The potential of active metabolites of antihistamines in the management of allergic disease.

Abstract

Since the discovery of histamine in the first decade of the 20th century, there has been increasing evidence that this biogenic amine, synthesized predominantly in mast cells and basophils, is released in inflammatory processes and plays a key role in the pathogenesis of urticaria and allergic airway diseases, including asthma, rhinitis, and urticaria ( 1-3). Studies have demonstrated that histamine levels are significantly increased in the bronchoalveolar lavage (BAL) of symptomatic asthmatics, compared with asymptomatic asthmatics ( 4, 5), and that allergen challenge leads to a marked increase in the levels of histamine in asthmatics ( 6, 7). Similarly, studies have demonstrated that allergen challenge also leads to significant increases in the levels of histamine in the nasal secretions of patients with allergic rhinitis ( 8-10). A comparison of patients with chronic urticaria and healthy subjects has also demonstrated that the former release greater amounts of histamine, both spontaneously and after antigen provocation ( 11-13). In addition, some studies have demonstrated that the responsiveness of the skin to histamine is slightly increased in patients with urticaria ( 11). Mechanistic studies have demonstrated that the action of histamine arises from its interaction with one of at least three specific histamine receptors, H1, H2, and H3, located on various histamine-responsive target tissues. Interaction of histamine with the H1 receptor leads primarily to smooth-muscle contraction, vasodilatation and hypotension, increased vascular permeability with formation of tissue oedema, increased respiratory mucus secretion, and parasympathetic nerve stimulation ( 14, 15). These effects can subsequently lead to bronchial obstruction in asthma; nasal blockage, sneezing, itching, and discharge in rhinitis; and itchy skin wheals/flares in urticaria. At the cellular level, histamine may also act on inflammatory cells and lead to release of mediators, such as leukotrienes and cytokines, and increased expression of class II antigens (HLA-DR) and ICAM-1 on epithelial cells ( 16, 17), effects which could, in turn, exacerbate the pathology and symptoms of allergic disease. In contrast, effects attributable to H2 receptors include augmentation of gastric acid secretion and increases in gastric and respiratory mucus secretion ( 14). H3 receptors have been implicated in autocrine regulation of histamine synthesis and release from nerve tissue ( 14). In view of the prominent and diverse role of histamine in the pathophysiology of allergic disease, it is not surprising that little effort has been spared in the development of therapeutic agents to counter the effects of histamine in allergic disease. The history of the first clinical use of a H1-receptor antagonist (generally referred to as an antihistamine) dates back to 1942 when Halpern described the use of antergan (N-1-N-dimethyl-N-1-benzyl-N-phenyl-ethylenediamine) in man ( 18). Since the introduction of antergan, many potent antihistamines have been developed and classified as either first- or second-generation antihistamines, depending on whether or not they cause any marked central nervous system (CNS) effects, particularly sedation ( Table 1). The currently available antihistamines, however, have mostly been used in the symptomatic relief of allergic rhinitis, conjunctivitis, and urticaria, and are not thought to have any significant clinical effect in moderate to severe persistent asthma. It has, however, been suggested that these drugs may significantly improve the symptoms of coexisting mild seasonal asthma during symptomatic treatment for allergic rhinitis ( 19). Although the antihistamines are not generally thought to influence the mechanisms underlying the pathogenesis of allergic disease, recent studies have shown that several antihistamines also possess anti-inflammatory properties, in addition to their antihistaminic properties, suggesting that these drugs may be useful in the management of inflammation in allergic disease. Indeed, it has been suggested that, in view of their cationic amphiphilic nature, many of these compounds will readily associate with and perturb the function of other non-H1-receptor cell membrane complexes and/or enzymes ( 20), possibly attenuating pathways which play a role in signalling and initiation of the inflammatory processes ( 21). Despite the high efficacy of the old first-generation antihistamines in providing symptomatic relief of allergic rhinitis, urticaria, and other disorders, a major limitation of