Frontiers in Clinical Drug Research – Anti Allergy Agents

The most common diseases affecting respiratory tract are bronchial asthma and chronic obstructive pulmonary disease (COPD). Both pathologies involve the genesis of an inflammatory response that induces airway hyperresponsiveness (AHR) and obstruction. Differences between both may include the cellular component: eosinophilia in atopic asthma and neutrophilia in COPD and also the nature of AHR which is generally reversible in asthma whereas in COPD this phenomenon culminates with the complete reduction of airflow. Because it represents the major global cause of disability and death, countless efforts have been underway for decades to develop therapies to alleviate their symptoms. Despite the fact that asthma is the result of a Th2 response in which IgE antibody is the main effector mechanism, the use of antibodies against cytokines of this profile did not show effectiveness until now. This could be because asthma is a multifactorial disease, depends also on the differentiation of TCD8+ lymphocytes type Tc2/Tc17 during the chronicity of the process. In contrast to asthma, inhaled glucocorticoids in COPD have a limited effect in resolving inflammatory symptoms, which could explain the high dependence on noxious stimuli such as smoke that aggravates the obstructive disease. The drugs tested so far cover the two main aspects of these pathologies: inhibition of a) functionality or activation of inflammatory response or b) tissue remodeling. In the first place, systemic antagonist of H1 and H2 receptors were widely used for decades in asthma as antipruritic and central sedatives, however their anti-inflammatory effects were modest, despite their important local effects in allergic reactions affecting skin such as dermatitis, rhinitis and conjunctivitis where the integrity of the epithelial barrier is more important in its genesis. Also, montelukast, an antagonist of cysteinyl-leukotriene C4 appears to affect both the inflammatory response and lung structure being successfully used in pediatric asthma. On the other hand, therapies with β2-agonist or anticholinergic drugs, widely used in COPD, have been shown to improve airway inflammation thickening. This review aims to provide a comprehensive overview of the available literature on the novel therapeutic targets; histamine, acetylcholine and cysteinyl-leukotrienes, with emphasis on the benefits and disadvantages of these clinical trials.

Allergic asthma is a worldwide chronic inflammatory disease characterized by cycles of airway obstruction due to recurrent episodes of respiratory smooth muscle contraction and bronchoconstriction. Public awareness of asthma has increased over the past few decades due to higher prevalence, especially among younger generations. Many research efforts are dedicated to the understanding of this complex disorder and the role of genetic and environmental factors. Emerging evidence from animal studies and clinical trials has identified oxidative stress (OS) as an important factor contributing to asthma pathogenesis. In addition, observational epidemiologic studies suggest a possible correlation between impaired intake of antioxidants and increased prevalence of allergic asthma. The imbalance between antioxidants and oxidants in the respiratory airway due to overproduction of reactive oxygen species (ROS) or overwhelmed antioxidant system indicates a strong association between ROS and asthma. Although physiological levels of ROS are essential for the modulation of cell signaling pathway, excessive ROS production can lead to worsened physiological conditions, including increased airway hyperresponsiveness, epithelial shedding, vascular permeability, mucus secretion, as well as other inflammatory responses through the upregulation of proinflammatory mediators. In particular, the exposure to sources such as allergens, air pollution, and tobacco smoke, not only triggers airway inflammation, but also provides exogenous ROS. Simultaneously, overreacted immune responses exacerbate ROS formation, which furthers the inflammation. Redox therapeutics has become a potential approach in alleviating OS and restoring oxidant-antioxidant balance. However, redox therapeutics is limited by ineffective measurement of lung redox status due to the lack of standard biomarkers of OS and antioxidant capacity. Moreover, the responses to antioxidants are largely dependent on the stage of the disease, genetic susceptibility, and external sources of OS. These aspects also pose a great challenge to the redox therapeutics. The antioxidants, either antioxidant enzymes or non-enzymatic antioxidants, are frequently used in the treatment for multiple diseases, including neurodegenerative, cardiovascular, skin, and liver diseases. Particularly, the intake of antioxidant supplements, such as vitamin C, and dietary changes are proposed to decrease asthma prevalence and enhance asthma control. However, limited data has displayed their beneficial effects on asthma subjects clinically. The exact mechanism by which ROS influence the lung tissue remains unclear. Future studies may be focused on the molecular mechanisms of redox processes as well as the development of treatments in allergic asthma.

