Current Pharmaceutical Design - Volume 13, Issue 22, 2007

For the last two years the field of COX inhibition has been involved in an intense and hot debate regarding the benefits and risks associated with the use of these drugs. For years, the benefits of these drugs were focused on the relief of pain and inflammation of different rheumatic conditions and the side effects on those located in the upper gastrointestinal tract. The introduction of the COX-2 selective inhibitors in the market brought new hope since the hypothesis was that these drugs were as effective as non-selective NSAIDs in treating rheumatic conditions, were associated with less gastrointestinal (GI) side effects than non-selective NSAIDs and were potentially useful in the treatment and prevention of different gastrointestinal and non-gastrointestinal malignancies. It was one of those long-term colon cancer prevention trials which showed that the use of rofecoxib was associated with increased incidence of vascular occlusive diseases vs. placebo [1]. Other studies have now shown that the effect observed with rofecoxib was not drug-specific, but extensive to all COX-2 selective inhibitors and probably to all non-selective NSAIDs [2,3]. Furthermore, the mechanisms behind these cardiovascular side effects are far from being clear. The COX-2 selective inhibition of endothelial derived prostacycline and the lack of inhibition of the COX-1 platelet dependent thromboxane synthesis do not fully explain the cardiovascular side effects associated with coxibs or non-selective NSAIDs. Now, more than two years after the withdrawal of rofecoxib from the market, there is a new situation and a new perspective for the use of these compounds, where many questions that were open then haven been, at least partially, answered. This issue of the Current Pharmaceutical Design Journal is written under the new perspective and focused on the effects of COX inhibition in rheumatology, in the cardiovascular system and overall in the gastrointestinal tract with an extensive update of the information available for traditional NSAIDs, celecoxib, rofecoxib and the newer coxibs available in the market. Under the general title of “COX-2 INHIBITION IN GASTROENTEROLOGY AND RHEUMATOLGY: CURRENT CHALLENGES AND PERSPECTIVES FOR THE FUTURE”, the first article is an extensive “in deep” review up to June 2006 of our current knowledge of the cardiovascular effect of COX-2 and/or COX-1 inhibition including the clinical manifestations and the mechanisms involved in those side effects. This article has been written by Prof. Badimon’s group that have made seminal contributions in the field of the cardiovascular system [4]. The next one is written by Dr. Herbert Baraf, a renowned expert on the rheumatology field, and it is mainly focused on the efficacy of the newest COX-2 selective inhibitors (etoricoxib and lumiracoxib) in patients suffering from different rheumatic conditions. The article has put the information in clear perspective when compared to non-selective NSAIDs and other COX-2 selective inhibitors and taking into account the potential side effects derived from their use [5]. From a GI perspective, Professor Richard Hunt and Dr Yuan from MacMaster University have written another extensive and outstanding review of the information available for both lumiracoxib and etoricoxib [6]. One of the most difficult questions in clinical practice is the management of patients who need NSAIDS and are taking low-dose aspirin. This is a frequent clinical situation that can be seen in more than 20% of patients who need NSAIDs. The combination of these drugs increases the risk of GI complications and probably the risk of developing cardiovascular side effects. Dr Sopena and myself have tried to put the issue in perspective and come out with practical recommendations based on the available evidence [7]......

Selective inhibitors of cyclooxygenase-2 (COX-2) were designed to minimize gastrointestinal complications of traditional non-steroidal anti-inflammatory drugs (NSAIDs) attributed to the suppression of COX-1-derived prostanoids. Selective COX-2 inhibitors (coxibs) are effective anti-inflammatory and analgesic drugs. However, recently it has become apparent that some coxibs increase the risk of serious cardiovascular events, including myocardial infarction and stroke. This has led to the withdrawal of rofecoxib from markets and has raised the concern about an inherent atherothrombotic risk of this class of drugs. This question should be carefully analyzed in the light of the current knowledge on COX-2 functions in the cardiovascular system. COX-2 is regarded as an inducible enzyme involved in the pathophysiology of inflammation and pain. In the cardiovascular system, COX-2 has also been associated with proinflammatory/ pro-atherogenic stages, due to its up-regulation in monocyte-derived macrophages present in atherosclerotic lesions. However, experimental and clinical studies suggest that COX-2 is “constitutively” expressed in some tissues, among them in the vascular endothelium, where COX-2-derived prostanoids, especially prostacyclin (PGI2), contribute in the maintenance of vascular homeostasis and integrity. This review provides an updated overview on the functions of COX-2 in the cardiovascular system addressing key issues that could help to understand why chronic COX-2 inhibition may have undesirable effects in patients at cardiovascular risk.

