Background: Cetirizine is a highly efficacious and long‐acting second‐generation H1‐receptor antagonist for the treatment of allergic diseases, such as allergic rhinitis and chronic idiopathic ...urticaria, in adults and children. Pharmacologic studies have demonstrated that cetirizine, a racemate mixture composed of equal amounts of two enantiomers, does not undergo hepatic metabolism to any significant level. The enantiomers are excreted mainly unchanged, predominantly in the urine and to a lesser extent in the faeces.
Methods: The pharmacologic activity and potency of the two enantiomers of cetirizine in the management of allergic skin conditions were investigated by studying the effect of treatment with 5.0 mg cetirizine; 2.5 mg levocetirizine, the (R)‐enantiomer; and 2.5 mg ucb 28557, the (S)‐enantiomer, on histamine‐induced wheal and flare response in 18 healthy volunteers. Each treatment was administered as a single oral dose in randomized, double‐blind, and crossover manner, and the efficacy of treatment was assessed over a period of 32 h, as per cent inhibition of the histamine‐induced wheal and flare areas before treatment. Blood and urine samples were collected in a time‐dependent manner and analyzed for the total amounts of each study drug, to elucidate their pharmacokinetic profiles.
Results: Both cetirizine and levocetirizine caused a marked inhibition of histamine‐induced wheal and flare, whereas ucb 28557 was inactive in this model. Inhibition of the wheal response observed for cetirizine and levocetirizine was apparent by 1 h after dosage and lasted for mean durations of 24.4 and 28.4 h, respectively. In addition, the response for cetirizine and levocetirizine became maximal by 6 h after treatment, rising to 79.5% and 83.8%. Similarly, cetirizine and levocetirizine also markedly inhibited the histamine‐induced flare response. This effect was evident for both drugs by 1 h after dosage and lasted over a mean period of 28.4 and 26.0 h, respectively, for cetirizine and levocetirizine. The inhibitory effect of these compounds on histamine‐induced flare response was also maximal by approximately 6 h after dosage, peaking at 88.5% and 83.6%, respectively. Statistical evaluation showed that cetirizine and levocetirizine were equivalent for maximum inhibition of histamine‐induced wheal and flare. However, levocetirizine was found to be superior to cetirizine when area under the curve was compared. In contrast, ucb 28557 was not found to inhibit histamine‐induced wheal and flare responses at any time during the study period. Plasma concentrations of levocetirizine were found to be approximately double those of ucb 28557 at 4 and 8 h after dosing, and 50–60% of the drugs were excreted unchanged in urine over a period of 32 h.
Conclusions: The finding that, in this model, levocetirizine 2.5 mg has comparable antihistaminic activity to cetirizine 5 mg, whereas its other enantiomer ucb 28557 has no pharmacodynamic effect, suggests that the antihistaminic properties of cetirizine observed in the management of allergic skin conditions are likely to be attributable to levocetirizine.
Airway epithelial cells, cytokines, and pollutants Mills, P R; Davies, R J; Devalia, J L
American journal of respiratory and critical care medicine,
11/1999, Letnik:
160, Številka:
5 Pt 2
Journal Article
Recenzirano
The airway epithelium is a complex physicochemical barrier that plays a pivotal role in host defense. Epithelial cells have been shown to be a rich source of several classes of modulatory compounds, ...of which the cytokines form the largest group and possibly play the most important role in the etiology of airway disease. Evidence suggests that there are differences in the airway epithelial cells of individuals with and without respiratory disease, both with regard to (1) their capacity to express and release different types and quantities of specific cytokines and (2) their reactivity to inhaled irritants. Consequently, it is tempting to speculate that differences in epithelial cell function are an important determinant of the predisposition to respiratory disease. However, whether the differences are a result of an intrinsic defect, an acquired property due to the disease process itself, or a combination of the two, remains to be determined. In view of advances that have been made in the understanding of the putative underlying mechanisms in airway diseases, it should be possible to formulate novel therapeutic agents in the form of specific monoclonal antibodies directed against specific proinflammatory cytokines. Mills PR, Davies RJ, Devalia JL. Airway epithelial cells, cytokines, and pollutants.
