Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 9, Issue 1, 2010

Advances in understanding of the pathology of immune based disorders and especially new developments in the field of biotechnology, have triggered great interest in the development of new therapies for inflammatory rheumatic diseases. Subsequently the treatment spectrum of rheumatic inflammatory diseases have increased by quantity and variety in the last years. Earlier uses of traditional disease modifying antirheumatic drugs, along with the arrival of newer therapies including the biologic agents, have provided better long term outcomes for patients suffering from these illnesses. In recent years our better understanding of these disorders has shifted treatment strategy from a more conservative approach to a much more aggressive one, especially in treatment of rheumatoid arthritis. Although conventional treatment modalities remain the mainstay and are sufficient in many of patients today we have clearly entered the “biologic treatment” era in the field of management of rheumatic diseases [1]. The term of biologic therapy have arised as term to define therapeutic agents with biologic properties and refers to treatment that boosts or restores the ability of the immune system to fight with inflammatory process which seen in arthritis. Efforts to develop new biologic agents for treating patients with refractory rheumatoid arthritis have been accelerated in 90's. Research focused on understanding the pathogenesis of rheumatoid arthritis has resulted in revolution therapeutic advances through the targeting cytokine mediators in the inflammatory cascade from late 1990s to 2005. Finally today a lot of biological agents have been approved for management of a various inflammatory arthritis by FDA [2]. New biological agents developed for treatment of inflammatory joint diseases in the last decade have proven to be effective for a majority of patients unresponsive to traditional therapies. As pathogenesis of rheumatoid arthritis becomes clear the proinflammatory role of cytokines, the involvement of different cell types and their surface molecules, provides the rationale for the development of highly specific therapeutics by targeting these molecules. These can be achieved by; first, the cytokines of interest may be prevented from binding to its cell surface receptors by soluble receptors, natural antagonists, or monoclonal antibodies. Second, anti-inflammatory cytokines such as IL-4, IL-10 or IL-13, can inhibit the production or expression of inflammatory cytokines. Third, biological agents targeted against differentiation or functionally associated cell surface antigens can lead to either elimination of the targeted cells or interference with cell function [3]. Most of the approved biologics explore the first strategy mentioned above; they impair the binding of proinflammatory cytokines to their receptors. Among them, tumor necrosis factor (TNF) and IL-1 have been the most intensively investigated. These biological agents are mostly product of recombinant DNA technology, also known as bioengineered replicas of human proteins, which should be administered by subcutaneous injection or intravenous infusion. These agents has quicker onset of action than traditional disease modifying anti-rheumatic drugs , produced rapid and sustained therapeutic responses, and did not require regular laboratory monitoring [2]. TNF-α antagonist are highly effective in the treatment of many chronic inflammatory diseases, as demonstrated in several randomized clinical trials, showing clinical and radiological improvement in treated patients. The different mechanism of action between monoclonal antibodies (infliximab and adalimumab) and soluble receptor (etanercept) for TNF-α is proved by the results of the switching in case of inefficacy and adverse events. IL-1 is a proinflammatory cytokine that shares many properties similar with TNF- α and is associated with the characteristic inflammatory joint destruction of rheumatoid arthritis (RA). Anakinra is a recombinant form of IL-1 receptor antagonist, a naturally occurring IL-1 receptor ligand that competes with IL-1 for binding to cell surface-bound IL-1 receptor, but does not induce intracellular signaling.In many controlled studies has been shown that Anakinra reduce signs and symptoms of synovitis and slow radiographic progression of joint damage in RA [3]. The development of new agents and widespread use of existing agents continues to be a highly active area of investigation among the rheumatic diseases. In the future, improved versions of existing drugs will become available. Already anti TNF- .. preparations that are given as monthly subcutaneous injections are currently being developed. Other targets for therapy such as IL6, CD22, CD40-CD40L, lymphostat B and many others are under study. Currently there is no doubt of improving outcomes for patients with rheumatic diseases by biological agents. As is known most of the clinical studies carried out with biologics are designed in RA patients. Biologics bring new hope to those patients that do not respond adequately to traditional DMARDs in the treatment of RA signs and symptoms and beyond that also ameliorate radiographic progression. But how to establish of these agents most safe, efficient, cost-effective means of delivering is needed to be explicated in well designed trials [4]. “Fear of the unknown should not preclude progress, but caution must be essential” I hope in this issue the reviews will guide the readers the appropriate way of use biologics and answer of most questions of curiosity about these new agents in treatment fields of rheumatology. Many thanks to all authors for their efforts and contributions.

