Comparison of the effects of parecoxib and diclofenac in preemptive analgesia: A prospective, randomized, assessor-blind, single-dose, parallel-group study in patients undergoing elective general surgery

Background:

Preoperative administration of analgesics may prevent or reducehyperalgesia, inhibit inflammation, and reduce pain by reducing the synthesis of prostaglandins in response to tissue damage caused by surgery. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a potent, widely used class of analgesic agents; however, they may not be as effective as selective cyclooxygenase (COX)-2 inhibitors.

Objective:

The aim of this study was to compare the efficacy and tolerabilityof the COX-2 inhibitor parecoxib sodium and the NSAID diclofenac sodium as preemptive analgesics in patients undergoing elective general surgery.

Methods:

This was a prospective, randomized, assessor-blind, single-dose,parallel-group, comparative trial. Patients aged 18 to 65 years undergoing elective general surgery were enrolled. A single IM injection of parecoxib 40 mg or diclofenac 75 mg was administered 30 to 45 minutes before the induction of anesthesia. Surgery was performed as per standard protocol. The primary measures of efficacy were pain intensity score (measured on a visual analog scale [VAS]), pain relief score, duration of analgesia, and platelet aggregation response to adenosine diphosphate. Tolerability assessment included monitoring of treatment-emergent adverse events (AEs), physical examination, laboratory analysis, electrocardiography, and chest radiography.

Results:

Eighty patients (56 men, 24 women; mean [SD] age, 45.96 [12.83] years) were enrolled in the study (40 patients per treatment group). All patients completed the trial. No pain was reported by any patient in the parecoxib group up to 12 hours; in the diclofenac group, no pain was reported up to 6 hours. At 12 hours, the mean (SD) VAS score was 2.33 (1.39) (moderate pain) in the diclofenac group and 0 (no pain) in the parecoxib group (P < 0.05). At 12 hours, total pain relief was reported by all 40 patients (100.0%) in the parecoxib group but by none (0.0%) in the diclofenac group, and 2 patients in the diclofenac group (5.0%) reported good pain relief (between-group difference for total + good pain relief, P < 0.05). Mean (SD) duration of analgesia was significantly longer in the parecoxib group than in the diclofenac group (19.48 [5.61] hours vs 8.32 [4.11 ] hours; P < 0.05). Platelet aggregation was significantly inhibited in the diclofenac group (change from baseline, 64.0%) but not in the parecoxib group (change from baseline, 12.0%) (P < 0.05). Both regimens were well tolerated, and no AEs were reported.

Conclusions:

In this study of patients undergoing elective general surgery,patients treated with the COX-2 specific inhibitor parecoxib experienced no pain at 12 hours, and the treatment was well tolerated. The results of this study suggest that good postoperative analgesia and minimal interference with platelet function may make parecoxib an alternative to the nonselective NSAID diclofenac in providing preemptive analgesia in patients undergoing general surgery.     

COX-2选择性抑制剂valdecoxib对LPS刺激牙龈成纤维细胞生成PGE2的影响

目的:观察valdecoxib对细菌脂多糖(lipopolysaccharides,LPS)刺激人牙龈成纤维细胞(human gingival fibroblasts,HGFs)生成前列腺素(prostaglandin E2,PGE2)水平的变化?方法:采用ELISA法定量检测LPS及valdecoxib处理后对体外培养的HGFs生成PGE2水平的改变?结果:1~100 ng/ml LPS处理可明显促进HGFs产生PGE2,其作用效果呈浓度依赖和时间依赖关系;6.25~100 μmol/L valdecoxib 能够明显抑制LPS促HGFs产生PGE2的作用,且其抑制作用呈剂量依赖性关系?结论:valdecoxib能明显抑制LPS促HGFs产生PGE2的作用?     