BACKGROUND Although sputum induction is used as a technique to investigate lower airway inflammation in asthmatic subjects, advantages over spontaneous sputum in patients with chronic obstructive ...pulmonary disease (COPD) have not been investigated. METHODS Samples of spontaneous sputum and sputum induced with 3% hypertonic saline for 14 minutes were collected from 27 patients with chronic obstructive pulmonary disease (COPD) who usually produced spontaneous sputum. Spirometric indices and oxygen saturation (Sao 2) were measured at seven minute intervals. The spontaneous, seven and 14 minute sputum samples were analysed for total and differential cell counts, cell viability, and interleukin 8 levels. RESULTS Analysis of the sputum revealed that median cell viability was higher in the seven minute (62.8%; p = 0.004) and 14 minute (65%; p = 0.001) induced sputum samples than in spontaneous sputum (41.2%). There was no significant difference in total and differential cell counts or in interleukin 8 levels between spontaneous and induced sputum. During the sputum induction procedure the mean (SD) fall in forced expiratory volume in one second (FEV1) was 0.098 (0.111) l (p < 0.001) and in forced vital capacity (FVC) was 0.247 (0.233) l (p < 0.001). There was a small but significant fall in Sao 2 during sputum induction (p = 0.03). CONCLUSIONS Induced sputum contains a higher proportion of viable cells than spontaneous sputum. There are no significant differences between the sputum samples obtained at seven minutes and at 14 minutes of hypertonic saline nebulisation. Sputum induction is safe and well tolerated in patients with COPD.
Animal studies have reported that diesel exhaust particles (DEP), which constitute an important fraction of particulate air pollution, lead to inflammation and/or damage of the airways. To ...investigate the mechanisms underlying DEP-induced airway disease in humans, we have cultured human bronchial epithelial cells (HBEC) from surgically obtained bronchial explants and investigated the effects of purified DEP on the permeability and ciliary beat frequency (CBF) of HBEC, and on the release of inflammatory mediators from these cells. Exposure to 10-100 microg/ml DEP and a filtered solution of 50 microg/ml DEP significantly increased the electrical resistance of the cultures, reaching a maximum of 200% over baseline after 6 h incubation with 100 microg/ml DEP. In contrast, movement of 14C-labeled bovine serum albumin across cell cultures was not significantly altered by incubation of HBEC with DEP. Exposure to 50 microg/ml DEP, filtered DEP solution, and 100 migrog/ml DEP significantly attenuated the CBF of these cells by 51%, 33%, and 73%, respectively, from baseline after 24 h incubation. Similarly, 50 microg/ml DEP, filtered DEP solution, and 100 microg/ml DEP significantly increased the release of interleukin-8 from 12.9 pg/microg cellular protein to 41.6, 114.9, and 44.3 pg/microg cellular protein, respectively, after 24 h incubation. The release of granulocyte-macrophage colony stimulating factor (GM-CSF) and soluble intercellular adhesion molecule-1 (sICAM-1) was also significantly increased after exposure for 24 h to 50 microg/ml DEP (GM-CSF from 0.033 pg/microg cellular protein to 0.056 pg/mug cellular protein and sICAM-1 from 7.2 pg/microg cellular protein to 12.5 pg/microg cellular protein). These results suggest that exposure of HBEC to DEP may lead to adverse functional changes and release of proinflammatory mediators from these cells, and that these effects may influence the development of airway disease.
Summary
Air pollution may enhance the airway response of asthmatic subjects to allergen inhalation. To test the hypothesis that sulphur dioxide and nitrogen dioxide alone or in combination could have ...a contributory role, we have studied the effect of 6 h exposure to air, 200 parts per billion (ppb) sulphur dioxide, 400 ppb nitrogen dioxide, and the two gases together on the airway response to inhaled allergen in ten volunteers with mild atopic asthma. The subjects were exposed to the gases in random order at weekly visits, then challenged with pre-determined concentrations of
Dermatophagoides pteronyssinusallergen 10 min after each exposure. The forced expiratory volume in 1 s (FEV
1), forced vital capacity (FVC), and cumulative breath units (CBU) of D
pteronyssinus allergen required to produce a 20% fall in FEV
1 (PD
2DFEV
1) were measured after each exposure. Compared with air, neither sulphur dioxide nor nitrogen dioxide nor the combination significantly altered FEV
1 or FVC. Although the decreases in PD
20FEV
1 after exposure to each agent alone were not significant (41·2%, p=0·125 after nitrogen dioxide; 32·2%, p=0·506 after sulphur dioxide) the decrease after exposure to the combination was significant (60·5 SE 8·1%, p=0·015).
Exposure to a combination of sulphur dioxide and nitrogen dioxide in concentrations that could be encountered in heavy traffic enhances the airway response to inhaled allergen, possibly as a result of previous airway inflammation.
