BACKGROUND/OBJECTIVES: The mechanical aerosol generator, MAGhaler, is a new chlorofluorocarbon-free inhalation device. The objective of this trial was to show equivalent efficacy and safety of beclomethasone dipropionate (BDP) delivered via the MAGhaler and the metered-dose inhaler (MDI) in patients with mild to moderate bronchial asthma. Moreover, user-friendliness and acceptance of the two devices were compared. METHODS: This was a double-blind, reference-controlled, 12-week trial in 171 patients with asthma receiving BDP (1,000 microg/day) delivered via either the MAGhaler or the conventional MDI. Respiratory function parameters, clinical symptoms, concomitant intake of salbutamol or fenoterol, adverse events (AEs), laboratory values, and concomitant medications and diseases were recorded. The primary efficacy parameter was mean forced expiratory volume in 1 s (FEV1), measured after 4, 8, and 12 weeks of therapy. RESULTS: The equivalence of the two devices was confirmed (p = 0.003) on the basis of the ratios of the mean FEV1 in weeks 4 to 12. Mean (+/- SD) FEV1 (MAGhaler was 2.24 +/- 0.60 l (baseline), 2.61 +/- 0.90 litres (week 4), and 2.62 +/- 0.87 litres (weeks 4-12). Mean FEV1 (MDI) was 2.28 +/- 0.59 litres (baseline), 2.53 +/- 0.82 litres (week 4), and 2.56 +/- 0.77 litres (weeks 4-12). In total, 33 AEs occurred in 26 (30.2%) patients (MAGhaler) and 51 AEs in 36 (42.4%) patients (MDI). Most of the AEs were of mild or moderate intensity. The relationship to treatment could not be excluded for 11 AEs in 11 patients (MAGhaler) and 23 AEs in 18 patients (MDI). Three serious AEs, all unrelated to treatment, occurred in 3 patients (MAGhaler: 2, MDI: 1). There were no clinically relevant changes in other safety parameters. Most patients either preferred the MAGhaler or rated the two devices as equally acceptable. CONCLUSION: The new MAGhaler was equivalent to the standard MDI in terms of the safety and efficacy of BDP. The improved user-friendliness and acceptance of the MAGhaler over the conventional MDI represent an important advance in the clinical management of bronchial asthma.

Adult↗

PubMedDate not supplied

Substance-P-induced histamine release from human nasal mucosa in vitro.

There is growing evidence that substance P (SP) is one of the main neuropeptides involved in neurogenic inflammation of the airways. However, a number of studies were not able to demonstrate histamine release from human mucosal mast cells after SP administration. Since cultures of isolated cell systems provide only a partial picture of the inflammatory processes in vivo, organ culture models promise to offer physiologically relevant assay systems for studying tissue interactions. Thus, we examined the influence of SP on histamine release and its morphological effects on human nasal mucosa using a previously described histoculture technique. Compared to controls, the histamine content in the culture bath was significantly elevated after SP stimulation (p < 0.05). Histomorphometry showed a decreased density of mast cells and an increased percentage of degranulated mast cells. These findings were dose and time dependent and support the hypothesis of a close interaction between C-sensory nerves and mast cells implying that these interactions are of pathogenetic importance in nasal mucosa inflammation.

Culture Media, Conditioned↗

PubMedDate not supplied

Ozone-induced augmentation of eicosanoid metabolism in human nasal mucosa in vitro.

The increase in airway responsiveness induced by ozone exposure is associated with airway inflammation as evidenced by an increase in inflammatory mediators such as cyclooxygenase and lipoxygenase product formation found in bronchoalveolar lavage fluid, nasal lavage fluid and epithelial cell cultures. To examine eicosanoid metabolism after exposure to ozone, human nasal mucosa derived from 21 patients undergoing surgical therapy for chronic nasal obstruction was cultured with a specially designed in vitro organ culture device and exposed to 0.1 ppm ozone for 24 h. Eicosanoid formation was analyzed by the release of cyclooxygenase and lipoxygenase products into the culture supernatant (measured by enzyme immunoassay). Experiments revealed ozone-induced increases in cyclooxygenase and lipoxygenase product formation with significant increases in prostaglandin F2alpha (PGF2alpha), thromboxane B2 (TXB2) and leukotriene B4 (LTB4) (p<0.05). Moreover, we found an increase in the concentration of LTC4/D4/E4 in the supernatant of ozone-exposed mucosal samples, which however does not reach statistical significance. There was a significant correlation between PGF2alpha and TXB2 (r = 0.71, p<0.001). These results extend previous results from in vivo chamber studies suggesting that the mode of action of ozone is an oxidative reaction resulting in an increased activity of arachidonic acid metabolism in the airways with a subsequent increase in the concentration of cyclooxygenase and lipoxygenase products.

