Efficacy Of Non-steroidal Anti-inflammatory Drugs Research Articles

Drugs for relief of pain in patients with sciatica: systematic review and meta-analysis

Objective To investigate the efficacy and tolerability of analgesic and adjuvant pain drugs typically administered in primary care for the management of patients with sciatica.Design Systematic review.Data source International Pharmaceutical...

The Effect of Nonsteroidal Anti-Inflammatory Drug Administration on Acute Phase Fracture-Healing: A Review

The analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established, and these agents often form an integral part of posttraumatic pain management. However, potentially deleterious effects of resulting prostaglandin suppression on fracture-healing have been suggested. A systematic literature review involving searches of electronic databases and online sources was performed to identify articles exploring the influence of NSAIDs on fracture-healing. A structured search approach identified 316 papers as potentially relevant to the topic, and these were manually reviewed. The majority described small-scale studies that were retrospective or observational in nature, with limited control of potentially confounding variables, or presented little key information that was not also present in other studies. Although increasing evidence from animal studies suggests that cyclooxygenase-2 (COX-2) inhibition suppresses early fracture-healing, in vivo studies involving human subjects have not provided convincing evidence to substantiate this concern. We found no robust evidence to attest to a significant and appreciable patient detriment resulting from the short-term use of NSAIDs following a fracture. The balance of evidence in the available literature appears to suggest that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture pain control, without a significantly increased risk of sequelae related to disrupted healing.

Current Use of Non-steroidal Anti-inflammatory Drugs in the Treatment of Ocular Inflammation Related to Cataract Surgery

Ocular inflammation and pain are a common consequence of cataract surgery, and if left untreated, may lead to extensive ocular damage, resulting in impaired vision as well as decreased satisfaction with the procedure. Effective management of ophthalmic inflammation after surgery is therefore vital. Topical ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs) have become a mainstay of management of ocular pain and inflammation as a result of their anti-inflammatory activity, analgesic property and established safety record. Numerous studies have demonstrated the efficacy of topical NSAIDs in post-operative prevention of ocular inflammation, inhibition of intra-operative miosis, reduction of pain associated with cataract surgery and pre-operative use to prevent cystoid macular oedema. Studies have also indicated that NSAIDs and steroids act synergistically when administered together, and that a combination of steroid and NSAID therapy is recommended to achieve successful outcomes. With appropriate administration, NSAIDs are safe and effective therapeutic agents, which rarely result in serious local and systemic responses.

Nonsteroidal Anti-Inflammatory Drugs in Schizophrenia

Mounting evidence suggests that inflammation is involved in the pathogenesis of schizophrenia. This evidence implies that anti-inflammatory agents are potentially useful therapeutic strategies in schizophrenia. This article quantitatively summarizes the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) to augment antipsychotic treatment to reduce schizophrenia symptom severity. An electronic search was performed using MEDLINE, Embase, the National Institutes of Health Web site clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. The following basic search terms were used: schizophrenia, nonsteroidal anti-inflammatory drug, and NSAID together with the name of each specific NSAID (ibuprofen, diclofenac, naproxen sodium, and acetylsalicylic acid). We applied no year or language restrictions. Studies were selected if they met the following inclusion criteria: (1) randomized, double-blind, placebo-controlled trials regarding augmentation of antipsychotic medication with an NSAID, (2) patients included had a diagnosis of a schizophrenia spectrum disorder according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, and (3) studies reported sufficient information to compute common effect size statistics, or corresponding authors could supply these data upon request. The primary outcome measure was the mean change in total score on the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures included positive and negative symptom subscores of the PANSS. We could include 5 double-blind, randomized, placebo-controlled trials, reporting on 264 patients. Four studies applied celecoxib, and 1 used acetylsalicylic acid. We found a mean effect size of 0.43, which was significant at P = .02 in favor of NSAIDs on total symptom severity. For positive symptom severity, the mean standardized difference was 0.34 (P = .02). For severity of negative symptoms the mean standardized difference was 0.26 (P = .03). These results suggest that NSAID augmentation could be a potentially useful strategy to reduce symptom severity in schizophrenia. As these are the first studies on a relatively new strategy and the included sample size is modest, these results should be interpreted with caution. However, augmentation with acetylsalicylic acid may have the additional benefit of reducing cardiac and cancer mortality in schizophrenia. We therefore believe that application of NSAIDs in schizophrenia deserves further investigation as augmentation of antipsychotic treatment and reducing comorbid somatic diseases.

