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Thalidomide New Uses of an Old Drug

Thalidomide New Uses of an Old Drug . Jeri Benton Johnson, MD Internal Medicine Resident Grand Rounds February 13, 2001. Case presentation.

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Thalidomide New Uses of an Old Drug

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  1. ThalidomideNew Uses of an Old Drug Jeri Benton Johnson, MD Internal Medicine Resident Grand Rounds February 13, 2001

  2. Case presentation • J.F. is a 42 year old HIV infected male with a CD4 T cell count of 240cells/mm3 who presents to ID clinic with recurrence of an esophageal ulcer. Patient was treated 2 months earlier with steroids. Patient is experiencing weight loss and dysphagia. He is compliant with his meds and has not been in the hospital for16 months. He now feels is quality of life is declining. What do you have to offer him at this point?

  3. Erythema nodosum leprosum Behcet’s syndrome Crohn’s disease Lupus Erythematosus Prurigo nodularis Multiple myeloma Wasting syndrome Aphthous ulcers Esophageal ulcers Rheumatoid Arthritis GVHD Kaposi’s sarcoma What is the role of Thalidomide in today’s medicine?

  4. History of thalidomide Reintroduction of thalidomide for ENL Mechanisms of action anti-inflammatory immunomodulatory anti-angiogenic Thalidomide’s effect on HIV RCT on thalidomide aphthous ulcers esophageal ulcers wasting syndrome Adverse reactions Future of thalidomide S.T.E.P.S. Conclusion Overall Goals

  5. Introduction of Thalidomide • Synthesized by W. Kunz and others in 1956 • Distributed in Europe, Australia, and Canada • Marketed as safe, potent, non-barbiturate sedative and antiemetic • Not approved by the FDA for use in the US

  6. Sir, Congenital abnormalities are present in approximately 1.5% of babies. In recent months I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide during pregnancy, as an antiemetic or as a sedative, to be almost 20%. These abnormalities are present in structures developed from mesenchyme-i.e., the bones and musculature of the gut. Bony development seems to be affected in a very striking manner, resulting in polydactyly, syndactyly, and failure of long bones. Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug during pregnancy? W.G.McBride The Lancet, December 16,1961

  7. Withdrawn from the world market • Withdrawn in December of 1961 • Exposure from day 21 through day 40 of gestation • 10,000 cases of birth defects worldwide • Only 17 infants in the USA • 10 from investigative use • 7 from exposure to sources outside US

  8. Amelia phocomelia hypoplasticity of the bones absence of bones external ear abnormalities facial palsy Eye abnormalities (anophthalmos, microphthalmos) Congenital heart defects Alimentary, urinary, and genital malformations Birth Defects

  9. Dr. Jacob Sheskin an Israeli physician in 1965 Treating ENL, Erythema nodosum leprosy Again used for its sedative properties ENL painful vasculitic rash fever muscle and joint pain malaise weight loss insomnia peripheral neuritis Reintroduction of Thalidomide

  10. Treating ENL • Dr Sheskin treated 6 cases of acute, severe leprosy reactions with resolutions of symptoms. • In 1965, Sheskin performed a series of placebo controlled trials which revealed resolution of symptoms associated with ENL • Sheskin surveyed data in 1980 from 4522 cases around the world and found 99% response rate • Thalidomide was shown not to have effect against Mycobacterium leprae

  11. Approval of Thalidomide for ENL • In a double-blind study in 1967 performed by World Health Organization helped confirm the drug’s efficacy • FDA approved the use of Thalidomide for erythema nodosum leprosum in July 16, 1998 • Thalidomide is now first line of tx for ENL

  12. Pharmokinetics • Metabolic route is not known in humans • Undergoes non-enzymatic hydrolysis in plasma • Renal clearance of 1.15mL/minute • Mean half-life ranges from 5 to 7 hours • No significant dose changes in those with HIV, renal or hepatic disease

  13. Immunomodulatory and Anti-inflammatory properties • Inhibits leukocyte chemotaxis in site of inflammation • Alters density of TNF-a induced adhesion molecules on leukocytes • Reduces phagocytosis by PMN leukocytes • Enhances mononuclear cell production of IL-4 and-5; inhibits interferon gamma production • Inhibits IL-12 • Inhibits production of TNF-alpha by monocytes and macrophages by reducing half-life of mRNA

  14. Anti-angiogenic properties • Thalidomide inhibits fibroblast growth factor • Thalidomide inhibits vascular endothelial growth factor • Plasma levels of angiogenic cytokines are often elevated in diseases such as multiple myeloma • Postulated thalidomide has a role in solid tumors

