Theophylline in the management of airflow obstruction. 2. Difficult drugs to use,few clinical indications.

The narrow therapeutic index, potential toxicity, and need to monitor plasma concentrations make theophyllines difficult to use. Other drugs provide comparable or better bronchodilator and prophylactic efficacy. In asthma theophyllines should be considered for chronic stable asthma when treatment with optimal doses of inhaled steroids and bronchodilators fails to provide adequate control; for nocturnal asthma; and for prophylaxis and relief of symptoms in children and adults when inhaled treatment cannot be given. In general, theophyllines cannot be recommended for chronic airflow obstruction. A trial of theophylline is reasonable in individual patients whose symptoms remain troublesome despite a trial of steroids and optimal doses of inhaled bronchodilators.     

Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.

OBJECTIVE--To compare safety of salmeterol and salbutamol in treating asthma. DESIGN--Double blind, randomised clinical trial in parallel groups over 16 weeks. SETTING--General practices throughout the United Kingdom. SUBJECTS--25,180 patients with asthma considered to require regular treatment with bronchodilators who were recruited by their general practitioner (n = 3516). INTERVENTIONS--Salmeterol (Serevent) (50 micrograms twice daily) or salbutamol (200 micrograms four times a day) randomised in the ratio of two patients taking salmeterol to one taking salbutamol. All other drugs including prophylaxis against asthma were continued throughout the study. MAIN OUTCOME MEASURES--All serious events and reasons for withdrawals (medical and non-medical) whether or not they were considered to be related to the drugs. RESULTS--Fewer medical withdrawals due to asthma occurred in patients taking salmeterol than in those taking salbutamol (2.91% v 3.79%; chi 2 = 13.6, p = 0.0002). Mortality and admissions to hospital were as expected. There was a small but non-significant excess mortality in the group taking salmeterol and a significant excess of asthma events including deaths in patients with severe asthma on entry. Use of more than two canisters of bronchodilator a month was particularly associated with the occurrence of an adverse asthma event. CONCLUSIONS--Treatment over 16 weeks with either salmeterol or salbutamol was not associated with an incidence of deaths related to asthma in excess of that predicted. Overall control of asthma was better in patients allocated to salmeterol. Serious adverse events occurred in patients most at risk on entry and were probably due to the disease rather than treatment.     

Short course of steroids in home treatment of children with acute asthma.

A double blind, randomised, placebo controlled study of the treatment of children with acute asthma at home showed that a three day course of prednisolone hastened improvement of both asthmatic symptoms and peak expiratory flow rates. Thus all asthmatic children who present with an acute attack should be considered for treatment with corticosteroids in addition to bronchodilators not only to prevent possible deterioration but also to speed recovery.     

Maternal asthma,asthma medication use,and the risk of congenital heart defects

BACKGROUND: Asthma is a common problem that complicates pregnancy. Several drugs are considered acceptable for use during pregnancy, although none have been classified as safe. Few studies have assessed the health impact of maternal asthma/medication use on the fetus. METHODS: A population‐based case‐control study was conducted in New York State to determine if cardiac congenital malformations in offspring were associated with maternal use of asthma medication and/or maternal asthma. Cases were cardiac anomalies in the New York State Congenital Malformations Registry. Controls were live births without any major birth defects randomly selected from birth certificates and frequency matched by year of birth. Data were collected through a 30 min telephone interview. Exposure was maternal asthma/medication use, maternal asthma/no medication use, no asthma/medication use, and no asthma/no medication use (reference). RESULTS: A total of 502 (59.4%) cases and 1,066 (53.8%) controls participated. A positive association was seen between any heart defect and women with asthma who used medication (OR 2.38; 95% CI: 1.18, 4.82). No significant associations were observed between heart defects and either women with asthma who did not use medication or women without asthma who used asthma medications. When considering types of medication used, offspring of women with asthma who used bronchodilators had an increased risk of any heart defect (OR 2.20; 95%CI: 1.05, 4.61). CONCLUSIONS: These results suggest that both maternal asthma status (controlled vs. uncontrolled; severe vs. mild) and asthma medication use, particularly bronchodilators, may play a role in cardiac malformations in offspring. Birth Defects Research (Part A), 2009. © 2008 Wiley‐Liss, Inc.     

