Objective To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs).Design Systematic review followed by a one stage bayesian individual patient data meta-analysis.Data sources Studies from Canadian and European healthcare databases.Review methods Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias. Exposure and outcomes Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction.Results A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations.Conclusions All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.
Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries.
Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and pre-malignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618-3627). The present paper summarizes the details of the structure-activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for their ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors implanted in the same mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2.
Chondroitin sulfate 800 mg/day (CS) pharmaceutical-grade in the management of symptomatic knee osteoarthritis consistent with the European Medicines Agency guideline.
Background The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. Methods Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. Results A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). Conclusions At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).
Exercise-induced muscle damage (EIMD) is a common condition resulting from a bout of vigorous exercise, particularly if the individual is unaccustomed to performance of the given movement. Symptoms of EIMD include delayed-onset muscle soreness (DOMS) and a loss of physical function. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely prescribed post-exercise to alleviate these symptoms and restore normal physical function. Of potential concern for those who use NSAIDs to treat EIMD is the possibility that they may impair the adaptive response to exercise. Specifically, there is emerging evidence that the action of cyclo-oxygenase (COX) enzymes, and COX-2 in particular, are important and even necessary to achieve maximal skeletal muscle hypertrophy in response to functional overload. Given that NSAIDs exert their actions by blocking COX and thus suppressing prostaglandin production, a theoretical rationale exists whereby these drugs may have detrimental effects on muscle regeneration and supercompensation. Therefore, the purpose of this article is to extensively review the literature and evaluate the effects of NSAIDs on muscle growth and development. Based on current evidence, there is little reason to believe that the occasional use of NSAIDs will negatively affect muscle growth, although the efficacy for their use in alleviating inflammatory symptoms remains questionable. Evidence on the hypertrophic effects of the chronic use of NSAIDs is less clear. In those who are untrained, it does not appear that regular NSAID use will impede growth in the short term, and at least one study indicates that it may in fact have a positive impact. Given their reported impairment of satellite cell activity, however, longer-term NSAID use may well be detrimental, particularly in those who possess greater growth potential.
In 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states' powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics).
This randomized clinical trial compares the efficacy and safety of oral oxycodone (an oral opioid) with naproxen (a nonsteroidal anti-inflammatory drug) in acute pain control in patients with soft tissue injury. It also evaluates the need for additional doses of analgesics in the first 24 hours of discharge from emergency department (ED).
Objective: Safety data regarding the usage of etoricoxib and other nonsteroidal anti-inflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. To estimate and compare rates of gastrointestinal, renovascular, and cardiovascular adverse events in patients exposed to etoricoxib, celecoxib, non-selective NSAIDs (nsNSAIDs) or totally unexposed to NSAIDs. Methods: This is a national register-based cohort study on patients with AS or SpA (N=21,872) identified in the Swedish national patient register (NPR) 1987 - 2009. Treatment exposure was assessed time-dependently based on the prescription drugs register from 2006 - 2009 adjusting for socio-demography, and comorbidities derived from national population-based registers. Results: Exposure to etoricoxib, celecoxib and nsNSAID were 7.6%, 3.9% and 71.2%, respectively. No major risk differences for serious cardiovascular, gastrointestinal or renal adverse events were seen among the three exposure groups. Patients unexposed to NSAIDs had more baseline co-morbidities and an increased relative risk for congestive heart failure events during the study period 2.0 (95% 1.3 to 3.2). The relative risk for atherosclerotic events was non-significant when compared to the nsNSAID group 1.0 (95% CI: 0.7 to 1.5), while the risk for gastrointestinal events was lower for unexposed patients 0.5 (0.4 to 0.7). Conclusion: Overall, serious adverse events related to nsNSAID, etoricoxib and celecoxib were similar and in the range of what would be expected in a group of SpA patients. Patients unexposed to NSAIDs had considerable more baseline co-morbidities and increased risk for congestive heart failure, reflecting a selection of patients being prescribed NSAID in clinical practice. This article is protected by copyright. All rights reserved.
The non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs in the control of postoperative pain. In choosing the NSAID to be used, it is essential to assess the most favorable risk/benefit ratio according to a careful assessment of intrinsic and extrinsic risk factors and cardiovascular, gastrointestinal, renal and metabolic patient comorbidities. Diclofenac dose of 150 mg/die is the NSAID that has wider literature that attests its efficacy and tolerability. Due to its high lipid solubility, it is one of the few NSAIDs that are able to cross the blood-brain barrier, with an action principally directed towards COX-2. Over time, several studies have been conducted to evaluate the side effects of NSAIDs. Regarding Diclofenac’s cardiovascular and gastrointestinal tolerability, recent studies indicate that the relative risk and absolute risk of complications of Diclofenac are similar to COXIB and inferior to other NSAIDs. Important feature of Diclofenac is that, unlike other NSAIDs, it does not interfere with the cardio-protective effect of acetyl-salicylic acid. Diclofenac potassium is instead indicated for use as an analgesic in headache and as an antipyretic in influenza-like symptoms. Studies with the aim of investigating the intestinal damage exacerbated by proton pump inhibitors drugs, when associated with NSAIDs, state that at least in part, they aggravate the intestinal damage induced by NSAIDs due to significant changes in intestinal microbial populations. The reference dose of Diclofenac used in all randomized controlled trials is 150 mg/die; this controlled release dosage allows to decrease the number of daily administrations, ensuring a better patient compliance, especially if elderly and/or in polytherapy.