RE-EMERGENCE OF THALIDOMIDE

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1 Indian Journal of Pharmacology 2003; 35: EDUCATIONAL FORUM RE-EMERGENCE OF THALIDOMIDE C. R. PATIL, S. B. BHISE* S. V. P. M. College of Pharmacy, Malegaon *Government College of Pharmacy, Aurangabad, Maharashtra. Manuscript Received: Revised: Accepted: ABSTRACT Thalidomide is the worst teratogen known in the history of medicine. Its teratogenic effects have resulted in congenital defects in thousands of fetuses. Even consumption of a single dose by pregnant women has been reported to result in severe limb deformities of the fetuses. Due to its side effects like teratogenicity and peripheral neuropathy, thalidomide was withdrawn from the worldwide market long back in Astonishingly, in July 1998, this notorious drug was again approved by US FDA for the treatment of an inflammatory complication of leprosy, erythema nodosum leprosum. Thalidomide has always attracted investigators attention and efforts are still going on to explain its mechanism of action as an immunomodulator, as a sedative and a teratogen. The present article aims to review the history, pharmacological actions, adverse reactions of thalidomide and its re-emergence as a potential drug for several disorders. KEY WORDS Immunomodulator teratogenicity angiogenesis Introduction Thalidomide was introduced, under the brand name Contergan, in 1956 by a West German company called Chemie Grunenthal 1, 2. When first launched, it was considered to be a safe, potent, rapid acting, hangover-free, non-barbiturate sedative without risk of respiratory depression. It was also prescribed as an antiemetic and was used in the nausea of firsttrimester morning sickness. Peripheral neuropathy was the first serious side effect of thalidomide to be detected 3, 4. This was followed by an alarming rise in the reports of catastrophic fetal abnormalities caused due to its use during pregnancy. Teratogenic effects of thalidomide characterized by severe fetal limb defects (phocomelia, dysmelia, amelia and seal limb syndrome) and internal organ deformities affected more than 10,000 cases worldwide 1,2. This resulted in the withdrawal of thalidomide from the market in early 1960 s 5. An Israeli physician, Dr. Jacob Sheskin first reported clinical efficacy of thalidomide in the treatment of erythema nodosum leprosum (ENL), an inflammatory complication of leprosy 6. This was again confirmed, in a double blind clinical trial carried out by the World Health Organization in Nearly three decades after this, in 1998, U. S. Food and Drug Administration approved thalidomide in the treatment of ENL. It has also been classified as an 'Orphan Drug' 8. Chemistry of thalidomide Thalidomide, a-(n-phthalimido) glutarimide, consists of a two-ringed structure with an asymmetric carbon in the glutarimide ring (Figure 1). It exists as an equal mixture of S-(-) and R-(+) enantiomers. These enantiomers rapidly get interconverted under physiological conditions 9. Thalidomide is sparingly soluble in water and ethanol, which to date had prevented its availability as an intravenous formulation 10. Other chemical names 1. 2-(2, 6 Dioxo-3- piperidinyl)-1h-isoindole-1, 3 (2H)- dione. 2. N (2, 6-dioxo-3 piperidyl) phthalimide. (Molecular formula: C 13 H 10 N 2 O 4. Mol. Wt. = ) Correspondence: C.R. Patil