Non-steroidal antiinflammatory drugs (NSAIDs) are standard treatment for the pain and inflammation associated with arthritis. Traditional NSAIDs and cyclooxygenase-2 (COX-2) selective inhibitors exhibit comparable efficacy, with different safety profiles. Traditional NSAIDs are associated with an increased risk of serious gastrointestinal (GI) adverse events versus COX-2 selective inhibitors, and chronic use frequently necessitates adjunctive therapy with gastroprotective agents. COX-2 selective inhibitors are often used in preference to avoid these GI adverse events. Recent studies have raised the concern that COX-2 selective inhibitors and traditional NSAIDs appear to be associated with a higher incidence of thrombotic cardiovascular events versus placebo. The key in prescribing these agents is for the physician to take a proactive approach to patient management and evaluation of GI and cardiovascular risk factors. This review examines the role of the newest COX-2 selective inhibitors, etoricoxib and lumiracoxib, in treating rheumatic disease.

Cyclo-oxygenase (COX)-2 selective inhibitors (coxibs) were designed to reduce the incidence of gastrointestinal (GI) adverse events (AEs) which occur with non-selective NSAIDs (ns-NSAIDs). Etoricoxib and lumiracoxib are regarded as second generation coxibs because of their higher COX-2 selectivity. There are three published pooled analyses relating to the GI tolerability of etoricoxib (60-120mg/day) and lumiracoxib (200-400mg/day) which used individual patient's data from studies sponsored by the manufacturers. We also reviewed new clinical trials published after the pooled analyses, to determine the global GI safety profiles of etoricoxib and lumiracoxib. We included discontinuations due to GI events, endoscopic ulcers, symptomatic ulcers, and ulcer complications. Current evidence suggests that etoricoxib and lumiracoxib have significantly more favorable GI profiles than ns-NSAIDs, and are similar to first generation coxibs with respect to GI safety. The most clinically important benefit of the coxibs is seen in the reduced rate of symptomatic ulcer and ulcer complications, which are still common in chronic NSAIDs users especially in high risk patients. In the largest GI outcome study of any coxib, TARGET, involving more than 18000 patients, lumiracoxib was associated with a 79% reduction in ulcer complications in patients not taking aspirin. The differences between etoricoxib or lumiracoxib and ns-NSAIDs in relation to ulcer complications are apparent early during treatment and remain constant over time during the course of treatment; therefore, benefit of etoricoxib and lumiracoxib can be seen in patients with high GI ulcer complication risk who require NSAIDs from the beginning of use to throughout the prescription duration.

NSAIDs are widely used all over the world. NSAID use is rising due to increasing availability without a prescription, use of aspirin for prevention of thrombotic disorders and the ageing population. Aspirin is used as an analgesic drug in many countries, but the main current indication is low-dose aspirin for the prevention of cardiovascular events. However, NSAIDs and aspirin use account for approximately 20-25% of all reported drug adverse events. Most of those are gastrointestinal including dyspepsia, hemorrhage, perforation and even death. The COX-2- selective inhibitors (coxibs) have demonstrated equivalent efficacy to nonspecific NSAIDs in the management of arthritis and pain but have less gastrointestinal adverse events, although coxibs and probably all NSAIDs, significantly increase risk of serious thromboembolic events. Concomitant use of low-dose aspirin is present in more than 20% of all patients taking either NSAIDs or coxibs, thus increasing the risk of gastrointestinal side effects. Furthermore, at present, it is not known whether aspirin decreases the cardiovascular risks of COX-2 inhibitors or NSAIDs. Appropriate strategies for gastrointestinal risk reduction with NSAIDs and aspirin must consider the overall health status of our patients including the presence of cardiovascular and gastrointestinal risk factors. Use of the lowest possible dose of these drugs, gastroprotectants, especially proton pump inhibitors and Helicobacter pylori eradication will reduce the risk of gastrointestinal side effects in patients taking low-dose aspirin and NSAIDs or coxibs

Epidemiological studies have shown that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction of gastrointestinal cancer risk. Since up-regulation of COX-2 has been reported in different stages of the esophageal and gastric carcinogenic sequence, the cyclooxygenase-2 selective inhibitors (COXIBs) were considered a good alternative to traditional NSAIDs since they cause less injury to the gastrointestinal mucosa. However, recent chemoprevention trial data reporting an increased risk of cardiovascular events have raised serious concerns on the safety of COXIBs in chemoprevention strategies. Moreover, low expression of COX-2 has been reported in a subset of gastrointestinal cancers due to COX-2 methylation, indicating that these patients could be less responsive to treatment by specific COX-2 inhibitors. Furthermore, the COX-1 isoform may have a potential role in the angiogenic process associated with esophageal adenocarcinoma, which suggests that inhibition of COX-1 may be another effective therapeutic target in upper gastrointestinal cancer. Finally, lipoxygenase-derived products may be increased following COX-inhibition due to shunting of the arachidonic acid metabolism. Specifically, the 5-LOX pathway seems to be relevant in gastrointestinal cancer development. Taken together, these data indicate that a re-evaluation of potential chemoprevention strategies for cancers of the upper gastrointestinal tract needs to be considered.

