Structural and clinical impact of anti-allergy agents: An overview
Graphical abstract
Introduction
Anti-Allergic Agents (AAA) are the agents used to treat allergic diseases/reactions and inflammation caused by such reactions. Many of these agent’s act either by preventing the release of inflammatory mediators or by inhibiting the actions of released mediators on their target cells. Most infections, allergic reactions and disorders have varying degrees of inflammation. Inflammation is a usual immune-defensive response to the presence of any foreign particles or allergens that when comes into contact affects the cells and tissues of the body. That allergic response symptom can range from mildly annoying to intensely bothersome to fatal. They can also lead to life-threatening cases of asthma, a condition closely related to allergies. About 1 out of every 5 Americans- roughly 50 million of them- suffer from allergies. Over 25 million Americans have hay fever (the normal medical name of which is allergic rhinitis). Close to 15 million have asthma, another 15 million have a variety of other allergic disorders. Von Pirquet’s definition includes not only hypersensitivity reactions, but also decreased immune reactions; this aspect has been lost today. We define allergy as “specific immunological hypersensitivity leading to disease”. A new consensus of the World Allergy Organization (WAO) on terminology of allergy has been published recently. The term hypersensitivity implies an increased response; the response is not always heightened but may, instead, be an inappropriate immune response to an antigen. These may be either IgE (Immunoglobulin E)-mediated (immediate) or non-IgE mediated (delayed) hypersensitivity reactions [1].
An allergic reaction can be triggered by plant sap, pollen, dust, mold, animal hair, food, medication, cosmetics, insect venom, and many other things found in our environment, including cold air. Allergies are believed to involve both environmental and inherited factors. The immune system is set up to recognize and attack substances called antigens. An antigen is a molecule that signals the presence of an invader in the body. When the immune system recognizes an antigen, it takes steps to repel the invader. It deploys two sets of weapons: antibodies and defensive cells. There are several kinds of interlinked cells and tissues designed to find antigens and respond to them. Lymphocytes, which are white blood cells, are among the most important cells. Not all antigens are immunogens but all immunogens are antigens. Many factors which determines immunogenicity includes chemical composition, molecular size, foreignness, complexity, susceptibility to antigen presentation and processing, dose, route of administration, genotype of the recipient animal (in particular its MHC, genes), and adjuvants (substances used to enhance the immunogenicity of the antigen with which it is mixed and injected). The sizes of B- cell epitopes (immunologically active regions of an immunogen that bind to secreted antibodies or to antigen-specific membrane receptors on lymphocytes) range widely. Some are quite small (e.g., small organic molecules or small peptides), and are often bound in deep pockets or narrow grooves of the antibody. Protein B-cell epitopes are much larger and interact with a flatter, larger complementary surface on the antibody molecule. Haptens are small molecules that can bind to antibodies. However, the conjugate formed by coupling a hapten to a large carrier protein is immunogenic and when injected into an animal elicits production of anti-hapten antibodies. Such injections also produce anti-hapten/carrier and anti-carrier antibodies as well. Formation of hapten-carrier conjugates is the basis of allergic responses to drugs in the body, such as penicillin. Research has shown exactly how the contact is made between the mast cells, the basophils and the allergen and what it causes. A basophil or mast cell springs into action when an allergen binds to two IgE antibodies that have attached themselves to the cell membrane. A number of chemicals called mediators, which are responsible for the symptoms of an allergic reaction- the itching of poison ivy, the runny nose of hay fever, and so on are then released by the cell. In severe cases, the allergic response caused by mediators can be life-threatening. The best-known mediator is histamine, which was discovered in the 1920s. Its discovery led to the use of antihistamines, drugs that relieve allergy symptoms by blocking histamine activity ex., Cyproheptadine, Ebastine, Cetirizine, Azelastine, Levocabastine, Desloratadine, Fexofenadine, Loratadin, etc. Antihistamines give only partial relief; they do not block other mediators, which are responsible for some symptoms. Other mediators include a family of compounds called kinins, which are released at the same time as histamine. Little later, mast cells release a number of other mediators- leukotrienes, bradykinin, prostaglandins and many more. Most of these mediators were discovered fairly recently, and research has yet to develop effective drugs to block their activity (Table 1). Antihistamines and other over-the-counter remedies can provide temporary relief for some allergy symptoms, but researchers have yet to discover a medication that can quell all allergic responses.
