Joop H. Dijkman

Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma

BACKGROUND Asthma is characterized by hyperresponsiveness of the airways to bronchoconstrictive stimuli. Long-acting beta 2-adrenoceptor agonists have been introduced as a new therapeutic approach, but there is growing concern about whether control of asthma may deteriorate with the regular use of these agents. We investigated the long-term effects of the beta 2 agonist salmeterol on bronchodilation and on airway hyperresponsiveness to the bronchoconstrictive agent methacholine in mild asthma. METHODS In a parallel, double-blind study, 24 patients with mild asthma were randomly assigned to treatment with either inhaled salmeterol (50 micrograms, twice daily) (n = 12) or placebo (n = 12) during an eight-week trial. Methacholine challenge was performed before, during, and after the treatment period. Methacholine responsiveness was measured as the provocative concentration (PC20) that caused a 20 percent decrease in the forced expiratory volume in one second (FEV1). RESULTS There was a significant increase in FEV1 one hour after the inhalation of salmeterol (P = 0.006), which did not differ significantly on days 0, 28, and 56 of the treatment period (increase, 9.8, 9.4, and 8.8 percent of predicted FEV1, respectively; P = 0.91). On the first treatment day, salmeterol afforded significant protection against methacholine-induced bronchoconstriction, as shown by a 10-fold increase in the PC20 as compared with the value at entry (P less than 0.001). After four and eight weeks of treatment, however, the salmeterol-induced change in the PC20 was significantly attenuated (P less than 0.001) to only a twofold increase. Two and four days after treatment ended, the PC20 was not significantly different from the value before treatment (P = 0.15). CONCLUSIONS Regular treatment of patients with mild asthma with salmeterol leads to tolerance to its protective effects against a bronchoconstrictor stimulus, in this case inhaled methacholine, despite well-maintained bronchodilation. This finding raises concern about the effectiveness of prolonged therapy with long-acting beta 2-adrenoceptor agonists in asthma.

The development of the ‘Quality-of-Life for Respiratory Illness Questionnaire (QOL-RIQ)’: a disease-specific quality-of-life questionnaire for patients with mild to moderate chronic non-specific lung disease

Chronic non-specific lung disease (CNSLD) encompasses asthma as well as chronic obstructive pulmonary disease (COPD). Recently in health care, there has been increasing awareness in the functional, psychological and social aspects of the health of patients; their quality of life (QOL). Quality-of-life research addressing CNSLD patients has been rather underdeveloped for a long period of time. Recently, however, the importance of QOL is being increasingly recognized, and several research groups have started to study QOL in CNSLD patients in more detail. This paper describes the construction of a disease-specific QOL instrument for patients with mild to moderately severe CNSLD. Items relating to several domains of QOL were listed, and 171 CNSLD patients in general practice were asked how much of a problem each item had been (assessed on a seven-point Likert scale). After applying an item-selection procedure, a uni-dimensional QOL questionnaire was constructed consisting of 55 items divided into seven domain subscales: breathing problems, physical problems, emotions, situations triggering or enhancing breathing problems, general activities, daily and domestic activities, and social activities, relationships and sexuality. Reliability estimates of the domain subscales of the constructed questionnaire varied from 0.68 to 0.89, and was 0.92 for the QOL for Respiratory Illness Questionnaire (QOL-RIQ) total scale. A first impression of the construct validity of the questionnaire was gained by investigation of the relationship between the QOL domain subscales and several indicators of illness severity, as well as the relative contribution of illness severity variables, background characteristics and symptoms to QOL, using regression analysis. Further research to validate the questionnaire to a greater extent (construct validity, test-retest reliability and responsiveness to change) is currently taking place.

The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease.

