Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry - Volume 12, Issue 1, 2013

Throughout the history of cardiology, physicians have attempted to treat cardiac inflammatory diseases in a multitude of different ways. In recent years, three major developments have confirmed the important role of antiinflammatory drugs in cardiology: the development of new, more powerful drugs, the advent of evidence-based medicine, and the decline of rheumatic disease in western countries. Thus, we aim to review the indications for anti-inflammatory drugs in pericarditis and myocarditis. The management of pericarditis has been improved following the publication of the European guidelines in 2004. Indeed, recent randomized controlled trials highlighted the role of colchicine to i) prevent and treat recurrences of acute pericarditis and ii) prevent post pericardiectomy syndrome and its complications. With regard to the management of myocarditis, significant advances have been made towards further understanding the mechanisms involved, and in the identification of its underlying causes (especially viral vs. autoimmune). In addition, cardiac MRI and endomyocardial biopsy are now used to detect rare etiologies of myocarditis, which may benefit from immunosuppressive therapy (giant cell and eosinophilic myocarditis, cardiac sarcoidosis). Although broad consensus has yet to be reached regarding the management of acute myocarditis, identifying viral vs. autoimmune myocarditis allows a tailored treatment using antiviral or immunosuppressive drugs.

Although colchicine, a natural product, is one of the oldest drugs still currently available, its possible functions seem to be surprisingly not well-known. Beyond its present medicinal use (gout, familial Mediterranean fever, Behcet's disease, chondrocalcinosis and other crystal arthritis), numerous other conditions have been recently proposed for the use of this drug, including pericardial diseases. However, colchicine appears as a double-edged sword, with underestimated toxicity and frequent side effects. In this review, we present the main pharmacologic features of this drug, with an emphasis on toxicity and highlight its possible applications in the cardiovascular field.

Although heart failure is predominantly caused by cardiovascular conditions such as hypertension, coronary heart disease and valvular heart disease, it can also be caused by adverse drug reactions. Several medications have been shown to have cardiotoxic effects. Among those therapeutic agents, anti-inflammatory drugs, including exogenous glucocorticoids, nonsteroidal anti-inflammatory drugs and biologics, which are used to treat a broad range of diseases that are associated with inflammatory processes, are widely prescribed in clinical practice. In this review, we discuss insights from experimental models on the beneficial and cardiotoxic effects of anti-inflammatory drugs.

Due to the widespread use of anti-inflammatory drugs in clinical practice in various clinical settings and the ease of issue without prescription, many patients are exposed to risks associated to these drugs and particularly to drug interactions. The purpose of this review is to deal with the safety parameters of main anti-inflammatory agents, especially NSAIDs including coxibs, and the different drug interactions with a special emphasis on clinical relevance and recommendations in current practice. We will present consecutively different interactions between anti-inflammatory agents and frequently used drugs. In particular, association between anti-inflammatory drugs and anticoagulants could induce severe complications. Hemorrhagic complications and particularly gastrointestinal bleeding will be discussed together with potential treatment adjustment and likely benefits of new therapies such as specific antagonist of active factor X or II. On the other hand, anti-hypertensive therapies, non specific cytochrome dysregulations and particularly the question of antiarrhythmic drugs, the problem of proton pump inhibitors and specific clinical settings such as drug interactions in elderly are discussed.

Recognition that inflammation may contribute to the pathogenesis of various cardiac diseases has naturally led to the evaluation of the therapeutic potential of a range of anti-inflammatory approaches. Unfortunately, results in most settings have been disappointing. The majority of novel approaches fail despite promising preclinical data, partly attributable to off-target effects. The purpose of this review, focused on inflammation following acute myocardial ischemia, is to give a brief overview of the new insights regarding research on pro-inflammatory signaling cascades that could be targeted for cardioprotective therapeutic developments.

Anti-inflammatory drugs consist of non-steroidal anti-inflammatory drugs (NSAIDs) including non-selective nsNSAIDs, aspirin, and cyclooxygenase-2 (COX-2)-selective inhibitors also referred to as coxibs, and glucocorticoids (GCs). They are worldwide prescribed drugs for many musculoskeletal conditions, such as osteoarthritis and inflammatory rheumatic diseases. Anti-inflammatory drugs can exert deleterious effects on the cardiovascular system, excluding aspirin. NSAIDs, especially coxibs, have been demonstrated to increase cardiovascular risk and have generated many concerns leading to the reassessment of their benefit/risk ratio. GCs may also induce cardiovascular events, but evidence seems to be less clear. Before prescribing these drugs, an assessment of cardiovascular risk may be judicious. In this review, anti-inflammatory drugs, coxibs, nsNSAIDs and GCs, and the risk of cardiovascular events will be discussed.

