We found a high prevalence of self-declared rhinitis symptoms in the Belgian population, AR being about three times more prevalent than NINA. In addition, AR patients suffered from a greater number of symptoms and displayed a more 'persistent' and 'moderate-severe' ARIA profile than NINA. About 75% of patients seeking medical help suffer from 'moderate to severe' forms of rhinitis.

Bronchial hyperresponsiveness (BHR), an abnormal increase in airflow limitation following the exposure to a stimulus, is an important pathophysiological characteristic of bronchial asthma. Because of heterogeneity of the airway response to different stimuli, the latter have been divided into direct and indirect stimuli. Direct stimuli cause airflow limitation by a direct action on the effector cells involved in the airflow limitation, while indirect stimuli exert their action essentially on inflammatory and neuronal cells that act as an intermediary between the stimulus and the effector cells.This manuscript reviews the clinical and experimental studies on the mechanisms involved in indirect BHR in patients with asthma. Pharmacological stimuli (adenosine, tachykinins, bradykinin, sodium metabisulphite/sulphur dioxide, and propranolol) as well as physical stimuli (exercise, nonisotonic aerosols, and isocapnic hyperventilation) are discussed.The results of the different direct and indirect bronchial challenge tests are only weakly correlated and are therefore not mutually interchangeable. Limited available data (studies on the effects of allergen avoidance and inhaled corticosteroids) suggest that indirectly acting bronchial stimuli (especially adenosine) might better reflect the degree of airway inflammation than directly acting stimuli. It remains to be established whether monitoring of indirect BHR as a surrogate marker of inflammation (in addition to symptoms and lung function) is of clinical relevance to the long-term management of asthmatic patients. This seems to be the case for the direct stimulus methacholine. More work needs to be performed to find out whether, indirect stimuli are more suitable in asthma monitoring than direct ones. Recommendations on the application of indirect challenges in clinical practice and research will shortly be available from the European Respiratory Society Task Force. Eur Respir J 2000; 16: 514±533.

Substance P (SP) and neurokinin (NK) A are members of the tachykinin peptide family and have been implicated as neurotransmitters which mediate the excitatory part of the nonadrenergic, noncholinergic (e-NANC) nervous system [1][2][3]. In the human airways, they are contained within sensory unmyelinated C nerve fibres, which are distributed beneath or within the airway epithelium, around blood vessels and glands, within the bronchial smooth muscle layer and around local ganglion cells [4][5][6][7][8]. Recent findings in both experimental animals and humans, however, suggest that non-neural cells (endothelial cells, eosinophils and macrophages), either resident or circulating, can also be a source of tachykinins and that immune stimuli can boost tachykinin production from immunocytes [9]. A reduced SP-like immunoreactivity (SP-LI) content of asthmatic airways compared with nonasthmatic subjects has been reported, suggesting an augmented SP release in asthma [10]. Supporting this hypothesis, bronchoalveolar lavage fluid [11] and induced sputum [12] from asthmatics were found to contain increased amounts of SP-LI. SP and NKA contract human airways in vitro and in vivo, NKA being more potent than SP and asthmatics being more sensitive than normal subjects [5,[13][14][15][16][17]. Other potentially important airway effects of tachykinins include mucus secretion, cough, vasodilatation, increased vascular permeability and a broad array of pro-inflammatory effects involving various types of leukocytes [1][2][3].SP and NKA interact with their target cells in the airways through specific tachykinin receptors, with SP being the preferential agonist for the tachykinin NK1 receptor and NKA the preferential agonist for the tachykinin NK2 receptor [18]. Increased expression of NK1 [19] and NK2 [20] tachykinin receptor gene messenger ribonucleic acid (mRNA) in asthmatic airways has been reported. In isolated normal human airways in vitro, tachykinin-induced bronchoconstriction is mediated predominantly by tachykinin NK2 receptors [8,[21][22][23]; recently, however, involvement of tachykinin NK1 receptors has also been noted [24,25]. Tachykinin NK1 receptor stimulation appears to be important in eliciting neurogenic inflammation [1][2][3]18]. On the screening day and during the study periods, increasing concentrations of NKA (3.3×10 -9 to 1.0×10 -6 mol·mL -1 ) were inhaled, until the forced expiratory volume in one second (FEV1) and specific airway conductance (sGaw) decreased by at least 20 and 50%, respectively. During the study periods, 100 mg SR 48968 or matched placebo was ingested in a double-blind, randomized, crossover fashion and NKA provocation was performed at 1.5 and 24 h after dosing. At 1.5 h, the mean (SEM) log10 provocative concentration of NKA causing a 20% fall in FEV1 (PC20 FEV1) was -6.25 (0.20) after SR 48968 and -6.75 (0.17) after placebo (p=0.05); the mean log10 provocative concentration of NKA causing a 35% fall in sGaw (PC35 sGaw) was -7.02 (0.28) after SR 48968 and -7.64 (0.19) after placebo (p=0.05). A...

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.

We assessed the systemic effects of budesonide (BUD) and fluticasone propionate (FP) in 23 patients with asthma, using a double-blind, placebo-controlled, double-dummy, and cross-over design. The following five treatments were given in a randomized order for 1 wk with a washout period in between of 2 wk: (1) placebo; (2) FP, 200 micrograms twice a day, inhaled from a Diskhaler; (3) FP, 1,000 micrograms twice a day, inhaled from a Diskhaler; (4) BUD, 200 micrograms twice a day, inhaled from a Turbuhaler; and (5) BUD, 800 micrograms twice a day, inhaled from a Turbuhaler. The primary variable was the area under the curve of serum cortisol versus time (AUC0-20), derived from serum samples taken every 2 h over a 20-h period following the last evening dose at 10:00 P.M. The lower doses of BUD and FLU did not cause any adrenal suppression. Compared with placebo, however, FP (1, 000 micrograms, twice daily and BUD (800 micrograms, twice daily) decreased the AUC0-20 by 34 and 16%, respectively. Fluticasone (1,000 micrograms, twice daily) was more suppressive than BUD (800 micrograms, twice daily) (p = 0.0006). The FEV1, measured the morning after the last inhalation, was significantly higher after the active treatments, compared with placebo (p < 0.02), but did not differ between all active treatments. We conclude that high doses of BUD and FP (in particular the latter), inhaled via their respective dry powder inhalers for 1 wk, result in a measurable systemic activity in patients with asthma.