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It is now over 100 years since the arrival of aspirin and, from the mid-20th Century onwards, we have seen numerous attempts at providing society with safer and more efficacious nonsteroidal drugs. Ironically, while aspirin went from strength to strength with an ever-increasing pharmaceutical profile, new nonsteroidal anti-inflammatory drugs arrived and disappeared with rapid succession. Finally, there appears to have been a breakthrough with the development of the coxibs but concern has recently developed because of potential toxic cardiovascular reactions. Although originally studied in rheumatoid arthritis and degenerative arthropathy, the coxibs have now been investigated in ankylosing spondylitis and efficacy appears to be favorable and, to date, there is little evidence of toxicity, although problems in the nonspondylarthropathic arena may spill over into the seronegative spondylarthritides. [ABSTRACT FROM AUTHOR]

Abstract: To uncover the full spectrum of its pharmacological activities, the selective COX-2 inhibitor celecoxib is routinely being used at concentrations of up to 100μM in cell culture. At these elevated concentrations, several COX-2-independent effects were identified, although many details of these events have remained unclear. Here, we report a COX-2-independent effect of celecoxib that might have profound consequences for the interpretation of previous results obtained at elevated concentrations of this drug in vitro. We found that celecoxib rapidly inhibits general protein translation at concentrations as low as 30μM. This appears to be a consequence of endoplasmic reticulum (ER) stress and entails the phosphorylation and inactivation of eukaryotic translation initiation factor 2 alpha (eIF2α). These effects were not achieved by other coxibs (rofecoxib, valdecoxib) or traditional NSAIDs (indomethacin, flurbiprofen), but were mimicked by the COX-2-inactive celecoxib analog, 2,5-dimethyl-celecoxib (DMC), indicating COX-2 independence. Considering the obvious impact of blocked translation on cellular function, we provide evidence that this severe inhibition of protein synthesis might suffice to explain some of the previously reported COX-2-independent effects of celecoxib, such as the down-regulation of the essential cell cycle regulatory protein cyclin D, which is a short-lived protein that rapidly disappears in response to the inhibition of protein synthesis. Taken together, our findings establish ER stress-induced inhibition of general translation as a critical outcome of celecoxib treatment in vitro, and suggest that this effect needs to be considered when interpreting observations from the use of this drug in cell culture. [Copyright &y& Elsevier]

Celecoxib (Celebrex) was developed as a selective cyclooxygenase-2 (COX-2) inhibitor for the treatment of chronic pain. However, it now appears that this compound harbours additional pharmacologic activities that are entirely independent of its COX-2-inhibitory activity. This review presents the recently emerged direct non-COX-2 targets of celecoxib and their proposed role in mediating this drug's antitumour effects. [ABSTRACT FROM AUTHOR]

A review of the literature on etoricoxib, a highly selective cyclooxygenase (COX)-2 inhibitor, or coxib, which has been approved in 62 countries, was undertaken by the authors. Etoricoxib is an effective analgesic drug that has shown advantages over traditional nonsteroid anti-inflammatory drugs. These advantages include a lower incidence of gastrointestinal adverse events, a similar thrombotic cardiovascular risk profile, rapid action, 27-h effect, sustained long-term effects and effectiveness in the treatment of gouty arthritis, rheumatoid arthritis, ankylosing spondylitis and osteoarthritis. The recently concluded Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) program compared etoricoxib with the most widely used NSAID in the world, diclofenac, in almost 35,000 patients with osteoarthritis and rheumatoid arthritis under clinical practice conditions. This study confirmed a similar incidence of cardiovascular thrombotic events and renal dysfunction, a higher incidence of edema and hypertension, and a lower incidence of gastrointestinal and hepatic adverse events in etoricoxib versus diclofenac. Etoricoxib is an appropriate choice for the treatment of osteoarthritis and rheumatoid arthritis and for the relief of gouty pain in patients with low cardiovascular risk but an increased risk of gastrointestinal complications. [ABSTRACT FROM AUTHOR]

The cyclooxygenase-2 (COX-2) enzyme is induced upon inflammation and in neoplastic tissues. It produces prostaglandins that stimulate tumor angiogenesis and tumor growth. Therefore, destruction and/or specific inhibition of COX-2 should be an important aspect of future tumor therapy. Recently, clinical application of specific COX-2 inhibitors called coxibs became doubtfully because they produce serious renal and cardiovascular complications under long term application. The exact underlying mechanisms are poorly understood and the different effects of diverse coxibs are not explained. It has been demonstrated before that COX-2 is degraded by the ubiquitin (Ub) proteasome system (UPS). However, how ubiquitination is accomplished and regulated was unclear. An important regulator of the UPS is the COP9 signalosome (CSN), which controls the stability of many proteins. Here we show that the proteasome-dependent degradation of COX-2 in HeLa cell lysate and in HeLa cells was stimulated by curcumin, an inhibitor of CSN-associated kinases. These data suggest a function of the CSN in the degradation of COX-2. In addition, proteolysis of COX-2 was significantly accelerated by parecoxib, but not by celecoxib or rofecoxib. By density gradient centrifugation and immunoprecipitation we demonstrate that COX-2 physically interacts with the CSN. Moreover, COX-2 is associated with large complexes consisting of the CSN, cullin-RING Ub ligases and the 26S proteasome. Pulldown experiments with Flag-COX-2 revealed cullin 1 and cullin 4 as components of the large super-complexes. Cullin 1 and 4 are scaffolding proteins of Ub ligases that presumably ubiquitinate COX-2. Treatment of HeLa cells with parecoxib results in an accelerated degradation of endogenous COX-2 accompanied by an increase of COX-2-Ub conjugates. In HeLa cells parecoxib is converted to the selective COX-2 inhibitor valdecoxib. Addition of valdecoxib also stimulates COX-2 degradation in HeLa cells. We therefore conclude that valdecoxib specifically interacts with COX-2 and induces a conformation accessible for ubiquitination and degradation. [ABSTRACT FROM AUTHOR]

