塞来昔布对人鼻咽癌细胞凋亡的促进作用

目的 研究塞来昔布对人鼻咽癌CNE细胞凋亡的促进作用.方法 以人鼻咽癌细胞株CNE为研究对象,设实验组（加入塞来昔布20mmol/L）及对照组,培养48h后,制备成超薄切片透射电镜观察塞来昔布对细胞凋亡的影响.取不同浓度塞来昔布（0 ×10-5mol/L、1.0 ×10-5mol/L、2.0 ×10-5mol/L、4.0 ×10-5mol/L）处理细胞,用流式细胞仪检测细胞周期分布及凋亡.TUNEL（DNA末端原位标记染色法）荧光染色法检测CNE细胞凋亡,计算凋亡率%=凋亡阳性细胞数/100个CNE细胞.结果 给予塞来昔布48 h后,透射电镜下CNE细胞染色质固缩边集,细胞器肿胀,胞浆内可见凋亡小体形成.流式细胞学结果显示塞来昔布对CNE细胞周期分布的影响S期细胞减少,G1期细胞增加,经浓度分别10mmol/L、20mmol/L、40mmol/L塞来昔布处理48h,随浓度增大,凋亡率增加.TUNEL结果显示：实验组凋亡细胞明显增多,CNE细胞凋亡百分比（4.3±2.21）%,明显高于对照组（0.9±0.99）%,差异有统计学意义（P〈0.01）.结论 本实验将塞来昔布作用于人鼻咽癌细胞株CNE细胞后,运用电镜观察到凋亡细胞增加.不同浓度的塞来昔布作用于人鼻咽癌细胞株CNE细胞后,流式细胞术、TUNEL荧光染色均证明环氧合酶-2抑制剂塞来昔布对凋亡有促进作用,塞来昔布（特异性环氧合酶-2抑制剂）已被认为肿瘤治疗新靶标,可为临床的肿瘤治疗提供新的方法.     

Celecoxib to prevent restenosis – results from the COREA-TAXUS trial

Celecoxib inhibits Akt, which is stimulated during restenosis. Cell and animal studies showed that celecoxib inhibited Akt stimulation and restenosis. Recently, the COREA-TAXUS (Effect of Celecoxib on Restenosis after Coronary Angioplasty with Taxus stent) trial was performed in subjects with angina or a positive-stress test receiving paclitaxel-eluting stents. The primary end point at 6 months was the in-stent, late luminal loss, which was 0.49 mm in the celecoxib-treated group; less than the 0.75 mm in the group not treated with celecoxib. The rate of revascularisation of the target lesion was lower in celecoxib-treated subjects (5%) than in the untreated subjects (15%). In conclusion, this is an excellent demonstration of translating a mechanism of action of a drug into a clinical use.     

Celecoxib-loaded poly(D,L-lactide-co-glycolide) nanoparticles prepared using a novel and controllable combination of diffusion and emulsification steps as part of the salting-out procedure

A novel procedure for the manufacture of celecoxib-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles is described that is based upon combining salting out and emulsion-evaporation steps. An entrapment efficiency, a measure of the actual to theoretical drug content, of 97.3% was achieved, being superior to that achieved when these popular techniques were used separately (emulsion evaporation, 40.1%; salting out, 10.0%). The ratio of a water miscible solvent (acetone) to a non water-miscible solvent (dichloromethane) was shown to be the primary determinants of size and drug loading. Once optimized, using an organic phase of 3?:?1 acetone?:?dichloromethane vol?:?vol ratio, further control on particle parameters could be exerted using modification of acetone diffusion by alterations in MgCl₂?·?6H₂O concentration. This step was shown to have a small effect on both the mean nanoparticle size and entrapment efficiency, but found to reduce the polydispersity considerably. Diffusion control using a 45% w/v MgCl₂?·?6H₂O solution produced nanoparticles with a mean size of 151.4?nm, a polydispersity index of 0.023 and 98.1% entrapment efficiency. Electron microscopy showed the particles to be smooth and spherical. Sheer homogenization during the emulsification step was shown to be not as effective as sonication, with the latter technique able to produce nanoparticles after 1?min of application. Drug release studies across a semi-permeable membrane demonstrated a reduction in the burst effect as the ratio of acetone in the organic phase was increased. Calorimetry studies suggested that celecoxib existed in the nanoparticle as a molecular dispersion, with additional evidence for a strong interaction between the PLGA and the absorbed poly(vinyl alcohol) stabilizer. Formation of a strong interaction between celecoxib and PLGA, together with the formation of a radial drug gradient give a release profile that does not possess the prevalent burst effect seen with other nanoparticulate drug-loaded systems.     