Eicosanoids↗

PubMedDate not supplied

Nasal polyps and their content of arachidonic acid metabolites.

In three different groups of patients with nasal polyps without or with bronchial hyperreactivity and aspirin-sensitivity the content of several prostaglandin metabolites and LTC4 were measured in the polyp-tissue. A significant elevation of Thromboxane formation (TxB2) was found. The pathophysiological importance of this finding for the development of bronchial hyperreactivity in these patients is seen in context with the non-cholinergic stimulating system with consecutive substance P-formation and the role of the eosinophil cell in chronic inflammation.

6-Ketoprostaglandin F1 alpha↗

PubMedDate not supplied

Recovery of pituitary-adrenal axis after withdrawal or reduction of systemic corticosteroids in patients with bronchial asthma.

In 36 patients with bronchial asthma a new inhalable corticosteroid (Fluocortin-butyl-ester) was administered to reduce systemic steroids and especially to study the recovery of pituitary-adrenal function. On the basis of the present results, it can be said that patients with the least degree of emphysema and obstruction and with good coughing dynamics and productive expectoration are most suitable for therapy with inhalable corticosteroids. If the systemic steroid reduction is adequate, the recovery phase of the pituitary-adrenocortical system begins after about 5 months and the response to ACTH appraoches normal values after about 8-9 months. About 4 mg prednisolone-equivalent per day can be assumed to be the systemically effective limiting dose. The reducibility as a percentage of the initial dose-regardless of its absolute value- and the maintenance dose achieved also appear to be of equal importance for the recovery of the functional reserve of the pituitary-adrenocortical system. No relationship to the duration of the disease and the initial steroid dose could be demonstrated. The clinical picture of the corticosteroid withdrawal syndrome is dependent on endogenous cortisol synthesis. The symptoms disappear spontaneously with increasing synthesis.

Adrenal Cortex Hormones↗

PubMedDate not supplied

Mode of action and indication for disodium cromoglycate (DSCG).

The possible mode of action for DSCG is described. It is assumed that DSCG has a cell specific effect on mast cells, smooth muscle cells, secretory cells and nerve endings. The main action is probably due to an influence upon the calcium channel opening receptors, thus preventing consecutive mediator release from these cells. The lack of efficacy in underlying diseases (rhinitis and bronchial asthma) is probably due to other pathophysiological mechanisms involved. The possible role of bradykinin as a potent mediator is discussed. The indication of DSCG is briefly summarized.

Animals↗

PubMedDate not supplied

Beta-adrenergic receptors in nasal tissue with reference to their role in asthma and atopy.

Thirty-three samples of nasal tissue (turbinates and polyps) were collected and assayed for beta-adrenergic receptor (BAR) sites (radio-ligand assay). Patients were divided into groups: 1) nasal turbinates, 2) nasal polyps, both under the aspects of atopy and bronchial hyperreactivity. Different radiobinding was found in both groups: Patients A with high BAR and patients B with low BAR numbers. There was no correlation between BAR numbers--clinical symptoms and bronchial hyperreactivity. Generally the BAR numbers were higher in turbinates (p less than 0.01) than in polyps and in nonatopic compared to atopic patients (p less than 0.005). "Affinity state 1" BAR are equal in all groups; however, "affinity state 2"BAR are significantly less in polyps (p less than 0.05). In 50% of the examined cases there was a combination of polyps, asthma and atopy putting foreward a common line of pathogenesis in this entity. It is discussed that the underlying inflammation (allergic and non-allergic) is the cause for reduced BAR numbers in the effected tissue. So far nasal tissue seems to be like a mirror compared to the results from lower respiratory tract tissue with respect to beta-adrenergic receptors.

Animals↗

PubMedDate not supplied

Normal and pathological pathways in the regulation of bronchomotor tone (with special reference to bronchial asthma).