  15. TNF-a Role in HIV • Serum TNF- a and soluble TNF- a receptor levels are elevated in those with HIV • TNF- a enhances replication of HIV-1 • TNF- a enhances a nuclear transcriptional factor used by the virus • HIV-1 induces TNF- a mRNA

  16. Makonkawkeyoon et al. • A study to evaluate the inhibitory effects of thalidomide on HIV-1 • A human monocytoid cell line was latently infected with HIV-1 and exposed to TNF-a • Fivefold increase in reverse transcriptase activity was noted after exposure to TNF-a

  17. Makonkawkeyoon et al continued • Addition of thalidomide to the cultures resulted in a decrease in the production of HIV-1 • Decrease of production of HIV was in a dose dependent manner • Associated with a decrease in TNF- a mRNA

  18. Thalidomide’s role in HIV • Aphthous ulcers • Wasting syndrome • Esophageal ulcers • Kaposi’s sarcoma • Diarrhea

  19. Aphthous and Esophageal Ulcers • 50% of ulcers in HIV-infected patients idiopathic • painful necrotic lesions • lead to weight loss and wasting syndrome • Relapse often common after treatment with corticosteroids

  20. Esophageal Ulcer

  21. Aphthous Ulcer

  22. Current Treatment for Ulcers • Oral corticosteroids • IV corticosteroids • Intralesional injection by endoscopy • Relapse is common after 2 months of successful oral therapy • Need for alternatives to corticosteroids for those ulcers which are refractory

  23. Jacobson, et al 1997Aphthous Ulcers • Study population: 29 patients with oral aphthous ulceration of at least 2 week duration; biopsy confirmed no infectious, neoplastic or other specific diagnosis. Surface diameter was at least 5mm for the largest ulcer. Hgb >8g per deciliter, and ANC >500 per cubic millimeter . Antiretroviral tx was held constant 4 week prior to study. • Exclusion criteria: neuropathy, pregnancy, tx for opportunistic infections, or anti-neoplastic alkylating agents

  24. Jacobson, et al continued • Stringent precautions were taken to prevent and detect pregnancy in women of childbearing potential including pregnancy testing prior to study entry, weekly while on the study, and 4 weeks after discontinuation of the drug. Patients were required to use 2 forms of birth control.

  25. Jacobson, et al continued • Methods • double-blind,randomized,placebo controlled study • 29 randomized to receive 200mg of thalidomide for 4 weeks • 28 randomized to placebo

  26. Jacobson, et al continued • Outcomes measured • resolution of ulcers • quality of life • evidence of toxicity • plasma TNF-a levels • soluble TNF-a receptors • HIV RNA

  27. Jacobson, et al continued • Results • 55% response to therapy at week 4 versus 7% response in placebo group (OR of 15; 95% CI 1.8-499) • 90% response at week 4 if you combine partial and complete response in thalidomide group versus 25% in placebo (OR 24;95% CI 5.2-162) • median time for survival is 3.5 weeks

  28. Jacobson et al continued • Results • TNF-a level increased in thalidomide group vs placebo group at week 4 (p=0.090) • TNF-a receptor increased in thalidomide group vs placebo group at week 4 (p=0.007) • HIV RNA median increase 0.42 log10 copies per milliliter at 4 weeks of therapy with thalidomide

  29. Most common > rash 7/29 had new or worsened peripheral neuropathy fever confusion headaches nausea Syncope lethargy elevated AST/ALT Estimated probability of remaining in the study without dose reduction was 52% in the thalidomide group. Jacobson, et al continuedSide effects

  30. Jacobson et alConclusion • Thalidomide is effective in healing aphthous ulcers in those with HIV • No significant difference in adverse outcomes in either group • Caution is urged for prolonged treatment with thalidomide because of the elevated HIV RNA.

  31. Ramirez-Amador, et al 1999Aphthous Ulcers • Study population • sixteen HIV infected patients with aphthous ulcers were enrolled from AIDs clinic in Mexico City • Biopsy from aphthous ulcers ruled out infectious or neoplastic conditions

  32. Ramirez-Amador, et al • Methods • double-blind, randomized placebo-controlled clinical trials • 10 patients received 400mg a day for 1 week followed by 200 mg a day for 7 weeks of thalidomide • 6 patients received placebo

  33. Ramirez-Amador, et al • Outcomes • complete absence of ulcers at 8 weeks • no new lesions after 8 weeks • Results • 9 of 10 patients (90%) responded in the thalidomide group versus 2 of 6 patients (33%) responded in the placebo group (p=.03)

  34. Ramirez-Amador, et al continued • Side effects: Rash(80%), somnolence, diarrhea, dizziness, anorexia, nausea; neuropathy was observed in 1 patient from each group.

