Recent Patents on Inflammation & Allergy Drug Discovery - Volume 3, Issue 1, 2009

In response to hypoxia, adaptive hypoxia-inducible factor-1 (HIF-1) signaling events are activated to increase oxygen transport, anaerobic energy production and protective pathways to minimize ischemic tissue damage. Although the activation and subsequent induction of gene transcription by HIF-1 is normally associated with hypoxia, it is now established that HIF-1 signaling can be triggered under inflammatory conditions. HIF-1 has been implicated in a number of inflammatory diseases including rheumatoid arthritis, allergic asthma, psoriasis and inflammatory bowel disease (IBD). In the gastrointestinal tract, HIF-1-regulated gene products, such as vascular endothelial growth factor, intestinal trefoil factor and CD73, have been shown to provide protection in animal models of intestinal inflammation. Given the importance of HIF-1 signaling in the aforementioned diseases, there exists considerable interest in the development of methods to modulate HIF-1 expression as well as down-stream signaling events. This review examines HIF-1 signaling with a special focus on the gastrointestinal tract. The patents pertaining to the modulation of HIF-1 signaling are summarized, and their relevance to the treatment of inflammatory bowel disease is discussed.

Chlamydophila pneumoniae is an intracellular pathogen and a major cause of pneumonia that can cause chronic, persistent, and often asymptomatic, infections in target cells such as monocytes, macrophages, endothelial cells, fibroblasts, and smooth muscle cells. Chlamydial infections play roles in new-onset wheezing, exacerbation of prevalent asthma, and long-term decrements in lung function. However, accurate standardized laboratory tests to diagnose infection with C. pneumoniae have not been established. Human and animal studies have clarified the molecular mechanisms of resistance to C. pneumoniae and have shown the importance of innate and mucosal immune responses to the microorganisms. A large number of genetic studies have intensively examined the associations between asthma and polymorphisms in the genes located at the interface between innate immune sensing and regulation. The rapid progress in understanding the immunology of infectious diseases and genetics of asthma is providing a better understanding of the pathogenesis of bronchial asthma, and that will help to define patient populations who are most likely to benefit from various treatments, and lead to development of new treatments. The review article also discussed some patent related to the field.

Despite advances in the development of powerful antibiotics and intensive care unit, sepsis is still life threatening and the mortality rate remains unchanged for the past three decades. Recent prospective trials with biological response modifiers have shown a modest clinical benefit. The pathological basis of sepsis is initially an excessive inflammatory response against invading pathogens, leading to systemic inflammatory response syndrome (SIRS). Evidence reveals that a variety of inflammatory mediators orchestrate the intense inflammation through complicated cellular interactions. More recent data indicate that most septic patients survive this stage and then subjected to an immunoparalysis phase, termed compensatory anti-inflammatory response syndrome (CARS), which is more fatal than the initial phase. Sepsis is a complicated clinical syndrome with multiple physiologic and immunologic abnormalities. In this review, we summarize the recent understandings of the pathophysiology of sepsis, and introduce recent patents on diagnosis, treatment and prophylaxis for sepsis.

Contact allergy to topical corticosteroids (TCs) is an emerging problem, whose diagnosis can be complex owing to the peculiar characteristics of steroid allergens and the possible inadequacy of current diagnostic methods, including concentration and vehicle used in patch testing. The occurrence of cross-reactions among different TCs is not rare, but prediction of these is not sufficiently reliable. Moreover, the distinction between true cross-reactivity and concomitant sensitization may be difficult. The original classification proposed by Coopman et al. has been distinguished corticosteroids into four groups according to their molecular structure. These authors hypothesized that allergic contact reactions were more frequent with corticosteroids belonging to the same group. However, the clinical practice has evidenced that cross reactivity exists also among corticosteroids belonging to different groups. The potential to cross-react among corticosteroids is thought to be related not only to the structural homology but also to the stereoisomerism and metabolism of these drugs. Recent evidence suggests that mechanisms responsible for cross-reactivity may occur at T lymphocyte level during antigen presentation. Further investigations are needed to gain a more complete understanding of this important topic. This article also reviews some patents related to the treatment of contact dermatitis and other inflammatory skin diseases.

