Design and Evaluation of Celecoxib Porous Particles using Melt Sonocrystallization

Purpose The purpose of the article was to study melt sonocrystallization (MSC) for a drug forming a viscous melt when processed below its glass transition temperature. Methods A molten mass of drug was poured in a vessel containing deionized water, maintained at 40°C using cryostatic bath, and sonicated for 1 min using probe ultrasonicator at an amplitude of 80% and a cycle of 0.8 per second. The product obtained after solidification of dispersed droplets was separated by filtration and dried at room temperature. MSC celecoxib was characterized by solubility determination, scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, and stability study. Results The MSC technique was designed for celecoxib, which undergoes fast solidification. The particles obtained by MSC were porous, irregular in shape, and amorphous in nature. An increase in the apparent solubility was observed for the MSC particles. These amorphous particles also exhibited a higher stability in the amorphous state as compared with particles obtained by melt quenching. Conclusions The reported MSC technique for celecoxib demonstrates advantages over other approaches and can be exploited in area of particle design for the amorphization of drugs.     

Combination chemotherapy with 13-cis-retinoic acid and celecoxib in the treatment of glioblastoma multiforme

Summary In a phase II clinical trial, we sought to determine if combining celecoxib with 13-cis-retinoic acid (13-cRA, Accutane™) was efficacious in the treatment of recurrent (progressive) glioblastoma multiforme (GBM). In parallel, we also sought to determine to what extent the outcomes from this clinical trial correlated with the findings from studies utilizing two murine intracerebral GBM models, U87MG and U251HF, to determine the predictive value of these murine models. In the clinical trial, 25 patients were studied at recurrence. Stable disease, which occurred in 44% of the patients, was the best response. The median progression-free survival (PFS) was 8 weeks, with a PFS at 6 months of only 19%. For the patients with stable disease, the median PFS was 24 weeks. The toxicity profile was unremarkable. The modest effect on PFS seen in this study agreed with the recent findings of another study, which showed a 19% PFS at 6 months in patients treated with 13-cRA alone. Thus, the combination of 13-cRA with celecoxib is not more effective than 13-cRA in the treatment of progressive GBM. In the murine model study, we found that long-term dosing with 13-cRA or celecoxib alone or in combination did not increase survival in animals with U87MG tumors but modestly increased survival in animals with U251HF tumors. There was no evidence of synergism between the two drugs. From this, we concluded that the animal studies generally predicted that the two agents would have only a modest effect alone and no additive effect when given in combination to patients.     

Adenocarcina of the mouse prostate growth inhibition by celecoxib: downregulation of transcription factors involved in COX-2 inhibition

BACKGROUND: Epidemiological studies have shown a decreased risk of prostate cancer among men who regularly take aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). In this study, we examined a dose-dependent effect of a cyclooxygenase-2 (COX-2) inhibitor, celecoxib against transgenic adenocarcinoma of the mouse prostate. METHODS: Efficacy of four different doses in parts per million of celecoxib, such as 200 ppm, 400 ppm, 600 ppm, and 1,000 ppm representing very low, moderate, and high doses, respectively were tested against adenocarcinoma of the mouse prostate using a transgenic adenocarcinoma of the mouse prostate (TRAMP) model assay. RESULTS: Dietary supplement of celecoxib at doses of 400 ppm, 600 ppm, and 1,000 ppm are most effective against mPIN (mouse prostatic intraepithelial neoplasia) and adenocarcinoma of the prostate. Tumor growth inhibition by celecoxib was associated with increased rate of apoptosis. At 1,000 ppm, a complete inhibition of the PIN lesions was extended to limit the growth of adenocarcinoma (from 85% to 15%) and metastasis of the mouse prostate. The chemopreventive effect was significant (P<0.01) at 400 ppm, 600 ppm, and 1,000 ppm doses compared to that at the lowest dose of 200 ppm and control. A dose-dependent effect on tumor growth inhibition was associated with reduced expression of NF-kappaBp65 and COX-2. CONCLUSIONS: Dietary supplementation of celecoxib at different doses provides evidence for the suppression of prostate adenocarcinoma tumor growth in a dose-dependent manner. Suppression of adenocarcinoma by celecoxib further limits the growth of metastatic prostate cancer.     

