Budesonide/formoterol (Symbicort) is well tolerated and effective in patients with moderate persistent asthma.

The aim of this study was to compare the safety and efficacy of budesonide/formoterol 160/4.5 microg, two inhalations twice daily, with that of the mono-products administered at the same daily doses via separate inhalers. A total of 586 patients (mean age 45 years) was included in this six-month, open, randomised, multicentre study. Patients received either budesonide/formoterol (n=390) or budesonide plus formoterol (n=190). Safety was assessed by adverse events, vital signs and laboratory values. Efficacy was evaluated using spirometry tests, the Mini Asthma Quality of Life Questionnaire and the Asthma Control Questionnaire. Both treatments were well tolerated, with no differences in safety parameters between the groups. Mean FEV1 increased by 5-6% over baseline in both groups. There was no significant difference in the change from baseline between the groups using the disease-specific questionnaires. Asthma exacerbations occurred with low frequency in both groups. Withdrawal rates were also comparable between the groups (p=0.085). Budesonide/formoterol in a single inhaler was as effective and as well tolerated as budesonide plus formoterol via separate inhalers.

Reflexology and bronchial asthma.

Many asthma patients seek alternative or adjunctive therapies. One such modality is reflexology, whereby finger pressure is applied to certain parts of the body. The aim of the study was to examine the popular claim that reflexology treatment benefits bronchial asthma. Ten weeks of active or simulated (placebo) reflexology given by an experienced reflexologist, were compared in an otherwise blind, controlled trial of 20+20 outpatients with asthma. Objective lung function tests (peak flow morning and evening, and weekly spirometry at the clinic) did not change. Subjective scores (describing symptoms, beta2-inhalations and quality of life) and also bronchial sensitivity to histamine improved on both regimens, but no differences were found between groups receiving active or placebo reflexology. However, a trend in favour of reflexology became significant when a supplementary analysis of symptom diaries was carried out. It was accompanied by a significant pattern compatible with subconscious unblinding, in that patients tended to guess which treatment they had been receiving. No evidence was found that reflexology has a specific effect on asthma beyond placebo influence.

The effect of high-dose fluticasone propionate and budesonide on lung function and asthma exacerbations in patients with severe asthma.

The purpose of this study was to investigate the comparative efficacy and safety of equal doses of inhaled fluticasone propionate (FP) and inhaled budesonide (BUD) using their respective dry powder inhalers in a population of severe asthmatics requiring high doses of inhaled corticosteroid. This double-blind double-dummy parallel-group study compared the effects of 24 weeks of treatment with FP (2000 micrograms daily via a Diskhaler inhaler; Glaxo Wellcome, Evreux, France) and BUD (2000 micrograms daily via a Turbuhaler inhaler; Astra Pharmaceuticals, Rijswijka, Netherlands) on lung function and asthma exacerbations in 395 patients with asthma. FP was statistically significantly superior to BUD with respect to the percentage of symptom-free days (P = 0.02), the incidence of days free from rescue bronchodilator usage (P = 0.02) and the distribution of change in peak expiratory flow (PEF) expressed as a percentage of the predicted PEF (P = 0.04). During the treatment period FP was statistically significantly superior to BUD for change in forced expiratory volume in 1 sec (FEV1) at 8, 16 and 24 weeks, change in the median daytime symptom score during weeks 5-16, for incidence of symptom-free days and incidence of days free from rescue bronchodilator usage during weeks 17-24. There was no significant difference between FP and BUD with respect to the number of patients experiencing one or more asthma exacerbation (33.8 and 28.4% of patients, respectively). There was, however, evidence that the exacerbations were clinically less severe in patients treated with FP, in that the time to resolution was quicker (11.0 vs. 14.7 days; P = 0.035), mean duration of all exacerbations (for an individual patient) tended to be shorter (18.5 vs. 23.6 days; P = 0.12), the time off work was reduced (4.2 vs. 7.6 days; P = 0.012) and the lowest PEF recorded during the exacerbation was higher (301 vs. 263 l min-1; P = 0.07). There were no clinically relevant differences in the safety (serum cortisol levels, markers of bone turnover, adverse events) of FP and BUD at these microgram equivalent doses. The patients recruited into this study, in retrospect, probably had no need for such high doses of inhaled corticosteroid but, irrespective of this, FP at microgram equivalent doses showed evidence of superior efficacy to BUD with respect to lung function and severity of asthma exacerbations without producing any greater adverse systemic effect.

[House dust mite allergens and mite allergy in Copenhagen dwellings. A cross-sectional study]. / Støvmideallergener og mideallergi i københavnske boliger. En tvaersnitsundersøgelse.