The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer. A systematic review of the literature

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol are used widely in the management of mild to moderate cancer pain and are frequently combined with opioids in the treatment of moderate to severe pain. Aim: To perform a systematic literature review of the evidence of the efficacy and toxicity of NSAIDs or paracetamol added to WHO Step III opioid treatment for cancer pain. Design and data sources: A systematic literature review of MedLine, EMBASE and Cochrane Central register of controlled trials database was carried out using both text words and MeSH/EMTREE terms. Results: Seven eligible papers were retrieved from the new search and five from the Cochrane review. Five of seven studies showed an additive effect of NSAIDs when combined with opioids either by improving analgesia (three studies) or by reducing the opioid dose (two studies). Paracetamol was only marginally effective in one of five trials. The study designs were not adequate to assess differences in side effects between the opioids alone and opioids in combination with NSAIDs or paracetamol. Conclusions: The evidence from the available clinical trials is of limited amount and quality, but it weakly supports the proposal that the addition of an NSAIDs to WHO Step III opioids can improve analgesia or reduce opioid dose requirement. There is insufficient evidence to support the use of paracetamol in combination with Step III opioids. Data on the toxicity of NSAIDs in this indication are insufficient owing to the small number of patients and the short duration of treatment reported in the studies.

New considerations in the design of clinical trials for spondyloarthritis

Inflammation in spondyloarthritis (SpA) primarily affects the axial skeleton including the sacroiliac joints, the spine and the peripheral joints. Currently, axial and peripheral SpA can be distinguished, and new criteria have been developed to classify these subtypes. Ankylosing spondylitis (AS; Bechterew’s disease) belongs to the spectrum of axial SpA. To date, randomized clinical trials in this field have usually been conducted in patients with AS, showing efficacy of non-steroidal anti-inflammatory drugs and of TNF-α-inhibiting biologicals on signs and symptoms of AS, on acute phase reactants and on inflammation on MRI of the spine and sacroiliac joints. In this article, classic trial design in AS is discussed, as well as the implications of the development of the new Assessment in Spondyloarthritis international Society criteria and new outcome measures in the field of SpA on future trial designs with regard to new drug development.

Prostaglandins and Inflammation

Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase isoenzymes, and their biosynthesis is blocked by nonsteroidal antiinflammatory drugs, including those selective for inhibition of cyclooxygenase-2. Despite the clinical efficacy of nonsteroidal antiinflammatory drugs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm.

Molecular Mechanisms and Therapeutic Application of NSAIDs and Derived Compounds in Alzheimers Disease

Alzheimer's disease (AD) is the most common form of neurodegenerative dementias worldwide. Amyloid-β deposition, neurofibrillary tangle formation and Neuroinflammation are the major pathogenetic mechanisms that in concert lead to memory dysfunction and decline of cognition. To date, there is no curative treatment for AD. Epidemiological analysis support the notion that sustained intake of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delay the onset of AD. In contrast, therapeutic studies testing NSAID efficacy in AD patients have not yielded positive results. This suggests that either the investigated drugs have not addressed the mechanism of action required for mediating beneficial effects or that NSAIDs are effective at stages way before clinical onset of symptoms. The NSAIDs concerned are pleiotrophic in nature and interact with more than one pathomechanism. Therefore evidence for more than one neuroprotective action of NSAIDs has been put forward and it seems likely that some of the drugs act at multiple levels through more than one molecular mechanism. Some, even may not only be beneficial, but negative actions may be overruled by protective effects. Within these mechanisms, modulation of γ-secretase activity, the activation of the peroxisome proliferator-activated receptor-γ, binding to prostaglandin receptors or interactions at the blood-brain barrier may account for the observed protection from AD. This article reviews the current knowledge and views on the above mechanisms and critically discusses current obstacles and the potential as future AD therapeutics.