Adverse events triggered by non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drug-related intolerance reactions in medicine; they are possibly related to inhibition of cyclooxygenase-1. Coxibs, preferentially inhibiting cyclooxygenase-2, may therefore represent safe alternatives in patients with NSAID intolerance. We reviewed the literature in a systematic and structured manner to identify and evaluate studies on the tolerance of coxibs in patients with NSAID intolerance. We searched MEDLINE (1966–2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966–2006) up to December 9, 2006, and analysed all publications included using a predefined evaluation sheet. Symptoms and severity of adverse events to coxibs were analysed based on all articles comprising such information. Subsequently, the probability for adverse events triggered by coxibs was determined on analyses of double-blind prospective trials only. Among 3,304 patients with NSAID intolerance, 119 adverse events occurred under coxib medication. All adverse events, except two, have been allergic/urticarial in nature; none was lethal, but two were graded as life-threatening (grade 4). The two non-allergic adverse events were described as a grade 1 upper respiratory tract haemorrhage, and a grade 1 gastrointestinal symptom, respectively. In 13 double-blind prospective studies comprising a total of 591 patients with NSAID intolerance, only 13 adverse reactions to coxib provocations were observed. The triggering coxibs were rofecoxib (2/286), celecoxib (6/208), etoricoxib (4/56), and valdecoxib (1/41). This review documents the good tolerability of coxibs in patients with NSAID intolerance, for whom access to this class of drugs for short-term treatment of pain and inflammation is advantageous. [ABSTRACT FROM AUTHOR]

Platelet hyper-reactivity is likely to play a role in cardiovascular disease, but there are no standardized tests to evaluate platelet responsiveness. A ‘platelet chip’ (a synthetic oligonucleotide microarray representing all platelet-restricted genes) is under development as a tool for high-throughput characterization of platelet-based bleeding and clotting disorders. In future, platelet gene profiling may be used to improve thrombohemorrhagic risk assessment and to guide antiplatelet therapy for patients at risk of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To bring together the most recent evidences concerning the utility and safety of perioperative anti-inflammatory drug use. Data sources: References were obtained from computerised bibliographic data banks (MeSH terms: NSAIDs, coxibs, steroids, surgery, anaesthesia), followed by manual search. Data synthesis: NSAIDs, coxibs and steroids used alone or in association have been demonstrated to be effective for relieving postoperative pain. However, the benefice of perioperative anti-inflammatory drug use may go beyond the postoperative analgesia. In some cases, anti-inflammatory drugs have been shown to decrease the incidence of morphine side-effects, postoperative nausea and vomiting or to improve postoperative recovery. Nevertheless, NSAIDs have been found to be a risk factor of severe postoperative bleeding requiring surgical haemostasis after some surgical procedures. In contrast, coxibs have been shown to promote arterial thrombosis after others surgical procedures. [Copyright &y& Elsevier]

The aim of the present study was, first to characterize profiles of coxibs’ prescribers [general practitioners (GPs) and rheumatologists] in 2002 in France and, secondly, to identify factors associated with modification of this profile 1 year later. All GPs and rheumatologists from Midi-Pyrenees, Aquitaine, Languedoc-Roussillon and Pays de Loire areas (South of France: 11 050 000 inhabitants) were included in the study. For each practitioner, we used data concerning all non-steroidal anti-inflammatory drugs (NSAIDs) including coxibs reimbursed during period 1 (P1; January–March 2002) and period 2 (P2; January–March 2003). The ratio between the number of coxibs’ prescriptions and the total number of NSAIDs’ prescriptions (including coxibs) was used to define the two profiles of prescribers, one with a low level of coxibs’ prescriptions and another one with a high level of coxibs’ prescriptions. Characteristics of practitioners and characteristics of their practices were compared according to this profile. In the second step, we investigated the characteristics (of practitioners and practices) associated with an increase in the level of coxibs’ prescriptions in P2 for practitioners with a low level of coxibs’ prescriptions in P1. Results are expressed as odds ratio with their 95% confidence intervals. A positive statistical link was found between a high level of coxibs’ prescriptions, the speciality of rheumatologist or extra costs for consultation. In contrast, a negative association was observed with female gender or age below 44 years. No relationship was found with the status of referent. Concerning practices’ characteristics of practitioners, there was a positive statistical link between a high ratio of coxibs’ prescriptions and high co-prescriptions of gastroprotective agents and a negative association with a high number of acts, a high proportion of patients with chronic disabling diseases (CDD) or a high number of patients between 15 and 64 years. There was no statistical link with proportion of patients covered by Universal Medical Coverage (UMC) or aged more than 65 years. Among the factors involved in the increase in the ratio (between P1 and P2), no relationship was found with practitioners’ characteristics. In contrast, some factors related to practices (level of gastroprotective co-prescriptions, number of acts, number of CDD patients) were related to a change in coxibs’ prescriptions between P1 and P2. This study allowed to discuss some relationships between coxibs’ prescription and practitioners’ (age, gender, medical speciality or extra costs for consultation) or practices’ (level of medical practice, patients’ age, number of CDD patients or level of gastroprotective prescriptions) characteristics. In contrast, some other factors like the referent status or the number of patients with UMC are not related. Physicians, initially low prescribers of coxibs and increasing their coxibs’ prescriptions during the period of our study, were those with a high level of gastroprotective prescriptions, a low number of acts or a small proportion of CDD patients. [ABSTRACT FROM AUTHOR]

Abstract: Background:: Based on a PubMed search of the literature using the terms parecoxib, platelets, thromboxane, bleeding, and platelet aggregation, the effects of parecoxib on platelet function have not fully been established under clinical conditions. Objective:: The aim of this study was to determine platelet aggregation, thromboxane B2 (TxB2) formation, and plasma concentrations with the use of parecoxib in postoperative pain management. Methods:: This double-blind, randomized, parallelgroup trial was conducted at the University Hospital for Orthopedic Surgery, Friedrichsheim, Frankfurt, Germany. Male and female patients aged 18 to 55 years and scheduled to undergo routine partial meniscectomy (or a similar arthroscopic procedure) were eligible. All patients received dose-adjusted enoxaparin before surgery and parecoxib 40 mg BID or dipyrone 1000 mg QID. Blood samples were drawn before first injection (predose) and at 0.5, 2, and 6 hours after injection. Platelet aggregation (expressed as percentage of the maximal light transmittance [Amax]) was induced with arachidonic acid (AmaxAA) and collagen (AmaxCO). TxB2 formation was determined using enzyme-linked immunosorbent assay. Results:: This study included 26 patients. In both treatment groups, 8 males and 5 females, all white, were enrolled. In the dipyrone group, the mean age was 48 years (range, 32–61 years) and the mean weight was 85 kg (range, 63–122 kg); in the parecoxib group, the mean age was 47 years (range, 31–61 years) and the mean weight was 81 kg (range, 57–100 kg). Median (interquartile range [IQR]) predose values for AmaxAA were 76% (65%–83%) in the parecoxib group and 87% (80%–89%) in the dipyrone group. At 0.5 hour after injection, AmaxAA was 52% (5%–77%) with parecoxib and 8% (0%–11%) with dipyrone (P = 0.004). At 2 hours after injection, AmaxAA was 78% (72%–80%) in the parecoxib group versus 7% (5%–11%) in the dipyrone group (P < 0.001). At 6 hours after study drug administration, no treatment differences were found. For AmaxCO, no statistically significant differences were found. Consistent with the stronger inhibition of aggregation, patients who received dipyrone had lower TxB2 formation values. Six hours after parecoxib administration, mean TxB2 formation was significantly enhanced compared with predose values (132 ng/mL [IQR, 62–228 ng/mL] vs 185 ng/mL [IQR, 135–239 ng/mL]; P = 0.05). Conclusions:: Platelet aggregation and TxB2 formation were significantly lower for 6 hours in dipyronetreated patients compared with parecoxib-treated patients. In contrast, TxB2 formation was increased with parecoxib 6 hours after administration compared with pretreatment values. In this small study, parecoxib did not affect platelet aggregation in a population of patients undergoing routine partial meniscectomy (or a similar arthroscopic procedure) under clinical conditions. [Copyright &y& Elsevier]

