Recent Patents on Inflammation & Allergy Drug Discovery - Volume 1, Issue 2, 2007

Both the increased knowledge of the mechanisms leading to allergy and the advent of molecular biology have offered a fertile soil for introducing new ideas for the control of allergic diseases. The control of the environment is no longer fashionable. The large majority of patents deal with either new forms of allergens, fragments of allergens and formulation, or interventions at the level of non-specific modifiers of the anti-allergen immune response. This review offers a synopsis of such recent patent applications in the field of allergy, with emphasis on the various aspects by which they integrate in the rapidly moving knowledge combining cell biology and animal models.

A major goal in studying occupational respiratory diseases is to show relationships between occupational exposures and health outcomes. Due to the nature of these diseases, accurate, practical, and objective measurement techniques are needed in field investigations. Pulmonary function tests, such as spirometry, are important objective health outcome measures. However, they reflect the functional changes of the lung, often in relatively late stages, which may be irreversible. Direct monitoring of airways inflammations, in response to occupational exposures, are receiving an increasing attention since they may pick up inflammatory changes before the injury becomes irreversible. Invasive approaches such as bronchoalveolar lavage and bronchial biopsies have been used to assess airways inflammation: but these methods are not practical for use in occupational field investigations. Thus, much work has focused on the development of noninvasive methods for monitoring inflammation in occupational respiratory diseases. The three recent most commonly used noninvasive techniques in occupational respiratory diseases investigations are induced sputum, exhaled breath condensate, and nasal lavage. In this review, we discuss the practical application of these techniques, patents and cytokines measured with them. Since variation of cytokine genes contribute to the inflammatory processes, we briefly discuss the genetic polymorphisms on the expression of occupational respiratory diseases. Details of genetic polymorphism were beyond the focus of this review. Our primary focus was cytokines measured with these three noninvasive techniques in occupational respiratory investigations.

The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs exert antiinflammatory and analgesic effects through the inhibition of prostaglandin synthesis by blocking COX activity. Currently two COX isoenzymes are known, COX-1 and COX-2. Prostaglandins influenced by COX-1 maintain the integrity of the gastric mucosa. On the other hand, prostaglandins influenced by COX-2 mediate the inflammatory process. The common anti-inflammatory drugs (like aspirin, ibuprofen, and naproxen) all act by blocking the action of both the COX-1 and COX-2 enzymes. The COX-2 inhibitors represent a new class of drugs that do not affect COX-1, but selectively block COX-2. This selective action provides the benefits of reducing inflammation without irritating the stomach. This review will focus on the most recent developments published in the field, paying particular attention to promising COX-2 inhibitors, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes. Moreover, we will discuss recent patents of structural analogs of the COX-2 inhibitors celecoxib and valdecoxib, and novel potential pyridazine, triazole, indole, thione derivatives as a future target for the treatment of inflammation, pain and other diseases.

The recently emerged Vcsa1 gene is one member of the variable coding sequence (VCS) multigene family of Rattus norvegicus. This gene encodes the precursor prohormone SMR1 (submandibular rat-1), which on enzymatic processing gives rise to several 5 to 11 amino acid peptides that modulate a variety of physiological functions. The analgesic pentapeptide sialorphin and anti-inflammatory heptapeptide submandibular gland peptide-T (TDIFEGG) are the most intensively studied. Although the Vcsa1 gene and its protein product are unique to rats, TDIFEGG or a derivative acts on all species examined to date, including human cells, in functions related to allergic reactions and inflammation. In this review, the patent and academic literature on SMR1 and its natural peptides and their derivatives are reviewed for consideration of biological targets and relevance to the development of novel therapeutic agents. The VCS gene family is discussed and we speculate on possible human homologs of these potent anti-inflammatory rat-derived peptides. The biologically active peptide products of SMR1 are considered and the mechanism of action and structure-activity relationships of the anti-inflammatory submandibular gland peptide-T and its derivatives are discussed.

Atopic dermatitis (AD) is a common, highly pruritic, and chronic, relapsing, inflammatory skin disorder. There are several modalities, which have been used in the treatment of AD, but current standard therapies have variable efficacy and potential systemic side effects. We reviewed the literature, recent patents and summarized the effective and potential effective treatment alternatives and constituted four categories and steps to achieve the best treatment modalities for each patient with AD. Supportive care, avoidance of skin irritants and allergens, topical creams, phototherapy and systemic drugs are still the best choices of treatment. Optimal effective treatment agents with low side effects are still requested.

One of the growth factors that appear to play a crucial role in the pathogenesis of systemic sclerosis is TGF-β. The three functionally and structurally similar human isoforms of TGF-β play important roles in embryonic development, in the regulation of tissue repair following injury and in immune responses. Systemic sclerosis fibroblasts express increased levels of TGF-β receptors on their surface which in turn results in increased signalimg of TGF-β induced collagen gene expression. Some of the patents and intricate pathways that mediate the stimulation of collagen gene expression by TGF-β have recently been described and a potential inhibition of these pathways may lead to novel therapeutic targets for systemic sclerosis.

The advent and evolution of corticosteroid treatment strategies over the preceding decades means that asthma is now at least controllable for the majority of asthmatics. The main mode of action for corticosteroids is the inhibition of the nuclear factor-kappaB (NF-kappaB) pathway which dampens the pulmonary inflammatory response associated with asthma pathology. The effectiveness of these drugs and the growing market means that there is strong competitive pressure for pharmaceutical companies to improve, or at the very least maintain, their intellectual property position in corticosteroid treatments for asthma. The most notable feature of the intellectual property situation for inhaled corticosteroids is the impending expiry of a large raft of patents associated with many of the market leading drugs. As efficacy of inhaled drugs is intimately related to how effectively the drug is delivered to the lung, there are a variety of options available for patent protection, including protecting the drug formulation itself as well as various components of a compatible delivery device. In the absence of new corticosteroid chemistries, such approaches will provide extended intellectual property protection and assist in the maintenance of market share for many of the leading inhaled corticosteroids.

The frequency of allergic diseases has increased in recent decades. Asthma is one of the most prevalent conditions and a leading cause of morbidity. It affects 3-4% of the population in our geographical setting and extrinsic allergens are detected as the disease's etiological agent in around half of these cases. IgE is one of the molecules involved in the allergic process. Most of the time and resources at asthma units are devoted to corticosteroid-dependent patients. International guidelines for asthma treatment recommend a stepwise therapeutic approach; in the last step, the use of oral corticosteroids is advised when control is not achieved with long-acting ß-2-agonists and high doses of inhaled corticosteroids. No alternatives or complements to oral corticosteroids had been proposed until November 2006, when the latest GINA update included the IgE blocker omalizumab in the last step of asthma treatment. In this paper we discuss the pathogenesis of the allergic reaction and the key importance of IgE in this process in order to highlight the beneficial effects of a drug able to block the circulation of the free form of this immunoglobulin. We also review the most important studies and patents for the efficacy and effectiveness of the drug in the treatment of adults and pediatric patients with asthma and other diseases.

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