Section snippets
Risk factors and clinical manifestations
Clinically allergy manifests (Fig. 1) as various different conditions such as urticaria, Angioedema [1], hay fever, allergic conjunctivitis, allergic bronchial asthma, anaphylactic shock, contact dermatitis, hypersensitivity pneumonitis, serum sickness, allergic vasculitis, granulomatous reactions, as well as the colorful spectrum of food- or drug-induced adverse reactions [2]. Almost every organ is indulged with allergies as shown in Table 2. However, most frequently it is the mucous membrane
Drug classification
Avoidance of the eliciting allergen is the most casual efficient method for allergy treatment. When it comes to abnormal pathologic immune reaction, allergen-specific immunotherapy (hyposensitization) is being the next therapeutic option. Relieving patients from symptoms is the key principle of any treatment. In general allergy treatment concept, the single steps do not exclude each other. Symptomatic treatment has to be given during allergen-specific immunotherapy. The most commonly used
Monoclonal antibodies in allergy
An entirely new approach towards treating allergy diseases has involved the development of monoclonal antibodies. IgE is found out to be the key player in allergic reactions being activated in minutes after exposure to an allergen or any foreign particle thus drugs affecting its activation will serve as prominent agents in allergy treatment. Omalizumab is a recombinant humanized monoclonal antibody (anti-IgE) which down-regulates FcεR-1 receptor present on mast cells and basophils, inhibits the
Future perspective
Constituting the fifth most common chronic diseases in all ages and the third most frequent in children allergic diseases serves as a major health problem affecting millions of lives globally. Anti-allergy drugs are the broad class of drugs intended to treat allergic diseases and reactions. Starting from 19th century where black coffee due to its high content of theophylline was prescribed as a treatment for asthmatic patients to the 20th century where bronchodilators were used as OTC
Concluding remarks
Based on our interest in medicinal chemistry [155], [156], in this review, considerable resources have been focused on reducing the incidence of the allergic response by developing new anti-allergic drugs and modifying existing therapeutics. The future strategy aimed at down-regulation of the allergic response can be classified into categories discussed. This chapter reviewed the current state of play with regard to the development of anti-allergic drugs. Extensive research on therapeutics to
Declaration of Competing Interest
The authors declared that there is no conflict of interest.
Acknowledgements
We acknowledge the faculty member of Apeejay Stya University and SVKM’s NMIMS, Hyderabad for their guidance and support.
References (156)
- et al.
revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization
J. Allergy Clin. Immunol.
(2004)et al.The care pathway for children with urticaria, angioedema, mastocytosis
World Allergy Organ. J.
(2015) - et al.
Portraits: Karl Hansen
Allergo J.
(1993) - et al.
Histamine receptors: Involvement in cardiac function and dysfunction
Antihistamines
- et al.
Effects of two antihistamine drugs on actual driving performance
Br. Med. J.
(1984) - et al.
Lack of subsensitivity to terfenadine during long-term terfenadine treatment
J. Allergy Clin. Immunol.
(1988) Role of cytochrome P450 enzymes in drug-drug interactions
Adv. Pharmacol.
(1997)- et al.
In vitro and in vivo drug interactions involving human CYP3A
Annu. Rev. Pharmacol. Toxicol.
(1998) - et al.
Ebastine in perennial allergic rhinitis
Ann. Allergy
(1991) - et al.
A 12-week, placebocontrolled study of the efficacy and safety of ebastine, 10 and 20 mg once daily, in the treatment of perennial allergic rhinitis
Multi-center Study Group. Allergy
(1999)
The effect of azelastine on the early allergic response
Clin. Exp. Allergy
Sedative effects of antihistamines
J. Allergy Clin. Immunol.
Levocabastine: pharmacological profile of a highly effective inhibitor of allergic reactions
Agents Actions
Double-blind comparison of levocabastine eye drops with sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis
Clin. Exp. Allergy
Levocabastine: an effective topical treatment of allergic rhinoconjunctivitis
Clin. Exp. Allergy
A double-blind evaluation of topical levocabastine, a new specific H1-antagonist in patients with allergic conjunctivitis
Allergy
Effect of race and sex on single- and multiple-dose pharmacokinetics of desloratadine
Clin. Pharmacokinet.
