A double prodrug system for colon targeting of benzenesulfonamide COX-2 inhibitors

The design, synthesis and delivery potential of a new type of benzenesulfonamide cyclo-oxygenase-2 (COX-2) inhibitor prodrug is investigated using celecoxib. The approach involves a double prodrug that is activated first by azoreductases and then by cyclization triggering drug release. We studied the intramolecular aminolysis of the acylsulfonamide. The cyclization was surprisingly rapid at physiological pH and very fast at pH 5. The prodrug is activated specifically under conditions found in the colon but highly stable in the presence of human and rodent intestinal extracts. Finally, the prototype with celecoxib was transported much more slowly in the Caco-2 transepithelial model than the parent. The design therefore shows significant promise for the site specific delivery of benzenesulfonamide COX-2 inhibitors to the colon.     

Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives

A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents.     

Short-term therapy with celecoxib and lansoprazole modulates Th1/ Th2 immune response in human gastric mucosa

Background: Selective cyclooxygenase‐2 (COX‐2) inhibitors and proton pump inhibitors may exert immune‐mediated effects in human gastric mucosa. T‐cell immune response plays a role in Helicobacter pylori‐induced pathogenesis. This study evaluated effects of celecoxib and lansoprazole on T‐helper (Th) 1 and Th2 immune response in human gastric mucosa. Methods: Dyspeptic patients with or without osteoarticular pain were given one of the following 4‐week therapies: celecoxib 200 mg, celecoxib 200 mg plus lansoprazole 30 mg, and lansoprazole 30 mg daily. Expression of COX‐2, T‐bet, and pSTAT6 and production of prostaglandin E₂ (PGE₂), interferon (IFN)‐γ, and interleukin (IL)‐4 were determined in gastric biopsies before and after therapy. Histology was evaluated. Results: Cyclooxygenase‐2 expression and PGE₂ production was higher, and Th1 signaling pathway was predominant in H. pylori‐infected vs. uninfected patients. T‐bet expression and IFN‐γ production increased, while STAT6 activation and IL‐4 production decreased following therapy with celecoxib and celecoxib plus lansoprazole, respectively. Th1 and Th2 signaling pathways down‐regulated after therapy with lansoprazole, and this was associated with an improvement of gastritis. Effect of therapy was not affected by H. pylori status. Conclusion: Celecoxib and lansoprazole modulate Th1/Th2 immune response in human gastric mucosa. The use of these drugs may interfere with long‐term course of gastritis.     

通滞苏润江胶囊联合塞来昔布对早期膝骨关节炎患者血清炎症因子和疼痛介质的影响

摘要 目的：观察通滞苏润江胶囊联合塞来昔布对早期膝骨关节炎（KOA）患者血清炎症因子和疼痛介质的影响。方法：选择2021年6月-2022年12月期间石家庄市人民医院收治的早期KOA患者80例,采用随机数字表法将患者分为对照组（塞来昔布,40例）和观察组（通滞苏润江胶囊联合塞来昔布,40例）。对比两组疗效、疼痛视觉模拟评分（VAS）、西安大略和麦克马斯特大学骨关节炎指数（WOMAC）评分、炎症因子和疼痛介质。结果：观察组临床总有效率高于对照组（P<0.05）。两组治疗1个月后VAS、WOMAC评分下降,且观察组低于对照组同时间点（P<0.05）。两组治疗1个月后肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）下降,且观察组低于对照组同时间点（P<0.05）。两组治疗1个月后前列腺素E₂（PGE₂）、P物质（SP）下降,且观察组低于对照组同时间点（P<0.05）。两组不良反应发生率对比未见统计学差异（P>0.05）。结论：塞来昔布和通滞苏润江胶囊联合治疗早期KOA患者,可缓解疼痛,提高临床治疗效果,改善关节功能,同时还可改善血清炎症因子和疼痛介质水平。     

Celecoxib抑制Lewis肺癌移植瘤淋巴管生成的作用机制及量效关系

目的:COX-2过度表达及淋巴管的生成与肺癌早期转移、不良预后密切相关。观察不同剂量COX-2特异性抑制剂Celecoxib对Lewis肺癌移植瘤生长、COX-2、VEGF-C表达和微淋巴管生成影响,探讨Celecoxib对Lewis肺癌移植瘤淋巴管生成可能作用机制及量效关系。方法:将Lewis肺癌细胞株接种于C57BL/6小鼠左侧腹股沟皮下建立移植瘤模型,随机分为4组:对照组、塞来昔布低剂量(30 mg·kg-1·d-1)、中剂量(90 mg·kg-1·d-1)、高剂量(180 mg·kg-1·d-1)组。观察荷瘤小鼠生存状态,瘤体积变化,计算抑瘤率,种瘤42天后牺牲小鼠,切取移植瘤组织,免疫组化染色检测COX-2、VEGF-C表达及微淋巴管密度(Lymphatic microvessel density,LMVD)。结果:塞来昔布低、中、高剂量组的抑瘤率分别为13.3%、46.8%和56.3%。塞来昔布高、中剂量组较对照组抑瘤作用明显,差异有统计学意义(P0.05),但低剂量组差异无统计学意义(P0.05)。免疫组织化学染色结果分析显示:塞来昔布高、中剂量组COX-2、VEGF-C的表达水平及微淋巴管密度均明显减低,差异有统计学意义(P0.05),低剂量组略有减低但差异无统计学意义(P0.05)。抑制程度呈明显的剂量依赖性。结论:塞来昔布抑制Lewis肺癌移植瘤的生长及淋巴转移,可能与下调COX-2的表达,减少VEGF-C的产生,抑制微淋巴管生成有关,该抑制作用呈一定的剂量相关性,为抗肺癌早期淋巴转移,改善患者预后的药物研发提供了一定的实验基础。     