2 RE-EMERGENCE OF THALIDOMIDE 205 Figure 1. Chemical structure of thalidomide. Mechanism of action and pharmacological effects of thalidomide (a) Sedative effect Thalidomide is one of the few hypnotics known to increase rapid eye movement (REM) sleep 11. However, the mechanism of this action is not clearly understood. Considerable differences between species have been reported in the sedative potentials of thalidomide. Species like rat, mice and guinea pig are sedated by large doses, while rabbits are resistant to the sedative effects of this drug. Human beings are uniquely sensitive to its sedative effects 12. (b) Immunomodulatory and anti-inflammatory effects Thalidomide has been proved to selectively suppress the release of certain cytokines. At the same time, it also causes stimulation of cytotoxic T-cells with overall increase in the number of T-lymphocytes 13. (i) (ii) (iii) O O N Effects on polymorphonuclear (PMN) cell functioning: Thalidomide reduces phagocytosis by polymorphonuclear leukocytes. It also inhibits monocyte phagocytosis without any sign of cytotoxicity 5, 14. Effects on T-cells: In healthy people, it decreases the ratio of circulating helper T cells to suppressor T cells, as a result of a reduction in a sub type of helper T cells and an apparent increase in suppressor T cells 3. Effects on helper T-cells: On two subtypes of T-helper cells, thalidomide has different effects. It induces T helper cell type-2 (Th2 cells producing IL-4, IL-5, IL-6, and IL-10) and inhibits T helper cell type-1 (Th1 cells producing predominantly interferon gamma, IL-12 and IL-2) cytokine production in mitogen and antigen O NH O (iv) stimulated peripheral blood mononuclear cell cultures 4, 15, 16. In culture of human mononuclear cells, thalidomide increases IL-2 production stimulated by concanavalin-a (a mitogen) and Staphylococcal endotoxin 17. It also increases mean plasma levels of IL-2 receptors 17. Effects on leukocyte adherence: Thalidomide down regulates the expression of surface adhesion molecules and major histocompatibility antigens on endothelial and epidermal cells and thereby causes reduction in leukocyte adherence 3,15,18. (c) Effects on TNF-a concentrations Human monocytes when stimulated in vitro by bacterial lipopolysaccharide or other agonists produce TNF-a. Such production of TNF-a is inhibited by thalidomide 2,12. This effect is exerted due to enhancement of degradation of TNF-a messenger RNA 19. Thalidomide does not directly influence the production of other lipopolysaccharide-induced cytokines like IL-1a, IL-6 or granulocyte-macrophage colony-stimulating factor (GMCSF). This effect is also beneficial in conditions where it is necessary to suppress TNF-a production, while at the same time preserving the host's cellular immunity However, a study has reported that, thalidomide may not reduce TNF-a level in vivo and its action may depend on the stimulator being used to induce the release of TNF-a 22. (d) Effects on angiogenesis Thalidomide possesses potent anti-angiogenic activity 23. However, the mechanism of this action is not clearly understood. This effect is considered to be due its metabolic product(s) Recently it has been proved that thalidomide inhibits Fibroblast Growth Factor (FGF-2) mediated angiogenesis in rabbit eye micro pocket assay 26. At the same time, it has been proved to be inactive as an anti-angiogenic in chick embryo Chorea-Allantoic Membrane (CAM) assay 23. This observation supports the hypothesis that metabolism of thalidomide is necessary for induction of anti-angiogenesis 24. However, it has been found that the cytochrome P450 system related metabolites, 5- hydroxy thalidomide and 5'-hydroxy thalidomide are inactive in the 'Endothelial Cell Tube Formation Assay', an in vitro model of human angiogenesis 25.

