选择性环氧合酶-2抑制剂的研究现状及进展

非甾体抗炎药（NSAIDs）是临床上应用非常广泛的一类药物，但严重的不良反应使其应用受到很大限制。研究已经发现，NSAIDs对炎症的有效治疗源干其对环氧合酶-2（COX-2）的抑制作用。综述了选择性COX-2抑制剂作用的分子基础、构效关系及其目前研究开发的现状和最新进展。     

药物性生理失调的后果-畅销镇痛药罗非昔布另解

Selective cyclo-oxygenase-2(COX-2) inhibitor, VI-OXX(rofecoxib), was voluntarily withdrawn worldwide from drugstores by its maker Merck & Co., Inc. on Sep-tember 30, 2004, for its potential lethal side effects of heart attack or stroke.     

Disturbance of vision by COX-2 inhibitors

In this review, 35 cases of acute, reversible, sometimes severe, disturbances of vision closely associated with the use of celecoxib or rofecoxib are described. These were identified from three different databases using strict selection criteria. The events included temporary blindness, visual field defect, scotoma, teichopsia, blurred vision, decreased vision and abnormal vision. The reactions had a mean onset time of 9.5 days and recovery occurred within 3 days following withdrawal of the drug. The reactions do not appear to be related to age, gender, dose, or indication for use. The incidence of reported cases is estimated to be not less than 5 per 10,000 patients. Possible mechanisms for this type of reaction are described. The most likely appears to be the result of interference with the retinal blood supply through reduced production of prostanoids. Genetic polymorphisms that affect drug metabolism or uptake could be risk factors and are discussed along with suggestions for research.     

The effects of non-steroidal anti-inflammatory drugs on the disposition of methotrexate in patients with rheumatoid arthritis

We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently taking the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, diclofenac, naproxen, indomethacin, and ibuprofen. The area under the curve, the total systemic clearance, the distribution volume, and the half-life of methotrexate in patients receiving concurrent NSAID therapy did not change significantly (at p <0.05). Concurrent treatment with NSAIDs resulted in increased inter-patient variability of methotrexate concentration, possibly as a result of biochemical interactions; however, it does not appear clinically relevant. The data suggest that the NSAIDs do not significantly affect the disposition of methotrexate, contrary to some of the earlier reports. © 1998 John Wiley & Sons, Ltd.     

The effects of a salicylate,ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis

Summary We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment).The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%.These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.     

泰安地区ALDH2基因多态性与急性冠脉综合征易感性的关系

目的：探讨乙醛脱氢酶2（ALDH2）基因多态性与急性冠脉综合征的相关性,为急性冠脉综合征患者的预防提供依据。方法：收集所有研究对象血液样本,包括健康体检者60例,入院确诊为急性冠脉综合征患者60例。血样采用PCR测序法进行基因多态性检测。对所有研究对象详细记录基本临床资料。所有数据分析运用SPSS 19.0统计软件进行处理。结果：泰安地区ALDH2基因型及等位基因G、A在急性冠脉综合征（ACS）组和正常组中分布具有显著性的统计学差异,ALDH2基因多态性可能是急性冠脉综合征发生的危险因素。经单因素Logistic回归分析结果提示ALDH2基因多态性、饮酒、高血压、糖尿病、既往急性心肌梗死病史以及性别与急性冠脉综合征发生的相关性,进一步经多因素Logistic回归分析结果显示年龄、饮酒、高血压、既往心肌梗死病史是急性冠脉综合征发生的独立危险因素。结论：泰安地区人口中急性冠脉综合征患者乙醛脱氢酶2基因多态性以及等位基因ALDH2*2的分布明显高于正常人群。年龄、饮酒、高血压、既往心肌梗死病史等成为影响急性冠脉综合征发生的危险因素。     

The upper gastrointestinal safety of rofecoxib vs. NSAIDs: an updated combined analysis*

SUMMARY

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific cyclo-oxygenase (COX-1/COX-2) inhibitors and are associated with gastrointestinal (GI) toxicity attributable to COX-1 inhibition. Rofecoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than NSAIDs.