To compare the magnitude of celecoxib versus rofecoxib on the cardiovascular risk. We performed adjusted indirect comparison of celecoxib versus rofecoxib for cardiovascular events using two data on The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial and Adenoma Prevention with Celecoxib (APC) trial. Baseline characteristics of the patients and placebos were comparable in both trials, in terms of age, sex, hypertension, diabetes mellitus, smoking, and hypercholesterolemia. The overall incidence of cardiovascular events was similar in both groups (rofecoxib 48/1,287 versus celecoxib 48/1,356, p = 0.79). The relative risks (RRs) of all myocardial infarction or sudden death from cardiac causes were increased in both rofecoxib and celecoxib groups [rofecoxib versus placebo; RR 1.35, 95% confidence interval (CI) 1.07–1.69, p = 0.03, celecoxib versus placebo; RR 1.35, 95% CI 1.14–1.51, p = 0.01]. The RRs for cardiovascular events derived from the adjusted indirect comparisons of the two coxibs did not significantly differ from unity (celecoxib versus rofecoxib; RR 0.95, 95% CI 0.76–1.19, p = 0.67). The adjusted indirect comparison analysis shows that celecoxib and rofecoxib may have similarly effect of cardiovascular events when used for 3 years. [ABSTRACT FROM AUTHOR]

Since selective cyclooxygenase-2 inhibitors (coxibs) entered the market, there has been concern about the cardiovascular safety of coxibs. In addition, recent data suggest that classical non-steroidal anti-inflammatory drugs (NSAIDs) have a similar cardiovascular risk. Importantly, all of the clinical trials with NSAIDs and coxibs so far were not purpose-designed to specifically and prospectively address cardiovascular safety and were clearly underpowered to detect any meaningful differences. In this current uncertainty about safety of NSAIDs and coxibs, the definitive answer as to the net effect of coxibs and NSAIDs on cardiovascular events can only be provided by well designed adequately powered, long-term clinical trials, which is now under way. [ABSTRACT FROM AUTHOR]

Abstract: We provide comprehensive knowledge on the differential regulation of expression and catalysis of cyclooxygenase (COX)-1 and COX-2 in health and disease which represents an essential requirement to read out the clinical consequences of selective and nonselective inhibition of COX-isozymes in humans. Furthermore, we describe the pharmacodynamic and pharmacokinetic characteristics of major traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and coxibs (selective COX-2 inhibitors) which play a prime role in their efficacy and toxicity. Important information derived from our pharmacological studies has clarified that nonselective COX inhibitors should be considered the tNSAIDs with a balanced inhibitory effect on both COX-isozymes (exemplified by ibuprofen and naproxen). In contrast, the tNSAIDs meloxicam, nimesulide and diclofenac (which are from 18- to 29-fold more potent towards COX-2 in vitro) and coxibs (i.e. celecoxib, valdecoxib, rofecoxib, etoricoxib and lumiracoxib, which are from 30- to 433-fold more potent towards COX-2 in vitro) should be comprised into the cluster of COX-2 inhibitors. However, the dose and frequency of administration together with individual responses will drive the degree of COX-2 inhibition and selectivity achieved in vivo. The results of clinical pharmacology of COX inhibitors support the concept that the inhibition of platelet COX-1 may translate into an increased incidence of serious upper gastrointestinal bleeding but this effect on platelet COX-1 may mitigate the cardiovascular hazard associated with the profound inhibition of COX-2-dependent prostacyclin (PGI2). [Copyright &y& Elsevier]

When broadband light illuminates clotting native blood, the reflectance at each wavelength traces a time course with four discernible regions. Clot formation occurs just before the second phase. Two wavelengths, 471 and 771 nm, were selected for more detailed study of the first two phases. Analysis of each time course in native blood demonstrates that both signals track a single process during the first phase, but distinct processes during the second. Experiments on citrated blood identified which blood components contribute to reflectance changes. Comparison of liquid and clotting blood reveals a single process during the first phase, entailing that rouleaux formation determines the time course at both wavelengths. Control experiments eliminate clot propagation and shape change of red cells or platelets as possible factors in the second phase. Exogenous ADP added to EDTA blood evokes the second-phase response at 471 but not 771 nm, a novel phenomenon that requires the presence of red cells. The descriptive name ‘ADP-end-response’ is suggested for this red cell process until it is further characterized. We propose that the ADP-end-response determines the 471-nm signal during the second phase of clotting native blood and depends upon platelets in the absence of exogenous ADP. The 771-nm signal reports fibrin cross-linking during the second phase. An earlier pilot study demonstrated that rofecoxib effects the 471-nm signal ex vivo, which indicates that reflectance spectroscopy may be useful in the assessment of drug effects on platelet-erythrocyte interactions. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A recent drug utilization study on antibiotics established a new indicator for evaluating appropriateness of clinical application. The calculation is based on the World Health Organization (WHO) anatomical therapeutic chemical classification system with defined daily doses (ATC/DDD) system. It combines two main indicators for drug i.e. dose and duration of treatment. The aim of current study was to describe the appropriateness of clinical application of coxibs and traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) that indicated for postoperative orthopaedics pain control.A drug utilization review of coxibs and tNSAIDs of an inpatient orthopaedics department of a private teaching hospital in the city of Seremban, Malaysia was conducted. The NSAIDs were classified and calculated according to the WHO ATC/DDD system. The formula for measuring the appropriateness of clinical application is by calculating the ratio of use density to use rate (UD/UR). A total of 195 patient records who received NSAIDs were randomly selected among 1169 cases. The tNSAIDs were dexketoprofen injection, diclofenac sodium tablet; and the coxibs were celecoxib capsule, etoricoxib tablet and parecoxib injection. The UD/UR for all NSAIDs were less than 100 except for etoricoxib tablet (105.75) and parecoxib injection (108.00). The UD/UR value more than 100, indicating a high possibility of irrational medication and may require of enhanced monitoring. The findings of this DUR study may suggest of applying new indicator for evaluating the appropriateness of clinical application of NSAIDs for postoperative orthopaedics pain control. [ABSTRACT FROM AUTHOR]