戊地昔布对直肠癌Colo320细胞增殖与凋亡的影响

目的 戊地昔布为第2代选择性环氧合酶-2(cyclooxygenase 2,COX-2)抑制剂,主要用于抗炎止痛,已被证实具有拮抗多种肿瘤细胞的作用,但其对直肠癌细胞的作用鲜有报道.本研究探讨其对人直肠癌细胞Colo320增殖与凋亡的影响并探讨其可能的机制.方法 以药物终浓度为0、5、10、25、50、100、200 μmol/L的戊地昔布分别处理Colo320细胞24、48、72及96h后,采用Cell Counting Kit-8(CCK-8)实验检测戊地昔布对细胞增殖能力的影响;采用细胞克隆形成实验检测戊地昔布对Colo320细胞克隆形成率的影响;采用流式细胞术检测戊地昔布对细胞凋亡率及细胞周期分布的影响;采用蛋白质印迹实验检测戊地昔布作用后细胞内COX-2蛋白的表达变化,以及凋亡相关蛋白Caspase-3、cleaved Caspase-3、Bax、Bcl-2、p38MAPK及P-p38MAPK蛋白的表达变化.结果 CCK 8结果经统计学分析提示,不同浓度(0、5、10、25、50、100、200 μmol/L)戊地昔布分别作用于直肠癌Colo320细胞24、48、72及96 h后,细胞增殖受到不同程度的抑制,并呈时间(r=0.686～0.972,P＜0.001)及浓度(r=0.829～0.976,P＜0.001)依赖性.24、48、72、96h的IC50值分别为582、153、136和61 μmol/L;细胞克隆形成实验显示,戊地昔布处理后细胞克隆形成率由(28.5±1.2)％下降至(3.3±1.0)％,各组比较差异有统计学意义,F=454.227,P＜0.001.流式结果显示,戊地昔布使细胞凋亡率明显增加,由9.3％增加到30.8％,除50 μmol/L组与对照组之间差异无统计学意义(t=3.849,P=0.613)外,其余各组之间差异有统计学意义(F=224.694,P=0.001),但对细胞周期阻滞现象不明显.蛋白质印迹实验结果显示,戊地昔布使细胞内COX-2表达量降低(F=36.771,P=0.002),cleaved Caspase 3/Caspase-3(F=161.097,P＜0.001)、P p38MAPK/p38MAPK(F=104.770,P＜0.001)和Bax/Bcl-2(F=370.001,P＜0.001)比率明显升高.结论 戊地昔布能够抑制直肠癌Colo320细胞增殖,促进其凋亡,可能是通过抑制COX-2蛋白的表达,调节凋亡相关蛋白Bax和Bcl-2的表达,及激活MAPK和Caspase信号通路而实现的.     

Presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects

BACKGROUND: Opioids are associated with numerous adverse effects. It is unclear if reduced postoperative opioid consumption lowers the incidence and severity of opioid-related adverse effects. This analysis -- from a multicenter, randomized, double-blind trial -- tested if the reduction of opioid consumption among patients who received intravenous preoperative parecoxib 40 mg, followed by oral valdecoxib 40 mg qd postoperatively, in Days 1-4 after outpatient laparoscopic cholecystectomy surgery, reduced opioid-related symptoms. METHODS: Patients received intravenous fentanyl for pain before discharge, and oral acetaminophen 500 mg hydrocodone 5 mg q 4-6 h prn postdischarge for up to 7 days postsurgery. Patients also received intravenous parecoxib 40 mg administered 30-45 min preoperatively, and valdecoxib 40 mg qd up to Day 4 and prn Days 5-7 postsurgery, or placebo. Patients completed an opioid-related Symptoms Distress Scale (SDS) questionnaire every 24 h for 7 days. Opioid use was converted to morphine-equivalent doses (MEDs). Clinically meaningful events (CMEs) for 12 opioid-related symptoms were assessed by three ordinal measures: frequency, severity, and bothersomeness. Reduction of CMEs on Day 1 and number of patient-days with CMEs on Days 1-4 were examined. RESULTS: Cumulative MEDs on Day 0, Day 1, and Days 1-4 were significantly lower in the parecoxib/valdecoxib group compared with the placebo group (P < 0.001). At the end of Day 1, parecoxib/valdecoxib-treated patients had significantly lower SDS scores (P < 0.02), a significantly reduced incidence of CMEs (P < 0.05), and significantly fewer patient-days with CMEs in Days 1-4 than placebo patients (P < 0.05). Patients in the parecoxib/valdecoxib group were less likely to have CMEs for multiple symptoms than those in the placebo group (P < 0.001). CONCLUSIONS: Treatment with parecoxib and valdecoxib significantly reduced the cumulative MED requirements, the incidence of opioid-related adverse effects, and patient-days with CMEs.     

