Drug treatment of asthma in the 1990s: achievements and new strategies.

Asthma is an inflammatory condition of the airways. First-line therapy involves the use of inhaled corticosteroids as anti-inflammatory agents to control the underlying process. Bronchodilators are used for symptom relief. Short-acting beta-agonists provide rapid relief of bronchoconstriction, whereas long-acting beta-agonists control the symptoms and reduce the frequency of exacerbations when combined with inhaled corticosteroids. Anticholinergic bronchodilators have a minor role in acute exacerbations and in patients troubled by adverse effects from beta-agonists. Theophylline has a bronchodilator action in asthma, but its role as an anti-inflammatory agent needs to be examined further. Because of their toxicity, corticosteroid-sparing agents have a limited role, being restricted to patients with severe uncontrolled asthma. New selective phosphodiesterase IV inhibitors show both anti-inflammatory and bronchodilator characteristics with fewer adverse effects. Other new approaches to the control of inflammation come from the antileukotriene drugs, which improve pulmonary function in patients with chronic asthma. The antileukotrienes have shown promising results, especially in the treatment of asthma caused by aspirin (acetylsalicylic acid), exercise and cold air. Other new therapies being studied include anti-immunoglobulin E, antitryptase and anti-CD4 agents. These newer possibilities suggest that the range of available treatment options will expand significantly over the next decade.

Inspiratory muscle strength in acute asthma.

STUDY OBJECTIVES: The aim of this study was to measure inspiratory pressure-generating capacity in patients presenting with acute asthma, as it has been suggested that inspiratory muscle fatigue may contribute to breathlessness and acute respiratory failure. DESIGN: Descriptive study. SETTING: Emergency departments of two inner-city hospitals. PATIENTS: Fifty-one patients with acute asthma, and 45 patients without respiratory disease who served as control subjects. MEASUREMENTS AND RESULTS: Maximum inspiratory pressure-generating capacity was measured soon after presentation by the sniff nasal inspiratory pressure (SNIP) method. The mean (SD) SNIP was 110 cm H(2)O (23 cm H(2)O) in men with asthma (mean for control subjects, 126 cm H(2)O [25 cm H(2)O]; p < 0.05) and 80 cm H(2)O [24 cm H(2)O] in women with asthma (mean for control subjects, 105 cm H(2)O (26 cm H(2)O); p < 0.01). In a second study of simultaneous SNIP and intrathoracic pressure measurements in a group of patients with acute asthma (n = 10) and control subjects (n = 11), the effect of airways obstruction on SNIP was assessed. The measurement of sniff esophageal pressure was more negative than SNIP by approximately 16% in asthmatic patients and by 4% in control subjects. Taking account of the likely effect of airways obstruction on SNIP, the reduction in inspiratory pressure-generating capacity that was observed in these patients with moderately severe acute asthma was minor and was consistent with the modest hyperinflation observed. CONCLUSIONS: This study did not find evidence of inspiratory muscle weakness or fatigue in patients with moderately severe acute asthma presenting to the emergency department.

Home nebulized therapy for patients with COPD: patient compliance with treatment and its relation to quality of life.

STUDY OBJECTIVES: To assess compliance with home nebulized therapy in patients with COPD. DESIGN: Patients' home nebulizers were replaced with nebulizers that recorded the date and time of each treatment over a period of 4 weeks. Poor compliance was defined as taking <70% of the prescribed dose (or <60% for those prescribed treatments five or more times daily). SETTING: Patients were seen at the hospital COPD outpatient clinic. The compliance data obtained were recorded while they were at home. PATIENTS: Ninety-three patients aged 44 to 76 years (mean, 64.9 years) were recruited from the hospital nebulizer database. MEASUREMENTS: Patients completed a self-reported quality of life scale, the St. George's Respiratory Questionnaire (SGRQ), both before (SGRQ1) and after (SGRQ2) the 4-week study period to look at whether quality of life was either predictive of or subsequent to level of compliance. RESULTS: Data were obtained from 82 patients. Mean compliance was 57% (range, 0 to 124%). Thirty-six (44%) patients were compliant and 46 (56%) were poorly compliant. There was no difference between the two groups in age or sex distribution. Compliance was negatively correlated with the total score on the SGRQ2 (p=0.03). CONCLUSION: The study shows that levels of compliance with nebulized therapy are low in a large proportion of patients with COPD and that patients with low levels of compliance report greater impairment in their quality of life.