Objective: To update the results of a previously performed analysis of the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs) with rofecoxib compared with non-selective NSAIDs.

Research design and methods: We compared the incidence of PUBs in a combined analysis of 20 randomized, double-blind, clinical trials of rofecoxib versus NSAIDs. Men and women (N = 17?072) from multinational trial sites with osteoarthritis or rheumatoid arthritis were studied. There was no upper age limit in any of the trials. Investigator-reported PUBs were reviewed by a blinded, external adjudication committee using pre-specified criteria. The incidence of confirmed PUBs, the main outcome measure, among patients treated with rofecoxib 12.5?mg, 25?mg, or 50?mg (combined, N = 10?026) was compared to that among patients treated with ibuprofen, diclofenac, nabumetone, or naproxen (combined, N = 7046).

Results: The incidence of PUBs over 24.8?months was significantly lower with rofecoxib vs. NSAIDs (cumulative incidence 1.6% vs. 3.1%, p < 0.001; rate/100 patient-years 0.74 vs. 1.87; relative risk 0.36, 95% CI 0.24, 0.54). Results of subgroup analyses and comparisons of rofecoxib with individual NSAID comparators were consistent with the primary result, as was an analysis in patients with no PUB risk factors.

Discussion: The analysis demonstrated a consistently lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 24.8?months. These results confirm those of a previous smaller combined analysis of clinical trials with rofecoxib vs. non-selective NSAIDs in OA patients only, in which the risk reduction for confirmed PUBs was approximately 50%. In addition, this analysis demonstrated risk reductions with rofecoxib vs. NSAIDs in risk subgroups and in patients who did not have any known risk factors for PUBs consistent with the primary result. Some of the studies in this analysis required scheduled endoscopies. Asymptomatic upper GI ulcers or bleeding diagnosed during scheduled procedures were not included in the primary endpoint, which may have caused a bias against rofecoxib.

Conclusions: Treatment with rofecoxib was associated with a statistically significantly (p < 0.001) lower incidence of PUBs than was treatment with NSAIDs. The difference was maintained in subgroups of patients with risk factors, as well as in those with no risk factors, for PUBs.     

A cross-sectional retrospective assessment of anti-arthritic drugs in patients with arthritis in Korea

SUMMARY

Background: Selective cyclo-oxygenase-2 (COX-2) inhibitors were recently introduced for the treatment of arthritis because of their lower rates of gastrointestinal adverse events compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs).

Objective: To examine the medication usage patterns for both osteoarthritis (OA) and rheumatoid arthritis (RA) in Korea.

Methods: The medical charts of a convenience sample of 402 patients with OA or RA were reviewed by the Arthritis Study Group in 14 hospitals and ten clinics in Korea.

Results: Traditional oral NSAIDs were the most commonly prescribed drugs for OA (68.3%) and RA (65.1%) patients. Two-thirds (66.7%) of the RA patients taking COX-2 inhibitors were prescribed

other arthritis medications concurrently and 85.1% of RA patients taking NSAIDs were prescribed other arthritis medications concurrently. Patients on NSAIDs were almost twice as likely to have a gastroprotective agent (GPA) concurrently compared to COX-2 inhibitor users (OA patients 38.1% vs 21.2%; RA patients 57.9% vs 30.6%). Overall, patients taking COX-2 inhibitors were less likely to take GPAs concurrently compared to patients not taking COX-2 inhibitors (unadjusted OR 0.36; adjusted OR 0.39).

Conclusions: Traditional oral NSAIDs were commonly prescribed to arthritis patients in Korea. In this study, patients taking COX-2 inhibitors were prescribed less adjunctive arthritis treatments and less gastroprotective agents than traditional oral NSAID users.     