A short history of allergological diseases and concepts
Case of a periodical affection of the eyes and chest
Med. Chir. Trans.
The classification of allergic reactions underlying disease
Allergie
Münch Med Wochenschr
Erstbeschreibung einer “atopischen Familien-Anamnese” im Julisch-Claudischen Kaiserhaus: Augustus, Claudius, Britannicus
Hautarzt
Les antihistaminiques de synthe‘se: essai de chimiothérapie des étatsallergiques
Arch. Int. Pharmacodyn. Ther.
Propriétés antihistaminiques de la N-p-mé-thoxybenzyl-N- diméthylaminoéthyl alpha aminopyridine
CR Soc. Biol.
The antihistamine properties of Benadryl, betadimethyl-aminoethyl benzhydryl ether hydrochloride
J. Pharmacol. Exp. Ther.
Pharmacodynamic studies of a new antihistamine agent, N′-pyridyl-N′-benzyl-N-dimethylethylene diamine HCl, pyribenzamine HCl. I. Effects on salivation, nictitating membrane, lachrymation, pupil and blood pressure
J. Pharmacol. Exp. Ther.
Histamine in allergic diseases
Histamine as a mediator of allergic inflammation
Pol. Merkuriusz. Lek.
Isolation of histamine-containing cells from rat gastric mucosa: biochemical and morphologic differences from mast cells
Gastroenterology
Histamine and asthma
Am. Rev. Respir. Dis.
Risk of first-generation H1-antihistamines: a GA(2)LEN position paper
Allergy
Some chemical and physical properties associated with histamine antagonism
Br. J. Pharmacol.
Pathogenesis of allergic rhinitis
J. Allergy Clin. Immunol.
The pharmacology and use of H1-receptor antagonist drugs
N. Engl. J. Med.
Antihistamines
Clinical comparison of histamine H1-receptor antagonist drugs
J. Allergy Clin. Immunol.
Pharmacology of antidepressants
Psychopathology
Antihistamine use in children
Arch. Dis. Child Educ. Pract. Ed.
Terfenadin und Kraftfahr-zeug-Führung: Eine Placebo-kontrollierte Doppelblind-Studie zum Einfluß verschiedener Anti-histaminika auf das Fahrverhalten
Med. Klin.
Möglichkeiten der Arzneitherapie allergischer Erkrankungen
Pharmakotherapie
The human adenoidal mast cell susceptibility to different secretagogues and secretion inhibitors
Int. Arch. Allergy Appl. Immunol.
Pharmacologic modulation of the whealing response to histamine inhuman skin: identification of doxepin as a potent in vivo inhibitor
J. Allergy Clin. Immunol.
Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials
Br. Med. J.
Continuous versus on demand treatment with cetirizine for allergic rhinitis
Ann. Allergy Asthma Immunol.
Azelastine nasal spray as adjunctive therapy to azelastine tablets in the management of seasonal allergic rhinitis
Ann. Allergy Asthma Immunol.
Lack of subsensitivity to loratadine during long-term dosing during 12 weeks
J. Allergy Clin. Immunol.
The metabolism of antihistamines and drug interactions: the role of cytochrome P450 enzymes
Clin. Exp. Allergy
Efficacy and tolerability of ebastine at two dose levels in the treatment of seasonal allergic rhinitis
Drug Invest.
A double-blind placebo-controlled study of the efficacy and tolerability of ebastine against hay fever in general practice patients
J. Int. Med.
Clinical studies of the efficacy and tolerability of ebastine 10 or 20 mg once daily in the treatment of seasonal allergic rhinitis in the US
Drugs
Comparison of the efficacy of ebastine 10 mg and 20 mg once daily with that of cetirizine 10 mg once daily in adults with seasonal allergic rhinitis. A multicenter double-blind study
Drugs
Placebo controlled comparison of acute effects of ebastine and clemastine on performance and EEG
Eur. J. Clin. Pharmacol.
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