Showing papers in "Clinical allergy and immunology in 2002"

Histamine receptors: specific ligands, receptor biochemistry, and signal transduction.

Abstract: During the past few years, there has been a tremendous increase in our understanding of the histamine receptors Important progress has been made in the development of H1-receptor agonists and the rationalization of H1-receptor-ligand interaction The recent observation of constitutive H1- and H2-receptor activity has led to a reclassification of H1- and H2-antagonists For the H3-receptor, a wide variety of selective and potent ligands are currently available and await clinical application The recent cloning of the H3-receptor gene and the anticipated generation of transgenic mice will facilitate this development Within the field of signal transduction, a previously unanticipated complexity has been unravelled With the cloning of the H3-receptor gene, a similar complexity is to be expected

H1-antihistamines in children.

Abstract: In children, as in adults, H1-antagonists are useful in the treatment of allergic rhinoconjunctivitis. Level 1 evidence for their efficacy in this disorder has been obtained in many well-designed pediatric studies. The widespread use of H1-antagonists in upper respiratory tract infections or otitis media in children is not supported by a strong scientific rationale. H1-antagonists are not harmful in children with asthma and, indeed, may have some beneficial effects in children with mild asthma. Their role in delaying or preventing asthma from developing in high-risk infants and toddlers is currently an important area of clinical investigation. The evidence base for their use in children with urticaria or atopic dermatitis still contains large gaps. First-generation H1-antagonists are presumed to be safe for use in infants and children. While they have undoubtedly been administered without apparent harm to millions in this age group, they impair CNS function far more commonly than is generally realized. Their use should be restricted to two uncommon situations: children with urticaria or atopic dermatitis whose pruritus is so severe that the sedation produced by an old H1-antagonist, such as hydroxyzine, is a benefit rather than a risk; and children with anaphylaxis who require intravenous diphenhydramine as adjunctive treatment to epinephrine and other modalities. Apart from these exceptions, in patients of all ages, second-generation H1-antagonists free from CNS adverse effects are clearly the medications of choice. Pediatric formulations of the new H1-antagonists cetirizine, fexofenadine, and loratadine are now available for use.

Histamine and antihistamines in anaphylaxis.

Abstract: Anaphylaxis and anaphylactoid reactions are potentially fatal. These disorders are sometimes iatrogenic, and increase with increased exposure to drugs, synthetic substances, and medical procedures. Non-IgE-mediated anaphylactoid reactions are common in medical settings and are clinically indistinguishable from anaphylaxis. These reactions may be unrecognized if a rigid classic definition of anaphylaxis is used. Histamine is a primary mediator of anaphylaxis and signs and symptoms of anaphylaxis can be reproduced by histamine infusion. Histamine triggers a cascade of inflammatory mediators and modulates its own release. H1-antihistamines are adjunctive treatment therapy for acute anaphylaxis and anaphylactoid reactions, in which many mediators of inflammation are involved. Compared with epinephrine, the first-response medication of choice, antihistamines have a slow onset of action, and they cannot block events that occur subsequent to histamine binding to its receptors. Antihistamines are an important component of regimens for the prevention of anaphylaxis and anaphylactoid reactions in patients at risk, and may eventually have more widespread application in the perioperative setting. In some instances, such as with exercise-induced anaphylaxis and reactions to latex in sensitized individuals, prophylaxis regimens are not always effective. H2-antagonists are not detrimental in the therapy of anaphylaxis and many studies show a favorable outcome when combining H1- and H2-antagonist therapy for prophylaxis. They should be added to therapy at the discretion of the treating physician. Because of decreased antimuscarinic and central nervous system side effects, the newer antihistamines can be given in high doses, allowing more complete blockade of histamine receptors. These agents should lead to a reevaluation of the usefulness of antihistamines in both the treatment of acute anaphylaxis and in prophylactic regimens. The unavailability of parenterally administered second-generation H1-antagonists limits their usefulness in acute anaphylaxis and perioperative prophylaxis.

Antiallergic anti-inflammatory effects of H1-antihistamines in humans.

