Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 4, Issue 3, 2005

Osteoarthritis (OA) is the oldest and most common type of arthritis characterized by the breakdown of joint cartilage. It affects middle-aged and older people, and can range from very mild to very severe. The cost of OA treatment in economy exceeds $100 billion per year in US. Research has proved that there are many factors causing OA; ageing, obesity, joint injuries, work-related activity, being the most known among others. In addition, genetics has a role in the development of OA, particularly in the hands. Treatment of osteoarthritis focuses on decreasing pain and improving joint movement, and may include: a) Exercises to keep joints flexible and improve muscle strength, b) Many different medications to control pain, including corticosteroids and NSAIDs, c) Naturocetic compounds, such as glucosamine and chondroitin sulfate have been recently applied, d) Heat/cold therapy for temporary pain relief, e) Joint protection to prevent strain or stress on painful joints, f) Surgery (sometimes) to relieve chronic pain in damaged joints and g) Weight control to prevent extra stress on weight-bearing joints. Recent research has been focused on the identification of the mechanisms of cartilage destruction, prevention and genetics of OA, as well as gene therapy approaches. This special issue of Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents is dedicated to Osteoarthritis and Its Treatment. Emphasis has been placed on the recent developments in Osteoarthritis' basic knowledge and the new pharmacotherapies employed for its treatment. Prominent leaders in this field have provided a current perspective and a comprehensive overview of the state of knowledge about OA. I would like to thank all the authors for generously contributing their time and expertise in the preparation of this publication. I greatly appreciate the honor given to me by the Editor-in-Chief, Dr. Bahar Tunctan, in entrusting me the responsibilities to serve as a Guest Editor of this special issue and for his unlimited collaboration in all steps necessary to prepare this issue. I would like to acknowledge Bentham Science Publishers for their assistance in bringing this issue to publication. From my personal point of vantage, I am thankful and amply rewarded for extending my knowledge on the field during the process of reading and editing the articles.

Osteoarthritis (sometimes called “arthrosis” or “osteoarthrosis”) often entails a slow and gradual deterioration of the joint that may sometimes lead to its total destruction and the need for an operation to replace it. However, for most patients with osteoarthritis, surgical treatment never becomes necessary, and their symptoms can be dealt with satisfactorily by self management, by non-pharmacological treatment or by pharmacological treatment. Osteoarthritis is not one single disease, but should rather be seen as a common final stage, joint failure, where the initial stages of the disease process can be triggered by many different causes. The main symptoms are joint pain, stiffness and limited mobility, which may lead to impairment and handicap. When the disease is far advanced an X-ray examination will show signs in the form of reduced joint space and osteophytes. These changes to the structure of the joint are caused by the destruction of the articular cartilage and the growth of bone deposits at the margins of the joints. Today there is no treatment which can stop the progress of the arthritic disease and joint destruction in osteoarthritis, but there is a series of treatments which can reduce the pain and help to maintain or improve function.

Several chemical entities have been carefully investigated for the symptomatic and structural management of osteoarthritis. The most compelling evidence of a potential for inhibiting the structural progression of osteoarthritis has been obtained with glucosamine sulfate. At any rate, this compound has clearly demonstrated a symptomatic action, mainly in osteoarthritis of the lower limbs, on pain relief and improvement of functional disability. An important issue is that all the conclusive studies with such chemical entities resulted from the use of prescription medicines and not over-thecounter pills of food supplements.

The aim of this review is to illustrate the structural biology and functions of chondroitin sulphate (CS) in the light of recent glycobiological studies suggesting its new fundamental biological functions, and to evaluate the literature on CS concerning the pathobiology of osteoarthritis (OA), to ascertain whether this agent should be classified as a symptomatic slow-acting drug (SYSADOA), a compound that has a slow onset of action in alleviating OA symptoms. A previous review [Volpi, N. The pathobiology of osteoarthritis and the rationale for the use of chondroitin sulfate for its treatment. Curr. Drug Targets Immune Endocr. Metabol. Disord., 2004, 4, 119] has been published on this topic and this article intends to extend and update CS data and its use in the treatment of OA. CS exhibits a wide range of biological activities and from a pharmacological point of view, it produces a slow but gradual reduction of the clinical symptoms of OA, and these benefits last for a long period after the end of treatment. Furthermore, many animal studies and clinical trials have proved the efficacy of CS as a structure-modifying OA drug agent able to reverse, retard, or stabilize the pathology of OA, thereby providing symptomatic relief in the long-term treatment. In addition, there are fewer side effects when compared with other drugs used to treat the symptoms of OA, as well as a lack of toxicity associated with long-term use of these agents. These properties are also related to the oral absorption of this molecule as high-molecular mass compounds having clusters of sulphate groups and high charge density, capable of exerting their chondroprotective activity in vivo.