Effect of indomethacin and selective cyclooxygenase-2 inhibitors on proteinuria and renal function in patients with AA type renal amyloidosis

AIMS: Because the cardiovascular system (CVS) side-effects of cyclooxygenase-2 (COX-2) selective inhibitors have recently been questioned, we aimed to compare the renal and haemodynamic effects of cyclooxygenase selective (celecoxib and rofecoxib) and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) (indomethacin) in patients with renal amyloidosis secondary to rheumatological diseases who required anti-inflammatory agents and are taking maximum tolerable dose of angiotensin-converting enzyme inhibitors. METHODS: The present study was performed on 11 patients with stable proteinuria who were diagnosed as AA amyloidosis secondary to rheumatological diseases confirmed by renal biopsies. The study had three consecutive stages (celecoxib 200 mg/day; indomethacin 100 mg/day; rofecoxib 25 mg/day.) Each was given for 4 weeks and a wash-out phase of 3 weeks was allowed between consecutive stages. RESULTS: Although the decrease of proteinuria in the celecoxib period was higher than in the rofecoxib and indomethacin periods, the difference was not statistically significant. No statistically significant differences were found between serum urea, creatinine, creatinine clearance and urinary sodium excretion. CONCLUSION: In this study, no differences were found between indomethacin and the two selective COX-2 inhibitors in respect to proteinuria and renal functions in 11 patients with renal amyloidosis secondary to rheumatological diseases with varying degrees of proteinuria. Routine doses of NSAIDs brought no additional benefit to the ACE inhibitor use in terms of proteinuria and renal functions. The use of selective COX-2 inhibitors should be limited to their anti-inflammatory and analgesic effects in this population.     

Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cells

Many tumors constitutively express high levels of the inducible form of proinflammatory enzyme, cyclooxygenase-2 (COX-2). Increased COX-2 expression is associated with tumor cell resistance to many cytotoxic chemotherapy drugs. Furthermore, increased resistance to cytotoxic antitumor drugs is also known to be dependent on associated stromal cells in many tumors. We investigated whether prostate tumor-associated stromal cells, marrow-derived osteoblasts, affect cytotoxicity of 2 antitumor drugs, COL-3 and docetaxel (TXTR), and whether it is dependent on COX-2 activity. We further examined whether inhibiting the activity of COX-2 negate the stroma-induced decrease in drug sensitivity in tumor cells. COX-2-specific inhibitor celecoxib (CXB) was used to inhibit COX-2 activity and associated alteration in cell death signaling was investigated. Coculturing PC-3ML cells with osteoblasts decreased the cytotoxicity of the tested antitumor drugs and was associated with increased COX-2 activity in PC-3ML cells. A significant decrease in drug-induced PGE(2) increase and an increase in cytotoxicity were observed when cells were treated with COL-3 or TXTR combined with CXB. Cytotoxicity of single or combination treatment increased apoptosis, which was associated with caspase-3 and -9 activation, PARP cleavage, increased BAD protein, but decreased protein levels of XIAP and BCL-(xL). Oral administration of CXB (40 mg/kg) to mice with PC-3ML tumors for 42 days increased tumor latency, decreased tumor growth and enhanced tumor control with COL-3 or TXTR. Overall, a synergistic enhancement of antitumor activity in combination treatment was observed in vitro and an additive effect in vivo. These observations suggest a potential clinical use of combined dosing of COX-2 inhibitors and cytotoxic drugs at lower, nontoxic dose than currently used to treat advanced prostate cancer.     

The anti‐inflammatory effect of celecoxib does not prevent liver fibrosis in bile duct‐ligated rats

Background/Aims: Celecoxib was used in the treatment of inflammation in patients with cirrhosis. However, data on the progression of liver fibrosis after treatment by celecoxib are not available. This study aims to elucidate the effects of celecoxib on cholestatic liver fibrosis in rats. Methods: Rats underwent bile duct ligation (BDL) for 1 or 2 weeks to induce hepatic fibrosis. Celecoxib was introduced on day 1 after operation. The effects of celecoxib were assessed by comparison of the severity of hepatic fibrosis. Results: Infiltration of inflammatory cells and proliferation of bile ducts was seen after 1 week of BDL and fibrosis was induced after 2 weeks. Reduced alanine aminotransferase (ALT) levels and blunted expression of inflammatory factors [tumour necrosis factor‐α, interleukin (IL)‐1β and IL‐6] were seen in the liver of BDL‐treated rats that received celecoxib at week 1. Although celecoxib was sufficient in suppressing the cyclo‐oxygenase (COX)‐2 expression in the control organ (kidney), it failed to suppress the enhanced hepatic COX‐2 expression. At week 2, celecoxib did not alter the ALT level, the severity of fibrosis and hepatic collagen contents. This was associated with unchanged α‐smooth muscle actin protein expression and tissue inhibitor of metalloproteinase‐2 (TIMP‐2), matrix metalloproteinase (MMP)‐2 and MMP‐9 mRNA expressions in the liver. Celecoxib had no effect on the BDL‐dependent increase in bilirubin levels at any time point. Conclusions: The present study provides morphological and molecular biological evidences for the role of celecoxib in cholestatic liver fibrosis. Celecoxib protects against hepatic inflammation in the early stage of BDL rats, but does not have an effect on liver fibrosis.     