Psoriasis is a common, chronic and relapsing autoimmune skin disease. Clinical characteristics of this disease are sharply-demarcated erythematous plaques covered with silver scales. Histologically, it is characterized by increased epidermal thickness, elongated papillae, and a moderate inflammatory infiltrate composed of lymphocytes, macrophages and neutrophils. The histological hallmark of psoriasis is Munro's microabscess, which is an accumulation of polymorphonuclear leukocytes in the keratinous layer. The mechanism of this disease is still an enigma, but genetic susceptibility, abnormal function of keratinocytes, or immunological disturbance, especially in T cells, are postulated. Over the past decades, there have been arguments about “keratinocyte-dependent” pathology as opposed to “immunocytedependent” pathology. Thus far, there have been some rodent models for psoriasis. Among them, the recent article from Rebholz et al. is quite intriguing because they explain the crosstalk between keratinocytes and lymphocytes: now evidence has been presented that while the aberrant NF-κB activation in either keratinocytes or lymphocytes could not reproduce psoriasis-like histology, such activation in both reproduced all of the aforementioned “hallmarks” of psoriasis pathology. Therefore, NF-κB may well act as a link between the T cell-mediated and keratinocyte-mediated arguments concerning the pathogenesis of psoriasis. This article also discusses some recent patent related to the field.

Since hyperlipidemia, inflammation and obesity are closely related to atherosclerosis, therefore management of these factors together would be beneficial for overall treatment approach for atherosclerosis. Although, Indian system of medicine, especially Ayurveda has several medicinal plants with proven beneficial claims towards these pathological conditions, but most of them lack enough experimental data. BHUx is a novel polyherbal formulation, consisting of 5 medicinal plants namely Termenalia arjuna, Strychnox nux vomica, Boswellia serrata, Commiphora mukul, and Semecarpus anacardium, which have history of clinical use as single or in other combinations, but these plant fractions were never tried collectively in this ratio as in BHUx, which has been found to be effective on all the etiological factors, together. In this paper, antioxidant, anti-inflammatory, hypo-lipidemic, anti-proliferative properties of BHUx have been studied on several experimental models based on chemical tests, cell culture, in vitro models, and in vivo experiments with normal and transgenic animals. A separate pre-clinical toxicity study has also been carried out to prove its safety margin in therapeutic doses. Further, clinical trail of BHUx is under way, before it comes to market for public use as functional food to maintain healthy heart. This article also review some patent related to the field.

Probiotics are usually defined as live microbial food ingredients beneficial to health which comprise of normal commensally bacteria as a part of the healthy human gut micro flora. The gut microflora is an important component of the gut defense barrier and have been shown to induce and maintain oral tolerance in experimental animal models. Functional foods, including probiotic bacteria, are an attractive medium for maintaining the steady nutritional state of the host with defective gut barrier functions. The gut-associated lymphoid tissue (GALT) embraces a crucial component of the total immunological capacity of the host in recognizing and selectively handling alien antigens for the initiation of immune responses. Normalization of increased intestinal permeability and altered gut micro ecology can ensure improvement of the function of the gut barrier. Probiotics do modify the composition of the gut microflora and, as a consequence, they have been shown to influence both intestinal and body functions. This review also discussed some patent related to the field.

Ulcerative colitis (UC) is a chronic, relapsing and debilitating idiopathic inflammation of the gastrointestinal tract. Dysregulation of the mucosal immune response toward commensal bacterial flora together with genetic and environmental factors plays an important role in the pathogenesis. Refractory UC refers to disease that does not respond to or responds poorly to the many drugs used to treat the disease. The aim of medical treatment is to induce and maintain clinical remission. The most commonly used drugs, including mesalazine, azathioprine, 6-mercaptopurine, cyclosporine, and more recently anti-tumor necrosis factor (TNF) monoclonal antibody (e.g., infliximab), are chosen to suppress the immune system in intestinal mucosa. Additionally, colectomy may be required if medical treatments are unsuccessful or if complications develop. Some of the recent patent related to the field also discuss in this review article.

Chronic inflammation is a pathological condition characterized by continued active inflammation response and tissue destruction. Many of the immune cells including macrophages, neutrophils and eosinophils are involved directly or by production of inflammatory cytokine production in pathology of chronic inflammation. From literatures, it is appear that there is a general concept that chronic inflammation can be a major cause of cancers and express aging processes. Moreover, many studies suggest that chronic inflammation could have serious role in wide variety of age-related diseases including diabetes, cardiovascular and autoimmune diseases. Inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor for cancer and age-related disorders. This article reviews the antioxidant defense systems, free radicals production and their role in cancer and age related diseases and also some of the recent patent relevant to the field. Study of the role of free radicals in human diseases can help the investigators to consider the antioxidants as proper agents in preventive medicine, especially for cancer and aging processes.

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