Frontiers in Clinical Drug Research – Anti Allergy Agents

Emollients have long been used to maintain the skin barrier function in patients with atopic dermatitis. For many years, topical corticosteroids have been mainstay for atopic dermatitis (AD) treatment. The introduction of topical calcineurin inhibitors represented the first new class of medication approved for the treatment of AD since topical corticosteroids. Topical calcineurin inhibitors, pimecrolimus and tacrolimus, were developed to provide an effective and safe alternative therapy for longterm control of the disease. They provide targeted anti-inflammatory activity without local or systemic side-effects seen with topical corticosteroids. They have been used not only in AD, but also in other inflammatory skin diseases such as psoriasis, lichen planus, seborrheic dermatitis, contact dermatitis, alopecia areata, acne rosacea, pyoderma gangrenosum and vitiligo.

In this chapter, mechanism of action, the efficacy, safety, adverse effects of topical calcineurin inhibitors and their innovative use in dermatology will be reviewed.

Allergic disorders are a group of multifactorial diseases increasing in prevalence in recent years. Steroids remain the cornerstone of symptomatic treatment, but advances in molecular biology have led to a better understanding of the pathogenesis of allergic diseases and multiple medications; especially monoclonal antibodies have been developed with different therapeutic targets.

Omalizumab (Anti-IgE) and mepolizumab (Anti-IL5) are some of the biological agents already available for the treatment of asthma and other allergic diseases, but many other molecules are currently being studied in clinical trials. In this chapter we review the different monoclonal antibodies that are being studied in allergic diseases with emphasis on the evidence of their use in asthma.

Regular physical activity is recommended for all individuals, but allergic athletes face special challenges managing their diseases while practicing sports. Exercise-induced hypersensitivity disorders are significant problems for both recreational and competitive athletes, occurring with higher prevalence than in the general population. Asthma is the most common chronic condition among athletes.

Athlete’s allergic diseases often perplex, frustrate and distress both patients and their physicians. Their treatment frequently poses several issues. In the specific case of asthma, multiple phenotypes exhibiting differences in response to treatment exist, which creates additional difficulties when managing these patients.

Optimal allergic diseases management aims to control both symptoms and inflammation, but when choosing treatment for a specific athletic population compared with the common allergic patient, some additional factors should be taken into account. For the top athlete it is important not only to control symptoms of allergy and prevent its progression, but it becomes equally imperative to reduce the impact upon sports performance, often practiced under extraordinary circumstances. Therefore, the possibility of side effects of the prescribed treatments should also be carefully considered, in a way to allow full participation in physical activity and sports.

Commonly used drugs include antihistamines, corticosteroids or β2-agonists. Oral H1- antihistamines are one of the first-line therapeutic options for allergic rhinitis, however they might affect vigilance and reaction time in athletes. Antileukotrienes efficacy has been questioned in athletes and inhaled corticosteroids are only partially effective. Also, some potential adverse events with the use of inhaled β2-agonists agents have been pointed out, and health care providers should be aware of these concerns. Moreover, as mechanisms and triggers of hypersensitivity disorders can be different in athletes compared to general population, and even vary between athletes practicing different sports, these patients should be managed sometimes in a singular and different way. On the other hand, a careful consideration of available therapies is required in order to comply with World Anti-Doping Agency regulations. Certain medications for athletes with asthma and rhinitis who participate in regulated competitions are not allowed, and as these guidelines often change, sometimes annually, the physician caring for subjects who are active in sports needs regular update.

The aim of this chapter is to increase physicians’ awareness of special treatment needs for such a prevalent heath problem among athletes, to demystify this issue and improve doctor’s confidence on prescribing anti-allergy agents to sports practicing patients.

The antibody omalizumab is a humanized anti-IgE monoclonal binding to IgE circulating preventing binding to receptors and thereby inhibiting the cascade of allergic inflammation. Besides achieving a reduction in expression of IgE receptors on the surface of basophils and expression of high affinity receptor for IgE on the surface of dendritic cells. Its use has been approved for patients aged 6 years old with moderate to severe allergic asthma, also has been effective in other diseases such as asthma of occupational origin, seasonal or perennial allergic rhinitis, chronic urticaria difficult to control and helping to better tolerance immunotherapy. The results obtained in different studies on treatment with omalizumab in severe atopic dermatitis are contradictory. While providing a promising effect in the treatment of food and drug allergy more longterm studies are needed.

