Management of sulfur mustard-induced chronic pruritus: a review of clinical trials.
ABSTRACT Skin is among the most heavily damaged organs upon sulfur mustard (SM) exposure. Chronic complications due to SM-induced dermatotoxicity are quite frequent among intoxicated patients. Nevertheless, the exact pathophysiology of SM-induced chronic cutaneous complications has not been well clarified yet. The present review highlights clinically important findings on the management of SM-induced chronic skin complications with a particular focus on pruritus as the most prevalent symptom that has a significant impact on patients' quality of life. Some methodological pitfalls that implicate the validity of the trials have also been identified.
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ABSTRACT: 1. The mechanism of toxicity of sulphur mustard was investigated by examining the biochemical effects of the analog 2-chloroethylethyl sulphide (CEES) in both human Jurkat cells as well as normal human lymphocytes. 2. Exposure of both types of cells to CEES resulted in a marked decrease in the intracellular concentration of the reduced form of glutathione (GSH), and CEES-induced cell death was potentiated by l-buthionine sulphoximine, an inhibitor of GSH synthesis. 3. CEES increased the endogenous production of reactive oxygen species (ROS) in Jurkat cells, and CEES-induced cell death was potentiated by hydrogen peroxide. 4. CEES induced various hallmarks of apoptosis, including collapse of the mitochondrial membrane potential, proteolytic processing and activation of procaspase-3, and cleavage of poly (ADP-ribose) polymerase. 5. The effects of CEES on the accumulation of ROS, the intracellular concentration of GSH, the mitochondrial membrane potential, and caspase-3 activity were all inhibited by pretreatment of cells with the GSH precursor N-acetyl cysteine or with GSH-ethyl ester. Furthermore, CEES-induced cell death was also prevented by these antioxidants. 6. CEES toxicity appears to be mediated, at least in part, by the generation of ROS and consequent depletion of GSH. Given that sulphur mustard is still a potential biohazard, the protective effects of antioxidants against CEES toxicity demonstrated in Jurkat cells and normal human lymphocytes may provide the basis for the development of a therapeutic strategy to counteract exposure to this chemical weapon.British Journal of Pharmacology 04/2004; 141(5):795-802. · 5.07 Impact Factor
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ABSTRACT: The purpose of this study was to measure the absorption and intra-epidermal fate of 35S-radiolabelled sulphur mustard (35SM) in human breast skin in vitro. Skin (full-thickness or heat-separated epidermis) was placed into static diffusion cells and was exposed to droplets of liquid 35SM or saturated 35SM vapour. Amounts of 35SM penetrating the skin were measured from which skin absorption rates were calculated. Unbound radiolabel was washed from the surface, extracted from the skin and analysed to determine the identity of the radiolabelled species in order to measure the extent of hydrolysis of sulphur mustard. Penetration rates of liquid 35SM measured in vitro (71-294 microg cm(-2) h(-1)) were in agreement with those measured previously in vivo using human volunteers (60-240 microg cm(-2) h(-1)). Rates of liquid 35SM skin absorption under occluded, infinite dose conditions were highest through heat-separated epidermal membranes (294+/-58 microg cm(-2) h(-1)) and lowest through full-thickness skin (71+/-14 microg cm(-2) h(-1)). Fluxes of saturated 35SM vapour (110+/-75 microg cm(-2) h(-1)) through heat-separated membranes were similar to those previously measured through human forearm skin in vivo (162 microg cm(-2) h(-1)). Although hydrolysis of 35SM did occur, both on the surface and within the skin, it accounted for only a small percentage of the total applied dose (<2.7+/-1.2%). The difference in total amount of liquid 35SM penetrated between occluded and unoccluded conditions in vitro (79+/-14%) was similar to that lost as vapour from unoccluded skin in vivo (80%). A substantial reservoir of 35SM (14-36% of the applied dose) was measured within heat-separated epidermal membranes for up to 24 h which may have significant implications for the management of personnel exposed to sulphur mustard.Journal of Applied Toxicology 01/2000; 20(5):349-55. · 2.60 Impact Factor
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ABSTRACT: There is a need for safe and effective therapies for inflammatory skin diseases. Current topical and systemic treatment of psoriasis is effective but suffers from side-effects or is inconvenient. The therapeutic armamentarium for atopic dermatitis is very limited and far from satisfactory. In vivo preclinical data are presented for SDZ ASM 981, a novel ascomycin macrolactam derivative with high anti-inflammatory activity. Anti-inflammatory activity was observed in mouse, rat and pig models of allergic contact dermatitis. In the pig model, topical SDZ ASM 981 was as effective as the ultrapotent corticosteroid clobetasol-17-propionate, and when compared with a series of commercial topical corticosteroid preparations, 0.1% SDZ ASM 981 had equivalent efficacy to clobetasol-17-propionate (0.05%), the most potent product on the market. Unlike the corticosteroid, however, SDZ ASM 981 did not cause skin atrophy in pigs. SDZ ASM 981 potently inhibited allergic contact dermatitis in mice and rats when given systemically, and oral treatment was more effective than cyclosporin A in rats. Furthermore, SDZ ASM 981 has a low potential for affecting systemic immune responses, as demonstrated in rat models of localized graft vs. host reaction and allogeneic kidney transplantation. Preclinical results suggest that SDZ ASM 981 has the potential to be a well-tolerated and effective drug for topical as well as oral treatment of inflammatory skin diseases.British Journal of Dermatology 11/1997; 137(4):568-76. · 3.76 Impact Factor