In vitro evaluation of the complexation of non-steroidal anti-inflammatory drugs with caffeine

Abstract The complexation of five non-steroidal anti-inflammatory drugs (NSAIDs) with caffeine was evaluated. Mixtures were prepared by powder mixing, trituration in a mortar with a pestle and recrystallisation from a common solvent. The properties of the mixtures and the recrystallised materials, evaluated by differential scanning calorimetry (DSC) and dissolution rate measurements, differed significantly (P<0.05). Disappearance of peaks in DSC thermograms, or lowering of melting points of the NSAIDs in NSAID-caffeine co-precipitates were ascribed to the complexation of caffeine with the NSAIDs. The dissolution rate of ketoprofen was not affected by the addition of caffeine but the dissolution rates of ibuprofen, mefenamic acid, naproxen and indomethacin were significantly enhanced (P0.05) after being co-precipitated, or mixed in a mortar or V-blender, with caffeine. Higher dissolution rates, because of the complexation of caffeine and the drugs in solution, could translate into changed bioavailability and different pharmacokinetic parameters. Less gastrointestinal irritation and quicker onset of required blood levels might improve the efficacy of NSAIDs, a factor that, if confirmed, should be considered when prescribing these drugs to patients.

Topical diclofenac in the treatment of osteoarthritis of the knee

Topical diclofenac in the treatment of osteoarthritis of the knee Niklas Schuelert, Fiona A Russell, Jason J McDougallDepartment of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaAbstract: Osteoarthritis (OA) is a common disease that affects millions of people worldwide. As there is no cure for OA, drug treatment to relieve symptoms is the main form of management. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac are the most commonly used drugs to treat knee OA pain. Unfortunately, these agents are associated with gastrointestinal and cardiovascular risks, which limit their chronic use. Topical NSAIDs are emerging as a viable alternative for managing OA pain. Because a pharmacologically effective dose can be restricted to the site of pain, there is superfluous systemic absorption, and the risk of related adverse effects is minimized. This article reviews the currently available preclinical and clinical information on topical diclofenac for the treatment of OA pain, including data from recently published randomized controlled trials regarding the efficacy and safety of topical diclofenac. Most studies confirm topical diclofenac to be as effective as oral diclofenac with significantly reduced side effects; however, the efficacy of NSAIDs is far from optimal, and more research needs to be done to investigate the underlying mechanisms of OA in order to improve treatment options, especially for patients with NSAID-resistant OA pain.Keywords: osteoarthritis, topical diclofenac, NSAID, joint pain

The Cyclooxygenase-Inhibiting Nitric Oxide Donator (CINOD) Compound NCX 429 Exhibits Reduced Gastrointestinal Toxicity as Compared with Naproxen in Arthritic and Aspirin-Treated Rats