The aim of the study was to investigate the influence of various environmental factors on occurrence of house dust mite allergens and the influence of allergen exposure on mite allergy. Ninety-two persons from a population study filled in a questionnaire, were skin prick and lung function tested and dust samples were collected from their mattresses for analyses. Two out of five patients with asthma had a positive skin reaction to house dust mite allergen in contrast to five out of 87 non-asthmatics. Fifty-nine per cent of the dust samples contained (group 1) mite allergen > 2 micrograms/g dust. Such mattresses were older (median 7 years, range 1-22) than mattresses with less allergen (median 4 years, range 1-20). In the six bedrooms reported to be humid or mouldy, mattresses contained high concentration of mite allergens. No other parameter investigated could predict the allergen contents. In almost all cases dust analyses are crucial to be able to advise patients with house dust mite allergy.

Histamine inhalation is a specific but insensitive laboratory test for migraine.

Migraine is a subjective complaint and no laboratory test has until now been of value. The aim of the present study is to evaluate whether histamine inhalation may be used as a diagnostic test for migraine. In a double-blind study design, 15 migraineurs and 15 control subjects scored headache intensity and characteristics before, during, and in the subsequent 12 h after inhalation of increasing doses of histamine (0, 2, 4, 8, 16, 32 and 64 mg/ml). During the histamine inhalations, headaches increased dose-dependently in both groups. Eleven of the migraineurs and eight of the healthy controls experienced headaches after the inhalations. These headaches fulfilled the IHS criteria for migraine without aura in six of the migraineurs, but in none of the control subjects. Using this as a test parameter, the specificity of the test was 1, but the sensitivity was only 0.4. Our results indicate that histamine inhalation is a specific but insensitive laboratory test for migraine. Migraineurs should be informed about the risk of a migraine attack being provoked before histamine inhalation in pulmonary laboratories.

[Adrenaline for self treatment of anaphylactic reactions. Indications, available preparations and prescription rules]. / Adrenalin til selvbehandling af anafylaktiske reaktioner. Indikationer, tilgoengelige praeparater og udleveringsregler.

Adrenaline is the drug of choice for the treatment of anaphylaxis. The indications, available formulations, and rules for prescribing adrenaline for self treatment of anaphylactic reactions in allergic subjects are summarized in this paper. Emergency kits containing adrenaline must be prescribed only to patients with a definite history of anaphylactic reactions or laryngeal oedema. A kit containing Adrenaline DAK 1 mg/ml in a traditional glass ampoule together with a 1 ml syringe and an i.m. cannula is the cheapest solution, and a usable alternative in the patient who after sufficient training feels safe to prepare his own injection. Ana-guard injector is recommended for the allergic adult due to its easy handling and the fact that it contains two doses of adrenaline 0.3 mg. For both children and adults with a low bodyweight, the Epi-Pen automatic injector is recommended. It contains one dose of adrenaline (0.15 or 0.30 mg) and requires no preparation before use. The Adrenalin Medihaler is recommended for the treatment of laryngeal oedema and threatened airway obstruction. Due to the low and unpredictable absorption after inhalation, adrenaline injection is recommended for the treatment of systemic symptoms. Prescribing adrenaline in semi-or automatic injectors requires special permission from the Danish Health Authorities.

[High dose inhaled steroids in the treatment of bronchial asthma. A comparison of the effects of budesonide and beclomethasone dipropionate on pulmonary function, symptoms, bronchial reactivity and adrenocortical function]. / Højdosis inhalerede steroider i behandlingen af asthma bronchiale. En sammenligning af effekten af budesonid og beklometason-dipropionat på lungefunktion, symptomer, bronkial reaktivitet og binyrebarkfunktion.

The effects of high-dose inhaled budesonide (800 micrograms twice daily) and those of inhaled beclomethasone dipropionate (750 micrograms twice daily) were compared with respect to lung function, symptoms, bronchial reactivity and adrenocortical function in a doubleblind, double-dummy cross-over study. The subjects were 40 adult patients suffering from either allergic or non-allergic asthma. The asthma was categorized as moderate to severe, and the asthma was insufficiently controlled on inhalational steroids given in doses of 300 to 500 micrograms daily. After a two week "run-in" period the patients were randomized to six weeks treatment with either budesonide or beclomethasone dipropionate, followed by six weeks treatment with the opposite drug. Both inhaled budesonide and inhaled beclomethasone dipropionate were able to improve objective measures of lung function and bronchial sensitivity to histamine. Neither drug affected adrenocortical function, and no serious side-effects were noted during the trial. It is concluded that budesonide and beclomethasone dipropionate are safe and effective drugs for the treatment of asthma in adults. The substances are equally effective taken microgram for microgram.