Patients with chronic inflammatory diseases such as rheumatoid arthritis have a higher risk of cardiovascular diseases and related mortality compared to the general population. This risk is first due to classical cardiovascular risk factors but also due to systemic inflammation which is independently involved, causing accelerated atherosclerosis, myocardial infarction, cerebrovascular disease and heart failure (HF). Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 and IL-6 could be major actors on this pathophysiology. Biologics are effective specific treatments in the management of inflammatory rheumatic and systemic diseases. In this review, beneficial and deleterious effects on the heart and vessels of the biologics used in the management of inflammatory arthritis and vasculitides will be discussed, focusing on TNF-alpha, IL-6 and IL-1 blockades, and anti-CD20. Noninflammatory cardiac conditions, such as heart failure, myocardial infarction, and cardiovascular conditions such as atherosclerosis, as well as inflammatory diseases including vasculitides will be discussed.

Inflammatory process is strongly associated with cardiac arrhythmia, either as a cause or a consequence. Antiinflammatory drugs are widely prescribed, and some of them have been associated with an increased cardiovascular risk. Then, the eventual pro- or anti-arrhythmic effect of these drugs is of high interest for clinical practice. This review summarizes pro- and anti-arrhythmic effects of anti-inflammatory drugs, based on the analysis of published clinical trials. Cardiac arrhythmias are divided into atrial fibrillation (AF) and ventricular arrhythmias. Based on the literature and on pathophysiology, post-operative AF and post-ablative AF are analyzed separately. After a brief overview of fundamental mechanisms of arrhythmia and their relationship to inflammation, we thought to examine corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and colchicine effects on cardiac arrhythmias. All anti-inflammatory drugs have demonstrated anti-arrhythmic properties in post operative AF. Apart from this specific condition, NSAIDs and corticosteroids increase the risk of AF. Regarding ventricular arrhythmias the effects of these drugs are not well established and would require further investigations.

Xanthine oxidoreductase (XOR) catalyzes the final two reactions that lead to uric acid formation. XOR is a complex molibdoflavoenzyme present in two different functional forms: dehydrogenase and xantine oxidase (XO). XO is a critical source of reactive oxygen species (ROS) that contribute to vascular inflammation. Under normal physiological conditions, it is mainly found in the dehydrogenase form, while in inflammatory situations, posttranslational modification converts the dehydrogenase form into XO. These inflammatory conditions lead to an increase in XO levels and thus an increased ROS generation by the enzymatic process, finally resulting in alterations in vascular function. It has also been shown that XO secondarily leads to peroxynitrite formation. Peroxynitrite is one of the most powerful ROS that is produced by the reaction of nitric oxide and superoxide radicals, and is considered to be a marker for reactive nitrogen species, accompanied by oxidative stress. Febuxostat is a novel nonpurine XO-specific inhibitor for treating hyperuricemia. As febuxostat inhibits both oxidized and reduced forms of the enzyme, it inhibits the ROS formation and the inflammation promoted by oxidative stress. The administration of febuxostat has also reduced nitro-oxidative stress. XO serum levels are significantly increased in various pathological states such as inflammation, ischemia-reperfusion or aging and that XO-derived ROS formation is involved in oxidative damage. Thus, it may be possible that the inhibition of this enzymatic pathway by febuxostat would be beneficial for the vascular inflammation. In animal models, febuxostat treatment has already demonstrated anti-inflammatory effects, together with the reduction in XO activity. However, the role of febuxostat in humans requires further investigation.

This mini review targets the inclusion of recent selected citations, between the year 2006 and 2012, that implement the qRT-rtPCR technology in their experimental designs, targeting the uncovering of the mechanism of food allergy. In addition, this same technology was implemented in specific experimental designs, aiming at finding novel nutritional, herbal medicine, and tolerance interventions against food allergy. The approach of using qRT-rtPCR technology helped in studying the dynamics of transcription of cytokines and chemokines in intestinal dendritic cells of the experimental animals during the allergic reaction to food. The suppression of transcription of specific cytokines or chemokines by nutritional, herbal medicine, and tolerance interventions was instrumental in the search for finding novel remedies for this health condition, that was traditionally managed by avoidance of offending foods in the diet.