Beta 2 agonists reduce airway hypersensitivity to bronchoconstrictor stimuli acutely in patients with asthma and chronic obstructive lung disease. To determine whether these drugs also protect against excessive airway narrowing, the effect of inhaled salbutamol on the position and shape of the dose-response curves for histamine or methacholine was investigated in 12 patients with asthma and 11 with chronic obstructive lung disease. After pretreatment with salbutamol (200 or 400 micrograms) or placebo in a double blind manner dose-response curves for inhaled histamine and methacholine were obtained by a standard method on six days in random order. Airway sensitivity was defined as the concentration of histamine or methacholine causing a 20% fall in FEV1 (PC20). A maximal response plateau on the log dose-response curve was considered to be present if two or more data points for FEV1 fell within a 5% response range. In the absence of a plateau, the test was continued until a predetermined level of severe bronchoconstriction was reached. Salbutamol caused an acute increase in FEV1 (mean increase 11.5% predicted in asthma, 7.2% in chronic obstructive lung disease), and increase in PC20 (mean 15 fold in asthma, fivefold in chronic obstructive lung disease), and an increase in the slope of the dose-response curves in both groups. In subjects in whom a plateau of FEV1 response could be measured salbutamol did not change the level of the plateau. In subjects without a plateau salbutamol did not lead to the development of a plateau, despite achieving a median FEV1 of 44% predicted in asthma and 39% in chronic obstructive lung disease. These results show that, although beta 2 agonists acutely reduce the airway response to a given strength of bronchoconstrictor stimulus, they do not protect against excessive airflow obstruction if there is exposure to relatively strong stimuli. This, together with the steepening of the dose-response curve, could be a disadvantage of beta 2 agonists in the treatment of moderate and severe asthma or chronic obstructive lung disease.

Validity of peak expiratory flow measurement in assessing reversibility of airflow obstruction.

BACKGROUND: Assessing the reversibility of airflow obstruction by peak expiratory (PEF) measurements would be practicable in general practice, but its usefulness has not been investigated. METHODS: PEF measurements were performed (miniWright peak flow meter) in 73 general practice patients (aged 40 to 84) with a history of asthma or chronic obstructive lung disease before and after 400 micrograms inhaled sulbutamol. The change in PEF was compared with the change in forced expiratory volume in one second (FEV1). Reversible airflow obstruction was analysed in two ways according to previous criteria. When defined as a 9% or greater increase in FEV1 expressed as a percentage of predicted values reversibility was observed in 42% of patients. Relative operating characteristic analysis showed that an absolute improvement in PEF of 60 l/min or more gave optimal discrimination between patients with reversible and irreversible airflow obstruction (the sensitivity and specificity of an increase of 60 l/min in detecting a 9% or more increase in FEV1 as a percentage of predicted values were 68% and 93% respectively, with a positive predictive value of 87%). When defined as an increase of 190 ml or more in FEV1, reversible airflow obstruction was observed in 53% of patients. Again an absolute improvement in PEF of 60 l/min or more gave optimal discrimination between patients with reversible and irreversible airflow obstruction (sensitivity 56%, specificity 94%, and positive predictive value 92%). CONCLUSION: Absolute changes in PEF can be used as a simple technique to diagnose reversible airflow obstruction in patients from general practice.

Auranofin in the treatment of steroid dependent asthma: a double blind study.

BACKGROUND: Long term administration of oral corticosteroids in patients with asthma may be associated with serious side effects. Non-steroidal anti-inflammatory drugs, including gold salts, have been shown to reduce the need for systemic corticosteroid treatment in uncontrolled studies. The effect of oral gold (auranofin) on asthma symptoms, lung function, and the need for oral prednisone treatment was investigated. METHODS: A 26 week randomised, double blind, placebo controlled, parallel group trial of auranofin was performed in 32 patients with moderately severe chronic asthma who required an oral corticosteroid dose of at least 5 mg prednisone a day (or equivalent) or 2.5 mg/day prednisone plus more than 800 micrograms/day inhaled corticosteroids. Auranofin was given orally in a dose of 3 mg twice daily. Asthma symptoms, lung function, and adverse effects were assessed at regular intervals. After 12 weeks of treatment prednisone dosage was tapered down by 2.5 mg every two weeks if the patient was clinically stable. Asthma exacerbations were treated with short courses of high doses of oral steroids. RESULTS: Twenty eight of the 32 patients, 13 in the placebo group and 15 in the auranofin group, completed the study. The total corticosteroid reduction achieved after 26 weeks of treatment was significantly greater (4 mg) in the auranofin group than in the placebo group (0.3 mg). The number of exacerbations requiring an increase of steroids was greater in the placebo group (2.1) than in the active group (0.9). A significant increase in FEV1 of 6.4% predicted occurred in the auranofin group during the study and there was a reduction of asthma symptoms such as wheezing and cough. There was no difference between the groups in peak flow measurements or in the number of asthma attacks. The incidence of side effects of auranofin was low, but exacerbations of constitutional eczema were noticeable. CONCLUSION: Auranofin provides an effective adjunct to treatment for steroid dependent asthma, leading to a reduction of oral steroid dose.

The effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man.

We have investigated the protective effects of the inhaled cysteinyl leukotriene antagonist, L-648,051, on allergen-induced early asthmatic response (EAR) and late asthmatic response (LAR) and the subsequent changes in bronchial responsiveness to methacholine. Ten atopic men with asthma participated in a double-blind, crossover, placebo-controlled trial. All subjects had documented EAR and LAR to house dust-mite extract. Responsiveness to methacholine was measured the day before and the day after a standardized allergen-challenge test. L-648,051 was inhaled in two doses of 12 mg 20 minutes before and 3 hours after the allergen challenge. The response was obtained from FEV1 and flows from maximal (V40m) and partial (V40p) expiratory flow-volume curves. All subjects had an EAR and LAR during placebo therapy, but only a minority demonstrated an increase in methacholine responsiveness of more than one doubling dose. The ratio of V40m to V40p during methacholine challenge was higher than during both EAR and LAR (p less than 0.05). There was no difference between drug- and placebo-therapy periods in baseline function, EAR, LAR, ratio of V40m to V40p, and the allergen-induced hyperresponsiveness (p greater than 0.1). These results indicate that an effective aerosolized leukotriene antagonist in man does not protect against allergen-induced airflow obstruction, despite the evidence of an inflammatory response to allergen challenge. This suggests that either the potency or duration of activity of L-648,051 is limited or that leukotrienes C4 and D4 do not play a causative role in human allergic asthma.

Proteinase inhibitory activities of antileukoprotease are represented by its second COOH-terminal domain

Antileukoprotease or secretory leukocyte proteinase inhibitor is a potent serine proteinase inhibitor produced by exocrine glands of the human body. This monomeric protein (107 amino acids) comprises two homologous domains. It is generally thought that Leu19-Arg20-Tyr21 in the NH2-terminal domain represent the trypsin inhibitory activity, whereas Leu72-Met73-Leu74 in the COOH-domain represent the chymotrypsin and elastase inhibitory activity. Besides Met73, antileukoprotease contains three additional methionine residues all located in the COOH-terminal domain. Treatment of antileukoprotease with different amounts of methionine-selective reagents such as myeloperoxidase in the presence of H2O2 and Cl-, or cis-platinumdiammine dichloride resulted in a dose-dependent inactivation of all inhibitory activities, suggesting that methionine residues are involved in these activities. By using specific synthetic substrates, it was observed that elastase is able to displace trypsin from the inhibitor molecule, indicating that the trypsin and elastase inhibitory sites are located close to each other or at the same site. Incubation of antileukoprotease or its recombinant COOH-terminal domain with an antileukoprotease-specific monoclonal antibody (MoAb15) resulted in a strong selective increase of the trypsin inhibitory activity. The results presented reveal strong evidence that the inhibitory activities of antileukoprotease against trypsin, chymotrypsin and elastase are represented by its COOH-terminal domain, and that methionine residues are involved in interactions with these proteinases.

Relation between small airways disease and parenchymal destruction in surgical lung specimens.

