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Anti-Inflammatory Activity of H^Sub 1^-Receptor Antagonists: Review of Recent Experimental Research

Posted on: Friday, 6 August 2004, 06:00 CDT

Key words: Anti-allergic effects - Fexofenadine - H^sub 1^- receptor antagonists - Histamine - IgE-mediated inflammatory mechanisms

SUMMARY

Objective: To compare the anti-inflammatory effects of fexofenadine with other H^sub 1^-receptor antagonists in vitro.

Data sources: Published literature.

Study selection: Recent experimental studies on anti- inflammatory effects of H^sub 1^-receptor antagonists. Databases searched: Medline, Medscape. Period covered: 1990-2003. Search terms: second-, third-generation antihistamines; sedating, nonsedating antihistamines; in vitro anti-inflammatory activity; cetirizine; ebastine; loratadine; fexofenadine; desloratadine.

Results: Second- and third-generation H^sub 1^-receptor antagonists may demonstrate significant in vitro anti-inflammatory activity at concentrations considered to be clinically relevant. In some instances, higher (supraclinical) concentrations are required to achieve comparable effects.

Conclusions: Experimental research suggests that second- and third-generation H^sub 1^-receptor antagonists may achieve anti- inflammatory effects in a clinical context. Further studies are required to support this conclusion.

Introduction

Research on the treatment of allergic rhinitis and other allergic diseases has focused on developing an oral, nonsedating antihistamine that is highly effective, but does not exhibit the drawbacks often associated with sedating or potentially sedating/ cardiotoxic compounds of this class, i.e. central nervous system (CNS) depression and cardiac arrhythmia.

The primary mechanism of action of the oral H^sub 1^-receptor antagonists is a competitive binding to the H^sub 1^-receptors found on nerve endings, smooth muscles, and glandular epithelia1. These drugs, newly redefined as inverse H^sub 1^-receptor agonists, stabilize an inactive conformation of the receptor, thereby preventing activation by histamine. In addition to their antihistaminic effects, it is now recognized that H^sub 1^-receptor antagonists possess other pharmacologie properties that are not uniformly distributed among drugs of this class2-5. For example, research is currently being conducted on the anti-inflammatory effects of H^sub 1^-receptor antagonists, including their effects on eicosanoid production and cytokine release, and their influence on the release rates of proinflammatory mediators6. Data from in vitro studies (discussed below) have shown important differences between H^sub 1^-receptor antagonists in achieving measurable anti- inflammatory effects at clinically relevant concentrations.

This review will summarize and compare recent (1990-2003) experimental data on second- and third-generation H^sub 1^-receptor antagonists that demonstrate potentially clinically relevant anti- inflammatory effects in addition to their anti-allergic effects on histamine production and the histamine-induced response3.

The allergic response: mechanisms, mediators, and targets

Allergic rhinitis and asthma demonstrate allergic response mechanisms and inflammatory processes in common3, comprising those of the respiratory inflammatory cascade (Figure I)7-12 and the arachidonic acid metabolic pathway (Figure 2)7,9.

Allergic airway responses include the recruitment and infiltration of TH2+ lymphocytes, B lymphocytes, mast cells, basophils, and eosinophils, each of which degranulates or is activated to release mediators, cytokines, and chemokines that contribute to respiratory inflammation. These mediators and cellular components, illustrated in Figures 1 and 2 and listed in Table 1, are potential therapeutic targets. The presence of eosinophil- derived proteins, such as eosinophil cationic protein (ECP), major basic protein (MBP), and eosinophil-derived neurotoxin (EDN), correlates strongly with the extent of eosinophilic infiltration of the airway and accompanying inflammation13.

