The effect of selective cyclooxygenase-2 inhibitor on human osteoclast precursors to influence osteoclastogenesis in vitro

The inducible prostaglandin synthesis enzyme, cyclooxygenase-2 (COX-2), is involved in bone resorption and osteoclastogenesis, and acts indirectly through prostaglandin E2 (PG E2) produced by osteoblastic cells. This study was undertaken to investigate whether celecoxib (a selective COX-2 inhibitor) has a direct effect on human osteoclast precursors to influence osteoclastogenesis in vitro. Human peripheral blood mononuclear cells (PBMCs) were cultured on glass coverslips and dentine slices with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage colony stimulating factor (M-CSF). COX inhibitors including celecoxib were added to the cultures. Osteoclast formation was assessed as the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs), and the functional evidence of lacunar resorption pits on dentine slices was assessed. Celecoxib and indomethacin inhibited osteoclast formation and the extent of lacunar resorption in a dose-dependent manner, but the effect of indomethacin was less than that of celecoxib. Mofezolac affected neither the number of TRAP-positive MNCs nor the extent of lacunar resorption pits. These results indicate that celecoxib influences not only osteoclast formation through osteoblastic cells but also acts directly on circulating osteoclast precursors to influence human osteoclast differentiation. The effect of celecoxib on osteoclast precursors may be related to the COX-2 signal pathway.     

The effect of selective cyclooxygenase-2 inhibitor on human osteoclast precursors to influence osteoclastogenesis in vitro

Abstract

The inducible prostaglandin synthesis enzyme, cyclooxygenase-2 (COX-2), is involved in bone resorption and osteoclastogenesis, and acts indirectly through prostaglandin E2 (PG E2) produced by osteoblastic cells. This study was undertaken to investigate whether celecoxib (a selective COX-2 inhibitor) has a direct effect on human osteoclast precursors to influence osteoclastogenesis in vitro. Human peripheral blood mononuclear cells (PBMCs) were cultured on glass coverslips and dentine slices with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage colony stimulating factor (M-CSF). COX inhibitors including celecoxib were added to the cultures. Osteoclast formation was assessed as the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs), and the functional evidence of lacunar resorption pits on dentine slices was assessed. Celecoxib and indomethacin inhibited osteoclast formation and the extent of lacunar resorption in a dose-dependent manner, but the effect of indomethacin was less than that of celecoxib. Mofezolac affected neither the number of TRAP-positive MNCs nor the extent of lacunar resorption pits. These results indicate that celecoxib influences not only osteoclast formation through osteoblastic cells but also acts directly on circulating osteoclast precursors to influence human osteoclast differentiation. The effect of celecoxib on osteoclast precursors may be related to the COX-2 signal pathway.     

Gastric effects of the selective cyclooxygenase-2 inhibitor, celecoxib, in the rat

BACKGROUND: Recent studies have revealed that cyclooxygenase-2 is involved in the protection of the damaged gastric mucosa, mediating, in particular, the acceleration of ulcer healing and angiogenesis; therein, it has been suggested that selective cyclooxygenase-2 inhibitors, although safe in healthy stomach, may have deleterious effects on the injured gastric mucosa. Moreover, no information is available about direct effects of these drugs on gastric surface epithelium. AIMS: To investigate the gastric effects of the selective cyclooxygenase-2 inhibitor, celecoxib, in healthy and damaged rat gastric mucosa. METHODS: Gastric toxicity was studied in the rat by measuring gastric potential difference and mucosal lesions. Celecoxib was administered intragastrically, either in basal conditions or in combination with damaging (acetylsalicylic acid and ethanol) or protective (sodium nitroprusside and lipopolysaccharides from Escherichia coli) agents. The anti-inflammatory activity was evaluated in the carrageenan-induced paw oedema assay. The non-selective inhibitors indomethacin and acetylsalicylic acid were used for comparison. RESULTS: In conscious rats celecoxib, indomethacin and acetylsalicylic acid significantly reduced the paw oedema induced by carrageenan. While acetylsalicylic acid and indomethacin significantly reduced basal gastric potential difference and caused gastric mucosal lesions, celecoxib was ineffective; moreover, it did not aggravate the direct damaging effect of intragastric ethanol or aspirin. Pretreatment with the non-selective nitric oxide synthase inhibitor N-nitro-L-argynine methyl ester did not significantly change the gastric effects of celecoxib. Both celecoxib and indomethacin prevented the gastroprotective effects induced by sodium nitroprusside (nitric oxide donor) or by bacterial lipopolysaccharides (inducer of nitric oxide synthesis). CONCLUSIONS. These data indicate that the selective cyclooxygenase-2 inhibitor celecoxib did not alter gastric mucosal barrier nor induced mucosal lesions in the healthy or nitric oxide-deficient rat gastric mucosa. However, cyclooxygenase-2 inhibition impaired nitric oxide-dependent gastroprotection, indicating that cyclooxygenase-2 derived prostaglandins may be involved in the gastric mucosal defence.     