The relation between small airways disease and parenchymal destruction was investigated in lungs and lobes removed at surgery from 27 patients aged 15-70 years. Eight of the 27 patients were life-long non-smokers. The degree of small airways disease was assessed by semi-quantitative grading (SAD score) and by measuring diameter and wall thickness of membranous bronchioles. Parenchymal destruction was measured in three ways. Firstly, the number of alveolar attachments on membranous bronchioles per millimetre of circumference (AA/mm) was counted; the number of broken attachments was subtracted from the total AA/mm to give the numbers of intact attachments (normal AA/mm). Secondly, a point counting technique was used to give a destructive index (DI). Thirdly, the mean linear intercept (Lm) was determined. Total and normal AA/mm correlated negatively with the SAD score of membranous bronchioles (rs = -0.48 and -0.51) and with wall thickness (rs = -0.37 and -0.45) and DI correlated with wall thickness (rs = 0.5) and with the SAD score of respiratory bronchioles (rs = 0.53). Lm did not correlate with indices of small airway disease and total and normal AA/mm did not correlate with diameter. Multiple regression analyses showed that the correlation of total AA/mm with the SAD score of membranous and respiratory bronchioles and with wall thickness were not confounded by age or smoking. It is concluded that small airways disease is related to destruction of peribronchiolar alveoli, and it is postulated that small airways disease has a direct role in the causation of centrilobular emphysema.

Intratracheally-instilled antileukoprotease and α1-proteinase inhibitor: effect on human neutrophil elastase-induced experimental emphysema and pulmonary localization

SummaryThe protective capacities of intratracheally-instilled antileukoprotease and α1-proteinase inhibitor towards human neutrophil elastase (HNE)-induced pulmonary injuries were compared in hamsters. The antiproteases were instilled in equimolar amounts up to 20 h before HNE instillation. At all intervals, both inhibitors were able to inhibit HNE-induced emphysema efficiently. At l h before HNE instillation, α1-proteinase inhibitor was more effective in this regard than antileukoprotease.α1 -Proteinase inhibitor, instilled 1 to 12 h before HNE, efficiently inhibited HNE-induced haemorrhage, while the antileukoprotease protected haemorrhage only when it was administered 1 h before HNE. The development of secretory cell metaplasia was affected only when both inhibitors were instilled 1 h before HNE. In a second series of experiments, the localization of the two antiproteases after intratracheal instillation in hamster was investigated using an indirect immunofluorescence technique. Up to 20 h after installation, antileukoprotease was found to be associated with elastin fibres at all points of time investigated. In contrast, α1-proteinase inhibitor was observed to be located in the alveolar lining and diffusely in the alveolar lung tissue at all points of time investigated. No association of the inhibitor with elastin fibres was found. We conclude that the fraction of antileukoprotease associated with the elastic fibre may be important in the protection of HNE-induced pulmonary emphysema.

In vitro effect of a mucolytic thiol agent on the activity of polymorphonuclear leucocyte elastase and antileucoprotease.

We have studied the effects of the mucolytic thiol agent mercapto-ethanesulphonate (mesna) on the activity of both polymorphonuclear leucocyte (PMN) elastase and antileucoprotease in vitro. In all tests a specific synthetic substrate was used to measure elastase activity, which was then related to enzyme activity in the absence of mesna. The relative elastase activity decreased to 67.5% of control values after the enzyme had been incubated in a 120 mmol/l mesna solution. In the sol phase of purulent sputum, elastase activity decreased to 45% after the sol phase had been incubated in a 600 mmol/l mesna solution. The inability to reverse the inhibition of mesna by increasing the substrate concentration indicated that mesna acts as a non-competitive inhibitor of PMN elastase. Incubation of elastase with antileucoprotease reduced the relative elastase activity to 21%. When antileucoprotease was preincubated in a 60 mmol/l mesna solution under identical assay conditions, a relative elastase activity of 39% was observed. Inhibition experiments with mesna treated antileucoprotease, in which sulphydryl groups were blocked with iodoacetamide, strongly suggested that the dissociation constant (Ki) of the fraction of antileucoprotease that retains activity after the incubation with mesna was not changed. Elastase inhibitory activity in mucoid sol phase, which can be ascribed mainly to antileucoprotease, decreased to 53% after incubation with mesna at a concentration of 960 mmol/l. Incubation of PMN elastase/antileucoprotease complex with mesna did not result in any release of active PMN elastase from the antileucoprotease. It is concluded that mesna and other thiol compounds, when locally administered, may influence the proteinase-antiproteinase balance in the airways by their effect on both PMN elastase and antileucoprotease.