Biomolecular regulation of the IgE immune response. I. Cell-associated IgE and in vitro IgE synthesis.

Several cell types, including mast cells, basophils, macrophages/monocytes, lymphocytes, platelets and eosinophils, may bind or contain IgE. To investigate the source of cell-associated IgE and its relation to spontaneous IgE synthesis, peripheral blood mononuclear cells from allergic and non-allergic donors were examined. Using a combination of different cell fractionation techniques and varying methods for extraction of cell-associated IgE, data were obtained indicating that monocytes constitute a major source of cell-associated IgE in human blood. The amount of cell-associated IgE in peripheral blood mononuclear cells from allergic and non-allergic donors varied more than 100-fold but correlated closely to the level of serum IgE (r = 0.84, p < 0.001, n = 38). Spontaneous and mitogen-induced in vitro syntheses of IgA, IgE and IgG were compared for allergic and non-allergic donors. Only one donor with very high serum IgE demonstrated spontaneous or mitogen-induced in vitro IgE synthesis despite synthesis of IgA and IgG.

Airway calibre as a confounder in interpreting bronchial responsiveness in asthma.

BACKGROUND: The relation between airway responsiveness to constrictor agents and forced expiratory volume in one second (FEV1) is important when interpreting change in airway responsiveness after an intervention. The aim of the study was to analyse the relation between FEV1 as a percentage of predicted values (% predicted) and airway responsiveness between and within asthmatic subjects. METHODS: Results of non-specific bronchial challenge tests were pooled from two randomised crossover studies comparing the effect of a non-sedative antihistamine with placebo in 35 patients with moderate asthma. The design of the two studies was similar: the provocative concentration of either histamine (first study) or methacholine (second study) resulting in a 20% decrease in ventilatory capacity (PC20) was repeated at two week intervals while patients were treated with the antihistamine or placebo. The dose of inhaled corticosteroid was gradually reduced during the study. Data were analysed with PC20 as the dependent variable in a general linear model so that the influence on PC20 of inhaled corticosteroid dose, antihistamine, and choice of bronchoconstricting agent could be separated from the influence of FEV1% predicted. RESULTS: The correlation coefficient between mean PC20 and mean prechallenge FEV1 for each patient was 0.45. In the general linear model two thirds (65%) of the variation in PC20 was due to variation between subjects. One third of the within subject variation in PC20 could be explained by variation in prechallenge FEV1% predicted (a change in FEV1 of 27% predicted was associated with one doubling or halving of PC20). Treatment with the antihistamine had no influence on PC20, except when histamine was used as the bronchoconstricting agent. The dose of inhaled corticosteroid had a small but significant effect. CONCLUSIONS: The variation in a patient's PC20 over time (several months) is related to changes in FEV1% predicted. Variation in FEV1% predicted explains less of the variation in bronchial responsiveness between subjects where a patient specific factor, which is probably related to the pathogenesis of bronchial asthma, seems to dominate.

High-dose inhaled steroids in the management of asthma. A comparison of the effects of budesonide and beclomethasone dipropionate on pulmonary function, symptoms, bronchial responsiveness and the adrenal function.

The efficacy of budesonide (800 micrograms b.d.) and beclomethasone dipropionate (750 micrograms b.d.) in controlling the symptoms of asthma, pulmonary function, bronchial responsiveness to histamine, and adrenal function, was assessed in a double-blind, double-dummy cross-over study of 36 adult chronic asthmatic patients. The patients, the majority of whom were assessed to be affected to a severe degree, were insufficiently controlled in their current regimen of inhaled steroids and/or inhaled and oral bronchodilators. A 2 weeks baseline period preceded 6 weeks of treatment with each of the study drugs. Both treatment groups showed improvements from baseline in clinical assessment of lung function carried out after the first 6 weeks of treatment. No significant differences were seen throughout the entire 12 weeks study, when comparing the effects of the treatments on FEV1, FVC, PEF or the histamine PC20. Asthma severity, symptom score and inhaled bronchodilator use showed the same results after both treatments. It is concluded that inhalations of budesonide and beclomethasone dipropionate in high doses are equally potent in the treatment of severe asthma. There is no significant influence on the adrenal function and no significant side effects during a period equal to that of the present study.

Effects, side effects and plasma concentrations of terbutaline in adult asthmatics after inhaling from a dry powder inhaler device at different inhalation flows and volumes.

