Impact of desloratadine and loratadine on the crosstalk between human keratinocytes and leukocytes: Implications for anti-inflammatory activity of antihistamines

BACKGROUND: Desloratadine is an H1-histamine antagonist which possesses additional anti-inflammatory properties through inhibition of leukocyte activation and reduction of ICAM-1 expression on mucosal epithelial cells. So far no studies have addressed the potential anti-inflammatory activities of desloratadine and loratadine on skin keratinocytes. OBJECTIVE: In this study the capacity of desloratadine and loratadine to counteract human keratinocyte activation by interferon-gamma (IFN-gamma) was analyzed. In particular, the chemokine release of kerationcytes and the crosstalk between keratinocytes and lymphocytes were examined. METHOD: Keratinocyte cultures established from normal skin of healthy donors were activated by IFN-gamma in the absence or presence of desloratadine and loratadine, and tested for the release of CCL5/RANTES, CXCL8/IL-8, CCL17/TARC and CXCL10/IP-10. Furthermore the supernatants of differentially stimulated keratinocytes were used for migration studies of human neutrophils, eosinophils and polarized Th1/Th2 clones. RESULTS: Desloratadine and loratadine inhibited the constitutive and IFN-gamma-induced release of CCL5, CXCL8 and CXCL10 from keratinocytes, while the low release of CCL17 remained unchanged. Furthermore the crosstalk between lymphocytes and keratinocytes was blocked as shown by a reduced capacity of desloratadine/loratadine-stimulated keratinocytes to attract human neutrophils, eosinophils and T cells. CONCLUSIONS: The results indicate that desloratadine has the capacity to block the IFN-gamma-induced activation of keratinocytes, and that it can thus exert important regulatory effects on cell-mediated immune responses in the skin. The rather high doses required for these effects argue for a topical application when trying to use desloratadine in epidermal inflammatory conditions.     

Vascular endothelial growth factor-mediated induction of angiogenesis by human rhinoviruses

BACKGROUND: Human rhinoviruses, major precipitants of asthma exacerbations, infect the lower airway epithelium inducing inflammation. The possibility that viral infection may mediate angiogenesis, thus contributing to airway remodeling, has not been evaluated. OBJECTIVE: To investigate whether epithelial infection with rhinovirus mediates angiogenesis in vitro, evaluate possible modulation by an atopic environment, and confirm angiogenic factor induction after in vivo rhinovirus infection. METHODS: Bronchial epithelial cells were infected with rhinovirus and levels of vascular endothelial growth factor (VEGF), and angiopoietins were measured. The angiogenic effect of epithelial products was assessed in in vitro models of angiogenesis. PBMCs, obtained from patients with atopic asthma and normal controls, were exposed to rhinovirus; the ability of supernatants from these cultures differentially to affect rhinovirus-mediated epithelial VEGF production was evaluated. VEGF levels were measured in respiratory secretions from patients with asthma, before and during rhinovirus-induced exacerbations. RESULTS: Epithelial infection with rhinovirus specifically stimulated mRNA expression and release of VEGF, but not angiopoietins, in a time-dependent and dose-dependent manner. Supernatants from these cultures were able to induce angiogenesis in vitro, significantly inhibited by a neutralizing anti-VEGF antibody. When bronchial cells were exposed to supernatants of rhinovirus-infected mononuclear cells from normal subjects or atopic patients with asthma, VEGF induction was significantly higher under the influence of the atopic environment. VEGF was elevated during rhinovirus-associated asthma exacerbations. CONCLUSION: Rhinovirus infection, a frequent event, induces VEGF production in bronchial epithelial cells and human airways, an effect enhanced in an atopic environment. Rhinovirus-associated, VEGF-mediated angiogenesis may contribute to airway remodeling in asthma.     