these drugs was that they penetrated the blood–brain barrier readily and caused marked CNS side-effects, such as sedation and impaired psychomotor activity, even at therapeutic doses ( 19, 22). In addition, these drugs were also associated with severe anticholinergic side-effects. In contrast, the characteristic feature of the second-generation antihistamines is that they exhibit fewer sedative and anticholinergic effects than their predecessors, probably as a result of the combination of their decreased ability to cross the blood–brain barrier and their high potency and specificity in H1-receptor antagonism ( 19, 23, 24). However, both subjective and objective cognitive and psychomotor tests have demonstrated that a very limited number of the second-generation antihistamines, including ebastine and fexofenadine, are virtually free of sedative effects ( 25).With the exception of astemizole, which has an onset of action of 3 days, most of the new agents have a much more rapid onset of action of 15–180 min ( 26) and a longer duration of activity of 24 h, allowing a once-daily treatment regimen and better patient compliance ( 27). Moreover, it is also possible to perform dose titration with these drugs (i.e., use at different dosages in different types of patients). However, some members of this class of drugs, particularly astemizole and terfenadine, have been shown to be associated with serious cardiac side-effects such as altered cardiac repolarization, leading to prolongation of the QT interval and serious ventricular arrhythmia (e.g., torsade de pointes) ( 22, 28, 29). These adverse cardiac effects may be exacerbated by concomitant administration of compounds, such as the macrolide antibiotics and some azole compounds, that inhibit the cytochrome P450 system and consequently interfere with the hepatic metabolism of these antihistamines ( 30, 31). Furthermore, studies of astemizole have suggested that not only the parent compound, but also its active metabolite desmethylastemizole is associated with serious cardiac side-effects ( 22). In contrast, studies of fexofenadine, the active metabolite of terfenadine, have demonstrated that this compound is not associated with cardiac toxicity ( 22, 29, 32, 33). The introduction of the second-generation antihistamines has transformed the way in which allergic disease, particularly allergic rhinitis, is treated, since many of these drugs are recommended as first-line medications in mild to moderate severity disease, and as combination medication with topical corticosteroids in more severe disease ( 3, 26, 34) ( Fig. 1). Although a large number of second-generation antihistamines are currently available for the treatment of allergic rhinitis and urticaria, most of the information on the efficacy and tolerance of this class of compounds has been derived from studies on the first few members of this class, including astemizole, terfenadine, cetirizine, and loratadine. Studies of astemizole and terfenadine have been widely documented and have demonstrated that both these drugs are highly effective in the treatment of seasonal and perennial allergic rhinitis and urticaria in children and adults, as indicated by significant attenuation of symptoms or decreased need for rescue medications ( 35-38). Both these drugs, however, are currently used with caution in clinical practice, primarily as a consequence of their cardiotoxic effects. Stepwise approach to treatment of seasonal allergic rhinitis (from van Cauwenberge, 1998 [ref. 34]; reprinted with permission). Similarly, double-blind, single- or parallel-group controlled trials of cetirizine ( 39, 40), ebastine ( 41, 42), and loratadine ( 43-45) have also been well documented, and they have demonstrated that these drugs are also significantly superior to placebo in attenuating nasal and/or ocular symptoms of seasonal or perennial allergic rhinitis or chronic urticaria. Although some comparative studies of cetirizine, the active metabolite of hydroxyzine (a first-generation antihistamine), have suggested that this compound may be slightly more efficacious than some of the other H1-receptor antagonists ( 40, 46-50), other studies have suggested that cetirizine is as effective as, but not superior to, other antihistamines ( 39). Despite the high efficacy of cetirizine, pooled data from early placebo-controlled and direct comparative trials have suggested that cetirizine, at or slightly above the therapeutic dose, may also cause sedation and impairment of performance ( 25, 39, 51). More recent data suggest that fexofenadine, one of the most recently available H1-receptor antagonists, is likely to achieve much