Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 11, Issue 3, 2012

Asthma is a heterogeneous disorder with a variable course. It begins very early in life and of different phenotypes. Mainstay treatment for asthma is corticosteroids as controller therapy and guidelines recommends the add-on and step-up or step-down strategies. This review will focus on the studies that enhanced our understandings of the effects of inhaled corticosteroids on the natural course of asthma in regard to symptoms control, protective effect on lung function and potential side effects encountered during the treatment. Studies that evaluated approaches on steroid sparing effects and the effect of asthma progression in children are also reviewed.

Reduction of lung inflammation is one of the goals in the treatment of cystic fibrosis (CF). As a result, antiinflammatory therapies are often used to decrease the excessive and persistent inflammatory response. Although effective, the use of systemic corticosteroids has been limited due to unacceptable adverse effects. Inhaled corticosteroids (ICS) are often used empirically to treat children and adults with CF despite the lack of evidence of their benefit. Concern about effects on growth and adrenal suppression have been reduced, but not eliminated with the use of ICS. Herein, mechanisms of action of corticosteroids, the effectiveness and safety of ICS usage in CF are reviewed.

Systemic corticosteroids (SCSs) have been widely used to treat various inflammatory respiratory diseases for many years despite the serious complications associated with them. Inhaled corticosteroids (ICSs) have been developed to reduce the harmful adverse effects of SCSs. Since their first introduction, ICSs have been used primarily for the treatment of asthma. However, certain individuals including those with chronic obstructive pulmonary disease or croup may respond to the beneficial effects of ICSs. In this review, we discuss the effectiveness of ICSs in the treatment of non-asthmatic inflammatory respiratory diseases in paediatric and adult populations.

It is well known that long-term treatment with systemic steroids exerts immune-suppressive effects on the cellular immune system and increase the susceptibility to all types of intracellular infections. Inhaled corticosteroids have been the mainstay treatment for asthma for a long period and are generally accepted as safe with no or minimal systemic absorption. Although, these medications are usually used for long periods and sometimes in high doses, there is scarce evidence on their impact on cell mediated immunity, reactivation of tuberculosis in tuberculin skin test positive patients, innate and anti-viral immunity. Hereby, the studies on immune-suppressive effects of inhaled steroids are discussed focusing on cell mediated and antiviral immunity.

Interleukin-26 (IL-26) is a member of the IL-10 cytokine family due to sequence homology. IL-26 was discovered, since the gene is strongly overexpressed in T cells which are growth transformed by herpesvirus saimiri. The IL-26 gene maps to human chromosome 12q15 between the genes for two other T-cellular class-II cytokines, namely interferon- γ(lFN-γ) and lL-22. IL-26, IL-22, and IFN-γ are co expressed by activated T cells and, especially, by Th17 cells. IL-26 forms homodimers and adheres to glycosaminoglycans on cell surfaces, presumably due to its positive charge. IL-26 specifically targets the lL-26-specific heterodimeric receptor complex consisting of IL-20R1 and IL-10R2 which is typically expressed on epithelial cells such as colon carcinoma cells or keratinocytes. IL-26 stimulation induces STAT1 and STAT3 phosphorylation, CD54 surface expression, and cytokine secretion as shown for IL-8 and IL-10. IL-26 seems to act as a cell surface-associated and rather proinflammatory T-cell cytokine at the epithelial barrier, possibly linking T-cell response with epithelial functions.

H1-antihistamines are inverse agonists that combine with and stabilize inactive conformation of H1-receptors. Thus they interfere with actions of histamine at H1-receptors. They are widely used for treatment of allergic rhinitis, allergic conjunctivitis, urticaria, coughs, colds and insomnia. H1-antihistamines are classified as older ‘first generation’ and newer ‘second generation’. First generation H1-antihistamines have poor receptor H1-receptor selectivity, and cross blood-brain-barrier. They have a lot of adverse events such as anti-muscarinic, anti-α-adrenergic, anti-serotonin, and sedative effects. In contrast, second generation H1-antihistamines were highly selective for the histamine H1-receptor, do not cross the blood brain barrier, and have minimal adverse events. The risks of first-generation H1-antihistamines have been clearly underestimated, particularly when purchased as nonprescribed over the counter medications by public. This review summarizes curent literature to evaluate antihistamines including their mechanism, indications and side-effects.

Human epidermis shows a non-neuronal cholinergic system including keratinocyte (kc) acetylcholine (Ach) axis which is composed by enzymes and two families of Ach receptors (muscarinic and nicotinic receptors). The activity of these two receptors can regulate the interkeratinocytes and kcs-extracellular matrix adhesion modifying the regulation of intercellular adhesion molecules like cadherins and integrins. Some authors demonstrate that acantholysis in pemphigus depends not only on anti desmogleins antibodies (abs) (mostly IgG) but even on other abs directed against kc membrane antigens (e.g. anti Ach receptors Abs). In the early phase of pemphigus pathogenesis, anti Ach receptors Abs block Ach signaling essential for cell shape and intercellular adhesion and increase the phosphorylation of adhesion molecules. Combined with the action of abs antidesmogleins, anti Ach receptors Abs cause the acantholytic phenomenon. In vitro experiments show that high doses of Ach in acantholytic kcs can rapidly reverse this pathologic event. In vivo experiments using neonatal mice model of Pemphigus have demonstrated that cholinergic agonists reduce these lesions. Therapy with pyridostigmine bromide and Nicotinamide per os or pilocarpine used topically, drugs that present cholinomimetic effects, has lead to encouraging results in patients affected by Pemphigus disease. Cholinergic agents could have a strategic role in the therapy of pemphigus since they could be responsible for the early stage of acantholytic diseases.

