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Rediscovering thalidomide: A review of its mechanism of action, side effects, and potential uses
CLINICAI REVIEW Rediscovering thalidomide: A review of its mechanism of action, side effects, and potential uses Stephanie Tseng, BA, Grace Pak, MD, Kenneth Washenik, MD, PhD, Miriam Keltz Pomeranz, MD, and Jerome L. Shupack, MD New York, New York Thalidomide, a hypnosedative drug introduced in the 1950s, has been used in a variety of dermatologic conditions during the past few decades. Although originally withdrawn from the world market on discovery of its teratogenic effect, it has since been selectively reintroduced for use in various disorders thought to have an autoimmune or inflammatory basis. A review of the literature focused on clinical uses of thalidomide in the treatment of dermatologic diseases was performed. Diseases for which thalidomide has been found effective include erythema nodosum leprosum, pmrigo nodularis, actinic pmrigo, discoid lupus erythematosus, aphthous stomatitis, Beh~et's syndrome, and graft-versus-host disease. Side effects such as teratogenicity and peripheral neuropathy remain its limiting factor. Thalidomide is a useful addition to the therapeutic armamentarium for treatment-resistant dermatoses as long as proper vigilance for adverse effects is maintained. (J Am Acad Dermatol 1996; 35:969-79.) Thalidomide, an oral drag marketed in the 1950s as a sedative, has been used to treat a variety of inflammatory skin disorders. Recent studies evaluating the use of thalidomide in HIV disease have sparked renewed interest. W e review the pharmacology and the potential uses of thalidomide in dermatology.
HISTORY Thalidomide was introduced to the German market as Contergan in 1956 by a West German company, Chemie Grunenthal. 1 It was subsequently marketed in the United Kingdom and other countries after 1958 as a sleeping aid notable for its prompt action, lack of hangover, and apparent safety.2 Thalidomide was never approved by the U.S. Food and Drug Administration and thus never entered the American market. When tested in rodent models, thalidomide showed such low toxicity that acute LDs0 values could not be determined. 3 Accidental overdosing or deliberate suicide attempts were foUowed by unFrom the Ronald O. Perelman Department of Dermatology, Dermatopharmacology section, New York University Medical Center. Reprint requests: Jerome L. Shupack, MD, Department of Dermatology, Dermatopharmacology Section, NYU Medical Center, 550 First Ave., New York, NY 10016. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0
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eventful recovery, even at doses as high as 14 grn. 1 Isolated reports of the development of peripheral neuropathy in patients using thalidomide for an extended time 4 surfaced in 1960 but were quickly overshadowed by separate reports by McBride and Lenz of an association between maternal thalidomide usage and infant limb defects (cited in GunzletS). An estimated 5000 to 6000 infants were reported with characteristic thalidomide-induced phocomelia, often accompanied by deformities of intemal organs. 2 Thalidomide was withdrawn from the world market in late 1961, remaining available only for strictly defined research purposes. Within a few years, however, Sheskin's serendipitous discovery of thalidomide's dramatic therapeutic effect on erythema nodosum leprosum (ENL) provided the impetus for new studies of the drug in other conditions thought to have an autoimmune or inflammatory basis (cited in Hendler and McCarty6). Thalidomide is currently available in the United States under investigational new drug status.
PHARMACOLOGY Structure and chemical properties Thalidomide, or o~-phthalimidoglutarimide (Fig. 1), is a derivative of glutamic acid that is chemically related to bemegdde (oL-ethyl-a-methyl-glutarim969
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3
Metabolism
o C--NH
// 0
0
Fig. 1. Structure of thalidomide. ide) and glutethimide ([3-ethyl-[3-phenyl-glutarimide), but has different pharmacologic properties. 7 It has two ring systems: a left-sided phthalimide and a right-sided glutarimide with an asymmetric carbon atom. Thalidomide exists in optically active L- and R-isomer forms, as well as the optically inactive racemic mixture used clinically. It remains unclear whether each enantiomer has distinct clinical properties. 5 There is evidence that thalidomide in vivo rapidly interconverts between isomeric forms, obviating any benefit of treating with one enantiomer alone. 8 Thalidomide is insoluble in ether and benzene; sparingly soluble in water, methanol, ethanol, acetone, and glacial acetic acid; and readily soluble in dioxane, dimethyl formamide, pyridine, and chloroform. 7 All four amide bonds are susceptible to hydrolytic cleavage in vitro at pH values higher than 6. 5 Pharmacokinetics The plasma pharmacokinetics and urinary excretion of thalidomide have been studied by high-performance liquid chromatographic assay. After a 200 mg oral dose, plasma concentration reached a mean peak of 1.15 _ 0.2 ~tg/ml at 4.39 - 1.27 hours, with a lag time of 0.41 _ 0.17 hours seen in six of eight healthy male volunteers. Volume of distribution for thalidomide was 120.69 _+ 45.36 L. Plasma concentration versus time curve fit a one-compartment model with first-order absorption and elimination; absorption half-life was 1.7 + 1.05 hours and elimination half-life was 8.7 _+ 4.11 hours. Total body clearance rate was 10.41 _+ 2.04 L/hr. Urinary excretion was only 0.6% -+ 0.22% of total dose over 24 hours, indicating a predominantly nonrenal route of excretion. No metabolites were found in either plasma or urine samples, but thalidomide itself could be detected in plasma up to 24 hours after a single 200 mg oral dose. 9
Thorough studies of metabolism in humans have not been done, but the main degradative pathway in animals appears to be nonenzymatic hydrolytic cleavage, z° Evidence exists that hepatic metabolism of thalidomide involves the cytochrome P-450 family, and only the parent compound is enzymatically modified. Thalidomide inhibits attachment of tumor cells to concanavalin A-coated polyethylene (an in vitro assay with correlation to chemical teratogenicity) when incubated with the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) and hepatic microsomes; activation of thalidomide is preventable with established P-450 inhibitors./1 MECHANISM OF ACTION Hypnosedative effect Thalidomide's hypnosedative properties are most likely mediated by its glutarimide ring; this moiety, substituted in the 3-position with a nonspecific space-filling group, is the configuration for several other sedative-hypnotic drugs. Thalidomide acts by a different mechanism than barbiturates, possibly involving activation of a sleep center in the forebrain) Even at large doses, it does not cause incoordination or respiratory depression. 7 Immunosuppression Thalidomide prolongs survival of homografts in mice, with most marked effects when both donor and recipient are treated with thalidomide. 12 It has also shown immunosuppressive properties in baboon and rhesus monkey renal allografts by lowering erythropoietin levels, considered a marker for progress of renal rejection. ~3 When studied in guinea pigs and rats with experimental allergic encephalomyelitis, allergic neuritis, nonspecific granulomata, or adjuvant disease (a disease induced in rats, with features resembling ENL), thalidomide reduced the sign of adjuvant disease slightly but had no effect in any of the other models for autoimmune disease. 14, 25 Other effects Multiple effects of thalidomide have been shown both in vivo and in vitro. Preincubation of polymorphonuclear cells with thalidomide inhibits chemotaxis, but direct addition of the drug to chemotactic factor does not. 16 At 10 lag/ml, thalidomide significantly decreases monocyte phagocytosis without apparent cytotoxicity. 17 Healthy volunteers given
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T a b l e I. Therapeutic uses of thalidomide No. of patients treated
No. of patients improved
Dosage (mg/day)
References No(s).
4522 16 124 112 175 29 58
99% 16 116 94 165 24 35
100-400 200-400 100-300 100-400 100-400 200-400 100-800
26 29-31 32-35 31, 38-40, 103 41-53 54-57 59-63
1 6 7 6 3 55%-57% 5 3 1 1 1 >50% 2 1 1
100-200 100-200 300-600 50-300 100-400 100 100 100-200 N/A 100-300 200-400 100-300 300 50-100 50-100
55 65, 66 67 68-72 73-75 76 77 78, 79 80 81 82 83 84 85 85
Efficacy seen in multiple series
Erythema nodosum leprosttm Pmrigo nodularis Actinic pururigo Discoid lupus erythematosus Aphthous stomatitis Beh~et's syndrome Graft-versus-host-disease
Efficacy seen in single series or case reports
Palmoplantar pustulosis Sarcoidosis Rheumatoid art_h.ritis Langerhans cell histiocytosis Pyoderma gangrenosum Uremic pruritus Jessner-Kanof disease Recurrent erythema mulliforme Cold hemagglutination disease Weber-Christian disease Ulcerative colitis Postherpetic neuralgia AIDS-associated proctitis Bullous pemphigoid Cicatricial pemphigoid
1 6 7 6 3 29 5 3 1 1 1 10 2 1 1
N/A, Not available. thalidomide showed a decrease in their circulating helper-T to suppressor-T cell ratio because of a highly significant drop in helper-T cells and an apparent increase in suppressor-T cells. 18 Thalidomide selectively inhibits rumor necrosis factor--~ (TNF-o0 production 19 by enhancing degradation of TNF-o~ messenger RNA, 2° without affecting production of interleukin-1 (IL-1), IL-6, granulocyte-macrophage colony-stimulating factor, or general proteins. 19 Specific thalidomide-induced inhibition of interferon gamma (WN--,/) production and enhancement of IL-4 and IL-5 production has been seen in human peripheral blood mononuclear cell cultures. 21 Formation of IgM antibody decreased when thalidomide was fed to mice for 5 to 7 days before immunization with sheep red blood cells. 22 Thalidomide suppressed activation of latent HIV-1 in an in vitro monocytoid line and in the peripheral blood of 16 of 17 patients with AIDS. 23 In another recent study, it inhibited basic fibroblast growth factor-induced angiogenesis in a rabbit cornea micropocket assay through an unknown mechanism. 24 When studied for effect on Wallerian
degeneration in rats (used as a model for reproducible cell proliferation), thalidomide decreased cellular proliferation, subperineurial edema, and myelin phagocytosis. Endoneurial cell counts at 10 to 15 days after transection of the sciatic nerve were also lowered. 25 THERAPEUTIC
USE
Thalidomide has shown good therapeutic effect in ENL, prurigo nodularis, actinic pmrigo, discoid lupus erythematosus (DLE), aphthous stomatitis, Behget's disease, and graft-versus-host-disease. Large controlled trials have been performed only in ENL and aphthous stomatitis. Efficacy in case reports or small series has also been reported in other mucocutaneous disorders (Table I). ENL
The World Health Organization conducted a double-blind study in 1967 confirming the drug's efficacy in ENL. Ten years after his first report, Sheskin 26 surveyed data from 4522 cases around the world and found a 99% response rate. Thalidomide has demonstrated no direct effect against Mycobac-
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terium leprae, but is currently first-line therapy for the treatment of ENL. Shesldn26 observed resolution of ENL lesions 24 to 48 hours after beginning thalidomide therapy. Other signs and symptoms such as headache, anorexia, vomiting, orchitis, arthralgia, myalgia, and hepatosplenomegaly were also quick to remit. Leukocyte count and erythrocyte sedimentation rate returned to normal. In long-term follow-up, motor conduction velocity in the ulnar nerve improved within 48 hours and returrled to near-normal levels after 2 weeks of treatment, supporting a beneficial effect of thalidomide on reactional neuritis or polyneuritis in ENL. 26 Elevated serum TNF-oL and associated elevated IFN-~/have been found in patients with systemic ENL, with positive correlation between intensity of inflammatory state and TNF-oL level. After thalidomide therapy, patients showed decreased serum TNF-a, decreased dermal infiltration of polymorphonuclear leukocytes and T cells, and intercellular adhesion molecule major histocompatibility complex class II antigens on epidermal keratinocytes. Fever, malaise, and arthritic/neuritic pain were alleviated within 24 to 48 hours; nodules showed involution by 3 days and disappeared within 10 days. 27 A selective decrease in serum IgM concentration22 and numbers of helper-T cells (often elevated in blood and skin lesions of patients with ENL during active episodes)28 have also been shown in patients with leprosy receiving thalidomide for ENL.