prominence as a highly efficacious therapy in allergic disease. Metabolic studies of fexofenadine have demonstrated that, like cetirizine, fexofenadine also does not undergo any significant hepatic metabolism and is excreted primarily un-changed in the faeces and urine ( 32). Consequently, it has been suggested that, in patients with hepatic impairment, it is not necessary to adjust the dosage of fexofenadine, unlike other antihistamines ( 52, 53). It has also been reported that fexofenadine is well tolerated in children and adults and, more importantly, has a wide margin of safety, as indicated by a lack of CNS effects, cardiotoxic side-effects, and clinically significant interactions with antiarrhythmic drugs, tricyclic antidepressant drugs, erythromycin, or ketoconazole ( 22, 29, 32, 54). Several controlled clinical trials have demonstrated that fexofenadine is also significantly more efficacious than placebo, and at least similar to other antihistamines, including cetirizine, in improving symptoms in patients with seasonal allergic rhinitis or chronic urticaria ( 22, 54-57). However, unlike cetirizine, fexofenadine has no sedative effects, and some studies have demonstrated that it may also be significantly more efficacious than placebo in relieving nasal blockage ( 55) ( Fig. 2), a property not generally observed for most other second-generation antihistamines. Effect of placebo (PL) or fexofenadine (60, 120, 240 mg b.i.d.) on symptoms of rhinitis (from Bernstein et al., 1997 [ref. 55]; reprinted with permission). Although histamine is one of the major effectors of the allergic reaction, it is far from being the only mediator, and many other mediators produced by different cell types are involved. Interestingly, considerable evidence is emerging that, in addition to H1-receptor antagonism, several antihistamines also possess antiallergic/anti-inflammatory activity, which may result in decreased release of both preformed and newly generated proinflammatory mediators from mast cells and basophils; decreased migration, accumulation, and activation of inflammatory cells; and decreased expression of cell adhesion proteins on epithelial cells. This anti-inflammatory activity of the antihistamines may explain the high efficacy of these agents in the treatment of allergic disease. Studies of azelastine, loratadine, and terfenadine have demonstrated that treatment with these compounds can decrease antigen-induced inflammatory cell infiltrate and levels of inflammatory mediators such as histamine, mast-cell tryptase, prostaglandin (PG) D2, leukotriene (LT) C4, and eosinophil cationic protein (ECP), in the nose and skin of allergic individuals ( 58-61) ( Fig. 3). Similarly, in vitro studies have also demonstrated that several antihistamines, including astemizole, azelastine, ebastine, ketotifen, loratadine, and terfenadine, can inhibit stimulated release of histamine and/or other inflammatory mediators from human lung, skin, and tonsillar mast cells/cell lines ( 20, 61); basophils/basophilic cell lines ( 20, 61); and epithelial cells/cell lines ( 21, 62). Other studies have demonstrated that azelastine, ebastine, ketotifen, loratadine, or terfenadine can also inhibit the viability, migration, or activation of human eosinophils, neutrophils, or lymphocytes ( 20). Effect of terfenadine on natural allergen-induced release of ECP and MPO in nasal secretions of patients with seasonal allergic rhinitis, before and after treatment (O: median values; modified from Ciprandi et al., 1995 [ref. 60]; reprinted with permission). Despite this evidence of the anti-inflammatory effects of some antihistamines, a major obstacle in the use of many of the antihistamines is that it has generally not been possible to attenuate allergen-induced inflammatory changes in the nose or skin with these agents in vivo ( 20). Moreover, when changes have been noted in vivo, these have been found to be small and inconsistent, particularly for the older first-generation antihistamines. Although a comparatively large number ofstudies have also demonstrated more varied types of anti-inflammatory effects for antihistamines in vitro, it appears that significant anti-inflammatory activity was observed only at relatively high concentrations which are unlikely to occur in clinical practice. Furthermore, there was inconsistency and variability in the magnitude of effects for the same drugs in different studies ( 20), presumably as a result of the different experimental conditions and models employed in these studies. These studies have also produced conflicting data for correlations between clinical efficacy and antiallergic effects, both