塞莱西布诱导胆囊癌细胞凋亡和生长抑制的作用

目的:研究塞莱西布对人胆囊癌细胞生长抑制及诱导凋亡的作用.方法:应用TUNEL,MTT法,流式细胞技术等方法对经塞莱西布作用的人胆囊癌细胞进行观察和检测.结果:塞莱西布对人胆囊癌细胞具有明显的生长抑制和促进调亡作用(P<0.05),在一定范围内存在时间依赖关系和剂量依赖关系(P<0.05).结论:塞莱西布诱导肿瘤细胞产生凋亡,是其对肿瘤细胞生长抑制作用的基础.     

塞来昔布预防根管治疗期间急症的临床评价

目的比较一次性和二次性根管治疗后根管治疗期间急症（EIAE）的发生率及急性发作程度（FUI）,评价应用塞来昔布的预防效果。方法按纳入标准选取在湖南旺旺医院口腔科就诊的225例牙髓坏死并有根尖周x线透射阴影需行根管治疗的患牙,采用逐步后退法制备根管,随后将患者随机分为两组：塞来昔布组113例,根管预备后口服塞来昔布,其中55例行一次性根管治疗,58例行二次性根管治疗;安慰剂组112例,根管预备后口服外形和颜色一致的安慰剂,一次性根管治疗和二次性根管治疗各56例。记录两组患者根管治疗后1周内出现的症状。结果一次性根管治疗组EIAE的发生率及FUI均值均明显高于二次性根管治疗组（P〈0．05）。塞来昔布组EIAE的发生率及FUI值分别为5．31％、（2．58±0．64）,明显低于安慰剂组的13．39％、（4．08±0．79）,差异有统计学意义（P〈0．05）。塞来昔布对一次性根管治疗术后的EIAE发生率及FUI值具有明显的抑制作用（P〈0．05）。结论根管制备后预防性服用塞来昔布可显著降低EIAE的发生率、减轻术后疼痛及肿胀程度。     

Survivin基因沉默抑制胃癌MGC-803细胞增殖并增强其对塞来昔布的敏感性

目的研究Survivin基因沉默对人胃癌MGC-803细胞增殖和对化疗药物塞来昔布敏感性的影响。方法设计合成Survivin的siRNA序列,LipofectamineTM2000转染入MGC-803细胞。采用RT-PCR和Western blotting检测Survivin在干扰后mRNA和蛋白的表达情况,利用流式细胞仪检测细胞周期。通过MTT法和细胞克隆形成试验法察Survivin基因沉默后MGC-803细胞对塞来昔布的敏感性。结果 Survivin基因沉默48 h后,MGC-803细胞的Survivin基因和蛋白表达明显降低(P<0.05)。细胞周期被阻滞在G0/G1期,S期细胞数减少(P<0.05)。Survivin基因沉默组细胞对塞来昔布的敏感性显著性增强(P<0.05)。结论 Survivin特异性siRNA能显著沉默MGC-803细胞Survivin基因,抑制细胞增殖,并增强MGC-803细胞对塞来昔布的敏感性。     

双靶点阻滞对肺腺癌细胞的协同抑制作用及其可能机制

目的探讨联合阻断表皮生长因子受体(EGFR)和环氧合酶-2(COX-2)对肺腺癌A549细胞株的协同抑制作用及其可能机制。方法采用不同药物干预肺癌A549细胞株,分为4组:正常对照组、单药吉非替尼组、单药塞来昔布组、联合用药组。药物干预细胞48 h后台盼蓝(trypan blue)染色法检测药物对细胞生长的影响;以Hoechst33258染色法和流式细胞术观察用药前后细胞凋亡和细胞周期的变化。采用Western blot检测EGFR和COX-2蛋白的表达情况。结果随着时间和剂量增加,单药吉非替尼与塞来昔布对A549细胞的抑制作用增强,加药48 h,联合用药组抑制率明显高于单药组(P0.01)。联合用药组细胞凋亡率明显高于单独用药组(32.40%vs7.12%和8.43%;P0.01)。联合用药组S期细胞比例为(3.2±0.9)%,较单药吉非替尼组[(37.4±1.6)%]和单药塞来昔布组[(21.0±3.1)%]明显减少(P0.01);联合用药组G0/G1期细胞比例为(87.2±6.4)%,较单药吉非替尼组[(61.4±5.2)%]和单药塞来昔布组[(51.8±4.7)%]明显增加(P0.01)。与单独用药组比较,联合用药组EGFR和COX-2蛋白的表达明显减弱(P0.05)。结论联合用药通过EGFR和COX-2双靶点阻滞发挥作用,有望为肺癌的化学预防和治疗提供新的策略。     