A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers

AIMS: To compare the effects of nabumetone and meloxicam, two cyclo-oxygenase-2 (COX-2) preferential nonsteroidal anti-inflammatory drugs (NSAIDs), on platelet COX-1 activity and platelet function. METHODS: Twelve healthy volunteers (3 male, 9 female, median age 22 years) participated in an open, randomized, cross-over trial of nabumetone 1000 mg twice daily vs meloxicam 7.5 mg twice daily during 1 week with 2 weeks wash-out. After a second 2 week wash-out period, one dose of indomethacin 50 mg was given as a positive control to check for NSAID induced inhibition of platelet function. COX-1 inhibition was measured as percentage inhibition of serum TXB2 generation in clotting whole blood, and as closure time with use of the platelet function analyser PFA-100. Data are reported as median with range. Paired variables were analysed using Wilcoxons signed rank test. RESULTS: TXB2 levels decreased significantly after all three medications, but percentage inhibition after nabumetone and indomethacin (88% and 97%, respectively) was significantly higher than after meloxicam (63%) (P<0.05). Closure times increased significantly after administration of all three medications (P<0.05). Increases in closure time after administration did not differ between nabumetone and meloxicam (24% and 14%, respectively), but were significantly larger after indomethacin administration (63%) (P<0.01). CONCLUSIONS: In the maximum registered dosage, nabumetone inhibits thromboxane production much more than meloxicam, signifying less COX-2 selectivity of the former. However, both nabumetone and meloxicam cause only minor impairment in platelet function in comparison with indomethacin and the difference between them is not significant.     

替罗非班在急性冠脉综合征患者中的合理应用及危险因素分析

目的根据替罗非班在急性冠脉综合征患者中应用的相关危险因素分析,探讨替罗非班在急性冠脉综合征患者中的合理应用。方法 102例>60岁的急性冠脉综合征患者接受替罗非班持续静脉滴注36 h～48 h,观察用药开始至停药3 d内患者出血情况,并对出血可疑危险因素进行单因素和多因素Logistic回归分析。结果发生出血9例(8.8%),其中重度出血1例,轻度出血8例。多因素Logistic回归分析表明,年龄>65岁、急诊PCI、肾功能不全是替罗非班发生出血并发症的独立危险因素。年龄每增加10岁,OR=1.4,95%CI 1.1～1.7;吸烟OR=3.2,95%CI 2.2～4.6;血小板聚集率每减少10%,OR=1.6,95%CI 1.2～1.9,肌酐清除率每减少10 mL.min-1,OR=1.2,95%CI 1.0～1.4;抗凝药及抗血小板药每增加1个,OR=4.2,95%CI 2.0～5.2。结论年龄>65岁、肾功能不全、急诊PCI是替罗非班治疗发生出血并发症的独立危险因素。抗血小板与抗凝药联合应用,吸烟、血小板聚集率下降、肌酐清除率降低为急性冠脉综合征患者应用替罗非班抗血小板治疗出血的主要危险因素。     

上海地区汉族人群护骨素基因G1181C多态性及其血清浓度与急性冠脉综合征的相关性研究

目的 探讨护骨素(osteoprotegerin,OPG)基因G1181C位点基因多态性及其血清浓度与急性冠脉综合征(acute coronary syndrome,ACS)的相关性.方法 134名胸痛患者根据冠状动脉造影及病史分为正常对照组65名和ACS组69名.ELISA法测定入院时血清OPG水平.介质纯化法提取白...     