in vivo and in vitro. However, more recent studies with the active metabolites of antihistamines have demonstrated that some of these have significant antiallergic/inflammatory effects at concentrations achieved at therapeutic dosage, suggesting a putative anti-inflammatory role in the management of allergic disease. To our knowledge, the active metabolites of the antihistamines that have been investigated for their anti-inflammatory properties in man to date include desmethylazelastine, cetirizine, fexofenadine, descarboethoxyloratadine, and carebastine. Cetirizine has been the most widely investigated of these compounds; consequently, this compound has set a precedent for the development and use of other antihistamine metabolites as antiallergic agents. Several studies have investigated the effect of cetirizine on mediator release, and activation and migration of inflammatory cells, particularly eosinophils ( 20, 39, 63). Okayama et al. ( 64) have investigated the effect of cetirizine on anti-IgE-mediated release of histamine and PGD2 from human lung, tonsil, and skin mast cells in vitro, and demonstrated that cetirizine led to partial inhibition of the release of both these mediators from all three cell types, albeit at comparatively high concentrations unlikely to be achieved in clinical dosage. More recent studies have demonstrated that cetirizine also inhibited fMLP and sodium fluoride (NaF)-induced synthesis of LTB4 from neutrophils ( 65). Although several studies have also documented the effect of cetirizine on mediator release in vivo, these have produced conflicting data. While some studies have not been able to demonstrate any significant effect of cetirizine on the release of mast-cell-derived mediators, others have demonstrated that cetirizine significantly inhibits the release of histamine, PGD2 and LTC4 ( 20, 39, 66). Studies investigating eosinophil chemotaxis have consistently demonstrated that this is inhibited by cetirizine, both in vivo and in vitro ( 63, 67). Similarly, studies on eosinophil adherence have demonstrated that PAF-induced adherence of human eosinophils to plasma-coated glass plates or cultured human umbilical vein endothelial cells was also blocked by cetirizine at physiological concentrations ( 68-70). Studies investigating the mechanisms underlying cell migration have suggested that leukocyte migration and accumulation at the site of allergic inflammation are dependent upon the expression of cell adhesion molecules, among which intercellular adhesion molecule-1 (ICAM-1) plays a pivotal role ( 71-73). Ciprandi et al. ( 74) have proposed that modulation of ICAM-1 expression represents an important therapeutic target in allergic disease, and have investigated the effect of treatment with several antihistamines, including azelastine, cetirizine, levocabastine, loratadine, oxatomide, and terfenadine, on natural or experimental allergen exposure-induced changes in the expression of ICAM-1 on nasal and conjunctival epithelial cells of pollen-sensitive rhinitics. These authors demonstrated that while treatment with cetirizine for a period of 2.5 days was sufficient to attenuate allergen challenge-induced expression of ICAM-1 and inflammatory cell infiltration into the conjunctiva of asymptomatic patients ( 75), treatment for 2–4 weeks was required to attenuate natural allergen-induced expression of ICAM-1 on the nasal epithelial cells of these individuals ( 76, 77). More recently, these authors compared the effect of continuous and on-demand treatment with cetirizine, over a 4-week period of natural allergen exposure, in patients with seasonal allergic rhinitis, and demonstrated that the continuous treatment not only provided significantly better symptom relief than on-demand treatment ( Fig. 4), but also significantly decreased the numbers of eosinophils and neutrophils in the nasal mucosa, compared with on-demand treatment ( 78). These results provide evidence of an association between decreased symptoms and decreased inflammation, as a consequence of antihistamine therapy, and suggest that antihistamines are likely to be clinically useful in the management of the inflammation underlying allergic disease, when used in a prophylactic manner. Comparison of effect of on-demand and continuous treatment with cetirizine on natural allergen-induced nasal symptoms in patients with seasonal allergic rhinitis (modified from Ciprandi et al., 1997 [ref. 78]; reprinted with permission). While most studies have evaluated cetirizine, the investigation of other antihistamine metabolites for anti-inflammatory properties has been increasing, particularly fexofenadine, the only