McCarberg Bill H, Cryer Byron
1School of Medicine, University of California San Diego, San Diego, CA; 2The Elizabeth Hospice, Escondido, CA; 3Neighborhood Healthcare, Escondido, CA; 4UT Southwestern Medical Center, Dallas, TX; and 5Dallas VA Medical Center, Dallas, TX.
Am J Ther. 2015 Nov-Dec;22(6):e167-78. doi: 10.1097/MJT.0000000000000123.
Nonsteroidal anti-inflammatory drugs (NSAIDs) possess potent anti-inflammatory and analgesic properties through inhibition of cyclooxygenase enzymes (COX-1 and COX-2), which are responsible for synthesis of proinflammatory mediators. NSAIDs are frequently used for treatment of acute and chronic pain conditions. However, their use is associated with serious dose-dependent gastrointestinal (GI), cardiovascular, renal, and hepatic adverse effects, which pose a serious clinical concern for both patients and physicians. During the past 2 decades, approaches to improving the tolerability of NSAIDs were mainly directed toward discovery of COX-2 selective NSAIDs (coxibs), which were expected to minimize the risk of GI injury. Unfortunately, the results from multiple clinical studies have shown that treatment with coxibs may increase the risk for cardiovascular complications. This review summarizes current strategies used to reduce the toxicity of NSAIDs and outlines novel therapeutic approaches still in preclinical development. To minimize the risk of GI ulcerations and bleeding, combination therapies with gastroprotective agents are currently recommended. The new therapeutic agents anticipated to have similar effects include nitric oxide- and hydrogen sulfide-releasing NSAIDs. Novel manufacturing technologies enhance dissolution and absorption of NSAID products, allowing for their administration at low doses, which could lead to improved drug tolerability without diminishing the analgesic and anti-inflammatory efficacy of NSAIDs. This principle is in line with the current recommendation by the US Food and Drug Administration that NSAIDs should be used at the lowest effective dosage. Finally, NSAID formulations targeted directly to the site of inflammation are expected to reduce systemic drug exposure and thus decrease the risk of systemic adverse effects.
非甾体抗炎药（NSAIDs）通过抑制环氧化酶（COX-1和COX-2）发挥强大的抗炎和镇痛特性，环氧化酶负责促炎介质的合成。NSAIDs常用于治疗急慢性疼痛病症。然而，其使用与严重的剂量依赖性胃肠道（GI）、心血管、肾脏和肝脏不良反应相关，这给患者和医生都带来了严重的临床担忧。在过去20年中，提高NSAIDs耐受性的方法主要集中在发现COX-2选择性NSAIDs（昔布类）上，人们期望这类药物能将GI损伤风险降至最低。不幸的是，多项临床研究结果表明，使用昔布类药物可能会增加心血管并发症的风险。本综述总结了目前用于降低NSAIDs毒性的策略，并概述了仍处于临床前开发阶段的新型治疗方法。为了将GI溃疡和出血风险降至最低，目前推荐使用与胃保护剂的联合疗法。预期具有类似效果的新型治疗药物包括释放一氧化氮和硫化氢的NSAIDs。新型制造技术可提高NSAID产品的溶解和吸收，使其能够低剂量给药，这可能会提高药物耐受性，同时又不降低NSAIDs的镇痛和抗炎功效。这一原则与美国食品药品监督管理局目前的建议一致，即NSAIDs应以最低有效剂量使用。最后，直接靶向炎症部位的NSAID制剂有望减少全身药物暴露，从而降低全身不良反应的风险。
