A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is characterised by lung cysts and airflow obstruction. Matrix metalloproteinases have been implicated in lung destruction in LAM. We performed a randomised, double-blind trial, comparing the matrix metalloproteinases inhibitor doxycycline with placebo on the progression of LAM. 23 females with LAM were randomised to doxycycline 100 mg daily for 3 months followed by 200 mg daily for 21 months, or matched placebo. Lung function, exercise capacity, quality of life and matrix metalloproteinases levels were measured. 21 patients completed 6 months of treatment, 17 completed 1 year of treatment and 15 completed 2 years of treatment. Eight withdrew from the trial due, four due to a pneumothorax and four because of other reasons. The mean±sd decline in FEV1, the primary endpoint, did not differ between the groups being -90±154 mL·year(-1) in the placebo group and -123±246 mL·year(-1) in the doxycycline group (difference -32.5, 95% CI -213-148; p=0.35). Doxycycline had no effect upon vital capacity, gas transfer, shuttle walk distance or quality of life. Urine matrix metalloproteinases-9 measurements were lower with doxycycline treatment (p=0.03). Although with limited numbers we cannot completely exclude an effect of doxycycline, the lack of effect on any outcome makes it unlikely that doxycycline has a useful effect in LAM.

Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial.

PURPOSE: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders. EXPERIMENTAL DESIGN: In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function. RESULTS: The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus. CONCLUSIONS: This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation.

Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial.

RATIONALE: Asthma exacerbations are unpredictable, disruptive, and frightening, and are therefore important to prevent. OBJECTIVES: We investigated whether a policy of quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate reduces asthma exacerbations requiring treatment with oral corticosteroids. METHODS: A total of 403 people with asthma were given a self-management plan and randomized to take an active or placebo corticosteroid inhaler in addition to their usual asthma treatment when their PEF fell by 15% on 2 consecutive days or by 30% on 1 day. The study inhalers provided a quadrupling or no change in corticosteroid dose. MEASUREMENTS AND MAIN RESULTS: Eighteen of 197 (9%) and 29 of 203 (14%) participants had an exacerbation of asthma requiring treatment with oral corticosteroids in the active and placebo groups, respectively, giving a risk ratio of 0.64 (95% confidence interval, 0.37-1.11, P = 0.11). Of the 94 participants who started the study inhaler far fewer required treatment with oral corticosteroids in the active compared with the placebo group: 12 of 56 (21%) in the active group and 19 of 38 (50%) in the placebo group, giving a risk ratio of 0.43 (95% confidence interval, 0.24-0.78, P = 0.004). CONCLUSIONS: Although our primary outcome did not reach statistical significance, quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate appears to reduce acute exacerbations of asthma and deserves further investigation. Clinical trial registered with www.controlled-trials.com (ISRCTN 46018181).

Effect of mouth taping at night on asthma control--a randomised single-blind crossover study.

BACKGROUND: Nose breathing ensures that inspired air is warm, filtered and moist and may therefore benefit patients with asthma. It features in some complementary approaches to treat asthma and is encouraged at night in the Buteyko technique by the use of mouth taping. In this pragmatic study we sought to determine whether taping the mouth at night has any effect on asthma control compared with usual breathing in patients with symptomatic asthma, since if it was effective it would be a simple intervention to implement. METHODS: This was a randomised, single-blind, crossover study of participants (n=51) with symptomatic asthma (mean FEV(1) 86% predicted). A 4-week period of usual breathing at night was followed by use of mouth taping with microporous tape, as in the Buteyko technique, or vice versa, with a 2-week run-in period and a minimum 2-week washout period of usual breathing between 'treatments'. Primary outcomes were morning peak expiratory flow and symptom scores (Asthma Control Diary). Outcomes were measured and analysed without knowledge of treatment allocation. RESULTS: Fifty participants completed the study and reported taping their mouth for a median 26 of 28 nights. Although 36 participants said mouth taping was very or fairly acceptable there were no differences between treatments for morning peak expiratory flow (mean difference -1l/min (95%CI, -9 to 7)) or symptoms scores (mean difference -0.12 (95%CI, -0.30 to 0.06)) nor for any secondary measures. CONCLUSIONS: Taping the mouth at night had no effect on asthma control in patients with symptomatic asthma.