The deficiency of conventional drugs that are used in inflammatory rheumatic diseases are not able to prevent from progression of diseases have resulted in the development of new drugs, such as TUMOR Necrosis Factor-α (TNF-α) blocking agents, Interleukin-1 (IL-1) receptor antagonist and Anti-B cell (CD20) antibody. Biologic agents are a clear advancement in drug therapy. These newer agents have mechanisms of action targeted toward specific components of the immune system, which enable them to provide more reliable outcomes with fewer limiting side effects. They are administered subcutaneously and/or intravenously. The goal of the biologic treatment is to slow or block specific components of the immune system and halt tissue destruction.

Rheumatoid arthritis (RA) is a chronic disease characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. Thus, treatment goals should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Conventional (nonbiologic) DMARDs use is the first step of this debilitating disease treatment but in many patients, this is inadequate and other forms of therapy are required. Advances in the current knowledge of pathogenetic mechanisms of rheumatoid arthritis have contributed to the development of biological therapy, and translated research findings into clinical practice. TNF-alpha (infliximab, etanercept, adalimumab), IL-1 (anakinra) and IL-6 (tocilizumab) inhibitors, a B-cell depleting agent (rituximab) and a drug blocking T-cell costimulation (abatacept) have been approved for rheumatoid arthritis. In this text, the biologic therapies which are currently used in the patients with RA will be reviewed in the company of latest evidences.

Rheumatoid arthritis is characterized by pain, swelling, and destruction of joints, with resultant disability. Only disease-modifying antirheumatic drugs can interfere with the disease process. Advances in the current knowledge of pathogenetic mechanisms of rheumatoid arthritis have contributed to the development of biologic agent therapy, and translated research findings into clinical practice. Therapeutics options for rheumatoid arthritis (RA) have increased tremendously in the past decade with the introduction of biologic agents in 1999. Especially inhibitors of tumor necrosis factor have allowed for hitherto unseen therapeutic benefit, although even with these drugs the frequency and degree of responses are restricted. Therefore, new agents are needed. And novel biologic agent compounds for treatment RA have already been used in practice or are on the horizon. TNF-α (infliximab, etanercept, adalimumab), IL-1 (anakinra) and IL-6 (tocilizumab) inhibitors, a B-cell depleting agent (rituximab) and a drug blocking T-cell costimulation (abatacept) have been approved for rheumatoid arthritis. The progress in manufacturing biotechnology has contributed to the development of several other prospective agents that may form the basis for the therapy of rheumatoid arthritis in the near future. The newer biologic agents appear to be well tolerated in the short to medium term (up to 1 year), with an acceptable tolerability profile. However, larger studies with longer follow-up times are needed to indicate both effects and adverse effects of these agents.

Ankylosing spondylitis (AS) is a chronic inflammatory disorder of the spine that can lead to significant disability if left untreated. Although conventional treatments can be successful in alleviating symptoms, they have not been shown to stop progression of the disease. The proinflammatory cytokine tumor necrosis factor (TNF) is central to the pathogenesis of AS. Several TNF-α blocker drugs such as infliximab, adalimumab, etanercept and golimumab have been developed and shown to control symptoms effectively, possibly preventing both clinical and radiographic progression of the disease in patients with AS. Acute inflammatory lesions in the spine and sacroiliac joints can be effectively suppressed by the TNF-α blockers in AS, suggesting that bone destruction and bone proliferation might be prevented.

