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

Leptin is an adipocyte-derived hormone with pleiotropic effects on energy homeostasis, endocrine and reproductive functions, and immune responses. The multiple actions of leptin have led to the design and development of several leptin-based approaches to modulate the metabolic and endocrine status, to reduce inflammation, and to improve immune responses. Here, we review the current patents on leptin in different clinic applications.

Statins, beyond their lipid lowering properties, have pleiotropic properties that may modulate the inflammatory cascade and potentially could be useful in the management of inflammatory conditions such as bacteremia and sepsis. In this article, we aimed to review significant patents and available evidence regarding the anti-inflammatory characteristics of these agents and their role in the clinical outcome of inflammatory conditions. Several studies have demonstrated beneficial effects of prior use of statins in the development and the progression of bacteremia, sepsis and pneumonia and there is evidence supporting that the use of statins may be associated with a decreased hospital mortality caused by the above disorders. These investigations also suggest that these agents are infrequently associated with adverse events and are generally safe and well tolerated. However, it should be underlined that these data come mainly from observational retrospective investigations and randomized prospective studies are warranted to confirm these encouraging results.

Targeting cell surface antigens or receptors with lytic monoclonal antibodies and specific ligand-directed fusion proteins in order to eliminate cancer cells has been in development for at least forty years. More recently, leukocyte populations known to drive a host of allergic, autoimmune and inflammatory diseases have been targeted. For fusion protein constructs, a number of different classes of cellular toxins have been fused to a variety of ligands such as monoclonal antibodies, growth factors and cytokines. Although there has been great clinical success using these biologics, there are some limitations. The target antigens are often expressed on normal cells leading to side effects. More recently, several groups have explored the use of chemokine receptor ligands and antibodies to target leukocytes and cancer cells. There are a number of inducible chemokine receptors that are only up-regulated in inflammation and their expression is relatively restricted to pathological cells. This confers another degree of specificity on biologics that are composed of chemokine receptor targeting agents. This review discusses articles, recent patents and patent applications that explore the selective depletion of pathological cells by targeting chemokine receptors with chemokine ligands, monoclonal antibodies and different bispecific constructs as a therapeutic strategy for allergic, autoimmune and inflammatory diseases.

The concern for management of intraocular inflammation has led to a continuing search for newer and more effective drugs. Though entry of antimetabolites, cytotoxic agents for the treatment of intraocular inflammation came as a great boon, latest research has been going on to improve the treatment modalities. Drugs like biologicals show effective anti inflammatory action in uveitis patients. The aim of the present work was to compile a bibliographic review of the diverse potentially anti-inflammatory drugs along with some recent patents in an effort to systematize the current knowledge on this topic. Also the present work intends to show the mechanism of action of different anti-inflammatory drugs which will be a good benefit in the treatment of uveitis.

Although pelvic radiotherapy, either alone or combined with chemotherapy, has proved to be successful in the treatment of patients with rectal, gynecological and urologic cancer, it is not devoid of side effects. Among patients receiving pelvic radiotherapy more than 70% develop acute inflammatory changes causing gastrointestinal symptoms during treatment. The most frequently reported symptom related to radiation-induced intestinal mucositis is diarrhoea. Among nutritional interventions used to manage radiation-induced diarrhoea, probiotics has gained popularity. This term describes organisms and substances that improve microbial balance in the intestines. Although encouraging results have been obtained in clinical trials, the potential of oral probiotics to manage gastrointestinal symptoms needs further research. The article also outlines recent patents related to probiotics therapy to reduce radiation induced mocositis.

Allergic disorders, including asthma, allergic rhinoconjunctivitis, atopic dermatitis, food allergies, urticaria and anaphylaxis have significant impacts on our daily lives. Innovation of novel treatment modalities targeting effector cells, cytokines, receptors or signaling pathways may bring new alternatives in the management of diseases, including allergic disorders. Understanding the mechanisms of allergic immune response is a requisite to plan or switch to a new or an adjunctive treatment course instead of or in addition to current conventional therapies, which are almost effective and safe in most of the cases. Monoclonal antibodies are major candidates that may act on the specific targets of allergic immune response in the treatment of these disorders. As monoclonal antibodies may contribute to our designing of new treatment options within the next years, specific concerns have to be considered such as efficacy, safety, long-term tolerability of these molecules as well as identifying associations with the mechanisms of disease pathogenesis. Hereby, it is aimed to review most of the currently published clinical studies in which some monoclonal antibodies were trialed for the management of allergic disorders. This review also addressed some recently patented monoclonal antibodies and their uses.

Dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA - S) are weak androgens produced in the adrenals and serve as primary precursors in biosynthesis of both, androgens and estrogens. These hormones are proposed to perform immunoenhancing activities and may play a crucial role in regulating cytokine production by Th1/Th2 cells; however, their role in immune-mediated diseases is controversial. The primary physiological role of DHEA-(S) and its mechanism is unclear. This review is a brief summary of relevant scientific basis as well as clinical research on the role of dehydroepiandrosterone in immune haemostasis and inflammatory diseases, including asthma, atopic diseases, chronic urticaria, pointing also to the significance of dehydroepiandrosterone therapy and the related US patents (1999-2005).

Laboratory and clinical data have implicated endotoxin as an important factor in the inflammatory response to cardiopulmonary bypass. Alkaline phosphatase prevents endotoxin-induced systemic inflammation in animals and humans. We assessed the effects of the administration of bovine intestinal alkaline phosphatase on surgical complications in patients undergoing coronary artery bypass grafting. In a double blind, randomized, placebo-controlled study, a total of 63 patients undergoing coronary artery bypass grafting were enrolled. Bovine intestinal alkaline phosphatase or placebo was administered as an intravenous bolus followed by continuous infusion for 36 hours. The primary endpoint was reduction of post-surgical inflammation. No significant safety concerns were identified. The overall inflammatory response to coronary artery bypass grafting with cardiopulmonary bypass was low in both placebo and bovine intestinal alkaline phosphatase patient group. Five patients in the placebo group displayed a significant TNFα response followed by an increase in plasma levels of IL-6 and IL-8. Such a TNFα response was not observed in the bovine intestinal alkaline phosphatase group, suggesting anti-inflammatory activity of bovine intestinal alkaline phosphatase. Other variables related to systemic inflammation showed no statistically significant differences. Bovine intestinal alkaline phosphatase can be administered safely in an attempt to reduce the inflammatory response in coronary artery bypass grafting patients with a low to intermediate EuroSCORE. The anti-inflammatory effects might be more pronounced in patients developing more fulminant postoperative inflammatory responses. This will be investigated in a further trial with inclusion of patients undergoing complicated cardiac surgery, demanding extended cardiopulmonary bypass and aortic cross clamp time. In this review article some recent patents related to the field are also discussed.

Corneal neovascularization (NV) is a significant complication of numerous infectious and non-infectious ocular surface disorders. Presence of newly formed blood vessels in the cornea can compromise clarity and therefore vision. Various growth factors and proteinases seem to be involved in the corneal NV. During corneal injury, angiogenic factors are released from corneal epithelial and stromal cells as well as infiltrating immune cells like macrophages. In fact, the balance between angiogenic and anti-angiogenic factors is shifted towards angiogenic molecules in the corneal NV. Numerous investigations support this idea that vascular endothelial growth factor (VEGF) plays a pivotal role in corneal NV by inducing endothelial cells proliferation, migration, and tubulogenesis. There is a growing body of evidence that corneal NV can be reduced by using anti-VEGF agents. This article reviews the most known molecular events in corneal NV and also some of the recent patents relevant to the field. Understanding the role of growth factors, proteinases and inflammatory cytokines in corneal NV can help the investigators to design therapeutic options for controlling this debilitating condition.

It is well established that airway inflammatory processes are pivotal as the pathological features of asthma. Prominent infiltration of eosinophils and Th2 lymphocytes is a hallmark of the allergic inflammation, and inhaled corticosteroids markedly suppress such inflammatory changes, resulting in clinical beneficial effects. Aerosol delivery of anti-asthma drugs such as corticosteroids is ideal from the standpoint of maximizing local effects in the lung as well as minimizing systemic side effects compared with oral therapy. The 1987 Montreal protocol banned chlorofluorocarbon (CFC) propellant in pressurized metered-dose inhalers (pMDIs), which has been replaced with hydrofluoroalkane (HFA) propellant. The aerodynamic diameters of HFA are much smaller than those of CFC, suggesting a greater distribution in peripheral airways. New types of dry powder inhalers (DPIs) and nebulizers, that do not use propellants, also have been introduced. Performance of each drug delivery device depends on a variety of factors including the device type, particle size and distribution, the product formulation and patient-related factors. Therefore, drug delivery can differ even when the same drug is delivered via an HFA pMDI, a CFC pMDI, a DPI or a nebulizer. New and advanced devices can be helpful to maximize the advantages of these modes of drug delivery, and patents of novel invention of inhalation devices are described.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets & therapeutic agents related to inflammation and allergy drug discovery.