C, Ventura A. Intestinal involvement in children with Behçet’s disease. Lancet 2002;359:2115.
32. Bariol C, Meagher AP, Vickers CR, et al. Early studies on the safety and efficacy of thalidomide for symptomatic inflammatory bowel disease. J Gastroenterol Hepatol 2002;17:135-9.
33. Bauditz J, Wedel S, Lochs H. Thalidomide reduces tumor necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn’s disease. Gut 2002;50:196-200.
34. Vasiliauskas EA, Kam LY, Abreu-Martin MT. An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn’s disease. Gastroenterology 1999; 117:1278-87.
35. Ehrenpreis ED, Kane SV, Cohen LB, et al. Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology 1999;117:1271-7.
36. Sabate JM, Villarejo J, Lemann M. An openlabel study of thalidomide for maintenance therapy in responders to infliximab in chronically active and fistulizing refractory Crohn’s disease. Aliment Pharmacol Ther 2002;16:1117-24.
37. Kane S, Stone LJ, Ehrenpreis E. Thalidomide as “salvage” therapy for patients with delayed hypersensitivity response to infliximab: a case series. J Clin Gastroenterol 2002; 35:149- 50.
38. Facchini S, Candusso M, Martelossi S, et al. Efficacy of long-term treatment with thalidomide in children and young adults with Crohn disease: preliminary results. JPGN 2001;32:178-81.
39. Marchetti F, Barbi E, Martelossi S, Ventura A. Use of thalidomide in patients with Crohn’s disease. BMJ 2002. Rapid response 18 december 2002.
40. Marchetti F, Martelossi S, Ventura A. Inflammatory bowel disease. N Engl J Med 2002;347:1982-4.
41. Gutierrez-Rodriguez O, Starusta-Bacal P, Gutierrez-Montes O. Treatment of refractory rheumatoid arthritis: the thalidomide experience. J Rheumatol 1989;16:158-63.
42. Stambe C, Wicks IP. TNF-alpha and response of treatment-resistant adult-onset Still’s disease to thalidomide. Lancet 1998;352: 544-5.
43. Lehman TJ, Striegel KH, Onel KB. Thalidomide therapy for recalcitrant systemic onset juvenile rheumatoid arthritis. J Pediatr 2002;140:125-7.
44. Huang F, Gu J, Zhao W. One-year open-label trial of thalidomide in ankylosing spondylitis. Arthritis Rheum 2002;47:249-54.
45. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187-93.
46. Asli B, Wechsler B, Lemaitre C. Inhibition of tumor necrosis factor alpha and ankylosing spondylitis. N Engl J Med 2003;348:359-61.
47. Drenth JP, Vonk AG, Simon A, et al. Limited efficacy of thalidomide in the treatment of febrile attacks of the hyper-IgD and periodic fever syndrome: a randomized, double-blind, placebo-controlled trial. J Pharmacol Exp Ther 2001;298:1221-6.
48. Wolkenstein P, Latarjet J, Roujeau JC, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 1998;352:1586-9.
49. Bastuji-Garin S, Ochonisky S, Bouche P, et al. Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients. J Invest Dermatol 2002; 119:1020-6.
50. Ochonisky S, Verroust J, Bastuji-Garin S, et al. Thalidomide neuropathy incidence and clinico-electrophysiologic findings in 42 patients. Arch Dermatol 1994;130:66-9.
51. Harland CC, Steventon GB, Marsden JR. Thalidomide-induced neuropathy and genetic differences in drug metabolism. Eur J Clin Pharmacol 1995;49:1-6
52. Chaudhry V, Cornblath DR, Corse A, et al. Thalidomide-induced neuropathy. Neurology 2002;59(12):1872-5.