COX-2 inhibitors

Cyclooxygenase-2 (COX-2) inhibitors constitute a new group of non-steroidal anti-inflammatory drugs (NSAIDs) which, at recommended doses, block prostaglandin production by cyclooxygenase-2, but not by cyclooxygenase-1. Two COX-2 inhibitors are currently available in Australia--celecoxib, which is taken twice daily, and rofecoxib, which is taken once daily. Both drugs act rapidly in providing pain relief and their anti-inflammatory analgesic effect in osteoarthritis and rheumatoid arthritis is equivalent to standard doses of non-selective NSAIDs. Celecoxib and rofecoxib show significantly lower incidences of gastrotoxicity (as measured by endoscopic studies and gastrointestinal ulcers and bleeds) than non-selective NSAIDs. There is Level 2 evidence that COX-2 inhibitors: reduce pain in classic pain models--third-molar extraction, dysmenorrhoea and after orthopaedic surgery; reduce pain and disability in osteoarthritis of the hip and knee; and reduce pain and disability in rheumatoid arthritis. Other adverse effects, such as interference with antihypertensive agents and the potential to produce renal dysfunction in patients with compromised renal function by COX-2 inhibitors, seem similar to those of non-selective NSAIDs.     

COX-2 inhibitors: exemplars of the drug-safety conundrum

Using clinical trials to assess long-term drug safety is problematic; in Australia, simple data linkage based on Medicare numbers may provide useful monitoring information.     

Risk of cardiovascular events associated with selective COX-2 inhibitors

Debabrata Mukherjee, MD; Steven E. Nissen, MD; Eric J. Topol, MD

JAMA. 2001;286:954-959.

Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies.

Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P = .002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P = .04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P = .02 compared with the placebo group of the meta-analysis).

The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.

     

Considerations for the safe prescribing and use of COX-2-specific inhibitors

The majority of the "Australian COX-2-Specific Inhibitor (CSI) Prescribing Group" endorse the following points: CSIs are equivalent to non-steroidal anti-inflammatory drugs (NSAIDs) as anti-inflammatory agents. CSIs and NSAIDs modify symptoms but do not alter the course of musculoskeletal disease. CSIs do not eliminate the occurrence of ulcers or their serious complications, but are associated with considerably fewer peptic ulcers, slightly fewer upper GI symptoms and, according to published reports, fewer serious upper GI complications, notably bleeding, than CSIs and NSAIDs have similar effects on renal function and blood pressure. Whether any CSI poses a risk to cardiovascular safety remains subject to debate. Comorbidities and coprescribed drugs must be considered before initiating CSI (or NSAID) therapy. Patients prescribed CSIs (or NSAIDs) should be reviewed within the first few weeks of therapy to assess effectiveness, identify adverse effects and determine the need for ongoing therapy.     

选择性COX-2抑制剂塞来昔布抗癌作用研究进展

选择性COX-2抑制剂塞来昔布(celecoxib)作为一种新型NSAIDs,是一种高选择性环氧化酶抑制剂,由于其靶向性强、副作用小,已在多种肿瘤预防和治疗中发挥作用,近年来发现celecoxib可以增加抗癌药物浓度,降低甚至逆转对抗癌药物的耐药性,增强细胞对化疗药物的敏感性的作用,增强常规化疗疗效,同时塞来昔布对放疗也有一定的增敏作用。     

COX-2-765GC与牙周炎和2型糖尿病的相关性研究

目的 研究环氧合酶-2(COX-2)- 765GC多态性与慢性牙周炎和2型糖尿病的相关性。方法 采用病例对照实验设计,将392名研究对象分为4组;应用聚合酶链反应- 限制性内切酶片段长度多态性基因分析方法(PCR-RFLP),采用2检验比较COX-2 - 765GC位点的基因型和等位基因频率在各组间的分布差异,应用logistic回归分析危险度(OR)。结果 对照组CC基因型或等位基因C的分布频率多于所有病例组,但无统计学差异（P >0.0083）;OR作年龄,性别,身高体重指数（BMI）,刷牙,教育,医疗保险,治疗等因素的调整后无统计学差异。结论 COX-2基因-765GC多态性与慢性牙周炎和2型糖尿病患者无相关性,多个危险因素在在本研究中具有混杂作用。     

环氧化酶-2 (COX-2)抑制剂联合白细胞介素-2 (IL-2)增强小鼠肾癌免疫治疗敏感性的研究

 目的  探讨环氧化酶-2 (cyclooxygenase-2,COX-2)抑制剂联合白细胞介素-2 (interleukin-2,IL-2)对小鼠肾癌免疫治疗的作用及其机制。方法  以Renca细胞建立Babl/c小鼠异位肾癌模型,共28只,随机等分成4组,不同组别予以不同给药,分别为IL-2组、NS-398(一种COX-2抑制剂)组、IL-2+NS 398组和空白对照组。在第14天、28天提取各组荷瘤小鼠外周血,用流式细胞术检测调节性T细胞(regulatory T cells,Treg)的变化;切取荷瘤小鼠瘤体及脾脏,免疫组化检测小鼠脾脏和肿瘤局部Treg的变化。 结果  小鼠异位肾癌在不同药物处理后,肿瘤体积出现明显变化,联合用药组肿瘤体积减小明显,经多组t检验,与其他组相比差异有统计学意义(P<0.05)。同时,COX-2抑制剂能下调荷瘤小鼠外周血、肿瘤及脾脏中Treg的表达,且与IL-2联合有协同作用(P<0.05)。结论  COX-2抑制剂联合IL-2可显著抑制荷瘤小鼠异位肾癌的发展,说明Treg的下调是抑制肾癌生长的可能机制之一。     

还氧合酶-2与鼻息肉发病的关系

目的探讨还氧合酶-2（COX-2）在鼻息肉组织中的表达,分析它在鼻息肉发病过程中的作用,为鼻息肉发病机制的研究提供理论依据,并为鼻息肉的药物治疗寻找新的特异性靶点。方法选取34例未应用任何药物的鼻息肉手术组织标本,根据1997年海口会议标准,分为鼻息肉A组（Ⅱ型12、期鼻窦炎鼻息肉）和鼻息肉B组（Ⅱ型3期及Ⅲ型鼻窦炎鼻息肉）。同时取10例手术患者的下鼻甲游离缘作为正常对照。采用免疫组织化学SP法对鼻息肉和正常下鼻甲黏膜组织中的COX-2进行观测并拍照。采用JD901图像分析软件分析阳性染色面积和染色密度。结果COX-2在正常下鼻甲黏膜组织中无或极少量表达,在鼻息肉组织中均显示高表达（P〈0.01）;Ⅲ型鼻息肉组织中的阳性表达面积和密度均高于Ⅱ型鼻息肉组（P〈0.05）。结论COX-2在鼻息肉组织中高表达,且与鼻息肉的分型有关,表明其催化产物PGE2参与了鼻息肉的发生发展。