Changes of immunomodulatory cytokines associated with omalizumab therapy for severe persistent asthma

Omalizumab is an anti-IgE monoclonal antibody that was proven effective for the treatment of severe asthma. IgE plays a central role in allergic asthma, and an anti-allergic effect of omalizumab has been confirmed in terms of its impact on Th2 cytokines. The objective of the present study is to determine the influence of omalizumab on clinical parameters and circulating immuoregulatory cytokines. Patients with severe allergic asthma were enrolled and given four months of omalizumab therapy. Changes of symptoms and other parameters were assessed, including the asthma control test (ACT) score, morning peak expiratory flow (PEF), peripheral eosinophil count, total serum IgE, and pulmonary function tests. The use of corticosteroids and short-acting bronchodilators, as well as the number of unscheduled hospital visits, were monitored. Circulating levels of cytokines were analyzed with a multiplex cytokine immunoassay in patients with or without omalizumab therapy. Asthma symptoms (evaluated by the ACT score and morning PEF) improved with omalizumab treatment, while total IgE was elevated. Use of corticosteroids and short-acting bronchodilators and the number of unscheduled hospital visits for exacerbation of asthma were all reduced by omalizumab treatment. The level of macrophage inflammatory protein 1-δ (MIP1-δ) was significantly reduced after omalizumab therapy and was high in patients without omalizumab. IL-16 also tended to decrease with omalizumab therapy. Both MIP1-δ and IL-16 decreased as asthma improved over the 4-month period of omalizumab therapy. These findings suggest that omalizumab may act via IgE-mediated immunoregulation of MIP1-δ and IL-16.     

Asthma mortality in Birmingham 1975-7: 53 deaths.

Out of 83 patients studied 72 were certified as dying from asthma, and 11 aged under 45 as dying from chronic bronchitis and pneumonia. Fifty-three deaths were thought to be due to asthma. There were avoidable factors associated with several of these deaths from asthma. Recent discharge from hospital (16%), non-availability of aerosol bronchodilators (45%), underuse of corticosteroids (66%), and lack of objective measurements of airflow obstruction (100%) were found in deaths outside hospital. Inadequate initial assessment including baseline spirometry and blood gases (50%), significant underusage of corticosteroids (93%) and intravenous and nebulised bronchodilators (100%), and failure to monitor treatment objectively (100%) were found in deaths in hospital. "False-positive" and "false-negative" certifications of asthma were studied, and the findings suggest that these may lead to appreciable inaccuracy in the reporting of deaths from asthma.     

How to achieve better outcome in treatment of asthma in general practice.

The symptoms of many asthmatic patients are poorly controlled, and there are several reasons why this may be so. Doctors fail to find out about symptoms that asthmatic patients are experiencing. Doctors wrongly assume that regular use of bronchodilators in small doses is satisfactory treatment for asthma and that taking high doses of bronchodilator in an asthma attack may be dangerous. Doctors think that inhaled steroids may be dangerous and are reluctant to use them in effective doses. Doctors do not check that patients can use their inhalers properly and do not make enough use of large volume spacers, the best available method for giving inhaled asthma treatment. Doctors undermine patients'' confidence in advice on treatment by failing to ensure that consistent advice is given and often make the management of asthma more troublesome for the patient than the symptoms of asthma.     

Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma

Asthma is an increasingly common disorder responsible for considerable morbidity and mortality. Although obesity is a risk factor for asthma and weight loss can improve symptoms, many patients do not adhere to low calorie diets and the impact of dietary restriction on the disease process is unknown. A study was designed to determine if overweight asthma patients would adhere to an alternate day calorie restriction (ADCR) dietary regimen, and to establish the effects of the diet on their symptoms, pulmonary function and markers of oxidative stress, and inflammation. Ten subjects with BMI>30 were maintained for 8 weeks on a dietary regimen in which they ate ad libitum every other day, while consuming less than 20% of their normal calorie intake on the intervening days. At baseline, and at designated time points during the 8-week study, asthma control, symptoms, and Quality of Life questionnaires (ACQ, ASUI, mini-AQLQ) were assessed and blood was collected for analyses of markers of general health, oxidative stress, and inflammation. Peak expiratory flow (PEF) was measured daily on awakening. Pre- and postbronchodilator spirometry was obtained at baseline and 8 weeks. Nine of the subjects adhered to the diet and lost an average of 8% of their initial weight during the study. Their asthma-related symptoms, control, and QOL improved significantly, and PEF increased significantly, within 2 weeks of diet initiation; these changes persisted for the duration of the study. Spirometry was unaffected by ADCR. Levels of serum beta-hydroxybutyrate were increased and levels of leptin were decreased on CR days, indicating a shift in energy metabolism toward utilization of fatty acids and confirming compliance with the diet. The improved clinical findings were associated with decreased levels of serum cholesterol and triglycerides, striking reductions in markers of oxidative stress (8-isoprostane, nitrotyrosine, protein carbonyls, and 4-hydroxynonenal adducts), and increased levels of the antioxidant uric acid. Indicators of inflammation, including serum tumor necrosis factor-alpha and brain-derived neurotrophic factor, were also significantly decreased by ADCR. Compliance with the ADCR diet was high, symptoms and pulmonary function improved, and oxidative stress and inflammation declined in response to the dietary intervention. These findings demonstrate rapid and sustained beneficial effects of ADCR on the underlying disease process in subjects with asthma, suggesting a novel approach for therapeutic intervention in this disorder.     

Mechanism for the emetic side effect of xanthine bronchodilators.

The usefulness of xanthine bronchodilators in the treatment of asthma is often limited by the side effects of nausea and vomiting. We investigated the mechanism of emesis induced by xanthines, by examining the roles of phosphodiesterase (PDE) inhibition and adenosine antagonism. Theophylline, enprofylline, 8-phenyltheophylline and isobutylmethylxanthine (IBMX), as well as vehicle, were given to ferrets at doses ranging from 0.1 to 150 mg/kg i.p. The potencies of these compounds in producing emetic responses were ranked IBMX greater than enprofylline greater than theophylline greater than 8-phenyltheophylline. These results correlate well with the relative potencies of the compounds as nonselective PDE inhibitors but do not correlate with their relative potencies as adenosine A1 or A2 receptor antagonists. The emetic responses also correlate well with the previously reported potencies of these xanthines as bronchodilators in guinea pigs. We conclude that the emetic side effect of xanthine bronchodilators results from the inhibition of one or more forms of PDE rather than from adenosine antagonism.     

Hypnosis for Asthma—a Controlled Trial: A Report to the Research Committee of the British Tuberculosis Association*

An investigation of hypnosis in asthma was made among patients aged 10 to 60 years with paroxysmal attacks of wheezing or tight chest capable of relief by bronchodilators. One group of patients was given hypnosis monthly and used autohypnosis daily for one year. Comparisons were made with a control group prescribed a specially devised set of breathing exercises aimed at progressive relaxation. Treatment was randomly allocated and patients were treated by physicians in nine centres. Results were assessed by daily diary recordings of wheezing and the use of bronchodilators, and by monthly recordings of F.E.V.₁ and vital capacity. At the end of the year independent clinical assessments were made by physicians unaware of the patients'' treatment.There were 252 patients (127 hypnosis and 125 controls) accepted for analysis, but a number of them did not continue the prescribed treatment for the whole year: 28 hypnosis and 22 control patients failed to co-operate, left the district, or had family problems; one hypnosis and one control patient died. Seven hypnosis and 17 control patients were withdrawn as treatment failures, the difference between the two groups being statistically significant.As judged by analyses based on the daily “score” of wheezing recorded in patients'' diaries, by the number of times bronchodilators were used, and by independent clinical assessors, both treatment groups showed some improvement Among men the assessments of wheezing score and use of bronchodilators showed similar improvement in the two treatment groups; among women, however, those treated by hypnosis showed improvement similar to that observed in the men, but those given breathing exercises made much less progress, the difference between the two treatment groups reaching statistical significance. Changes in F.E.V.₁ and V.C. between the control and hypnosis groups were closely similar.Independent clinical assessors considered the asthma to be “much better” in 59% of the hypnosis group and in 43% of the control group, the difference being significant There was little difference between the sexes. Physicians with previous experience of hypnosis obtained significantly better results than did those without such experience.     