Figure 1. The respiratory inflammatory cascade. Primary airway cellular responses to allergens generate mediators that trigger activities such as eosinophil recruitment and proliferation, synthesis of IgE by B lymphocytes, and degranulation of mast cells. Mast cells in the airway express mediators at the same time that their cell membrane phospholipids are being broken down to form arachidonic acid. The metabolic pathway of arachidonic acid then contributes additional mediators and markers of the inflammatory response. Key: APC, activated protein C; GM-CSF, granulocyte- macrophage colony-stimulating factor; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoyyeicosatetraenoic acid; Ig, immunoglobulin; IL, interleukin; LT, leukotriene; PAF, platelet-activating factor; PG1 prostaglandin; Tx, thromboxane; FCAM, vascular cell adhesion molecule. Adapted from Pearlman7; American Academy of Allergy, Asthma, and Immunology8; Wenzel9; Triggiani et al.10; Simons11; and Casale and McCarthy12

Histamine and tryptase are each by-products of mast-cell activation and degranulation. Simultaneous with mast-cell degranulation, mast-cell membrane phospholipids are broken down by phospholipase A, leading to the production of arachidonic acid, which, when metabolized, yields mediators such as leukotrienes, prostaglandins, and other eicosanoids. Additional mediators and markers generated during the respiratory inflammatory response, the presence of which indicates the extent and severity of airway inflammation, are listed in Table 1.

The anti-inflammatory response of second-generation antihistamines

Cetirizine

The anti-inflammatory effect of the second-generation antihistamine cetirizine on human eosinophils from patients with allergic rhinitis was studied in vitro by Sedgwick and Busse14. In the presence of interleukin (IL)-5 (but not IL-3 or granulocyte- macrophage colony-stimulating factor (GM-CSF), cetirizine 100 mol/l significantly inhibited eosinophil survival at 48 h (p = 0.0201) and 72 h (p = 0.0025). This effect did not occur at < 0.1 ng/ml IL-5, nor did it occur at cetirizine concentrations of < 100 mol, which is much higher than the tissue levels achieved by clinical dosages of cetirizine.

Figure 2. The arachidonic acid metabolic pathway. The mediator enzymes and eicosanoids shown are potential targets of therapy to inhibit the inflammation present in allergic airway disease. At the end of the cascade are mediators that are responsible for airway edema, cough, nasal mucus production, bronchoconstriction, bronchial mucus production, neutrophil/eosinophil chemoattraction, leukocyte adhesion molecule expression, vascular permeability, and airway hyperreactivity. Key: HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LT, leukotriene; PG, prostaglandin; Tx, thromboxane. Adapted from Pearlman7 and Wenzel.9

Table 1. Proinflammatory mediators and markers in the airway allergic response*

Other studies15,16 also demonstrated that high concentrations (~100 mol/l) of cetirizine were required to achieve eosinophil inhibition in vitro. In contrast, some investigations reported significant eosinophil inhibition in vitro at cetirizine concentrations within the therapeutic range, i.e. at 0.1 g/ml17, and cetirizine inhibition of monocytes and T cells in vitro with 0.25- 2.5 g/ml18.

Ebastine, Carebastine

In an in vitro nasal polyp study, ebastine and its metabolite, carebastine, were shown to block the release of anti-IgE-induced eicosanoids (prostaglandin (PG) D^sub 2^ and leukotriene (LT) C^sub 4^/D^sub 4^) in vitro. Ebastine inhibited release of the two mediators by 30% at clinically relevant concentrations (2.57-9.6 mol)6. Carebastine's effect on PGD^sub 2^ was less strong - 30% inhibition at a concentration of 8.14 mol/l. Ebastine and, to a lesser extent, carebastine, also inhibited the release of cytokines in vitro.

Loratadine

The in vitro effect of loratadine on human eosinophils (from allergic patients) was investigated by Eda et al.19. Loratadine significantly inhibited platelet-activating factor (PAF)-induced eosinophil chemotaxis at concentrations that were equivalent to serum concentrations achieved after a single oral administration of 20 or 40 mg. There was no effect on PAF-induced ECP release. These findings suggest that loratadine has a direct inhibitory effect on eosinophil activation.

In another study20, loratadine (and desloratadine) 10 mol/l significantly inhibited expression of intercellular adhesion molecule-1 (ICAM-l) and human leukocyte class II antigen (HLA-DR) in nasal epithelial cells in vitro. These studies suggest that loratadine may exert an in vivo anti-inflammatory effect.