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Adrenergic alpha-Antagonists↗

PubMedDate not supplied

The possible role of bradykinin as a mediator in bronchial asthma.

A variety of antiasthmatic drugs were examined in a bioassay of uterine cornua of rats for determining their influence upon Bradykinin induced contractions. 4 different actions were seen: pronounced, moderate and weak suppression of enhancement of Bradykinin-activity. The most pronounced blocking effect was seen with Fenoterol, Adrenaline and Pheniramine, a moderate effect with Prednisolone and Tolazoline, a weak effect with Propranolol and DSCG. Noradrenaline showed a stimulating effect. It is postulated that Bradykinin acts via alpha-stimulation with concomitant cAMP-decrease after specific binding to Bradykinin-receptors. The results of the study suggest that Bradykinin still must be discussed as a possible mediator in obstructive airway-disease.

Animals↗

PubMedDate not supplied

Histopathological examinations of local granulomas during specific hyposensitization.

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Aluminum Hydroxide↗

PubMedDate not supplied

Semi-depot hyposensitization in severe hay fever: its clinical effectiveness and the therapeutic problems. (A four year study using intranasal challenge testing to monitor success).

Hyposensitization treatment for at least two years using pyridine-extracted alum precipitated (PEAP) extracts was carried out on 332 cases of severe hay fever, some of which were steroid dependent. Subjective self-assessment and weekly average use of additional medication were recorded, nasal challenge tests were conducted before and during treatment and related to the clinical picture. Successful treatment was unrelated to age, though distinctly limited where there was a history of more 15 years illness. It was however related to the pollen count from 1973 to 1976 and to the type and number of the antigens to which there was a clinical response. In spite of specific hyposensitization 4,2% of the pollinosis cases developed additional pollen asthma. In the course of treatment there were several instances of an enlargement of the individual antigen spectrum; sensitization to pollen, mould fungi, house dust and animal epithelia were recorded. In a total of 11,850 injections there were severe local reactions in 16,2% rhinoconjunctivitis in 1,6% asthma in 0,4% and urticaria in 0,4%. One female patient went into anaphylactic shock 12 hours after the administration of the antigen extract. In about 20% of the injections granulomas developed, about the size of a cherry-stone, which persisted for up to six months and which in some instances were reactivated by severe exposure to allergens. There was an unusually high percentage of organ and generalised reactions whenever the treatment was continued using a new antigen solution without reducing the dose.

Administration, Intranasal↗

PubMedDate not supplied

Influence of salmeterol, a long-acting beta 2-adrenoceptor agonist, on IgE-mediated histamine release from human basophils.

Salmeterol, a long-acting beta 2-adrenoceptor agonist, prevents early and late asthmatic responses in atopic asthmatics and inhibits the release of inflammatory mediators from various cells and tissues. We investigated the effect of salmeterol on in vitro basophil histamine release (BHR). Washed basophil leukocytes from allergic (n = 6) and nonallergic subjects (n = 18) were preincubated for 10 min with different concentrations of salmeterol prior to stimulation with antigens (Ag) and anti-IgE for 45 min. BHR was detected by an automated fluorometric assay. If control BHR (without inhibition) reached > or = 30% of the total histamine content, maximal % inhibition (Imax, mean +/- SEM) and the concentration of salmeterol causing 30% inhibition (IC30, geometric mean) were calculated. At concentrations of between 1 and 100 microM salmeterol, concentration-dependent inhibition of release was found for Ag- and anti-IgE-mediated BHR. The Imax of anti-IgE-mediated BHR reached 46 +/- 16% at 30 microM salmeterol. IC30 values were 12 microM for Ag- and 8 microM for anti-IgE-induced BHR. Higher concentrations of salmeterol induced BHR in all subjects (n = 24, 100 microM: 28 +/- 5% BHR), overlapping the inhibitory effect on BHR. Kinetic studies using 30 microM salmeterol (n = 10) showed > 30% inhibition with short preincubation periods (< 10 s). Salbutamol, an older, widely used beta 2-adrenoceptor agonist, had no effect on IgE-mediated BHR (n = 8). We conclude that salmeterol significantly inhibits IgE-mediated histamine release from human leukocytes in the micromolar range.

Adrenergic beta-Agonists↗