Circumstances of death from asthma.

Mortality from asthma in England and Wales has remained unchanged for at least 20 years, even in the age group 15-44. Yet in those 20 years "modern" drugs have been introduced for the treatment of asthma, such as beta 2 agonist bronchodilators and corticosteroids. Why do patients still die? Detailed review of the circumstances of 90 deaths from asthma showed that a few were inevitable but that in the remainder four main sets of circumstances in the fatal attack contributed to the death. These were, firstly, the patient''s failure to recognise the severity of the asthma; secondly, very rapid progress in the severity of the attack; thirdly, misjudgment in the management of the attack; and, fourthly, delay from many causes. Patients admitted to hospital with severe acute asthma usually survive. Those at risk of a life threatening attack should be identified and taught to monitor the severity and progress of their asthma objectively. Their direct admission to hospital should be facilitated.     

Current prospective of aldose reductase inhibition in the therapy of allergic airway inflammation in asthma

The prevalence of asthma and costs of its care have been continuously increasing, but novel therapeutic options to treat this inflammatory disease have not been brought to the US market. Current therapies such as inhaled steroids, long-acting beta-agonist bronchodilators, antihistamines and immunomodulators may control the symptoms of allergic asthma but fail to modify the underlying disease. Excessive use of steroids and other immunosuppresents alter the patient's quality of life, produce undesirable toxicities, and increase the risk of other pathologies such as diabetes. Hence novel therapeutic options to manage asthma are desirable. In the present review, we have discussed the role of the polyol pathway enzyme aldose reductase (AR) in the amplification of allergic airway inflammation. Recent studies have indicated that AR inhibition prevents the NF-κB-dependent generation of pro-inflammatory cytokines and chemokines in mouse models of allergic airway inflammation indicating the potential use of AR inhibition as a novel tool to control allergic responses. Since orally available AR inhibitors have already undergone phase III clinical trials for diabetic neuropathy and appear to have a manageable side effects profile, they could be readily developed as potential new drugs for the treatment of asthma and related complications.     

Effectiveness of routine self monitoring of peak flow in patients with asthma. Grampian Asthma Study of Integrated Care (GRASSIC).

OBJECTIVE--To evaluate the effectiveness of routine self monitoring of peak flow for asthma outpatients. DESIGN--Pragmatic randomised trial. SETTING--Hospital outpatient clinics and general practices in north east Scotland. MAIN OUTCOME MEASURES--Use of bronchodilators and inhaled and oral steroids; number of general practice consultations and hospital admissions for asthma; sleep disturbance and other restrictions on normal activity; psychological aspects of health including perceived control of asthma. RESULTS--After one year there were no significant differences between patients randomised between self monitoring of peak flow and conventional monitoring. However, those given a peak flow meter recorded an increase in general practice consultations that was nearly significant. Among patients whose asthma was judged on entry to be more severe, those allocated to self monitoring used more than twice as many oral steroids (2.2; 95% confidence interval 1.1 to 4.6). Patients who already possessed a peak flow meter at the start of the study recorded higher morbidity over the course of the year than those eligible for randomisation. CONCLUSION--Prescribing peak flow meters and giving self management guidelines to all asthma patients is unlikely to improve mortality or morbidity. Patients whose asthma is severe may benefit from such an intervention.     

Remote Monitoring of Inhaled Bronchodilator Use and Weekly Feedback about Asthma Management: An Open-Group,Short-Term Pilot Study of the Impact on Asthma Control

Objective

Adequate symptom control is a problem for many people with asthma. We asked whether weekly email reports on monitored use of inhaled, short-acting bronchodilators might improve scores on composite asthma-control measures.

