Clinical Anti-Inflammatory & Anti-Allergy Drugs (Discontinued) - Volume 1, Issue 1, 2014

Patients with severe asthma have disease that is poorly controlled despite use of standard combination therapies consisting of high doses of inhaled corticosteroids with other controller medications. Given the persisting disease and burden of morbidity for many of these patients, there remains a significant need for the development of new therapeutics to treat severe asthma. Preclinical studies have established a model of asthma pathogenesis that is driven by type 2 inflammation. Based on this paradigm, a number of therapeutic agents that target key features of type 2 inflammation, such as immunoglobulin E (IgE), mast cells, eosinophils, and type 2 inflammatory cytokines, have been generated and progressed into clinical development. Coupled with recent insights into the heterogeneity of asthma that have led to the development of diagnostic biomarkers to help select patients who may experience greater clinical benefit from these agents, several of these therapeutics have shown promising effects in clinical studies, with one therapeutic currently on the market. Here we review the results of clinical studies for these therapeutics and discuss how our understanding of asthma pathogenesis and disease heterogeneity may be leading to a new generation of therapies for severe asthma.

Acute pancreatitis (AP) is an acute inflammatory process of the pancreas which involves a complex cascade of events initializing in pancreatic acinar cells. This, in turn leads to an inflammatory response, which results in the pathology of acute pancreatitis. In this review, we describe the role of different cell types and inflammatory mediators in the pathogenesis of acute pancreatitis.

Depletion of IgE-switched B cells may be an efficacious therapy for the treatment of allergic asthma. A humanized monoclonal IgG1 antibody against the M1 prime segment of human membrane IgE on IgE-switched B cells can reduce serum IgE by depleting IgE-producing cells. Here we report that removal of the core fucose in the Fc glycan of this anti-M1 prime antibody increases its binding affinity for human FcγRIII receptors compared to the wildtype antibody. The enhancement in binding to FcγRIII results in increased antibody potency for the in vitro depletion of IgE-positive cells in antibody-dependent cell-mediated cytotoxicity assays and for the in vivo reduction of serum IgE in mice reconstituted with human immune cells. This afucosylated anti-M1 prime antibody is known as quilizumab and is in clinical development for the treatment of allergic asthma.

Objectives. To analyze the relationship between in vitro cytokine production in proliferating CD4+ T cells and the effect of anti-TNF-alpha (tumor necrosis factor-alpha) agents (TNF-alpha blockers) in patients with rheumatoid arthritis (RA). Methods. Peripheral blood mononuclear cells (PBMCs) from RA patients (n=19) were labeled with CFSE [5 (and 6) carboxyfluorescein diacetate, succinimidyl ester] and cultured with ConA. CD4+ T cells were assessed for production of IFN-gamma, IL-4 and TNF-alpha, and proliferation by flow cytometry. We examined association of these parameters with clinical response of TNF-alpha blockers in short, medium and long term studies. Results: Clinically good response of TNF-alpha blockers was associated with lower TNF-alpha production in proliferating CD4+ T cells in short term study (p<0.05). Increased production of IFN-gamma (p<0.05) in proliferating CD4+ T cells was associated with good response in long term study. Conclusions: In vitro evaluation of cytokine production in proliferating CD4+ T cells, prior to treatment of TNF-alpha blockers, may provide possible information of efficacy of TNF-alpha blockers in RA patients.

Facile synthesis of some novel anti-inflammatory and analgesic agents was established by initially treating 3- acetyl indole (1) with the various aromatic aldehydes (2) which afforded the corresponding 3-chalconylindoles 3a-e. These products 3a-e upon treatment with hydrazine hydrate gave the resultant pyrazoline derivatives 4a-e. Also, the diazotized salt of aniline, when reacted with these pyrazoline indoles 4a-e yielded azo derivatives of pyrazoline indoles 5a-e. These newly synthesized compounds were screened for the mentioned activities and were found to possess good potential to act against inflammation and pain.

Activin-A is a member of the TGF-β superfamily, initially identified as an inducer of follicle-stimulating hormone secretion. Activin-A is highly conserved in evolution and modulates fundamental biological processes such as embryonic development, stem cell maintenance and differentiation, hematopoiesis, cell proliferation and fibrosis. Emerging data support a role for activin-A as a true cytokine that can exert both pro- and anti-inflammatory activities depending on the cell type, the cytokine micromilieu and the context of the immune response. Interestingly, a large body of evidence suggests that activin-A is increased in experimental models of allergic airway inflammation and in the airways of individuals with asthma. Importantly, in vivo functional studies have uncovered a key role for activin-A in the suppression of allergen-driven T helper (Th) type 2 cell responses and the amelioration of experimental asthma manifestations through the induction of strongly suppressive IL-10-producing regulatory T cells (Tregs). Of clinical relevance, activin-A and its signaling components are activated in the airways of individuals and asthmatics, pointing to a role for activin-A in the regulation of human allergic responses. Here, we provide an overview of the biology of activin-A and review the recent studies implicating activin-A in the modulation of experimental and human allergic asthma.

Hydrogen sulfide (H2) is a gaseous molecule that is produced by the body. Elevated levels of H2 can result in a number of physiological responses. The specific mechanisms in which H2 directly facilitates these responses have not yet been well characterized, however, it has recently been established that sulfhydration of proteins is integral to the effects of H2. A growing field of research is the development of new drugs which suppress endogenous hydrogen sulfide synthesis, as well as novel H2 donors. Evidence suggests that modulation of the H2 signaling system may be an excellent therapeutic approach for a range of clinical conditions including heart failure, inflammatory diseases, hypertension, acute myocardial infarction, gastrointestinal diseases and cancer. In this review, we describe an overview of the physiological and pathophysiological roles of H2. We further discuss the current research of H2 modulating drugs and suggest potential approaches for the continued development of novel drugs.