Anti-inflammatory effects of third-generation antihistamines

Fexofenadine

The third-generation, H^sub 1^-receptor antagonist fexofenadine has been investigated for its effects on the following antigen- induced inflammatory response mechanisms:

* In vitro eosinophil-induced changes in epithelial permeability and cytokine release in nasal cells from patients with seasonal allergic rhinitis (SAR)21

* Airway hyper-responsiveness (AHR) following T-cell transfer in animals22

* Preformed and newly synthesized mediators from human basophils and mast cells in vitro23

* Intercellular adhesion molecule-1 expression in vitro in human epithelial cells and fibroblasts24

* Activity of human eosinophils in vitro25

Table 2. In vitro effects of fexofenadine on markers for the allergic or inflammatory res\ponse in human nasal epithelial cell cultures (HNEC) from patients with seasonal allergic rhinitis

Eosinophil-induced Changes in Epithelial Permeability and Cytokine Release

A study by Abdelaziz et al.21 assessed the in vitro effects of fexofenadine on human nasal epithelial cells (HNEC) cultured from biopsy specimens of patients with SAR. HNEC were incubated in the presence of eosinophils treated with opsonized latex beads to significantly reduce the cells' electrical resistance. The cultures were then treated with fexofenadine (Kh^sup -9^ O^sup -3^ mol/l). Eosinophil-induced changes in electrical resistance were assessed to measure permeability and rate of release of proinfiammatory mediators. Effects of fexofenadine on eosinophil chemotaxis and adherence to endothelial cells induced by the conditioned medium from the HNEC cultures were also assessed.

Results showed that while the incubated HNEC exhibited a significant decrease in electrical resistance, treatment with 10^sup -9^-10^sup -3^ mol/l fexofenadine nullified this effect. Similarly, fexofenadine significantly attenuated the increased basal release of several substances that occurred in relation to the incubated HNEC: the chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), IL-8; GM-CSF, and soluble ICAM-1. Conditioned medium from the HNEC cultures also increased eosinophil chemotaxis and adherence to cultured endothelial cells, and the addition of fexofenadine (10^sup -6^-10^sup -3^ mol/l) significantly attenuated these effects (Table 2)21. These results suggest that fexofenadine may reduce nasal inflammation by modulating the release of proinflammatory mediators and adhesion molecules from the HNEC.

Inhibition of Airway Hyper-responsiveness Following T-cell Transfer in Vivo

Gelfand et al.22 identified potential fexofenadine targets in the inhibition of AHR, and determined the effects of fexofenadine on the ability of T cells to mediate AHR in vivo. BALB/c J mice were sensitized to ovalbumin by intraperitoneal injection on days 1 and 14, followed by airway challenge with aerosolized 1% ovalbumin on days 26, 27, and 28. Fexofenadine (2.5 mg b.i.d.) or placebo was administered daily from day 23 to day 28. Purified T cells from lung mononuclear cells of these mice were obtained on day 30 and transferred into naive animals. Following T-cell transfer, the naive animals were subjected to six airway challenges with 1% ovalbumin on consecutive days, 48 h after which whole-body barometric plethysmography was used to evaluate airway responsiveness to inhaled methacholine. No increase in methacholine reactivity was observed in animals receiving fexofenadine-treated T cells. However, a greater than two-fold increase in AHR was noted in animals receiving T cells from placebo-treated mice. Relative to the recipients of T cells from fexofenadine-treated mice, the placebo mice also showed a significantly increased number of lymphocytes in their bronchoalveolar lavage fluid. The absence of increased reactivity to challenge in the recipients of fexofenadine-treated T cells suggests anti-inflammatory properties for fexofenadine apart from the allergic response, i.e. H^sub 1^-receptor antagonism.

Inhibition of Preformed and Newly Synthesized Mediators from Human Basophils and Mast Cells

In a 1999 study, de Paulis et al.23 characterized effects of fexofenadine on the release of histamine and LTC^sub 4^ from mast cells purified from human lung parenchyma and human basophils in vitro, as well as effects of fexofenadine on secretion of IL-4 from human basophils in vitro following anti-IgE induction. Mast cells and basophils were separately preincubated with fexofenadine (10^sup -6^-10^sup -3^ mol/l) before anti-IgE challenge, and basophils were preincubated with fexofenadine (10^sup -6^-10^sup -3^ mol/l) before challenge with house dust mite (Derp I) antigen. A concentration- dependent inhibition of IL-4 release was seen with basophils preincubated with fexofenadine prior to anti-IgE challenge. Basophils preincubated with fexofenadine also had reduced histamine and LTC^sub 4^ release mediated by Der p I antigen, or when challenged with anti-IgE (Figure 3)23. Similarly, mast cells preincubated with fexofenadine mediated the release of histamine and tryptase following anti-IgE challenge. These results show that fexofenadine possesses anti-inflammatory activity through inhibition of the release of preformed and newly synthesized mediators from human lung mast cells and human basophils.