ALB-dNLR评分对急性冠状动脉综合征患者行介入治疗预后的影响

目的 分析白蛋白-衍生的中性粒细胞与淋巴细胞比值（ALB-dNLR）评分对急性冠状动脉综合征（ACS）患者行经皮冠状动脉介入治疗（PCI）预后的影响。方法 连续入选确诊ACS并行PCI的患者共1 744例,收集患者临床资料。患者出院后通过门诊复诊、电话等方式随访,记录其主要不良心血管事件（MACE）。采用受试者工作特征（ROC）曲线确定各炎性指标预测MACE的最佳界值。分析ALB和dNLR与各炎性指标的相关性。通过Kaplan-Meier曲线和Cox 回归模型分析患者发生MACE的影响因素。结果 共纳入1 539例患者,中位随访时间1 141 d,其中MACE组60例,Non-MACE组1 479例。MACE组中性粒细胞计数、dNLR、中性粒细胞与淋巴细胞比值（NLR）、血小板与淋巴细胞比值（PLR）、单核细胞与淋巴细胞比值（MLR）、系统免疫炎性指数（SII）、肌酸激酶同工酶和肌酐水平均较Non-MACE组升高,而淋巴细胞计数、ALB水平较Non-MACE组下降。ALB、dNLR、ALB-dNLR、NLR、PLR、MLR、SII的ROC曲线下面积分别为0.619、0.600、0.645、0.619、0.576、0.587、0.611（均P<0.05）。dNLR与NLR、PLR、MLR、SII均呈正相关（均P<0.05）。ALB≤40.72 g/L、dNLR≥2.30和ALB-dNLR评分升高均为ACS患者PCI术后发生MACE的独立危险因素（P<0.05）。结论 ALB-dNLR评分是ACS患者PCI术后发生MACE的独立预测因素,有望成为预后评估的新型指标。     

Effects of esomeprazole on glutathione levels and mitochondrial oxidative phosphorylation in the gastric mucosa of rats treated with indomethacin

Proton pump inhibitors exert their preventive and healing effects on gastropathy induced by nonsteroidal anti-inflammatory drug (NSAIDs) by a dual action: the antisecretory and the antioxidant effect. The latter was investigated by using esomeprazole against indomethacin-induced gastric mucosa lesions in rats and assessed by a histomorphometric analysis. Treatment by intragastric gavage were 1% methocel as vehicle; esomeprazole 10, 30, or 60 μmol/kg; indomethacin 100 μmol/kg; and esomeprazole 10, 30, or 60 μmol/kg plus indomethacin 100 μmol/kg. The evaluation of glutathione (GSH) levels and respiratory chain complex activities [nicotinamide adenine dinucleotide, reduced (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome C reductase, cytochrome oxidase] was performed in the isolated gastric mucosa. Esomeprazole (10–60 μmol/kg) dose dependently reversed, up to complete recovery, the inhibitory effect of indomethacin on GSH levels (approximately 60% inhibition) and mitochondrial enzyme activities (inhibition ranging from 60% to 75%). Indomethacin-induced mucosal injuries were reduced by esomeprazole. Thus, in addition to inhibiting acid secretion, the gastroprotective effect of esomeprazole can be ascribed to a reduction in gastric oxidative injury.     

自由基清除剂与亚低温结合治疗急性脑梗死的临床探讨

目的：探讨自由基清除剂与亚低温结合治疗急性脑梗死的临床价值。方法选取本院2012年6月~2013年6月之间收治的100例急性脑梗死患者为研究对象,随机将其分为对照组和实验组,两组患者均接受常规基础性治疗,实验组在此基础上接受自由基清除剂,依达拉奉注射液联合亚低温治疗,回顾分析两组患者的临床疗效。结果实验组患者临床治疗后血糖、血乳酸、并发症发生率、神经功能缺损评分和治疗总有效率均明显优于对照组,差异有统计学意义（P〈0.05）。结论自由基清除剂联合亚低温治疗急性脑梗死,具有较为理想的临床疗效,因而推广和应用价值较高。     

高龄急性冠脉综合征患者介入及药物治疗并发严重出血高危因素的研究

目的探讨高龄（≥75岁）急性冠脉综合征（ACS）患者介入及药物治疗并发严重出血发生率及其高危因素。方法高龄ACS患者162例,根据治疗方法分为经皮冠状动脉介入术（PCI）组121例及药物治疗组41例,比较2组间院内严重出血发生率,采用Logistic回归分析严重出血的独立危险因素。结果总体出血发生率为4.3%（7/162）,PCI组与药物治疗组出血发生率分别为4.8%（2/41）与4.1%（5/121）,2组比较差异无统计学意义（P〉0.05）。年龄〉80岁、氯吡格雷、替罗非班负荷治疗可增加严重出血发生风险。结论同药物治疗相比,PCI治疗未增加高龄ACS患者出血并发症。年龄〉80岁、氯吡格雷、替罗非班负荷治疗增加严重出血发生率。