This review focuses on bacterial induction and release of inflammatory cytokines and adhesion molecules by human bronchial epithelial cells, with special reference to Haemophilus influenzae, a ...pathogen commonly associated with chronic bronchitis. Studies investigating the mechanisms underlying bacterial colonization of the airways and bacterial-induced chronic airway inflammation have suggested that these are likely to involve localization of bacteria to the site(s) of infection in the respiratory tract and induction of a local airway inflammation resulting in the initiation of epithelial damage. We have hypothesized that the gross airway epithelial damage observed in chronic infective lung disease is an indirect consequence of proteolytic enzymes and toxic oxygen radicals generated by large numbers of neutrophils infiltrating the airways. Furthermore, the infiltration and activation of the neutrophils is a consequence of increased release of proinflammatory mediators from the host respiratory epithelium, induced by bacterial products, such as endotoxin. This hypothesis is based on studies which have demonstrated that the concentrations of circulating cytokines, such as interleukin (IL)-8 and tumour necrosis factor-alpha (TNF-alpha), which have profound effects on neutrophil activity, are increased in endotoxaemia and that airway epithelial cells are a rich source of these cytokines. Support for this hypothesis is provided by studies of cultured human bronchial epithelial cells incubated either in the absence or presence of purified endotoxin preparations from nontypable and type b H. influenzae strains which have demonstrated that these endotoxins lead to significantly increased expression and/or release of proinflammatory mediators, including IL-6, IL-8, TNF-alpha and intercellular adhesion molecule-1 (ICAM-1). Treatment of the cells with steroids can downregulate the expression and/or release of these inflammatory mediators. Additionally, these studies have demonstrated that culture medium collected from endotoxin-treated cultures, 24 h after treatment, significantly increases neutrophil chemotaxis and adhesion to human endothelial cells in vitro.
Although several studies have demonstrated that low-dose, long-term erythromycin treatment is effective in the management of patients with chronic lower respiratory tract infections, such as chronic ...bronchitis, bronchiolitis and bronchiectasis, the mechanisms underlying the action of erythromycin are not clear. We have cultured human bronchial epithelial cells (HBEC) as explant cultures from surgical tissue, and have investigated the effect of erythromycin on H. influenzae endotoxin (HIE)-induced release of inflammatory mediators in these cultures. Confluent epithelial cell cultures were incubated with 100 micrograms.mL-1 HIE +/- 0.1-10 micrograms.mL-1 erythromycin and were investigated for interleukin-6 (IL-6), interleukin-8 (IL-8) and soluble intercellular adhesion molecule-1 (sICAM-1) released into the culture medium after 24 h. HIE significantly increased the release of IL-6 from 3.9 +/- 1.5 pg.micrograms-1 cellular protein (in control untreated cultures) to 12.1 +/- 1.5 pg.micrograms-1 cellular protein, and IL-8 from 83.7 +/- 8.2 pg.micrograms-1 cellular protein (in control cultures) to 225.7 +/- 44.8 pg.micrograms-1 cellular protein. Similarly, HIE led to a significantly greater release of sICAM-1 from 0.04 +/- 0.01 ng.microgram-1 cellular protein, in control cultures, to 3.8 +/- 0.9 ng.microgram-1 cellular protein. Incubation of the epithelial cultures in the presence of 0.1-10 micrograms.mL-1 erythromycin significantly blocked the HIE-induced release of IL-6, IL-8, and sICAM-1, at all concentrations of erythromycin investigated. Erythromycin also attenuated neutrophil chemotaxis and adhesion to human endothelial cells, mediated by incubation with conditioned medium obtained from HIE-exposed epithelial cell cultures, in vitro. These results suggest that H. influenzae-induced release of inflammatory mediators from airway epithelial cells could contribute to chronic airway inflammation, and that this effect may be modulated by treatment with erythromycin.
