Celecoxib versus diclofenac plus omeprazole in high-risk arthritis patients: results of a randomized double-blind trial

BACKGROUND & AIMS: The gastric safety of cyclooxgenase-2 inhibitors and prophylactic antisecretory therapy in high-risk arthritis patients is unclear. We studied the ulcer incidence and factors predicting ulcer recurrence in a prospective, double-blinded trial. METHODS: We studied patients who presented with nonsteroidal anti-inflammatory drug-associated ulcer bleeding. After ulcer healing, patients who were negative for Helicobacter pylori were randomly assigned to celecoxib 200 mg twice a day plus omeprazole placebo once daily or diclofenac 75 mg twice daily plus omeprazole 20 mg once daily for 6 months. Patients underwent endoscopy if they developed recurrent bleeding. Those without recurrent events underwent endoscopy at their last follow-up visit. RESULTS: Two hundred eighty-seven patients were enrolled; 24 had recurrent gastrointestinal complications. Among 259 patients without events, 222 underwent endoscopy (116 received celecoxib and 106 received diclofenac plus omeprazole). The probability of recurrent ulcers in 6 months was 18.7% in the celecoxib group and 25.6% in the diclofenac plus omeprazole group (difference, -6.7%; 95% CI: -17.8% to 3.9%) (P = 0.21). Combining bleeding and endoscopic ulcers, 24.1% in the celecoxib group and 32.3% in the diclofenac plus omeprazole group had recurrent ulcers in 6 months (difference, -8.2%; 95% CI: -19.5% to 2.9%) (P = 0.15). Treatment-induced significant dyspepsia (hazard ratio, 5.3; 95% CI: 2.6-10.8), age > or =75 (hazard ratio, 2.0; 95% CI: 1.1-3.5), and comorbidity (hazard ratio, 2.1; 95% CI: 1.2-3.7) independently predicted ulcer recurrence. CONCLUSIONS: Among patients with previous ulcer bleeding, neither celecoxib nor diclofenac plus omeprazole adequately prevents ulcer recurrence. Treatment-induced significant dyspepsia is an indication for endoscopic evaluation.     

Bradykinin and angiotensin-converting enzyme inhibition in cardioprotection

OBJECTIVES:

To show that angiotensin-converting enzyme (ACE) inhibition potentiates subthreshold ischemic preconditioning (IPC) via the elevation of bradykinin activity, leading to a fully delayed cardioprotective response.

METHODS:

On day 1 of the experiment, pigs were subjected to sham (group 1, controls) or IPC protocols. In groups 2 and 3, 4×5 min and 2×2 min of IPC, respectively, were elicited by occluding the left anterior descending coronary artery with percutaneous transluminal coronary angioplasty inflatable balloon catheter. Group 4 was subjected to the ACE inhibitor perindoprilate only. In group 5, the pigs were pretreated with perindoprilate (0.06 mg/kg) and then subjected to 2×2 min IPC. In group 6, intracoronary HOE 140 (a selective bradykinin B₂ receptor antagonist) was added before the perindoprilateaugmented subthreshold (2×2 min) PC stimulus. On the second day, all animals underwent 40 min left anterior descending coronary artery ligation and 3 h reperfusion, followed by infarct size analysis using triphenyl tetrazolium chloride staining.

RESULTS:

The rates of infarct size and risk zone were the following in the experimental groups: group 1, 42.8%; group 2,19.5% (P<0.05); group 3, ischemia/reperfusion (I/R) 33.4%; group 4, I/R 18.4% (P<0.05); group 5, I/R 31.2%; and group 6, I/R 36.3%. A significant increase of nuclear factor kappa B activation in groups 2 and 4 was seen.

CONCLUSIONS:

Results confirm that ACE inhibitors do not give total pharmacological IPC, but they enhance the induction effect of small ischemic insults, which raises the ischemic tolerance of myocardium. It was determined that enhanced bradykinin activity leads to downstream nuclear factor kappa B activation in this model.     

持续静脉输注吗啡用于腹部手术后的镇痛效果

应用微量输液泵持续静脉输注吗啡（ＣＩＭ）进行腹部手术后镇痛的前瞻性临床研究，４０例腹部大中手术患者随机分入两组，实验组接受ＣＩＭ法镇痛，对照组采用常规间断肌注哌啶镇痛（ＩＭＰ）。实验组２０例术后２４ｈ内镇痛效果均达Ⅰ～Ⅱ级，而对照组肌注哌啶后２ｈ内有７０％患者达Ⅰ～Ⅱ级，仅１０％患者在肌注２ｈ后仍保持Ⅰ～Ⅱ级的镇痛效果。实验、对照组患者术后２４ｈ睡眠时间分别为６．２±１．９ｈ和４．０±１．２ｈ（Ｐ＜０．０１）。ＣＩＭ法术后肠道通气时间短于ＩＭＰ法，分别为５４±１３ｈ和６６±１１ｈ（Ｐ＜０．０１）。两组呼吸频率、心率、血压、ＳｐＯ＿２等无明显差别。结果表明，微量泵持续静脉输注吗啡法镇痛效果优于常规方法，是一种简便、安全、有效的术后镇痛方法。     