Prurigo nodularis S h e s k i n 29 gave a preliminary report in 1975 of good results in three patients with prurigo nodularis at a dose of 300 to 400 mg daily. Van den Broek3° followed with a report of flattening of lesions and disappearance of pruritus over a 3-month period in a patient given thalidomide, 200 mg/day. Eosinophilia was noted as the only change. Twelve additional patients treated in separate studies had reduction of pruritus in 2 to 3 weeks and resolution of severely lichenified lesions in several months. 31
Actinic prurigo Londono 32 treated 34 patients with actinic pmrigo with an average thalidomide dose of 300 mg/day tapered to maintenance doses as low as 15 mg/day. All but two showed good improvement within 21 to 91 days (average, 50 days) with no major side effects, and in all cases discontinuation of thalidomide led to
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recurrence.32 Saul, Flores, and Novales 33 treated 25 patients with various forms of polymorphous light eruption at 100 to 200 rag/day for 45 to 150 days, with excellent or good results in 88%, fair results in 8%, and poor results in 4%. Improvement was first noticed after an average of 15 days. Twelve patients remained asymptomatic 1 year after treatment ended. Calnan and Meara 34 confirmed the efficacy of thalidomide in actinic pmrigo in a series of 51 patients. Lovell et al.35 treated 14 patients with actinic prurigo with 100 to 200 mg/day, leading to prolonged improvement in 11. Three remained clear after treatment ended; the other eight required maintenance doses of 50 to 100 mg/week. A study of 15 randomly selected patients with actinic pmrigo given thalidomide 100 mg/day for 2 months showed decreased CD3 ÷ and CD4 ÷ levels during the first 45 days, with levels rising again after day 45. No significant changes were noted in CD8 ÷ levels or B-cell counts. 36
Discoid lupus erythematosus Barba-Rubio and Franco-Gonzalez were the first to use thalidomide in discoid lupus erythematosus, with theft results confirmed by Grosshans and Illy31 in an open study of 25 patients. After reviewing 156 reported cases, they concluded that thalidomide had a failure rate of less than 10%. An initial dose of 100 to 200 mg gave results within 2 weeks in most patients; 75% required maintenance therapy of 25 to 50 mg/day. A later review by Lo, Berg, and Tomecki37 revealed similar conclusions. In one series of 60 patients with a mean intake of 85 gm of thalidomide (range, 15.5 to 132 gm), the appearance of mild to moderate polyneuritic symptoms in 25% led the authors to recommend restricting thalidomide to cases resistant to topical steroids and systemic antimalarials. 38 Thalidomide in patients with systemic lupus erythematosus (SLE) seems to improve cutaneous and articular symptoms without affecting visceral features of the disease. A study of 23 patients with SLE and cutaneous lesions unresponsive to standard therapies had a 90% rate of complete remission and a significant reduction in average dose of prednisone required (from 40.5 mg/day down to 17.4 mg/day) while receiving thalidomide, 300 mg/day. Thirtyfive percent had recurrence from 2 months to 4 years after the drug was discontinued. A significant drop in the gammaglobulin level was seen in 10 of 13 patients. 39 In another study, three patients with SLE
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showed stable immunologic indices (antinuclear antibody, anti-DNA antibodies, and complement) and good control of skin and articular manifestations while receiving thalidomide.4°
Aphthous stomatitis Mascaro, Lecha, and Torras 41 reported successful use of thalidomide in six patients with recurrent and necrotic mucocutaneous aphthae; at 100 mg/day, aphthae were painless by the third day and had healed in 7 to 10 days. Grinspan42 treated 40 patients with aphthous manifestations including bipolar (oral and genital) aphthae and Sutton' s disease (periadenitis mucosa necrotica recurrens) with 100 to 300 mg/day for 1 to 3 months, resulting in 35% remissions and 40% marked improvement. Efficacy in severe orogenital ulceration was seen in a doubleblind controlled trial of thalidomide versus placebo in 15 patients, with complete clearing in 14 and significant improvement in the remaining patient. 43 Success with thalidomide in five patients with recurrent, deep necrotic aphthae44 and another patient with Sutton's disease45 was also reported. A multicenter crossover randomized trial of thalidomide versus placebo was conducted by Revuz et al. 46 in patients with severe aphthous stomatitis of greater than 6 months' duration. Complete remission was seen in 32 of 73 patients (44%) receiving thalidomide versus 6 (8%) taking placebo, with most others showing a dramatic decrease in the number of aphthae while receiving the drag. Thalidomide showed a suppressive effect only because relapses were regular after discontinuation, with a mean duration of remission of 20 days. Youle et al.47 reported rapid healing of resistant aphthous ulcers in seven patients with HIV given 100 mg/day for 2 weeks. Multiple case reports of patients with AIDS and hyperalgic ulcerations of unknown cause including esophageal ulcerations interfering with eating have shown dramatic response within 2 weeks to thalidomide, 100 rag/ day.48-52 Paterson et al.53 performed a retrospective review of 20 patients with HIV receiving thalidomide from 1989 to 1993 for painful refractory ulcerative disease of the oropharynx, esophagus, and rectum. Viral, fungal, and spirochetal causes of ulceration had been previously excluded. A standard treatment of 200 mg/day was given for 2 weeks; four patients with recurrences were given an additional course of treatment. Fourteen patients had complete healing and all others had improvement so that an-
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algesics or local treatment were no longer needed. CD4 + cell counts did not change during or after treatment.53
Beh~et's syndrome After reports of its beneficial effect in recurrent mucocutaneous aphthae, thalidomide (400 mg/day for the first 5 days, then 200 mg/day for 15 to 60 days) was administered to 22 patients with flatly developed Beh~et's syndrome. Oral and genital lesions healed almost immediately, with recurrences becoming milder and less frequent. No effect was seen on ocular lesions. 54 Treatment of a patient with Beh~et' s syndrome in association with palmoplantar pusmlosis (200 mg/day for 2 months followed by 100 mg for 12 months) resulted in complete clearing of both the palmoplantar pustulosis and the mucocutaneous lesions within 2 weeks. 55 In a patient with complete Beh~et's syndrome given thalidomide as a final pharmacologic measure to avoid colectomy, 300 rag/day resulted in normalization of stools (including negative testing for blood) within a day, followed by rapid normalization of rectal mucosa. The dose was tapered to 200 mg after 2 weeks, then 100 mg after an additional week, Oral ulcers and pleural effusion disappeared, and symptoms did not recur during a 5-month follow-up. 56 In another study, four patients with Behqet' s syndrome and one with bowel-associated dermatosisarthritis syndrome received sequential 4-week " o n " and "off" thalidomide therapeutic cycles (total study period, 12 weeks). The dose was 200 mg/day during the active treatment periods. Three patients who finished the study had complete cleating of mucocutaneous lesions and arthritic symptoms. All patients had recurrence of lesions and symptoms within 1 to 2 days of discontinuing thalidomide. In this small sample, no effect was seen on neutrophil migration or the LFA-1/Mac-1/p150,95 family of glycoproteins associated with neutrophil adherence. During therapy, three of four patients converted from positive to negative for circulating immune complexes after histamine injection, possibly supporting an inhibitory effect of thalidomide on vasculitisinduced by these complexes.57
Graft-versus-host disease When tested in a rat MHC mismatch model (used previously in cyclosporine studies), thalidomide was effective both as prophylaxis and in established acute graft-versus-host disease (GVHD). 5s Single patients with acute cutaneous G V H D , 59 sclerotic chronic
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cutaneous GVHD, 6° chronic GVHD involving airway disease, and chronic GVHD evolved into a generalized sicca syndrome61 showed progressive improvement when treated with thalidomide. Four of six other patients with severe chronic GVHD showed marked improvement in skin texture and mobility as well as oral mucocutaneous symptoms, with the best responses in chronic cutaneous GVHD and the poorest responses in multiple-system disease. 62 In a preliminary trial of 44 patients with refractory or "high-risk" chronic GVHD, Vogelsang et al.63 administered thalidomide for 3 to 6 months at a dose of 800 mg/day for an average size adult. Fourteen patients showed a complete response (complete clearing of disease in all organ systems), 12 showed a partial response (improvement of more than 50% but less than 100% in all affected organ systems), and 18 showed no response. Survival rate was 76% among patients receiving thalidomide for refractory GVHD and 48% in the high-risk group. 63 Thalidomide' s mode of action in GVHD has been suggested as involving metabolites of thalidomide acting at an early stage in the antigen recognition-activation pathway of graft T lymphocytes to downregulate normal lymphocyte responses. 64
Sarcoidosis The efficacy of thalidomide in sarcoidosis was first reported by Barfiere65 in four patients, two with cutaneous manifestations and two with cutaneous and pulmonary manifestations. Recently, Carlesimo et al.66 treated two patients: one with systemic sarcoidosis and the second with pulmonary sarcoidosis in whom Kaposi's sarcoma developed after corticosteroid therapy. Reduction was noted in cutaneous lesions, hilar lymphadenopathy, and Kaposi's sarcoma after 2 weeks of thalidomide, 200 rag/day. Elevated serum angiotensin-converting enzyme levels returned to normal, suggesting an inhibitory effect of thalidomide on macrophage function, which includes synthesis and release of large amounts of angiotensin-converting enzyme.