Experimental rhinovirus 16 infection increases intercellular adhesion molecule-1 expression in bronchial epithelium of asthmatics regardless of inhaled steroid treatment

BACKGROUND: Rhinovirus infections in airway epithelial cells in vitro have been shown to upregulate intercellular adhesion molecule-1 (ICAM-1) expression. Epithelial ICAM-1, in its dual role as the major rhinovirus receptor and as adhesion molecule for inflammatory cells may be involved in the pathogenesis of rhinovirus-induced exacerbations of asthma. OBJECTIVE: We aimed to investigate the effect of experimental rhinovirus 16 (RV16) infection on ICAM-1 expression in bronchial mucosal biopsies in asthma. In addition, the effect of 2 weeks pretreatment with inhaled budesonide (800 microg b.d.) on RV16-associated changes in ICAM-1 expression was studied. METHODS: The study had a parallel, placebo-controlled design in 25 steroid-naive nonsmoking atopic asthmatic subjects. After 2 weeks budesonide (BUD) or placebo (PLAC) pretreatment bronchoscopy was performed 2 days before (day -2) and 6 days after (day 6) RV16 inoculation (on days 0 and 1). Immunohistochemical staining for ICAM-1 was performed on snap-frozen bronchial biopsies. ICAM-1 staining intensity on the basal epithelial cells was scored semiquantitatively from 1 (weak) to 3 (intense). Similarly, epithelial intactness was noted (1 = basal cells only, 2 = basal and parabasal cells, 3 = intact epithelium). RESULTS: ICAM-1 scores were not significantly different between the groups at day -2 (P > or = 0.08). Subsequent RV16 infection was associated with a trend towards an increase in ICAM-1 expression in the BUD-group (P = 0.07), whereas the increase was significant in the PLAC-group (P = 0.03). However, the increase was not significantly different between the groups (P = 0.74). Epithelial intactness score was not different between the groups before RV16 infection (P > or = 0.07), and no significant changes were observed in either group (P > or = 0.59). Moreover, ICAM-1 score did not correlate significantly with epithelium score in either group, at any time-point (P > or = 0.27). CONCLUSION: We conclude that an RV16 common cold in atopic asthmatic subjects is associated with increased ICAM-1 expression in the bronchial epithelium, which is not related to epithelial intactness. Glucocorticoid treatment does not appear to prevent the RV16-associated increased ICAM-1 expression. This suggests that other treatment modalities are required to protect against the spreading of infection during rhinovirus-induced exacerbations in asthma.     

Desloratadine inhibits constitutive and histamine-stimulated nuclear factor-kappaB activity consistent with inverse agonism at the histamine H1 Receptor

BACKGROUND: The human histamine H1 receptor is constitutively active and exhibits basal activation of nuclear factor-kappaB (NF-kappaB), an important modulator of allergic inflammation. Certain H1 antihistamines have recently been shown to inhibit basal NF-kappaB activity by stabilizing the H1 receptor in an inactive state, a phenomenon called 'inverse agonism'. METHODS: We evaluated the effect of the new H1 antihistamine, desloratadine, on basal and histamine-stimulated NF-kappaB activity and compared it with the activities of other H1 antihistamines. RESULTS: Transiently transfected COS-7 cells co-expressing NF-kappaB-luciferase and the H1 receptor exhibited constitutive NF-kappaB activity. H1 antihistamines reduced basal NF-kappaB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine). Histamine stimulated basal NF-kappaB activity 8-fold, which was blocked by H1 antihistamines (rank order of potency: desloratadine > cetirizine > pyrilamine > loratadine > fexofenadine). Neither histamine nor antihistamines had any effect on NF-kappaB activity in the absence of the H1 receptor. CONCLUSIONS: Desloratadine, acting through the histamine H1 receptor, inhibited basal NF-kappaB activity and can thus be classified as an inverse agonist. Inhibition of basal and histamine-stimulated NF-kappaB activity may help to explain previously reported inhibitory effects of desloratadine on allergic inflammatory mediators.     