塞来昔布联合survivin反义寡核苷酸对胰腺癌荷瘤裸鼠的治疗作用

目的:探讨环氧化酶-2(COX-2)抑制剂塞来昔布和survivin反义寡核苷酸(ASODN)联合作用对胰腺癌荷瘤裸鼠的治疗作用。方法:构建胰腺癌荷瘤裸鼠模型,将成瘤裸鼠随机分为4组:对照组、塞来昔布组(给予1000ppm的塞来昔布饮水)、survivin ASODN组(瘤内注射40μg/200μL的survivin ASODN)、联合组(给予1000ppm的塞来昔布饮水的同时瘤内注射40μg/200μL的survivin ASODN);观测裸鼠肿瘤生长情况并测量不同时间的体积变化,于接种肿瘤的35天处死裸鼠,测瘤体质量,应用cas- pase-3试剂盒检测caspase-3活性,免疫组织化学法检测肿瘤增殖指数(PI)和微血管密度(MVD)。结果:治疗组平均体积均明显低于对照组(491.97±4.62mm~3,427.34±14.62mm~3,300.39±6.59mm~3 vs 703.56±12.51 mm~3,P<0.01),其中联合治疗组体积明显低于塞来昔布组或survivin ASODN组(P<0.01);平均抑瘤率分别为32.26%、50.86%、62.07%。治疗组caspase-3相对活性明显高于对照组(0.026±0.003、0.040±0.018、0.059±0.005 vs 0.006±0.001,P<0.01),其中联合治疗组caspase-3相对活性明显高于塞来昔布组(P<0.01)或survivin ASODN组(P<0.05);治疗组平均PI和MVD均明显低于对照组(P<0.01,或P<0.05),其中联合治疗组平均PI和MVD明显低于塞来昔布组或survivin ASODN组(P<0.01,或P<0.05)。结论:COX-2抑制剂塞来昔布和survivin ASODN联合应用可显著抑制荷胰腺癌裸鼠的肿瘤生长,其作用机制可能是通过共同提高caspase-3活性来诱导细胞凋亡,通过抑制肿瘤细胞的增殖和新生血管的形成来发挥抗肿瘤效应,为胰腺癌的治疗提供了新的思路。     

塞来西布及5- 氟尿嘧啶对人胆管癌QBC939 细胞生长抑制 及诱导凋亡的影响

目的:研究塞来西布(Celecoxib)和5-氟尿嘧啶(5-FU)对人胆管癌QBC939细胞生长抑制和凋亡的影响。方法:体外培养人胆管癌QBC939细胞,噻唑兰比色实验(MTT)观察Celecoxib和5-FU对胆管癌QBC939细胞生长抑制作用;流式细胞术检测细胞生长周期和凋亡率改变。结果:不同浓度的Celecoxib和5-FU可抑制胆管癌QBC939细胞的生长,细胞生长抑制率呈时间-浓度依赖性(P<0.01);实验组QBC939细胞凋亡率随药物浓度的升高逐渐增高(P<0.01),S期细胞逐渐减少(P<0.05),G1期细胞逐渐增加(P<0.05),G2期细胞无明显变化。结论:Celecoxib和5-FU可抑制人胆管癌QBC939细胞的增殖,诱导其凋亡;联合用药效果优于Celecoxib和5-FU单药效果。     

Formulation and development of floating capsules of celecoxib: In vitro and in vivo evaluation

The objective of the present study was to develop a hydrodynamically balanced system for celecoxib as single-unit floating capsules. Various grades of low-density polymers were used for formulation of these capsules. The capsules were prepared by physical blending of celecoxib and the polymer in varying ratios. The formulation was optimized on the basis of in vitro buoyancy and in vitro release in citrate phosphate buffer pH 3.0 (with 1% sodium lauryl sulfate). Capsules prepared with polyethylene oxide 60K and Eudragit RL100 gave the best in vitro percentage release and were used as the optimized formulation. By fitting the data into zero-order, first-order, and Higuchi models, we concluded that the release followed zero-order kinetics, as the correlation coefficient (R value) was higher for zero-order release. For gamma scintigraphy studies, celecoxib was radiolabeled with technetium-99m by the stannous reduction method. To achieve the maximum labeling efficiency the process was optimized by studying the reaction at various pH conditions and stannous concentration levels. The radiolabeled complex was added to the optimized capsule, and dissolution studies were performed to ensure that there was no leaching of radioactivity from the capsules. Gamma imaging was performed in rabbits to assess the buoyancy of the optimized formulation. The optimized formulation remained buoyant during 5 hours of gamma scintigraphic studies in rabbits.