Clinical safety of SonoVue, a new contrast agent for ultrasound imaging, in healthy volunteers and in patients with chronic obstructive pulmonary disease.

RATIONALE AND OBJECTIVES: To evaluate the safety profile of SonoVue, a new echo-contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles, in healthy volunteers and in patients with chronic obstructive pulmonary disease (COPD). METHODS: Safety and tolerability of SonoVue were evaluated in 66 healthy volunteers during two placebo-controlled phase I studies (a single intravenous ascending-dose study in 36 volunteers given SonoVue doses of 0.003 to 0.12 mL/kg and a multiple-dose study in 30 subjects given cumulative doses of 0.15 to 0.6 mL/kg) and in 12 patients with COPD of various degrees of clinical severity, who were given SonoVue at a dosage of 4 mL (corresponding to 0.057 mL/kg in a 70-kg patient). Adverse events were monitored up to 48 to 72 hours after administration. All volunteers underwent extensive safety assessments (monitoring of vital signs, electrocardiogram, blood oxygen saturation, laboratory assessments, and Mini-Mental test) up to 24 to 72 hours after administration. In addition, patients with COPD underwent specific lung function tests, such as forced expiratory volume, forced vital capacity, and forced midexpiratory flow. RESULTS: No serious adverse events occurred throughout the study. All nonserious adverse events were minor, mild, and rapidly self-resolving. No difference in the incidence of adverse events was observed among the various dosages of SonoVue and between SonoVue and placebo. There were no clinically significant changes in any of the safety assessments. No statistically significant differences between SonoVue and placebo were observed in mean forced expiratory volume, forced vital capacity, or forced midexpiratory flow levels. No substantial changes from baseline in blood oxygen saturation were observed for either study agent at any postinjection time point. CONCLUSIONS: SonoVue showed a good safety profile both in healthy subjects and in patients with COPD.

Theophylline. Current thoughts on the risks and benefits of its use in asthma.

Theophylline and its derivatives have been used in the treatment of asthma for over 50 years, but since the advent of more potent bronchodilators their use has become cloaked in controversy. Their continued existence results from their undoubted usefulness in severe acute asthma, nocturnal asthma, childhood asthma and moderate to severe chronic airflow limitation, and because of habitual use by physicians in other situations. The precise mechanism of action of theophylline remains uncertain. The role of phosphodiesterase inhibition and adenosine antagonism has been reviewed and the clinical significance of the anti-inflammatory action of theophylline discussed. Theophylline has unpredictable metabolism when first administered, and continued monitoring of drug concentrations is essential. Commonly encountered adverse effects may occur at therapeutic serum concentrations, frequently necessitating drug withdrawal. The overlapping therapeutic and toxic theophylline serum ranges can lead to life-threatening adverse effects at the upper end of the therapeutic range, especially in the elderly in whom special precaution is required.

An outbreak of multi-drug-resistant tuberculosis in a London teaching hospital.