3 206 Table 1. Pharmacological actions of thalidomide. Actions Inhibits leukocyte chemotaxis into site of inflammation 5 References A potent sedative and increases the duration REM sleep 9, 10 Reduces phagocytosis by polymorphonuclear leukocytes 14 Enhances mononuclear cell production of cytokines like IL-2, IL-4, IL-5, IL-10 and inhibits IL-12 production 15, 17, 18 Increases mean plasma levels of IL-2 receptors 16 Reduces TNF-a production by decreasing the half-life of related mrna 19, 20, 21 Inhibits FGF-2 mediated angiogenesis 24 Possesses potent teratogenic actions 1, 2, 28, 29 (e) Effects on genesis of fetal organs Thalidomide consumption by pregnant women during the first trimester of pregnancy is known to induce dysgenesis of fetal organs. Thalidomide is proposed to cause blunting of the growth of long bones in fetal body due to its antiangiogenic effects 28. A study has reported that thalidomide metabolism generates free radicals, which cause oxidative damage to the embryonic cellular macromolecules. Such oxidative stress caused by metabolites of thalidomide may also contribute to its teratogenic potentials 29. Pharmacokinetics of thalidomide in human population: The pharmacokinetic data of thalidomide in healthy human population is scarce. The data regarding its pharmacokinetics in various patient populations in whom it is prescribed for ENL, prostate cancer or HIV related complications and in patients of graft versus host disease (GVHD) is now becoming available 16, (a) Absorption and distribution Due to poor aqueous solubility (50 mg/ml at ph = 7), the absolute bioavailability of thalidomide is unknown 30. The absorption and distribution profile of thalidomide in different diseases are given in Table 2. The extent of plasma protein binding of thalidomide is unknown. (b) Metabolism Significant hepatic metabolism of thalidomide has not yet been identified, however the presence of antiangiogenic active metabolite(s) is anticipated 23. Thalidomide is considered to undergo non-enzymatic hydrolysis under physiological conditions. The hepatic metabolites, 5-hydroxy thalidomide and 5'-hydroxy thalidomide which are formed in very less concentrations by cytochrome P-450 enzyme system catalyzed metabolism, have been found to be inactive in endothelial cell tube formation assay, a model of human angiogenesis 24. Thalidomide is not known to induce or inhibit its own metabolism. (c) Elimination Though the clearance of thalidomide does not vary much in different disease conditions, the elimination half life does. The data are given in Table 3. Clinical uses of thalidomide Use of thalidomide in the treatment of Erythema Nodosum Leprosum (ENL) depended upon the earlier findings of its efficacy in reducing clinical manifestations of this condition 6, 7. However, now it is proved that thalidomide selectively suppresses the synthesis of TNF-a and certain cytokines This is considered to be its major mechanism of action 9. TNFa along with other cytokines has been proved to be responsible for the degenerative processes related to diseases like ENL 19, rheumatoid arthritis 34, AIDS related wasting syndrome 35, inflammatory bowel diseases 36 and bacterial meningitis 37. Apart from its actions on TNF-a and cytokines, thalidomide also possesses potent antiangiogenic action 27. Thus, due to its characteristic actions, thalidomide is being studied for its usefulness in the treatment of a number of diseases involving role of TNF-a, cytokines and angiogenesis process. US-FDA approved use in the treatment of ENL8, 17 Thalidomide was approved by the US-FDA on July 16, 1998 for the treatment, prevention and suppression of ENL. A cutaneous manifestation of leprosy called, ENL is characterized by painful vasculitic rash that may occur together with systemic symptoms of fever, muscle pain, joint pain, malaise, lymphadenopathy, insomnia and weight loss. Peripheral neuritis is often

4 RE-EMERGENCE OF THALIDOMIDE 207 Table 2. Absorption and distribution profile of thalidomide. Population Oral dose Tmax Cmax Vd Reference (mg / day) (Hours) (mg / ml) (litres) HIV infected < Elderly prostate hyperplasia Cancer Hansen's disease < GVHD < Healthy volunteers GVHD - Graft versus host disease. Table 3. Elimination of thalidomide. Population Oral dose Half-life Clearance Reference (mg / day) (h) (litres / h) AIDS Elderly prostate cancer ± ± ±2.89 Hansen s disease < Healthy volunteers ± ± associated with ENL and is the most important pathological manifestation of leprosy. Thalidomide has been designated as an 'orphan drug' in the maintenance and treatment of reactional lepromatous leprosy 6. Other uses of thalidomide under evaluation (a) In treating AIDS related aphthous ulcers Aphthous ulceration of the mouth and esophagus is often self-limited in immunocompetent individuals, while in severely immunocompromised patients aphthous stomatitis and recurrent aphthous ulcers is a common problem. In patients with HIV, aphthous ulcers frequently become a progressively debilitating illness. Often extremely painful, necrotic lesions resemble those of Behcet s syndrome. As hypopharynx and esophagus often get involved, these ulcers lead to decrease in nutritional intake and