Autoimmune diseases such as rheumatoid arthritis and gastrointestinal disorders such as stomach ulcers are often treated with drugs. NSAIDs, a common treatment in rheumatoid arthritis, may cause stomach ulcers which call for additional medications, notably antacids in the sense of drugs that suppress acid secretion by the stomach. Infection with Helicobacter pylori also plays a role in the ulcers. The infection is typically treated with antibiotics added to antacids. Considering NSAIDs and antacids, we suspect that overmedication is common to the extent that particular diets are a better option. Current research and current treatments with these drugs are also problematic since circadian rhythms are mostly disregarded. All the processes involved in the disorders treated show marked variations in the course of the day. Hence experiments conforming to the guidelines of evidence-based medicine, and treatments in line with them, have outcomes strongly depending on the time factor. This calls for reforms in medicine with fresh inputs from biology. [ABSTRACT FROM AUTHOR]

Abstract: Cyclooxygenase (COX) is a rate-limiting enzyme that catalyzes the conversion of arachidonic acid, an essential fatty acid present in cell membrane phospholipids and liberated by phospholipase, into prostaglandins (PGs) and prostanoids. COX has two distinct membrane-anchored isoenzymes; COX-1 and COX-2. COX-1 is a constitutively expressed and found in most normal body tissues; COX-2 is expressed in normal tissues at low levels and is highly induced by pro-inflammatory mediators in the setting of inflammation, injury, and pain. Inhibitors of COX activity include: (1) conventional non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs); (2) selective COX-2 inhibitors (COXIBs); and (3) COX-1 inhibitors. Non-selective NSAIDs, at therapeutic doses, inhibit both COX-1 and COX-2. The anti-inflammatory benefits of these drugs are primarily derived from COX-2 inhibition, while inhibition of COX-1 often elicits gastrointestinal (GI) toxicity. Therefore, COXIBs were developed to provide a selective COX-2 agent, i.e., one, that at fully therapeutic doses demonstrated comparable therapeutic benefit to non-selective NSAIDs, without the attendant COX-1-mediated GI toxicities. In this review, we evaluate available literature describing the pathophysiologic role of cyclooxygenases and the effects of their inhibition in GI system in experimental and domestic animal species. [Copyright &y& Elsevier]

Although outpatient knee arthroscopy is probably by far the most frequently performed orthopaedic procedure, there are limited guidelines or consensus concerning the peroral postoperative pain management. A diversity of analgesics both in potency and action is prescribed. The purpose of the present investigation was to grade the pain and need for rescue medication during the first 4 days after the knee arthroscopy, comparing a conventional nonsteroidal anti-inflammatory drug (NSAID) with a selective cox-II-inhibitor (coxib) as postoperative pain medication. One hundred and twenty-two patients scheduled for primary elective knee arthroscopy in general anaesthesia were randomised to either a NSAID (lornoxicam) or a selective cox-II-inhibitor (rofecoxib) postoperatively. Pain ratings and the need for rescue medication were followed for four consecutive days. Side effects were also registered. The need for rescue analgesics was highest the evening after surgery, when 42% of patients required one, or more, oral additional analgesics. The use of rescue medication decreased with time and 30, 25, 16 and 11% of the patients required additional analgesics for day 1 to 4, respectively, still 50% of all patients required at some point one or more rescue analgesics. Overall pain ratings were low, and showed similar pattern with evening and day, 50% of all patients required at some point one or more rescue analgesics. We found, however, no differences in pain ratings, or need for rescue analgesics between the two groups, conventional NSAID and coxib as well as no difference in side-effect profile. In conclusion, patients do require proper pain management also after minor outpatient surgical procedures such as knee arthroscopy. The traditional NSAIDs seem to be the first choice for analgesic and anti-inflammatory effects, when needed after elective arthroscopy of the knee. [ABSTRACT FROM AUTHOR]

Randomised clinical trials and observational studies have shown an increased risk of myocardial infarction, stroke, hypertension and heart failure during treatment with cyclooxygenase inhibitors. Adverse cardiovascular effects occurred mainly, but not exclusively, in patients with concomitant risk factors. Cyclooxygenase inhibitors cause complex changes in renal, vascular and cardiac prostanoid profiles thereby increasing vascular resistance and fluid retention. The incidence of cardiovascular adverse events tends to increase with the daily dose and total exposure time. A comparison of individual selective and unselective cyclooxygenase inhibitors suggests substance-specific differences, which may depend on differences in pharmacokinetic parameters or inhibitory potency and may be contributed by prostaglandin-independent effects. Diagnostic markers such as N-terminal pro brain natriuretic peptide (NT-proBNP) or high-sensitive C-reactive protein might help in the early identification of patients at risk, thus avoiding the occurrence of serious cardiovascular toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Celosomy is a term used for a group of congenital anomalies characterized by opening of the somatic wall with evisceration. The most common types of celosomy are gastroschisis and omphalocele. They have been associated with maternal age, cigarette smoking, environmental pollution, as well as prenatal exposure to vasoconstrictors and recreational drugs. The aim of this study was to evaluate the effect of prenatal exposure to various selective and non-selective cyclooxygenase-2 (COX-2) inhibitors on the abdominal wall defects in rat. A retrospective statistical analysis was performed on the basis of data collected in our laboratory in the years 1997–2004, during different teratological studies with COX-inhibitors (aspirin, DFU, DuP-697, ibuprofen, paracetamol, piroxicam, propyphenazone, tolmetin). Out of 6744 live born fetuses celosomy was revealed only in four animals exposed to different non-selective COX inhibitors. A single case of gastroschisis was also found in a rat exposed to the selective COX-2 inhibitor. The fetal body weight was significantly lower in COX-exposed group of fetuses when compared with untreated control. It was also significantly decreased in non-malformed fetuses prenatally exposed to COX inhibitors when compared with untreated control. The fetal body weight and length were lower in fetuses born with gastroschisis than with omphalocele. However, when animals with both anomalies were pooled in one group the mean fetal body weight was marginally lower (p =0.0523) when compared with non-malformed group, while no statistically significant differences were found for fetal length. The pooled statistical analysis done for the concurrent and our own historic data showed that only aspirin statistically increased the risk of abdominal wall defects in rat fetuses. The expected ratio for aspirin is 56.41 per 10,000 offsprings (p <0.05), which is over 10-times higher than ratio for all non-selective COX inhibitors, including aspirin (6.01/10,000; p <0.05). No differences were found for selective COX-2 inhibitors. It could be stressed that aspirin, unlike other non-selective and selective COX-2 inhibitors increases the risk of the abdominal wall defects, which are observed more often in growth-retarded fetuses. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia in the elderly. The AD brain pathology is characterized by deposits of amyloid-β (Aβ) peptides and neurofibrillary tangles but also (among other aspects) by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. Classical targets of NSAIDs include cycloxygenase, nuclear factor κB, and peroxisome proliferator-activated receptors. Modulation of these pathways, all of which have been implicated in AD pathogenesis, could explain the NSAID effect on AD progression. However, recent studies indicate that a subset of NSAIDs such as ibuprofen, indomethacin, and flurbiprofen may have direct Aβ-lowering properties in cell cultures as well as transgenic models of AD-like amyloidosis. A renewed interest in the old and a discovery of new pharmacological properties of these drugs are providing vital insight for future clinical trials. In this review we will summarize how the combination of traditional (anti-inflammatory) and new (anti-amyloidogenic) properties of some NSAIDs is providing unprecedented opportunities for drug discovery and could potentially result in novel therapeutic approaches for the treatment of AD. [ABSTRACT FROM AUTHOR]