Effects of Fexofenadine on ICAM-1 Expression in Human Epithelial Cells and Fibroblasts

Paolieri et al.24 determined the effects of fexofenadine on adhesion molecule expression (CD54/ICAM-1 and CD29) from continuously cultured human conjunctival epithelial and fibroblast cell lines. Using flow cytometry, ICAM-1 and CD29 expression were analyzed at baseline and after interferon (INF)-? or tumor necrosis factor (TNF)-[alpha] stimulation in the presence of fexofenadine. The basal expression of ICAM-1 by human conjunctival epithelial cells was significantly reduced (p < 0.03) by fexofenadine 50 g/ml (Figure 4A). This concentration also significantly attenuated the INF-[gamma]-induced expression of soluble ICAM-I by both human conjunctival epithelial cells (p < 0.03) (Figure 4B) and fibroblasts (p < 0.03) (Figure 5)24. Fexofenadine did not significantly affect the TNF-[alpha]-induced, up-regulation of ICAM-1 in fibroblasts. These results suggest that fexofenadine exerts a direct biologic effect on epithelial cells and fibroblasts, resulting in reduced ICAM-1 expression and a possible reduction of soluble ICAM-I release.

Figure 3. Inhibition of histamine and leukotriene C^sub 4^ release. Basophils preincubated with fexofenadine resulted in inhibition of histamine and leukotriene (LT) C^sub 4^ release, as mediated by Der p I antigen. Preincubated basophils showed similar results when challenged with anti-immunoglobulin E. From de Paulis et al.23

Figure 4. Fexofenadine attenuation of basal expression by human conjunctival epithelial cells of intercellular adhesion molecule-1 (ICAM-1) (A)1 and interferon-g-induced soluble ICAM-1 (B) ("p < 0.03, Student's t-test). Reprinted with permission from Paolieri et al.24

Figure 5. Fexofenadine attenuation of intercellular adhesion molecule-1 (ICAM-I) expression by fibroblasts stimulated with interferon-g. *Statistically significant reduction in ICAM-1 expression by fexofenadine; p < 0.03, Student's t-test. Reprinted with permission from Paolieri et al.24

Activity of Fexofenadine on Human Eosinophils

A study by Amon et al.25 evaluated the direct effects of fexofenadine on eosinophil and basophil activation in vitro as a measure of anti-inflammatory activity. Basophils and eosinophils from healthy human donors were preincubated with fexofenadine and then activated with various concentrations of a secretagogue, A23187, after which histamine release and ECP levels were measured. The A23187-induced release of ECP from eosinophils was significantly reduced by fexofenadine, with concentrations as low as 1 nmol/l producing an inhibition of 40.4 2.3% in contrast to the control (1 mol A23187 without fexofenadine). Although the inhibition of ECP release was dependent on the length of preincubation, fexofenadine inhibited ECP release by 50%, even after the stimulation buffer was removed. At concentrations below 1 mol/l; fexofenadine did not inhibit the anti-IgE-induced release of histamine by basophils or significantly influence basophil priming by IL-3; this was true even after subsequent stimulation via Fc[epsilon]RI. Thus, fexofenadine suppressed the release of ECP from eosinophils.

Desloratadine

Desloratadine, another third-generation antihistamine, has also been shown to have direct effects on inflammatory mediators in vitro. These effects were manifested at both therapeutic and supratherapeutic concentrations. Thus, Schroeder et al.26 demonstrated that desloratadine (100 nmol/1-10 mol/l) inhibited both IgE-mediated and non IgE-mediated generations of IL-4 and IL-13 by human basophils in vitro. In another in vitro study27, 10 fmol/l-10 mol/l desloratadine inhibited release of proinflammatory cytokines, such as IL-6 and IL-8, from basophils and mast cells. A study by Genovese et al. demonstrated that desloratadine (300 nmol/l-100 mol/ l) inhibited anti-Fc[epsilon]RI-induced release of PGD^sub 2^, histamine, and tryptase (Figure 6), as well as LTC^sub 4^28. Although some of these concentrations were supratherapeutic, many were in the therapeutic range, and therefore of potential clinical utility29.