Systemic and bronchodilator effects of inhaled rac-formoterol in subjects with chronic obstructive pulmonary disease: a dose-response study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The long-acting inhaled beta(2)-agonist formoterol has systemic effects when taken in high doses. It can be used as relief medication in asthma and there is interest in this approach in chronic obstructive pulmonary disease (COPD). Relief medication can involve high doses, and in subjects with COPD who have limited ability to bronchodilate the adverse effects can outweigh the benefits. There are concerns with the overall safety of high-dose beta(2)-agonists in subjects with COPD, and this study looks at the balance of beneficial and adverse effects of a range of doses of inhaled formoterol. WHAT THIS STUDY ADDS: Among subjects with COPD, high-dose inhaled formoterol produced a dose-related increase in forced expiratory volume in 1 s without a corresponding reduction in dyspnoea or increase in walk distance. Systemic effects were modest, however, and high doses did not appear to reduce patient satisfaction. Although further safety data are needed, inhaled formoterol may have a role as relief medication in COPD. AIMS Rac-formoterol is effective as maintenance treatment for both asthma and chronic obstructive pulmonary disease (COPD) and is now used as relief therapy in asthma. Using rac-formoterol for relief and maintenance treatment could involve inhalation of high doses, and whether this is of benefit in COPD is uncertain. Our aim was to determine whether higher doses of inhaled rac-formoterol produce systemic adverse effects that outweigh the limited bronchodilator benefit seen in subjects with COPD. METHODS: We examined airway and systemic effects of 6, 12, 24 and 48 microg rac-formoterol and placebo on separate days in 20 subjects with symptomatic COPD [forced expiratory volume in 1 s (FEV(1)) 47% predicted]. FEV(1), oxygen saturation, dyspnoea, 6-min walk distance, patient satisfaction and systemic effects were measured and treatment was assessed against placebo and for dose-response effects. RESULTS: FEV(1)[area under the time-response curve (AUC)] and satisfaction scores increased with all formoterol doses compared with placebo, as did AUC tremor with the 24- and 48-microg doses and AUC heart rate with the 48-microg dose. A dose-response relationship was seen with FEV(1) and tremor, but not with satisfaction scores. There was no difference between placebo and rac-formoterol for other variables. CONCLUSIONS: Our results show that in patients with COPD rac-formoterol improves FEV(1) and patient satisfaction without a corresponding reduction in dyspnoea. Since the systemic effects from a relatively high dose were minimal, its use as relief medication in COPD merits further evaluation.

Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler containing budesonide and formoterol help?

BACKGROUND: Poor adherence with inhaled corticosteroids is an important problem in asthma management. Previous approaches to improving adherence have had limited success. AIM: To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids. DESIGN OF STUDY: Randomised, parallel group, open-label trial. SETTING: Forty-four general practices in Nottinghamshire. METHOD: Participants who used less than 70% of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were randomised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required (control group), or budesonide/formoterol 200/6 microg one puff once daily and as required (active group) for 6 months. The primary outcome was inhaled corticosteroid dose. RESULTS: Seventy-one participants (35 control, 36 active group) were randomised. Adherence with budesonide in the control group was approximately 60% of the prescribed dose. Participants in the active group used approximately 80% more budesonide than participants in the control group (448 versus 252 microg/day, mean difference 196 mug, 95% confidence interval 113 to 279; P<0.001) and were less likely to withdraw from the study (3 versus 13; P<0.01). No safety issues were identified. CONCLUSION: Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken, suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids.

Plasma concentrations of fluticasone propionate and budesonide following inhalation: effect of induced bronchoconstriction.

AIMS: To determine whether and to what extent bronchoconstriction affects plasma concentrations of fluticasone and budesonide following inhalation. METHODS: Twenty people with mild asthma inhaled 1000 microg fluticasone (Accuhaler) plus 800 microg budesonide (Turbohaler) on two visits. On one occasion, prior to drug inhalation, FEV(1) was decreased by at least 25% using inhaled methacholine. Plasma drug concentrations were measured for each drug over 5 h and area under the plasma concentration-time curve (AUC(0,5 h)) compared between visits. RESULTS: The mean difference in FEV(1) prior to drug inhalation on the 2 days was 33%. AUC(0,5 h) values for fluticasone and budesonide were lower by a median of 60% (IQR 36-75) and 29% (IQR 2-44), respectively, when administered following bronchoconstriction; the reduction was greater for fluticasone than for budesonide, P = 0.007. CONCLUSIONS: The lower plasma concentrations of fluticasone and, to a lesser extent, budesonide seen when the drugs were inhaled following induced bronchoconstriction, is likely to reflect variations that will occur with fluctuations in airway caliber in asthma.

Current issues with beta2-adrenoceptor agonists: historical background.

The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900 following a vogue for studying organotherapy at the end of the 19th century. The adrenal hormone adrenaline was found to have sympathomimetic properties and was isolated and synthesized in 1901. The first nonselective beta-agonist, isoproterenol, was isolated in 1940, followed by the development of selective beta2-agonists in the 1960s and the introduction of the long-acting beta2-agonists in the 1990s. The introduction of beta2-selectivity reduced adverse effects, as did developments in inhaler technology that allowed subjects to inhale much smaller doses of drug selectively to the airways. The beta2-agonists are some of the more important drugs to have been developed in the 20th century. Excessive doses can cause problems, and attempts to maximize the benefit from beta2-agonists and to reduce adverse effects has led to considerable epidemiological, clinical, and mechanistic research over the last 50 yr.