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Objective: To evaluate the prescription modalities of general practitioners (GPs) and specialists in symptomatic osteoarthritis (OA) patients enrolled in the AMICA study. Patients and methods: This study started in 2001 as a cohort investigation of OA patients seen by 2764 GPs and 316 specialists. Enrolled were 28,981 patients with symptomatic OA of the hand, hip, or knee. Results: GPs and physical medicine specialists treated OA less frequently with pharmacological therapy than rheumatologists (OR 0.35; CI 0.26 to 0.47) or orthopedic surgeons (OR 0.65; CI 0.54 to 0.77). Pharmacological therapies (alone or in association with nonpharmacological modalities) were selected by 97% of the GPs, 96% of the rheumatologists, 94% of the orthopedic surgeons, and 85% of the physical medicine specialists. In comparison with GPs, all of the specialists more frequently used disease-modifying OA drugs (DMOADs) (rheumatologists: OR 6.86, CI 6.03 to 7.80; orthopedic surgeons: OR 2.20, CI 1.94 to 2.49; physical medicine specialists: OR 2.11, CI 1.69 to 2.63). Nonpharmacological therapies were selected by 44% of the GPs, 54% of the rheumatologists, 71% of the orthopedic surgeons, and 90% of the physical medicine specialists. They were used alone uncommonly (by 3% of the GPs, 3% of the rheumatologists, 6% of the orthopedic surgeons, and 15% of the physical medicine specialists). GPs use nonpharmacological treatment less than specialists: OR 0.53; CI 0.47 to 0.60 versus rheumatologists; OR 0.20; CI 0.18 to 0.21 versus orthopedic surgeons; and OR 0.07; CI 0.05 to 0.09 versus physical medicine specialists. Ultrasound (US) (11%) and transcutaneous electrical nerve stimulation (TENS) (7%) were the nonpharmacological therapies most frequently prescribed by GPs. Among the specialists, physical medicine specialists most frequently prescribed US (35%) and TENS (21%); US was also preferred by rheumatologists, whereas the orthopedic surgeon''s choice was magnetotherapy (21%). Exercises and other passive or active rehabilitation strategies were prescribed for only 13% of the patients seen by GPs, but all 3 categories of specialists prescribed exercises and manual techniques far more frequently: rheumatologists, OR 1.63: 1.40 to 1.63; orthopedic surgeons, OR 1.67: 1.48 to 1.88; physical medicine specialists, OR 3.19: 2.66 to 3.82. Conclusions: Italian rheumatologists and orthopedic surgeons are the specialists who most frequently use pharmacological treatment for OA. Nonpharmacological treatment is used commonly among both GPs and specialists but rarely as single therapy. Exercise and passive or active rehabilitation strategies are not frequently prescribed, although they are recommended by all the published guidelines. [Copyright &y& Elsevier]

Five historical viewpoints are presented, each foreshadowing to some degree that it was only a matter of time before we would (re)learn that imbalanced anti-prostanoid therapy was a potentially lethal strategy. Positive outcomes from this coxib debacle might be more willingness to (i) acknowledge our lack of understanding concerning normal homeostatic mechanisms involving the autopharmacology and pleiotropic functions of prostanoids and acyclic eicosanoids (leukotrienes, lipoxins, resolvins, etc.); (ii) revisit the question of salicylate versus aspirin for therapies not requiring anti-thrombotic prophylaxis; (iii) re-examine some leads provided by natural/alternate therapies for inflammatory disorders; and (iv) reconsider the downside of over-reliance upon the present patent system as the main shield and driver of drug innovation. [ABSTRACT FROM AUTHOR]

Since their development and licencing no class of drug has received as much attention both in the scientific and lay press as the cyclo-oxygenase 2 (COX-2) inhibitors. These compounds, also known as coxibs, were developed as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs) due to their reduced propensity to cause gastrointestinal (GI) irritation. However, an unforeseen complication was identified of increased cardiovascular (CV) morbidity and mortality. This observation threw into question the true 'safety' of the class and their subsequent role, if any, in patient management. The amount of information and misinformation regarding the coxibs is vast and as this field is in a state of flux much more will be forthcoming. This article will attempt to review the data regarding coxibs and make some recommendations regarding their ongoing use. [ABSTRACT FROM AUTHOR]

In 1999, drug manufacturers introduced a class of NSAIDs called COX-2 inhibitors or coxibs. The drugs were avidly promoted directly to the consumers and became bestsellers from the start. Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain, bleeding and other side-effects. In the year after their introduction, doctors wrote over 100 million prescriptions for celecoxib (Celebrex) and rofecoxib (Vioxx). Celebrex is the sixth best-selling drug, with sales of more than US$ 4 billion since its debut in 1999. Vioxx had sales of US$ 2.6 billion in 2001. However, the coxibs increase the risk of heart attacks and strokes, and their price, in the USA, is obscene. The manufacturers faced a possibly complicit, toothless and bloodless FDA, and used every maneuvering to fleece the patients. We must now reflect on attitudes that we thought only belong to the tobacco industry. Fortunately, safe and active alternatives exist. [ABSTRACT FROM AUTHOR]

