Photosensitivity drugs(I) Photodegradation of calcium channel blockers(II) Photoproducts of NSAIDs and their anti-inflammatory activities

• Main Authors: Su-Hui Chao, 趙素慧
• Other Authors: 吳安邦
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/89841605521014148399

博士 === 臺北醫學大學 === 藥學研究所 === 95 === Photosensitivity is a commonly adverse effect of drugs. The purpose of the first part of this study is focus on the photodegradation of nicardipine. When nicardipine was exposed to the Hg lamp, eight photoproducts of nicardipine were identification by LC/MS. The main degraded product was a pyridine analogue (NIC-7). Nicardipine apparently undergoes a series of nitro group photo-reduction pathways under irradiation leading to a complex formation of mainly the reduced products. A reaction scheme of nicardipine was proposed. The second part, gives a study on the photochemical behavior when NSAIDs (flurbiprofen and indomethacin) in alcoholic solvents are exposed to Hg lamps. GC/MS and LC/MS were applied to determine the structure of photoproducts. In addition, some pharmacological effects were also examined. In total, ten and four photoproducts derived from flurbiprofen and indomethacin methanolic samples, respectively, were identified by GC/MS and LC/MS. Furthermore, the reaction schemes of flurbiprofen and indomethacin in methanol are proposed. As to the study of pharmacological effects, results suggested that among all the related photoproducts, Indomethacin stand out and showed the strongest hydroxyl radical-scavenging effect with an IC50 of 65 µM and the strongest xanthine oxidase inhibitory effect with an IC50 of 86 µM. We also found that the methyl ester derivatives of indomethacin (IN-3) could more-potently inhibit PGE2 and NO production and iNOS and COX 2 protein expression from LPS-stimulated RAW 264.7 cells than indomethacin, similar to the effect of a typical NSAID. The cytotoxic effects of the test samples were measured using the MTT assay. The results showed that IN-3 with an IC50 value maintained at 36.9 ?慊/mL for 12 h that exhibited stronger cytotoxicity than indomethacin in HL-60 cells. Moreover, IN-3 caused apoptotic bodies, DNA fragmentation, and enhanced PARP and pro-caspase 3 degradation in HL-60 cells as determined by a series of biochemical analyses. The above results indicated that the photoproduct, IN-3, had stronger anti-inflammatory in LPS-stimulated RAW 264.7 cells and cytotoxicity effects in HL-60 cells than the parent drug, indomethacin.