Rheumatoid arthritis In an open trial of seven patients, Gutierrez-Rodriguez67 began thalidomide treatment at 300 mg/day, increasing the dose by 100 mg every 1 to 2 weeks until joint pain disappeared. Five patients reached a maximum dose of 600 mg, one patient 500 mg, and
one patient 400 mg without side effects other than drowsiness, constipation, and lower limb edema. Pain and joint inflammation disappeared after seve r n weeks, and four patients had prolonged posttreatmentremission. All had normalization or marked reduction of their erythrocyte sedimentation rate and several showed a decrease in rheumatoid factor titer. Rheumatoid nodules in one patient shrank by the third week and disappeared by the twelfth week.
Langerhans cell histiocytosis A dramatic effect of thalidomide on vulvar eosinophilic grannloma as part of "histiocytosis X " was first reported by Gnassia et al.68 Another patient with cutaneous histiocytosis resembling sinus histiocytosis experienced complete remission after 1 month at 300 mg/day without recurrence after discontinuation. 69 Four additional cases of adult cutaneous Langerhans cell histiocytosis remitted after 1 to 3 months of therapy with frequent recurrences after stopping treatment. Thalidomide appeared to have little or no effect on the visceral manifestations of disease. 7°-72Histopathologic examination showed disappearance of the histiocytic infiltrate after treatment, suggesting an effect of thalidomide on the proliferative Langerhans cell population. 7°
Pyoderma gangrenosum Administration of 100 rag/day of thalidomide to a 3-year-old girl with extensive pyoderma gangrenosum refractory to corticosteroids or clofazimine led to complete recovery.7s Skin lesions typical of pyoderma gangrenosum have been reported in association with Behqet's syndrome in only a few patients, with thalidomide therapy tried in two isolated cases. In both patients, thalidomide at an initial dose of 400 mg/day (tapered to 50 to 100 mg/day) led to almost immediate improvement, with complete heating of skin lesions and no new appearance of mucosal ulcerations.74, 75
Other In a crossover, randomized, double-blind trial of 29 hemodialysis patients with refractory uremic pruritus, there was a 55% response rate (78% mean reduction in pruritus) in patients on 100 mg/day of thalidomide, compared with no response in the control group. During the second phase of the trial, patients receiving thalidomide had a 57%
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response (81% mean reduction) compared with 25% response (54% mean reduction) in those receiving placebo. 76 Therapeutic results with thalidomide in JessnerKanof disease] 7 recurrent erythema multiforme,7s, 79 cold hemagglutination disease, 8° Weber-Christian disease, 81 ulcerative colitis, 82 postherpetic neuralgia, 83 and painful AIDS-associated proctitis 84 have been reported. Naafs and Faber, 85 in an open trial of 35 patients with a variety of dermatologic conditions, also noted thalidomide's efficacy in a patient with bullous pemphigoid and a patient with cicatricial pemphigoid. Thalidomide's ability to inhibit production of TNF-o~, which plays a role in the activation of latent HIV, has made it the subject of phase IBI trials in patients with HIV. In addition to suppressing HIV replication and viral burden, it may enhance patient well-being by reducing TNF-oL-induced fever, malaise, muscle weakness, and cachexia.23 Theoretically, the use of an immunomodulatory drag such as thalidomide in an already immunosuppressed population may carry the risk of further worsening their immune status. 5, 86
ADVERSE EFFECTS Teratogenicity A distinct window for thalidomide's embryopathic effect has been well established. The sensitive period is estimated to be from 34 to 50 days after conception; a single dose of 100 mg during this time (leading to a plasma concentration of approximately 1 rag/L) is sufficient to produce malformations.5 The actual mechanism of action of thalidomide embryopathy remains unknown, despite numerous studies during the past three decades. In a review of 24 proposed mechanisms acting on the biochemical, cellular, or tissue-organ levels, Stephens s7 noted that eight proposals have been refuted by other experimental or observational data and the remaining 16 stand primarily because they have not been rigorously tested. Observation of thalidomide' s neurotoxic effect on both sensory and motor rabbit fetal nerve roots has suggested an effect on neural as well as limb development, as Limb defects secondary to an inhibition of blood vessel growth in the developing fetal limb bud have also been postulated. Electron microscopic studies showed similarities between ultrastmcmral changes in the vasculamre of deformed embryo limb
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buds and the inhibition of corneal neovascularization in thalidomide-treated rabbits, a4
Peripheral neuropathy Early reports of peripheral neuropathy in patients taking thalidomide described mostly sensory symptoms, sometimes accompanied by mild proximal muscle weakness or evidence of mild pyramidal tract damage. Although muscle weakness decreased rapidly after discontinuation of drag, sensory deficits were slow to improve, and occasionally worsened even while the patients were not taking thalidomide. 89 The clinical features of thalidomide-induced neuropathy have since been well characterized as predominantly symmetric painful paresthesias of the hands and feet, frequently accompanied by lower limb sensory loss. 88 Muscle weakness, muscle cramps, signs of pyramidal tract involvement, and carpal tunnel syndrome have been reported in many patients.88, 9o-92An unpleasant feeling of "tighmess around the feet" was described with an incidence of 8% to 47% in larger series. 9° Electrophysiologic findings are consistent with axonal neuropathy, showing reduced sensory nerve action potential amplitude on the sural, median, and peroneal nerves with relative conservation of conduction velocities. 88'9° Increased somatosensoryevoked potential latency after sural nerve stimulation can be seen in thalidomide-treated patients in the absence of clinical abnormalities. 93 Pathologic findings on sural nerve biopsy reveal selective loss of large diameter fibers without segmental demyelination88, 94; occasional marked increases in the number of small fibers may be indicative of regeneration.88 In a follow-up of patients with thalidomideinduced neuropathy for 4 to 6 years after ending treatment, 25% had full recovery, another 25% had some improvement, and 50% had no change in sensory symptoms and signs. Improvement was notably slow to occur and in a few patients did not begin for years, as The incidence of thalidomide-induced neuropathy has been variously estimated in retrospective studies from less than 1% in patients treated for lepra reactions to more than 70% in patients treated for pmrigo nodularis. 90,91,95 Dose-dependent development of neuropathy has been suggested by some authors 88, 9o with symptoms beginning after a cumulative dose around 40 to 50 gm, 89 although no relation to dose
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Table II. Clinical side effects
BriNe fingernails Constipation Decreased libido Dizziness Drowsiness Endocrine effects Exfofiative/erythrodermicreaction Face/limb edema Increased appetite Menstruation abnormalities Mood changes Nausea Peripheral neuropathy t5"ufitus Red palms Teratogenicity Xerostomia
has been found in other studies. 92, 96 Special consideration must be given to patients with HIV because the higher incidence of preexisting neuropathy in this group (estimated to be 15% to 50%) may make them particularly sensitive to thalidomide's neurotoxic effects.6 A recent retrospective review of patients treated with thalidomide for various dermatologic conditions found the incidence of thalidomide-induced neuropathy to be between 21% and 50%, with the highest risk in women and elderly patients. No relation was found to dose or duration of treatment, with neuropathy beginning at a cumulative dose of only 3 to 6 gm in some. Individual susceptibility with a possible genetic predisposition was suggested as more relevant to the development of neuropathy than dose or duration of therapy.92 A possible relation between slow acetylators and development of thalidomide-induced neuropathy has also been suggested. 96 Occasional worsening of electrophysiologic abnormalities after drug withdrawal suggests a prolonged action of thalidomide.93 Serum from patients with symptoms of thalidomide-induced neuropathy induced morphologic changes in cultured rat dorsal root ganglion cells, characterized by altered appearance of nerve cell soma, maintained integrity of axons and myelin sheath, and infiltration by macrophages. This was true even of serum samples obtained 16 months after discontinuation of thalidomide, indicating the presence of a neurotoxic factor that remains in serum for more than a year. A direct
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neurotoxic effect was ruled out because serum obtained from an asymptomatic patient also receiving thalidomide did not cause morphologic changes. Given the drug's excretion pharmacokinetics, there is also no evidence that the neurotoxic factor is residual thalidomide.95 Because of the severity and possible irreversibility of thalidomide-induced peripheral neuropathy, baseline and follow-up electrophysiologic testing with expedient dosage reduction upon abnormal results may reduce risk before the often rapid emergence of clinical symptoms. 93 E n d o c r i n e effects
Thalidomide slightly depresses thyroid secretory activity, an effect common to other sedative drugs that may be secondary to reduction in body activity7 or inhibition of thyroid-stimulating hormone production. 97 It has also been reported to stimulate ACTH and prolactin production or secretion97 and cause hypoglycemia. Other
Drowsiness, dizziness, mood changes, constipation, and xerostomia are often reported in patients taking thalidomide.5, 31, 85, 98 Other clinical side effects occurring less frequently include brittle fingernails, red palms, increased appetite, loss of libido, face/limb edema, nausea, pruritus, menstmal abnormalities, and galactorrhea (Table ID. Exfoliative99 and erythrodermic100 reactions have occasionally been reported. Thalidomide has also been rarely reported to induce allergic vasculitis and thrombocytopenic purpura. 3 Hypersensitivity reactions have been reported in patients with AIDS receiving thalidomide and may be more common in this population. 1°1 DRUG INTERACTIONS
Thalidomide enhances the activity of barbiturates, alcohol, chlorpromazine, and reserpine. It also antagonizes the action of histamine, serotonin, acetylcholine, and prostaglandins in organ bath experiments .5 CONCLUSION Treatment with thalidomide has given good to excellent results in various mucocutaneous conditions. It occasionally produces dramatic improve-
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m e n t in p a t i e n t s u n r e s p o n s i v e to m u l t i p l e o t h e r therapies. D e s p i t e its d a n g e r s , m o s t n o t a b l y teratogenicity and peripheral neuropathy, thalidomide m a y p r o v e h i g h l y u s e f u l in a p p r o p r i a t e l y s e l e c t e d patients.