选择性环氧合酶-2抑制剂塞莱希布对大鼠肝纤维化的作用

目的:探讨选择性COX-2抑制剂塞莱昔布对CCl4诱导的大鼠肝纤维化的作用.方法:5-6周龄的♂SD大鼠50只,随机分为6组.A组(肝纤维化模型组):10只,50%CCl4橄榄油溶液1mL/kg,每周2次皮下注射,同时给予生理盐水灌胃;B组(早期治疗组):10只,造模同时给予塞莱昔布15mg/kg溶于生理盐水中灌胃,每天1次;C组(中期治疗组):10只,造模同时给予生理盐水灌胃,第3周起改为塞莱昔布灌胃;D组(晚期治疗组):10只,造模同时给予生理盐水灌胃,第5周起改为塞莱昔布灌胃;E组:5只,给予相同体积的橄榄油皮下注射,同时给予相同剂量的塞莱昔布灌胃;F组:5只,给予相同体积的橄榄油皮下注射和生理盐水中灌胃.上述处置共8wk.实验结束后腹主动脉取血,取肝组织,检测血清谷丙转氨酶(ALT)、透明质酸(HA)、层粘连蛋白(LN)水平;病理组织学HE染色及Masson染色观察肝纤维化严重程度并评分,免疫组织化学方法检测肝组织Ⅰ胶原、α-SMA、COX-1、COX-2的表达.结果:A组与F组相比,可见显著的肝纤维化改变(P<0.01);与A组相比,B组病理染色可见肝纤维化程度明显减轻(P<0.01),血清ALT、...     

The cytotoxicity of celecoxib towards cardiac myocytes is cyclooxygenase-2 independent

The cyclooxygenase (COX)-2 inhibitors celecoxib and rofecoxib were studied for their effects on neonatal rat cardiac myocytes as a possible model for the adverse cardiovascular effects that this class of compounds have shown in their clinical use. Celecoxib, but not rofecoxib, as measured by lactate dehydrogenase release was toxic to myocytes in the low micromolar concentration range. This toxicity shown by celecoxib was also associated with a high degree of myofibrillar disruption similar to that caused by doxorubicin. As measured by induction of caspase-3/7 activity and by changes in nuclear morphology, neither celecoxib nor rofecoxib strongly induced apoptosis in myocytes. The stable prostacyclin analog iloprost was unable to reduce celecoxib-induced damage, which suggested that celecoxib exerted its cytotoxicity through prostacyclin-independent pathways. Celecoxib treatment did not increase intracellular oxidation of 2',7'-dichlorofluorescin in myocytes, which suggested that its cytotoxicity was not due to reactive oxygen species generation. The evidence supports the conclusion that celecoxib exerts its cytotoxicity towards myocytes through COX-2-independent mediated pathways.     