Determinants of Long-Term Outcome of Patients with Reflux-Related Ear, Nose, and Throat Symptoms

Gastroesophageal reflux disease (GERD) is present in up to 75% of patients with chronic refractory ear, nose, and throat (ENT) symptoms, and proton pump inhibitor (PPI) therapy induces symptom relief in the majority of these patients. It has been suggested that endoscopic findings and quantification of esophageal acid exposure may help to predict the long-term outcome of medical therapy, but prospective studies that confirm this hypothesis are lacking. The aim of the present study was to investigate the relationship of endoscopic findings and quantification of reflux with long-term outcome in patients with reflux-related ENT symptoms. One hundred six consecutive patients with chronic refractory unexplained ENT symptoms underwent upper GI endoscopy, 24-hr dual-channel esophageal pH and Bilitec (n = 35) monitoring, and esophageal manometry. Subsequently, all were treated with omeprazole, 20 mg b.i.d., and patients were followed at 2-week intervals until symptom relief. Four weeks later, omeprazole therapy was gradually decreased and the lowest effective omeprazole maintenance dose, if any, was determined. Eighty-one patients (49 men; mean age, 50) experienced a clear or excellent therapeutic response after, on average, 4 weeks of omeprazole, 20 mg b.i.d. In 36 patients (44%; group A), PPI treatment could be stopped completely, 27 patients (33%; group B) required a maintenance dose of omeprazole, 20 mg/day, and 18 patients (22%; group C) required maintenance with omeprazole, 40 mg/day. The prevalence of reflux esophagitis was significantly lower in group A patients, who also had significantly lower distal esophageal acid exposure, proximal esophageal acid exposure, and esophageal duodenogastroesophageal reflux exposure compared to groups B and C. Multivariate analysis identified the presence of esophagitis and pathological distal esophageal acid exposure as risk factors for the need of maintenance therapy. In patients with reflux-related ENT symptoms, initial findings on upper GI endoscopy and 24-hr pH-metry help to predict the need for maintenance therapy.     

Calcineurin and matrix protein expression in cardiac hypertrophy

In the compensatory state of human left ventricular hypertrophy (LVH), the remodeling processes in the extracellular matrix and the role of calcineurin (Cn) are not completely understood. The present work aimed to analyze the expression and activity of matrix metalloproteinases (MMPs), their endogenous inhibitors (TIMPs), and of Cn in patients with compensated LVH. By semiquantitative RT-PCR, Western blotting, and gelatine zymography, we determined mRNA, protein, and/or enzyme activity levels of MMPs, TIMPs, atrial natriuretic peptide (ANP), Cn subunits, and of the modulatory calcineurin-interacting protein (MCIP) 1. Myocardial samples from patients showing severe aortic stenosis, normal ejection fraction, and compensated LVH were compared with autopsy samples from healthy hearts. LVH patients showed upregulation of CnA-β mRNA but downregulation of both CnB-α mRNA and protein. Total Cn activity (as determined through NF-AT phosphorylation and MCIP1 mRNA expression) was unchanged. There were no differences in gene expression and activities of MMP-2, MMP-9, and of TIMPs 1–4 between LVH patients and controls. As expected, ANP mRNA expression was high in LVH patients. We propose a prominent role for CnB in controlling Cn activity in compensated LVH. At this stage of the disease, MMP and TIMP activities are balanced. Drs. Grammer and Bleiziffer contributed equally to the study Returned for 1st revision: 23 February 2006 1. revision received: 8 April 2006     

Sustained phosphorylation of Bid is a marker for resistance to Fas-induced apoptosis during chronic liver diseases

BACKGROUND & AIMS: Increased rates of apoptosis have been reported to play a role in the pathophysiology of many disorders, including liver diseases. Conversely, genetic mutations that result in impairment of programmed cell death have been associated with cancer development. However, apoptosis resistance can also be the result of nongenetic stress adaptation, as seen in the cancer-prone metabolic liver disease hereditary tyrosinemia. To clarify whether stress-induced apoptosis resistance is a general feature of chronic liver diseases, an animal model of chronic cholestasis was examined. METHODS: Studies were performed with mice before and 2 weeks following bile duct ligation and with Fah-/- and Fah/p21-/- mice before and after NTBC withdrawal. RESULTS: Here we show that bile duct ligation induced profound resistance against Fas monoclonal antibody-mediated hepatocyte death. The apoptosis signaling pathway was blocked downstream of caspase-8 activation and proximal to mitochondrial cytochrome c release. In controls, activation of the Fas receptor resulted in rapid dephosphorylation of Bid and its subsequent cleavage, whereas Bid remained phosphorylated and uncleaved in chronic cholestasis and other models of hepatic apoptosis resistance. CONCLUSIONS: We propose a model in which the phosphorylation status of Bid determines the apoptotic threshold of hepatocytes in vivo. Furthermore, resistance to apoptosis in chronic cholestasis may contribute to the long-term risk of cancer in this setting.     

