Induction of apoptosis and inhibition of cell proliferation by the cyclooxgenase enzyme blocker nimesulide in the Ishikawa endometrial cancer cell line

Objectives

Endometrial cancer remains a leading cause of death in women and therefore the development of new therapies is essential. The present study evaluated the effects of nimesulide alone, cisplatin alone, and combination of cisplatin and nimesulide on an Ishikawa cell line with respect to cytotoxicity and induction of apoptosis in vitro.

Study design

Ishikawa cells were treated with increasing doses of nimesulide alone, cisplatin alone, and a combination of cisplatin and nimesulide. Subsequently their effects on cytotoxicity were investigated by MTT assay, while apoptosis was investigated by DAPI and JC-1 staining and caspase-3 colorimetric assays.

Results

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that nimesulide alone and combination of cisplatin and nimesulide have growth inhibitory effect on Ishikawa cells. Nimesulide alone and the combination of cisplatin and nimesulide induced apoptosis. Apoptosis induced by nimesulide might be related to caspase-3 activation.

Conclusions

These results suggest that nimesulide treatment is as effective as cisplatin treatment in Ishikawa cells. The combination of cisplatin and nimesulide treatment is more effective than cisplatin alone in Ishikawa cells.     

选择性COX-2抑制剂尼美舒利对肺癌放射治疗增敏作用及其机制研究

目的 观察选择性环氧化酶抑制剂与放射治疗联合应用对人肺腺癌A549裸鼠移植瘤生长的影响并进一步探讨其放疗增敏机制.方法 首先构建人肺腺癌A549裸鼠移植瘤模型,待裸鼠移植瘤长至最长径6.0 mm时随机分为4组:对照组、尼美舒利组、放疗组、尼美舒利联合放疗组.尼美舒利溶于0.5％羟甲基纤维素钠中,采用灌胃方式给药,剂量为60 mg·kg1·d-1,共28 d.移植瘤最大径长至6.0 mm时予以局部单次大剂量放疗10 Gy.观察各组移植瘤最长径由6 mm长至12 mm所需时间,以移植瘤体积绘制生长曲线,计算抑瘤率,用免疫组化方法检测增殖细胞核抗原(PCNA)、前凋亡蛋白Bax、凋亡抑制蛋白Bcl-2在组织中表达情况,应用流式细胞技术测定细胞周期分布及凋亡率.结果 尼美舒利联合放疗对肺腺癌裸鼠移植瘤生长有明显抑制作用.对照组移植瘤最长径由6 mm增长至12 mm所需时间为(7.12±0.72)d,放疗组为(8.34±0.71)d,尼美舒利组为(11.29±0.78)d,尼美舒利联合放疗组为(14.62±0.19)d.放疗组抑瘤率为21.2％,尼美舒利组为18.3％,尼美舒利联合放疗组为41.7％.应用免疫组化方法检测移植瘤中PCNA和Bcl-2表达的阳性面积百分比及灰度值:尼美舒利联合放疗组、放疗组、尼美舒利组均低于对照组(P值均＜0.05),且尼美舒利联合放疗组低于放疗组及尼美舒利组(P值均＜0.05);Bax表达阳性面积百分比及灰度值:尼美舒利联合放疗组、放疗组、尼美舒利组均高于对照组(P值均＜0.05),且尼美舒利联合放疗组高于放疗组及尼美舒利组(P值均＜0.05).流式细胞仪检测细胞凋亡率及细胞周期分布:尼美舒利联合放疗组、放疗组、尼美舒利组凋亡率均高于对照组(P值均＜0.05),且尼美舒利联合放疗组高于放疗组及尼美舒利组(P值均＜0.05);G0/G1期各组差异无统计学意义(F＝2.731,P＞0.05);S期尼美舒利联合放疗组、放疗组、尼美舒利组均低于对照组(P值均＜0.05),且尼美舒利联合放疗组低于放疗组及尼美舒利组(P值均＜0.05);G2/M期尼美舒利联合放疗组同其他各组相比增多(P值均＜0.05),对照组、放疗组、尼美舒利组差异无统计学意义(P＞0.05).结论 尼美舒利可抑制人肺腺癌A549裸鼠移植瘤的生长,尼美舒利增强人肺腺癌A549裸鼠移植瘤对放射治疗的敏感性.其机制可能同抑制PCNA表达,从而抑制肿瘤细胞的生长,并通过抑制Bcl-2表达、增强Bax表达,而诱导A549细胞凋亡有关;还可能与细胞周期分布中对放疗不敏感的S期细胞数减少而对放疗敏感的G2/M期细胞数增加有关.     