Purpose: The efficacy of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) for the treatment of inflammation and pain is well recognized. Nonetheless, their long-term use poses challenges due to gastrointestinal (GI) and cardiovascular safety concerns. All NSAIDs, even COX-2 inhibitors, induce GI damage in susceptible patients, such as aspirin (ASA) users. In the constant quest for NSAIDs with improved tolerability, an approach using nitric oxide (NO) has been made. Cyclooxygenase-Inhibiting Nitric Oxide Donators (CINODs) are anti-inflammatory compounds designed to concomitantly inhibit cyclooxygenase (COX) and donate NO, with the aim of mitigating the side effects derived from COX inhibition. We studied the anti-inflammatory activity and GI tolerability of NCX 429, and reference NSAIDs naproxen and celecoxib, in rats with arthritis or pre-treated with ASA. Methods: Rats displaying Freund's complete adjuvant (FCA)-induced arthritis were orally treated for 14 days (twice daily, starting day 7 after arthritis induction) with vehicle, NCX 429 (16 mg/kg), naproxen (10 mg/kg) or celecoxib (10 mg/kg). Paw volume was measured by plethysmography. At sacrifice (day 21), stomach and intestine were excised and examined for damage (expressed as the sum of the length in mm of all lesions). In a separate setting, ASA (30 mg/kg) was administered to fasted rats 30 min before gavage with vehicle, NCX 429 (49 or 98 mg/kg), naproxen (30 mg/kg) or celecoxib (20 mg/kg). Gastric damage was measured 4 hours after drug treatment. Results: NCX 429, naproxen and celecoxib, all similarly and significantly reduced paw edema in arthritic rats. NCX 429 displayed significantly reduced gastric and intestinal damage (1.4±0.7 and 1.0±1.0 mm, respectively) than equimolar naproxen (6.2±1.8 and 8.4±3.5mm, respectively, p<0.01), and not differently from celecoxib. In fasted rats, ASA administration caused gastric mucosal damage (4.1±1.2mm, p<0.05 vs. control), which was reduced by NCX 429 (2.2±1.2mm at the maximal dose tested) but conversely exacerbated by naproxen and celecoxib (15.3±4.4 and 10.2±3.3mm, respectively, p<0.05). Conclusion: The CINOD NCX 429 shows effective anti-inflammatory activity in arthritic rats similarly to reference NSAIDs, naproxen and celecoxib. NCX 429 features a GI sparing profile over naproxen. Moreover, oppositely to naproxen and celecoxib, NCX 429 reduces ASA-induced gastric lesions, supporting the NO donating approach aimed at potentially mitigating gastric damage. This experimental evidence, needing clinical validation, would suggest a potential for CINODs in the treatment of inflammatory pathologies, especially individuals at risk for GI damage. Disclosure: Drs Bastia, Monopoli, Bolla, Viappiani - Empoyee: Company NicOx Drs Coruzzi, Guaita, Morini, Wallace - Consultant: Company NicOx. This study has been supported by a grant from NicOx SA to Drs Coruzzi and Wallace.

Chronic lumbosacral pain: diagnosis and treatment

The paper considers the causes and risk factors of chronic lumbosacral pain. Particular emphasis is placed on the differential diagnosis of specific and nonspecific low back pain. It analyzes in detail the efficiency of various treatment modalities for chronic low back pain in the context of evidence-based medicine and the efficacy of nonsteroidal anti-inflammatory drugs.

Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors

Anti-inflammatory efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been related to their properties as inhibitors of cyclooxygenase (COX)-mediated prostaglandin (PG) synthesis. However, recent studies have suggested that variations of the in vivo anti-inflammatory actions among different NSAIDs could not be solely explained by COX inhibition. Here, we have analyzed the effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole anti-inflammatory drugs with different potencies as COX-2 inhibitors, namely E-6087, E-6232, E-6231, E-6036 and E-6259 as well as the chemically related COX-2 inhibitor Celecoxib. These drugs inhibited mitogen-mediated T cell proliferation as well as Interleukin (IL)-2, tumor necrosis factor (TNF)-α and Interferon (IFN)-γ synthesis by activated T cells, independently of their ability to inhibit COX-2 enzymatic activity. Immunosuppressive effects of these drugs seem to be due to their interference on transcription factor activation as induced transcription from Nuclear Factor (NF)-κB and Nuclear Factor of Activated T cells (NFAT)-dependent enhancers was inhibited in a dose-dependent manner, being the latter effect the most sensitive to the action of those compounds. Both NFAT dephosphorylation, required for its nuclear translocation, as well as transcriptional activity of a GAL4-NFAT chimera were diminished in the presence of these compounds. These findings provide new insights into the molecular mechanisms involved in the immunomodulatory and anti-inflammatory actions of NSAIDs, which may have important implications in anti-inflammatory therapy, through inhibition of NFAT.

In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1.

The detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC50, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy.