Age and rising rates of cyclooxygenase-2 inhibitor use

BACKGROUND: Cyclooxygenase-2 (COX-2) inhibitors were widely prescribed in the years following their introduction, but little is known about the frequency and context of their use across different age groups. OBJECTIVE: To determine patterns and context of COX-2 inhibitor use in younger and older adults. DESIGN: Cross-sectional surveys conducted each year from 1998 to 2002. PARTICIPANTS: National Ambulatory Medical Care survey, a nationally representative sample of patient visits to community-based outpatient practices. MEASUREMENTS: New or preexisting medication use recorded at the patient visit. RESULTS: Cyclooxygenase-2 inhibitor use rose rapidly in all age groups, particularly in elders. By 2002, COX-2 inhibitors accounted for 67% of recorded nonsteroidal anti-inflammatory drug (NSAID) uses in visits by patients age 65 and older, compared with 33% of NSAID uses in adults age 18 to 44 and 54% in adults age 45 to 64 (P<.001). Coadministration of proton pump inhibitors or misoprostol with NSAIDs was low throughout the study period in all age groups, ranging from 6.7% of all NSAID users in 1998 (the year before COX-2 inhibitors were introduced) to 8.2% in 2002 (P=.68). For both older and younger adults, use of these gastroprotective agents occurred at similar rates among persons taking COX-2 inhibitors compared with those taking nonselective NSAIDs. Among elderly NSAID users in 2001 to 2002, elders with cardiovascular disease were more likely to receive COX-2 inhibitors than those without cardiovascular disease (86% vs 66%, P<.001). CONCLUSIONS: Cyclooxygenase-2 inhibitors were rapidly adopted among all age groups, but particularly among the elderly, where use in patients with cardiovascular disease was especially high. Use of these agents largely supplemented, rather than replaced, older forms of gastroprotective therapy. The rapid and widespread use of COX-2 inhibitors in spite of their higher cost and potential for complications provides important lessons for physicians' approach to new and highly promoted drugs.     

Rituximab for adolescents with haemophilia and high titre inhibitors

Neutralizing alloantibodies (inhibitors) to factor VIII or factor IX develop in approximately 25% of patients with haemophilia A and <3% of patients with haemophilia B treated with factor concentrate. Patients with high titre inhibitors, in whom immune tolerance therapy fails, have few treatment options. Targeted anti-B-cell therapy with rituximab (chimeric anti-CD20) has been useful in several antibody-mediated autoimmune states. Case reports of rituximab treatment in small numbers of haemophilia patients with inhibitors have been inconclusive. We describe three adolescent patients with severe haemophilia and inhibitors treated with four weekly doses of rituximab, 375 mg m(-2). Treatment with rituximab was effective in reducing the inhibitor titre in two of three patients. Rituximab may be beneficial for patients with severe haemophilia and inhibitors in whom standard therapies have failed, but larger prospective studies are required to determine safety, efficacy and predictors of success.     

Early administration of abciximab bolus in the emergency department improves angiographic outcome after primary PCI as assessed by TIMI frame count: results of the early ReoPro administration in myocardial infarction (ERAMI) trial.

OBJECTIVES: We assessed the safety and efficacy of early administration of abciximab prior to percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients. BACKGROUND: Research suggests that platelet glycoprotein IIb/IIIa receptor inhibitors, e.g. abciximab, may improve myocardial perfusion. In particular, early administration in the emergency department, prior to PCI, may result in more effective reperfusion. METHODS: Eighty AMI patients with planned PCI were randomized in a double-blind fashion to receive a 0.25 mg/kg abciximab bolus either "early" in the emergency department or "late" in the catheterization laboratory after angiographic assessment. In total, 74 patients underwent PCI after diagnostic angiography, all of which then received an abciximab infusion of 0.125 microg/kg/min for 12 hr. RESULTS: Prior to PCI, no significant differences were observed between the two groups regarding the angiographic endpoints or ST-segment resolution. After PCI, thrombolysis in MI (TIMI) frame count (TFC) was significantly improved in patients treated early rather than in those treated late (23 +/- 10 vs. 41 +/- 35; P = 0.02). Consistent trends, also favoring early treatment, were observed for TIMI flow grade 3 (TFG 3), corrected TFC (CTFC), and TIMI myocardial perfusion grade 3 (TMPG 3). Nine deaths (4 early, 5 late) and six significant bleeds (4 early, 2 late) were observed at 30 days after randomization. CONCLUSIONS: Early administration of abciximab is both feasible and safe in patients planned for primary PCI, increasing coronary flow and myocardial reperfusion after PCI, as demonstrated by significantly decreased TFC scores and trends toward improvements in TFG, CTFC, and TMPG.