19.
20.
REFERENCES
1. Mellin GW, Katzenstein M. The saga of thalidomide: neuropathy to embryopathy, with case reports and congenital abnormalities. N Engl J Med 1962;23:1184-90. 2. D'Arcy PF, Griffin JP. Thalidomide revisited. Adverse Drug React Toxicol Rev 1994;13:65-76. 3. Koch HP. Thalidomide and congeners as anti-inflammatory agents. Prog Med Chem 1985;22:165-242. 4. Mellin GW, Katzenstein M. The saga of thalidomide (concluded). N Engl J Med 1962;24:1238-44. 5. Gunzler V. Thalidomide in human immunodeficiency vires (HIV) patients: a review of safety considerations. Drug SaY 1992;7:116-34. 6. Hendler S, McCarty M. Thalidomide for autoimmune disease. Med Hypotheses 1983;10:437-43. 7. Somers GF. Pharmacological properties of thalidomide (c~-phthalimido glutafimide), a new sedative hypnotic drug. Br J Pharmacol 1960;15:111-6. 8. Eriksson T, Bjorkman S, Roth B, et al. Sterospecific determination, chiral inversion in vitro and pharmacoldnetics in humans of the enantiomers of thalidomide. Chirality 1995;7:44-52. 9. Chen TL, Vogelsang GB, Petty BG, et al. Plasma pharmacokinetics and urinary excretion of thalidomide after oral dosing in healthy male volunteers. Drug Metab Dispos 1989;17:402-5. 10. 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;25:338-51. 11. Braun AG, Harding FA, Weinreb SL. Teratogen metabolism: thalidomide activation is mediated by cytochrome P-450. Toxicol Appl Pharmacol 1986;82:175-9. 12. Hellman K, Duke DI, Tucker DF. Prolongation of skin homograft survival by thalidomide. Br Med J 1965; 2:687-9. 13. Murphy GP, Mirand EA, Groenewald JG, et al. Erythropoietin release in renal allografted baboons, with and without immunosuppression. Invest Urol 1970;7:271-82. 14. Goihman-Yahr M, Requena MA, Vallecalle-SuegartE, et al. Autoimmune diseases and thalidomide: I. adjuvant disease, experimental allergic encephalomyelitis and experimental allergic neuritis of the guinea pig. hat J Lepr 1972;40:133-41. 15. Goihman-Yahr M, RequenaMA, Vallecalle-SuegartE, et al. Autoimmune diseases and thalidomide: 11. adjuvant disease, experimental allergic encephalomyelitis and experimental allergic neuritis of the rat. Int J Lepr 1974; 42:266-75. 16. Faure M, Thivolet J, Gaucherand M. Inhibition of PMN leukocytes chemotaxis by thalidomide. Arch Dermatol Res 1980;269:275-80. 17. Bamhill RL, Doll NJ, Millikan LE, et al. Studies on the anti-inflammatory properties of thalidomide: effects on polymorphonuclear leukocytes and monocytcs. J Am Acad Dermatol 1984; 11:814-9. 18. Gad SM, Shannon EJ, Krotoski WA, et al. Thalidomide induces imbalances in T-lymphocyte sub-populations in
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the circulating blood of healthy males. Lepr Rev 1985; 56:35-9. Sampaio EP, Samo EN, Galilly R, et al. Thalidomide selectively inhibits minor necrosis factor c~ production by stimtflated human monocytes. J Exp Med 1991;173:699703. Moreira AL, Sampaio EP, Zmuidzinas A, et al. Thalidomide exerts its inhibitory action on tumor necrosis factor ~x by enhancing mRNA degradation. J Exp Med 1993; 177:1675-80. McHugh SM, Rifldn IR, Deighton J, et al. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Thl cytokine production in mitogen- and antigen-stimulated human peripheral blood mononnclear cell cultures. Clln Exp Immunol 1995;99:160-7. Shannon EJ, Mirand RO, Morales M J, et al. Inhibition of de novo IgM antibody synthesis by thalidomide as a relevant mechanism of action in leprosy. Scand J Immunol 1981;13:553-62. Makonkawkeyoon S, Limson-Pobre RNR, Moreira AL, et al. Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proc Nail Acad Sci U S A 1993;90:5974-8. D'Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Nail Acad Sci U S A 1994;91:4082-5. Schroder JM, Sellhans B, Wohrmann T. Inhibitory effects ofthafidomide on cellularproliferation,endoneurial edema and myelin phagocytosis during early Wallerian degeneration. Acta Neuropathol 1995;89:415-9. Sheskin J. The treatment of lepra reaction in lepromatous leprosy: fifteen years' experience with thalidomide. Int J Dermatol 1980;19:318-22. Sampaio EP, Kaplan G, Miranda A, et al. The influence of thalidomide on the cfinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis 1993; 168:408-14. Shannon EJ, Ejigu M, Haile-Mariam HS, et al. Thalldomide's effectiveness in erythema nodosum leprosum is associated with a decrease in CD4+ cells in the peripheral blood. Lepr Rev 1992;63:5-11. Sheskin J. Zur therapie der pnkrigo nodularis hyde mit thalidomid. Hautarzt 1975;26:215-7. Van den Broek H. Treatment of pmrigo nodniaris with thalidomide. Arch Dermatol 1980;116:571-2. Grosshans E, llly G. Thalidomide therapy for inflammatory dermatoses, hat J Dermatol 1984;23:598-602. Londono F. Thalidomide in the treatment of actinic prurigo. Int J Dermatol 1973;12:326-8. SaulA, Flores O, Novales J. Polymorphous light eruption: treatment with thalidomide. Australas J Dermatol 1976;17:17-21. Calnan CD, Meara RH. Actinic pmrigo (Hutchinson's summer prurigo). Clin Exp Dermatol 1977;32:365-72. Lovell CR, Hawk JLM, Calnan CD, et al. Thalidomide in actinic pmrigo. Br J Dermatol 1983;108:467-71. Bernal JE, Duran MM, Londono F, et al. Cellular immune effects of thalidomide in actinic prurigo [letter]. Int J Dermatol 1992;31:599-600. Lo JS, Berg RE, Tomecki KJ. Treatment of discoid lupus erythematosus. Int J Dermatol 1989;28:497-507. 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. Atra E, Sato EI. Treatment of the cutaneous lesions of
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systemic lupus erythematosus with thalidomide. Clin Exp Rheum 1993;11:487-93. Bessis D, Guillot B, Monpoint S. Thalidomide for systemic lupus erythematosus. Lancet 1992;339:549-50. Mascaro JM, Lecha M, Torras H. Thalidomide in the treatment of recurrent, necrotic, and giant mucocutaneous aphthae and aphthosis [letter]. Arch Dermatol 1979; 115:636-7. Grinspan D. Significant response of oral aphthosis to thalidomide treatment. J Am Acad Dermatol 1985; 12:85-90. Jenkins JS, Allen BR, Maudce PD, et al. Thalidomide in severe orogenital ulceration. Lancet 1984;2:1424-6. Knrkcuoglu N, Atakan N, Eksioglu M. Thalidomide in the treatment of recurrent necrotic mucocutaneous aphthae (letter). Br J Dermatol 1985; 112:632. Laccourreye O, Fadlallah JP, Pages JC, et al. Sutton's disease (periadenitis mucosa necrotica recurrens). Ann Otol Rhinol Laryngol 1995;104:301-4. Revuz J, Gttillaume JC, Janier M, et al. Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis. Arch Dermatol 1990;126:923-7. Youle M, Clarbour J, Farthing C, et al. Treatment of resistant aphthous ulceration with thalidomide in patients positive for H1V antibody. Br Med J 1989;298:432. Gorin I, Vilette B, Gehanno P. Thalidomide in hyperalgic pharyngeal ulceration of AIDS [letter]. Lancet 1990;335:1343. Radeff B, Kuffer R, Samson J. Recurrent aphthous ulcer in patient infected with human immunodeficiency vires: successful treatment with thalidomide. J Am Acad Dermatol 1990;23:523-5. Ryan J, Colman J, Pedersen J, et al. Thalidomide to treat esophageal ulcer in AIDS [letter]. N Engl J Med 1992; 327:208-9. Ghigfiotti G, Repetto T, Farris A, et al. Thalidomide: treatment of choice of aphthous ulcers in patients seropositive for human immunodeficiency virus. J Am Acad Dermatol 1993;28:271-2. NaumSM, MolloyPJ, KaniaRJ, et al. Use ofthalidomide in treatment and maintenance of idiopathic esophageal ulcers in HIV+ individuals. Dig Dis Sci 1995;40:1147-8. Paterson DL, Georghiou PR, Allworth AM, et al. Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection. Clin Infect Dis 1995;20:250-4. Saylan T, Saltik I. Thalidomide in the treatment of Behcet' s syndrome [letter]. Arch Dermatol 1982; 118:536. Hamza M. Behcet's disease, palmoplantar pusmlosis and HLA-B27: treatment with thalidomide [letter]. Clin Exp Rheumatol 1990;8:427. Larsson H. Treatment of severe colitis in Beh~et's syndrome with thalidomide (CG-217). J Int Med 1990; 228:405-7. Jorizzo JL, Schmalsteig FC, Solomon AR. Thalidomide effects in Behget's syndrome and pustular vasculitis. Arch Intern Med 1986;146:878-81. Vogelsang GB, Hess AD, Santos GW. Thalidomide for treatment of graft-versus-host disease. Bone Marrow Transplant 1988;3:393-8. Llm SH, McWhannell A, Vora AJ, et al. Successful treatment with thalidomide of acute graft-versus-host disease after bone-marrow transplantation [letter]. Lancet 1988;1:117. Sanrat JH, Camenzind M, Helg C. Thalidomide for graftversus-host disease after bone marrow transplantation [letter]. Lancet 1988;1:359.