In Vitro and In Vivo Evaluation of Core–Shell Mesoporous Silica as a Promising Water-Insoluble Drug Delivery System: Improving the Dissolution Rate and Bioavailability of Celecoxib With Needle-Like Crystallinity

The objective of our study was to prepare mesoporous silica nanoparticles with a core–shell structure (CSMSNs) and improve the dissolution and bioavailability of celecoxib (Cxb), a water-insoluble drug, by changing its needle-like crystal form. CSMSNs are prepared by a core-shell segmentation self-assembly method. The S_BET and V_t of CSMSNs were 890.65 m²/g and 1.23 cm³/g, respectively. Cxb was incorporated into CSMSNs by the solvent evaporation method. The gastrointestinal irritancy of the CSMSNs was evaluated by a gastric mucosa irritation test. In vitro dissolution and in vivo pharmacokinetic tests were carried out to study the improvement in the dissolution behavior and oral bioavailability of Cxb. In conclusion, gastric mucosa irritation study indicated the good biocompatibility of CSMSNs. The cumulative dissolution of CSMSNs-Cxb is 86.2% within 60 min in SIF solution, which may be ascribed to the crystal form change caused by control of the nanochannel for CSMSNs. Moreover, CSMSNs could enhance the 9.9-fold AUC of Cxb. The cumulative dissolution and bioavailability of Cxb were both significantly enhanced by CSMSNs. CSMSNs with a core–shell structure are suitable as a carrier for a poorly water-soluble drug (Cxb).     

Phase II study of celecoxib with docetaxel chemoradiotherapy followed by consolidation chemotherapy docetaxel plus cisplatin with maintenance celecoxib in inoperable stage III nonsmall cell lung cancer

1 Title

Phase II study of celecoxib with docetaxel chemoradiotherapy (CRT) followed by consolidation chemotherapy docetaxel plus cisplatin with maintenance celecoxib in inoperable stage III nonsmall cell lung cancer.

2 Introduction

Concurrent CRT has been associated with improvement in absolute 5‐year survival by 10% and is the standard of care for inoperable stage III nonsmall cell lung cancer. Preclinical evidence suggests that cyclooxygenase‐2 inhibition may increase the efficacy of CRT.

3 Methods

Patients were treated with CRT (weekly docetaxel at 30 mg/m² over 6 weeks with concurrent external beam radiotherapy with 60 Gy in 30 fractions) followed by consolidation chemotherapy with docetaxel and cisplatin, each at 75 mg/m² given 3 weekly for four cycles. Patients were to receive celecoxib 400 mg twice daily during treatment. Prophylactic cranial irradiation (30 Gy in 15 fractions) was offered if there was disease response.

4 Results

Twenty‐four patients commenced CRT. Nineteen patients commenced consolidation therapy with 14 patients completing treatment. Twelve patients had treatment with celecoxib. In the total cohort, the median overall survival (mOS) was 21 months and progression‐free survival (PFS) was 16 months. Overall response rate was 59% and disease control rate was 82%. Three patient deaths occurred. Significant grade 3/4 toxicity included radiation pneumonitis (17%), febrile neutropenia (17%), infection/sepsis with or with neutropenia (25%) and esophagitis (12.5%). Retrospective analysis of celecoxib versus no celecoxib treatment showed favorable mOS 26.5 versus 17.5 months and PFS 22 versus 16 months, but this did not reach statistical significance.

5 Conclusions

The activity of this regimen has been demonstrated. Treatment‐related toxicity was substantial. The role of celecoxib in addition to CRT could not be demonstrated in this study because of the small number of patients.