Juvenile Idiopathic Arthritis (JIA) is an “umbrella” term which is used to cover Juvenile Rheumatoid Arthritis (JRA) and Juvenile Chronic Arthritis (JCA). Biologic agents are needed when others like NSAIDs (Non-steroidal antiinflammatory agents), DMARDs (Disease modifying antirheumatic drugs) cannot provide or maintain clinical remission, and patients are mainly bound on steroids, which are potential anti-inflammatory drugs with serious well-known side effects to the growing child. TNF-α antagonists are the first anti-cytokine agents introduced in the last decade. However, there are important subtypes, such as systemic JIA which are resistant to these drugs, because IL-1 β (Interleukin 1 β) activation is shown to be the main pathway. One of the most frequently asked questions about biologics, particularly ETN (Etanercept), is the duration of the treatment, regarding both the safety and efficacy. Regarding the current literature, ETN seems to be effective and safe in treating the children with JIA. The high dose regimen (6 mg/kg) of infliximab, a TNF monoclonal antibody, has achieved better results on JIA and is now used in pediatric rheumatology practice. Adalimumab, another TNF inhibitor and abatacept (CTLA-4) were also shown to be effective and safe in JIA. Anakinra, canakinumab, and tocilizumab are the ones recently studied, and they are shown to be effective particularly for systemic arthritis.

Biologic agents are commonly used in treatment of rheumatoid diseases today. While being very potent in preventing the progression of diseases both clinical and radiological, they have far too many adverse effects as well. Infections, malignity, congestive cardiac failure, injection site reactions, vasculitis, neurological complications and dermatological complications can be mentioned among these adverse effects. In this composition, adverse effects and drug interactions of these biologic agents have been presented in details and with up-to date articles.

Allergic and auto-immune inflammatory diseases are a worldwide medical concern. Present therapeutics are effective in disease maintenance, allowing relief of symptoms, but are frequently accompanied by unacceptable side effects when given chronically for long periods. Immunotherapy for allergies is effective at inducing anergy to some allergens clinically, but for others it is either ineffective or has a risk of an adverse response. Similarly glucocorticoids, and nonsteroidal anti-inflammatory drugs, which are widely used to treat inflammatory auto immune diseases, are associated with debilitating side effects. Nanoparticles, derived from a variety of different molecular approaches, provide a means to deliver drugs to target organs and cells, lowering the dose requirement and potentially overcoming problems associated with systemic drug delivery. Novel therapeutics in the form of small molecules, proteins, DNA or small inhibitory RNAs, are advancing at a rapid rate toward the clinic and may suffer similar problems to those of current therapeutics. A large body of evidence using nanoparticles for delivery in both allergy and auto-immune disease models demonstrates improvement in alleviating disease. Delivery of current anti-inflammatory drugs, as well as novel therapeutics via nanoparticles also show improved attenuation of disease. The several chemically distinct nanoparticle structures, combined with the currently used drugs, the new wave of drug targets, and novel gene targeted approaches may provide the opportunity to discover optimal combinations for treating allergic and inflammatory disease.

Thalidomide (α-N-phthalimidoglutarimide) was a widely used drug in the late 1950s as a hypnotic/ sedative agent. Thalidomide was subsequently withdrawn from the market due to teratogenicity in the early 1960s. Surprisingly, even after the initial impact of the thalidomide disaster, the drug was still used in the therapy of many diseases, and research studies in the field of thalidomide derivatives have significantly increased because of its tumor necrosis factor (TNF-α) production regulating effect. Recently, novel thalidomide derivatives have been synthesized as anti-inflammatory lead -candidates. This review will summarize the recent development of thalidomide derivatives which possess antiinflammatory activity.

It has been extensively shown that statins, inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase can effectively be used in the treatment of hypercholesterolemia. Indeed, coronary morbidity and mortality related to atherosclerotic plaque dependent cardiovascular diseases have been greatly reduced by their employment. Recently, it has been shown that statins can affect cell growth and survival of solid tumours and leukaemic cells. Indeed, it has been proposed their employment in multiple myeloma treatment in association with thalidomide or its derivatives. On the other hand, statins have strong anti-inflammatory and immunomodulatory effects and thus they may have a role in the regulation of anti-tumour immunity. Indeed, there are several evidences that inflammation may promote oncogenesis and, on the other hand, inflammation may participate in cancer rejection. Herein, we analyze the effects that statins can exert on cancer cells, stromal cells in tumor microenvironment and anti-tumor cytolytic activity of human natural killer cells.