塞来昔布用于围手术期多模式镇痛的疗效与安全性评价

目的:探讨塞来昔布用于围手术期多模式镇痛的疗效与安全性。方法:将2008年1月—2009年1月收治的围手术期镇痛的126例患者,随机分为观察组64例和对照组62例,两组患者各项情况相比差异无显著性(P>0.05),具有可比性。观察组术前3 d服用塞来昔布200 mg,每日2次,术后使用患者自控镇痛泵(PCA泵)并联用塞来昔布200 mg,每日2次,对照组术后仅使用PCA泵。主要观察指标为术中出血量、术后VAS评分、PCA泵中阿片类药物的用量及恶心、呕吐、便秘及呼吸抑制等副作用。结果:观察组与对照组比较,其VAS评分、PCA中药物用量以及副作用明显降低,有统计学意义(P<0.05),而术中出血量比较无统计学意义(P>0.05)。结论:塞来昔布用于围手术期多模式镇痛可以显著提高痛阈,降低术后VAS评分数值、PCA泵用量以及阿片类的副反应,且不影响出血,适合临床推广使用。     

F 15845, a new blocker of the persistent sodium current prevents consequences of hypoxia in rat femoral artery

Background and purpose:

Selective cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib (Vioxx) and celecoxib (Celebrex) were developed as NSAIDs with reduced gastric side effects. Celecoxib has now been shown to affect cellular physiology via an unexpected, COX-independent, pathway – by inhibiting K_v2.1 and other ion channels. In this study, we investigated the mechanism of the action of celecoxib on K_v2.1 channels.

Experimental approach:

The mode of action of celecoxib on rat K_v2.1 channels was studied by whole-cell patch-clamping to record currents from channels expressed in HEK-293 cells.

Key results:

Celecoxib reduced current through K_v2.1 channels when applied from the extracellular side. At low concentrations (≤3 µM), celecoxib accelerated kinetics of activation, deactivation and inactivation. Recovery of rat K_v2.1 channels from inactivation could be characterized by two components, with celecoxib selectively accelerating the slow component of recovery at ≤10 µM. At >3 µM, celecoxib led to closed-channel block with relative slowing of activation. At 30 µM, it additionally induced open-channel block that manifested in use-dependent inhibition and slower recovery from inactivation.

Conclusions and implications:

Celecoxib reduced current through K_v2.1 channels by modifying gating and inducing closed- and open-channel block, with the three effects manifesting at different concentrations. These data will help to elucidate the mechanisms of action of this widely prescribed drug on ion channels and those underlying its neurological, cardiovascular and other effects.     

Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern

Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins. In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease. To study the functional effects of COX-2 activity, male and female bigenic mice (amyloid precursor protein with Swedish mutation [APPswe]-presenilin-1 protein with deletion of exon 9 [PS1dE9] and trigenic COX-2/APPswe-PS1dE9) were behaviorally tested +/-administration of the selective COX-2 inhibitor celecoxib. Behavioral testing included a three-trial Y maze that measures spatial working and recognition memories and an open field task that tested levels of hyperactivity. Overexpression of COX-2 in APPswe-PS1dE9 mice resulted in specific deficits in spatial working memory in female but not male mice. These sex-specific deficits were abolished by pharmacological inhibition of COX-2 activity. Importantly, COX-2-associated deficits were dependent on co-expression of all three transgenes since COX-2 single transgenic and APPswe-PS1dE9 bigenic mice showed normal memory. Quantification of amyloid plaque load and total Abeta 40 and 42 peptides did not reveal significant differences in trigenic versus bigenic mice treated with either vehicle or celecoxib. Taken together, these data indicate an interaction between the effects of COX-2 and Abeta peptides on cognition that occurs in a sex-specific manner in the absence of significant changes in amyloid burden. These findings suggest that pathological activation of COX-2 may potentiate the toxicity of Abeta peptides, particularly in females, without significantly affecting Abeta accumulation.