Gastrointestinal bleeding associated with low-dose aspirin use: relevance and management in clinical practice

Since 1998, two selective inhibitors of COX-2 have been approved in many countries for the treatment of rheumatoid arthritis, osteoarthritis and acute pain. These new drugs have a significantly reduced gastrointestinal toxicity when compared with non-selective COX inhibitors. However, the results of two large clinical trials conducted in patients with osteoarthritis and rheumatoid arthritis have recently raised some concerns regarding the cardiovascular safety of these new drugs. The purpose of this paper is to review the potential mechanisms whereby selective COX-2 inhibitors could increase the cardiovascular risk of patients and to analyse the data indicating that this clinical risk indeed exists. The authors’ analysis shows that even though there are pathophysiological mechanisms which could explain why selective COX-2 inhibition might increase the cardiovascular risk in patients, the actual level of evidence demonstrating that the risk is indeed increased is weak. Because of the importance of the issue, additional studies must be conducted with this class of agents. Meanwhile, it is crucial to emphasise that neither selective COX-2 inhibitors nor conventional NSAIDs replace aspirin in patients with a high cardiovascular risk.     

两种剂量艾瑞昔布和塞来昔布对中轴脊柱关节炎疗效的随机对照研究

目的：观察两种选择性环氧化酶（Cyclooxygenase,COX）-2抑制剂艾瑞昔布和塞来昔布对中轴型脊柱关节炎（Axial Spondyloarthritis,ax-SpA）患者的疗效和不良反应。方法：某院风湿免疫科就诊的ax-SpA患者180例,诊断符合2009年ASAS推荐的ax-SpA分类标准;分别随机给予艾瑞昔布0.1,0.2 g或塞来昔布0.2 g,每天2次,主要疗效指标为12周末患者背痛视觉模拟评分（Visual Analogue Scale,VAS）总体评分,次要疗效指标包括Schober试验、Bath强直性脊柱炎病情活动指数（Bath Ankylosing Spondylitis Disease Activity Index,BASDAI）、Bath强直性脊柱炎功能指数（Bath Ankylosing Spondylitis Functional Index,BASFI）、ESR、CRP的变化和不良反应。结果：最终完成12周随访者168例,其中艾瑞昔布0.2 g·d^-1组55例,艾瑞昔布0.4 g·d^-1组57例,塞来昔布组56例。12周时与基线期相比,艾瑞昔布组与塞来昔布组患者背痛VAS总体评分、Schober试验、BASDAI评分、ESR、CRP均较基线期改善有统计学意义（P<0.05）,艾瑞昔布0.4 g·d^-1和塞来昔布0.4 g·d^-1之间差异无统计学意义（P>0.05）,患者背痛VAS总体评分、Schober试验、BASDAI评分优于艾瑞昔布0.2 g·d^-1组。随访12周3组患者不良反应发生均轻微可控。结论：艾瑞昔布0.4 g·d^-1和塞来昔布0.4 g·d^-1在ax-SpA治疗中具有相似的疗效和不良反应,在症状控制和功能改善方面均优于艾瑞昔布0.2 g·d^-1。     

Celecoxib but not the combination of celecoxib+atorvastatin prevents the development of monocrotaline-induced pulmonary hypertension in the rat

The present study aimed to assess the effects of a COX-2 inhibitor, celecoxib, a HMG-CoA reductase inhibitor, atorvastatin, and the association of both on monocrotaline (MC)-induced pulmonary hypertension in rats. Celecoxib (Cib, 25 mg kg(-1) day(-1)), atorvastatin (AS, 10 mg kg(-1) day(-1)) or vehicle, were given orally, separately or in combination, for 26 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed a severe pulmonary hypertension, with an increase in lung to body weight ratio (L/BW), right ventricular pressure (RVP in mmHg, 31 +/- 3 and 14 +/- 1 for MC and control groups, respectively, P < 0.05) and right ventricle/left ventricle + septum weight ratio (RV/LV+S) associated with a decrease in acetylcholine- and sodium-nitroprusside-induced pulmonary artery vasodilation in vitro. Hypertensive pulmonary arteries exhibited an increase in wall thickness (wall thickness to external diameter ratio, 0.42 +/- 0.01 vs 0.24 +/- 0.01 for MC and control groups, respectively, P < 0.001). Whole lung eNOS expression was decreased, and an increase in apoptosis, evaluated by cleaved caspase-3 expression, was evidenced by Western blotting. Cib (RVP in mmHg, 19 +/- 3 and 31 +/- 3 for MC+Cib and MC groups, respectively, P < 0.05), but neither AS nor AS+Cib significantly limited the development of pulmonary hypertension (P < 0.05), although the three treatments exhibited protective effects against MC-induced lung and right ventricle hypertrophy evaluated by L/BW and RV/(LV+S) ratios, respectively (P < 0.05). AS, Cib and AS+Cib treatments reduced MC-induced thickening of small intrapulmonary artery wall (0.42 +/- 0.01, 0.24 +/- 0.01, 0.26 +/- 0.01 and 0.28 +/- 0.01 for MC, MC+AS, MC+Cib and MC+AS+Cib groups, respectively, P < 0.001). In control rats, Cib reduced acetylcholine-induced pulmonary artery vasorelaxation. Treatment of MC rats by either Cib or AS did not modify acetylcholine-induced pulmonary artery relaxation, whereas combination of both drugs significantly worsened it (P < 0.05). AS, but neither Cib nor the combination of both, prevented apoptosis (AS, P < 0.05) and partially restored eNOS expression (AS, P < 0.05) in whole lung of MC rats. In conclusion, celecoxib exhibited beneficial effects against the development of monocrotaline-induced pulmonary artery hypertension and right ventricular hypertrophy. These beneficial effects of celecoxib might be, at least partly, explained by its effects on pulmonary artery thickening and pulmonary hypertrophy, even if it did not show any effect on pulmonary artery vasorelaxation and whole lung eNOS expression or apoptosis. The combination of celecoxib and atorvastatin was unable to prevent MC-induced pulmonary hypertension, decreased endothelium-dependent vasorelaxation and showed a trend toward an increased in RVP that deserves further studies.     