In this chapter, we will discuss the specific antioxidants from supplement and diet that are potential agents for the treatment and prevention of asthma. The pathogenesis of allergic asthma and its correlation with inflammation and ROS/OS will be presented. The development of potential biomarkers of OS and effective therapeutic redox intervention will be discussed in this chapter.

The inflammatory liver diseases with a metabolic origin, such as alcoholic liver disease (ALD) and nowadays, non-alcoholic fatty liver disease (NAFLD) associated to the growing epidemic of metabolic syndrome, are two important health care problems and common causes of cirrhosis and its complications in developed countries and worldwide. The physiopathology of these conditions, importantly involves oxidative stress. In ALD, alcohol metabolism comes from oxidative and nonoxidative pathways. The oxidative pathway involves two major enzymes, alcohol dehydrogenase (ADH), which oxidizes alcohol to acetaldehyde, and acetaldehyde dehydrogenase (ALDH) that transforms acetaldehyde to acetate. Acetaldehyde is a cardinal toxin involved in alcohol-related liver injury. Reduced nicotinamide dinucleotide (NADH) generated by these enzymatic reactions also contributes to harm. The oxidation of alcohol also occurs via cytochrome P450 to cause liver damage by producing reactive oxygen species (ROS) that are guilty of activating redox-sensitive transcription factors, such as nuclear factor-kappaB (NF-kB), triggering and perpetuating a pro-inflammatory status. Similarly, oxidative stress, in addition to insulin resistance, is considered as a main factor contributing to liver injury in patients with non alcoholic steatohepatitis (NASH). Recently, oxidative stress constitutes a novel and attractive target for therapy, in ALD, NAFLD and NASH.

Allergic rhinitis (AR) is characterized by Ig-E mediated inflammation of the nasal mucosa and paranasal sinuses [1]. Classical symptoms of AR are “watery nasal discharge (rhinorrhoea), nasal itching, nasal obstruction and sneezing”. Pathophysiological pathways of AR are triggered with the repeated exposure of the allergen with the sensitive nasal mucosal lining. After the interaction of “antigen” and “sensitized mast cell”, immediate hypersensitivity reaction occurs and various preformed and newly produced molecules became released. To understand these cellular and molecular and even chronobiological bases of AR is crucial to maintain optimal and satisfactory results on the pharmacological treatment of AR. While “systemic or intranasal antihistamines, intranasal corticosteroids, leukotriene receptor antagonists, topical anticholinergics and mast cell stabilizers” have been shown to be superior than placebo in the treatment of AR, other drugs such as “decongestants, mucolytics, saline” can be used in order to achieve temporary and symptomatic relief. Besides these much known medications, numerous experimental and clinical studies are ongoing about capsaicin and recombinant-humanized-monoclonal anti-IgE antibody in the treatment of AR. Immunotherapy is a good alternative for the selected patients who are resistant to allergen avoidance and medical treatment and shown to be sensitized to a specific allergen. In this chapter, we aimed to discuss pharmacological treatment options of AR and review the literature in the light of the recent developments and researches in the field of AR. We also aimed to overview some important and updated consensus reports such as “Allergic Rhinitis and its Impact on Asthma” (ARIA) in the beginning of the chapter to summarize the current treatment strategies against AR. Finally we highlighted a section about the treatment of pediatric AR patients to mention the differences between adults and children.

In recent times, allergy has become a financial, physical and psychological burden to the society as a whole. The rise in allergy trends has reached panic proportions since the early 1990’s and well into the 21st century. As suggested by the hygiene hypothesis, a western way of life paves way to an atopic individual with a weaker, more prone immune system, which is synonymous with excessive IgE antibody production. Allergy affects people from all walks of life; young and old and can be lifethreatening in some situations. Recently, cytokines IL-4 and IL-13 have been identified as the main interleukins that play a critical role in allergy. In atopic individuals, a Th2 type profile of T cells exists rather than the Th1 subset in non-atopic individuals. This Th2 cell variation results into a different profile of cytokines such as IL-4 and IL-13. This consequently shifts antibody production from one of IgG to IgE profile. Upon exposure to foreign antigens or allergens, these cytokines cause a cascade of events eventually leading to the release of chemical mediators such as histamine that cause the allergy symptoms.

