Frontiers in Clinical Drug Research – Anti Allergy Agents

Histamine is a potent chemical mast cell and basophil messenger able to stimulate vasodilatation, gastrointestinal, respiratory and cardiac muscle contractions. At least four types of histamine receptors exist with varying physiological effects including vasodilatation, gastric acid secretion, brain chemistry and the cardiovascular system. Pharmacological antagonists are in common usage to at least two types of these receptors, H1 and H2; H1 being the classical “antihistamine” used in allergic conditions and H2 antagonism primarily associated with the prevention of gastric acid secretions. The first use of antihistamines to treat allergies was made over seventy years ago and these agents have undergone many chemical derivations since in order to maximize their H1 selectivity. In order to fully understand the underlying biochemistry of allergic disease, physiological roles of mast cells and basophils will be discussed together with a review of the mechanism through which histamine stimulates the H1 receptor. This chapter will delve into the history of the discovery of histamine, development of the antihistamines and the different pharmacological generations of drugs that have occurred since. Finally, we will conclude with a discussion of the new H1antihistamines currently under development together with potential future directions for this class of pharmaceuticals.

Chronic spontaneous urticaria (CSU) is defined as the presence of recurrent urticaria for more than 6 weeks. The exact etiology of CSU has not been elucidated. Multiple studies have shown that the screening with multitude of laboratory tests infrequently identifies a disease causing abnormality and rarely changes clinical management or outcomes. Management of patient with CSU may be challenging, as many require more than two anti-allergy medications that require close monitoring. Current published guidelines recommend a step-wise approach for the treatment of CSU, newer drugs such as omalizumab, a monoclonal anti-IgE antibody; have been successfully used to treat refractory disease. In this chapter, we will review the common therapeutic agents used in the management of CSU, their side effects, monitoring parameters and the level of evidence as described in the current literature.

Although eosinophilic inflammation in airways is a fundamental pathophysiology of bronchial asthma, there are no anti-inflammatory agents available other than glucocorticosteroid. Moreover, airway remodeling is caused not only by airway eosinophilia but also by bronchoconstriction independent of inflammation. However, glucocorticosteroid does not directly relax airway smooth muscle. Conversely, bronchodilaters such as β2-adrenoceptor agonists and muscarinic receptor antagonists do not clinically improve eosinophilic inflammation. Therefore, research and development for anti-asthmatic agents that are effective for both inflammation and contraction in the airway are needed to innovate pharmacological therapy for bronchial asthma. Airflow limitation, airway hyperresponsiveness, β2-adrenergic desensitization, and airway remodeling, which are caused by airway eosinophilia, are characteristic features of this disease. Alteration of contractility in airway smooth muscle contributes to airflow limitation, airway hyperresponsiveness, and β2-adrenergic desensitization. Furthermore, alteration of cellular protein synthesis contributes to airway remodeling via facilitation of the proliferation and migration of airway smooth muscle cells. Such phenotype plasticity means that airway smooth muscle cells can change the degree of a variety of functions, including contraction, proliferation, migration and the secretion of inflammatory mediators. Airway smooth muscle is involved in the pathophysiology of bronchial asthma not only via tension but also via inflammation. Alterations in contractile and synthetic phenotypes are caused by various factors, and Ca2+ homeostasis (Ca2+ dynamics and Ca2+ sensitization) in airway smooth muscle cells plays an important role in these alterations. Modulation of Ca2+ dynamics through the large conductance Ca2+-activated K+ channel / L-type voltage dependent Ca2+ channel linkage and store-operated Ca2+ influx, and of Ca2+ sensitization through the RhoA / Rho-kinase pathway contribute not only to alterations in the contractile phenotype involved in airflow limitation, airway hyperresponsiveness and tolerance to β2- adrenoceptors but also to alteration of the proliferative phenotype involved in airway remodeling. Therefore, these processes for Ca2+ signaling may provide therapeutic molecules for bronchial asthma, and research in these areas using airway smooth muscle may provide novel strategies for the development of pharmacological therapy (bronchodilation and anti-inflammation) towards the improvement of current control and towards reduction of future risk in bronchial asthma. Moreover, changing the phenotype in airway smooth muscle cells by focusing on modulation of Ca2+ dynamics and Ca2+ sensitization may play key roles in research and development for asthmatic agents.

This chapter focuses on the effects of Allergic Rhinitis (AR) on communication skills of the patients. Since AR is one of the most common chronic diseases and a global health issue, it is important to focus on its effects on human communication process. Therefore, it affects patient’s daily life. We used literature review and the patient interviews for this study. The common symptoms of AR, which is a chronic disease and the treatment process goes on for a long time, are runny nose, nasal congestion, sneezing and itching. Preventive measures, medications and sometimes immunotherapy are needed for the patients’ well-being. Due to the nasal discharge and congestion, headache, sleep problems, and sometimes learning problems may be observed. In patients with AR, there are also behavioral signs; in order to relieve the irritation or flow of mucus, patients may do an action known as the "nasal salute" or the "allergic salute". AR mainly influences the psychological status of persons who may demonstrate psychological imbalance or affective or other psychological disturbances. Depression, social introversion and poorer psychological functioning were reported in allergic rhinitis patients. This chapter describes the effects of AR on communication skills mainly in three categories: physiological, psychological and behavioral. AR has effects on all of these categories, and brings emotional, mental and physical problems to the communication process.

Toll-like receptors (TLRs) are major components of the innate immune system playing an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs).Till date, thirteen mammalian TLR members (TLR1-13) have been identified, ten in human and thirteen in mice. The human TLRs are further divided into two subgroups: six surface bound (TLR 1, 2, 4, 5, 6 and 10) and four within the intracellular endosomal compartment (TLR 3, 7, 8, and 9) of TLR-expressing cells. Extracellular TLRs identify structural components of pathogens like lipopolysaccharides, peptidoglycan, βglucan etc. Whereas endosomal TLRs are specific to pathogenic nucleic acids viz. double-stranded RNA (dsRNA), single-stranded RNA (ssRNA) CpG ODN etc. These sensors are expressed in a number of cell types including conventional dendritic cells (cDCs), plasmacytoid DCs (pDCs), macrophages, and B cells. Interaction with specific pathogenic antigens incites TLRs to trigger the transcription followed by synthesis of pro-inflammatory cytokines. Both the groups of TLRs have been particularly implicated in the pathogenesis of cancer, allergy and autoimmune disorders. However the present chapter is focused on endosomal TLRs and their crucial role in inflammation and related diseases. The initial part is focused on structural features of TLRs, specific ligands and thereafter intracellular signaling arbitrating the release of inflammatory mediators. In addition the role of endosomal TLRs in disease aggravation is also discussed. Moreover, the inhibition of activation or ability of modulation of these endosomal TLRs with specific ligands has also been illustrated as complementary therapeutic agents to combat various human ailments.