We describe the epidemiology and control of a hospital outbreak of multi-drug-resistant tuberculosis (MDR-TB). A human immunodeficiency virus (HIV)-negative patient with drug-sensitive tuberculosis developed MDR-TB during a period of unsupervised therapy. She was admitted to an isolation room in a ward with HIV-positive patients, but the room, unbeknown to hospital staff, was at positive-pressure relative to the main ward. Seven HIV-positive contacts developed MDR-TB. The diagnosis in the second patient was delayed, partly because acid-fast bacilli in his sputum were assumed to be Mycobacterium avium-intracellulare. All the available Mycobacterium tuberculosis isolates were indistinguishable by molecular typing. Nearly 1400 staff and patient contacts were offered screening, but the screening programme detected only one of the cases. Despite therapy, the index patient and two of the contacts died. HIV-positive patients are more likely than others to develop tuberculosis after exposure, and the disease may progress more rapidly. In these patients the possibility that acid-fast bacilli may represent M. tuberculosis must always be considered. Patients with tuberculosis (suspected or proven) should not be nursed in the same wards as immunosuppressed patients, and should be isolated. MDR-TB cases must be isolated in negative-pressure rooms. Hospital side-rooms may be positive-pressure as a fire safety measure; infection control teams must be aware of the airflows in all isolation rooms, and must be consulted during the design of hospital buildings. Good communication between infection control teams and clinicians is important, and all medical and nursing staff must be aware of the principles of management of patients with proven or suspected tuberculosis and MDR-TB.

Pharmacokinetics of oral acyclovir (Zovirax) in the eye.

Patients due for cataract extraction received 5 doses of 400 mg acyclovir (Zovirax) orally during the 24 hours prior to surgery. Aqueous humour levels of acyclovir (mean 3.26 microM) were well above the normal ED50 range for herpes simplex virus type 1, and showed a significant correlation with plasma concentrations (mean 8.74 microM). There was also a correlation between the age of the patient and the concentration of acyclovir in the plasma. Oral acyclovir was well tolerated.

Oral acyclovir in the management of dendritic herpetic corneal ulceration.

A controlled trial of oral acyclovir in herpetic dendritic corneal ulcers was carried out on 31 patients. All patients received minimal wiping debridement of the ulcer, following which they were randomly allocated to receive either oral acyclovir or placebo for 7 days. At the end of treatment 67% of dendritic ulcers in patients receiving acyclovir had healed compared with 43% in placebo recipients. The proportion of ulcers healed in the 2 groups at 7 days showed no significant difference (p = 0.18), but the rate of healing was significantly faster in acyclovir group (p = 0.03).

Oral acyclovir (Zovirax) in herpes simplex dendritic corneal ulceration.

Sixty patients with simple dendritic corneal ulceration were randomly assigned to double blind treatment with either acyclovir tablets (400 mg) or acyclovir ophthalmic ointment administered five times daily. There was no significant difference in the proportions of patients healed in either treatment group (88.9% on oral acyclovir and 96.6% on acyclovir ointment). The median healing time was five days in both groups. No systemic or significant local side effects were noted in either treatment group. Trough levels of acyclovir in the tear fluid of those who received the oral preparation were within or above the range of mean in-vitro ID50 levels for herpes simplex virus type 1. We conclude that oral administration of acyclovir (400 mg, five times daily) may be an effective alternative to topical therapy in selected patients.

Randomised double-blind trial of acyclovir (Zovirax) and adenine arabinoside in herpes simplex amoeboid corneal ulceration.

Fifty-one patients were treated in a dual-centre, double-blind comparison of acyclovir and adenine arabinoside in herpetic amoeboid (geographic) corneal ulceration. Twenty-four of the 25 patients receiving acyclovir healed in a mean time of 12.2 days, while 24 of the 26 patients treated with adenine arabinoside healed in a mean time of 11.0 days. There was no statistically significant difference between the two groups in terms of healing. A second analysis, excluding any patients who had received antiviral treatment immediately prior to entry into the study, showed that 18 of the 19 who received acyclovir healed in an average of 11.7 days and 18 of the 19 recipients of adenine arabinoside healed in a mean time of 11.2 days. Again the difference was not statistically significant.

The effect of oral corticosteroids on bronchodilator responses in COPD.