Use of Nonsteroidal Anti-Inflammatory Drugs in Patients With Cardiovascular Disease

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit production of prostaglandins by acting on cyclooxygenase (COX) isoenzymes 1 and 2. Nonselective NSAIDs inhibit both COX 1 and 2 isoenzymes (eg, ibuprofen and naproxen). Selective NSAIDs act on COX-1 (eg, aspirin) or COX-2 (eg, celecoxib) isoenzymes, respectively. Prostaglandins are produced in platelets and gastric mucosal cells through constitutively expressed COX-1 isoenzyme. They are involved in the regulation of hemostasis, functional integrity of the gastrointestinal and renal tracts, platelet function, and macrophage differentiation. Inhibition of COX-1 isoenzymes impedes platelet aggregation, impairs maintenance of protective gastric mucosal barrier, and affects renal function. Prostaglandin production in inflamed tissue results from de novo induction of COX-2 expression by inflammatory cytokines and other noxious stimuli. Thus, COX-2 isoenzyme inhibition either selectively or nonselectively helps in reducing inflammation in the setting of musculoskeletal disorders. Safety and efficacy of NSAIDs are related to their relative actions on COX-1 or COX-2 inhibition. Given the multisystem (gastrointestinal, hematopoietic, and renal) adverse effect profile of COX-1 inhibition, formulation of NSAIDs with relative COX-2 selectivity became a highly desirable target during the 90's. However, studies in the first half of this decade revealed adverse effects of COX-2 inhibition on the cardiovascular system, including increased risks of myocardial infarction, exacerbation of stable congestive heart failure, and worsening high blood pressure. Randomized trials and meta-analyses confirmed these findings, which led to withdrawal of some of the COX-2 inhibitors from the market by the federal Food and Drug Administration a few years ago. Here, we review the effects of COX-2 isoenzyme inhibitors on the cardiovascular system to provide a safe strategy for prescribing these agents in patients with existing cardiovascular disease. We did not find adequate long-term randomized controlled trials appropriately powered to evaluate cardiovascular outcomes. Potentially, all NSAIDs possess a fair risk of adverse effects on gastrointestinal, cardiovascular, and renal systems. Until more evidence for safety via randomized trials is available, we recommend caution in prescribing COX-1 and 2 inhibitors for musculoskeletal disorders in patients with existing gastrointestinal or cardiovascular conditions.

A Practice Guide for Continuous Opioid Therapy for Refractory Daily Headache: Patient Selection, Physician Requirements, and Treatment Monitoring

To provide a guide to the use and limitations of continuous opioid therapy (COT, or daily scheduled opioids) for refractory daily headache, based on the best available evidence and expert clinical experience. There has been a dramatic increase in opioid administration over the past 25 years, with limited evidence of efficacy for either pain reduction or increased function, and increasing evidence of adverse effects, including headache chronification. To date, there has been no consensus on headache-specific guidelines for selecting patients for COT, physician requirements, and treatment monitoring. A multidisciplinary committee of physicians and allied health professionals with extensive experience and expertise in the administration of opioids to headache patients, undertook a review of the available evidence from the research and clinical literature (using the PubMed database for articles through December 2009) to develop headache-specific treatment recommendations. This guide reflects the opinions of its authors and is not an official document of the American Headache Society. The guide identifies factors that would qualify or disqualify the use of COT, including, determination of intractability prior to initiating COT, requisite experience of the prescriber, and requirements for a formal monitoring system to assess appropriate use, safety, efficacy, and functional impact. An appendix reviews the available evidence for efficacy of COT in chronic headache and noncancer pain, paradoxical effects (opioid-induced hyperalgesia, medication overuse headache, opioid-related reduction in triptan and nonsteroidal anti-inflammatory drug efficacy), other adverse effects (nausea and constipation, insomnia and sleep apnea, respiratory depression and sudden cardiac death, reductions in sex hormones, issues during pregnancy, neurocognitive functioning), and issues related to comorbid psychiatric disorders. Only a select and very limited group (estimate of 10-20%) of refractory headache patients who meet criteria for COT respond with convincing headache reduction and functional improvement over the long-term. Conservative and empirically based guidelines will help identify those patients for whom a COT trial may be appropriate, while protecting their welfare and safety.

Mechanisms of Action of Non-Steroidal Anti-Inflammatory Drugs for the Prevention of Alzheimers Disease

Alzheimer's disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDs). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDs cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD subjects have failed, and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review.