subsequent wasting. In such conditions, thalidomide treatment has been found to exert beneficial effects in patients 22, 38, 39. (b) In AIDS related wasting syndrome During late stage of AIDS, wasting syndrome occurs either associated with opportunistic infections or as chronic progressive weight loss. The pathogenesis of this condition is multi-factorial. As thalidomide selectively inhibits the production of TNF-a by human peripheral blood cells, it is proposed that it might play a role in treating wasting syndrome. Few clinical studies have reported the role of thalidomide in treating AIDS related wasting syndrome 40. (c) In tumors and multiple myeloma Based on the actions of thalidomide on immune system and angiogenesis, it is proposed that it might have a role in the treatment of multiple myeloma and other solid tumors 15, 41. (d) Other potential oncology related uses Thalidomide may possess curative abilities in the cancerous diseases like AIDS-related Kaposi's sarcoma 42-45, Plasma cell leukemia, cancer cachexia 46

5 208 and other types of advanced solid tumors (like breast, CNS, prostate) 32, (e) In preventing graft versus host disease (GVHD) after transplantations Thalidomide has been shown to be effective in the treatment of GVHD in certain clinical trials 3, 15, 45, 51. In certain studies, paradoxical results have been reported, where thalidomide itself has precipitated the GVHD 51. (f) In rheumatoid arthritis Thalidomide is also being clinically studied in the treatment of rheumatoid arthritis The process of bone and cartilage destruction related to rheumatoid arthritis is considered to involve T-cells cytokines such as TNF-a, interleukin-1 and metalloproteinases 54. Hence, thalidomide, by its action on the cytokine production may have a role in the treatment on rheumatoid arthritis. A clinical study evaluating the efficacy of combined treatment with thalidomide 100 mg/day and pentoxifylline 400 mg /day for 12 weeks, concluded that, this treatment was only partially effective and the risk of adverse effects outweighed the limited efficacy of the combined therapy in treatment of rheumatoid arthritis 52. However, in other studies, thalidomide (300 mg / day) as an adjunct to the other antirheumatic drugs has shown promising activities in the treatment of rheumatoid arthritis 55. (g) In ankylosing spondylitis 53 Thalidomide has been reported to markedly improve the symptoms of ankylosing spondylitis, like motor disability and spinal pain. However, its beneficial effects were found to subside after the cessation of treatment 53. (h) In Crohn's disease and Behcet's syndrome Clinical trials related to efficacy of thalidomide in treatment of the refractory cases of other autoimmune diseases like Crohn's disease and Behcet's syndrome are also being conducted 37, 56. A study involving 12 male patients with active refractory Crohn's disease, reported that 70% patients achieved a clinical response, while 20% had remission after a 12 weeks treatment with thalidomide. All patients were able to reduce their steroid dose by more than 50%, while 44% of patients stopped steroids completely 56. Another study including 21 patients reported that, out of the 14 patient who successfully completed the twelve-week trial, 12 showed clinical response while 2 had remission. It was concluded in both these trials that thalidomide is efficacious in some patients with refractory Crohn's disease 57. Thalidomide also has been reported to exert prompt curative effects in oral and genital ulcers along with follicular lesions of Behcet s syndrome. However, it was not found to be a disease-modifying drug and relapses were seen after cessation of the treatment 58. Thalidomide reduces mortality due to mycobacterial meningitis in rabbits 59. However, clinical usefulness of this effect in mycobacterial meningitis in humans has not been established. Adverse reactions to thalidomide (a) Teratogenicity Recent studies propose that teratogenicity may be mediated by reactive oxygen species generated during metabolism of thalidomide. It has been noticed that a sensitive species like rabbit is more responsive to the oxidative stress of thalidomide (or its metabolites) than the resistant species like rats 60. There is a considerable species difference in the teratogenicity of thalidomide. Rat, mice, cat and hamsters are resistant while rabbits and chicken show sensitivity to its teratogenic effects Thalidomide causes birth defects in humans only when administered during a three weeks period early in pregnancy. The critical period of exposure extends from day 21 through day 40 of gestation. Although not recorded precisely, almost 100% of pregnant women exposed to thalidomide during the critical period gave birth to babies with defects 3. The teratogenicity of thalidomide may be manifested in different forms like phocomelia, malformation of cranium, microphthalmia, anophthalmia, deformities or absence of the pinna and atresia of external canal with low set ears, saddle nose, cleft palate, malformations of respiratory system, cardiovascular anomalies, malformations of gastrointestinal tract, absence of gall bladder and common bile duct, urinary tract and kidney anomalies 63.

