Recent Patents on Inflammation & Allergy Drug Discovery - Volume 4, Issue 1, 2010

Phosphoinositide 3-kinase gamma (PI3Kγ) is a lipid kinase in leukocytes that generates phosphatidylinositol 3,4,5-trisphosphate to recruit and activate downstream signaling molecules. Distinct from other members in the PI3K family, PI3Kγ is activated by G-protein coupled-receptors responding to chemotactic ligands. PI3Kγ plays an important role in migration of both myeloid and lymphoid cells. It is also required for other leukocyte functions such as neutrophil oxidative burst, T cell proliferation and mast cell degranulation. Mice with inactivated PI3Kγ by genetic or pharmacological approaches are protected from disease development in a number of inflammation and autoimmune disease models. The function of PI3Kγ depends on its kinase activity and therefore it has been suggested by many reports that small molecules inhibiting its kinase activity could be promising for the treatment of inflammation and autoimmune diseases. Over the last five years, a number of pharmaceutical companies have reported a wide variety of PI3Kγ inhibitors, of which several x-ray crystal structures with PI3Kγ have been elucidated. The structural characteristics and selectivity profiles of these inhibitors, in particular thiazolidinones, 2-aminoheterocycles, and those disclosed in related patent applications are summarized in this review.

In this review we discuss current challenges faced by researchers and clinician-scientists in the pursuit of therapeutics to treat hypoxic-ischemic (HI) brain injury in term infants. At present, there is an absence of neuroprotective drugs that are safe and effective for the protection of neonates from neurological sequels after HI. We discuss secondary neurotoxic processes elicited by HI that may be targets for therapeutic interventions with a specific focus on inflammatory mechanisms. Advances in research to unravel these cellular processes and molecular mechanisms that drive injurious processes after HI have traditionally been plagued by conflicting results when assessing different times for intervention, different models for brain injury, and the adult versus neonate brain. We attribute impeded drug development in part to such disparate results and general difficulties to conduct a stringent, comprehensive analysis of candidate drugs prior to clinical trials. It will be imperative to implement changes in the clinic and laboratory in order for future drug initiatives to achieve success. We also provide a brief discussion on the pursuit of anti-inflammatory molecules and monitoring methods that are the focus of current patents and that, in our opinion, may lead to important new developments in the treatment of HI brain injury in newborn infants.

Sucralfate is a basic aluminium salt of sucrose octasulphate which was orally employed for prevention and treatment of several gastrointestinal diseases including gastroesophageal reflux, gastric and duodenal ulcer. Recent studies have employed sucralfate as a topical drug for the healing of several types of epithelial wounds such as ulcers, inflammatory dermatitis, mucositis and burn wounds. Epithelial wound healing is a well orchestrated process involving hemostasis, inflammatory reaction, cell proliferation and tissue remodeling which leads to granulation tissue development and filling of the wound space. This report will review clinical evidence on the use of topical sucralfate for the management of epithelial lesions and deal with the current knowledge on the molecular mechanisms of action of this compound towards the epithelial wound healing process and will also discuss relevant patents.

Allergic bronchial asthma is a chronic inflammatory disorder of the airways characterized by a T helper 2 (TH2) cell triggered airway eosinophilia, development of airway hyperresponsiveness, mucus hypersecretion and structural changes of the airway wall summarized as airway remodeling. Current asthma therapy aims at controlling the inflammatory response in the airways by using corticosteroids in mild-moderate asthmatics. With increasing disease severity addition of further medication is required and includes long acting β2-agonists or even immune suppressive drugs such as azathioprine, methotrexate or cyclophosphamide. Due to considerable side effects of these drugs especially under high dose treatment conditions controlling moderate-severe asthma represents an unmet medical need. Over the last 15 years mouse models of allergic asthma increased the knowledge about the pathophysiology of allergic asthma dramatically and led to several new therapeutic approaches such as the development of a monoclonal antibody against IgE. However, since TH2 cells seem to play a pivotal role in orchestrating the inflammatory response underlying asthma pathology these cells are predisposed as targets for therapeutic intervention. Thus, the present article further discusses several relevant patents and the current status of experimental approaches towards asthma therapy that aim at neutralizing TH2 cell effector functions, TH2 cell development, TH2 cell recruitment, and immunomodulation.

Obstructive sleep apnea syndrome (OSAS) is associated with inflammatory processes and elevated plasma cytokines. Inflammatory processes associated with OSAS may also act as potential mediators of cardiovascular morbidity in these patients. OSAS is associated with elevated levels of C reactive protein (CRP), as a marker of inflammation and cardiovascular risk. At the inflammatory point of view, the levels of TNF-α, IL-6, hsCRP, adhesion molecules, monocyte chemoattractant protein-1 and resistin were markedly and significantly elevated in patients with sleep apnea than those in normal control subjects. We reviewed several recent patents and literature in English about OSAS and upper airway inflammation relation since 1966 from the Medline database.

Topical ketoprofen (KP) is widely used because of its anti-inflammatory effect. Parallel with its popular usage, the number of reported cases of ketoprofen-induced photoallergic contact dermatitis has increased. A review of the literature was made to evaluate the spectrum of cross sensitization in patients with ketoprofen-induced photoallergic contact dermatitis using ketoprofen and other structurally similar chemicals and sunscreens, fragrance components, as well as the presence of prolonged photosensitivity related to it. Furthermore, the distinction between true cross-reactivity and concomitant sensitization may be difficult. Therefore, further investigations are needed to gain a more complete understanding of this important topic. This article also reviews some patents related to alternative treatment of musculoskeletal diseases and/or treatment of allergic reactions due to NSAIDs use.

Occupational healthcare may expose to various allergens and irritants. Thus, the allergic manifestations in nursing staff are frequent and their prevalence is increasing all over the world. In fact, many new substances continuously appear in the medical practices. These allergic manifestations include a wide spectrum of clinical symptoms such as ocular, nasal and especially bronchial symptoms, which can be isolated or associated. These diseases can be a source of many problems related to the occupational aptitude. All these conditions justify prevention procedure strengthening, which mainly consist in substituting the sensitizing agents, and applying collective and individual prevention measures. This article also refers to some patents on the treatment of allergy.

Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase associated with the common gamma chain that is activated by multiple T-cell growth factors including IL-2, -4, -9, -15, and -21. From the recent reports, genetic absence or ablation of JAK3 is associated with defective T-cell immunity that results in severe combined immunodeficiency (SCID) and pharmacological inhibition has prolonged allograft survival in some models of organ transplantation. This review would provide an overview of some patents along with the role of JAK3 in the immune system and efficacy of JAK3 inhibitors in experimental allograft rejection and autoimmune disease.

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.