第二代环氧酶-2特异性抑制剂的研究进展

为降低NSAIDs类药物的典型胃肠道不良反应，人们开发了选择性更高的第二代环氧酶-2(COX-2)特异性抑制剂。已开发的代表性化合物有戊地昔布、帕瑞昔布、依地昔布和氯美昔布等。临床试验证实，这些药物具有可靠的抗炎和止痛作用，其中帕瑞昔布作为第一个注射用NSAIDs类药物，可用于治疗手术后疼痛。本文综述该领域的研究进展。     

五味子提取物定性鉴别和含量测定研究

目的建立五味子提取物的定性鉴别和含量测定标准。方法采用TLC鉴别五味子;采用紫外可见分光光度法,570nm波长,测定五味子木脂素含量;采用RP-HPLC,以甲醇-乙腈-水（1∶1∶1）为流动相,250nm为检测波长,测定五味子醇甲、五味子甲素、五味子乙素含量。结果供试品色谱中,在与对照品和对照药材色谱相应的位置上,显示相同颜色的荧光斑点;五味子木脂素以乙素计,在0.0055～0.0267mg·mL^-1内,线性关系良好,平均回收率101.4%（RSD=2.5%）;五味子醇甲在0.275～1.375μg（r=0.9997）内、五味子甲素在0.125～0.625μg（r=0.9997）内、五味子乙素在0.160～0.800μg（r=0.9997）内,线性关系良好,平均回收率分别为97.9%（RSD=1.4%）、99.0%（RSD=1.9%）、98.2%（RSD=1.9%）。结论采用方法简便、准确、快速,可对五味子提取物进行有效的质量控制。     

COX-2参与戊地昔抑制Lewis肿瘤生长

目的探讨戊地昔布对Lew is肿瘤的抑制作用及与抑制环氧化酶-2(COX-2)是否有关。方法用W estern b lot检测COX-2的表达,用ELISA检测前列腺素E2(PGE2),用HE染色检测肿瘤组织淋巴细胞的浸润。结果戊地昔布可抑制肿瘤生长,提高荷瘤小鼠的生存率;戊地昔布对COX-2表达没有明显影响,但降低肿瘤部位PGE2的含量;戊地昔布增加肿瘤组织淋巴细胞浸润,不影响荷瘤小鼠胃肠道上皮细胞结构以及出、凝血时间。结论戊地昔布可抑制Lew is肿瘤的生长,与抑制肿瘤组织COX-2的活性,降低PGE2含量有关。     

选择性和非选择性环氧合酶抑制剂对慢性压力小鼠模型具有保护作用(英文)

目的环氧合酶是广泛表达于大脑各区域的一类同功酶,主要用于治疗疼痛与炎症。最近研究还发现环氧合酶在大脑相关疾病的病理生理过程中扮演关键角色。本文运用慢性压力动物模型,对环氧合酶抑制剂的保护作用做一探讨。方法每只小鼠每天被迫游泳 6 min,共持续 15 天。结束后进行行为学(包括活动能力、焦虑以及记忆能力)和生化指标(包括脂质过氧化、亚硝酸盐水平、还原性型谷胱甘肽和过氧化氢酶水平)的检测。结果持续15天的强迫性游泳会损伤小鼠活动能力,引起焦虑样行为的产生,并削弱记忆力。在生化指标方面,脂质过氧化和亚硝酸盐水平均显著提高,还原型谷胱甘肽和过氧化氢酶活力则显著降低。此外,环氧合酶抑制剂,包括甲氧萘丙酸、罗非考昔、美洛昔康、尼美舒利和伐地考昔,都能显著减缓这些损伤。结论环氧合酶抑制剂可被用来治疗慢性疲劳综合症。