Doxycycline hydrogels as a potential therapy for ocular vesicant injury.

PURPOSE: The goals of this study were (1) to compare the injury at the basement membrane zone (BMZ) of rabbit corneal organ cultures exposed to half mustard (2 chloroethyl ethyl sulfide, CEES) and nitrogen mustard with that of in vivo rabbit eyes exposed to sulfur mustard (SM); (2) to test the efficacy of 4 tetracycline derivatives in attenuating vesicant-induced BMZ disruption in the 24-h period postexposure; and (3) to use the most effective tetracycline derivative to compare the improvement of injury when the drug is delivered as drops or hydrogels to eyes exposed in vivo to SM. METHODS: Histological analysis of hematoxylin and eosin­stained sections was performed; the ultrastructure of the corneal BMZ was evaluated by transmission electron microscopy; matrix metalloproteinase-9 was assessed by immunofluorescence; doxycycline as drops or a hydrogel was applied daily for 28 days to eyes exposed in vivo to SM. Corneal edema was assessed by pachymetry and the extent of neovascularization was graded by length of longest vessel in each quadrant. RESULTS: Injury to the BMZ was highly similar with all vesicants, but varied in degree of severity. The effectiveness of the 4 drugs in retaining BMZ integrity did not correlate with their ability to attenuate matrix metalloproteinase-9 expression at the epithelial­stromal border. Doxycycline was most effective on organ cultures; therefore, it was applied as drops or a hydrogel to rabbit corneas exposed in vivo to SM. Eyes were examined at 1, 3, 7, and 28 days after exposure. At 7 and 28 days after SM exposure, eyes treated with doxycycline were greatly improved over those that received no therapy. Corneal thickness decreased somewhat faster using doxycycline drops, whereas the hydrogel formulation decreased the incidence of neovascularization. CONCLUSIONS: Corneal cultures exposed to 2-chloroethyl ethyl sulfide and nitrogen mustard were effective models to simulate in vivo SM exposures. Doxycycline as drops and hydrogels ameliorated vesicant injury. With in vivo exposed animals, the drops reduced edema faster than the hydrogels, but use of the hydrogels significantly reduced neovascularization. The data provide proof of principle that a hydrogel formulation of doxycycline as a daily therapy for ocular vesicant injury should be further investigated.

Synthesis of analogues of (E)-1-hydroxy-2-methylbut-2-enyl 4-diphosphate, an isoprenoid precursor and human gamma delta T cell activator.

(E)-1-Hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) is an intermediate in the non-mevalonate pathway for the biosynthesis of isoprenoids and also serves as a very strong activator of human gamma delta T cells expressing Vgamma9Vdelta2 receptors. This paper describes the synthesis of analogues of HMBPP, in which the diphosphate group is replaced by potential isosteric moieties, i.e., carbamate, N-acyl-N'-oxy sulfamate, or aminosulfonyl carbamate functionalities. The potential of the synthesized analogues to stimulate Vgamma9/Vdelta2 T cell response or to inhibit GcpE and LytB, the last enzymes in the non-mevalonate pathway, was assessed.