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61. McCarthy DM, Kanfer E, Taylor J, et al. Thalidomide for graft-versus-host disease [letter]. Lancet 1988;2:1135. 62. Heney D, Norfolk R, Wheeldon J. Thalidomide treatment for chronic graft-versus-host disease. Br J Haematol 1991;78:23-7. 63. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med 1992;326:1055-58. 64. Wood PMD, Proctor SJ. The potential use of thalidomide in the therapy of graft-versus-host disease: a review of clinical and laboratory information. Leuk Res 1990;14: 395-9. 65. Barriere H. Sarcoides cutanees: Traitement par la thalidomide [letter]. Presse Med 1983;12:963. 66. Carlesimo M, Giustina S, Rossi A, et al. Treatment of cutandous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol 1995;32:866-9. 67. Gutierrez-Rodriguez O. Thalidomide: a promising new treatment for rheumatoid arthritis. Arthritis Rheum 1984;27:1118-21. 68. Gnassia AM, Gnassia RT, Bonvalet D, et al. Histiocytose X avec 'granulome eosinophile vulvaire': effet spectaculaire de la thalidomide. Ann Dermatol Venereol 1987; 114:1387-9. 69. Viraben R, Dupre A, Gorguet B. Pure cutaneous histiocytosis resembling sinus histiocytosis. Clin Exp Dennatol 1988;13:197-9. 70. Thomas L, Ducros B, Secchi T, et al. Successful Ireatment of adult's Langerhans cell histiocytosis with thalidomide. Arch Dermatol 1993;129:1261-4. 71. Misery L, Larbre B, Lyonnet S, et al. Remission of Langerhans cell histiocytosis with thalidomide treatment [letter]. Clin Exp Dermatol 1993;18:487. 72. Mennier L, Marck Y, Ribeyre C. Adult cutaneous Langerhans cell histiocytosis: remission with thalidomide treatment [letter]. Br J Dermatol 1995;132:1. 73. Venencie PY, Saurat JH. Pyoderma gangrenosum chez un enfant: traitement par la thalidomide. Ann Pediatr 1982; 29:67-9. 74. Rustin MHA, Gilkes JJH, Robinson TWE. Pyoderma gangrenostun associated with Beh~et' s disease: treatment with thalidomide. J Am Acad Dermatol 1990;23:941-4. 75. Munro CS, Cox NH. Pyoderma gangrenosum associated with Behget's syndrome: response to thalidomide. Clin Exp Dermatol 1988;13:408-10. 76. Silva S, Viana PC, Lugon NV, et al. Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial. Nephron 1994;67:270-3. 77. Moulin G, Bonnet F, Barrut D. Traitement de la maladie de Jessner et Kanof par la thalidomide. Ann Dermatol Venereol 1983; 110:611-4. 78. Bahmer FA, Zann H, Luszpinski P. Thalidomide treatment of recurrent erythema multfforme. Acta Derm Venereol (Stockh) 1982;62:449-50. 79. Moisson YF, Janier M, Civatte J. Thalidomide for recurrent erythema mulliforme [letter]. Br J Dermatol 1992; 126:92-3. 80. Lewis HB, Albert-Recht F, Walker W. Cold haemagglutination disease treated by thalidomide. Br Soc Haematol 1968;15:322. 81. Eravelly J, Waters MF. Thalidomide in Weber-Christian disease [letter]. Lancet 1977;1:251. 82. Waters MF, Laing AB, Ambikapathy A, et al. Treatment of ulcerative colitis with thalidomide. Br Med J 1979; 1:792. 83. Barnhiil RL, McDougall AC. Thalidomide: use and pos-
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sible mode of action in reactional lepromatous leprosy and in various other conditions. J Am Acad Dermatol 1982; 7:317-23. Wallach FR, Murray HW. Thalidomide in painful AIDSassociated proctitis [letter]. J Infect Dis 1992;166:939. Naafs B, Faber WR. Thalidomide therapy: an open trial. Int J Dermatol 1985;24:131-4. Gunzler V. Thalidomide: A therapy for the immunological consequences of HIV infection? Med Hypotheses 1989;30:105-9. Stephens TD. Proposed mechanisms of action in thalidomide embryopathy. Teratology 1988;38:229-39. De Iongh RU. A quantitative ultrastmcmral study of motor and sensory lumbosacral nerve roots in the thalidomide-treated rabbit fetus. J Neuropathol Exp Neurol 1990; 49:564-81. Fullerton PM, O'SullivanDJ. Thalidomide neuropathy: a clinical, electrophysiological, and histological follow-up study. J Neurol Neurosurg Psychiatry 1968;31:543-51. Clemmensen OJ, Olsen PZ, Andersen KE. Thalidomide neurotoxicity. Arch Dermatol 1984;120:338-41. Wulff CH, Hoyer H, Asboe-Hansen G. Development of polyneuropathy during thalidomide therapy. Br J Dermatol 1985;112:475-80. Ochonisky S, Verroust J, Bastuji-Garin S, et al. Thalidomide neuropathy incidence and clinicoelectrophysiologic findings in 42 patients. Arch Dermatol 1994;130:66-9.
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93. Lagueny A, Rommel A, Vignolly B, et al. Thalidomide neuropathy: an electrophysiologic study. Muscle Nerve 1986;9:837-44. 94. Fuller GN, Jacobs JM, Guiloff RJ. Thalidomide, peripheral neuropathy and AIDS. Int J STD AIDS 1991;2:36970. 95. Aronson IK, Yu R, West DP, et al. Thalidomide-induced peripheral neuropathy. Arch Dermatol 1984;120:146670. 96. Hess CW, Hunziker T, Kupfer A, et al. Thalidomide-induced peripheral neuropathy: a prospective clinical, neurophysiological and pharmacogenetic evaluation. J Neurol 1986;233:83-9. 97. Locker D, Supersane E, Sulman FG. The mechanism of the push and pull principle VIII: endocrine effects of thalidomide and its analogues. Arch Int Pharmacodyn Ther 1971;194:39-55. 98. Revuz J. Actualite du thalidomide. Ann Dermatol Venereol 1990; 117:313-21. 99. Salafia A, Kharkar RD. Thalidomide and exfollative dermatitis. Int J Lepr 1988;56:625. 100. Bielsa I, TeLxido J, Ribera M, et al. Erythroderma due to thalidomide: report of two cases. Dermatology 1994; 189: 179-81. 101. Williams I, Weller IVD, Malin A, et al. Thalidomide hypersensitivity in AIDS. Lancet 1991;337:436-7.
B O U N D V O L U M E S A V A I L A B L E TO S U B S C R I B E R S
Bound volumesof the Journalof the AmericanAcademyof Dermatologyare availableto subscribers(only)for the 1996 issues from the Publisherat a cost of $92.50 for domestic, $118.24 for Canadian,and $110.50 for internationalfor volume 34 (January-June)and volume 35 (July-December).Shippingcharges are included.Each bound volumecontainsa subjectand authorindex and all advertisingis removed. Copies are shipped within 60 days after publicationof the last issue in the volume.The bindingis durablebuckramwith the journal name, volumenumber,and year stampedin gold on the spine.Payment must accompany all orders. ContactMosby-YearBook, Inc., Subscription Services, 11830 WestlineIndustrialDr., St. Louis, MO 63146-3318. USA: phone (800) 453-4351; (314) 453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.