6 RE-EMERGENCE OF THALIDOMIDE 209 Recently, concurrent administration of acetyl salicylic acid (ASA) has been shown to reduce the thalidomide induced teratogenicity in rabbits 64. In this study, it is proposed that thalidomide is metabolized to teratogenic compounds by prostaglandin-h 2 synthase (PHS) enzyme. PHS is irreversibly inhibited by ASA, which probably results in inhibition of PHS dependent metabolism of thalidomide. Thus, reduced teratogenicity of thalidomide after concurrent administration of ASA supports the hypothesis that, PHS catalyzed metabolism of thalidomide is necessary for its teratogenic actions. (b) Neuropathy Chronic thalidomide therapy can produce peripheral neuropathy. Such neuropathy results from axonal degeneration without demyelination in the sensory fibers of the lower and occasionally upper extremities 64. Risk of peripheral neuropathy appears to rise with patient's age and cumulative dose of thalidomide 65. This toxicity is initially manifested as numbness of toes and feet, then superficial sensory loss in feet and hands. If therapy is not discontinued, the paresthesias of feet and hands become permanent and progress proximally 3, 66, 67. (c) Drowsiness Dose-dependent somnolence and dizziness are the most common adverse effects of thalidomide. Tolerance to sedation usually develops over time 68. (d) Skin rashes Thalidomide-induced pruritic erythematous macular rash, usually involving the trunk and back, has been reported. Such rashes disappear after discontinuation of thalidomide with or without the use of antihistamines 3. It is also known to cause severe lifethreatening epidermal damage, allergic vasculitis and thrombocytopenia 69. Severe skin rashes are more common in patients with AIDS on thalidomide 68,70. (e) Constipation Constipation is a common side effect experienced by 3% to 30% of patients at low doses. The constipation is usually mild and responsive to mild laxatives (e.g., milk of magnesia, lactulose and psyllium) 68. (f) Chronic graft versus host disease (CGVHD) A double-blind randomized clinical trial, to determine the efficacy of thalidomide as a prophylactic against CGVHD following allogeneic bone marrow transplantation (allobmt), has reported paradoxical results. Out of the 54 evaluated patients, 26 were randomized to placebo and 28 received thalidomide 200 mg orally twice a day, beginning 80 days before the transplantation. It was concluded that thalidomide prophylaxis in allobmt recipients results in a paradoxical increase in evidence of CGVHD 52. (g) Increase in cancer metastasis Thalidomide has also been shown to promote the metastasis of prostate adenocarcinoma cells in rats 71. Other side effects of thalidomide include endocrine effects 58, 65 like slight decrease in secretion of follicle stimulating hormone (FSH), leuteinizing hormone (LH), thyroid stimulating hormone (TSH), thyroid secretions and increase in the secretion of corticotropin and prolactin. It has been reported to induce face and/or limb edema, increased appetite, menstruation abnormalities, mood changes, nausea, pruritus, red palms, xerostomia, brittleness of the fingernails and decreased libido 3. Thalidomide induced changes in immunity after its long-term use may also increase the possibility of life threatening infections 3, 72. (k) Drug interactions Drug-drug interactions with thalidomide have not been systematically evaluated. Thalidomide has been reported to enhance the sedative activity of other central nervous system depressants such as barbiturates, alcohol, chlorpromazine, and reserpine 67. Thalidomide 200 mg/day was found not to affect the pharmacokinetics of an oral contraceptive containing norethindrone acetate and ethinylestradiol 73. It has also been found that thalidomide antagonizes the actions of histamine, serotonin, acetylcholine and prostaglandins in organ bath experiments on isolated tissues 68. Future of thalidomide Thalidomide derivatives are now being synthesized and tested in the treatment of different immune system related conditions. Derivatives of thalidomide have been found to possess diverse activities like inhibition of cytokines and phospho-di-esterase (PDE-4) and