Allergy is defined as an inappropriate immune response in atopic individuals to antigens called as allergens capable of mediating type I hypersensitive reactions. Prevalence of allergic diseases is on the rise and has reached epidemic proportions. Extensive research over the past few decades on pathogenesis of allergic diseases and the molecular mechanisms involved has led to many therapeutic approaches. Management of allergic diseases includes allergen avoidance, pharmacotherapy and allergen specific immunotherapy (SIT). Though allergen avoidance has proved to be effective, it is not feasible to control the exposure of allergens. Pharmacotherapy includes a vast range of strategies and therapies for managing allergic diseases of which inhaled corticosteroids (ICSs) form the first line of treatment. Though ICSs are highly effective, in severe asthma cases other class of medications like β2 agonists, antihistamines, omalizumab etc., in combination with ICSs are recommended. Allergen specific immunotherapy (SIT) is the only treatment modality that acts on effector cells and prevents progression of mild allergy to severe allergic diseases. Inspite of these therapies for allergic disease many patients have poorly controlled symptoms. A better understanding of the complex aetieology of insights into molecular mechanisms will lead to development of new therapeutics with improved efficiency and minimal side effects.

Food allergies have been increasing in prevalence over the last 10 years. Currently, about 2-8% of the population of Western countries suffers from some type of food allergy whose impact ranges from a mere inconvenience to a life threatening condition. While allergy immunotherapy has been successfully used to treat other allergies such as hay fever, it is nearly recent that it has begun to be used in the treatment of food allergy. Nowadays, avoidance therapy is the best measure for the prevention of any food allergic reaction, although can be difficult in cases of common foods such as milk, egg, soy, wheat and peanut. There are a number of promising emerging therapeutic modalities for food allergy, including allergen-specific and allergen non-specific immunotherapeutic approaches, that we would like to review in this chapter. Among allergen-specific immunotherapy we should distinguish oral immunotherapy (OIT), where gradually increasing amounts of allergens are directly swallowed; from sublingual immunotherapy (SLIT), where allergen dose is before placed under the tongue. In both cases, a desensitization process to specific foods is expected. Considering that the characterization of epitopes on food allergens is becoming the target for the development of novel diagnostic tools and for specific therapy, it is important to highlight the use of recombinant food proteins or peptides. With these proteins antigen-specific T cells stimulation is preserved without triggering mast cell activation. Allergen non-specific immunotherapy approaches are being developed for individuals with multiple food allergies. In this sense, the use of anti-IgE, for instance, could decrease the amount of IgE available to bind an allergen. The idea would be to obtain a suppressive effect on all or some part of Th2-mediated immunity. It has been also proven that the use of traditional Chinese herbs in rodent models of peanut allergy is translated in lower peanut-specific IgE and higher peanut-specific IgG2a. This and other alternative strategies addressed in the text are currently being tested in clinical trials. The aim of this chapter is to provide an overview of the ongoing projects in order to develop safe and effective treatments for food allergy.

The pathophysiology of several diseases, including allergy and asthma, is linked to increased reactive oxygen or nitrogen species and inflammatory cytokines. These oxidative and inflammatory mediators in turn alter the organization and functioning of the extracellular matrix (ECM). Hence anti-oxidative and antiinflammatory vitamins may alleviate the pathology.

The etiological factors that produce inflammation and oxidative stress are intrinsic and environmental. The inflammatory and oxidative process consists of the breakdown of membrane lipids to generate important inflammatory mediators (prostaglandins, platelet activating factor) that activate immune cells, degranulate eosinophils, and mediate vascular alterations. The vascular changes are also from tissue damage, which induces plasma mediators by the kinin, fibrinolytic, and clotting pathways. The activated immune cells secrete three predominant inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Collectively, the lipid mediators, plasma mediators and inflammatory cytokines facilitate infiltration of immune cells into tissue, their activation and respiratory burst to release reactive oxygen and nitrogen species: all of which cause breakdown of the structural extracellular matrix proteins, including collagen and elastin, and the stimulation of proteolytic enzymes such as elastases and collagenases. In addition, these mediators activate the inflammatory transcription factor NF-kB to act at the gene level.

