Thalidomide: a novel template for anticancer drugs.

Thalidomide is an immunomodulatory agent that is approved for use in patients with cutaneous manifestations of erythema nodosum leprosum (ENL). It is currently under clinical investigation in a wide range of malignancies and immunologic-based disorders. Structural analogs of thalidomide have been synthesized in order to explore potential molecular targets of thalidomide, as well as to identify new therapeutics. Members of one class of analogs, termed immunomodulatory drugs (IMiD), are 100 to 1,000 times more potent than thalidomide in regulating cytokine production by peripheral blood mononuclear cells and providing a costimulatory signal for T-cell proliferation. Notably, the nature of the stimulus and the cell type are important determinants as to whether the IMiDs or thalidomide cause an inhibitory or stimulatory effect. The IMiD CDC-501 has been selected for clinical development; it had been safely administered to volunteers in single doses of 50 to 400 mg and in multiple doses of 100 mg for 7 days. Phase I/II studies of CDC-501 in multiple myeloma are in progress.

[Minocycline]. / Minocycline.

Minocycline belongs to the second generation class of cyclines. It was synthesized in 1967 and marketed in 1972. Minocycline has an antiinfectious activity with a spectrum similar to that of other cyclines, notably against Chlamydias, Treonema and Proprionibacterium acenes. The antiinflammatory activity is associated with this antiinfectious action is greater than that of first generation cyclines with specifically a modulator effect on epidermal cytokines. The pharmokinetics of minocycline is characterized by an excellent absorption, a long half-life and an important lipophilic property inducing good tissue distribution. Clinical trials of minocycline have mainly been performed in sexually transmissible diseases and in acne, a field where randomized studies are the most frequent. These trials show that the effect of minocycline is not stronger than first generation cyclines or doxycycline, but that the action is quicker than that of tetracycline at the dose of 500 mg a day. Minocycline is also efficient in nocardiasis, mycobacteriosis, leprosy, Lyme disease, pyoderma gangrenosum, autoimmune bullous dermatitis, Carteaud disease, and prurigo. However, the effect of minocycline in these different conditions has always been evaluated in open trials with a small number of patients. The usual side effects of cyclines, i.e. digestive problems, fungal infections, are less frequent than with first generation cyclines. No photosensitivity has been demonstrated although pigmentations have been described. Dizziness is a specific side effect of minocycline. Furthermore, rare but severe side effects have been reported, including hypersensitivity syndrome, autoimmune hepatitis, and lupus. Regular indications for minocycline in dermatology are acne and three sexually transmissible diseases (mycoplasm, chlamydia, treponema). Proposed dosage is 100 mg per day in sexually transmissible disease with a reduction to 50 mg per day after 15 days in acne.

Steroids in leprosy type 1 (reversal) reactions: mechanisms of action and effectiveness.

Steroids are widely used for the treatment of leprosy reactions. The effectiveness of steroid treatment is variable, with only 60% of patients regaining nerve function. Sequential skin biopsy specimens, obtained from 15 patients with type 1 (reversal) reactions, have been studied to document the cytokine profile and cellularity of the lesions. All of the patients were placed on a standard course of steroids after the first biopsy. Subsequent biopsies were performed seven, 28 and 180 days later. The specimens were stained for interferon-gamma (IFN gamma), interleukin-12 (IL-12) and inducible nitric oxide synthase (iNOS). After the first biopsy, all patients were placed on a standard reducing course of steroids beginning at 30 mg daily. By day 7, treatment with prednisolone showed little effect on the cellularity and cytokine profiles. However, by day 28, significant decreases of IFN-gamma, IL-12 and iNOS were found for most patients. Some patients maintained cytokine production at day 28 and even at day 180. These data illustrate the strong Th1 profile of type 1 reactional lesions, the relatively slow response to therapy, and the continuing activity after treatment with steroids for 180 days. The variation of individual responses emphasizes their importance. Additional prospective studies will be required to determine whether patients with high intra-lesional levels of cytokine are at risk of recurrent reactions. The need for studies both of different glucocorticoids and of other non-steroidal immunosuppressants for the treatment of reactions is discussed.

Cytokines in leprosy, II. Effect of treatment on serum cytokines in leprosy.

BACKGROUND: Multidrug therapy (MDT) causes a decrease in the bacterial burden in leprosy patients. Does the decrease in the antigenic stimulation of the immune system have an effect on cytokine production? METHODS: The effect of treatment on serum cytokines was evaluated in 36 leprosy patients and 35 reactional leprosy patients and compared with that in 20 age- and sex-matched healthy individuals. The enzyme-linked immunosorbent assay (ELISA) technique was used to measure serum levels of interleukin-2 receptor (IL-2R), interleukin-10 (IL-10), and interleukin-1beta (IL-1beta) before and after treatment. These cytokines represent T-helper 1 (TH1), T-helper 2 (TH2), and macrophage cytokines, respectively. RESULTS: The studied serum cytokines were significantly reduced after 1 year of treatment in leprosy patients. The degrees of reduction were significantly positively correlated with a reduction in the bacterial index (BI) and morphologic index (MI). After 1 year of MDT (but not 6 months), paucibacillary (PB) patients showed a significant reduction in all the studied serum cytokines to levels comparable with those of healthy controls. Multibacillary (MB) patients also showed a significant reduction in all the studied serum cytokines, but the levels were still significantly higher than those of healthy controls. Leprosy patients with high levels of serum IL-1beta were more susceptible to the development of reactions after the initiation of treatment. Corticosteroid therapy of reactional patients resulted in a significant reduction in the studied serum cytokines to levels similar or lower than those of nonreactional leprosy patients. The dose of steroids showed a significant positive correlation with the amount of decrease in IL-1beta. CONCLUSIONS: MDT caused a reduction in serum cytokines correlated with a reduction in the bacterial burden. It is advisable to continue MDT for PB patients for 1 year. Serum IL-1beta levels may have a prognostic value for the susceptibility of leprosy patients to the development of reactions.