Osteoarthritis (OA) is by far the most prevalent arthritic disease affecting around 10% of the world's population and approximately 60% of 60-year-olds. It is also one of the most common arthritic diseases seen by general practitioners and rheumatologists. The increased frequency of OA with age, makes it a growing social health concern, as it is a disease associated with disability and pain. In the US today, the immediate cost of the disease is estimated at approximately 60 billion dollars a year. Despite the clinical success of non-steroidal anti-inflammatory drugs (NSAIDs) and of anti-cyclooxygenase (COX)-2 in treating symptoms, there is no cure for the disease to date. However, our knowledge of its etiopathogenesis has progressed significantly in the past few decades. Based on studies of human cells and animal models, targets for therapeutic intervention have been put forward and major efforts are underway to bring about new therapies that can reduce or stop the progression of the disease. This review should help the reader better understand the most recent advances regarding inflammatory and growth factors as new targets in reducing or stopping OA.

Osteoarthritic joint disease is characterized by the progressive loss of articular cartilage resulting in functional impairment, pain and discomfort. The major components in cartilage, collagen and aggrecan, are lost during disease through the action of degradative proteolytic enzymes. The proteases responsible for aggrecan degradation are termed aggrecanases. The aggrecanases represent a family of enzymes with great therapeutic potential as targets for the treatment of osteoarthritis. Here we review the family of aggrecanases and the progress made toward the identification of potent and selective enzyme inhibitors for use as therapeutic agents.

Articular cartilage injuries and osteoarthritis are very frequent clinical problems for which no satisfactory treatment has been established yet. Therapeutic strategies aim at an inhibition of matrix degradation and/or the stimulation of cartilage anabolism in the diseased joint. In a number of studies, the administration of anti-catabolic or antiinflammatory cytokines such as IL-1Ra, sTNFαR, IL-4, IL-10 or IL-11 to joints affected by cartilage destruction has proven to be beneficial. However, the clinical utility of this strategy is limited by the enormous costs due to the short halflifes of these proteins in vivo. The transfer of the respective genes may provide a more sustained delivery of such molecules at the desired location. Lesions with substantial loss of cartilage tissue and final stages of osteoarthritis require the generation of new hyaline cartilage, because the lesions hardly show any endogenous repair response. Surgical approaches such as subchondral drilling or transplantation of cells or tissue grafts often fail to restore the articular surface, facing the problem of incomplete chondrogenesis or rapid degradation of the repair tissue. In experimental studies, certain growth and differentiation factors including members of the TGF-ß superfamily, IGF-1 or FGF as well as transcription factors such as SOX-9 have proven their potential to stimulate chondrogenesis and synthesis of cartilage-specific matrix components, allowing the formation of a hyaline cartilage-like repair tissue. Targeted cell-mediated gene transfer could ideally combine the supply of chondroprogenitor cells with the production of therapeutic factors directly at the site of the lesion. This review summarizes the relevant pathomechanisms and different gene therapy strategies for the treatment of cartilage injuries and osteoarthritis. The advantages and disadvantages of different therapeutic genes, target cells and vectors for intraarticular gene transfer are discussed on the basis of the results of gene therapy studies on various animal models.

