Hawkey C J, Jones J I, Atherton C T, Skelly M M, Bebb J R, Fagerholm U, Jonzon B, Karlsson P, Bjarnason I T
Division of Gastroenterology, University Hospital Nottingham, Nottingham, UK.
Gut. 2003 Nov;52(11):1537-42. doi: 10.1136/gut.52.11.1537.
Cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs that may minimise gastrointestinal toxicity compared with standard non-steroidal anti-inflammatory drugs (NSAIDs) by virtue of nitric oxide donation.
A proof of concept study of the gastrointestinal safety of AZD3582, the first CINOD available for human testing, was conducted. Thirty one subjects were randomised to receive placebo, naproxen 500 mg twice daily, or its nitroxybutyl derivative AZD3582 in an equimolar dose (750 mg twice daily) for 12 days in a double blind three period crossover volunteer study. At the start and end of each dosing period, gastroduodenal injury was assessed by endoscopy and small bowel permeability by differential urinary excretion of lactulose and L-rhamnose. Pharmacokinetic profiles were assessed at steady state.
On naproxen, the mean total number of gastroduodenal erosions was 11.5 (and one subject developed an acute ulcer) versus 4.1 on AZD3582 (p<0.0001). More than half of the subjects had no erosions on AZD3582. Differences were seen for both the stomach and duodenum. Naproxen increased intestinal permeability (lactulose:L-rhamnose ratio 0.030 before v 0.040 after treatment) whereas AZD3582 (0.029 before, 0.029 after; p=0.006 v naproxen) and placebo (0.030 before, 0.028 after; p<0.001 v naproxen) did not. The steady state bioavailability of naproxen metabolised from AZD3582 was 95% (95% confidence interval 87-101%) of that after naproxen administration.
This human study supports animal data showing reduced gastrointestinal toxicity with the CINOD AZD3582. The potential combination of effective pain relief and gastrointestinal protection offered by AZD3582 warrants further evaluation in human clinical studies.
环氧化酶抑制性一氧化氮供体（CINODs）是一类新型抗炎和镇痛药，与标准非甾体抗炎药（NSAIDs）相比，因其能释放一氧化氮，可能将胃肠道毒性降至最低。
对首个可用于人体试验的CINOD——AZD3582的胃肠道安全性进行了概念验证研究。在一项双盲三期交叉志愿者研究中，31名受试者被随机分配接受安慰剂、每日两次服用500毫克萘普生或其等摩尔剂量（每日两次750毫克）的硝氧丁基衍生物AZD3582，为期12天。在每个给药期开始和结束时，通过内镜检查评估胃十二指肠损伤，并通过乳果糖和L-鼠李糖的尿排泄差异评估小肠通透性。在稳态下评估药代动力学特征。
服用萘普生时，胃十二指肠糜烂的平均总数为11.5（1名受试者出现急性溃疡），而服用AZD3582时为4.1（p<0.0001）。超过一半的受试者服用AZD3582时没有糜烂。胃和十二指肠均出现差异。萘普生增加肠道通透性（治疗前乳果糖：L-鼠李糖比率为0.030，治疗后为0.040），而AZD3582（治疗前0.029，治疗后0.029；与萘普生相比p=0.006）和安慰剂（治疗前0.030，治疗后0.028；与萘普生相比p<0.001）则没有。从AZD3582代谢而来的萘普生的稳态生物利用度为服用萘普生后生物利用度的95%（95%置信区间87-101%）。
这项人体研究支持了动物数据，表明CINOD AZD3582可降低胃肠道毒性。AZD3582提供的有效止痛和胃肠道保护这一潜在组合值得在人体临床研究中进一步评估。