Role of rhinovirus infections in asthma

Human rhinoviruses are not only the main pathogens responsible for the common cold, but are now recognized to have a major impact on asthma pathogenesis. There is evidence that rhinovirus infections play a role in asthma development, asthma exacerbations and, potentially, airway remodeling. Children who experience repeated rhinovirus-induced wheezing episodes in infancy have a significantly increased risk of developing asthma, even when compared to children who experience wheezing induced by respiratory syncytial virus. Rhinovirus is also the dominant virus type associated with acute exacerbations of asthma. The epithelial cell is the principal site of rhinovirus infection in both the upper and lower airways and there is strong evidence that virus-induced alterations of epithelial cell biology play a critical role in regulating clinical outcomes. This includes rhinovirus-induced epithelial generation of a variety of chemokines, cytokines and growth factors that likely play a role in viral modulation of airway inflammation. It has also become clear, however, that epithelial cells play an important role in the innate antiviral response to rhinovirus infection, raising the possibility that the relative induction of epithelial host innate antiviral responses versus proinflammatory responses may be one factor regulating the susceptibility of asthmatic subjects to virus-induced disease exacerbations. Recent evidence has also highlighted that rhinovirus infection induces epithelial production of a number of growth factors and other mediators that could contribute to the development and progression of airway remodeling processes in asthma. The current article reviews our current state of knowledge in these areas.     

Rhinovirus infections: induction and modulation of airways inflammation in asthma

There is renewed interest in the role of respiratory virus infections in the pathogenesis of asthma and in the development of exacerbations in pre-existing disease. This is due to the availability of new molecular and experimental tools. Circumstantial evidence points towards a potentially causative role as well as to possibly protective effects of certain respiratory viruses in the cause of allergic asthma during early childhood. In addition, it now has become clear that exacerbations of asthma, in children as well as adults, are mostly associated with respiratory virus infections, with a predominant role of the common cold virus: rhinovirus. Careful human in vitro and in vivo experiments have shown that rhinovirus can potentially stimulate bronchial epithelial cells to produce pro-inflammatory chemokines and cytokines, may activate cholinergic- or noncholinergic nerves, increase epithelial-derived nitric oxide synthesis, upregulate local ICAM-1 expression, and can lead to nonspecific T-cell responses and/or virus-specific T-cell proliferation. Experimental rhinovirus infections in patients with asthma demonstrate features of exacerbation, such as lower airway symptoms, variable airways obstruction, and bronchial hyperresponsiveness, the latter being associated with eosinophil counts and eosinophilic cationic protein levels in induced sputum. This suggests that multiple cellular pathways can be involved in rhinovirus-induced asthma exacerbations. It is still unknown whether these mechanisms are a distinguishing characteristic of asthma. Because of the limited effects of inhaled steroids during asthma exacerbations, new therapeutic interventions need to be developed based on the increasing pathophysiological knowledge about the role of viruses in asthma.     

Interferon-gamma enhances rhinovirus-induced RANTES secretion by airway epithelial cells

Respiratory viruses, including rhinoviruses, infect respiratory epithelium and induce a variety of cytokines and chemokines that can initiate an inflammatory response. Cytokines, such as interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, could enhance epithelial cell activation by inducing virus receptors. To test this hypothesis, effects of IFN-gamma or TNF-alpha on expression of intercellular adhesion molecule (ICAM)-1, rhinovirus binding, and virus-induced chemokine secretion on A549 and human bronchial epithelial cells (HBEC) were determined. The results varied with the type of cell. IFN-gamma was a stronger inducer of ICAM-1 and viral binding on HBEC, whereas TNF-alpha had greater effects on A549 cells. In addition, IFN-gamma, but not TNF-alpha, synergistically enhanced regulated on activation, normal T cells expressed and secreted (RANTES) mRNA expression and protein secretion induced by RV16 or RV49. To determine whether IFN-gamma could enhance RANTES secretion independent of effects on ICAM-1 and RV binding, HBEC were transfected with RV16 RNA in the presence or absence of IFN-gamma. RV16 RNA alone stimulated RANTES secretion, and this effect was enhanced by IFN-gamma. These results demonstrate that IFN-gamma can enhance rhinovirus-induced RANTES secretion by increasing viral binding, and through a second receptor-independent pathway. These findings suggest that IFN-gamma, by upregulating RANTES secretion, could be an important regulator of the initial immune response to rhinovirus infections.     

