Department of Physiology and Pharmacology, City University of New York Medical School, 138th St. and Convent Ave., New York, NY 10031, USA.
J Pharmacol Exp Ther. 2010 Nov;335(2):443-50. doi: 10.1124/jpet.110.171017. Epub 2010 Aug 2.
Chronic inflammation is an underlying etiological factor in carcinogenesis; nonsteroidal anti-inflammatory drugs (NSAIDs) and their chemically modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. The aim of this study was to conduct a head-to-head comparison between two NO-ASAs possessing different NO donor groups, an organic nitrate [3-nitrooxyphenyl acetylsalicylate (NO-ASA; NCX-4016)] and an N-diazeniumdiolate [NONO-ASA, O(2)- (acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA; CVM-01)], as antiulcerogenic, analgesic, anti-inflammatory, and antipyretic agents. All drugs were administered orally at equimolar doses. For antiulcerogenic study, 6 h after administration, the number and size of hemorrhagic lesions in stomachs from euthanized animals were counted. Tissue samples were frozen for prostaglandin E(2) (PGE(2)), superoxide dismutase (SOD), and malondialdehyde determination. For anti-inflammatory study, 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 6 h. For antipyretic study, 1 h after dosing, fever was induced by intraperitoneal LPS, and body core temperatures measured for 5 h. For analgesic study, time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered 30 min after carrageenan. NO-ASA and NONO-ASA were equipotent as analgesic and anti-inflammatory agents but were better than aspirin. Despite a drastic reduction of PGE(2) in stomach tissue, both prodrugs were devoid of gastric side effects. Lipid peroxidation induced by aspirin was higher than that observed by prodrugs. SOD activity induced by both prodrugs was similar, but approximately 2-fold higher than that induced by aspirin. CVM-01 is as effective as NCX-4016 in anti-inflammatory, analgesic, and antipyretic assays in vivo, and it showed an equivalent safety profile in the stomach. These results underscore the use of N-diazeniumdiolate moieties in drug design.
慢性炎症是致癌作用的一个潜在病因；非甾体抗炎药（NSAIDs）及其化学修饰的一氧化氮供体前药（NO-NSAIDs）是很有前途的化学预防剂。本研究的目的是对两种具有不同一氧化氮供体基团的 NO-ASA 进行头对头比较，一种是有机硝酸盐[3-硝基氧苯乙酰水杨酸（NO-ASA；NCX-4016）]，另一种是 N-二氮烯二酸盐[N-（乙酰水杨酰氧基甲基）-1-（吡咯烷-1-基）二氮烯-1-1,2-二醇盐（NONO-ASA；CVM-01）]，作为抗溃疡、镇痛、抗炎和退热剂。所有药物均以等摩尔剂量口服给药。在抗溃疡研究中，给药 6 小时后，对安乐处死动物的胃中出血性病变的数量和大小进行计数。组织样品被冷冻，用于测定前列腺素 E2（PGE2）、超氧化物歧化酶（SOD）和丙二醛。在抗炎研究中，给药后 1 小时，测量角叉菜胶诱导的大鼠足肿胀体积 6 小时。在退热研究中，给药后 1 小时，通过腹腔内 LPS 诱导发热，5 小时测量核心体温。在镇痛研究中，通过角叉菜胶诱导的痛觉过敏评估前药的时间依赖性镇痛作用。给药后 30 分钟给予药物。NO-ASA 和 NONO-ASA 作为镇痛和抗炎剂与阿司匹林具有同等效力，但优于阿司匹林。尽管胃组织中 PGE2 明显减少，但两种前药均无胃部副作用。阿司匹林引起的脂质过氧化高于观察到的前药。两种前药诱导的 SOD 活性相似，但比阿司匹林高约 2 倍。CVM-01 在体内抗炎、镇痛和退热试验中与 NCX-4016 同样有效，在胃中表现出相同的安全性。这些结果强调了在药物设计中使用 N-二氮烯二酸盐部分。