Abstract: Data from in vitro, in vivo, and ex vivo studies suggest that second-generation antihistamines have a number of antiallergic, anti-inflammatory properties that appear to be independent of their H1-blockade activity. First-generation antihistamines also have antiallergic, anti-inflammatory properties, as suggested by the studies with azatadine, chlorpheniramine, mepyramine, and promethazine; most other first-generation antihistamines have not been studied for these properties. In vitro studies have shown that H1-antihistamines reduce the release of proinflammatory mediators from mast cells and basophils, the chemotaxis and activation of inflammatory cells (especially eosinophils), and the expression of adhesion molecules induced by immunological and nonimmunological stimuli in epithelial cell lines. Nasal allergen challenge models have similarly demonstrated that H1-antihistamines inhibit mediator release from mast cells and basophils, and that they decrease inflammatory cell infiltration and the expression of adhesion molecules on epithelial cells. The results of published studies of the effects of H1-antihistamines on nasal allergic inflammation in humans have been summarized in this chapter. Recent investigations indicate that H1-antihistamines may modulate airway inflammation by downregulating the activity of airway epithelial cells, which have an important role in allergic airway inflammation. The modulation of adhesion molecules and of inflammatory cell infiltration by H1-antihistamines may be beneficial during long-term treatment in patients with allergic rhinitis. The rationale for this hypothesis is the persistence of inflammation on the nasal epithelial cells even when patients are symptom-free (16). All of the events affected by H1-antihistamines are important in the allergic inflammation cascade. The underlying mechanisms for such effects remain unclear, but are unrelated to H1-antagonist activity. Several studies have demonstrated that H1-antihistamines can form an ionic association with cell membranes and inhibit calcium ion influx into the mast cell or basophil plasma membrane, or inhibit Ca2+ release within the cells, and may therefore influence the signal transduction pathways. However, these effects appear to occur at concentrations higher than those achieved in therapeutic practice (126-128). It has recently been hypothesized that the anti-inflammatory activity of H1-antihistamines may be a consequence of their ability to influence the activation of genes responsible for the expression and synthesis of proinflammatory mediators (129). The contribution of the antiallergic effects of H1-receptor antagonists to their clinical efficacy is not fully understood. There have been no data suggesting that H1-antihistamines with well-documented antiallergic properties are superior to the others for which such properties have not been as extensively investigated. Additional studies are needed to elucidate the mechanisms(s) by which H1-antihistamines exert anti-inflammatory effects. This knowledge might lead to the development of novel therapies with more potent and specific anti-inflammatory effects.

H1-antihistamines and the central nervous system.

Abstract: An extensive body of research exists on CNS effects of H1-antagonists. There is great interest in this area due to the well-known adverse CNS effects associated with first-generation H1-antagonists, and the many new second-generation agents claiming to have nonsedative properties. Because the CNS effects of H1-antagonists are complex and cannot be reflected in one measurement, a variety of assessments of CNS function are required. These range from the subjective (e.g., self-rating of drowsiness) to the objective (e.g. 24 h EEG sleep latency, P300), and from the simple (e.g., critical flicker fusion) to the complex (e.g., actual driving). When these tests are applied to the evaluation of the H1-antagonists currently available, it is clear that there is a real distinction between the older first-generation H1-antagonists and the newer second-generation ones. At the recommended dosages, all the second-generation H1-antagonists are clearly less sedating in more patients than their predecessors. These newer medications do not cross the blood-brain barrier readily; are highly specific for H1-receptors; have little to no anticholinergic, antiserotoninergic, or anti-alpha-adrenergic effects; and do not enhance the adverse CNS effects of alcohol or other CNS-active substances such as the benzodiazepines. Since most second-generation H1-antagonists are found to be relatively nonsedating, their benefit/risk ratios will be determined more by their other properties such as non-CNS adverse effects (e.g., potential to cause cardiac arrhythmias), potency, onset of action, duration of action, ease of administration, and cost. The future role and usefulness of the older sedating H1-antagonists, given the availability of the safer second-generation agents, are unclear at the present time. When H1-antagonist treatment is indicated, physicians should recommend an effective H1-antagonist with a favorable clinical pharmacology profile and a wide margin of safety in patients of all ages. The common, often subclinical, adverse CNS effects produced by the old H1-antagonists remain a major concern and, therefore, these compounds are no longer medications of choice in the treatment of allergic rhinitis, allergic conjunctivitis, or urticaria.