Human rhinovirus-induced inflammatory responses are inhibited by phosphatidylserine containing liposomes

Human rhinovirus (HRV) infections are major contributors to the healthcare burden associated with acute exacerbations of chronic airway disease, such as chronic obstructive pulmonary disease and asthma. Cellular responses to HRV are mediated through pattern recognition receptors that may in part signal from membrane microdomains. We previously found Toll-like receptor signaling is reduced, by targeting membrane microdomains with a specific liposomal phosphatidylserine species, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-L-serine (SAPS). Here we explored the ability of this approach to target a clinically important pathogen. We determined the biochemical and biophysical properties and stability of SAPS liposomes and studied their ability to modulate rhinovirus-induced inflammation, measured by cytokine production, and rhinovirus replication in both immortalized and normal primary bronchial epithelial cells. SAPS liposomes rapidly partitioned throughout the plasma membrane and internal cellular membranes of epithelial cells. Uptake of liposomes did not cause cell death, but was associated with markedly reduced inflammatory responses to rhinovirus, at the expense of only modest non-significant increases in viral replication, and without impairment of interferon receptor signaling. Thus using liposomes of phosphatidylserine to target membrane microdomains is a feasible mechanism for modulating rhinovirus-induced signaling, and potentially a prototypic new therapy for viral-mediated inflammation.     

Cetirizine counter-regulates interleukin-8 release from human epithelial cells (A549)

BACKGROUND: Cetirizine, a H1-receptor antagonist, exerts besides its well-known anti-allergic potential an array of anti-inflammatory activities. In particular epithelial cells activated in the presence of cetirizine showed a reduced ICAM-1 cell surface expression and a diminished release of sICAM-1. OBJECTIVE: We wondered whether cetirizine might influence the release of interleukin-8 (IL-8) from human epithelial cells activated with agonists distinct from histamine. METHODS: We used the human lung epithelial cell line A549 for our in vitro studies. IL-8 release was determined by IL-8 enzyme immunoassay, the intracellular staining for IL-8 and NF-kB was analysed by FACS analysis and IL-8 mRNA steady state level was studied by Northern blot analysis. Confluent epithelial cell monolayer were pre-incubated with cetirizine (0.01 -1.0 micromol/L) for 30 min and afterwards activated with pro-inflammatory cytokines (TNF-alpha IL-1beta, IL-6, IFN-gamma) or different agonists (PMA, NaF, respiratory syncytial virus [RSV]) for 24 h. RESULTS: Epithelial cells stimulated with TNF-alpha IL-1beta, PMA and RSV, respectively, showed a significantly increased release of IL-8. Pre-incubation with cetirizine diminished the IL-8 release from cells activated with TNF-alpha or PMA in a significant manner. The reduced IL-8 release coincided with a diminished percentage of cells expressing IL-8. Northern blot analysis revealed a reduced steady state level of IL-8 mRNA in cells pretreated with cetirizine and stimulated with TNF-alpha. Furthermore, a decreased amount of accessible DNA-binding sites of the nuclear factor kappa B (NF-kB) was determined by FACS analysis. CONCLUSIONS: These results suggest that cetirizine reduced the release of IL-8 from A549 cells stimulated with PMA and TNF-alpha, respectively, by lowering IL-8 gene expression. Therefore, cetirizine might exert anti-inflammatory effects beyond its H1-receptor antagonistic activity in the course of inflammatory respiratory tract disorders such as bronchial asthma and allergic rhinitis.     

Association of Rhinovirus Infections with Asthma

Rhinoviruses are the most common cause of the common cold, but they can cause more severe illnesses in people with underlying lung disorders such as asthma, chronic obstructive pulmonary disease, or cystic fibrosis. Epidemiologic studies with sensitive detection methods such as PCR have identified rhinovirus infection as a major source of asthma exacerbations in both children and adults, especially during the spring and fall. Since rhinoviruses cause little tissue destruction, it is presumed that the immune response to the infection may play an important role in the pathogenesis of rhinovirus-induced exacerbations of asthma. This review examines the epidemiologic association between rhinovirus infections and exacerbations of asthma and outlines current information on immune responses to rhinovirus infection and potential connections between antiviral responses and preexisting allergic inflammation. Finally, current and future strategies for treating rhinovirus infections and virus-induced exacerbations of asthma are discussed.     