Overexpression of cyclooxygenase-2 in human HepG2, Bel-7402 and SMMC-7721 hepatoma cell lines and mechanism of cyclooxygenase-2 selective inhibitor celecoxib-induced cell growth inhibition and apoptosis

AIM: To investigate the cyclooxygenase-2 (COX-2) expression level in human HepG2, Bel-7402 and SMMC-7721 hepatoma cell lines and the molecular mechanism of COX-2 selective inhibitor celecoxib-induced cell growth inhibition and cell apoptosis. METHODS: Hepatoma cells were cultured and treated with celecoxib. Cell In situ hybridization (ISH) and immunocytochemistry were used to detect COX-2 mRNA and protein expression. Proliferating cell nuclear antigen and phosphorylated Akt were also detected by immunocytochemistry assay. Cell growth rates were assessed by 3-(4, 5-dimethylthiazol-2-yl-2, 5-diphenylte-trazolium (MTT) bromide colorimetric assay. Celecoxib-induced cell apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and flow cytometry (FCM). The phosphorylated Akt and activated fragments of caspase-9, caspase-3 were examined by Western blotting analysis. RESULTS: Increased COX-2 mRNA and protein expression were detected in all three hepatoma cell lines. Celecoxib could significantly inhibit cell growth and the inhibitory effect was in a dose- and time-dependent manner evidenced by MTT assays and morphological changes. The apoptotic index measured by TUNEL increased correspondingly with the increased concentration of celecoxib and the reaction time. With 50 μmol/L celecoxib treatment for 24 h, the apoptotic index of HepG2, BEL-7402 and SMMC-7721 cells was 25.01±3.08%, 26.40±3.05%, and 30.60±2.89%, respectively. Western blotting analysis showed remarkable activation of caspase-9, caspase-3 and dephosphorylation of Akt (Thr308). Immunocytochemistry also showed the reduction of PCNA expression and phosphorylation Akt (Thr308) after treatment with celecoxib. CONCLUSION: COX-2 mRNA and protein overexpression in HepG2, Bel-7402 and SMMC-7721 cell lines correlate with the increased cell growth rate. Celecoxib can inhibit proliferation and induce apoptosis of hepatoma cell strains in a dose- and time-dependent manner.     

The efficacy of rebamipide add-on therapy in arthritic patients with COX-2 selective inhibitor-related gastrointestinal events: a prospective, randomized, open-label blinded-endpoint pilot study by the GLORIA study group

Objective

We aimed to confirm the effect of combined treatment with celecoxib and rebamipide would be more effective than celecoxib alone for prevention of upper gastrointestinal (GI) events.

Methods

Patients with rheumatoid arthritis, osteoarthritis, and low back pain were enrolled in this study. Patients were randomized to two groups: a monotherapy group (100 mg celecoxib twice daily) and a combination therapy group (add on100 mg of rebamipide three times a day). The GI mucosal injury was evaluated by endoscopic examination before treatment and at 3 months. The primary endpoint was to evaluate the preventive effect of the combination therapy group for GI events, endoscopic upper GI ulcers and intolerable GI symptoms, compared with the monotherapy group.

Results

Seventy-five patients were enrolled. Sixty-five patients were analyzed (16 males, 49 females; mean age: 67 ± 13 years). The prevalence of upper GI events, five of endoscopic GI ulcers and one of intolerable GI symptoms, were 6/34 (17.6 %) in the monotherapy group and 0/31 in the combination therapy group, p = 0.0252.

Conclusions

The combination therapy group was more effective than the monotherapy group for prevention of upper GI events in this study. Rebamipide might be a candidate for an option to prevent COX-2 selective inhibitor-induced upper GI events.     

A comparison of the efficacy and safety of celecoxib 200 mg and celecoxib 400 mg once daily in treating the signs and symptoms of psoriatic arthritis