Discussion

Evidence suggests that the continual release of histamine from lung cells of asthma patients may contribute to lung tissue inflammation and remodeling, and may affect lymphocytes, monocytes, basophils, epithelial cells, and macrophages by modulating the release of proinflammatory and immunoregulatory mediators and cytokines10,30,31. The anti-inflammatory activities of second- and third-generation H^sub 1^-receptor antagonists have been evaluated in vitro. These studies have shown that many second-generation H^sub 1^-receptor antagonists (considered potentially or minimally sedating) and third-generation H^sub 1^-receptor antagonists (considered nonsedating) inhibit release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, and IL-13; PGD^sub 2^; LTC^sub 4^; tryptase; histamine; and the TNF-[alpha]- induced chemokine RANTES, as well as eosinophil chemotaxis and adhesion31.

In the studies of anti-allergic activities of the second-and third-generation antihistamines reviewed here, some effects on the allergic inflammatory response were achieved at high drug concentrations with no clinical relevance, in contrast to clinically relevant concentrations of other H^sub 1^-receptor antagonists in similar in vitro studies (Table 3)6,10,14,18,21-25,30. For example, one in vi\tro study of the second-generation drug cetirizine on the inhibition of IL-5-dependent eosinophil survival required a concentration of the drug (100 mol/l) that is much higher than that used clinically14.

Table 3. Studies on dose-related anti-allergic effects of second- and third-generation H^sub 1^receptor antagonists in vitro and in vivo

Because fexofenadine does not cross the blood-brain barrier, it is considered free of the most common adverse CNS effect, i.e. sedation, often observed with older antihistamines. In one study, at concentrations of 50 g/ml, or 100-fold the peak pharmacologic concentration, fexofenadine remained clinically nonsedating32,33. In another clinical review of fexofenadine, the drug displayed no sedative effects at dosages of 240 mg/day, or twice the recommended daily dosage34. In contrast, the second-generation agent cetirizine, even at recommended clinical dosages of 10-20 mg/day, has been shown to impair performance and cognition35. Cetirizine has also been associated with subjectively reported impairment of sensorimotor speed at less than the recommended dosage, i.e. 2.5 mg/day16. Although cetirizine is much less sedating than its parent compound hydroxyzine, it appears to be more sedating than loratadine, desloratadine, or fexofenadine37,38. In fact, the incidence of drowsiness with cetirizine has been estimated to be approximately twice that seen with fexofenadine or placebo38.

Figure 6. Effect of increasing concentrations of desloratadine on anti-Fc[epsilon]RI-induced release of histamine, tryptase, and PGD^sub 2^ from human skin mast cells (HSMC). p < 0.01 compared with mediator release induced by anti-Fc[epsilon]RI alone. Reprinted with permission from Genovese et al.28

Conclusions

Antihistamines that show anti-inflammatory effects at therapeutic concentrations may modify the effects of inflammatory mediators in vivo at doses comparable to those used clinically. Conversely, if clinical antiinflammatory effects necessitate dosages higher than those usually recommended for allergic reactions, H^sub 1^-receptor antagonists with the widest therapeutic window and the lowest potential for dose-limiting sedation and cognitive impairment may offer the greatest therapeutic potential22.

Exploration of the anti-inflammatory actions of specific nonsedating H^sub 1^-receptor antagonists may help to differentiate these agents. The in vitro anti-allergic effects described should lead to future research to characterize the clinical impact of these effects in patients with allergic rhinitis and allergic asthma.

Acknowledgment

Supported in part by Aventis Pharmaceuticals, Inc.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2409, Accepted for publication: 15 September 2003

Published Online: 29 October 2003

doi:10.1185/030079903125002586

Erwin W. Gelfand1, Sireesh Appajosyula2, and Suzanne Meeves2

1 Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, USA

2 Aventis Pharmaceuticals, Bridgewater, New Jersey, USA

Address for correspondence: Dr Erwin W. Gelfand, Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206, USA. Tel: 303-398-1196; Fax: 303-270-2105; email: gelfande@njc.org

Copyright Librapharm Jan 2004

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