Oxidative stress and apoptosis are the states that can contribute to the pathogenesis of sepsis. In this study we aimed to investigate whether mitogen-activated protein kinase kinase 1 (MEK1)/extracellular signal-regulated kinase 1/2 (ERK1/2)/inducible nitric oxide synthase (iNOS) pathway plays a role in oxidative stress and apoptosis in endotoxemic rats. Systemic total antioxidant, SOD, GPx, and GR activities as markers of oxidative stress, and tissue caspase-3 enzyme activity as a marker of apoptosis were measured in sera and thoracic aortae of male Wistar rats sacrificed 4 h after being treated with saline (vehicle) or lipopolysaccharide (LPS) (10 mg/kg, i.p.). A decrease in total antioxidant activity and caspase-3, SOD, GPx, and GR enzyme activities was occured by LPS. These changes caused by LPS were prevented when a selective iNOS inhibitor, 1,3-PBIT (10 mg/kg, i.p.) or a selective inhibitor of ERK1/2 phosphorylation by MEK1, U0126 (5 mg/kg, i.p.) were given 1 h after administration of LPS. Our results suggest that decreased activity of MEK1/ERK1/2/iNOS pathway prevents oxidative stress by increasing systemic antioxidant enzyme activities and restores decreased caspase-3 activity in thoracic aorta in endotoxemic rat.

This study was designed to evaluate the anti-inflammatory action of four dihydroxy flavone derivatives; 3,3'- dihydroxy flavone, 5,6-dihydroxy flavone, 3,7-dihydroxy flavone and 6,3'-dihydroxy flavone and to further investigate the multiple cellular mechanisms underlying the anti-inflammatory effect of these compounds. The effect of dihydroxy flavones on acute inflammation was studied in rats employing carrageenan induced hind paw edema method. Further, the role of proinflammatory cytokines like TNF-α and IL-1β, cyclooxygenases (COX-1 and COX-2), and free radicals in the action of flavone derivatives was investigated using in vitro assays. All the four dihydroxy flavone derivatives exhibited time and dose dependent inhibition of carrageenan induced paw edema. In addition, the investigated compounds inhibited both the isoforms of cyclooxygenase and cytokines in a concentration dependant manner and also suppressed the release of reactive oxygen species. The anti-inflammatory effect of dihydroxy flavones may be through mechanisms that involve an interaction with cyclooxygenases, cytokines and reactive oxygen species.

A Fourier transform infrared (FT-IR) spectrometric method was developed for the rapid, and direct measurement of piroxicam (Pir) in pharmaceutical drugs. Pir is a well known and very effective antiinflammatory drug. Pir can be determined by various methods and now we are adding a new one that uses a Fourier transform infrared spectrophotometric technique. Conventional spectra were compared for best determination of active substance in pharmaceutical formulations. The Beer-Lambert law and two chemometric approaches, partial least squares (PLS) and principal component regression (PCR&plus) methods, were tried in data processing.

Ischemia/reperfusion (I/R)-induced injury is a pathophysiological process consisting of a complex cascade characterized by an increase in reactive oxygen species production, pro-inflammatory cytokine release, and activated endothelial cells leading to cell damage and death. The aim of this study was to investigate effects of substituted 2- benzylbenzimidazole derivatives, 2-(3-methoxybenzyl)benzimidazole (BB3) and 2-(4-methoxybenzyl)benzimidazole (BB4), on I/R-induced changes in the markers of oxidative stress, apoptosis, and angiogenesis in rats. BB3 and BB4 were synthesized with microwave irradiation and conventional Phillips methods. I/R was performed by occlusion of femoral artery. Catalase activity and reduced gluthatione (GSH) levels as well as caspase-3, -8, and -9 activities were measured in muscle tissues as an index for oxidative stress and apoptosis, respectively. Vascular endothelial growth factor (VEGF) levels as an index for angiogenesis were also measured in the muscle tissues and sera. I/R decreased GSH levels, increased catalase activity and VEGF levels, and did not change caspase-3, -8, and -9 activities compared to control groups. BB3 and BB4 caused a further decrease in GSH levels and increased caspase-3, -8, and -9 activities in I/R group. These compounds caused a further increase in catalase activity and prevented the increase in VEGF levels induced by I/R. These data suggest that BB3 and BB4 exhibit apoptotic and anti-angiogenic activity with pro-oxidative effects resulting in oxidative stress in pathophysiological process of I/R-induced hind limb injury in rats.