1. The efficacy of a metered dose inhaler (MDI) is highly dependent on the mode of inhalation. The relatively high built-in resistance in the Turbohaler (TBH), a new dry powder inhaler device for inhalation of terbutaline sulphate and budesonide, reduces the flow during inhalation. We compared five different modes of inhalation using the terbutaline TBH in 10 stable asthmatic subjects, who were tested on 5 consecutive days. 2. Measurement of 10 different parameters of pulmonary function indicated that the full bronchodilatory effect of an inhaled dose was already achieved at 5 min after the inhalation. Inspiratory flows through the TBH varying from 34 to 88 l min-1 resulted in comparable bronchodilation, and a previous exhalation to residual volume proved of no value. However, if, prior to inhalation, an exhalation through the device was performed, a substantially reduced effect was seen. 3. Reducing the inspiratory flow to approximately 34 l min-1 produced slightly reduced side effects and lower plasma terbutaline concentrations.

Bronchial allergen challenge: dose versus concentration.

This study was designed to investigate if two equivalent doses of allergen administered by different dosing regimes--two breaths and 10 breaths of each concentration--would result in the same magnitude of the early and late asthmatic response. Fifteen patients with extrinsic allergic asthma were challenged twice with either two or 10 breaths of twofold increasing allergen concentrations. The challenge was continued until a 20% decrease in FEV1 had been achieved. A non-cumulative PC20FEV1 allergen was derived, and the cumulative dose of allergen given was similarly derived. In order to assess the reproducibility of the challenge, seven patients were challenged twice with two-breath regime. The mean value of allergen PC20 obtained by the two-breath regime was 4.1 fold (95% CI: 2.3-7.1 fold) greater than those obtained by the 10-breath regime (P less than 0.05), whereas the difference was 1.4 fold (95% CI: -3.3-0.5 fold) for the cumulative dose (P greater than 0.05). A statistically significant larger magnitude of the early asthmatic response, as determined by the maximum per cent fall in FEV1, and late asthmatic response determined by the maximum per cent fall in peak expiratory flow domiciliary recorded during the following 24 hr after challenge, was observed in favour of the 10-breath regime compared to the two-breath regime (mean difference 6%, 95% CI: 0.6-11%). The reproducibility of the provocation test was acceptable (+/- 1.8 two-fold concentration difference). These results confirm the 'equivalent dose hypothesis', and demonstrates that dosage rather than concentration appears to determine the early and late asthmatic response after bronchial allergen challenge.

Single-dose inhaled budesonide in subjects with chronic asthma.

In 30 stable asthmatics, a comparison was made between the changes in pulmonary function (FEV1, FVC, PEF, MEF75, MEF50 and MEF25) hourly for 9 h after a single dose of inhaled budesonide 1,600 micrograms, and placebo. All subjects used inhaled steroids daily; this medication was, however, withheld 8 days prior to the study. For all parameters of pulmonary function, a significant difference in favour of budesonide was demonstrated. The effect tended to decrease after 9 h, and had abated within 24 h. FEV1 age, sex, smoking habits, or results of an inhaled beta 2-agonist reversibility test could not be demonstrated as predictors of those subjects to react with the most pronounced responses to budesonide. In conclusion, our results demonstrate an effect 3 h after administration of an inhaled glucocorticosteroid in adult outpatients with chronic asthma. These results parallel previous findings in highly selected asthmatics and after systemic administration of glucocorticosteroids. Single-dose administration and subsequent monitoring for 8-9 h may therefore prove valuable in evaluating new prophylactic agents for the treatment of asthma.

Glucocorticosteroid therapy in acute severe asthma--a critical review.

Glucocorticosteroid (GCS) therapy is one of the corner-stones in the treatment of asthma. Its value in acute severe asthma is still open for debate. Many of the papers published on the topic are subject to methodological problems. In 8 of 13 placebo-controlled studies, GCS therapy proved to be superior to placebo, evaluated either as result of pulmonary function, blood gas tension, or hospital admission rate. The most important point for GCS therapy in acute severe asthma seems to be frequent dosage, typically 4 times daily. Oral and intravenous administration seem to have equal efficacy. Only 2 of 10 studies were able to prove a dose-response relationship. Both studies included very low doses of GCS. Doses of 100-200 mg of methylprednisolone for 24 h seem as effective as high doses. A protective effect against relapses within a certain time after the GCS therapy has been demonstrated only for periods not exceeding 4 weeks, and only in children. So far, no study has been able to depict the categories of patients who may or may not benefit by the addition of GCS therapy to the symptomatic treatment of acute severe asthma.