HISTORY Thalidomide was introduced to the German market as Contergan in 1956 by a West German company, Chemie Grunenthal. 1 It was subsequently marketed in the United Kingdom and other countries after 1958 as a sleeping aid notable for its prompt action, lack of hangover, and apparent safety.2 Thalidomide was never approved by the U.S. Food and Drug Administration and thus never entered the American market. When tested in rodent models, thalidomide showed such low toxicity that acute LDs0 values could not be determined. 3 Accidental overdosing or deliberate suicide attempts were foUowed by unFrom the Ronald O. Perelman Department of Dermatology, Dermatopharmacology section, New York University Medical Center. Reprint requests: Jerome L. Shupack, MD, Department of Dermatology, Dermatopharmacology Section, NYU Medical Center, 550 First Ave., New York, NY 10016. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0
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eventful recovery, even at doses as high as 14 grn. 1 Isolated reports of the development of peripheral neuropathy in patients using thalidomide for an extended time 4 surfaced in 1960 but were quickly overshadowed by separate reports by McBride and Lenz of an association between maternal thalidomide usage and infant limb defects (cited in GunzletS). An estimated 5000 to 6000 infants were reported with characteristic thalidomide-induced phocomelia, often accompanied by deformities of intemal organs. 2 Thalidomide was withdrawn from the world market in late 1961, remaining available only for strictly defined research purposes. Within a few years, however, Sheskin's serendipitous discovery of thalidomide's dramatic therapeutic effect on erythema nodosum leprosum (ENL) provided the impetus for new studies of the drug in other conditions thought to have an autoimmune or inflammatory basis (cited in Hendler and McCarty6). Thalidomide is currently available in the United States under investigational new drug status.
PHARMACOLOGY Structure and chemical properties Thalidomide, or o~-phthalimidoglutarimide (Fig. 1), is a derivative of glutamic acid that is chemically related to bemegdde (oL-ethyl-a-methyl-glutarim969
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3
Metabolism
o C--NH
// 0
0
Fig. 1. Structure of thalidomide. ide) and glutethimide ([3-ethyl-[3-phenyl-glutarimide), but has different pharmacologic properties. 7 It has two ring systems: a left-sided phthalimide and a right-sided glutarimide with an asymmetric carbon atom. Thalidomide exists in optically active L- and R-isomer forms, as well as the optically inactive racemic mixture used clinically. It remains unclear whether each enantiomer has distinct clinical properties. 5 There is evidence that thalidomide in vivo rapidly interconverts between isomeric forms, obviating any benefit of treating with one enantiomer alone. 8 Thalidomide is insoluble in ether and benzene; sparingly soluble in water, methanol, ethanol, acetone, and glacial acetic acid; and readily soluble in dioxane, dimethyl formamide, pyridine, and chloroform. 7 All four amide bonds are susceptible to hydrolytic cleavage in vitro at pH values higher than 6. 5 Pharmacokinetics The plasma pharmacokinetics and urinary excretion of thalidomide have been studied by high-performance liquid chromatographic assay. After a 200 mg oral dose, plasma concentration reached a mean peak of 1.15 _ 0.2 ~tg/ml at 4.39 - 1.27 hours, with a lag time of 0.41 _ 0.17 hours seen in six of eight healthy male volunteers. Volume of distribution for thalidomide was 120.69 _+ 45.36 L. Plasma concentration versus time curve fit a one-compartment model with first-order absorption and elimination; absorption half-life was 1.7 + 1.05 hours and elimination half-life was 8.7 _+ 4.11 hours. Total body clearance rate was 10.41 _+ 2.04 L/hr. Urinary excretion was only 0.6% -+ 0.22% of total dose over 24 hours, indicating a predominantly nonrenal route of excretion. No metabolites were found in either plasma or urine samples, but thalidomide itself could be detected in plasma up to 24 hours after a single 200 mg oral dose. 9
Thorough studies of metabolism in humans have not been done, but the main degradative pathway in animals appears to be nonenzymatic hydrolytic cleavage, z° Evidence exists that hepatic metabolism of thalidomide involves the cytochrome P-450 family, and only the parent compound is enzymatically modified. Thalidomide inhibits attachment of tumor cells to concanavalin A-coated polyethylene (an in vitro assay with correlation to chemical teratogenicity) when incubated with the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) and hepatic microsomes; activation of thalidomide is preventable with established P-450 inhibitors./1 MECHANISM OF ACTION Hypnosedative effect Thalidomide's hypnosedative properties are most likely mediated by its glutarimide ring; this moiety, substituted in the 3-position with a nonspecific space-filling group, is the configuration for several other sedative-hypnotic drugs. Thalidomide acts by a different mechanism than barbiturates, possibly involving activation of a sleep center in the forebrain) Even at large doses, it does not cause incoordination or respiratory depression. 7 Immunosuppression Thalidomide prolongs survival of homografts in mice, with most marked effects when both donor and recipient are treated with thalidomide. 12 It has also shown immunosuppressive properties in baboon and rhesus monkey renal allografts by lowering erythropoietin levels, considered a marker for progress of renal rejection. ~3 When studied in guinea pigs and rats with experimental allergic encephalomyelitis, allergic neuritis, nonspecific granulomata, or adjuvant disease (a disease induced in rats, with features resembling ENL), thalidomide reduced the sign of adjuvant disease slightly but had no effect in any of the other models for autoimmune disease. 14, 25 Other effects Multiple effects of thalidomide have been shown both in vivo and in vitro. Preincubation of polymorphonuclear cells with thalidomide inhibits chemotaxis, but direct addition of the drug to chemotactic factor does not. 16 At 10 lag/ml, thalidomide significantly decreases monocyte phagocytosis without apparent cytotoxicity. 17 Healthy volunteers given
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T a b l e I. Therapeutic uses of thalidomide No. of patients treated
No. of patients improved
Dosage (mg/day)
References No(s).
4522 16 124 112 175 29 58
99% 16 116 94 165 24 35
100-400 200-400 100-300 100-400 100-400 200-400 100-800
26 29-31 32-35 31, 38-40, 103 41-53 54-57 59-63
1 6 7 6 3 55%-57% 5 3 1 1 1 >50% 2 1 1
100-200 100-200 300-600 50-300 100-400 100 100 100-200 N/A 100-300 200-400 100-300 300 50-100 50-100
55 65, 66 67 68-72 73-75 76 77 78, 79 80 81 82 83 84 85 85
Efficacy seen in multiple series
Erythema nodosum leprosttm Pmrigo nodularis Actinic pururigo Discoid lupus erythematosus Aphthous stomatitis Beh~et's syndrome Graft-versus-host-disease
Efficacy seen in single series or case reports
Palmoplantar pustulosis Sarcoidosis Rheumatoid art_h.ritis Langerhans cell histiocytosis Pyoderma gangrenosum Uremic pruritus Jessner-Kanof disease Recurrent erythema mulliforme Cold hemagglutination disease Weber-Christian disease Ulcerative colitis Postherpetic neuralgia AIDS-associated proctitis Bullous pemphigoid Cicatricial pemphigoid
1 6 7 6 3 29 5 3 1 1 1 10 2 1 1
N/A, Not available. thalidomide showed a decrease in their circulating helper-T to suppressor-T cell ratio because of a highly significant drop in helper-T cells and an apparent increase in suppressor-T cells. 18 Thalidomide selectively inhibits rumor necrosis factor--~ (TNF-o0 production 19 by enhancing degradation of TNF-o~ messenger RNA, 2° without affecting production of interleukin-1 (IL-1), IL-6, granulocyte-macrophage colony-stimulating factor, or general proteins. 19 Specific thalidomide-induced inhibition of interferon gamma (WN--,/) production and enhancement of IL-4 and IL-5 production has been seen in human peripheral blood mononuclear cell cultures. 21 Formation of IgM antibody decreased when thalidomide was fed to mice for 5 to 7 days before immunization with sheep red blood cells. 22 Thalidomide suppressed activation of latent HIV-1 in an in vitro monocytoid line and in the peripheral blood of 16 of 17 patients with AIDS. 23 In another recent study, it inhibited basic fibroblast growth factor-induced angiogenesis in a rabbit cornea micropocket assay through an unknown mechanism. 24 When studied for effect on Wallerian
degeneration in rats (used as a model for reproducible cell proliferation), thalidomide decreased cellular proliferation, subperineurial edema, and myelin phagocytosis. Endoneurial cell counts at 10 to 15 days after transection of the sciatic nerve were also lowered. 25 THERAPEUTIC
USE
Thalidomide has shown good therapeutic effect in ENL, prurigo nodularis, actinic pmrigo, discoid lupus erythematosus (DLE), aphthous stomatitis, Behget's disease, and graft-versus-host-disease. Large controlled trials have been performed only in ENL and aphthous stomatitis. Efficacy in case reports or small series has also been reported in other mucocutaneous disorders (Table I). ENL
The World Health Organization conducted a double-blind study in 1967 confirming the drug's efficacy in ENL. Ten years after his first report, Sheskin 26 surveyed data from 4522 cases around the world and found a 99% response rate. Thalidomide has demonstrated no direct effect against Mycobac-
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terium leprae, but is currently first-line therapy for the treatment of ENL. Shesldn26 observed resolution of ENL lesions 24 to 48 hours after beginning thalidomide therapy. Other signs and symptoms such as headache, anorexia, vomiting, orchitis, arthralgia, myalgia, and hepatosplenomegaly were also quick to remit. Leukocyte count and erythrocyte sedimentation rate returned to normal. In long-term follow-up, motor conduction velocity in the ulnar nerve improved within 48 hours and returrled to near-normal levels after 2 weeks of treatment, supporting a beneficial effect of thalidomide on reactional neuritis or polyneuritis in ENL. 26 Elevated serum TNF-oL and associated elevated IFN-~/have been found in patients with systemic ENL, with positive correlation between intensity of inflammatory state and TNF-oL level. After thalidomide therapy, patients showed decreased serum TNF-a, decreased dermal infiltration of polymorphonuclear leukocytes and T cells, and intercellular adhesion molecule major histocompatibility complex class II antigens on epidermal keratinocytes. Fever, malaise, and arthritic/neuritic pain were alleviated within 24 to 48 hours; nodules showed involution by 3 days and disappeared within 10 days. 27 A selective decrease in serum IgM concentration22 and numbers of helper-T cells (often elevated in blood and skin lesions of patients with ENL during active episodes)28 have also been shown in patients with leprosy receiving thalidomide for ENL.