There have been suggestions that corticosteroid treatment might improve bronchodilator responses in chronic obstructive pulmonary disease (COPD). We have studied bronchodilator responses to salbutamol and to oxitropium bromide in 20 patients with stable moderate to severe COPD. Dose responses to the two bronchodilators were tested before and after 3 week courses of placebo and 30 mg prednisolone. Thirteen patients were taking inhaled corticosteroids. There were no significant changes in numbers of responses or maximum bronchodilator effects from either bronchodilator, although there was a trend towards higher maximum levels after 3 weeks of prednisolone. Spirometry measured at home each morning before and after oxitropium bromide showed no difference between prednisolone and placebo periods. This study provides no evidence for a significant effect on bronchodilator responses to beta-agonists or anticholinergic agents from 3 weeks of oral prednisolone in moderately severe COPD.

Bronchodilator responses to salbutamol followed by ipratropium bromide in partially reversible airflow obstruction.

We have performed a retrospective survey on 296 patients, who attended the Respiratory Function Unit at Guy's Hospital to have their bronchodilator responses (BR) tested. The aim of the study was to see the effect of ipratropium bromide (IB) in a group of patients with incomplete reversibility after salbutamol (S). Patients were routinely given salbutamol and ipratropium bromide sequentially by inhalation, and spirometric changes were recorded after each drug. We identified two groups: Group A, 95 patients with FEV1 response greater than or equal to 0.2 l after either drug and FEV1 less than 80% predicted after salbutamol; and, Group B, 49 with change in FEV1 less than 0.02 l, FVC less than 80% predicted after salbutamol and an improvement in FVC greater than or equal to 0.33 l. Seventy-nine of the 95 patients in Group A also had an FVC response. In Group A, age was negatively correlated with response to salbutamol (r = -0.41, P less than 0.0001), and within Group B baseline FVC was negatively correlated with response to ipratropium bromide (r = -0.30, P = 0.03). There were no differences in age, sex, or doses given to each group (median dose: salbutamol, 800 micrograms, ipratropium bromide 120 micrograms). Baseline FEV1 and FVC (% predicted) were significantly higher in FEV1 responders. Mean (SD) FEV1 were 43% (14) in Group A vs. 29% (14) in Group B, while FVC were 62% (16) vs. 47% (13), P less than 0.001. Responses to ipratropium bromide were more frequent in Group B; in Group A 87% improved after salbutamol and 26% after ipratropium bromide, while in Group B 68% responded to salbutamol and 47% to ipratropium bromide (P = 0.03). Most patients responded to salbutamol, but in 33% ipratropium bromide had an additional effect. The FEV1 response to salbutamol declined with age. Isolated volume responders had more severe airflow obstruction, had less responses to salbutamol and were more likely to show a response to ipratropium bromide. These results support a trial of ipratropium bromide in patients with inadequate beta responsiveness, especially in those with severe airflow obstruction.

High-dose nedocromil sodium as an addition to inhaled corticosteroids in the treatment of asthma.

In a double-blind placebo-controlled trial nedocromil sodium in a dose of 8 mg four times daily or matching placebo was added to the treatment of 29 asthmatic patients. All patients were taking inhaled corticosteroids in a dose of up to 1000 micrograms daily. The trial agents were given for 6 weeks after a 2-week run-in period. Twenty-four patients completed the study, three withdrew because of adverse effects, two on placebo. Daytime asthma symptoms were significantly reduced on nedocromil compared to placebo (-0.46 vs. +0.09, P = 0.03). Night-time asthma and morning tightness were not changed significantly. Bronchodilator use in the night and day were lower on nedocromil but the differences were not significant. Morning peak flow rates were higher on nedocromil (+22.2 vs. +0.08, P = 0.06) and physicians opinions of overall effectiveness favoured nedocromil (U = 35.0, P = 0.04). These results confirm that nedocromil sodium may be a useful addition in asthma to low to medium doses of inhaled corticosteroids. The effects of 32 mg nedocromil daily were comparable to previous reports with lower doses.

Maximum achievable bronchodilatation in asthma.