胸腺肽和转移因子联合尼美舒利治疗非特异性肋软骨炎疼痛的疗效观察

【摘要】 目的 探索胸腺肽、转移因子联合尼美舒利治疗非特异性肋软骨炎的疗效。方法 选择2010年1月~2012年6月于我院外科门诊就诊的134例肋软骨炎患者作为研究对象,分尼美舒利单药治疗组(n=67)和胸腺肽、转移因子联合尼美舒利治疗的联合治疗组(n=67),比较两组患者的疗效。结果〓联合用药组非特异性肋软骨炎的总体有效率95.5%(64/67),尼美舒利单药治疗组为53.7%(36/67),两组治疗效果差异有统计学意义。结论〓胸腺肽和转移因子联合尼美舒利治疗非特异性肋软骨炎的疗效优于单药尼美舒利。     

儿童口服尼美舒利安全性的系统评价

目的 评价儿童口服尼美舒利的安全性。方法 计算机检索PubMed、EMBASE、Cochrane图书馆（2011年第3期）、Cochrance 临床对照试验数据库、中国生物医学文献光盘数据库、中国期刊全文数据库、中国维普科技期刊数据库和万方数据库,检索时间均从建库至2011年3月。手工检索中国《药品不良反应信息通报》、WHO Pharmaceuticals Newsletter、MHRA Drug Safety Update和FDA Drug Safety Newsletter。获得儿童尼美舒利安全性评价的队列研究、病例对照研究、RCT研究、非随机分组的对照研究和病例报告,此外还获取上市后药物不良反应监测,各国药物监督和管理机构对尼美舒利的风险利益评估、适应证修改等资料。按纳入和排除标准筛选文献,评价文献质量,提取资料。RCT文献采用 RevMan 5.0 软件进行Meta分析,余文献采用描述性分析,采用WHO-UMC评价体系评价病例报告中不良反应与尼美舒利的关联性。结果 未检出儿童尼美舒利安全性评价的队列研究和病例对照研究。检出符合纳入标准的RCT文献43篇,病例报告9篇,尼美舒利上市后不良反应监测1篇。①RCT文献结果：儿童口服尼美舒利不良反应包括胃肠道反应、体温过低、皮疹,肝酶升高和神经系统不良反应（嗜睡或烦躁）。胃肠道反应发生率低于布洛芬（P<0.000 01）和对乙酰氨基酚（P=0000 9）;体温过低（P=0.01）和神经系统不良反应（P=0.03）发生率高于布洛芬;ALT和（或）AST升高发生率与布洛芬、对乙酰氨基酚差异均无统计学意义。 ②病例报告分析结果：报道3例严重肝脏不良反应,其中2例死亡;1例很可能由尼美舒利引起,2例可能由尼美舒利引起;报道5例血尿,均很可能由尼美舒利引起。③上市后不良反应监测结果：未检索到中国尼美舒利不良反应监测数据;印度监测4 092例患儿,报告肾脏不良反应13例,未报告肝脏不良反应。④中国食品药品监督管理局于2008年6月修改尼美舒利说明书,仅用于1岁以上儿童,用于退热疗程不超过3 d;欧洲药品管理局于2007年评估尼美舒利风险和效益后,限制其适应证仅为止痛,不用于退热,且疗程不超过15 d,12岁以下儿童禁用;2011年2月印度卫生部禁止12岁以下儿童使用尼美舒利。结论 儿童口服尼美舒利胃肠道反应发生率可能低于布洛芬和对乙酰氨基酚,体温过低和神经系统不良反应发生率可能高于布洛芬,肝酶升高发生率可能与布洛芬和对乙酰氨基酚相似,严重肝脏不良反应有待进一步研究明确其与尼美舒利的因果关系。     