Patients suffering from menstrual migraine (MM) may be ideal candidates for an intermittent prophylaxis, usually termed short-term or mini-prophylaxis. It covers the whole period of vulnerability, e. g., the perimenstrual period, starting some days before the expected onset of MM attack. Theoretically MM attacks are an optimal target for drugs specifically developed for acute head pain. Unfortunately, due to their particular tendency to be longer, more intense and less responsive to analgesics, symptomatic approaches alone are not often able to completely control pain and its correlates. Many drugs have been proposed for short-term prophylaxis of MM. In this paper we analyse only non-steroidal anti-inflammatory drugs, coxibs and triptans (especially those with longer half-life, naratriptan and frovatriptan). Moreover, MM can be prevented by a variety of hormonal manipulations, including oral contraceptives, which may be administered with an extended-dosing strategy; oestrogen replacement therapy; antioestrogen agents (danazol, tamoxifen); gonadotropin-releasing hormone agonists followed by oestrogen add-back therapy. Finally, the use of some products, such as magnesium and phytoestrogens, that probably meet the requirements of those patients that appreciate a more “natural” approach, is discussed. [ABSTRACT FROM AUTHOR]

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Abstract: It is now established that prostanoids play important roles in many cellular responses and pathophysiologic processes including modulation of the inflammatory reaction, erosion of cartilage and juxtaarticular bone, gastrointestinal cytoprotection and ulceration, angiogenesis and cancer, hemostasis and thrombosis, renal hemodynamics, and progression of kidney disease. The initial step in the formation of prostanoids, i.e., the conversion of free arachidonic acid (AA) to prostaglandin (PG)G2 and then to PGH2, is controlled by two PGH synthases (COX-1 and COX-2). Selective inhibitors of COX-2 (coxibs) have established efficacy in the treatment of pain and inflammation comparable to that of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) but exhibit enhanced gastrointestinal safety. Several lines of evidence suggest a critical role of COX-2 expression in cancer and selective COX-2 inhibitors may represent novel chemopreventive tools. Moreover, it has been suggested that COX-2 inhibitors may contribute to maintain high levels of chemotherapeutics in tumor tissues by preventing the overexpression of the multidrug resistance protein MDR1/P-gp. The place of COX-2 inhibitors in neurological diseases continues to attract basic and clinical investigation. The possible involvement of COX-2 in neurodegeneration, substained by the results of epidemiological studies with nonselective NSAIDs, has not been confirmed by the results of initial clinical trials with coxibs in Alzheimer''s disease. Recently, the involvement of COX-2 in endogenous cannabinoid system has been suggested. Interestingly, COX-2-mediated oxygenation of arachidonylethanolamide (anandamide, AEA) and 2-arachidonylglycerol (2-AG) provides diverse sets of novel lipids that are structurally related to prostaglandins. [Copyright &y& Elsevier]

Cyclooxygenase 2-selective non-steroidal anti-inflammatory drugs (NSAIDs, coxibs) are recommended primarily for patients at high risk of gastrointestinal bleeding, most of them being elderly. Our objective was to describe and analyse patient- and physician-related factors affecting the adoption of celecoxib and rofecoxib 2 years after their launch in Finland.Retrospective analysis of the nationwide Prescription Register. Physicians who had issued at least 200 reimbursed prescriptions in 2002 (n = 12 033, 80% of working-age Finnish physicians) were involved in the analysis.Excluding patients with rheumatoid arthritis (RA), almost one-fifth (18%) of NSAIDs prescriptions were for coxibs. In patients with RA the share was 25%. The share of coxib prescriptions of all NSAIDs increased with age of the patient. Over one half (58%) of coxib prescriptions were issued for patients under 65 years of age. Specialists in physical and rehabilitation medicine were the fastest adopters of coxibs: one-third of their NSAID prescriptions in 2002 were for coxibs. Primary care physicians were the most conservative both in adopting and favouring coxibs.Coxibs have gained the status of standard prescription NSAIDs within a few years. Their use should be restricted to patients who could benefit most from the use. Routine prescribing of expensive new drugs increases the drug bill without additional health gain. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the toxicity of non-selective (tolmetin, ibuprofen and piroxicam) and selective (DFU) cyclooxygenase-2 inhibitors on pregnant and non-pregnant rats. The drugs were administered orally once (DFU, piroxicam) or three times (tolmetin, ibuprofen) a day from days 8 through 21 of gestation experiment in three doses. The initial dose was similar to the human antiinflammatory one and set as 8.5 mg/kg (tolmetin, ibuprofen), 0.3 mg/kg (piroxicam) and 0.2 mg/kg (DFU). The middle dose was increased 10 times and the highest one 100 times the initial dose. The highest dose for ibuprofen was set at 200 mg/kg due to high mortality. On gestation/experimental day 21 animals were sacrificed, blood was collected and abdominal organs were taken for pathological examination. Activity of alanine and asparate aminotransferases and levels of total protein and urea were determined. Stomach, small and large intestines, and liver were grossly and histologically examined. Dose-dependent mortality, signs of gastrointestinal toxicity, and significant changes of biochemical parameters were found in groups exposed to non-selective COX inhibitors in both pregnant and non-pregnant rats. Mild regressive structural hepatic changes were observed. Significant decrease of protein level in non-pregnant rats treated with high DFU dose, and occasionally observed gastrointestinal changes were the only changes noted in groups exposed to the selective COX-2 inhibitor. Tolerability of non-selective COX inhibitors was lower in both pregnant and non-pregnant groups when compared with DFU. Insignificant mortality and histological changes were noted between pregnant and non-pregnant groups. [Copyright &y& Elsevier]