Methods

Through an investigational electronic medication sensor attached to each participant''s inhaler, we monitored 4 months'' use of inhaled, short-acting bronchodilators. Participants completed surveys, including the Asthma Control Test^TM (ACT), to assess asthma control at entry and monthly thereafter. After the first month, participants received weekly email reports for 3 months. The reports summarized inhaled bronchodilator use during the preceding week and provided suggestions derived from National Asthma Education and Prevention Program (NAEPP) guidelines. Paired t-tests and random-effects mixed models were implemented to assess changes in primary asthma endpoints.

Results

Thirty individuals participated in the 4-month study; 29 provided complete asthma control information. Mean age was 36.8 years (range: 19–74 years); 52% of respondents were female. Mean ACT scores were 17.6 (Standard Deviation [SD]  = 3.35) at entry and 18.4 (SD = 3.60) at completion of the first month. No significant difference appeared between ACT values at entry and completion of the first month (p = 0.66); however, after participants began receiving email reports and online information about their inhaler use, mean ACT scores increased 1.40 points (95% CI: 0.61, 2.18) for each subsequent study month. Significant decreases occurred in 2-week histories of daytime symptoms (β = −1.35, 95% CI: −2.65, −0.04) and nighttime symptoms (β = −0.84, 95% CI: −1.25, −0.44); no significant change in activity limitation (β = −0.21, 95% CI: −0.69, 0.26) was observed. Participants reported increased awareness and understanding of asthma patterns, level of control, bronchodilator use (timing, location) and triggers, and improved preventive practices.

Conclusions

Weekly email reports and access to online charts summarizing remote monitoring of inhaled bronchodilator frequency and location were associated with improved asthma control and a decline in day-to-day asthma symptoms.     

High-dose corticosteroids in severe acute asthma.

Twenty-six patients admitted to hospital for treatment of severe exacerbations of asthma unresponsive to bronchodilators were assigned to high-, medium-, or low-dose corticosteroid treatment regimens. The rates of recovery were assessed by changes in pulse rate, peak expiratory flow rate, and spirometric measurements and were not related to the dose of corticosteroids given. Very high systemic doses of corticosteroids do not offer significant advantages in treating severe exacerbations of asthma.     

Asthma: where beyond steroids?

The prevalence of asthma is increasing dramatically despite major changes in monitoring and treatment of this disease. Currently available bronchodilators and anti-inflammatory drugs are effective in most patients, although these can have side effects and are mainly symptomatic. Many drugs are now in development for the treatment of asthma. Most of these new therapies are aimed at inhibition of the inflammatory components, with better safety profiles than steroids.     

Integrated care for asthma: a clinical,social, and economic evaluation. Grampian Asthma Study of Integrated Care (GRASSIC)

OBJECTIVES--To evaluate integrated care for asthma in clinical, social, and economic terms. DESIGN--Pragmatic randomised trial. SETTING--Hospital outpatient clinics and general practices throughout the north east of Scotland. PATIENTS--712 adults attending hospital outpatient clinics with a diagnosis of asthma confirmed by a chest physician and pulmonary function reversibility of at least 20%. MAIN OUTCOME MEASURES--Use of bronchodilators and inhaled and oral steroids; number of general practice consultations and hospital admissions for asthma; sleep disturbance and other restrictions on normal activity; psychological aspects of health including perceived asthma control; patient satisfaction; and financial costs. RESULTS--After one year there were no significant overall differences between those patients receiving integrated asthma care and those receiving conventional outpatient care for any clinical or psychosocial outcome. For pulmonary function, forced expiratory volume was 76% of predicted for integrated care patients and 75% for conventional outpatients (95% confidence interval for difference -3.6% to 5.0%). Patients who had experienced integrated care were more likely to select it as their preferred course of future management (75% (251/333) v 62% (207/333) (6% to 20%)); they saved 39.52 pounds a year. This was largely because patients in conventional outpatient care consulted their general practitioner as many times as those in integrated care, who were not also visiting hospital. CONCLUSION--Integrated care for moderately severe asthma patients is clinically as effective as conventional outpatient care, cost effective, and an attractive management option for patients, general practitioners, and hospital consultants.     