Postoperative pain and edema control following different protocols of preemptive analgesia in the surgical removal of impacted third molars: A triple-blind parallel randomized placebo-controlled clinical trial

This randomized controlled clinical trial aimed to evaluate the preemptive effects of acetaminophen, ibuprofen, ketoprofen, nimesulide or dexamethasone on postoperative pain and edema in the surgical removal of impacted third molars.Participants underwent bilateral surgeries at 2 different times and were randomly given the test drug or placebo (split-mouth). Postoperative pain, edema and rescue medication were evaluated at different times. Study power was >80% for the observed effect size in the crossover repeated measures design. Differences between test drug and placebo were the response variable. Generalized Estimation Equation models were adjusted for each outcome.Sample comprised 5 groups (n = 20 each). Ibuprofen and nimesulide showed higher overall effects on pain scores over time, with no differences between them (p = 0.557). Acetaminophen showed significantly lower overall effects in edema control over time, when compared to other test drugs, that showed similar effects. Lower quantity of rescue medication were also observed for ibuprofen and nimesulide, with no differences between them (p = 0.999). Ibuprofen and nimesulide showed beneficial overall preemptive effects. Hence, in the decision-making process for preemptive analgesia in impacted third molar surgeries, ibuprofen and nimesulide should be considered on a case-by-case basis as the drugs of choice.     

Distribution of oral nimesulide in female genital tissues

Nimesulide is a non-steroidal anti-inflammatory agent which has proved to be effective in reducing menstrual discomfort in dysmenorrhoeaic women. To determine the concentrations of this drug in the uterus (fundus, cervix), oviduct, and ovaries and to correlate these findings with plasma concentrations, a single oral dose of 100 mg nimesulide was administered 1 to 6 h before surgery to 12 women undergoing hysterectomy and salpingo-oophorectomy, mainly for fibroids. Tissue samples were taken, concentration of nimesulide measured by HPLC, and findings compared with plasma concentrations. One patient not undergoing treatment served as control. Nimesulide concentration in the tissues studied was highest 3 h after administration, as expected from the drug's pharmacokinetic profile. The highest tissue/plasma ratio (0.5) was also found at that time. Average tissue concentrations at 1, 2, 3, and 6 h after drug intake ranged from 0.3 to 1.8 micrograms g-1, and plasma concentrations from 2.6 to 4.1 micrograms ml-1. Nimesulide was evenly distributed in the tissues studied.     

