Current Pharmaceutical Design - Volume 12, Issue 26, 2006

This volume is dedicated to hypersensitivity reactions to drugs, which are increasing, partly because of indiscriminate consumption of the latter. In fact, in industrialized countries drug abuse represents one of the greatest problems of public health. The revised nomenclature for allergies [1], which is based on the mechanisms that initiate and mediate hypersensitivity reactions, classifies such reactions to drugs as either allergic or non-allergic. The former are mediated by immunologic mechanisms, either antibodies or cells; all other reactions should be referred to as nonallergic drug hypersensitivity. In addition, allergic reactions to drugs are classified as IgE-mediated or non-IgEmediated; some of the latter are cell-mediated. In IgE-mediated reactions, the drug or drug metabolite reacts with IgE bound to the surface of mast cells and leads to the activation, degranulation, and release of mast-cell vasoactive mediators like histamine and tryptase. In cell-mediated allergic reactions, CD4+ and CD8+ T cells recognize drugs through their αβ receptors. Drug-specific T cells generate inflammatory reactions, mainly cutaneous, through the release of various cytokines (e.g., interleukin-5, interferon) and chemokines (e.g., interleukin-8). Non-allergic immediate hypersensitivity reactions to drugs (i.e., occurring less than one hour after drug administration) are frequent, and their symptoms are similar to those observed in IgE-mediated allergic reactions. Non-allergic reactions may involve different pathogenic mechanisms, such as the capability of iodinated contrast media (ICM) of releasing mediators through a non-immunologic mechanism and the inhibitory effect on cyclooxygenase-1 of nonsteroidal anti-inflammatory drugs (NSAIDs). This volume contains articles by researchers and clinicians belonging to the European Network for Drug Allergy (the European Academy of Allergology and Clinical Immunology's interest group on drug hypersensitivity). In preparing this issue, we have tried to meet the needs of readers who wish to learn about the latest developments regarding this subject, particularly those concerning pathogenic mechanisms and diagnostic aspects. In the first article, Guglielmi and coworkers [2] focus their attention on the risk factors of hypersensitivity reactions to drugs, which are related to the latter and the treatment regimens, as well as to the host. As far as genetic factors are concerned, most studies regard HLA haplotype association or polymorphisms in genes encoding drugmetabolising enzymes. There are also studies concerning single nucleotide polymorphisms, which may be involved in multifactorial and multigenic diseases, and aimed at enabling patients at risk for hypersensitivity reactions to be identified. The following three articles [3-5] provide data on hypersensitivity reactions to antibacterial drugs such as quinolones and β-lactams. The review by Schmid and coworkers [3] analyzes the different pathogenic mechanisms involved in hypersensitivity reactions to quinolones, with special attention to T cell-mediated ones. The authors also provide data on IgE-mediated reactions, such as anaphylactic shock, urticaria and angioedema, and highlight the usefulness of the sepharose radioimmunoassay of serum-specific IgE against quinolones in the diagnosis of such reactions. They also stress that cross-reactivity among quinolones at both the IgE- and T-cell level is clinically well documented. Therefore, patients with hypersensitivity reactions to any quinolone should not be re-exposed to any antimicrobial agents of that class. The paper by Antunez and coworkers [4] focuses its attention on diagnostic tests for IgE-mediated hypersensitivity reactions to β-lactams, mainly penicillins. Diagnostic work-ups for such reactions include skin tests, serum-specific IgE assays, flow cytometric basophil activation tests and, in case of negative responses to these in vivo and in vitro tests, controlled administrations of suspect antibiotics. The authors emphasize the importance of the side-chain antigenic determinants of the various β-lactams and thus the need to use in diagnosis the suspect β-lactams themselves. In fact, hypersensitivity reactions to β-lactams may not be detected by tests performed only with penicillin determinants in cases where side-chain determinants play an important role in sensitization. The article by Guéant et al. [5] demonstrates the usefulness of skin testing with responsible cephalosporins, the sepharose radioimmunoassay of serum-specific IgE against cephalosporins, and challenges in diagnosing immediate reactions to these β-lactams....

Drug allergies are heterogeneous and multifactorial diseases and are always the consequence of an exaggerated immune-mediated reaction. Previously described models of immunologic mechanisms (mainly based on Gell and Combs' classification) cannot fully explain the physiopathology of these diseases; it seems therefore important to identify risk factors. Clinical and biologic tests are helpful diagnostic tools but are limited in their sensitivity and reliability and are certainly not predictive. Epidemiologic data supply information concerning the prevalence of drug hypersensitivity: female gender, concomitant infections (HIV, herpes) and concurrent illnesses (systemic lupus erythematosus) are all significant risk factors. Another host-related factor is the genetic predisposition of patients and is currently under investigation in our laboratory. Most genetic studies concern HLA haplotype association or polymorphism in genes encoding drugmetabolising enzymes. A current study by our group seems to implicate polymorphisms within the promoter of IL-10, a cytokine with anti-inflammatory properties. The chemical properties of the drug and the treatment regimen also influence the development of drug allergies.