We have examined the effects of combinations of three bronchodilator drugs in 37 patients with poorly reversible asthma. In each case FEV1 was less than 90% predicted before administration of the third drug. Nineteen patients took increasing doses of salbutamol by inhalation followed by 160 micrograms ipratropium bromide and intravenous aminophylline, 5.6 mg kg-1. FEV1 increased by at least 200 ml in 18 patients after salbutamol. Subsequently, ipratropium bromide increased FEV1 by 200 ml in three patients while aminophylline did not produce a further 200 ml rise in any patient in this group. Nine patients were given aminophylline followed by ipratropium bromide and salbutamol and nine took ipratropium bromide then aminophylline and salbutamol. Eleven of the 18 patients in these latter two groups had a 200 ml increase in FEV1 using salbutamol as the third drug. Significant increases in pulse rate were only seen after aminophylline or salbutamol administered as the third drug. These results suggest that maximal bronchodilatation in poorly reversible asthma can usually be achieved by increasing doses of beta agonist up to a therapeutic plateau. A further response, if required, may be achieved in some patients with ipratropium bromide.

Amiodarone pneumonitis: no safe dose.

Pneumonitis is a serious adverse effect of amiodarone therapy, which is related to the average daily dose. A case of pneumonitis is described which developed after exposure to a low dose of amiodarone. This challenges the concept that low dose amiodarone therapy is safe.

Pulmonary echinococcosis with chest wall involvement in a patient with no apparent risk factors.

Pulmonary hydatid disease is rare in the U.K., and chest wall involvement has to our knowledge not previously been described in this country. We report the case of a 72-year-old man who was found to have a left upper lobe opacity on his chest radiograph. He declined further investigation at the time, but 2 years later developed a palpable mass over his left lateral chest wall. Fine-needle aspiration-biopsy of this mass revealed the diagnosis of pulmonary hydatid disease. Despite thorough questioning, no risk factor could be identified for the development of the disease. Hydatid disease should be remembered as a rare cause of mass lesions identified on chest radiographs even in non-endemic regions. Spread to the chest wall may mimic malignancy.

Current treatment of asthma--focus on leukotrienes.

Since their identification in 1979, the cysteinyl leukotrienes (cysLTs) have been shown to be prominent in many inflammatory conditions, including asthma, allergic rhinitis, rheumatoid arthritis, psoriasis, cystic fibrosis and inflammatory bowel disease. They are potent pro-inflammatory agents, as well as causing bronchoconstriction, and undoubtedly have a role in asthma. The cysLTs are products of arachidonic acid metabolism and have been shown to have effects via a cysteinyl leukotriene receptor (CysLTR1) on vascular permeability, mucus production, chemotaxis and bronchial smooth muscle. Their detection in certain body fluids in allergic, aspirin-sensitive and exercise-induced asthma is well documented and potential roles in pathogenesis, proposed. The development of agents affecting production or action offers an exciting new approach to the treatment of asthma. Two approaches to antileukotriene therapy have been developed: blocking their production by inhibiting the action of 5-lipoxygenase enzyme or blocking the CysLTR1. Both approaches have been tried in studies in asthma and overall the results are encouraging, with a decrease in both daytime and nocturnal symptoms, a decrease in additional beta 2 agonist usage and improvement in lung function. The changes, however, are small in some studies. This may be a reflection of disease severity in the study subjects, but of note is a heterogeneity of response to these treatments that may be genetically determined. Antileukotriene therapy has been shown to have an effect in specific types of asthma where the role of cysLTs seems well established--aspirin-sensitive/intolerant asthma and exercise-induced asthma. Longer term studies are needed in other areas such as severe asthma and chronic persistent asthma in both children and adults to provide evidence for the appropriate placement of antileukotriene treatment in current asthma guidelines, in comparison with other established treatments.

Sleep apnoea in diabetic patients with autonomic neuropathy.

Breathing during sleep was monitored in 8 diabetic patients with objective evidence of autonomic neuropathy and in 8 diabetic patients without neuropathy. Thirty or more periods of apnoea lasting 10 seconds or longer during one night's sleep were demonstrated in 3 of the diabetic patients with autonomic neuropathy. Such apnoeic periods may be related to the high incidence of cardiorespiratory arrests reported in such patients, particularly in association with anaesthesia or pneumonia.