Prurigo nodularis S h e s k i n 29 gave a preliminary report in 1975 of good results in three patients with prurigo nodularis at a dose of 300 to 400 mg daily. Van den Broek3° followed with a report of flattening of lesions and disappearance of pruritus over a 3-month period in a patient given thalidomide, 200 mg/day. Eosinophilia was noted as the only change. Twelve additional patients treated in separate studies had reduction of pruritus in 2 to 3 weeks and resolution of severely lichenified lesions in several months. 31
Actinic prurigo Londono 32 treated 34 patients with actinic pmrigo with an average thalidomide dose of 300 mg/day tapered to maintenance doses as low as 15 mg/day. All but two showed good improvement within 21 to 91 days (average, 50 days) with no major side effects, and in all cases discontinuation of thalidomide led to
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recurrence.32 Saul, Flores, and Novales 33 treated 25 patients with various forms of polymorphous light eruption at 100 to 200 rag/day for 45 to 150 days, with excellent or good results in 88%, fair results in 8%, and poor results in 4%. Improvement was first noticed after an average of 15 days. Twelve patients remained asymptomatic 1 year after treatment ended. Calnan and Meara 34 confirmed the efficacy of thalidomide in actinic pmrigo in a series of 51 patients. Lovell et al.35 treated 14 patients with actinic prurigo with 100 to 200 mg/day, leading to prolonged improvement in 11. Three remained clear after treatment ended; the other eight required maintenance doses of 50 to 100 mg/week. A study of 15 randomly selected patients with actinic pmrigo given thalidomide 100 mg/day for 2 months showed decreased CD3 ÷ and CD4 ÷ levels during the first 45 days, with levels rising again after day 45. No significant changes were noted in CD8 ÷ levels or B-cell counts. 36
Discoid lupus erythematosus Barba-Rubio and Franco-Gonzalez were the first to use thalidomide in discoid lupus erythematosus, with theft results confirmed by Grosshans and Illy31 in an open study of 25 patients. After reviewing 156 reported cases, they concluded that thalidomide had a failure rate of less than 10%. An initial dose of 100 to 200 mg gave results within 2 weeks in most patients; 75% required maintenance therapy of 25 to 50 mg/day. A later review by Lo, Berg, and Tomecki37 revealed similar conclusions. In one series of 60 patients with a mean intake of 85 gm of thalidomide (range, 15.5 to 132 gm), the appearance of mild to moderate polyneuritic symptoms in 25% led the authors to recommend restricting thalidomide to cases resistant to topical steroids and systemic antimalarials. 38 Thalidomide in patients with systemic lupus erythematosus (SLE) seems to improve cutaneous and articular symptoms without affecting visceral features of the disease. A study of 23 patients with SLE and cutaneous lesions unresponsive to standard therapies had a 90% rate of complete remission and a significant reduction in average dose of prednisone required (from 40.5 mg/day down to 17.4 mg/day) while receiving thalidomide, 300 mg/day. Thirtyfive percent had recurrence from 2 months to 4 years after the drug was discontinued. A significant drop in the gammaglobulin level was seen in 10 of 13 patients. 39 In another study, three patients with SLE
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showed stable immunologic indices (antinuclear antibody, anti-DNA antibodies, and complement) and good control of skin and articular manifestations while receiving thalidomide.4°
Aphthous stomatitis Mascaro, Lecha, and Torras 41 reported successful use of thalidomide in six patients with recurrent and necrotic mucocutaneous aphthae; at 100 mg/day, aphthae were painless by the third day and had healed in 7 to 10 days. Grinspan42 treated 40 patients with aphthous manifestations including bipolar (oral and genital) aphthae and Sutton' s disease (periadenitis mucosa necrotica recurrens) with 100 to 300 mg/day for 1 to 3 months, resulting in 35% remissions and 40% marked improvement. Efficacy in severe orogenital ulceration was seen in a doubleblind controlled trial of thalidomide versus placebo in 15 patients, with complete clearing in 14 and significant improvement in the remaining patient. 43 Success with thalidomide in five patients with recurrent, deep necrotic aphthae44 and another patient with Sutton's disease45 was also reported. A multicenter crossover randomized trial of thalidomide versus placebo was conducted by Revuz et al. 46 in patients with severe aphthous stomatitis of greater than 6 months' duration. Complete remission was seen in 32 of 73 patients (44%) receiving thalidomide versus 6 (8%) taking placebo, with most others showing a dramatic decrease in the number of aphthae while receiving the drag. Thalidomide showed a suppressive effect only because relapses were regular after discontinuation, with a mean duration of remission of 20 days. Youle et al.47 reported rapid healing of resistant aphthous ulcers in seven patients with HIV given 100 mg/day for 2 weeks. Multiple case reports of patients with AIDS and hyperalgic ulcerations of unknown cause including esophageal ulcerations interfering with eating have shown dramatic response within 2 weeks to thalidomide, 100 rag/ day.48-52 Paterson et al.53 performed a retrospective review of 20 patients with HIV receiving thalidomide from 1989 to 1993 for painful refractory ulcerative disease of the oropharynx, esophagus, and rectum. Viral, fungal, and spirochetal causes of ulceration had been previously excluded. A standard treatment of 200 mg/day was given for 2 weeks; four patients with recurrences were given an additional course of treatment. Fourteen patients had complete healing and all others had improvement so that an-
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algesics or local treatment were no longer needed. CD4 + cell counts did not change during or after treatment.53
Beh~et's syndrome After reports of its beneficial effect in recurrent mucocutaneous aphthae, thalidomide (400 mg/day for the first 5 days, then 200 mg/day for 15 to 60 days) was administered to 22 patients with flatly developed Beh~et's syndrome. Oral and genital lesions healed almost immediately, with recurrences becoming milder and less frequent. No effect was seen on ocular lesions. 54 Treatment of a patient with Beh~et' s syndrome in association with palmoplantar pusmlosis (200 mg/day for 2 months followed by 100 mg for 12 months) resulted in complete clearing of both the palmoplantar pustulosis and the mucocutaneous lesions within 2 weeks. 55 In a patient with complete Beh~et's syndrome given thalidomide as a final pharmacologic measure to avoid colectomy, 300 rag/day resulted in normalization of stools (including negative testing for blood) within a day, followed by rapid normalization of rectal mucosa. The dose was tapered to 200 mg after 2 weeks, then 100 mg after an additional week, Oral ulcers and pleural effusion disappeared, and symptoms did not recur during a 5-month follow-up. 56 In another study, four patients with Behqet' s syndrome and one with bowel-associated dermatosisarthritis syndrome received sequential 4-week " o n " and "off" thalidomide therapeutic cycles (total study period, 12 weeks). The dose was 200 mg/day during the active treatment periods. Three patients who finished the study had complete cleating of mucocutaneous lesions and arthritic symptoms. All patients had recurrence of lesions and symptoms within 1 to 2 days of discontinuing thalidomide. In this small sample, no effect was seen on neutrophil migration or the LFA-1/Mac-1/p150,95 family of glycoproteins associated with neutrophil adherence. During therapy, three of four patients converted from positive to negative for circulating immune complexes after histamine injection, possibly supporting an inhibitory effect of thalidomide on vasculitisinduced by these complexes.57
Graft-versus-host disease When tested in a rat MHC mismatch model (used previously in cyclosporine studies), thalidomide was effective both as prophylaxis and in established acute graft-versus-host disease (GVHD). 5s Single patients with acute cutaneous G V H D , 59 sclerotic chronic
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cutaneous GVHD, 6° chronic GVHD involving airway disease, and chronic GVHD evolved into a generalized sicca syndrome61 showed progressive improvement when treated with thalidomide. Four of six other patients with severe chronic GVHD showed marked improvement in skin texture and mobility as well as oral mucocutaneous symptoms, with the best responses in chronic cutaneous GVHD and the poorest responses in multiple-system disease. 62 In a preliminary trial of 44 patients with refractory or "high-risk" chronic GVHD, Vogelsang et al.63 administered thalidomide for 3 to 6 months at a dose of 800 mg/day for an average size adult. Fourteen patients showed a complete response (complete clearing of disease in all organ systems), 12 showed a partial response (improvement of more than 50% but less than 100% in all affected organ systems), and 18 showed no response. Survival rate was 76% among patients receiving thalidomide for refractory GVHD and 48% in the high-risk group. 63 Thalidomide' s mode of action in GVHD has been suggested as involving metabolites of thalidomide acting at an early stage in the antigen recognition-activation pathway of graft T lymphocytes to downregulate normal lymphocyte responses. 64
Sarcoidosis The efficacy of thalidomide in sarcoidosis was first reported by Barfiere65 in four patients, two with cutaneous manifestations and two with cutaneous and pulmonary manifestations. Recently, Carlesimo et al.66 treated two patients: one with systemic sarcoidosis and the second with pulmonary sarcoidosis in whom Kaposi's sarcoma developed after corticosteroid therapy. Reduction was noted in cutaneous lesions, hilar lymphadenopathy, and Kaposi's sarcoma after 2 weeks of thalidomide, 200 rag/day. Elevated serum angiotensin-converting enzyme levels returned to normal, suggesting an inhibitory effect of thalidomide on macrophage function, which includes synthesis and release of large amounts of angiotensin-converting enzyme.