Inflammation is the physiological protective response of the organism to stimuli ranging from a transient, self-limited and localized response to a complex, sustained response involving the whole organism. Inflammatory processes are characterized by the stimulation of humoral and cellular signaling systems and, as a result, mediators of inflammation, such as interleukins-1, and-6 and tumor necrosis factor-α are expressed and released at the site of injury by diverse cell types. An increase in the levels of inflammatory mediators can result in alterations in microvascular tone and permeability, in addition to activating pathways for the synthesis of eicosanoids, such as prostaglandins (PGs) and leukotrienes (LTs), which are lipid mediators involved in the regulation of the complex inflammatory reaction. PGs, such as PGE2 and prostacyclin (PGI2), induce vasodilation and edema development, and contribute to hyperalgesia at the site of inflammation. Additionally, fatty acid peroxides and LTs cause an increase in local permeability and are potent neutrophil chemoattractants. The study of the inflammatory process provides opportunities for impacting many diseases, including allergies, asthma, arthritis and autoimmune diseases, as well as cardiovascular, neuromuscular and gastrointestinal diseases. In this special edition of AIAA the pathophysiology of many inflammatory disorders are discussed. Recent advances in the cell and molecular biology of inflammation and the capacity for manipulation of gene expression in injured tissues now facilitate and enhance our knowledge and provide novel avenues to unravel the complex pathogenesis of inflammatory diseases. This will guide our efforts to develop new approaches toward diagnosis, prevention and therapy. The themes covered in this edition include a discussion on atherosclerosis which, as an inflammatory disease, contributes to the pathological process that culminates in coronary artery disease. Recently, it has been shown that inflammation is involved in plaque formation, progression and rupture. At the molecular level nuclear factor kappa-B (NF-kB) activation has been implicated in lesion formation and progression. In their manuscript “Inflammation in Atherosclerosis: a New Therapeutic Target”, Skouri and co-workers discuss the mechanism of action of NF-kB activation and the effect of inhibitors of NF-kB activity on the inflammatory processes. Mourad in “Designing and Testing New Therapeutic Modalities for Treatment of Inflammatory Bowel Disease: Role of Experimental Animal Models“, discusses the pathogenesis of inflammatory bowel disease (IBD) and highlights potential targets for therapeutic intervention. The author presents insights on the use of experimental models to understand the pathogenesis and to define rational cell and molecular targets, at multiple levels, for IBD therapy. Available therapies for the treatment of inflammatory bowel disease are not satisfactory and are only effective in around 50% of the patients. In the following manuscript, “Biologic and Novel Therapy of the Inflammatory Bowel Diseases“, Makrauer and Burakoff focus their review on new experimental biologic therapies, their actions and potential benefits. Inhibitors of inflammatory cytokines, such as anti-tumor necrosis factor agents (anti-TNF); antagonists of TNF; anti-interleukin-12; antiinterleukin- 2 receptor; inhibitors of lymphocyte trafficking; and anti-adhesion molecules, as potential therapeutic agents is highlighted. Haddad, Saade' and Safieh-Garabedian in “Thymulin: an Emerging Anti-Inflammatory Molecule“ discuss thymulin, an endogenous neuroendocrine hormone with immunoregulatory actions, which has recently been shown to possess antinociceptive effects in hyperalgesia and in pain of neurogenic origin. The authors also describe the anti-inflammatory actions of thymulin in autoimmune diseases, rheumatoid arthritis and in peripheral and/or central nervous system inflammation. Finally, Arayssi and Hamdan in “Update on the Therapy of Behçet's Disease“, review Behçet's Disease which is a chronic inflammatory systemic disorder that remains elusive to therapy. The authors describe the pathogenesis, diagnosis and clinical manifestations of the disease and describe the many therapies that are available or are under development, their mechanism of action and their efficacy.

Coronary artery disease (CAD) is still the leading cause of death in men and women, despite our better understanding of the disease process. Atherosclerosis, the underlying pathological process that leads to CAD, was considered a disorder of lipid metabolism and deposition of lipid material in the vessel wall. Today however, it is viewed as an inflammatory disease and it is evident that inflammation is involved in every step of plaque formation, progression and rupture. At the cellular level, recent studies on human and animal models illustrated the involvement of nuclear transcription factors in early lesion formation and lesion progression. Nuclear factor Kappa-B (NF-kB) activation can result in a proinflammatory, atherogenic process while peroxisome proliferator-activated receptors (PPARs) and their ligands have an atheroprotective, anti-inflammatory effect. Many drugs and compounds have been shown to block NF-kB or reduce its effects while others activate PPARs and slow or halt the inflammatory process. In this review, we will discuss the contribution of NF-kB and PPARs to the different inflammatory pathways that contribute to atherosclerosis. We will also discuss the effect on the inflammatory pathways by different therapeutic options like the angiotensin converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARBs), insulin and insulin sensitizers, statins and fibrates, aspirin and salicylates, and antibacterial and antiviral therapy.

Experimental models of inflammatory bowel disease (IBD) have provided important information on the pathogenesis of this disease and tremendously helped in designing and testing some new treatment strategies. Every single step during the inflammatory process has been targeted to inhibit or induce a certain specific pathway. Among others, biologic therapy seems to be the most promising future therapy in IBD. Replenishing the microflora by probiotics showed beneficial results in experimental models. Agents that inhibit inflammatory cytokines and effector cells such as antibodies to tumor necrosis factor alpha, interleukin 12 (IL-12), interferon gamma and CD40L lymphocytes, as well as proinflammatory cytokines such as IL-10, IL-11 and transforming growth factor alpha were found to be effective in decreasing the inflammatory reaction in many animal models. Other candidates remain to be tested. A relatively new therapeutic approach is the blockade of effector cell recruitment into the lesions. In this regard, multiple agents were tested in animals and are already in clinical trials including antibodies to α4 integrins, to α4β7 integrins, to mucosal addressin cell adhesion molecule 1, and inhibitors of endothelial intercellular adhesion molecule 1 expression. Another approach aims at the use of growth factors such as growth hormone, trefoil factors and keratinocyte growth factors that have an important role in the healing of the inflamed intestine. Other strategies include transcription factor inhibitors, anti-coagulation and reactive oxygen scavengers. Herbal medicine has also been tried in animals and the possible mode of action has been investigated. Finally, new ways of delivering drugs, antibodies or anti-inflammatory cytokines to the site of inflammation using viral vectors, microsheres or lymphocytes are promising future approaches.