OBJECTIVE: To evaluate the efficacy of the cyclooxygenase-2 selective inhibitor celecoxib in treating patients with psoriatic arthritis (PsA) in flare. METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study compared the efficacy and safety of celecoxib 400 mg (n=201) or celecoxib 200 mg (n=213) once daily (qd) with placebo (n=194) in treating the signs and symptoms of PsA in flare. The primary efficacy measure was the number of patients responding to treatment according to the American College of Rheumatology Responders Index 20% (ACR-20) at week 12. Efficacy and safety were assessed for all randomized patients who received at least 1 dose of study medication. RESULTS: At the week-12 primary endpoint, approximately 50% of patients in each treatment group were responders according to the ACR-20 criteria, and no statistically significant treatment differences between treatment groups were observed. However, at week 2, the ACR-20 response rates for the celecoxib 400 mg (49%) and 200 mg (39%) groups were significantly higher than for the placebo group (28%) (P<0.001 and P=0.016, respectively). Within the celecoxib 400 mg group, ACR-20 response rates were similar at weeks 2, 6 (46%), and 12 (49%). In contrast, in the celecoxib 200 mg and placebo treatment groups, ACR-20 response rates increased 7 and 16%, respectively, from week 2 to week 6, and remained relatively unchanged from week 6 to week 12. There were no statistically significant differences in ACR-20 response rates between the celecoxib 400 mg and 200 mg groups at any time point. Treatment with celecoxib 200 and 400 mg qd was statistically superior to placebo treatment at weeks 2 and 6 for Patient's Assessment of Arthritis Pain. Both doses of celecoxib were well tolerated. CONCLUSIONS: Celecoxib 400 mg and 200 mg qd were efficacious and well tolerated in treating the signs and symptoms of PsA in flare after 2 weeks of treatment. However, although the clinical effects of celecoxib 400 mg and 200 mg qd were observed for 12 weeks, there was a high placebo response at these time points, and there were no differences relative to placebo treatment at week 12.     

Effect of celecoxib on cyclooxygenase-2 expression and possible variants in a patient with Barrett''s esophagus

Cyclooxygenase-2 (COX-2) expression is increased in metaplastic and dysplastic Barrett's esophageal epithelium and it is thought that selective COX-2 inhibitors could offer hope as chemoprevention therapy. The aim of the study was to investigate the in vivo effect of celecoxib on COX-2 expression in patients with Barrett's esophagus and no recent history of non-steroidal anti-inflammatory drug use. Endoscopic mucosal biopsy specimens were collected at baseline and after 28 days of therapy in a patient treated with celecoxib 200 mg twice daily. Samples were analyzed for COX-2 expression by immunoblot analysis with chemiluminescence detection. COX-2 expression was found to decline 20% and 44% at two different biopsy sites compared to the baseline sample. Longer exposures revealed a number of previously unidentified proteins above and below the 67 kDa COX-2 protein including 38 kDa and 45 kDa proteins which were present only at study completion consistent with up-regulation after celecoxib therapy. Further investigations of the 38 kDa and 45 kDa proteins were undertaken using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) with immunoblot and MALDI-TOF (matrix assisted laser desorption ionization - time of flight) analysis but no matches were found and results were inconclusive. Unmatched masses from MALDI-TOF peptide mass fingerprinting were compared with human COX-2 (67 kDa) and COX-2b (39 kDa) using unspecific cleavage. Peptide sequence homology with COX-2 and COX-2b was found for a length of 19 amino acids. Based on immunodetection, molecular weight and equivical MALDI-TOF results, one of these up-regulated proteins may be COX-2b.     

选择性COX-2抑制剂塞来昔布对肝星状细胞增殖及活化的影响

目的通过观察选择性COX-2抑制剂塞来昔布对肝星状细胞增殖及活化的影响,以探讨COX-2在肝纤维化中的作用。方法用不同浓度的选择性COX-2抑制剂塞来昔布作用于体外培养的人肝星状细胞株LI-90,采用MTT法和半定量RT-PCR法检测塞来昔布对肝星状细胞增殖及活化的影响。结果塞来昔布可显著抑制体外培养的肝星状细胞LI-90的增殖和活化,随着药物剂量的增加和时间的延长,肝星状细胞LI-90的增殖和活化明显抑制,呈剂量和时间依赖性。结论塞来昔布对肝星状细胞增殖和活化的抑制作用是研究肝纤维化预防和治疗的重要方向之一。     

Elevated cyclooxygenase-2 expression in patients with early gastric cancer in the gastric pylorus