Quinolones are one of the most important classes of antimicrobial agents discovered in the recent years and one of the most widely used classes of antibiotics in clinical medicine. Their broad spectrum of activity and pharmacokinetic properties make them ideal agents for treating a variety of infections. Their clinical importance is further demonstrated by their activity against a wide range of diseases of public health importance such as anthrax, tuberculosis, bacterial pneumonia, and sexually transmitted diseases. Like other antibiotics, quinolones can cause various, sometimes dangerous hypersensitivity reactions. The underlying pathomechanisms are only poorly understood. Some are thought to be partly non-immune mediated reactions, others are considered to be IgE- or T cell-mediated reactions. This review gives an insight into the different immunological mechanisms leading to the diverse symptoms of quinolone-induced hypersensitivity reactions, with special emphasis on the role of T cells in such reactions.

Immediate hypersensitivity reactions to betalactams are IgE mediated and constitute the most frequent allergic reactions mediated by specific immunological mechanisms. IgE responses to benzyl penicillin (BP), the first antibiotic producing the benzyl penicilloyl structure (BPO), are characterized by a quick release of inflammatory mediators, resulting in anaphylactic shock, urticaria and angioedema. With the progressive appearance of other structures, comprising cephalosporins, carbapenems, monobactams and clavulanic acid, IgE selective responses and cross-reactivity reactions were observed. The diagnosis of betalactam hypersensitivity, classically based on skin testing with major and minor determinants of benzyl penicillin or in vitro IgE antibodies to BP, has been modified by the inclusion of different determinants generated from these compounds, for which amoxicillin (AX) is the most relevant, followed by cephalosporins. Some subjects develop positive responses to several betalactams, mostly within the same family, but others develop a selective response. These are relevant for the appropriate selection of antimicrobial drugs in patients who have immediate hypersensitivity to betalactams.

Like penicillins, cephalosporins may cause IgE-mediated reactions such as urticaria, angioedema, and anaphylactic shock, which occur because of sensitization to determinants shared with penicillins or to unique cephalosporin haptens. In particular, side-chain structures may be responsible for selective sensitization or cross-reactivity. For this reason, individual free cephalosporins are usually employed in skin testing, in addition to the classic penicillin reagents. Cephalosporin skin tests are sensitive in diagnosing immediate hypersensitivity to these betalactams. As far as in vitro tests are concerned, IgE assays for cephalosporins, specifically sepharose-radioimmunoassays, are a potentially useful tool in evaluating immediate reactions and could be used as complementary tests. In selected cases displaying negative results in both skin tests and IgE assays, a graded challenge with the implicated cephalosporin can be performed. Cephalosporin IgE-mediated hypersensitivity may be a transient condition; therefore, allergologic exams should be repeated in patients with negative initial allergologic work-ups, including challenges. Performing allergologic tests with cephalosporins other than the culprit, as well as with penicillin reagents, allows the identification of cross-reactivity with penicillins, selective responses, or cross-reactivity among cephalosporins. In the latter group, cross-reactivity is more frequently related to R1 than to R2 side-chain recognition. In assessing the selectivity of the response, negative results in skin testing with cephalosporins other than the responsible one appear to be a reliable indicator of tolerability.

Hypersensitivity to aspirin and other non steroidal anti-inflammatory drugs (NSAIDs) manifesting in the airways (rhinosinusitis, polyps, asthma) or in the skin (urticaria, angioedema) is the second most frequent untoward allergic reaction to drugs. Various aspects of this syndrome, such as its clinical features, the cell types and mediators involved, the role of underlying chronic inflammatory processes, the patterns of cross-reactivity between NSAIDs, the major role of sulfidoleukotrienes (LTC4) and of some other mediators such as prostaglandin E2 (PGE2) and C5a are briefly reviewed. It has been assumed for a long time that there were no reliable in vitro tests for that condition and that diagnostic confirmation can only be ascertained by provocation challenge. This appears no longer to be true, since several recent studies using a leukotriene release test (CAST) or a basophil activation test (BAT) on blood basophils, or a combination of both tests, yields positive results (70 - 75%) in a sizeable number of clinically validated cases, with a high specificity (above 85%). The finding in that syndrome of hyperreactive basophils suggests that the NSAID hypersensitivity syndrome is due to the associated effect of several factors : 1) Localized inflammatory processes causing a non specific cellular hyperreactivity; 2) An abnormal pharmacogenetic reaction to NSAIDs resulting in a hyperproduction of LTC4 and other mediators by activated mast cells, basophils and eosinophils.