Vitamins, such as ascorbate, lutein, and nicotinamide, exhibit anti-inflammatory and anti-oxidative properties and effects. Ascorbate is a potent antioxidant physiologically via the scavenging of reactive oxygen species (ROS), reactive nitrogen species and lipid hydro peroxides. Ascorbate also regenerates other cellular antioxidants such as vitamin E, glutathione (GSH) and beta-carotene from their radical species. Lutein (a nonvitamin A carotenoid) accumulates in the macula of the eye, where it prevents macular degeneration through the scavenging of ROS. Nicotinamide inhibits inflammatory cytokines and plasma mediators, and in addition generates nicotinamide adenine dinucleotide for energy production. In addition, research in our laboratory suggests beneficial regulation of the ECM by these vitamins.

Ascorbate, lutein, and nicotinamide as supplements in the therapy of allergy or allergy may be beneficial in the prevention of the fragmentation of the collagen/elastin network, edema, vascular alterations, and inflammation in the lungs and skin.

Diseases of allergy affecting respiratory and integumentary systems are costly in terms of public health and finance worldwide. Epidemiologic data reveal upwards of 40% of the population in many countries are sensitized to environmental allergens such as grass, tree pollen, dust mite excreta, and animal dander, and exhibit a preponderance of allergic disease. In the face of limited available pharmaceutics, efficacious therapies (particularly those modifying or halting disease progression), are in great need. Despite intense research, a complete understanding of allergic etiology remains elusive. During allergic exacerbation, polarization of T-lymphocyte responses enhances secretion of cytokines involved in regulation of immunoglobulin E, mast cells, basophils, and eosinophils, ultimately provoking inflammation and disease. Traditional pharmacotherapy for allergic disease focuses upon ameliorating the immune response flare to allergen sensitization. A comprehensive understanding of the cellular and molecular mechanisms of allergic disease atop the complex contribution of both genetic and environmental factors will reveal new potential interventions augmenting public health. In 1995, discovery of the novel adipocytokine (a signaling hormone of adipose origin) adiponectin garnered great attention for the protein’s potential role in diabetic and metabolic pathophysiology. In the decades since, research has demonstrated the protein’s strong potential link with asthma. Beyond its essential role in sex hormone signaling, the estrogen membrane receptor also exerts antiinflammatory properties. We shall review the most current information regarding adiponectin and estrogen in context to allergic pathology, encompassing asthma, allergic rhinitis, and immune system components pertaining to inflammation. We will discuss antiinflammatory mechanisms underlying non-traditional pathways of these proteins, including adiponectin’s AMPK-independent signaling pathway and estrogen’s effects via its membrane receptor. Finally, we will provide perspective about the future of research concerning these proteins, and assess their potential therapeutic benefits for allergic disease.

Experts agree that prompt use of intramuscular adrenaline is beneficial for patients experiencing anaphylaxis. Adrenaline is administered using autoinjectors, which are indicated in patients with a high risk of anaphylaxis, namely, those who have already experienced anaphylactic reactions and have comorbid persistent asthma, those who have reacted to trace amounts of allergen, those who have experienced mild reactions to peanut or tree nut, those with mastocytosis and finally adolescents.

However, the frequency of administration of adrenaline by patients and physicians in clinical settings is low. Autoinjectors are prescribed in less than 50% of cases; availability and use by patients can be less than 75%. Administration of adrenaline in emergency departments is also uncommon, in many cases less than 50%, although many series show increased use of adrenaline when anaphylaxis is severe.

Our main objectives are to conduct a comprehensive review and update of the use of epinephrine in anaphylaxis episodes (the first and recurrences) both by patients and by the emergency services, after synthesizing the most accepted indications of epinephrine use in anaphylaxis. All this information remains dispersed in the literature on anaphylaxis.