Muscará M N, McKnight W, Asfaha S, Wallace J L
Department of Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
Br J Pharmacol. 2000 Feb;129(4):681-6. doi: 10.1038/sj.bjp.0703112.
Selective cyclo-oxygenase (COX)-2 inhibitors and nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit reduced toxicity in the gastrointestinal tract, but may affect wound healing in other tissues. In this study, we have compared the effects of a selective COX-2 inhibitor (celecoxib), a nitric-oxide releasing derivative of naproxen (HCT-3012) and naproxen in a model of wound collagen deposition in the rat. Polyvinyl alcohol sponges were implanted subcutaneously in rats. The rats were treated daily for 5 days with the test drugs at equieffective anti-inflammatory doses. Naproxen (10 mg kg(-1)) significantly decreased (45%) collagen deposition at the wound site relative to the vehicle-treated control group. In contrast, HCT-3012 (14.5 mg kg(-1)) significantly increased (62%) collagen deposition, while celecoxib (10 mg kg(-1)) had no effect. Naproxen and HCT-3012 suppressed prostaglandin (PG) E(2) levels at the wound site and whole blood thromboxane synthesis to similar degrees. Celecoxib had no significant effect on wound fluid PGE(2) levels, but slightly reduced whole blood thromboxane synthesis (by 17%). COX-1 mRNA and protein were expressed in the wound exudate, the skin surrounding the wound and in normal skin. In contrast, COX-2 mRNA, but not protein, was expressed in wound and normal skin. These results demonstrate that HCT-3012 can significantly enhance collagen deposition at a wound site, despite inhibiting prostaglandin synthesis to the same extent as the parent drug. Nitric oxide-releasing NSAIDs may represent a safer alternative to standard NSAIDs for use as anti-inflammatory and analgesic agents by post-surgery patients.
选择性环氧化酶（COX）-2抑制剂和释放一氧化氮的非甾体抗炎药（NSAIDs）在胃肠道中的毒性较低，但可能会影响其他组织的伤口愈合。在本研究中，我们比较了选择性COX-2抑制剂（塞来昔布）、萘普生的一氧化氮释放衍生物（HCT-3012）和萘普生在大鼠伤口胶原沉积模型中的作用。将聚乙烯醇海绵皮下植入大鼠体内。用等效抗炎剂量的受试药物对大鼠进行每日一次、为期5天的治疗。与赋形剂处理的对照组相比，萘普生（10 mg kg⁻¹）使伤口部位的胶原沉积显著减少（45%）。相比之下，HCT-3012（14.5 mg kg⁻¹）使胶原沉积显著增加（62%），而塞来昔布（10 mg kg⁻¹）则无作用。萘普生和HCT-3012对伤口部位的前列腺素（PG）E₂水平和全血血栓素合成的抑制程度相似。塞来昔布对伤口液PGE₂水平无显著影响，但使全血血栓素合成略有减少（17%）。COX-1 mRNA和蛋白在伤口渗出液、伤口周围皮肤及正常皮肤中均有表达。相比之下，COX-2 mRNA在伤口和正常皮肤中有表达，但蛋白无表达。这些结果表明，尽管HCT-3012与母体药物对前列腺素合成的抑制程度相同，但它能显著增强伤口部位的胶原沉积。对于术后患者用作抗炎和镇痛药而言，释放一氧化氮的NSAIDs可能是比标准NSAIDs更安全的选择。