Rheumatoid arthritis In an open trial of seven patients, Gutierrez-Rodriguez67 began thalidomide treatment at 300 mg/day, increasing the dose by 100 mg every 1 to 2 weeks until joint pain disappeared. Five patients reached a maximum dose of 600 mg, one patient 500 mg, and
one patient 400 mg without side effects other than drowsiness, constipation, and lower limb edema. Pain and joint inflammation disappeared after seve r n weeks, and four patients had prolonged posttreatmentremission. All had normalization or marked reduction of their erythrocyte sedimentation rate and several showed a decrease in rheumatoid factor titer. Rheumatoid nodules in one patient shrank by the third week and disappeared by the twelfth week.
Langerhans cell histiocytosis A dramatic effect of thalidomide on vulvar eosinophilic grannloma as part of "histiocytosis X " was first reported by Gnassia et al.68 Another patient with cutaneous histiocytosis resembling sinus histiocytosis experienced complete remission after 1 month at 300 mg/day without recurrence after discontinuation. 69 Four additional cases of adult cutaneous Langerhans cell histiocytosis remitted after 1 to 3 months of therapy with frequent recurrences after stopping treatment. Thalidomide appeared to have little or no effect on the visceral manifestations of disease. 7°-72Histopathologic examination showed disappearance of the histiocytic infiltrate after treatment, suggesting an effect of thalidomide on the proliferative Langerhans cell population. 7°
Pyoderma gangrenosum Administration of 100 rag/day of thalidomide to a 3-year-old girl with extensive pyoderma gangrenosum refractory to corticosteroids or clofazimine led to complete recovery.7s Skin lesions typical of pyoderma gangrenosum have been reported in association with Behqet's syndrome in only a few patients, with thalidomide therapy tried in two isolated cases. In both patients, thalidomide at an initial dose of 400 mg/day (tapered to 50 to 100 mg/day) led to almost immediate improvement, with complete heating of skin lesions and no new appearance of mucosal ulcerations.74, 75
Other In a crossover, randomized, double-blind trial of 29 hemodialysis patients with refractory uremic pruritus, there was a 55% response rate (78% mean reduction in pruritus) in patients on 100 mg/day of thalidomide, compared with no response in the control group. During the second phase of the trial, patients receiving thalidomide had a 57%
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response (81% mean reduction) compared with 25% response (54% mean reduction) in those receiving placebo. 76 Therapeutic results with thalidomide in JessnerKanof disease] 7 recurrent erythema multiforme,7s, 79 cold hemagglutination disease, 8° Weber-Christian disease, 81 ulcerative colitis, 82 postherpetic neuralgia, 83 and painful AIDS-associated proctitis 84 have been reported. Naafs and Faber, 85 in an open trial of 35 patients with a variety of dermatologic conditions, also noted thalidomide's efficacy in a patient with bullous pemphigoid and a patient with cicatricial pemphigoid. Thalidomide's ability to inhibit production of TNF-o~, which plays a role in the activation of latent HIV, has made it the subject of phase IBI trials in patients with HIV. In addition to suppressing HIV replication and viral burden, it may enhance patient well-being by reducing TNF-oL-induced fever, malaise, muscle weakness, and cachexia.23 Theoretically, the use of an immunomodulatory drag such as thalidomide in an already immunosuppressed population may carry the risk of further worsening their immune status. 5, 86
ADVERSE EFFECTS Teratogenicity A distinct window for thalidomide's embryopathic effect has been well established. The sensitive period is estimated to be from 34 to 50 days after conception; a single dose of 100 mg during this time (leading to a plasma concentration of approximately 1 rag/L) is sufficient to produce malformations.5 The actual mechanism of action of thalidomide embryopathy remains unknown, despite numerous studies during the past three decades. In a review of 24 proposed mechanisms acting on the biochemical, cellular, or tissue-organ levels, Stephens s7 noted that eight proposals have been refuted by other experimental or observational data and the remaining 16 stand primarily because they have not been rigorously tested. Observation of thalidomide' s neurotoxic effect on both sensory and motor rabbit fetal nerve roots has suggested an effect on neural as well as limb development, as Limb defects secondary to an inhibition of blood vessel growth in the developing fetal limb bud have also been postulated. Electron microscopic studies showed similarities between ultrastmcmral changes in the vasculamre of deformed embryo limb
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buds and the inhibition of corneal neovascularization in thalidomide-treated rabbits, a4
Peripheral neuropathy Early reports of peripheral neuropathy in patients taking thalidomide described mostly sensory symptoms, sometimes accompanied by mild proximal muscle weakness or evidence of mild pyramidal tract damage. Although muscle weakness decreased rapidly after discontinuation of drag, sensory deficits were slow to improve, and occasionally worsened even while the patients were not taking thalidomide. 89 The clinical features of thalidomide-induced neuropathy have since been well characterized as predominantly symmetric painful paresthesias of the hands and feet, frequently accompanied by lower limb sensory loss. 88 Muscle weakness, muscle cramps, signs of pyramidal tract involvement, and carpal tunnel syndrome have been reported in many patients.88, 9o-92An unpleasant feeling of "tighmess around the feet" was described with an incidence of 8% to 47% in larger series. 9° Electrophysiologic findings are consistent with axonal neuropathy, showing reduced sensory nerve action potential amplitude on the sural, median, and peroneal nerves with relative conservation of conduction velocities. 88'9° Increased somatosensoryevoked potential latency after sural nerve stimulation can be seen in thalidomide-treated patients in the absence of clinical abnormalities. 93 Pathologic findings on sural nerve biopsy reveal selective loss of large diameter fibers without segmental demyelination88, 94; occasional marked increases in the number of small fibers may be indicative of regeneration.88 In a follow-up of patients with thalidomideinduced neuropathy for 4 to 6 years after ending treatment, 25% had full recovery, another 25% had some improvement, and 50% had no change in sensory symptoms and signs. Improvement was notably slow to occur and in a few patients did not begin for years, as The incidence of thalidomide-induced neuropathy has been variously estimated in retrospective studies from less than 1% in patients treated for lepra reactions to more than 70% in patients treated for pmrigo nodularis. 90,91,95 Dose-dependent development of neuropathy has been suggested by some authors 88, 9o with symptoms beginning after a cumulative dose around 40 to 50 gm, 89 although no relation to dose
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Table II. Clinical side effects
BriNe fingernails Constipation Decreased libido Dizziness Drowsiness Endocrine effects Exfofiative/erythrodermicreaction Face/limb edema Increased appetite Menstruation abnormalities Mood changes Nausea Peripheral neuropathy t5"ufitus Red palms Teratogenicity Xerostomia
has been found in other studies. 92, 96 Special consideration must be given to patients with HIV because the higher incidence of preexisting neuropathy in this group (estimated to be 15% to 50%) may make them particularly sensitive to thalidomide's neurotoxic effects.6 A recent retrospective review of patients treated with thalidomide for various dermatologic conditions found the incidence of thalidomide-induced neuropathy to be between 21% and 50%, with the highest risk in women and elderly patients. No relation was found to dose or duration of treatment, with neuropathy beginning at a cumulative dose of only 3 to 6 gm in some. Individual susceptibility with a possible genetic predisposition was suggested as more relevant to the development of neuropathy than dose or duration of therapy.92 A possible relation between slow acetylators and development of thalidomide-induced neuropathy has also been suggested. 96 Occasional worsening of electrophysiologic abnormalities after drug withdrawal suggests a prolonged action of thalidomide.93 Serum from patients with symptoms of thalidomide-induced neuropathy induced morphologic changes in cultured rat dorsal root ganglion cells, characterized by altered appearance of nerve cell soma, maintained integrity of axons and myelin sheath, and infiltration by macrophages. This was true even of serum samples obtained 16 months after discontinuation of thalidomide, indicating the presence of a neurotoxic factor that remains in serum for more than a year. A direct
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neurotoxic effect was ruled out because serum obtained from an asymptomatic patient also receiving thalidomide did not cause morphologic changes. Given the drug's excretion pharmacokinetics, there is also no evidence that the neurotoxic factor is residual thalidomide.95 Because of the severity and possible irreversibility of thalidomide-induced peripheral neuropathy, baseline and follow-up electrophysiologic testing with expedient dosage reduction upon abnormal results may reduce risk before the often rapid emergence of clinical symptoms. 93 E n d o c r i n e effects
Thalidomide slightly depresses thyroid secretory activity, an effect common to other sedative drugs that may be secondary to reduction in body activity7 or inhibition of thyroid-stimulating hormone production. 97 It has also been reported to stimulate ACTH and prolactin production or secretion97 and cause hypoglycemia. Other
Drowsiness, dizziness, mood changes, constipation, and xerostomia are often reported in patients taking thalidomide.5, 31, 85, 98 Other clinical side effects occurring less frequently include brittle fingernails, red palms, increased appetite, loss of libido, face/limb edema, nausea, pruritus, menstmal abnormalities, and galactorrhea (Table ID. Exfoliative99 and erythrodermic100 reactions have occasionally been reported. Thalidomide has also been rarely reported to induce allergic vasculitis and thrombocytopenic purpura. 3 Hypersensitivity reactions have been reported in patients with AIDS receiving thalidomide and may be more common in this population. 1°1 DRUG INTERACTIONS
Thalidomide enhances the activity of barbiturates, alcohol, chlorpromazine, and reserpine. It also antagonizes the action of histamine, serotonin, acetylcholine, and prostaglandins in organ bath experiments .5 CONCLUSION Treatment with thalidomide has given good to excellent results in various mucocutaneous conditions. It occasionally produces dramatic improve-
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m e n t in p a t i e n t s u n r e s p o n s i v e to m u l t i p l e o t h e r therapies. D e s p i t e its d a n g e r s , m o s t n o t a b l y teratogenicity and peripheral neuropathy, thalidomide m a y p r o v e h i g h l y u s e f u l in a p p r o p r i a t e l y s e l e c t e d patients.
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