Desloratadine prevents compound 48/80-induced mast cell degranulation: visualization using a vital fluorescent dye technique

BACKGROUND: Desloratadine is a selective H1-antihistamine used in the treatment of allergic rhinitis and chronic idiopathic urticaria. Desloratadine inhibits the release of allergic inflammatory mediators in vitro. We studied the impact of desloratadine on mast cell degranulation due to activation and re-activation by the secretagogue, compound 48/80. METHODS: Rat peritoneal eluate containing 5-6% mast cells were activated by a low concentration of compound 48/80 in a medium containing the vital fluorescent dye, Sulforhodamine-B (SFRM-B, 200 microg/ml), which is engulfed by activated mast cells. The fluorescent image of activated mast cells was captured digitally and the total fluorescent area was analyzed when desloratadine was applied before or after compound 48/80. RESULTS: Mast cells were not activated by desloratadine (10(-4) M), SFRM-B (200 microg/ml), or diluent alone. A low concentration of compound 48/80 (0.125 microg/ml) induced fluorescence, while mast cells lost fluorescent images due to further degranulation on re-exposure to compound 48/80. Desloratadine (10(-8)-10(-4) M), inhibited compound 48/80-induced mast cell degranulation in a concentration-dependent manner. Desloratadine also reduced the loss of fluorescent images due to re-exposure to compound 48/80. CONCLUSIONS: Desloratadine may have a mast cell stabilizing effect at low concentrations in response to repeated mast cell activation in vitro.     

Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion.

BACKGROUND: Antihistamines relieve most seasonal allergic rhinitis (SAR) symptoms, with the exception of nasal congestion, which is often the most troublesome symptom for patients. A nonsedating antihistamine that significantly decreases nasal congestion and improves symptoms of seasonal allergic asthma would be a significant advance in therapy. OBJECTIVES: To evaluate the safety and efficacy of desloratadine 5 mg in patients experiencing moderate SAR, nasal congestion, and symptoms of seasonal allergic asthma. METHODS: This 4-week, multicenter, parallel-group, double-blind study evaluated desloratadine treatment (5 mg once daily) versus placebo in 331 subjects with SAR and mild seasonal allergic asthma. Subjects evaluated SAR and asthma symptoms twice daily, recording 12-hour reflective and instantaneous severity evaluation scores. The primary efficacy parameter was the difference from baseline in AM/PM reflective total symptom scores. Changes in individual SAR and asthma symptoms were also analyzed. RESULTS: Compared with placebo, desloratadine significantly reduced mean AM/PM reflective total symptom scores for SAR, beginning with the first dose (P < 0.001) and continuing throughout days 1 to 15 (-4.90 vs -2.98; P < 0.001) and days 1 to 29 (-5.47 vs -3.73; P < 0.001). Desloratadine significantly decreased AM/PM reflective total asthma symptom scores for days 1 to 15 (P = 0.023) and AM/PM reflective nasal congestion scores over days 1 to 15 and days 1 to 29 (P = 0.006 and P = 0.014, respectively). Desloratadine was safe and well tolerated; adverse events were similar to placebo overall. CONCLUSIONS: Desloratadine provided significant relief from the signs and symptoms of SAR, including nasal congestion. In this patient population, symptoms of seasonal allergic asthma also improved.     

Inhibition of cytokine generation and mediator release by human basophils treated with desloratadine

