Recent Patents on Inflammation & Allergy Drug Discovery - Volume 7, Issue 3, 2013

Seasonal allergic rhinitis is characterized by seasonal rhinorrhea, nasal congestion/stuffiness, nasal and ocular pruritus, and paroxysmal sneezing. Allergen avoidance is the first step in the management. Symptomatic relief and improved quality of life can be achieved in the majority of patients by the appropriate use of pharmacotherapy. Mild to moderate cases can be managed with either an oral/intranasal second generation antihistamine or an intranasal corticosteroid alone. More severe cases may require treatment with an intranasal corticosteroid in combination with various agents. Patients who require medications for more than 6 months per year, two or more seasons of unacceptable pollinosis, or have intolerable side effects from pharmacotherapy, especially those with co-morbid conditions are candidates for immunotherapy. This review article also discusses recent patents related to the field.

Autophagy is a complex process in which cell homeostasis of proteins, organelles, exocytic and endocytic vacuoles is controlled. There is a direct link between autophagy and cell death with antigen processing, generation of inflammatory response and immune response. In different diseases, deficiencies in autophagy have been reported. In cancer, it has been proposed that autophagy, at its beginning, is capable of inducing cell death; however, in aggressive tumours and metastasis, the process is responsible for pharmacologic resistance and tumour survival. More research has to be done in order to allow us to understand the process and generate therapeutic options in different pathologies important for the human being. Some patents focused on methodology of autophagosome formation and analysis which seem to be important for pathological description and eventually in future therapeutic approaches have also been reviewed in this article.

During the last few years, fixed combinations of intranasal antihistamines and corticosteroids have been introduced for treatment of allergic rhinitis. The aim of this systematic review was to assess recent patents and clinical evidence for fixed combinations of intranasal antihistamines and intranasal corticosteroids in allergic rhinitis. Data base searches revealed that intranasal combinations of the antihistamine azelastine with the corticosteroids mometasone furoate, ciclesonide and fluticasone propionate, respectively, have been patented. Four randomized, double-blinded, parallelgroup, placebo-controlled, multicenter trials sponsored by the manufacturer evaluated the fixed combination of intranasal azelastine 125µg and fluticasone propionate 50µg administered as one dose per nostril b.i.d. in patients with moderate-tosevere symptomatic allergic rhinitis ≥ 12 years of age. Three of the studies were published as a meta-analysis which found the fixed combination of azelastine and fluticasone propionate statistically significantly more efficacious in reducing baseline total nasal symptom score by 5.7 as compared to azelastine (4.4; P < 0.001), fluticasone propionate (5.1; P < 0.001) and placebo (3.0; P < 0.001). The findings were supported by secondary assessments of scores of specific nasal and ocular symptoms. Pharmacokinetic studies have revealed no drug-drug interactions but a discrete increase in bioavailability of fluticasone propionate which was considered clinically unimportant. Further efficacy and quality-of-life studies of combination products of nasal antihistamines and corticosteroids are needed, especially, in primary care settings and in children before fixed combination treatment can be considered first line therapy in allergic rhinitis. Fixed combination treatment of azelastine and fluticasone propionate may offer additional benefit to selected populations of adolescents and adults with moderate-to-severe symptoms.

Caspases, or cysteinyl-aspartate specific proteases, are major contributing enzymes in inflammation. Caspases are highly specific cysteine proteases closely involved in inflammatory responses that are associated with programmed cell death, or apoptosis. Inappropriate regulation of cell death, therefore, substantially results in a wide array of diseases including, but not limiting to, neurodegenerative disorders, ischemic disorders, and cancer. The key molecular genes that control cell death are those cell death effectors (pro-apoptosis) of the caspase family, on one hand, and the cell death inhibitors (anti-apoptosis) of the Bcl-2 family, on the other hand. This unequivocal and unprecedented equilibrium between caspases and Bcl-2-related molecules essentially controls cells’ final demise. Caspases and related proteases are potential therapeutic targets in a variety of acute and chronic diseases. Current design of biologically active molecules in recent technology is dependent on DNA-based scanning of the genome to engineer a variety of molecules such as apoptosis inhibitors, caspase regulators and caspase activators, and cytokines involved in caspase signaling. This synopsis aims to review relevant patents and to unravel the discovery of small-molecule caspase protease inhibitors and their clinical ramifications, and further sheds light on recent experimental and clinical trials, emphasizing a small molecule dubbed 3-[2-[(2- tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid (IDN- 6556/PF-03491390). Current opinion on investigational drugs targeting caspases and caspase-like proteases bears the significance of understanding the mechanisms of alleviating inflammatory-related acute and chronic conditions and their biomedical applications and repercussions.

Imatinib mesylate is a selective protein tyrosine kinase inhibitor, which can inhibit BCR/Abl, PDGF-R, c-KIT, c-fms, TCR/Abl, Lck, FLT-3 and MAPKs activities on various cell types. On immune system, imatinib has antiproliferative activity and immunomodulatory effects in lymphocytes, macrophages, mast cells and dendritic cells with abrogating multiple signal transduction pathways involved in pathogenesis of autoimmune diseases e.g. inhibiting IFN-γ, TNF-β, IL-1β and IL-17 pro-inflammatory cytokines and MMPs secretion. To date, the efficacy of imatinib in numerous animal model of autoimmune diseases (rheumatoid arthritis, multiple sclerosis, autoimmune diabetes and glomerulonephritis) has been demonstrated, but application of this drug in human autoimmune diseases should be tested in future clinical trials. This review provides an update on the use of tyrosine kinase inhibitor imatinib mesylate in treatment of autoimmune diseases and its related recent patents that could be developed as a novel and available therapy for the management of the autoimmunity improvement.

Background: Paracetamol (acetaminophen) is a widely used analgesic/antipyretic drug for which hypersensitivity reactions appear to be increasingly frequent. Objective: We report the case of a woman who experienced several delayed selective reactions induced by paracetamol: fixed drug eruptions (FDEs) with typical features but an unusual distribution (hard palate and a maculopapular rash. Methods: Skin tests: prick, intradermal and patch tests as well as a single-blind oral challenge test (OCT) were performed. Results: Skin tests were negative. The OCT was necessary to confirm the diagnosis. Interestingly, the challenge test elicited an FDE-type lesion instead of a maculopapular rash. Conclusions: Our findings could reflect 2 different clinical patterns of delayed allergic reactions, or, more probably, the initial phase of a unique clinical entity that was stopped by the corticosteroids prescribed during the challenge. However, we were unable to confirm these hypotheses. The uncommon anatomical site of the lesions (hard palate) is noteworthy. Some relevant patents are also summarized in this paper.