Potential anti-inflammatory treatments against cutaneous sulfur mustard injury using the mouse ear vesicant model.

In spite of several decades of research, no effective treatment to skin injuries following exposure to sulfur mustard (HD) has yet been found. In the present study, the mouse ear vesicant model was applied to awake mice in order to evaluate the efficiency of potential anti-inflammatory treatments in preventing HD-induced skin damages. Clinical follow-up and histological evaluation were used to characterize the injuries to the skin and to evaluate the efficiency of the drugs that were applied. Thus, the extent of mouse ear oedema and the histopathological changes following a single application of 0.2 or 1 microL of neat HD for 10 min (representing moderate and severe lesions, respectively), were monitored. Typical HD skin lesions were observed including epithelial and dermal damage. The development of the injury in mouse ears was found to be very similar to that reported in human skin. Screening of post-exposure topical steroids and non-steroidal antiinflammatory drugs (NSAIDs) proved that HD-induced inflammation could be diminished significantly as long as the treatment was applied during the early stages following exposure. A combined application of these drugs approved to be particularly effective in reducing inflammation.

Beneficial effects of topical anti-inflammatory drugs against sulfur mustard-induced ocular lesions in rabbits.

Ocular injuries following sulfur mustard (HD) exposure are characterized by an inflammatory response, observed as eyelid swelling, conjunctivitis, corneal oedema and cellular infiltration starting 1-4 h after exposure, depending on dose. These effects heal partially during the first 1-2 weeks after exposure, with the later appearance of neovascularization, recurrent erosions and recurrent oedema of the cornea (delayed response). We have shown previously that topically applied steroid treatment, administered after HD exposure, attenuated the extent of neovascularization, one of the characteristics of delayed ocular pathology in rabbits. The present study was designed to characterize further the initial inflammatory response and to elucidate the role of anti-inflammatory (AI) drugs as a potential therapy. Rabbit eyes were exposed to HD vapour (390 microg l(-1) for 2 min) and were treated with a topical commercial ophthalmic solution of dexamethasone or diclofenac, starting 1 h post-exposure (four times a day). Inflammation was evaluated by clinical observations, biochemical analysis of aqueous humour and by histology. Sulfur mustard exposure initiated typical clinical ocular symptoms within 4-6 h after exposure. Biochemical analysis of aqueous humour showed that protein content and prostaglandin E (PGE) increased significantly at 6 h and were still high 48 h after HD exposure. Light microscopy evaluation revealed severe damage to the cornea, characterized by epithelial denudation, oedema and cellular infiltration (mostly eosinophiles) in the stroma. Both treatments were effective in alleviating the clinical symptoms and in preventing the HD-induced increase in protein and PGE in the anterior chamber, as well as the cellular infiltration, in the corneal stroma. However, the AI treatments had no therapeutic effect on corneal erosions, and a short delay in epithelial regeneration was noted. It is concluded that AI drugs are potential candidates for the treatment of ocular lesions following HD exposure.

Treatment of skin injuries induced by sulfur mustard with calmodulin antagonists, using the pig model.

Sulfur mustard (HD) is a potent cutaneous vesicant that penetrates rapidly through the skin, causing prolonged injuries and leading to severe incapacitation. Although there has been long and intensive efforts to find a treatment for HD skin lesions, no effective treatment is available for HD-induced skin injuries. Recently, ointments containing calmodulin antagonists were found to be effective in preventing skin injuries induced by HD in hairless mice. The present study was designed to investigate the beneficial effects of topical treatments with calmodulin antagonists against HD skin lesions in the pig model. The pig is used as a preferred animal model for human skin in many studies, including vesicants. Neat HD, either in liquid form (0.2-1 microl droplets) or as vapour, was applied to the back skin of female pigs (a cross Large White & Landrace, 10-12 kg) for various exposure durations. Evaluation was based on quantitative analysis of the degree of erythema and area of the lesions, as well as histological evaluation. Calmodulin antagonists (10% pentamide, 1% trifluoperazine, 2% thioridazine) and anaesthetics (20% lidocaine and 3% benoxinate) were dissolved in pluronic F-127 base according to Kim et al. (Eur. J. Pharmacol. 1996; 313: 107-114) or in saline, and were applied either topically as ointments or by intradermal injection, as early as 5 min post-exposure (twice a day for at least 3 days). The results demonstrated that topically applied pluronic base ointments containing lidocaine or pentamide produce beneficial effects when applied immediately after short-term HD exposure to pig skin.