Background Duodenogastric reflux after surgery increases the risk of gastric carcinoma. To determine whether bile reflux influences the development of gastric cancer in patients who have not had surgery, we compared cyclooxygenase-2 (COX-2) immunoreactivity in early gastric cancer originating from the gastric pylorus and that originating from other locations. We also examined the effects of bile acids on the expression and activity of COX-2 in gastric cells in vitro.Methods Tumor sections from 79 patients who underwent endoscopic mucosal resection for early intestinal-type gastric carcinoma were stained using a COX-2-specific monoclonal antibody. Immunoblotting of COX-2 was used to assess the effects of bile acids on COX-2 expression and activity in human gastric cell lines.Results Among the 79 early gastric cancer lesions studied, 13 (16%) arose in the gastric pylorus. In this group, COX-2 immunoreactivity was negative to weak in 38% (5 of 13 lesions) and moderate to strong in 62% (8 of 13 lesions). In the control group, COX-2 immunoreactivity was negative to weak in 70% (46 of 66 lesions) and moderate to strong in 30% (20 of 66 lesions). COX-2 expression was significantly elevated in early gastric cancer located in the gastric pylorus, compared with that in the other locations. In human gastric cell lines, bile acids induced COX-2 expression, mediated by the ERK 1/2 mitogen-activated protein kinase pathway.Conclusions COX-2 expression is elevated in early gastric cancer of the gastric pylorus, a common site of gastric cancer. Bile acids induced COX-2 expression in human gastric cell lines, suggesting a role of bile reflux in gastric carcinogenesis.     

The renal effects of the addition of low-dose aspirin to COX-2 selective and nonselective antiinflammatory drugs

Objective: We aimed to evaluate the effect on renal functions and blood pressure of the addition of low dose aspirin (LDA) to cyclooxygenase-2 (COX-2) inhibitors or nonselective NSAIDs. Methods: Two groups each containing 14 patients with one group using celecoxib and the other indomethacin regularly for at least 1 week were included into the study. Both groups were initially administered 100 mg/day (week 1), and later 300 mg/day (week 2) aspirin. Baseline and weekly serum creatinine, uric acid, electrolytes, creatinine clearance (CrCl) and blood pressure were obtained. Results: Contrary to the celecoxib group, in the indomethacin group, both after the first and the second weeks the mean serum creatinine increased and CrCl decreased when compared to baseline values (p values<0.05). In the indomethacin group, when compared to baseline values systolic blood pressure was significantly higher after week 1 and uric acid level after week 2 (p values=0.01). The frequency of patients with a 20% decrease in CrCl at the end of week 2 was higher in the indomethacin group than in the celecoxib group (42.9% vs. 0%, p=0.016). The difference between the mean creatinine (p=0.017) and CrCl values (p=0.007) from baseline until after week 2 was more significant in the indomethacin group than in the celecoxib group. Conclusions: The addition of LDA to patients using indomethacin led to significant renal dysfunction. Subjects using celecoxib seem to have been protected from the renal side effects of LDA.A conflict of interest statement: There are no conflicts of interest.     

Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin production by inhibiting cyclooxygenase (COX); they are believed to cause gastroduodenal damage by inhibiting the COX-1 isoform and to have analgesic and anti-inflammatory effects by inhibiting the COX-2 isoform. As compared to conventional NSAIDs, celecoxib, a COX-2 specific inhibitor, has been shown in previous single posttreatment endoscopy studies to be associated with lower gastroduodenal ulcer rates. In response to concerns that such studies may under-represent ulceration rates, the present serial endoscopy study was designed to compare cumulative gastroduodenal ulcer rates associated with the use of celecoxib to those of naproxen, a conventional NSAID. METHODS: In this double-blind, parallel-group, multicenter study, 537 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were randomized to treatment with celecoxib 200 mg b.i.d. (n = 270) or naproxen 500 mg b.i.d. (n = 267) for 12 wk. Gastroduodenal damage was determined from esophagogastroduodenoscopy after 4, 8, and 12 wk of therapy. Arthritis efficacy was evaluated with Patient's and Physician's Global Assessments. RESULTS: Gastroduodenal ulcer rates after celecoxib and naproxen treatment were 4% versus 19% in the 0-4 wk interval (p < 0.001), 2% versus 14% in the 4-8 wk interval (p < 0.001), and 2% versus 10% in the 8-12 wk interval (p < 0.001), respectively. After 12 wk of treatment, the cumulative incidence of gastroduodenal ulcers was 9% with celecoxib and 41% with naproxen. In the celecoxib group, gastroduodenal ulcers were significantly associated with Helicobacter pylori status (p < 0.05), concurrent aspirin usage (p = 0.001), and a history of ulcer (p = 0.010), but not with disease type (OA/RA), age, gender, other relevant medical histories, or concurrent corticosteroid or disease-modifying antirheumatic drugs usage (p > 0.05). Celecoxib produced a significantly lower incidence rate of both gastric (p < 0.001) and duodenal (p < 0.030) ulcers. The two agents produced similar improvements in Patient's and Physician's Global Assessments of arthritis efficacy. The incidence of adverse events and withdrawal rates did not differ significantly between treatments. CONCLUSIONS: As compared to naproxen (500 mg b.i.d.), use of celecoxib (200 mg b.i.d.), a COX-2 specific agent, at the recommended RA dose and twice the most frequently prescribed OA dose, was associated with lower rates of gastric, duodenal, and gastroduodenal ulcers but had comparable efficacy, in patients with OA and RA.     