Treatment of Asthma by a Controlled-Release Theophylline Tablet Formulation: A Review of the North American Experience with Nocturnal Dosing

As many as 80 percent of asthmatics experience nighttime or early-morning episodes, which are difficult to treat and potentially fatal. The greater-than-normal amplitude of circadian airflow variation in many asthmatics contributes heavily to the genesis of the early ‘morning dip’. Beta-agonists and corticosteroids are of limited usefulness in nocturnal asthma, and slow-release theophylline drugs, while potentially effective, vary in 24-hr blood profile and hence their influence on nocturnal episodes. Traditional 12-hr ‘symmetric’ theophylline regimens, instead of meeting increased nocturnal demands, may actually produce lower night- than daytime blood levels. On the other hand, appropriately timed administration of a once-daily theophylline drug might provide maximum blood levels when needed and help stabilize 24-hr airflow.

Accumulated data, summarized in this review, demonstrate the chronotherapeutic potential of single-daily evening doses of a controlled-release theophylline preparation (Uniphyl® 400-mg tablets*) in nocturnal and early morning asthma. Nighttime blood concentrations with this regimen were higher than were those with Theo-Dur® tablets, ? B.I.D., in the same total daily doses, or with once-daily morning Uniphyl administration. In fed and fasted subjects, evening administration of Uniphyl 400-mg tablets was well tolerated and did not lead to ‘dose dumping.’ Clinically, this treatment demonstrated advantages over B.I.D. theophylline, over single-daily morning regimens, and over prior theophylline therapy. Advantages of the evening regimen included better early-morning airflow (without significant decline later in the day), more effective symptom control, better patient acceptance, fewer night awakenings, and the obvious convenience of once-daily dosing. In addition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with traditional 12 hr dosing.

Uniphyl 400-mg tablets may be administered once daily to provide maximum blood levels at the time of peak bronchoconstriction, whether at night or during the day.     

Treatment of asthma by a controlled-release theophylline tablet formulation: a review of the North American experience with nocturnal dosing

As many as 80 percent of asthmatics experience nighttime or early-morning episodes, which are difficult to treat and potentially fatal. The greater-than-normal amplitude of circadian airflow variation in many asthmatics contributes heavily to the genesis of the early 'morning dip'. Beta-agonists and corticosteroids are of limited usefulness in nocturnal asthma, and slow-release theophylline drugs, while potentially effective, vary in 24-hr blood profile and hence their influence on nocturnal episodes. Traditional 12-hr 'symmetric' theophylline regimens, instead of meeting increased nocturnal demands, may actually produce lower night- than daytime blood levels. On the other hand, appropriately timed administration of a once-daily theophylline drug might provide maximum blood levels when needed and help stabilize 24-hr airflow. Accumulated data, summarized in this review, demonstrate the chronotherapeutic potential of single-daily evening doses of a controlled-release theophylline preparation (Uniphyl 400-mg tablets) in nocturnal and early morning asthma. Nighttime blood concentrations with this regimen were higher than were those with Theo-Dur tablets, B.I.D., in the same total daily doses, or with once-daily morning Uniphyl administration. In fed and fasted subjects, evening administration of Uniphyl 400-mg tablets was well tolerated and did not lead to 'dose dumping.' Clinically, this treatment demonstrated advantages over B.I.D. theophylline, over single-daily morning regimens, and over prior theophylline therapy. Advantages of the evening regimen included better early-morning airflow (without significant decline later in the day), more effective symptom control, better patient acceptance, fewer night awakenings, and the obvious convenience of once-daily dosing. In addition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with traditional 12 hr dosing. Uniphyl 400-mg tablets may be administered once daily to provide maximum blood levels at the time of peak bronchoconstriction, whether at night or during the day.