Adverse reactions after iodinate contrast media (ICM) administration have been observed, which can be classified as immediate (i.e., occurring within one hour after administration) and delayed or non-immediate (i.e., occurring more than one hour after administration). Even though the incidence of ICM adverse reactions has been significantly reduced by the introduction of non-ionic compounds, immediate reactions still occur in about 3% of administrations. Different pathogenic mechanisms have been suggested for ICM reactions, including immunologic ones. Basophils and mast cells participate in immediate reactions through the release of mediators like histamine and tryptase, whereas a T-cellmediated pathogenic mechanism is involved in most non-immediate reactions, particularly maculopapular rashes. Skin tests and specific IgE assays are carried out to diagnose immediate hypersensitivity reactions, while both delayed-reading intradermal tests and patch tests are usually performed to evaluate non-immediate reactions. However, in vitro specific IgE assays are not commercially available. As far as in vitro tests are concerned, a response involving ICM-related T-cell activity may be assessed by the lymphocyte transformation test. Allergologic evaluation appears to be indicated in hypersensitivity reactions to ICM, although the sensitivity, specificity, and predictive values of allergologic tests have not yet been established. This paper summarizes the current state of the art and addresses the research that is still needed on the pathogenic mechanisms, diagnosis, and prevention of ICM-induced hypersensitivity reactions.

Aromatic antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, and phenobarbital) are frequently associated with cutaneous eruptions. A cell-mediated pathogenic mechanism has been demonstrated in most of such reactions on the basis of positive responses to patch tests and/or lymphocyte transformation tests. Therefore, such tests are useful tools for evaluating anticonvulsant hypersensitivity reactions. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in a large percentage of patients with hypersensitivity reactions to aromatic anticonvulsants. Although several hypersensitivity reactions to sequential exposure to more than one aromatic anticonvulsant (i.e., clinical cross-reactivity) have been reported, there are few studies performed with patch tests and/or lymphocyte transformation tests assessing immunologic cross-reactivity, and their data are contradictory. In any case, considering studies performed in samples of at least 10 patients, the immunologic cross-reactivity rate among aromatic anticonvulsants appears to be low. On the other hand, the reported rate of the toxic cross-reactivity (i.e., assessed by lymphocyte toxicity assays) is high. Further in vivo and in vitro studies in large samples of subjects are needed to evaluate cross-reactivity among aromatic anticonvulsants.

In the last few decades, glucocorticoids have received increasing attention for their capability of provoking systemic hypersensitivity reactions, when administered orally, parenterally, or intralesionally, as well as allergic skin and mucosal symptoms, when applied locally to the skin in patients with contact dermatitis or to the mucosa in patients with asthma and/or rhinitis. However, because of their anti-inflammatory and immunosuppressive properties, glucocorticoids are often not suspected of such hypersensitivity reactions. In addition, because glucocorticoids retain their antiinflammatory potential, even if they act as sensitizers, the signs and symptoms of allergic reactions are not always obvious, particularly when they overlap with those caused by the very diseases glucocorticoids are used to treat. Moreover, interpretation of diagnostic tests, specifically that of patch-test reactions, can be difficult. In this review, particular attention is addressed to the problem of allergenic cross-reactivity among topical and systemic glucocorticoids. We also look at the clinical and practical aspects of both cell-mediated and IgE-mediated hypersensitivity reactions to glucocorticoids and their consequences on anti-inflammatory therapeutic choices.

Complementary and alternative medicine (CAM) is becoming increasingly popular, and is often used for treating hypersensitivity diseases. Virtually all alternative remedies can cause hypersensitivity reactions, but the most frequently involved ones are tea tree oil, members of the Compositae family, propolis, oils used in aromatherapy, substances responsible for photosensitization, and metal-containing compounds. The main target organ is skin, with manifestations ranging from contact dermatitis (the most common) to urticaria-angioedema, maculopapular eruptions, photosensitivity reactions, and the Stevens-Johnson syndrome. Other types of reactions are possible, including respiratory and anaphylactic ones. Different pathogenic mechanisms have been suggested for CAM product reactions, including immunologic ones. Basophils and mast cells participate in IgE-mediated reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most delayed reactions, particularly contact dermatitis and maculopapular eruptions. Skin tests and serum specific IgE assays are carried out to diagnose immediate hypersensitivity reactions, while patch tests and lymphocyte transformation tests are usually performed to evaluate delayed hypersensitivity reactions. Thus clinicians should know about the potential of CAM products for causing adverse reactions. Our study is aimed at highlighting the risk of hypersensitive reactions to CAM remedies on the basis of the numerous cases reported in the literature. Because little is known about adverse reactions to CAM products, further systematic studies and an appropriate regulation by heath authorities are necessary.