Use of inhaled corticosteroids and the risk of fracture.

BACKGROUND: Previous studies have found an association between the use of inhaled corticosteroids and fracture, but the extent to which this association is due to inhaled corticosteroids or to related factors, such as the severity of airflow obstruction, is disputed. We report a new approach in which we combine data on people with airflow obstruction from a large Medical Research Council study of the assessment and management of older people in the community with longitudinal data from their computerized general practice records. METHODS: Our cohort includes 1,671 study participants with a diagnosis of asthma or COPD (mean age, 80.6 years). We determined the dose-response relationship between inhaled corticosteroid exposure and time to first fracture using Cox regression, allowing for a wide range of potential confounding factors. RESULTS: During a mean follow-up period of 9.4 years, 982 patients (59%) received a prescription for an inhaled corticosteroid and 187 patients had a fracture. After adjusting for the effects of age and gender, we found a dose-related increase in fracture risk with exposure to inhaled corticosteroids (rate ratio for mean daily dose > 601 mug, 2.53; 95% confidence interval [CI], 1.65 to 3.89; overall trend p < 0.0001). The results were similar after adjusting for oral corticosteroid exposure, airflow obstruction diagnosis, historical fracture, and bronchodilator use (rate ratio, 4.21; 95% CI, 2.19 to 8.13), and also in the subset of people with no exposure to oral corticosteroids (rate ratio, 4.54; 95% CI, 1.23 to 16.74). CONCLUSIONS: Our findings provide further evidence that inhaled corticosteroid use is an independent risk factor for fracture.

Plasma concentrations of inhaled corticosteroids in relation to airflow obstruction in asthma.

AIMS: To compare the pharmacokinetic profiles of beclometasone, budesonide, fluticasone and mometasone following inhalation in patients with asthma, and explore the relationship between lung function and plasma drug concentrations. METHODS: Thirty subjects with asthma and a forced expiratory volume in 1 s (FEV(1)) ranging from 36 to 138% predicted, inhaled 800 microg beclometasone, budesonide and mometasone and 1000 microg fluticasone in random order. Plasma drug concentrations were measured over 8 h and the relationship between the area under the plasma concentration-time curve (AUC(0-8)) and lung function was modelled using linear regression. Estimated AUC(0-8) values at 50 and 100% predicted FEV(1) were compared for each drug. RESULTS: Pharmacokinetic profiles differed markedly between the drugs. Correlation coefficients for the relation between FEV(1)% predicted and AUC(0-8) values for beclometasone, budesonide, fluticasone and mometasone were 0.37 (P = 0.05), 0.33 (P = 0.08), 0.25 (P = 0.2) and 0.52 (P = 0.004), respectively, and estimated AUC(0-8) values were 1.3 [95% confidence interval (CI) 1.0, 1.8], 1.3 (95% CI 1.0, 1.8), 1.4 (95% CI 0.9, 2.2) and 2.2 (95% CI 1.3, 3.5) times higher for the four drugs, respectively, at 100 compared with 50% predicted FEV(1.) CONCLUSION: The higher plasma concentrations of inhaled corticosteroids in patients with a higher FEV(1)% predicted suggests that, for any given dose, these patients will be at greater risk of developing adverse systemic effects with long-term use.

Effects of rac-albuterol on arterial blood gases in patients with stable hypercapnic chronic obstructive pulmonary disease.

AIMS: Many patients with chronic obstructive pulmonary disease (COPD) are treated with high dose beta(2)-adrenoceptor agonists, which can increase ventilation/perfusion mismatching, and tremor and cardiac output, thereby increasing oxygen uptake and carbon dioxide output (VCO(2)). Patients with severe COPD and hypercapnia may be unable to increase ventilation in response to increased VCO(2), in which case arterial carbon dioxide tension (P(a)CO(2)) may rise. Our aim was to determine whether high dose nebulized rac-albuterol could increase P(a)CO(2) in patients with COPD, limited bronchodilator reversibilty and hypercapnia. METHODS: We compared 10 mg and 400 microg rac-albuterol, given in two doses 1 h apart on nonconsecutive days, in a double-blind randomized crossover study in 14 patients with severe COPD. P(a)CO(2), arterial oxygen tension (P(a)O(2)) and heart rate were measured over 120 min and change from baseline was plotted against time to obtain an area under the curve. RESULTS: Mean P(a)CO(2) fell slightly over 120 min, with no difference between treatments (0.03 kPa h(-1) (95% confidence interval 0.02, 0.04)) and only three subjects had an increase in P(a)CO(2) after high dose rac-albuterol. High dose rac-albuterol caused a greater fall in P(a)O(2)[0.1 kPa h(-1) (95% confidence interval 0, 0.2)] and increase in heart rate than the low dose, although the differences were small. CONCLUSIONS: Under stable conditions most subjects with severe COPD and hypercapnia will have a fall in P(a)CO(2) and P(a)O(2) following 10 mg rac-albuterol, suggesting that they maintain capacity to respond to any increase in VCO(2) and prevent a rise in P(a)CO(2).

