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Toxic epidermal necrolysis (TEN), or Lyell's syndrome,1 holds a unique place among dermatologic diseases for its frightening, rapidly progressive, and all too often tragic outcome. Our lack of understanding of the pathogenesis of this disease, coupled with its infrequency and the lack of objective laboratory criteria for its diagnosis, have created considerable confusion and controversy over its nosology.Still, we have made some important progress in differentiating TEN from staphylococcal scalded skin syndrome (SSSS),2,3 in providing supportive care,4,5 and in determining the prognosis of cases.6,7 Yet investigators both at the bedside and in the laboratory have been impeded by a disease that seemingly can have varied presentations and an unpredictable course, and can be triggered by a panoply of causes; eg, drug,8 infectious,9 and immunologic factors.10,11 Although there is general agreement that TEN is characterized by widespread blistering of the skin with a

We report the pharmacokinetics, biodistribution and metabolism of phospho-sulindac (PS) in a hydrogel formulation efficacious in dry eye disease (DED) administered once daily. PS 0.2% and 0.7% was studied in Dutch-Belted black and New Zealand white rabbits with and without DED. Levels of PS and its metabolites were determined by HPLC. The two rabbit strains gave similar results. PS and its metabolites were limited to the anterior chamber of the eye and undetectable in peripheral blood. DED did not affect the PK, biodistribution or metabolism of PS. Drug levels were dose dependent. PS had a rapid uptake (Tmax15–30 min) and short t1/2(0.6–0.9 h), being undetectable at 8h. Of the anterior chamber tissues, cornea and conjunctiva had >90% of the total PS. PS metabolism was rapid and complete, generating all its known in vivo metabolites, except for glucuronidation products. Rabbits with DED had 1.8-fold longer precorneal residence time of PS. The prolonged efficacy of PS despite its limited presence in ocular tissues suggests a vigorous downstream action suppressing ocular surface inflammation of DED. The properties of this formulation, especially the combination of superior efficacy with once-a-day dosing are a major improvement over previous formulations for the treatment of DED.