  35. Ramirez-Amador et alConclusions • Thalidomide heals aphthous ulcers in those infected with HIV • Side effects are common although transient and mild • Obvious limitation is due to the small study size

  36. Jacobson, et alEsophageal ulcers • Study population • 24 HIV infected patients with esophageal ulcer > 5mm • Biopsy ruled out infectious or neoplastic condition • CD4 T cell count < 200 • Dysphagia or odonyphagia for > 2 weeks

  37. Jacobson, et al Esophageal ulcers • Exclusion criteria • Peripheral neuropathy • pregnancy • Corticosteroid therapy • Antiretroviral therapy was held constant 4 weeks prior to study entry

  38. Jacobson, et alEsophageal Ulcers • Methods • multi-center,double-blind, randomized placebo-controlled trial • 11 patients were randomized to receive 200mg of thalidomide for 4 weeks • 13 patients were randomized to placebo

  39. Jacobson, et alEsophageal Ulcers • Outcomes • resolution of IEU by EGD at week 4 • quality of life • TNF-a levels • soluble TNF-a receptor levels • HIV RNA

  40. Jacobson, et alEsophageal Ulcers • Results • 8 of the 11 patients (73%) responded to therapy versus 3 of the 13 patients (23%) in placebo group had resolution of IEU (OR13;CI 1.2-823;p=0.03) • 9 of the11 patients (82%) responded if partial and complete response are combined versus 4 of 13 patients(31%) in placebo group ( OR 11;CI 1.16-195;p=0.033)

  41. Jacobson, et al Esophageal Ulcers • Results • TNF-a levels and TNF-a receptor levels were elevated in thalidomide group compared to placebo group • No changes in CD4 or CD8 T cell count in either group • HIV RNA elevated in the thalidomide group although not statistically significant

  42. Jacobson, et alEsophageal Ulcers • Side effects • 5 of 11 patients (45%) randomized to placebo group discontinued the study drug • 3 developed peripheral sensory neuropathy • other SE included rash, somnolence, fever, nausea, dehydration, and seizures

  43. Jacobson, et alEsophageal Ulcers • Conclusions • Thalidomide heals IEU in HIV patients • Concern for the high incidence of peripheral neuropathy in such a small group • Thalidomide did not prove to be a systemic TNF-a inhibitor • Modest increase in HIV RNA which contradicts studies in vitro

  44. Wasting Syndrome in HIV • Pathogenesis is multifactorial • Cytokines like TNF-a are implicated • Wasting syndrome • opportunistic infections • chronic progressive weight loss from the virus • Proposed thalidomide might play a role • few studies • one RCT

  45. Gustavo, et al 1996Wasting Syndrome • Study population: • 28 adults with advanced HIV being treated with antiretroviral therapy at least 12 weeks prior to study • progressive loss of >10% of usual body weight in 6 months • patients did not have an active opportunistic infection • CD4 T cell count < 500cells/mm3

  46. diarrhea immunosuppressors opportunistic infection Kaposi’s sarcoma hemoglobin <9.5g/dl Platlet count<75,000 Creatinine >2mg/dl AST >3times normal Total granulocyte <1000 cells/mm3 Gustavo, et al continuedExclusion Criteria

  47. Gustavo, et al continued • Methods • Randomized,double-blind placebo controlled trial to evaluate thalidomide’s role on wasting syndrome • 14 of 28 patients received 100mg Q.I.D. • 14 of 28 patients received placebo Q.I.D. • Outcomes • Weight gain , CD4 T cell count, HIV load

  48. Gustavo, et al continued • Results • median weight change in placebo group was -1.30kg • median weight change in thalidomide group was + 4.05kg (p=0.0001) • median calculated muscle mass in placebo group was -1.10kg • median calculated muscle mass in thalidomide group was +1.00kg (p=0.0001)

  49. Gustavo, et al continued • Secondary endpoints • CD 4 T+ cell counts and viral burden did not change in either group • Adverse Outcomes • transient somnolence in 11 of 14 in tx group vs 5 of 14 in placebo (p=0.02) • skin rash in 11 of 14 in tx group vs 3 of 14 in placebo (p=0.017)

  50. Adverse Reactions to Thalidomide in HIV • Haslett, et al performed 3 prospective studies to evaluate the tolerance and SE of thalidomide in HIV population. • 56 patients were treated with 200-300mg of thalidomide for 14-21 days • 24(43%)of 56 did not complete course • CD4 T cell counts in 20 pts and HIV RNA titers in 16 pts were followed

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