Benefit versus risk for oral, inhaled, and nasal glucocorticosteroids.

Many factors affect the benefit-to-risk analysis of the use of the glucocorticosteroids in the treatment of allergic inflammation. For most patients the benefit-to-risk ratio favors topical over oral administration, but in severe disease oral administration may be required. It is clear from pharmacokinetic and pharmacodynamic studies that inhaled glucocorticosteroids in particular are absorbed into the systemic circulation and that they can have clinical adverse effects when given in high doses. Therefore, with inhaled and nasal glucocorticosteroids, the dose that will achieve the optimal benefit/risk ratio is the lowest dose that controls symptoms and prevents exacerbations requiring treatment with oral glucocorticosteroids. This optimal dose needs to be determined on an individual basis and is likely to vary as disease severity changes over time.

Use of upper limb exercise to assess breathlessness in patients with cancer: tolerability, repeatability, and sensitivity.

We report the development of an arm exercise test to assess breathlessness in patients with lung cancer who are breathless at low levels of exertion. Exercise consisted of raising the arm over 40 cm, either the dominant arm only (n=10) or both arms alternating at minute intervals (n=12). Subjects breathed through a mouthpiece, and ventilation (VE) and oxygen uptake (VO(2)) were measured. Following familiarization, three tests were performed over one week to explore repeatability, and sensitivity was assessed in a fourth test. Arm exercise was generally well tolerated and increased breathlessness, VE, and VO(2). The commonest factor limiting exercise was arm fatigue, although four patients in the two-arm test also reported breathlessness. Repeatability for breathlessness score and VE was best in the two-arm test. The added resistance used to assess sensitivity could not be detected. The two-arm test offers a potential means of assessing the effects of an intervention on breathlessness and E in patients for whom a cycle or treadmill exercise test is unsuitable.

A benefit-risk assessment of inhaled long-acting beta2-agonists in the management of obstructive pulmonary disease.

The two inhaled long-acting beta2-adrenoceptor agonists, salmeterol and formoterol, have been studied extensively since their introduction in the early 1990s. In this review we consider the evidence for their efficacy and safety in adults with asthma and chronic obstructive pulmonary disease (COPD), by reviewing long-term prospective studies in which these drugs have been compared with placebo or an alternative bronchodilator. We have also assessed safety, including data from postmarketing surveillance studies and case-control studies using large databases. In patients with asthma, salmeterol and formoterol increase lung function, reduce asthmatic symptoms and improve quality of life when compared with placebo. Both drugs protect against exercise-induced asthma, although some tolerance develops with regular use. Tolerance to the bronchodilator effects of formoterol has also been seen, although this is small and most of the beneficial effects are maintained long-term. Both drugs have been shown to reduce asthma exacerbations but only in studies in which most patients were taking an inhaled corticosteroid. Adding a long-acting beta2-agonist provided better control than increasing the dose of inhaled corticosteroid in several studies. Long-acting beta2-agonists also provide better asthma control than use of regular short-acting beta2-agonists and theophylline. Their relative efficacy compared with leukotriene antagonists is uncertain as yet. Formoterol appears to be at least as safe and effective as a short-acting beta2-agonist when used on an 'as required' basis. In patients with COPD, both salmeterol and formoterol offer improved lung function and reduced COPD symptoms compared with placebo, and quality of life has been improved in some studies. Some tolerance to the bronchodilating effect of salmeterol was seen in one study. Most studies have not found a significant reduction in exacerbations in COPD. Both drugs have provided greater benefit than ipratropium bromide or theophylline; there are limited data on tiotropium bromide. The long-acting beta2-agonists cause predictable adverse effects including headache, tremor, palpitations, muscle cramps and a fall in serum potassium concentration. Salmeterol can also cause paradoxical bronchospasm. There is some evidence that serious adverse events including dysrhythmias and life-threatening asthma episodes can occur; however, the incidence of such events is very low but may be increased in patients not taking an inhaled corticosteroid. Salmeterol 50 microg twice daily and formoterol 12 microg twice daily are effective and safe in treating patients with asthma and COPD. Higher doses cause more adverse effects, although serious adverse events are rare.