In the third millennium preventive medicine is becoming a corner stone in our concept of health. Colorectal cancer (CRC) fits the criteria of a disease suitable for prevention interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths annually. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 10-15 years, providing a window of opportunity for effective interventions and prevention. Indeed, CRC is preventable in up to 90% of the cases. Simple life style modifications (balanced diet avoidance of smoking and alcohol, and moderate physical activity) can prevent up to 50% of the cases of colorectal cancer. compliance with current screening methods is a major barrier to the achievement of optimal results, a large part of the average risk population has not been screened by any method. Several newly developed screening modalities, such as the virtual colonoscopy and stool genetic testing may improve compliance. In addition, chemoprevention, a new science that has emerged during the last decade, presents an alternative approach to reducing mortality from colorectal cancer as well as other cancers. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent or even reverse the development of adenomas in the large bowel. In light of the recent evidence of the efficacy of chemoprevention in persons at high risk for CRC cancer, it seems only appropriate to consider similar strategies for the general population.

The widespread emergence of pathogenic bacterial strains with resistance to antibiotics is becoming a serious threat to public health. Continuous development of novel antibacterials therefore remains one of the biggest challenges to science and unmet needs in the clinics. The biosynthetic pathway of bacterial peptidoglycan, an essential building block of cell walls, has been well studied and appears to be a rich source of attractive enzyme targets for new antibacterials. We have therefore reviewed the intracellular part of peptidoglycan biosynthesis, including the enzymes GlmS, GlmM, GlmU for formation of UDP-GlcNAc, subsequent pentapeptide synthesis by MurAMurF, and its connection to lipid carrier by MraY and MurG. Naturally occurring inhibitors and the development of low-molecular weight inhibitors of the intracellular part of peptidoglycan synthesis are presented.

Neither any neuroprotective drug has been shown to be beneficial in improving the outcome of severe traumatic brain injury (TBI) nor has any prophylactically-induced moderate hypothermia shown any beneficial effect on outcome in severe TBI, despite the optimism generated by preclinical studies. This contrasts with the paradox that hypothermia still is the most powerful neuroprotective method in experimental models because of its ability to influence the multiple biochemical cascades that are set in motion after TBI. The aim of this short review is to highlight the most recent developments concerning the pathophysiology of severe TBI, to review new data on thermoregulation and induced hypothermia, the regulation of core and brain temperature in mammals and the multiplicity of effects of hypothermia in the pathophysiology of TBI. Many experimental studies in the last decade have again confirmed that moderate hypothermia confers protection against ischemic and non-ischemic brain hypoxia, traumatic brain injury, anoxic injury following resuscitation after cardiac arrest and other neurological insults. Many posttraumatic adverse events that occur in the injured brain at a cellular and molecular level are highly temperature-sensitive and are thus a good target for induced hypothermia. The basic mechanisms through which hypothermia protects the brain are clearly multifactorial and include at least the following: reduction in brain metabolic rate, effects on cerebral blood flow, reduction of the critical threshold for oxygen delivery, blockade of excitotoxic mechanisms, calcium antagonism, preservation of protein synthesis, reduction of brain thermopooling, a decrease in edema formation, modulation of the inflammatory response, neuroprotection of the white matter and modulation of apoptotic cell death. The new developments discussed in this review indicate that, by targeting many of the abnormal neurochemical cascades initiated after TBI, induced hypothermia may modulate neurotoxicity and, consequently, may play a unique role in opening up new therapeutic avenues for treating severe TBI and improving its devastating effects. Furthermore, greater understanding of the pathophysiology of TBI, new data from both basic and clinical research, the good clinical results obtained in randomized clinical trials in cardiac arrest and better and more reliable cooling methods have given hypothermia a second chance in treating TBI patients. A critical evaluation of hypothermia is therefore mandatory to elucidate the reasons for previous failures and to design further multicenter randomized clinical trials that would definitively confirm or refute the potential of this therapeutic modality in the management of severe traumatic brain injuries.