Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 3, Issue 2, 2004

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in the world and the impact of this respiratory pathology is expected to increase over the coming years. Currently available information suggests that genetic factors, environmental factors and genotype-environment interactions influence the disease. This complex pathology is characterised by airflow obstruction, which is generally progressive and largely irreversible. It is always associated with structural remodeling and chronic inflammation of the respiratory tract and neutrophils, macrophages and CD8+ lymphocytes all appear to participate in the inflammatory process. Several therapeutic classes of compounds are used in the treatment of COPD such as bronchodilators, corticosteroids and antibiotics (in the treatment of exacerbations caused by bacterial infections). Although these therapies improve the clinical symptoms and decrease the airway inflammation, they do not reduce significantly the long-term progression of the disease. Thus, new drugs that may affect the underlying causes of COPD such as the inflammatory and destructive processes of the disease are required. The aim of this review is to provide a critical evaluation of current pharmacotherapy in COPD and an overview of new therapeutic strategies for the treatment of this progressive disorder.

New dimensions in our understanding of immune cell trafficking have been opened by the discovery of chemokines and their receptors. This family of chemo-attractant cytokines shares a high degree of structural homology, performing essential roles in the recruitment and subsequent positioning of leucocyte subsets within tissue microenvironments. Diverse roles have been demonstrated in inflammation, tumorigenesis and haematopoiesis, in addition to crucial roles in tissue and lymphoid development. Investigation of chemokine networks offers a novel approach to many of the poorly understood mysteries of persistent inflammatory diseases such as rheumatoid arthritis, where evidence is mounting that the inappropriate temporal and spatial expression of chemokines and / or their receptors may impair the resolution of leucocyte infiltrates, thereby giving rise to persistent inflammation. However, while they offer ready targets for pharmacological intervention, the complexity of chemokine / chemokine receptor interactions renders their therapeutic manipulation in clinical practice challenging. We review the structure and function of chemokines and their receptors, and discuss the problems involved in potential therapeutic applications. We then review the most recent data on therapeutic applications of molecules interacting with the chemokine system with specific reference to rheumatoid arthritis.

Great progress has been made in recent years in the management of patients with autoimmune diseases, such as rheumatoid arthritis (RA). This progress is largely due to the advances in our understanding of cellular and molecular mechanisms involved in the pathogenesis of inflammation and autoimmunity, and the improved knowledge of molecular biology. Immunotherapy has the potential to modify or re-balance the immune system and hence useful in the management of autoimmune conditions. In this review, we first focus on new biotherapies currently developed in clinic for the treatment of RA. We also outline the limitations of such approaches and review perspectives raised by the current studies on innovative alternatives, such as gene and cell therapy. Immuno-modulation through dendritic cells or mesenchymal stem cells, functionally and / or genetically modified, is under increasing number of investigations and thus will also be discussed. Strategies include the inhibition of pro-inflammatory cytokines, blockade of cartilage-degrading enzymes, inhibition of synovial cell activation or apoptosis of synovial cells and manipulation of the Th1-Th2 cytokine balance. Both viral and non-viral gene transfer vector systems have been used to deliver therapeutic genes systemically or directly to arthritic joints. Animal models of RA have been essential not only for better understanding of the RA mechanisms, but also in serving as basic experimental tools to evaluate candidate gene products with anti-arthritic properties and develop therapeutic strategies. Better understanding of autoimmune mechanisms, advances in vectorology, and combination of immunosuppressive gene / cell therapies promise better immunotherapy for RA in the near future.

Eicosanoids are a family of lipid mediators derived from the metabolism of arachidonic acid. The cascade involves two major pathways: the lipoxygenase is the first enzyme in a cascade which produces leukotrienes (LTs); while cyclooxygenase (COX) initiates the cyclic pathway leading to prostanoids. These eicosanoids have a wide range of biological actions including potent effects on inflammation and immunity. This paper contains a QSAR study for LOX inhibitors. It reveals that in almost all cases, the clog P parameter plays an important role in the QSAR relationships (linear or bilinear model). In some cases the steric factors, such as the overall molar refractivity (CMR) or molar refractivity of the substituents (MR), are important. Electronic effects are comparatively unimportant. The study shows that log P as calculated from the Clog P program is suitable for this form of QSAR study.

Cysteinyl leukotrienes (cys-LTs) have emerged as important mediators of inflammation. Interest in these molecules have been amplified by recent introduction of the drugs which can either inhibit their biosynthesis or interfere with their binding to specific receptors. Biosynthesis of cys-LTs starts with the action of 5-lipoxygenase on arachidonic acid, liberated from membrane phospholipids and leads to formation of leukotriene A4 (LTA4). Cells, which express leukotriene C4 synthase (LTC4S), conjugate LTA4 with reduced glutathione to leukotriene C4 (LTC4), the first derivative of the family of cysteinyl leukotrienes. This in turn can be converted to leukotriene D4 (LTD4) and then to leukotriene E4 (LTE4). Cys-LTs powerfully affect cardiopulmonary functions. Thus, they contribute to bronchoconstriction, mucous secretion, edema migration of eosinophils into airways, and constriction of vessels including coronary arteries. A welldefined clinical syndrome, which affects about 10 % of adult asthmatics, i.e. called aspirin-induced asthma (AIA), is characterized by overproduction of cys-LTs. Chronic treatments of AIA patients with leukotriene biosynthesis inhibitors produce clinical benefits and improvement in pulmonary function tests. 5-LO inhibitors can be classified into several classes of compounds; redox, and non-redox inhibitors, first and second generation N-hydroxyurea derivatives, and FLAP inhibitors. From the clinical point of view, the most important group of inhibitors are the first N-hydroxyurea derivatives e.g. zileuton. They show clinical efficacy in asthma and provide a rationale for envisioning novel leukotriene - based approaches in therapy.

The basophil granulocyte is a circulating cell constituting less than 1% of the blood leukocytes. It is believed to take part in inflammatory reactions of the skin and airways and in particular it is involved in the late phase reaction of IgE-allergic reactions and diseases such as asthma, rhinitis, and urticaria. In spite of great similarity between basophils and mast cells there are also differences in regard to stimulation and secretion of mediators. Nevertheless the basophil serves as a model for study of allergic reactions. Experimental models for study of basophil biology are the basophil histamine release test and the basophil adhesion assay. Various endogenous stimuli have been used to characterize these models with respect to the signal transduction mechanisms involved in degranulation, mediator release and adhesion. Moreover, the basophil histamine release assay allows for the differentiation of IgE- and non-IgE-mediated responses. Drugs and experimental substances known to inhibit basophils functions are mentioned and their applicability for development of anti-allergic therapy is discussed. A number of drugs and experimental substances are known to activate basophils: opioids, X-ray contrast media, newer protein-based drugs and food proteins. In conclusion the basophil may be used as a screening tool both for anti-allergic treatments and for potential allergic or allergy-like side effects of new drugs.