BACKGROUND: Desloratadine is a non-sedating, clinically effective, anti-allergic therapy that has been shown to exhibit anti-inflammatory properties that extend beyond its ability to antagonize histamine at H(1)-receptor sites. This latter effect has been shown in vitro to be both IgE-dependent and -independent. OBJECTIVE: In this study, we addressed the ability of desloratadine to inhibit the in vitro generation of interleukin (IL)-4 and IL-13 from human basophils while concurrently comparing its efficacy in preventing mediator release by these cells. METHODS: Basophil-enriched suspensions were treated with various concentrations of desloratadine for 15 min before stimulating with either anti-IgE antibody, calcium ionophore, IL-3 or phorbol ester. Histamine (fluorimetry), LTC(4) (RIA) and IL-4 (ELISA) were all assayed using the same 4-h culture supernatants. IL-13 (ELISA) was measured in supernatants harvested after 20 h incubation. IL-4 mRNA expression (dilutional RT-PCR) was also examined. RESULTS: Desloratadine was found to be nearly six-seven times more potent in preventing the secretion of IL-4 and IL-13 induced by anti-IgE than it was at inhibiting the release of histamine and LTC(4). These cytokines were equally inhibited by desloratadine following activation with ionomycin despite the lack of an effect on the histamine induced with ionomycin. Desloratadine had a lesser effect regarding inhibition of the IL-13 secreted in response to IL-3 and PMA. There was no evidence that desloratadine mediated its inhibitory effects by causing decreased cell viability. Finally, IL-4 mRNA accumulation was remarkably inhibited, by as much as 80%, following pretreatment with desloratadine. CONCLUSION: While capable of inhibiting histamine and LTC(4) release by human basophils, desloratadine is more effective at targeting the signals regulating IL-4 and IL-13 generation in these cells. This inhibitory effect on cytokine generation provides additional evidence that this antihistamine exerts anti-inflammatory properties.     

Combination therapy: Synergistic suppression of virus-induced chemokines in airway epithelial cells

Viruses are associated with the majority of exacerbations of asthma and chronic obstructive pulmonary disease. Virus induction of neutrophil and lymphocyte chemokines in bronchial epithelium is important in exacerbation pathogenesis. Combined corticosteroid/beta2 agonists synergistically suppress airway smooth muscle chemokine production. Because bronchial epithelium expresses glucocorticoid and beta2 receptors, we investigated whether combination therapy can synergistically suppress rhinovirus-induced bronchial epithelial cell neutrophil (CXCL5, CXCL8) and lymphocyte (CCL5, CXCL10) chemokine production. We investigated modulation of rhinovirus- and IL-1beta-induced bronchial epithelial cell chemokine production by salmeterol and fluticasone propionate, used at therapeutic concentrations, alone and in combination. After 1 h pretreatment, combined treatment significantly inhibited rhinovirus 16, 1B, and IL-1beta-induced CCL5 and CXCL8 protein and mRNA production in BEAS-2B cells compared with fluticasone alone. When used 4 h after treatment, the combination significantly reduced virus-induced CCL5 but not CXCL8. Salmeterol alone had no effect; therefore, this inhibition was synergistic. Kinetic analysis demonstrated that combination therapy reduced by 5-fold the concentration of corticosteroid required to inhibit CXCL8 mRNA expression. In primary cells, salmeterol alone reduced rhinovirus-induced CCL5 and CXCL10 and increased CXCL5 production in a dose-dependent manner but had no effect on CXCL8. Fluticasone alone reduced CCL5, CXCL8, and CXCL10 but had no effect on CXCL5. Combination therapy augmented inhibition of CXCL8, CCL5, and CXCL10 but had no effect on CXCL5. Corticosteroids and beta2 agonists suppress rhinovirus-induced chemokines in bronchial epithelial cells through synergistic and additive mechanisms. This effect was greater for lymphocyte- than for neutrophil-related chemokines.     