Potential cardiac toxicity of H1-antihistamines.

Abstract: Nonsedating H1-antihistamines are widely prescribed for the treatment of allergic disorders because of their lack of sedative and anticholinergic effects; however, certain nonsedating antihistamines such as terfenadine and astemizole are now known to cause QT prolongation and TdP, particularly in overdosage or with concomitant ingestion of imidazole antifungals or macrolide antibiotics. Mechanistic studies showed that the cardiotoxic effects of some nonsedating antihistamines are due to the inhibition of repolarization potassium channels, particularly IKr, which leads to prolongation of the action potential and QT interval, and the development of early after-depolarization, which triggers TdP. Patients at risk of developing TdP, such as those with congenital long QT syndrome, cardiac disease, liver disease, electrolyte disturbance, or those taking drugs that can prolong QT interval, should avoid nonsedating antihistamines that are also capable of prolonging the QT interval. Many questions still need to be answered, such as the role of other potassium channels (IKs, ITo, and Iped) and the relative expression of various potassium channels in different individuals, which may be important in the pathogenesis of TdP with nonsedating antihistamines. There is also a lack of information on the cardiac actions of newer nonsedating antihistamines. The evidence so far indicates that the potential to cause ventricular arrhythmias is not a class effect and that loratadine, cetirizine, and fexofenadine are not associated with QT prolongation, TdP, or other ventricular arrhythmias. It is hoped that with a better understanding of the arrhythmogenic mechanism of nonsedating antihistamines, we will be able to identify patients at risk and prevent any cardiac toxicity associated with H1-antihistamines, and ultimately, death.

Lipid inflammatory mediators: leukotrienes, prostaglandins, platelet-activating factor.

Abstract: The lipid mediators, leukotrienes, prostaglandins, and PAF play an important role in the complex inflammatory process of airway eosinophilia, edema hypersecretion of mucus, and AHR observed in patients with asthma These mediators are also likely key participants in the pathogenesis of other allergic diseases An important goal of future research is to clarify the complex interactions between the lipid mediators and the inflammatory stimuli that regulate their production Novel inhibitors and antagonists of the lipid mediators, such as the CysLT1 receptor antagonists, have recently been developed that have great promise in the treatment of allergic diseases

Histamine in health and disease.

Abstract: Histamine is a potent vasoactive agent, bronchial smooth muscle constrictor, and stimulant of nociceptive itch nerves. Activation of H1-receptors plays a central role in the immediate allergic reaction, but has less of an impact in chronic allergic disorders where inflammatory infiltrates, additional mediators such as LTC4/D4/E4 and cytokines, and structural remodeling occur. Histamine, through its H1-receptor-mediated activities, appears to be primarily a proinflammatory agent, yet it does have some homeostatic functions in gastric acid production (H2-receptors) and the central nervous system (predominantly H3-receptors) (97, 98). The realization that first-generation antihistamines often had mixed pharmacological properties (e.g., anticholinergic actions) and crossed the blood-brain barrier led to the development of the second-generation drugs, which are more selective for H1-receptors, have less access to the central nervous system, and, therefore, a more favorable benefit-to-risk ratio (therapeutic index). The potential for combined H1-H3-antagonists remains to be fully explored, but offers another exciting opportunity for this ever-expanding family of beneficial drugs.

Antihistamines in urticaria and angioedema.

Abstract: H1-antihistamines are the cornerstone of symptomatic treatment in acute and chronic urticaria, in which they not only relieve itching, but also reduce the number, size, and duration of urticarial lesions. Relief of whealing, flaring, and erythema may be incomplete as the vascular effects of histamine are mediated to its action at H2-receptors as well as at H1-receptors, and other vasoactive substances may also be involved. In randomized, prospective, placebo-controlled, double-blind studies, the new low-sedating H1-antihistamines have been found to be effective and safe in urticaria. Sedating antihistamines, although effective, place patients at risk for adverse effects, including decreased psychomotor performance. The response to H1-antihistamines in some types of urticaria, for example, in urticarial vasculitis, is unsatisfactory. An H2-antihistamine administered concurrently with an H1-antihistamine may modestly enhance relief of itching and wheal formation in some patients with urticaria refractory to treatment with an H1-antihistamine alone. The available evidence does not justify the routine addition of H2-antihistamine treatment to H1-antihistamine treatment.