Objectif. –Comparer les modalités de prescription du rofécoxib, un inhibiteur sélectif de la cyclo-oxygénase 2 ou coxib, à celles des anti-inflammatoires non stéroïdiens (AINS) classiques en médecine générale en France.Méthode. –Un échantillon représentatif de 1010 médecins généralistes Français a participé à ce travail. Pour toute prescription d'AINS entre le 1er juillet 2001 et le 30 juin 2002, ces médecins notaient les caractéristiques démographiques des malades, leurs antécédents et les traitements médicamenteux suivis.Résultats. –Les modalités de prescription du rofécoxib étaient comparables pour les deux formes commercialisées (12,5 et 25 mg). La proportion de malades âgés de 65 ans et plus était notablement plus élevée dans le groupe rofécoxib (48 %) que dans le groupe AINS conventionnels (37,3 %). Des antécédents d'ulcère gastroduodénal ou d'hémorragie digestive étaient plus fréquents dans le premier (4,8 %) que dans le second (2,1 %) groupe. La prise concomitante d'aspirine à visée antithrombotique ou d'un antihypertenseur était observée dans 6,1 et 34,8 % des cas, respectivement, sous rofécoxib contre 2,3 et 15,6 %, respectivement, sous AINS classiques. Le pourcentage de patients traités par un inhibiteur de la pompe à protons (IPP) ne différait pas substantiellement entre les deux groupes (16,9 % sous rofécoxib et 18,6 % sous AINS classiques). Néanmoins, le pourcentage de patients prenant un IPP avant la mise en route du rofécoxib (10,4 %) était plus élevé qu'avant celle d'un AINS classique (3,7 %). Conclusion. –Ces données montrent que les ... [Copyright 2004 Elsevier]

To compare the efficacy and adverse effects of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with naproxen, a non-steroidal anti-inflammatory drug, and placebo in the treatment of painful temporomandibular joints (TMJs). In this randomized, double-blind, placebo-controlled trial, 68 subjects with painful TMJs secondary to disc-displacement with reduction, received celecoxib 100 mg twice a day; naproxen, 500 mg twice a day; or placebo for 6 weeks. Subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analogue scale, maximal comfortable mandibular opening, and quality of life (SF-36), at baseline (1 week after discontinuing previous analgesic therapy) and again after 6 weeks of drug treatment. Naproxen significantly reduced the symptoms of painful temporomandibular joint disc-displacement (TMJ DD) with reduction as determined by most efficacy measures. Significant improvement in pain intensity occurred within 3 weeks of treatment, and was sustained throughout the 6-week study. Clinically significant improvement in mandibular range of motion was observed for naproxen compared to celecoxib and placebo. Celecoxib showed slightly better pain reduction than placebo, but was not significantly effective for temporomandibular disorder pain. Celecoxib and naproxen were well tolerated, with similar number of reported adverse effects. Dual COX-1 and COX-2 inhibition with naproxen was demonstrated to be effective for the treatment of painful TMJs, as seen by significant improvement in clinical signs and symptoms of TMJ DD with reduction compared to celecoxib and placebo. Inhibition of both COX isozymes is needed to achieve effective analgesia for this type of musculoskeletal pain. [Copyright &y& Elsevier]

Non steroidal anti-inflammatory drugs (NSAIDs) are one of the categories of drugs most frequently used by elderly people, and maybe the most self-prescribed drugs. Both coronary events, and stroke, can be prevented by daily aspirin assumption. Other NSAIDs, except selective COX-2 inhibitors (coxibs), seem to reduce the incidence of cardiovascular events, but a definitive judgement is yet impossible. Moreover, these drugs cause more than 100,000 serious gastric adverse events each year in the US, and the risk increases exponentially in the elderly. Coxibs cause less gastric damage, but their cost is very high. Moreover, NSAIDs inhibit renal function and reduce the efficacy of diuretics and angiotensin converting enzyme (ACE) inhibitors, often used by elderly patients. Recent studies show that even COX-2 is important in the renal physiology, so that even coxibs appear not to be avoided of renal toxicity. Both gastric and renal toxicity induced by traditional NSAIDs and coxibs seem to be related to the fact that these drugs inhibit the synthesis of prostaglandins (PGs), but not those of leukotrienes (LTs), important mediators of inflammation and of many other physiopatological events. Newly developed anti-inflammatory drugs block both COX and the 5-LOX metabolic pathways, inhibiting the formation of PGs, thromboxanes (TXs) and LTs. The inhibition of the LT synthesis increases the anti-inflammatory efficacy (especially in pneumological and rheumatological diseases), reducing the risk of gastric damage. Even if preliminary data seem to be very interesting, further clinical safety data on these drugs obtained from elderly oriented trials need to be available before to give a final evaluation. [Copyright &y& Elsevier]

Cyclooxygenase-2 (COX-2) is an inducible enzyme that regulates prostaglandin synthesis and is overexpressed at sites of inflammation and in several epithelial cancers. Recently, a causal link for COX-2 in epithelial tumorigenesis was shown in genetically-manipulated animal models of colon and breast carcinoma. Data indicate that COX-2 is involved in the regulation of apoptosis, angiogenesis, and tumor cell invasiveness, which appear to contribute to its effects on tumorigenesis. Multiple studies have shown that nonselective COX and selective COX-2 inhibitors effectively prevent experimental colon cancer. Furthermore, sulindac and the selective COX-2 inhibitor celecoxib were shown to regress colorectal polyps in patients with familial adenomatous polyposis. Although the exact anti-tumor mechanisms of these agents await further study, data indicate that both COX-dependent and COX-independent mechanisms may be important. In this review, the association between COX-2 and colorectal tumorigenesis and potential mechanisms of this effect are discussed. Additionally, evidence supporting the role of NSAIDs and selective COX-2 inhibitors for the prevention and treatment of human colorectal cancer is reviewed. [ABSTRACT FROM AUTHOR]

Emerging data indicate a link between genetic instability and up-regulation of cyclooxygenase-2 (COX-2). To see if individuals at high risk of oral cancer are candidates for treatment with selective COX-2 inhibitors (coxibs), levels of COX-2 expression in healthy, premalignant and cancerous oral mucosa were compared with the occurrence of DNA ploidy status as a genetic risk marker of oral cancer. COX-2 gene product was evaluated immunohistochemically in 30 healthy persons, in 22 patients with dysplastic lesions without previous or concomitant carcinomas, and in 29 patients with oral carcinomas. The immunohistochemical findings were verified by western blotting. COX-2 expression was correlated to DNA content as a genetic risk marker of oral cancer. COX-2 was up-regulated from healthy to premalignant to cancerous oral mucosa. Thus, COX-2 expression was found in 1 case of healthy oral mucosa (3%). All specimens from healthy mucosa had a normal DNA content. In patients with premalignancies. In 29 patients with oral carcinomas, cyclooxygenase-2 expression was observed in 26 (88%), and aneuploidy was observed in 25 cases (94%, P=0.04). Notably, of 22 patients with dysplastic lesions, COX-2 was exclusively expressed in a subgroup of nine patients (41%) identified to be at high risk of cancer by the aberrant DNA content of their lesions. Seven of these patients were followed for 5 years or more. An oral carcinoma developed in six of them (85%; P=0.02). These findings emphasize the need to determine whether coxibs can reduce the risk of oral cancer in patients with high-risk precancerous lesions. [Copyright &y& Elsevier]

Presents an index related to pharmacology published in the June 15, 2003 issue of the journal 'Alimentary Pharmacology & Therapeutics.'