Desloratadine: A new, nonsedating, oral antihistamine

Desloratadine is a new, selective, H(1)-receptor antagonist that also has anti-inflammatory activity. In vitro studies have shown that desloratadine inhibits the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, PGD(2), leukotriene C(4), tryptase, histamine, and the TNF-alpha-induced chemokine RANTES. Desloratadine also inhibits the induction of cell adhesion molecules, plateletactivating factor-induced eosinophil chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol myristate acetate-induced superoxide generation in vitro. In animals desloratadine had no effect on the central nervous, cardiovascular, renal, or gastrointestinal systems. Desloratadine is rapidly absorbed, has dose-proportional pharmacokinetics, and has a half-life of 27 hours. The absorption of desloratadine is not affected by food, and the metabolism and elimination are not significantly affected by the subject's age, race, or sex. There are no clinically relevant interactions between desloratadine and erythromycin, ketoconazole, or grapefruit juice. Desloratadine is not a significant substrate of the P-glycoprotein transport system. Once daily administration of desloratadine rapidly reduces the nasal and nonnasal symptoms of seasonal allergic rhinitis, including congestion. In patients with seasonal allergic rhinitis and concomitant asthma, desloratadine treatment was also associated with significant reductions in total asthma symptom score and use of inhaled beta(2)-agonists. Use of desloratadine in patients with chronic idiopathic urticaria was associated with significant reductions in pruritus, number of hives, size of the largest hive, and interference with sleep and daily activities. Clinical experience in over 2300 patients has shown that the adverse event profile of desloratadine is similar to that of placebo; desloratadine has no clinically relevant effects on electrocardiographic parameters, does not impair wakefulness or psychomotor performance, and does not exacerbate the psychomotor impairment associated with alcohol use.     

Nitric oxide and the common cold

PURPOSE OF REVIEW: The common cold is a clinical syndrome triggered by a variety of viral pathogens, but rhinoviruses are the most frequent cause. Complications of such infections include sinusitis, otitis media, and exacerbations of asthma and chronic obstructive lung disease. There is growing interest in host innate defence responses that may regulate the severity of viral responses. We will review recent evidence that nitric oxide is an important contributor to the host response during colds. RECENT FINDINGS: Infection of human airway epithelial cells with human rhinovirus has been shown to lead to the increased expression of inducible nitric oxide synthase both in vitro and in vivo. This increase in epithelial inducible nitric oxide synthase correlates with increased levels of nitric oxide in exhaled air. Importantly, nitric oxide can inhibit human rhinovirus-induced epithelial expression of several pro-inflammatory cytokines and can inhibit viral replication in epithelial cells in vitro. Moreover, nitric oxide can modulate several signal transduction pathways that are associated with cytokine generation. Nitric oxide can also nitrosylate viral proteases and can interact with the immune system. Consistent with these observations, pilot studies have indicated that the increased generation of nitric oxide during rhinovirus infections is associated with fewer symptoms and more rapid viral clearance. SUMMARY: Further studies are warranted to evaluate the role of nitric oxide in colds and to determine whether the administration of nitric oxide donor compounds could be a viable therapeutic approach for viral exacerbations of airway diseases.     

Regulation of NF-kappaB and ICAM-1 expression in human airway epithelial cells.

The aim of this study was to elucidate the redox regulation of cytokine-induced NF-kappaB activation and NF-kappaB mediated gene induction in A549 cells and primary cultures of human airway epithelial cells. In A549 cells, Western blot analysis showed transient depletion of IkappaBalpha after 15 min IL-1beta treatment followed by its reappearance after 60 min, indicating efficient NF-kappaB-driven gene induction. A similar pattern was observed in primary epithelial cells however, the kinetics were slower and depletion was less. In primary airway epithelial cells IkappaBalpha levels were 59.8+/-8.5% of control following 30 min treatment with IL-1beta and in A549 cells 29.1+/-8.5% of control following 15 min IL-1beta treatment. Cytokine-induced IkappaBalpha depletion was associated with NF-kappaB nuclear accumulation and subsequent resynthesis of IkappaBalpha and upregulation of ICAM-1 in both cell types. The antioxidant, NAC (20 mM) had no effect on the kinetics of cytokine-induced IkappaBalpha depletion or NF-kappaB p65 nuclear translocation in either cell type and failed to influence kappaB dependent IkappaBalpha resynthesis. H2O2 treatment alone or in combination with cytokines had no significant effects on IkappaBalpha depletion, NF-kappaB p65 nuclear translocation or ICAM-1 expression in either cell type but did cause significant activation of p38 MAPK. These results suggest that cytokine-induced NF-kappaB activation in cultured human airway epithelial cells does not involve an NAC-sensitive oxidant stress and that H2O2-induced oxidant stress does not result in effective NF-kappaB activation and NF-kappaB mediated gene induction.