other antihistamine metabolite approved for human use. However, studies of fexofenadine and some of the other antihistamine metabolites that have been documented to date also provide convincing evidence, similar to that for cetirizine, of their antiallergic potential in the management of allergic disease. Studies of fexofenadine have suggested that this agent may exhibit significant antiallergic effects at concentrations that are clinically relevant. Abdelaziz et al. ( 79) have employed a complex in vitro coculture model of eosinophils and epithelial cells derived from nasal biopsies of patients with seasonal allergic rhinitis to investigate the effects of 10−9–10−3 M fexofenadine on both eosinophil activity directly, and eosinophil-induced changes in epithelial cell permeability and release of proinflammatory mediators from these cells, thereby reflecting the in vivo situation more closely. These authors demonstrated that 10−9 M fexofenadine, a concentration that is achieved in the plasma at clinical dosage (fexofenadine Cmax≃10−6 M) ( 80), significantly blocked the increases in epithelial cell permeability and release of granulocyte macrophage-colony stimulating factor (GM-CSF) and soluble ICAM-1 induced by eosinophils activated with opsonized latex beads ( Fig. 5). The release of IL-8 was also significantly attenuated at a concentration of 10−6 M fexofenadine. An investigation of the direct effects of fexofenadine on eosinophil activity demonstrated that 10−6 and 10−3 M fexofenadine significantly decreased eosinophil chemotaxis and adherence of eosinophils to human umbilical vein endothelial cell cultures. Although fexofenadine was also found to decrease the release of ECP from eosinophils activated by incubation with opsonized latex beads and epithelial cells, this was not found to be significant. However, a preliminary study by Amon et al. ( 81) has recently shown that 10−9–10−3 M fexofenadine significantly inhibited Ca-ionophore-induced release of ECP from isolated eosinophils by 40–50%. It is possible that the difference between the findings of Abdelaziz et al. and those of Amon et al. may be the result of the different stimuli used to induce the ECP release. Effect of fexofenadine on activated eosinophil-induced release of IL-8, GM-CSF, and sICAM-1 from cultured nasal epithelial cells of patients with seasonal allergic rhinitis (modified from Abdelaziz et al., 1998 [ref. 79]; reprinted with permission). Another study recently investigated the effect of 0.5–50 μg/ml fexofenadine and 0.01–1.0 μg/ml terfenadine on basal (baseline) and IFN-γ-induced ICAM-1 expression and release of mediators from cultured human conjunctival epithelial and fibroblast cell lines ( 82). This study demonstrated that although fexofenadine and terfenadine both significantly decreased basal expression of ICAM-1 on the conjunctival epithelial cells, only fexofenadine was found to be effective in attenuating IFN-γ-induced ICAM-1 expression. Furthermore, only fexofenadine significantly attenuated IFN-γ-induced expression of ICAM-1 and release of IL-6 in the fibroblast cell line. In common with several in vitro studies, however, significant effects of fexofenadine were observed only at the highest concentration of the drug investigated. The authors suggested that the lack of significant effects of fexofenadine at the lower concentrations was possibly a consequence of the low solubility of the drug at pH 7.4, the level employed for the culture conditions, rather than low efficacy, since the solubility of fexofenadine has been shown to be sensitive to the effects of pH and is minimum in the pH range 3–8. More recently, it has been shown that fexofenadine inhibited both Der p 1- or anti-IgE-induced release of histamine and LTC4 from human basophils and lung parenchyma mast cells, and anti-FcεRI-induced release of IL-4 from FcεRI+ cells, suggesting that this compound may also exert antiallergic effects by modulating immunologic release of proinflammatory mediators ( 83). Studies of descarboethoxyloratadine (DCL), the active metabolite of loratadine, have demonstrated that this compound also has significant antiallergic effects in vitro. Genovese et al. ( 84) have recently demonstrated that preincubation of purified basophils with either loratadine or DCL inhibited Der p 1 antigen- or anti-FcεRI-induced release of histamine and LTC4. In addition, these authors found that both drugs led to a significant inhibition in the release of histamine, LTC4, PGD2, and tryptase from purified human lung and skin mast cells immunologically challenged with anti-FcεRI ( Fig. 6). In contrast, Vignola et al. ( 85) have investigated the