The effect of celecoxib, a selective COX-2 inhibitor, on liver ischemia/reperfusion-induced oxidative stress in rats.

This study examined the effects of celecoxib on hepatic ischemia/reperfusion (I/R) injury in rats. A total of 40 male Sprague-Dawley rats weighing 190-210g were randomized into 4 groups of 10: (1) controls: data from unmanipulated animals; (2) sham group: rats subjected to the surgical procedure, except for liver I/R, and given saline; (3) I/R group: rats that underwent liver ischemia for 1h followed by reperfusion for 45min; (4) I-R/Celecoxib group: rats pretreated with celecoxib (3mgkg(-1), i.p.) 40min before liver I/R. Tc-99m sulfur colloid images were used to measure the uptake ratio and perfusion index. Liver tissues were taken to determine SOD, CAT, GSH-Px, and MDA levels and for biochemical and histological evaluation. The plasma ALT, AST, GGT, and LDH activities were higher in group 3 than in group 4. The uptake ratio was significantly lower in group 3 compared to groups 1, 2, and 4. In addition, in group 4, the uptake ratio and perfusion index were also significantly higher compared to group 3. MDA values and the hepatic injury score decreased, while the SOD, CAT, and GSH-Px values increased in group 4 compared to group 3. In group 3, hepatocytes were swollen with marked vacuolization. Group 4 showed well preserved liver parenchyma with hepatocytes arranged radially around the central vein; there were regular sinusoidal structures with normal morphology without any signs of congestion. We showed that celecoxib has beneficial effects in hepatic I/R injury and may protect the liver.     

Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib

To determine whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib affects cardiovascular thrombotic risk, we analyzed the incidence of cardiovascular events for celecoxib, placebo, and nonsteroidal anti-inflammatory drugs (NSAIDs) in the entire controlled, arthritis clinical trial database for celecoxib. The primary analysis used the Antiplatelet Trialists' Collaboration end points, which include: (1) cardiovascular, hemorrhagic, and unknown deaths, (2) nonfatal myocardial infarction, and (3) nonfatal stroke. Other secondary thrombotic events were also examined. Separate analyses were performed for all patients and for those not taking aspirin. Data from all controlled, completed arthritis trials of > or =4 weeks duration, including 13 new drug application studies and 2 large post-marketing trials (CLASS and SUCCESS) were included for analyses. Patients were randomized to celecoxib at doses from 100 to 400 mg twice daily (18,942 patients; 5,668.2 patient-years of exposure), diclofenac 50 to 75 mg twice daily, ibuprofen 800 mg thrice daily, naproxen 500 mg twice daily (combined NSAID exposure of 11,143 patients; 3,612.2 patient-years), or placebo (1,794 subjects; 199.9 subject-years). Data from a long-term uncontrolled trial with 5,209 patients (6,950 patients-years) treated with celecoxib were included in a supplemental analysis. The entire 15-trial database was searched for possible serious thrombotic events as well as to identify all deaths. For these patients, detailed clinical data were obtained and reviewed by 2 of the investigators (WBW and JSB), who were independently and blinded to exposure, to classify the event as primary, secondary, or neither. All analyses were done using the intent-to-treat population, and time-to-event analyses were performed using per-patient data. To examine heterogeneity of results among studies, tests of interaction were performed using the Cox model. Incidences of the primary and secondary events were not significantly different between the celecoxib and placebo groups, nor for the celecoxib group compared with the NSAIDs group, regardless of aspirin use and NSAID type. The relative risks comparing celecoxib with the NSAIDs for the primary events were 1.06 (95% confidence interval 0.70 to 1.61, p = 0.79) for all patients, and 0.86 (95% confidence interval 0.48 to 1.56, p = 0.62) for the subgroup not taking aspirin. Similarly, for secondary cardiovascular end points, all relative risks were < or =1 for celecoxib compared with either placebo or NSAIDs. These comparative analyses demonstrate no evidence of increased risk of cardiovascular thrombotic events associated with celecoxib compared with either conventional NSAIDs or placebo.     

