As discussed above, thalidomide has been used for the treatment of leprosy, graft versus host disease, rheumatoid arthritis, aphthous ulcers associated with AIDS, and various dermatologic disorders. The side effects of thalidomide have been well documented and they include: drowsiness, constipation, peripheral sensory neuropathy, swelling of the limbs, erythema of the limbs, hair loss, fever, rash, and amenorrhea. Dizziness and mood changes occurred in 33-100% of all patients. Other frequent adverse effects are xerostomia, increased appetite, loss of libido, nausea, pruritus, and menstruation abnormalities have been occasionally observed. The most serious of these side effects is peripheral neuropathy. Its incidence has been estimated to be approx 1% in patients treated for lepra reactions (81), 12% in rheumatoid arthritis (65), 22% in prurigo nodularis (66), and 25% in patients with discoid lupus erythematosus (67). Based on electrophysiologic studies the incidence was estimated at 21% (68). Peripheral neuropathy consists clinically of a symmetrical distal paresthesia with sensory loss in distal limbs, predominately the toes. Motor involvement is rare but can occur later, especially if the drug is continued despite development of sensory involvement. While some studies noted a dose dependent pattern with neuropathies occurring only after cumulative doses of greater than 40 grams (69,70), other studies have not demonstrated a correlation between the incidence of the neuropathy and the dose or duration of thalidomide treatment (68,71). Paresthesias are often noted early in the course of the neuropathy, before other neurologic signs develop (68). A higher incidence of neuropathy has been reported in females and the elderly (72). The neuropathy does not appear to progress after discontinuation of the drug (71). In many cases the neuropathy appears to be reversible if treatment is discontinued once it is detected (73,74).
A group from Columbia reported treating 17 patients with arthritis with a dose of400-600 mg/d of thalidomide (mean duration of therapy, 24.8 mo, range 7-65 wk) (75). They found that two patients developed symptoms of peripheral sensory neuropathy that was reversed on discontinuation of therapy. Crawford reported that 25% of patients (n = 60) receiving thalidomide for the management of chronic discoid lupus erythematosus developed neuropathies, and all patients (n = 8) receiving it for nodular prurigo and aphthous stomatitis were found to have neuropathies (76). Sheehan reported the development of neurological complications in 2 of 5 patients receiving thalidomide for prurigo nodularis (77). Polyneuropathy persisted in one of those patients for >12 mo after the discontinuation of therapy. Aronson et al. reported the development of sensory peripheral neuropathies (onset 2-12 mo into therapy) in 3 of 4 patients with prurigo nodularis that were receiving thalidomide (100-300 mg/d) (78). Their in vitro work went on to show that thalidomide induced primary neuronal degeneration. Schroder et al. reported that there was a reduction in myelin thickness of sural nerve fibers (reduction in sheath thickness) and a decrease in conduction velocity in thalidomide-treated New Zealand white rabbits as compared to controls (79). Patients with pre-existing neuropathies may be particularly sensitive to the development of thalidomide polyneuritis (75,80). On the other hand, peripheral nerve abnormalities are affected in lepromatous leprosy. Neuritis is present during ENL episodes, resulting in neuralgia and decreased motor conduction velocity. Thalidomide treatment improves these symptoms because of suppression of the inflammatory process (36,81). Thalidomide neuropathy was not observed after repeated ENL episodes treated with thalidomide (81), but it may be difficult to differentiate from the neuropathological changes caused by the underlying disease.
Effects of thalidomide on the endocrine system have been consistently observed in both clinical trials and animal experiments. These actions may be the result of an effect of the drug on the hypothalamus (82). In humans, a tendency to normalize hyperthyroid states has been noted. Iodine uptake by the thyroid gland was slightly decreased, and myxedema was occasionally observed. Increased urinary secretion of 17-hydroxycorti-costeroids associated with hypoglycemia has been reported. Thalidomide was found to antagonize the action of histamine, serotonin, acetylcholine, and prostaglandins in organ bath experiments, but had no influence on the uterine reaction to oxytocin, vasopressin, and histamine (82).
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