Adverse reactions after administration of ophthalmic products have frequently been observed. These reactions can be provoked by both active principles and excipients. Different pathogenic mechanisms have been suggested for such reactions, including immunologic ones. Basophils and mast cells participate in IgE-mediated reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most delayed reactions, particularly conjunctival ones and eyelid dermatitis. Prick tests and immediate-reading intradermal tests are carried out to diagnose immediate hypersensitivity reactions, while patch tests are usually performed to evaluate delayed reactions. Other diagnostic tests, such as serum-specific IgE assays in immediate reactions, as well as delayed-reading intradermal tests and/or lymphocyte transformation tests in delayed ones, are rarely performed. In this review, particular attention is addressed to the clinical and practical aspects of both cell-mediated and IgE-mediated hypersensitivity reactions to ophthalmic products.

Dehydroepiandrosterone (DHEA) is the most abundant adrenal androgenic steroid in young adult humans. The physiological functions of DHEA in preventing human carcinogenesis are still controversial, but a lot of reports have shown that pharmacological doses of DHEA show chemopreventive and anti-proliferative effects on tumors in rodents. Although a therapeutic dose of DHEA has been reported to promote hepatocarcinogenesis in rats due to peroxisomal proliferation, it remains unclear whether DHEA is a peroxisome proliferator in human liver. The chemopreventive and anti-proliferative effects of DHEA are not explained by a single mechanism, and at least four mechanisms seem to contribute to these effects: 1) depletion of NADPH and ribose-5-phosphate due to the inhibition of glucose-6-phosphate dehydrogenase activity, 2) suppression of cholesterol biosynthetic pathway by inhibition of HMG-CoA reductase, 3) interference with cell proliferation signaling pathways, and 4) suppression of nitric oxide generation through down-regulation of nitric oxide synthase II. In addition to studies of the mechanisms underlying the anti-neoplastic effects, searches for more potent and less androgenic DHEA derivatives are ongoing. A small amount of DHEA is endogenously metabolized to 7-oxygenated DHEA, and this may represent a metabolic pathway to more potent steroid hormones. Androsterone, epiandrosterone and etiocholanolone have been considered to be merely inactive end products of DHEA, but may in fact be physiological effectors in their own right. In addition, DHEA analogs such as 3β-methyl-5-androsten-17-one, 16α-fluoro-5-androsten-17-one and 16α-fluoro- 5α-androstan-17-one have been synthesized and shown to be more effective inhibitors of tumor growth, compared with DHEA itself. However, to design potent and safe DHEA derivatives, identification of the DHEA receptor and clarification of the mechanisms of DHEA action are required.

Kinins are synthesized from their precursors by different enzymes and participate in the regulation of cardiovascular function through bradykinin (BK) B1 and B2 receptors. They modulate blood coagulation by exerting antithrombotic and profibrinolytic actions. By activating B2 receptors that results in the release of nitric oxide and prostacyclin, kinins inhibit vascular smooth muscle growth and neointima formation, which may play an inhibitory role on the atherosclerosis development, while through the activation of B1 receptors, they may play a deleterious role in this disease. Kinins are potent endogenous vasodilators that are involved in the regulation of coronary vascular tone. However, due to their metabolic characteristics, these peptides act mainly as an autocrine/paracrine factor to locally regulate blood perfusion of organs. By modulating cellular energy metabolism and myocardial oxygen consumption, they protect cardiac and vascular endothelial function in myocardial ischemia and heart failure. Finally, mounting evidence indicates that kinins are involved in the actions of some drugs actually used in the treatment of cardiovascular diseases such as angiotensinconverting enzyme inhibitors and angiotensin AT1 receptor antagonists. Taken together, the kinin system constitutes a potential therapeutic target for cardiovascular diseases. Experiments in animals attempted to explore the kinin system as a therapeutic means, including the mobilization of endogenous kinins using pharmacological agents, searching BK analogs with long-acting properties and gene therapies. However, the potential values of the kinin system have not been taken into consideration in clinical practice for cardiovascular indications.