effect of loratadine and DCL on the expression of ICAM-1 and human leukocyte class II antigen (HLA-DR) on nasal epithelial cells cultured from nasal turbinates and polyps, and have demonstrated that both compounds significantly decreased histamine-induced expression of ICAM-1 on nasal epithelial cells in vitro. Similarly, Davies et al. ( 86) have investigated the effect of loratadine and DCL on nitrogen dioxide (NO2)-induced release of inflammatory mediators from primary human bronchial epithelial cell (HBEC) cultures, and have demonstrated that both compounds attenuated the release of IL-8, RANTES, and sICAM-1 from these cultures. Although significant effects of DCL were observed in both these studies, these were achieved at comparatively high concentrations of 10 and 25 μM DCL, respectively. Consequently, the clinical relevance of these findings is not apparent immediately. It is possible that the lack of efficacy of DCL at lower concentrations is a consequence of optimal concentrations of DCL not being achieved in these model systems, as was speculated for fexofenadine ( 82). Despite this limitation, these studies nevertheless demonstrate that DCL, and probably other antihistamines, have the capacity to attenuate nonimmunologic release of proinflammatory mediators. Effect of DCL on anti-FcεRI-induced release of histamine (○), tryptase (▪), and PGD2 (●) from human skin mast cells (from Genovese et al., 1997 [ref. 84]; reprinted with permission). In contrast to fexofenadine and DCL, there is comparatively little information on the antiallergic properties of carebastine, the active metabolite of ebastine. A preliminary study by Campbell et al. ( 62) has investigated the effect of ebastine and carebastine on the release of eicosanoids and cytokines from human dispersed polyp cells and demonstrated that, while ebastine blocked the release of cytokines and anti-IgE-induced PGD2 and LTC4/D4, carebastine inhibited the release of PGD2 and LTC4/D4, with little effect on cytokine release ( Table 2). The effects on LTC4/D4, however, were observed at comparatively high concentrations. From the plethora of controlled trials in adults and children, there is little doubt that the second-generation antihistamines are a highly efficacious, fast-acting, and safe therapy for symptomatic control of allergic rhinitis and chronic idiopathic urticaria. Moreover, two multicentre studies in the USA and Europe have recently demonstrated that treatment with fexofenadine also significantly improves disease-specific quality of life (QoL) and patient-reported performance-impairment measures, compared with placebo treatment ( 87, 88). Indeed, a comparison between fexofenadine and loratadine demonstrated that fexofenadine was also significantly better than loratadine at improving QoL measures in patients with seasonal allergic rhinitis ( 88). These findings have important socio-economic implications, since they suggest that treatment with antihistamines, particularly the newer antihistamine metabolites, may indirectly decrease the health-care costs by increasing productivity in treated patients. Furthermore, many recent studies have provided incontrovertible evidence that these agents also exhibit antiallergic/anti-inflammatory effects that are quite distinct from the classical antihistaminic effects, and therefore offer great potential for use in the management of allergic disease. Although the clinical relevance of the antiallergic activity of the antihistamines has been questioned in view of the lack of significant effects at therapeutic dosage and lack of direct correlations between decreased symptoms and antiallergic effects, it is possible that this may be a consequence of variability in the pharmacokinetic and/or pharmacodynamic profiles of the antihistamines, resulting from their metabolism, rather than the low efficacy of the agents. Indeed, studies of the active antihistamine metabolites, particularly cetirizine and fexofenadine, which undergo minimal metabolism and biotransformation compared to their parent compounds, have demonstrated that these compounds are highly efficacious in providing symptomatic relief in both allergic rhinitis and chronic urticaria, and also have the capacity for significant antiallergic effects at therapeutic dosages. Thus, it is possible that, in forthcoming clinical trials, the real clinical relevance of the antiallergic effects of the newer antihistamines may be borne out by the following combination: the use of an active antihistamine metabolite manipulation of the dosage regimen (continuous or on-demand treatment) administration by an alternative route (topical instead of oral).