Although studies of nitrogen dioxide (NO2) inhalation, in both animals and humans, have demonstrated that this agent can cause epithelial cell damage and inflammation of the airway epithelium, the ...mechanisms underlying these effects are not well understood. We have cultured human bronchial epithelial cells, as explant cultures from surgical tissue, and studied these firstly from their ability to constitutively synthesize specific proinflammatory cytokines and then investigated the effect of exposure to NO2 on the generation of these cytokines. Constitutive synthesis of cytokines was evaluated by analysis of both the expression of the mRNA for interleukin (IL)-1 beta, IL-4, IL-8, granulocyte/macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), by the polymerase chain reaction (PCR), and by immunocytochemical staining for the presence of cell-associated IL-1 beta, IL-8, GM-CSF, TNF-alpha, and IFN-gamma, using specific monoclonal and polyclonal antibodies directed towards these cytokines. Release of IL-4, IL-8, GM-CSF, TNF-alpha, and IFN-gamma following exposure to 5% CO2 in air or 400 ppb and 800 ppb NO2 for 6 h was investigated by enzyme-linked immunosorbent assay. PCR demonstrated that the human bronchial epithelial cells expressed the mRNA for IL-1 beta, IL-8, GM-CSF, and TNF-alpha but not for IL-4 and IFN-gamma. Immunocytochemical staining confirmed the presence of endogenous IL-1 beta, IL-8, GM-CSF, and TNF-alpha.
Recent studies have suggested that antihistamines, widely used in the treatment of symptoms of patients with allergic rhinitis, may also possess antiinflammatory properties. The mechanisms underlying ...this property, however, are not clearly understood. We have cultured epithelial cells from nasal biopsy specimens from patients with seasonal allergic rhinitis outside the pollen season and studied the effect of 0 to 10
-3 mol/L fexofenadine, the main active metabolite of terfenadine, on eosinophil-induced changes in electrical resistance (measure of permeability) and release of proinflammatory mediators from these cells. Additionally, we have studied the effect of this drug on eosinophil chemotaxis and adherence to endothelial cells induced by conditioned medium from these human nasal epithelial cell (HNEC) cultures. Incubation of HNEC in the presence of eosinophils treated with opsonized latex beads significantly decreased the electrical resistance of these cultures, an effect that was abrogated by treatment of the cultures with 10
-9 to 10
-3 mol/L fexofenadine. Similarly, incubation of HNEC in the presence of eosinophils treated with latex beads also significantly increased the basal release of the chemokine “regulated upon activation, normal T cell expressed and secreted” (RANTES) (from 96.0 to 613.0 fg/μg cellular protein;
p
< 0.05), IL-8 (from 42.0 to 198.5 pg/μg cellular protein;
p
< 0.05), granulocyte-macrophage colony-stimulating factor (GM-CSF) (from 0.54 to 3.4 pg/μg cellular protein;
p
< 0.05), and soluble intercellular adhesion molecule-1 (sICAM-1) (from 7.8 to 18.4 pg/μg cellular protein;
p
< 0.05) from HNEC. The eosinophil-induced release of IL-8, GM-CSF, and sICAM-1 from the HNEC was significantly attenuated by treatment with fexofenadine. Analysis of the effects of conditioned medium from HNEC demonstrated that this significantly increased both eosinophil chemotaxis and adherence to endothelial cells. Addition of 10
-6 to 10
-3 mol/L fexofenadine to the conditioned medium significantly attenuated eosinophil chemotaxis and adherence to endothelial cells. These results suggest that fexofenadine may reduce nasal inflammation by modulating the release of proinflammatory mediators and adhesion molecules from HNEC. (J Allergy Clin Immunol 1998;101:410-20.)
We previously demonstrated that chronic intratracheal instillation of diesel exhaust particles (DEP) induces airway inflammation and hyperresponsiveness in the mouse, and that these effects were ...partially reversed by the administration of superoxide dismutase (SOD). In the present study, we have investigated the involvement of superoxide in DEP-induced airway response by analyzing the localization and activity of two enzymes: (1) a superoxide producer, NADPH cytochrome P-450 reductase (P-450 reductase), and (2) a superoxide scavenger, SOD, in the lungs of the exposed mice and controls. P-450 reductase was detected mainly in ciliated cells and clara cells; its activity was increased by the repeated intratracheal instillation of DEP. While CuZn-SOD and Mn-SOD were also present in the airway epithelium, their activity was significantly decreased following DEP instillation. Exposure to DEP doubled the level of nitric oxide (NO) in the exhaled air. DEP exposure also increased the level of constitutive NO synthase (cNOS) in the airway epithelium and inducible NO synthase (iNOS) in the macrophages. Pretreatment with N-G-monomethyl L-arginine, a nonspecific inhibitor of NO synthase, significantly reduced the airway hyperresponsiveness induced by DEP. These results indicate that superoxide and NO may each contribute to the airway inflammation and hyperresponsiveness induced by the repeated intratracheal instillation of DEP in mice.
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