7 210 reduction of TNF-a levels. Through clinical studies, various exploitable therapeutic potentials of thalidomide and its derivatives are also being explored 7,74. Thalidomide, once discarded as the worst teratogen, is again regaining status as a drug in the treatment of many diseases like ENL, GVHD, cancers, autoimmune conditions and AIDS related complications. REFERENCES 1. Gilbert WM, Michael KS. The saga of Thalidomide. N Eng J Med 1962;267: Klausner J, Freedman V, Kaplan G.Thalidomide as an anti- TNF-a inhibitor: Implications for Clinical Use. Clin Immunol Immunopath 1996;81: Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering Thalidomide: A review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 1996;35: Crawford CL. Use of thalidomide in leprosy. Toxicol Rev 1994;13: Pfeiffer RA, Kosonow W. Thalidomide and congenital abnormalities. Lancet 1962;1: Sheiskin J. Thalidomide in treatment of lepra reactions. J Clin Pharmacol Ther 1965;6: Iyer CG, Languillon J, Ramanujam K, Tarabini-Castellani G, De las Aguas JT, Bechelli LM, et al. WHO coordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. Bull World Health Organ 1971;45: Calabrese L, Fleischer A. Thalidomide: current and potential clinical applications. Am J Med 2000;108: Muller GW. Thalidomide: From Tragedy to New Drug Discovery. Chemtech 1997;1: Nico PEV, Johan MK. Stereoselective biotransformation: Toxicological consequences and implications. In: Wainer IW, editor. Drug Stereochemistry, Analytical Methods and Pharmacology. 2nd ed. New York: Marcel Dekker Inc; p Kanbayashi T, Shimatzu T, Takahashi Y, Kitajima T, Takahashi K, Saito Y, et al. Thalidomide increases both REM sleep and stage 3-4 sleep in human adults: A priliminary study. Sleep 1999;22: Fabro S, Schumacher H, Smith RL, Stagg RBL, Williams RT. The metabolism of thalidomide: Some biological effects of thalidomide and its metabolites. Br J Pharmacol 1965;25: Haslett PAJ, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T-lymphocytes, preferentially inducing proliferation, cytokine production and cytotoxic response in the CD8+ subset. J Exp Med 1998;187: Barnhill RL, Doll NJ, Millikan LE, Hastings RC. Studies on anti-inflammatory properties of Thalidomide: Effects on PMN leukocytes and monocytes. J Am Acad Dermatol 1984;11: Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddleman P, Munshi N, et al. Antitumor activity of Thalidomide in refractory multiple myeloma. N Eng J Med 1999;341: McHugh S, Rifkin R, Deighton J, Wilson AB, Lachmann PJ, Lockwood CM, et al. The immunosuppressive drug Thalidomide induces T helper cell type 2 and concomitantly inhibits Th1 cytokine production in mitogen-and antigenstimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 1995;99: Shannon EJ, Sandoval F. Thalidomide increases the synthesis of IL-2 in cultures of human peripheral blood mononuclear cells stimulated with Concanavallin-A, Staphylococcus enterotoxin-a and purified protein derivatives. Immunopharmacol 1995;31: Piscitelli SC, Figg WD, Han B, Kelly G, Thomas S, Walker RE. Single dose Pharmacokinetics of Thalidomide in HIV infected patients. Antimicrob Agent Chem 1997;41: Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mrna degradation. J Exp Med 1993;177: Somers GF. Pharmacological properties of Thalidomide (phthalimido glutarimide), a new sedative hypnotic drug. Br J Pharmacol 1960;15: Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor production by stimulated human monocytes. J Exp Med 1991;173: Jacobson J, Greenspan J, Spritzler J, Kettler N, Fahey JL, Jackson JB, Fox L, et al. Thalidomide for the Treatment of Oral aphthous Ulcers in Patients with Human Immunodeficiency Virus. N Eng J Med 1997;336: D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994;91:

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9 212 chronic graft-versus-host disease. Biol Blood Marrow Transplant 1996;2: Huizinga TW, Dijkmans BA, Velde EA. An open study of pentoxyfylline and thalidomide as adjunctive therapy in the treatment of rheumatoid arthritis. Ann Rheum Dis 1996;55: Amor B, Breban M, Gombert B. Thalidomide: A New Use in Ankylosing Spondylitis? Rheum Arthr Res News 2000;19: Arend WP, Dayer JM. Inhibition of production and effects of IL-1 and TNF-a in Rheumatoid Arthritis. Arthr Rheum 1995;88: Gutierrez-Rodriguez, Bascal PS, Montes OG. Treatment of refractory rheumatoid arthritis: The thalidomide experience. J Rheumatol 1989;16: Vasiliauskas EA, Kan LY, Abreu-Martin MT, Hassard PV, Papadakis KA, Yang H, et al. An open-label pilot study of low-dose thalidomide in chronically active, steroid dependent Crohn's disease. Gastroenterology 1999;117: Ehrenpreis Ed, Kane SV, Cohen LB, Cohen RD, Hanauer SB. Thalidomide therapy for patients with refractory Crohn's disease: an open-label trial. Gastroenterology 1999;117: Gardner-Medvin JM, Smith NJ, Powell RJ. Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behcet s disease: use of neurophysiological studies to detect thalidomide neuropathy. Ann Rheum Dis 1994;53: Tsenova L, Sokol K, Freedman VH, Kaplan GA. Combination of thalidomide and antibiotics protects rabbits from mycobacterial meningitis associated with death. J Inf Dis 1998;177: Jason MH, Katie KH, Martin AP, Craig H. Thalidomide modulates Nuclear redox status and preferentially depletes Glutathione in Rabbit limb versus Rat limb. J Pharmacol Exp Ther 2002;300: Somers GF. Foetal toxicity of thalidomide: European Society Study. Drug Toxicity 1963;1: Kemper F. Thalidomide and congenital abnormality. Lancet 1962;2: Melin GW, Katzenstein M. The saga of thalidomide. N Eng J Med 1962;267: Arlen RR, Wells PG. Inhibition of thalidomide teratogenicity by Acetyl salicylic acid: Evidence for PGH synthase catalyzed bioactivation of thalidomide to a teratogenic reactive intermediate. J Pharmacol Exp Ther 1996; 277: Ochonisky S, Verroust J, Bastuji-Garin S. Thalidomide neuropathy incidence and clinicoelectrophysiologic findings in 42 patients. Arch Dermatol 1994;130: Fullerton PM, O'Sullivan DJ. Thalidomide neuropathy: a clinical electrophysiological and histological follow-up study. J Neurol Neurosurg Psychiatry 1968;31: Wullf CH, Hoyer H, Asboe-Hansen G. Development of polyneuropathy during thalidomide therapy. Br J Dermatol 1985;112: Gunzler V. Thalidomide in human immunodeficiency virus (HIV) patients: a review of safety considerations. Drug Safety 1992;7: Koch HP. Thalidomide and congeners as anti-inflammatory agents. In: Ellis GP, West GP, editors. Progress in Medicinal Chemistry. 3rd ed. Elsevier Publications p Willimas I, Weller IVD, Malin A, Anderson J, Waters MF. Thalidomide hypersensitivity in AIDS. Lancet 1991;337: Pollard M. Thalidomide promotes metastasis of prostate adenocarcinoma cells (PA-III) in L-W rats. Cancer Lett 1996;101: Hosein S. A warning toxicity: Caution about thalidomide. Treatment Update 1995;7: Saphir A. Jekyll and Hyde: A new license for thalidomide? J Natl Cancer Instt 1997;89: Corral LG, Haslett PA, Mullar GW. Differential cytokine moduaion and T- cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-a1. J Immunol 1999;163: Join "IndPharm" IJP uses "IndPharm" to broadcast announcements. Want to join? Please

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