选择性COX-2抑制剂Nimesulide对肝肿瘤细胞HepG2增殖与凋亡的影响

目的观察环氧合酶(COX)-2抑制剂尼美舒利(Nimesulide)对肝肿瘤细胞HepG2增殖和凋亡的影响.方法用不同浓度(100、200、300μmol/L)的Nimesulide处理HepG2细胞,采用四甲基偶氮唑蓝法检测Nimesulide对HepG2细胞增殖的影响;Western印迹法检测HepG2细胞半胱氨酸-天冬氨酸特异性蛋白酶(Caspase)-3表达,流式细胞术检测细胞凋亡.用放射免疫测定法检测Nimesulide对HepG2细胞PGE2释放水平,反映Nimesulide对COX-2活性的影响.结果 100、200、300μmol/L的Nimesulide作用于HepG2细胞,其A值分别为1.69±0.16,1.06±0.09,0.62±0.06,与对照组(3.09±0.28)相比,差异有非常显著性(P＜0.01).Nimesulide诱导HepG2细胞的凋亡率分别为(4.53±2.15)、(6.02±3.50)、(16.24±7.92),与对照组比较(2.84±1.88,P＜0.01).Nimesulide干预的HepG2细胞的Caspase-3的蛋白表达均明显升高,A值分别为(46.96±2.86)、(60.28±3.05)、(76.59±4.26),与对照组相比(32.57±1.83)差异有非常显著性(P＜0.01).Nimesulide可明显诱导HepG2细胞Caspase-3蛋白活性的升高,A值分别为(0.46±0.03)、(0.73±0.06)、(0.91±0.12),与对照组相比(0.28±0.02),差异有显著性(P＜0.01).Nimesulide可明显抑制HepG2细胞PGE2释放水平,其值分别为(72.34±6.64)、(51.67±4.37)和(30.28±2.67),与对照组比较差异有非常显著性(P＜0.001).结论 Nimesulide抑制肝肿瘤细胞HepG2增殖,促进肿瘤细胞凋亡.     

国产尼美舒利的药效学研究

本文研究了国产尼美舒利在小鼠、大鼠及家兔体内的抗炎、镇痛和解热作用.结果表明.尼美舒利抑制巴豆油致小鼠耳廓肿胀(ED_(50)为49.2mg·kg~(-1));抑制角叉菜胶致大鼠足肿(ED_(50)为2.75mg·kg(-1));0.6mg·kg~(-1)剂量对大鼠佐剂关节炎有显著预防和治疗作用。100mg·kg~(-1)对小鼠醋酸扭体法的抑制率为68％;对热板法致痛的痛阈提高率为55％。ip给药对蛋白胨致家兔发热的解热作用.其最小有效剂量为2mg·kg~(-1);5mg·kg~(-1)ig可显著降低啤酒酵母致大鼠升高的体温.证实国产尼美舒利具有很强的抗炎、镇痛和解热作用。     

尼美舒利联用亚胺培南西司他丁钠致耳聋1例

1例52岁男性患者,因高热8h内使用尼美舒利片150mg,亚胺培南西司他丁钠0.5g静脉给药后,约2h后出现耳聋。耳鼻喉内窥镜检查示双侧鼓膜未见明显异常。听力学纯音测听:500Hz、1000Hz、2000Hz平均听阈示左耳90dB、右耳80dB。听力学声导抗示左耳鼓室图C型、右耳鼓室图A型,双耳镫骨肌声反射均未引出。停用尼美舒利、亚胺培南西司他丁钠,予乳酸钠林格注射液补液,甲泼尼龙片、甲钴胺片等对症处理,听力逐渐恢复,出院后30d复诊,听力好转。     

通络开痹片联合尼美舒利治疗急性痛风性关节炎的临床观察

目的观察通络开痹片联合尼美舒利治疗急性痛风性关节炎的临床疗效。方法选取2017年6月～2018年5月我院ICU治疗的急性痛风性关节炎患者50例,并将其随机分为两组,每组25例。对照组单纯采用尼美舒利治疗,治疗组在对照组的基础上加服通络开痹片;观察两组患者治疗后的综合疗效、疼痛评分、中医证候积分、相关生化指标的变化及不良反应情况。结果治疗后,治疗组总有效率达(92.00%)显著高于对照组(80.00%),差异具有统计学意义(P0.05);治疗后,治疗组中医证候积分、疼痛评分,ESR、CRP、UA等生化指标水平的改善均显著优于对照组,差异有统计学意义(P0.05)。两组患者在治疗过程中,均未出现疼痛加剧等不良反应。结论中西医结合治疗痛风性关节炎疗效更好、安全性更高;且虽然血尿酸显著下降,但治疗组未出现急性痛风加重的病例。