Design, synthesis, biological evaluation, and nitric-oxide release studies of a novel series of celecoxib prodrugs possessing a nitric-oxide donor moiety

A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs), in which an O 2-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-aminosulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids (6a-c), were synthesized. A low amount of NO was released from the diazen-1-ium-1,2-diolate compounds 6a-c upon incubation with phosphate buffer saline (PBS) at pH 7.4 (range: pH 7.97-8.51), whereas, the percentage of NO released was significantly higher (84.5%-85.05% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum. These incubation studies demonstrated that both NO and the anti-inflammatory 1-(4-aminosulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3-carboxylic acid (4a-c) would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. The parent compounds 4a-c displayed good anti-inflammatory effects (ID50=81.4-112.4 mg/kg p.o.) between those exhibited by the reference drugs, aspirin (ID50=114.3 mg/kg p.o.) and celecoxib (ID50=12.6 mg/kg p.o.). Hybrid ester anti-inflammatory/NO-donor prodrugs (NONO-coxibs) offer a potential drug-design concept directed toward the development of anti-inflammatory drugs that are lacking adverse ulcerogenic and/or cardiovascular effects.

Transverse keratotomy for correction of low astigmatism: evaluation of a simplified nomogram

To evaluate a simplified nomogram for the correction of low amounts of astigmatism by transverse keratotomy. Methods Transverse keratotomy for correction of astigmatism was performed on 109 eyes of 71 myopic astigmatic patients [age range, 21 to 45 years; mean 33 years] in whom refractive astigmatism ranged from 1.0 to 3.0 diopters [D] [mean, 1.68D]. The number of transverse incisions and the size of the optical zone were selected on the basis of a simple nomogram modified from the nomograms developed by Thornton and Casebeer. All procedures were performed by the same surgeon and were combined with radial keratotomy for correction of myopia. The results were evaluated using simple analysis and vector analysis. The follow up period ranged from 6 months to 2 years [mean, 13.2 months]. At the final postoperative visit, the mean residual astigmatism was 0.54D [SD = 0.48; range, 0 to 2.25D]. The width of the 90% confidence interval for the residual astigmatism was 1.25D [range, 0 to 1.25D]. The mean decrease in astigmatism was 1.14D. Surgically induced astigmatism in the desired axis within 0.50D of preoperative astigmatism was achieved in 81 eyes [74.3%]. The axis of the surgically induced astigmatism deviated by less than 100 from the desired axis in 71.6% of eyes. Astigmatism can be effectively corrected by transverse keratotomy. The nomogram evaluated here is simple and reliable for correction of astigmatism up to 3.0D