A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice

AIMS: The new cyclooxygenase-2 (COX-2) selective inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx), have been widely prescribed since their launch. No reviews currently appear in the literature of prescribing patterns in Australia. This paper describes a self-audit of the clinical use of selective COX-2 inhibitor therapy undertaken with rural general practitioners (GPs) in Australia. METHODS: A structured audit form was developed and distributed to interested GPs. The form was self-administered and focused on issues about COX-2 inhibitors and the types of patients who were receiving them, e.g. indications, patient demographics, risk factors and drug interactions. RESULTS: A total of 627 patients were recruited (569 celecoxib and 58 rofecoxib). A range of doses was prescribed. Osteoarthritis was the most common indication (68.1%). Risk factors known for the nonselective nonsteroidal anti-inflammatory drugs were identified in 65.1% of patients, with the most common being advanced age, hypertension and previous peptic ulcer disease. Potential drug interactions were common. A variety of reasons for initiation of therapy was identified; these included perceived increased efficacy, safety and failure of other treatment. CONCLUSIONS: These results show that COX-2 inhibitors are being prescribed for patients with multiple risk factors that may place the patient at increased risk of adverse drug reactions to a COX-2 inhibitor. The perception of improved safety and efficacy was common and is of concern. Limitations of the study include the reliance on self-reporting.     

Safety profile of non-vitamin K oral anticoagulants (NOACs) from a patient perspective: a web-based cohort event monitoring study

Objectives: Non-vitamin K oral anticoagulants (NOACs) are a relatively new group of anticoagulants. Characteristics of adverse drug reactions (ADRs) as experienced by patients in everyday use have not yet been fully clarified. The aim was to gain insight into the safety profile of NOACs from a patient’s perspective.

Methods: This was a prospective, observational web-based cohort event monitoring study among first-time users of NOACs. Patients were recruited between July 2012 and April 2017. They were invited to complete four web-based questionnaires 2 weeks, 5 weeks, 3 months and 6 months after starting treatment. Information was collected about patient characteristics, drug use, and characteristics of ADRs.

Results: 1748 NOAC users were included. 661 (38%) experienced at least one ADR. The reported ADRs were comparable with the information described in the Summary of Product Characteristics and generally occurred within 1 week after the start. In 59% of ADRs the patients recovered. These ADRs had no impact on the use and dosage of the NOAC in 68%. In total, 9% of the patients discontinued the NOAC because of ADRs.

Conclusion: Overall NOACs were well tolerated by the participants. Most reported ADRs occurred within 1 week after the start. Patients recovered from most ADRs without changes to the use of the NOAC.     

Selective COX-2 inhibitors as anticancer agents: a patent review (2014-2018)

Introduction: COX-2 is a key enzyme in the process of prostaglandins (PGs) synthesis. The products of this enzyme could play a major role as the mediators of the inflammatory response and some other medical states such as cancer. The design and synthesis of novel selective COX-2 inhibitors have always been attractive to researchers. This review discusses the structures of novel COX-2 inhibitors synthesized during the last five years and describes their efficacy as anticancer agents.

Areas covered: It is well established that COX-2 is overexpressed in many different cancers and treatment with selective COX-2 inhibitors could relieve their symptoms and limit their adverse sequences.

Expert opinion: The diversity of selective COX-2 inhibitors is mainly related to the types of scaffolds. Monocyclic, bicyclic, tricyclic, and acyclic scaffolds with different pharmacological effects and toxicological profiles could be found in the family of selective COX-2 inhibitors. The great interest of the researchers in this field is due to the importance of selective COX-2 inhibitors as a relatively safe and effective set of compounds which could present different properties such as antirheumatic, anti-inflammatory, antiplatelet, anti-Alzheimer’s disease, anti-Parkinson’s disease, and anticancer.     

Recent development on COX-2 inhibitors as promising anti-inflammatory agents: The past 10 years

Cyclooxygenases play a vital role in inflammation and are responsible for the production of prostaglandins. Two cyclooxygenases are described, the constitutive cyclooxygenase-1 and the inducible cyclooxygenase-2, for which the target inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins are a class of lipid compounds that mediate acute and chronic inflammation. NSAIDs are the most frequent choices for treatment of inflammation. Nevertheless, currently used anti-inflammatory drugs have become associated with a variety of adverse effects which lead to diminished output even market withdrawal. Recently, more studies have been carried out on searching novel selective COX-2 inhibitors with safety profiles. In this review, we highlight the various structural classes of organic and natural scaffolds with efficient COX-2 inhibitory activity reported during 2011–2021. It will be valuable for pharmaceutical scientists to read up on the current chemicals to pave the way for subsequent research.     

A study of cardiovascular disease,depression and antidepressants on a computerised general practice database

Previous evidence suggests there is an association between cardiovascular disease and depression. Tricyclic antidepressants (TCAs) are contraindicated in patients with a recent history of cardiovascular disease. 5678 patients between the ages of 50 and 79 years and with a new acute cardiac event were selected from a computerised general practice database and followed up for one year. ‘New episodes’ of diagnosed depression were identified and treatment with antidepressants was investigated. 183 656 patients aged 50–79 years without a cardiac event were used for comparison. A significant association was found between cardiovascular disease and a new diagnosis of depression (adjusted OR=2.23, 95 per cent CI 1.90–2.62). Patients who had suffered a recent cardiac event were less likely to be prescribed a TCA than an SSRI (adjusted OR=0.59, 95 per cent CI 0.41–0.85). However, 35 per cent of patients with a recent cardiac event were initially prescribed a TCA. The findings indicate that general practitioners recognise the dangers of prescribing TCAs to patients with a recent history of cardiovascular disease. However, a substantial minority of cardiac patients were prescribed TCAs where they may not have been the optimal choice. Copyright © 1999 John Wiley & Sons, Ltd.     

Risk of serious upper gastrointestinal events with concurrent use of NSAIDs and SSRIs: a case-control study in the general population

Objectives To study the risk of serious upper gastrointestinal (GI) events associated with the concurrent use of selective serotonin re-uptake inhibitors (SSRIs) and different types of non-steroidal anti-inflammatory drugs (NSAIDs). Methods This was a nationwide, register-based matched case-control study on non-institutionalized residents of Finland during the period 2000–2004. Patient-cases with serious upper GI events (n = 9191) were drawn from the Hospital Discharge Register, and individually matched controls (n = 41,780) were drawn from the Population Register. Logistic regression was applied in the data analysis, and adjustments were made for various co-morbidities and the use of other drugs associated with the risk of serious upper GI event. Results The adjusted odds ratio (AOR) of serious upper GI events for SSRI use compared to non-use of SSRIs or NSAIDs was 1.30 [95% confidence interval (95%CI: 1.13–1.50)], and the AOR for concurrent SSRI and NSAID use compared to the non-use of either drug was 4.19 (95%CI: 3.30–5.31). The AOR of upper GI events for the concurrent use of SSRIs with NSAIDs compared to patients using NSAIDs only was 1.57 (95%CI: 1.24–1.99). The respective AOR for traditional, non-selective NSAIDs was 1.77 (95%CI: 1.31–2.38), for semi-selective NSAIDs (nimesulide, nabumetone, meloxicam, and etodolac) 1.30 (95%CI: 0.76–2.24) and for COX-2 selective NSAIDs 1.33 (95%CI: 0.70–2.50). Conclusions The concurrent use of SSRIs and NSAIDs is associated with a moderate excess relative risk of a serious upper GI event when compared with NSAID use alone. Financial disclosure: Timo Klaukka has been employed by the financier and organizer of the national sickness insurance scheme, including drug reimbursements. No other conflict of interests has been announced. Funding: The Centre for Pharmacotherapy Development funded the statistical analysis. The funding source was not involved in the analysis.     

Gastrointestinal tolerability of NSAIDs in elderly patients: a pooled analysis of 21 randomized clinical trials with celecoxib and nonselective NSAIDs

Abstract

Background:

Gastrointestinal (GI) tolerability is an important treatment consideration for physicians when choosing a nonselective nonsteroidal anti-inflammatory drug (NSAID) for their elderly arthritis patients. The objective of this study was to compare the GI tolerability of the cyclooxygenase-2 selective NSAID celecoxib and nonselective NSAIDs in elderly patients with arthritis aged 65 years or older.     

Safety profiles of biologic agents for inflammatory bowel diseases: a prospective pharmacovigilance study in Southern Italy

Abstract

Introduction

Inflammatory bowel diseases (IBDs) are a public health issue with over 3.5 million patients in Europe, but the advent of several biologic agents has completely changed their management. Pharmacovigilance is needed to early detect expected/unexpected adverse events (AEs) to assess the safety of drugs in a real-world setting. Aim of this prospective pharmacovigilance study was to evaluate the occurrence of AEs in patients treated with biologic drugs in gastroenterology units in Southern Italy.