Allergic symptoms may vary from a mild sneeze to a full-blown anaphylactic shock, which may result in death. Developments in allergy drugs have been limited to counteracting the symptoms but not the allergic cascade itself raising concerns about quality of life. However, new frontiers in clinical drug research have been unfolded in recent years to tackle this problem. Drugs such as antihistamines and non-steroidal antiinflammatories are in use for suppressing allergy symptoms. Other techniques such as specific immunotherapy, antibodies and most recently peptide antagonists have been investigated for their potentiality against cytokines and allergy. However, a shadow of skepticism and doubt still persists with all these developments. Many researchers have drawn their attention particularly to IL-4 and IL-13 cytokines along with their receptors as novel therapeutic targets for allergy intervention. This chapter will focus on recent developments in this particular field and shed some light on anti-allergy agents that inhibit cytokines.

General interrelationships between peripheral inflammation and hyperalgesia are discussed, citing previous reports. Neuroinflammatory substances and their intracellular mediators are briefly introduced. Algogenic substances (chemicals and natural products), their receptors, and anti-inflammatory drugs interrupting receptors, channels, and intracellular messengers are particularly highlighted. TRP channels are expressed on almost every tissue and cell type and conduct important regulation in the diverse cell functions. Allergic reactions are associated with thermosensing TRP channels (TRPV, TRPA, and TRPM). TRP channels are also expressed in immune cells and are therefore closely correlated with itching and inflammation. Nine thermosensing channels are the focus in allergies under normal and pathophysiological conditions. Although it is known that a proinflammatory cytokine (interleukin-1β: IL-1β) released from spinal microglia plays a crucial role in the induction and maintenance of acute and chronic pain states, the cellular basis of this action remains to be elucidated. The action of IL-β on synaptic transmission in spinal lamina II (substantia gelatinosa: SG) neurons has a pivotal role in the regulation of nociceptive transmission from the periphery. The experiment applied the whole-cell patchclamp technique to SG neurons in rat spinal cord slices and revealed that IL-1β pre- and postsynaptically enhanced glutamatergic spontaneous excitatory transmission while inhibiting spontaneous inhibitory transmission. These IL-1β actions could contribute to central sensitization and hyperalgesia in SG neurons.

Allergic diseases are a major health problem that affects millions of people worldwide. They constitute the fifth most common chronic diseases in all ages, and the third most frequent in children. The human and economic loads associated with these conditions are severe and harmfully affecting the socioeconomic welfare of the community. Anti-allergy drugs are the broad term for drugs known to treat allergic reactions. Starting from the second part of the 19th century where black coffee (a drink with a high content of theophylline) was prescribed as a treatment for asthmatic patients, to the first half of the 20th century where bronchodilators were used as over the counter medicine for asthma. Due to their slow action and quite low efficiency rate, the development of anti-allergy drugs was criticized at its early stage. Most of current anti-allergy drugs' mode of action is to either prevents the release of inflammatory mediators or inhibits the actions of these mediators on their target cells. Current therapeutic approaches are effective in treating only the symptoms of allergic diseases, not preventing the start of allergies. Lately, major advances in the understanding of allergic diseases have been achieved; as a result, new treatment modalities have been designed: DNA vaccines with Th1-promoting properties and balancing Th2-mediated immune reactions became a promising substitute for immunotherapy against allergy. Alteration of IgE binding sites, i.e. allergens epitopes, as well as new antibodies directed against human IgE could be another approach to attenuate allergic reactions as well as treatment with an enterovirus vaccine. Other potential new methods for treatment are the use of anti-cytokine directed therapy e.g. anti-TNF alpha, anti-IL-13 antibodies and the use of Toll-like receptor modulators. While there are numerous possible strategies to develop a new drug every day, treatments that aim at immune deviation, immunotherapy with its modalities, have gained significant attention as they may hold the hope of modifying the disease or reaching a long-term cure. The present chapter describes the current as well as new patents as well as the promising medications in the treatment of allergy.