Clinical pharmacology of H1-antihistamines.

Abstract: H1-antagonists have similar efficacy in the treatment of patients with allergic rhinitis or urticaria; however, they are diverse with regard to their chemical structure (Fig. 1), clinical pharmacology, and potential for toxicity (1). The scientific foundation for using these medications with optimal effectiveness in all patient populations, including the very young, the elderly, and those with hepatic or renal dysfunction, or those taking other medications concurrently, is provided by results of pharmacokinetic and pharmacodynamic studies (2).

H1-Antihistamines in the Elderly

Abstract: In the elderly, H1-antihistamine therapy is commonly prescribed for treatment of rhinitis, conjunctivitis, pruritus, eczema, urticaria, and for prophylaxis of anaphylactoid reactions. Second-generation H1-receptor antagonists provide excellent, safe, and effective alternatives to first-generation antihistamines in this population, as in younger patients. As with all medications, the choice of which agent to use must be tailored to the needs of the individual. Treatment should be planned with consideration of concomitant medications and potential drug-drug interactions and drug-disease interactions. First-generation antihistamines should not be used for treatment of allergic rhinitis or urticaria in the elderly. Age-related physiological changes can enhance or complicate the actions of H1-receptor antagonists, especially when these drugs are taken concurrently with other medications and/or in the presence of comorbid disease. Adjustments in dosages are necessary when some agents are used in patients with renal and/or hepatic disease; however, overall, the use of the newer nonsedating antihistamines is safe, effective, and gratifying in the elderly.

H1-antihistamines in pregnancy and lactation.

Abstract: Antihistamines may be used for the treatment of allergic rhinitis, upper respiratory infections, urticaria/angioedema, atopic dermatitis, and, rarely, as adjunctive treatment for anaphylaxis, during pregnancy. Because these illnesses may affect maternal comfort and safety as well as threaten the fetus directly (anaphylaxis) or indirectly, they often require therapy during pregnancy. Based on the information available to date, in this chapter we have attempted to provide rational guidelines for the gestational use of H1-receptor antagonists in a manner that will lead to the optimal well-being of both the mother and her infant. As more information becomes available, the recommendations herein may require modification. Although this chapter has dealt specifically with gestational management, a case can be made for considering this information when making therapeutic decisions in all women of childbearing potential. First, most pregnancies are unplanned, and the peak period of fetal vulnerability to drug-induced teratogenesis begins the day a woman's period is due. Second, during gestation, substantial alterations in a previously successful but not optimal-for-pregnancy chronic therapeutic regimen may be psychologically threatening to the patient and may lead to either uncontrolled disease or unanticipated side effects. Thus, pregnancy-appropriate regimens should ideally be discussed with all women of childbearing age as part of the informed therapeutic decision-making process.

H1-antihistamines in asthma.

Abstract: Histamine released from mast cells and basophils is an important mediator of airway inflammation in asthma, particularly in the development of the early allergic response. Although histamine has been shown to contribute significantly to the bronchoconstrictor response to allergen or exercise, leukotrienes are likely to play a more prominent role in these responses in asthma. The improved specificity, tolerability, and safety profile of the second-generation H1-antagonists associated with anti-inflammatory activities and bronchodilator activities, may contribute to relieve the symptoms of the upper and lower airways in patients with coexistent mild seasonal asthma and allergic rhinitis. Considering the global rise in the prevalence of allergy and asthma, the suggestion that H1-antagonists may delay the onset of asthma in infants is of considerable interest and merits further assessment. Although it is unlikely that monotherapy with most currently available H1-antagonists will provide significant clinical benefit in asthma, the potential of combined antihistamine and antileukotriene therapy may prove useful, particularly in subjects with poor compliance to inhaled corticosteroid therapy.