House dust mite allergens on different types of mattresses.

Beds and especially mattresses are important breeding grounds for house dust mites. We investigated whether supposed differences in the microclimate on water, spring and foam mattresses were reflected in the occurrence of house dust mite major allergens (Der fI, Der mI, and Der pI) in mattress dust. Fifty-one mattresses that had been in use for 8-25 months were sampled. Median concentration of total major allergens was 0.5 microgram/g dust (range 0-45) with little difference between the three major allergens and between the three types of mattresses. Occurrence of mattresses with concentrations above and below the proposed risk level (2 micrograms/g) was similar in the mattress groups. However, the allergen concentration was above risk level in 56%, if washable underblankets were not applied, compared with only 21% in the group with such underblankets. In conclusion, mattresses tend to accumulate allergen rather rapidly. Neither heated water mattresses, spring nor foam mattresses seem to be of any advantage for mite allergics, whereas underblankets made of synthetic fibres in a cotton or synthetic cover, commonly used in Denmark, might play a beneficial role in reducing allergen exposure.

Diagnosis of house dust mite allergy.

The medical history may be conclusively descriptive in house dust mite allergy in patients with asthma and rhinoconjunctivitis. Often the patients have both diseases. Sensibilization to D. pteronyssinus and D. farinae can be demonstrated by skin prick testing. If the diagnosis is still doubtful, the next step will be to perform a RAST test or a histamine release test. It is also important to investigate for mite exposure at the patient's residence, if the patient is suspected to be mite-allergic. Allergen challenge test in the shock organ should be performed, if hyposensitization is considered, or if, in a few cases, the mite diagnosis is still doubtful.

Immunological and physical properties of allergen solutions. Effects of nebulization.

Lyophilised birch pollen allergen extracts, reconstituted with different diluents (H2O, saline, Albumin diluent (AD] were investigated to determine whether the allergen activity and quality of the extracts deteriorated by nebulization with different nebulizers (Pari, Wright, and Sandoz). Allergen activity was measured by IgG4 RAST inhibition technique and allergen quality was analysed by crossed immunoelectrophoresis (CIE). The distribution of particle sizes of aerosols of different allergen solutions was determined by a TSI Aerodynamic Particle Sizer. A significant difference (P less than 0.05) in allergen activity was found between the AD and H2O diluents before and after using a Sandoz nebulizer and a Wright nebulizer equipped with a small chamber. This suggested greater allergen activity in AD-diluted solutions, and the pattern was repeated with the other two nebulizers, but was not statistically significant. The samples diluted with saline showed no significant differences in quality after nebulization except for the impacted aerosol in which one of the precipitates was slightly diminished. In the AD-diluted sample one of the precipitates disappeared from the impacted aerosol and from the nebulization chamber after 2 min nebulization. To elucidate whether the extract proteins had been bound by albumin, samples were submitted to CIE with rabbit anti-human albumin in an intermediate gel. By this procedure one precipitate was transformed to a precipitate in the intermediate gel, indicating that one or more proteins in the extracts may associate with albumin. No significant difference in output was observed between the nebulizers. The particle size distribution curves for each diluent (saline, AD) were identical for the Wright nebulizer with 99% of the dry particles distributed within 0.5-2.0 microns.(ABSTRACT TRUNCATED AT 250 WORDS)

Peak inspiratory flow and inspiratory vital capacity of patients with asthma measured with and without a new dry-powder inhaler device (Turbuhaler).

In 101 asthmatic adults with varying degrees of bronchial obstruction, lung function tests including peak inspiratory flow (PIF), inspiratory vital capacity (IVC), peak expiratory flow (PEF), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) measurements were made. Significant correlations between inspiratory and expiratory volumes were found. In most patients, PIF was less reduced than the expiratory parameters of pulmonary function. When inhalation was performed through the new multi-dose, dry-powder inhalation device, Turbuhaler (PIF-TBH), it was significantly lower than PIF measured without Turbuhaler. In previous studies, PIF-TBH of 30 l.min-1 or more has proven sufficient to produce a therapeutic dose of terbutaline, and to produce significant bronchodilatation. Of 101 asthmatics in the present study, only four had PIF-TBH of less than 30 l.min-1. Although no parameters of spirometry could accurately predict PIF-TBH, there was a tendency for patients with severely impaired ventilatory capacity to produce lower PIF-TBH than patients with normal or near-normal ventilatory capacity. If patients with severely impaired ventilatory capacity are to receive inhalation therapy through Turbuhaler, either PIF or PIF-TBH should be measured, or the effect should be carefully monitored.