IBD is now best considered as a group of genetic disorders of immune dysregulation with failure of downregulation of the intestinal mucosa's normal immune response to its intraluminal commensal bacterial milieu combined with inappropriate migration of antigenic material triggered by multiple host (appendectomy, pregnancy, breast feeding, age) and environmental factors (tobacco smoking, birth control pill, NSAIDS). The result is the predominance of an effector or pro-inflammatory cytokine response due to clonal expansion of T1 and T2 helper lymphocytes (Th1 and Th2 response) combined with an inadequate regulatory cytokine response by T3 helper (Th 3) and T1 regulatory (Tr1) lymphocytes. The persistence of this imbalance in the inflammatory response then leads to tissue damage resulting in both local and systemic illness. In human IBD, a distinction can now be drawn between Crohn's disease with its Th1 effector response characterized by high levels of the cytokines interleukin-12 (IL-12), interferon gamma (IFNγ) and tumor necrosis factor (TNF) leading to transmural inflammation with granulomas, and ulcerative colitis with a Th2 effector response, high levels of interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), and interleukin-13 (IL-13) characterized by strictly mucosal inflammation. The difficulty with adherence to current maintenance therapy for the inflammatory bowel diseases as well as the toxicity and relative ineffectiveness of induction therapy has provided the impetus for the development of new biologic and novel therapies which will be reviewed in this article. Biologic therapy has been divided into five areas of study: 1) native biologic preparations and isolates such as vaccines, hormone fragments and blood products, 2) recombinant peptides or proteins, including granulocyte macrophage colony stimulating factor, 3) monoclonal antibody-based therapies, 4) anti-sense nucleotides to nucleic acids, and 5) cell and gene therapies. Since the early 1990's, investigation in all five of these areas has yielded numerous potential agents for use in treating IBD more effectively and safely. While only one, infliximab (Remicade), is FDA-approved, several additional agents should be available for clinical use in the near future with the promise of more to follow. Our discussion of biologic and novel therapies represents a review of the most promising treatments and a status report of on-going clinical trials. Peripheral leukocyte apheresis and stem cell transplants, while suggesting an exciting new pathway for investigation, will not be reviewed. Our discussion is organized by each agent's hypothesized mode of intervention in altering the pathogenesis of IBD.

Thymulin is a neuroendocrine hormone with immunoregulatory actions. Originally known as 'serum thymic factor' (FTS), thymulin binds to a carrier protein and zinc (Zn2+) to exert its biologic properties. Thymulin, albeit an essential hormone for the T lymphocyte differentiation and the normalization of the ratio of T-helper cells to suppressor cells, accumulating evidence suggests its involvement in inflammations of various etiologies. Recently, thymulin has been shown to have anti-nociceptive effects in hyperalgesia and in pain of neurogenic origin, ostensibly through action on sensory afferents and the release of anti-inflammatory mediators. Given its anti-inflammatory potential, thymulin downregulates the release of inflammatory mediators, such as cytokines and chemokines, upregulates anti-inflammatory factors, such as interleukin (IL)-10, and exerts molecular control via the regulation of transcription factors and mediators. Recent evidence tends to indicate that thymulin can be a therapeutic agent in many inflammatory diseases and in pathological conditions affecting the peripheral and/or the central nervous system. This review discusses current concepts in the antiinflammatory actions of thymulin and correlates this activity with an emerging theme for therapeutic treatment.

Behçet's disease is a chronic inflammatory systemic disorder, characterized by a relapsing and remitting course. The main histopathological finding is a widespread vasculitis of the arteries and veins of any size. The prevalence of BD is highest in the Middle East, Mediterranean region and Asia. The usual age of onset is around 30, and the male to female ratio varies with the ethnic background. The cause of BD remains unknown. It is presumed to be multifactorial involving infectious triggers, genetic predisposition, and dysregulation of the immune system. The main objectives of therapy of BD are to relieve its symptoms, decrease recurrences and prevent irreversible damage. This choice, however, is limited by the paucity of high quality therapy trials. Therapy studies for this disease in general, lack high methodological quality and common outcome measures, making treatment of this disease for the most part empirical. Most randomized studies have focused on the treatment of ocular, mucocutaneous and musculoskeletal diseases, while data on the treatment of the other manifestations is based on uncontrolled data.