Antihistamines in rhinoconjunctivitis.

Abstract: In allergic rhinoconjunctivitis, histamine is known to contribute predominantly to nasal itch, sneeze, rhinorrhea, conjunctival itch, and lacrimation and these symptoms benefit most from H1-antihistamine therapy. The discovery in the early 1980s of nonsedating H1-receptor antagonists contributed dramatically to the more widespread acceptance of this mode of therapy. This also led to the undertaking of well-designed clinical trials that have added significantly to our understanding of allergic rhinitis. Oral treatment modifies both nasal and ocular symptoms and provides effective control throughout a 24-h period with once- or twice-daily medication. The advent of topical H1-receptor antagonists offers a wider choice of treatments and provides equal or greater efficacy with lower systemic bioavailability. While having a major impact on rhinoconjunctivitis symptoms, H1-antihistamines do not fully modify disease since histamine is not the only contributor to symptom generation in allergic rhinoconjunctivitis. While the search for oral H1-antihistamines with more widespread "antiallergic" activity continues, the currently available medications modify predominantly histamine-regulated events despite in vitro evidence of greater potential. The development of these new medications may be the next significant advance in this mode of treatment.

Allergic Eye Disorders

Abstract: The eye is a common target of inflammatory disorders that can either be triggered from external agents or from systemic immunologic hypersensitivity reactions. Due to the prominent vascularity of the eye embedded in a transparent medium, inflammatory reactions are immediately noticed by the patient. The eye and its surrounding tissues are also involved in a variety of other immunologically mediated disorders. When such reactions occur, they are not infrequently seen first by the primary care physician, who then is in the position to correlate ocular and systemic findings and to coordinate therapy so as to treat underlying disease (if present) rather than only local eye symptoms.

Cost-effectiveness of H1-antihistamines.

Abstract: In the health care arena, assessment of a medication's clinical efficacy is no longer enough It is important to confirm the medication's cost-effectiveness and the improvement in quality of life it provides in relationship to other options in therapy H1-antagonists are widely used in the treatment of many atopic disorders, especially allergic rhinitis This review has pointed out cost-effectiveness and quality-of-life studies comparing the different H1-antagonists among themselves, and with other treatments used in allergic rhinitis, such as intranasal corticosteroids and allergen immunotherapy Cost-effective analyses among H1-antagonists in other allergic diseases, such as atopic dermatitis, urticaria and angioedema, and asthma, are lacking at this time

DNA immunomodulation of asthma.

Abstract: This is an exciting time in the chronology of asthma and allergic diseases. Although the pharmacopeia for treatment of these diseases has advanced greatly, most of our current therapies are aimed at the symptoms, rather than the underlying mechanism. Immunotherapy remains the only therapeutic modality that addresses the underlying mechanism, albeit by effects are still not fully understood. The approaches summarized in this chapter, alone or in combination, may yet allow one to reverse the atopic state. Meanwhile, other innovative DNA-based approaches are being developed, including the use of allergen DNA with or without CpG. Because most of the Th2 cytokines are on chromosome 5, the completion of the human genome project may open whole new venues of research aimed at controlling these cytokines at the chromosomal level.

Anti-IgE antibody therapy.

Abstract: From the published studies of E25, it is now clear that this approach to treating atopic disease can be successful. But there remain many issues, both practical and biological. For the study of atopic disease, a potentially excellent new tool has been provided that could allow IgE to be effectively eliminated, given the correct-dosing regimen, and provide the investigator with a means to ask questions about the role of IgE in the expression of a particular disease. No place is this more evident than in the study of asthma for which a long-standing debate revolves around the precise contribution of atopy to the genesis and maintenance of this disease. Furthermore, use of the drug may finally resolve questions about the role of IgE in parasitic rejection. From the perspective of the patient, at a minimum, the drug provides a proof-of-concept for all potential therapies seeking to reduce circulating IgE levels. With proper consideration of dosing, the drug appears as if it could provide remarkable improvement in the course of atopic disease. Some concerns still revolve around the improvement roles IgE may play in parasitic diseases, the cost of therapy, and that very long-term treatment effects have yet to be studied.