甲硝唑对大鼠NSAIDs肠道损伤COX-2表达的影响

目的通过口服双氯芬酸建立大鼠非甾体抗炎药（NSAIDs）肠道损伤模型,观察NSAIDs对肠黏膜COX-2表达的影响及甲硝唑干预后肠黏膜COX-2表达的变化,探讨可能机制。方法24只SD雄性大鼠随机分为空白组、模型组、甲硝唑组,每组8只。双氯芬酸7．5mg／kg,1mL／100g体质量,2次／d,灌胃制备大鼠肠黏膜损伤模型。空白组于造模当日按1mL／100g体质量蒸馏水灌胃,2次／d,共5d;模型组于造模当日7．5mg／kg双氯芬酸灌胃,2次／d,共5d;甲硝唑组造模前一日50mg／kg甲硝唑灌胃,共2次,次日起每次甲硝唑给药1h后均予7．5mg／kg双氯芬酸灌胃,共5d。5d后处死所有大鼠,观察肠黏膜大体形态学改变、组织学损伤评分、免疫组化法检测肠黏膜COX-2表达。结果模型组大鼠肠道大体损伤及病理组织学评分中位数分别为3．5和5．0,较空白组（0．0）均明显升高（P均〈0．01）;模型组肠黏膜COX-2表达明显高于空白组（P〈0．05）;甲硝唑组COX-2表达明显低于模型组（P〈0．05）。结论口服双氯芬酸可成功制备大鼠NSAIDs肠道损伤模型;COX-2可能参与了NSAIDs肠道损伤的发生;甲硝唑对NSAIDs肠道损伤具有一定的保护作用,其机制可能与抑制COX-2的表达有关。     

Over and under-utilization of cyclooxygenase-2 selective inhibitors by primary care physicians and specialists

OBJECTIVES: To compare prescribing trends and appropriateness of use of traditional and cyclooxygenase-2 selective (COX-2) nonsteroidal anti-inflammatory drugs (NSAIDs) by primary care physicians (PCPs) and specialists. DESIGN: Retrospective cohort study. PATIENTS: One thousand five hundred and seventy-six adult patients continuously enrolled for at least 1 year with an independent practice association of a University-associated managed care plan who were started on a traditional NSAID or a COX-2 inhibitor from 1999 to 2002 and received at least 3 separate medication fills. MEASUREMENTS: Physician specialty was identified from office visits. Appropriateness of utilization was based on gastrointestinal risk characteristics. RESULTS: Primary care patients were younger and less likely to have comorbid conditions. Despite similar GI risk, COX-2 use among patients seen by PCPs was half that of patients seen by specialists (21% vs 44%, P<.001). While PCPs overused cyclooxygenase-2-specific inhibitors (COX-2s) less often than specialists (19% vs 41%, P<.001), they also tended to underuse COX-2s in patients who were at increased GI risk (46% vs 32%, P=.063). This represents a 3-fold and 8-fold difference in overuse versus underuse for PCPs and specialists, respectively. CONCLUSIONS: Using COX-2s as a model for physician adoption of new therapeutic agents, specialists were more likely to use these new medications for patients likely to benefit but were also significantly more likely to use them for patients without a clear indication. This study demonstrates the tension between appropriate adoption of innovative therapies for those individuals who would benefit from their use and those individuals who would receive no added clinical benefit but would incur added cost and be placed at increased risk.