Objective and methods. – To evaluate patients’ opinions about the gastrointestinal safety and areas for improvement of conventional nonsteroidal antiinflammatory drug (NSAID) therapy for musculoskeletal pain, the Louis Harris Institute conducted a survey in 401 patients selected in France using a quota sampling method.Results. – Three hundred and five patients (76%) described their pain as incapacitating. Nearly, one-third of the patients (125/401, 31%) reported gastrointestinal side effects, which prompted endoscopy in 24 (24/125, 20%) and gastroprotective drug treatment (usually by a proton pump inhibitor) in 100 (100/125, 82%). NSAID discontinuation or dosage reduction because of gastrointestinal side effects occurred in 55 patients (55/125, 45%), at the cost of symptom exacerbation, including worse pain, in over half the cases. Among the 401 patients, 304 (76%) wanted more effective NSAIDs and 174 (43%) wanted better gastrointestinal tolerability.Conclusion. – Under everyday conditions, the use and effectiveness of conventional NSAID therapy are limited by gastrointestinal side effects. Furthermore, patients want NSAIDs with better risk/benefit ratios to control musculoskeletal pain. [Copyright &y& Elsevier]

Objective and methods. – To evaluate patients’ opinions about the gastrointestinal safety and areas for improvement of conventional nonsteroidal antiinflammatory drug (NSAID) therapy for musculoskeletal pain, the Louis-Harris Institute conducted a survey in 401 patients selected in France using a quota sampling method.Results. – Three hundred and five patients (76%) described their pain as incapacitating. Nearly one-third of the patients (125/401, 31%) reported gastrointestinal side effects, which prompted endoscopy in 24 (24/125, 20%) and gastroprotective drug treatment (usually by a proton pump inhibitor) in 100 (100/125, 82%). NSAID discontinuation or dosage reduction because of gastrointestinal side effects occurred in 55 patients (55/125, 45%), at the cost of symptom exacerbation, including worse pain, in over half the cases. Among the 401 patients, 304 (76%) wanted more effective NSAIDs and 174 (43%) wanted better gastrointestinal tolerability.Conclusion. – Under everyday conditions, the use and effectiveness of conventional NSAID therapy are limited by gastrointestinal side effects. Furthermore, patients want NSAIDs with better risk/benefit ratios to control musculoskeletal pain. [Copyright &y& Elsevier]

Background. Non-steroidal anti-inflammatory drugs (NSAID) are important for the treatment of inflammation and pain. In equal doses these drugs provide more or less equal effects. As a result of the prostaglandin inhibition they cause gastrointestinal adverse effects, disturbances of kidney function and blood coagulation. Clinically significant are their gastrointestinal adverse effects, manifested as perforations, ulcerations and hemorrhages. Non-steroidal anti-inflammatory drugs differ in their potency of inhibition of two cyclooxygenase isoforms. Their adverse effects are primarily due to the inhibition of constitutive cyclooxygenase 1. Consequently, the treatment of choice is a less harmful nonsteroidal anti-inflammatory drug, which is a less potent inhibitor of cyclooxygenase 1. The newer drugs of the class of coxibs have a less potent effect on the gastrointestinal prostaglandins, so they cause fewer gastrointestinal adverse effects, however they inhibit the constitutive cyclooxygenase 2 in the kidneys. In this way they reduce prostaglandin synthesis and blood flow in the kidneys. Contraindications for their use are similar to those characteristic of conventional nonsteroidal anti-inflammatory drugs, especially heart and kidney failure, gastrointestinal ulcerations and bleeding, and inflammatory bowel disease. An additional new indication has been established for these drugs – treatment of familial adenomatous polyposis.Conclusions. The conventional nonsteroidal anti-inflammatory agents are relatively safe drugs when used in lower doses and for the shortest possible time. Safe use of these drugs is based on correct intake, careful selection of patients and protection of patients who present with risk factors for gastrointestinal adverse effects.

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed pharmacological groups, especially in elderly patients., Areas Covered: The main GI and CV adverse events associated with NSAID use are reviewed. Risk factors and prophylactic strategies are also covered., Expert Opinion: COX-2 selective agents are safer to the GI tract but have a worst CV profile. On the contrary, naproxen seems safer for CV system, but it is one of the NSAIDs with higher GI toxicity. Co-therapy with aspirin reduces the GI benefits of COX-2 selective agents, whereas ibuprofen and naproxen may neglect the antiplatelet effect of aspirin. NSAIDs increase the risk of both upper and lower GI complications. Co-therapy with PPI reduces the risk of upper but not lower GI complications, and seems to induce dysbiosis in the small bowel, which may be implicated in the damage induced by NSAIDs. Celecoxib, a COX-2 selective agent, seems safer for both the upper and the lower GI tract. Prescription of type and dose of NSAIDs must be individualized based on the stratification of the CV and GI risk of patients.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes., Objective: In the present study, a new series of 2-substituted benzoxazole derivatives 2(a-f) and 3(ae) were synthesized in our lab as potent anti-inflammatory agents with outstanding gastro-protective potential. The new analogs 2(a-f) and 3(a-e) were designed depending upon the literature review to serve as ligands for the development of selective COX-2 inhibitors., Methods: The synthesized analogs were characterized using different spectroscopic techniques (FTIR, 1 HNMR, 13 CNMR) and elemental analysis. All synthesized compounds were screened for their binding potential in the protein pocket of COX-2 and evaluated for their anti-inflammatory potential in animals using the carrageenan-induced paw edema method. Further 5 compounds were selected to assess the in vivo anti-ulcerogenic activity in an ethanol-induced anti-ulcer rat model., Results: Five compounds (2a, 2b, 3a, 3b and 3c) exhibited potent anti-inflammatory activity and significant binding potential in the COX-2 protein pocket. Similarly, these five compounds demonstrated a significant gastro-protective effect (**p<0.01) in comparison to the standard drug, Omeprazole., Conclusion: Depending upon our results, we hypothesize that 2-substituted benzoxazole derivatives have excellent potential to serve as candidates for the development of selective anti-inflammatory agents (COX-2 inhibitors). However, further assessments are required to delineate their underlying mechanisms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)