Polymorphisms in inflammatory pathway genes and their association with colorectal cancer risk

Chronic inflammation is an established risk factor for colorectal cancer (CRC), and polymorphisms in genes regulating inflammatory processes appear to alter the risk for neoplasia and the efficacy of nonsteroidal anti-inflammatory drugs in CRC chemoprevention. We examined the association between selected inflammation gene polymorphisms and CRC risk. In a large population-based case-control study with 1,795 CRC cases and 1,805 controls from the German DACHS study, we evaluated 5 putative functional inflammatory pathway polymorphisms in PRODH, PTGS1 and UBD genes. PTGS1 G213G was significantly associated with an increased CRC risk [odds ratio (OR), 1.19; 95% confidence interval (CI), 1.03-1.39; p = 0.02] comparing minor allele carriers with major allele homozygotes. This risk estimate was consistent across locations and stages of CRC (range of ORs, 1.15-1.20). Carriage of the minor allele of UBD I68T was significantly associated with advanced stages of CRC and with CRC below 65 years of age (OR, 1.23; 95% CI, 1.04-1.45; p = 0.02 and OR, 1.32; 95% CI, 1.05-1.67; p = 0.02, respectively). Our results support a role of variants in inflammatory pathway genes in CRC susceptibility and progression.

Effectiveness of diclofenac versus acetaminophen in primary care patients with knee osteoarthritis: [NTR1485], DIPA-Trial: design of a randomized clinical trial

BackgroundOsteoarthritis is the most frequent chronic joint disease which causes pain and disability of especially hip and knee. According to international guidelines and the Dutch general practitioners guidelines for non-traumatic knee symptoms, acetaminophen should be the pain medication of first choice for osteoarthritis. However, of all prescribed pain medication in general practice, 90% consists of non-steroidal anti-inflammatory drugs compared to 10% of acetaminophen. Because general practitioners may lack evidence showing a similar efficacy of acetaminophen and non-steroidal anti-inflammatory drugs, we present the design of a randomized open-label trial to investigate the efficacy of a non-steroidal anti-inflammatory drug (diclofenac) compared with acetaminophen in new consulters with knee osteoarthritis in general practice.Methods/DesignPatients aged 45 years or older consulting their general practitioner with non-traumatic knee pain, meeting the clinical American College of Rheumatology criteria, and with a pain severity score of 2 or higher (on a 0-10 scale), will be randomly allocated to either diclofenac (maximum daily dose of 150 mg) or acetaminophen (maximum daily dose of 3000 mg) for 2 weeks and, if required, an additional 1-2 weeks, with a total follow-up period of 12 weeks. The primary outcomes are knee pain measured with a daily diary, and pain and function measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS) at baseline, and at 3, 6, 9, and 12-weeks follow-up. Secondary outcomes are patients' perceived recovery, quality of life, medical, patient, and productivity costs, compliance to therapy, co-interventions, and adverse reactions.DiscussionThe successful completion of this trial would lead to a better understanding of which medication should be used in the treatment of primary care patients with mild knee osteoarthritis.Trial registrationDutch trial registry NTR1485.

Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor

Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E 2 (PGE 2) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis and inflammatory pain, largely attributed to the inhibition of PGE 2 synthesis, provides a rationale for exploring mPGES-1 inhibition as a potential novel therapy for these diseases. Toward this aim, we identified PF-9184 as a novel mPGES-1 inhibitor. PF-9184 potently inhibited recombinant human (rh) mPGES-1 (IC 50 = 16.5 ± 3.8 nM), and had no effect against rhCOX-1 and rhCOX-2 (>6500-fold selectivity). In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression was induced in cell context- and time-dependent manner, consistent with the kinetics of PGE 2 synthesis. In rationally designed cell systems ideal for determining direct effects of the inhibitors on mPGES-1 function, but not its expression, PF-9184 inhibited PGE 2 synthesis (IC 50 in the range of 0.5–5 μM in serum-free cell and human whole blood cultures, respectively) while sparing the synthesis of 6-keto-PGF 1α (PGF 1α) and PGF 2α. In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE 2, PGF 1α and PGF 2α synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention.