Salmeterol provides prolonged protection against exercise-induced bronchoconstriction in a majority of subjects with mild, stable asthma.

In patients with asthma, exercise-induced symptoms are well recognized and frequently limiting. Currently available beta 2-receptor agonists have a short duration of action and breakthrough symptoms may occur. We studied the efficacy of the recently developed long acting inhaled beta 2-agonist salmeterol with respect to protection against exercise-induced bronchoconstriction. Twelve patients with mild to moderate, stable asthma were recruited (age range 21-33 years). They each underwent treadmill exercise tests, with target heart rate of approximately 90% of predicted maximum, 1, 6 and 12 h after a single dose of salmeterol 50 micrograms, salbutamol 200 micrograms and placebo. Patients breathed through a two-way valve, inspiring dry air from a compressed air cylinder via a Douglas bag to maintain constant humidity. The primary efficacy variable analysed was the maximum percentage fall in FEV1 and FVC from pre-exercise readings within the first 30 min post-exercise. At 1 h post-dose there was significant protection in terms of fall in mean +/- SEM FEV1 in response to exercise challenge after either salmeterol (0.83 +/- 6.2%) or salbutamol (3.8 +/- 5.5%) as compared with placebo (27.1 +/- 7.3%). At 6 h post-dose, fall in FEV1 on salmeterol was 11.3 +/- 3.8% as compared with salbutamol, 28.0 +/- 5.7% and placebo, 32.0 +/- 7.0%. At 12 h post-dosing there was still significant protection in terms of fall in FEV1 in the salmeterol treated group, 12.8 +/- 4.9%, as compared with salbutamol, 28.7 +/- 4.9% and placebo, 25.4 +/- 7.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol.

The purpose of the present study was to assess the degree of protection of inhaled salmeterol against exercise-induced bronchoconstriction (EIB) after chronic compared with single dosing in patients with asthma. Twelve patients with exercise-induced asthma took part in a randomized double-blind crossover study to compare the duration of action of inhaled salmeterol 50 micrograms twice daily for 4 weeks with that of placebo. A standardized exercise test was performed at 6 h and 12 h after dosing on the first and last day of each treatment period. Salmeterol produced significant protection against EIB at 6 and 12 h after the first dose in comparison with placebo, whereas there was no significant attenuation of EIB after 4 weeks of chronic treatment with salmeterol. The percentage fall in FEV1 after exercise challenge at 6 h was (first dose): placebo 34.8 +/- 4.9% vs. salmeterol 11.9 +/- 2.8% (P < 0.05); (4 weeks): placebo 32.9 +/- 5.3% vs. salmeterol 24.0 +/- 4.4% (NS). These results suggest that tachyphylaxis may develop to the functional antagonism of salmeterol against EIB.

The addition of salmeterol 50 microg bid to anticholinergic treatment in patients with COPD: a randomized, placebo controlled trial. Chronic obstructive pulmonary disease.

BACKGROUND: In the past, the role of long-acting beta(2-) agonists in chronic obstructive pulmonary disease (COPD) relative to other agents has been unclear. OBJECTIVES: To compare the effect of adding salmeterol (50 microg bid) or placebo to concurrent anticholinergic therapy on symptom scores, quality of life, prebronchodilator lung function and exacerbations in patients with moderately severe COPD. METHODS: This was a double-blind, randomized, parallel-group study in patients aged 40 years or older receiving anticholinergic medication. Patients were randomly assigned to treatment with placebo (n=207) or salmeterol (n=201) via a Diskus/Accuhaler inhaler for 24 weeks. RESULTS: The morning trough (prestudy drug) forced expiratory volume in 1 s (FEV(1)) increased significantly above baseline levels among the salmeterol-treated patients. Improvement in FEV(1) was greater in the salmeterol group than in the placebo group at four weeks (difference 0.06 L, P<0.005), eight weeks (0.06 L, P<0.005) and 16 weeks (0.05 L, P<0.05) after the start of treatment. There was a nonsignificant trend in favour of salmeterol after 24 weeks of treatment (P=0.198). Improvements in morning peak flow were significantly greater in the salmeterol group over 24 weeks (P<0.01). Although symptom scores were numerically higher in the salmeterol group than in the placebo group and there was less requirement for rescue bronchodilator use, these differences were not statistically significant. In the salmeterol group, fewer patients had exacerbations of COPD, and there was a trend toward an improved quality of life. The safety profile of the two groups was similar. CONCLUSIONS: Salmeterol has a beneficial effect when added to existing anticholinergic therapy in patients with COPD. The regular use of salmeterol for six months was not associated with worsening of the underlying airflow obstruction; rather, there was a tendency for the trough FEV1 to improve above the baseline levels over the treatment period.

A case of eosinophilic pleural effusion complicating multiple myeloma.

Pleural effusion is a rare complication of multiple myeloma. We report the first case of eosinophilic effusion due to light chain type disease and review the recent literature.

An unusual presentation of SLE.

SLE presenting initially with isolated pneumonitis is uncommon. We report a case of SLE which presented as an apparent infective lobar pneumonia without other definite evidence of SLE. Laboratory investigations eventually confirmed the diagnosis and clinical signs developed after the diagnosis was made.

A repeat audit of hospital discharge letters in patients admitted with acute asthma.

Subsequent to the implementation of recommendations from a previous audit of acute asthma admission discharge letters from our specialist respiratory unit, a repeat audit of typed discharge letters of 86 patients (33 male, mean age 29 SD 9 years) admitted with acute asthma to the same unit over a 12 month period was performed. There was significant improvement in the discharge letter documentation of precipitating factors (p < 0.001), previous admissions with acute asthma (p < 0.01), admission arterial blood gas analysis (p < 0.001), admission peak flow rates (p < 0.05), discharge peak flow rates (p < 0.001), corticosteroid (p < 0.01) and inhaled beta 2 agonist (p < 0.01) prescription on discharge and on the specification of inhaler delivery device on discharge (p < 0.001). No significant differences in discharge letters were found in the documentation of acute therapy or post discharge follow up plan. The improvement in discharge letter quality was attributed to closing the feed back loop from the previous audit though continuing deficiencies in discharge letter contents have been identified again. These deficiencies need to be rectified and the results reaudited.

Reaudit of acute asthma admissions using a severity marker stamp and determinants of an outcome measure.

Subsequent to the implementation of a severity marker stamp in case notes, an audit was performed in 86 admissions with acute asthma to a specialist centre over a 12 month period. Compared to previous audit the documentation of severity markers was significantly better (PEFR: 52% vs 83% p = 0.001, Respiratory rate: 44% vs 81% p = 0.001, ABG: 72% vs 80% p = 0.04, air entry: 58% vs 86% p = 0.001, speech: 27% vs 86% p = 0.001, exhaustion: 4% vs 86% p = 0.001). In contrast to the previous audit where no patient received FiO2 > 0.35, 66% of the cases in the repeat audit received FiO2 0.60 (p = 0.001). The mean duration of admission was five days and showed highest partial correlation (r = 0.6) to the time in hours for the pulse to fall to 80/min. Multiple linear regression showed that this was the only variable best predicting the duration of admission (R2 = 0.3). Admission pulse rate (p = 0.04) and serum K+ (p = 0.04) best discriminated between patients admitted for over and under five days. Logistic regression identified only the admission pulse as significant in calculating the odds of the patient staying in the hospital for > 5 days.

Respiratory stimulation by almitrine during acute or chronic hypoxia/hypercapnia in rats.

In anaesthetized rats studied in a body plethysmograph, 1-(4'6-diallylamino-2'-triazinyl)-4(bis parafluorobenzydryl) piperazine (almitrine) caused large increases in ventilation (VE) which were abolished by cutting the IXth and Xth cranial nerves. Maximal effects followed infusions of 0.5-1 mg X kg-1; the solvent had no action. When the rats breathed 10% O2 or 10% O2 + 5% CO2, gas mixtures which increased VE, almitrine caused further increases in VE and improved blood gas tensions. Chronically hypoxic (4 weeks in 10% O2) and chronically hypoxic and hypercapnic rats (4 weeks in 10% O2 + 4% CO2), kept in an environmental chamber, were similarly studied. While they breathed, under anaesthesia, the gas mixture to which they had been chronically exposed, infusions of almitrine caused further large increases in VE and improved blood gas tensions. Thus almitrine stimulates VE, probably through peripheral chemoreceptors, when these are already strongly stimulated. This drug increased both tidal volume and frequency and thus increased alveolar ventilation. No convulsant action was observed. It caused a fall in blood pressure which lasted 5-10 min and was seen with urethane but not pentobarbitone anaesthesia; it was not due to the solvent.

Comparison of salmeterol with placebo in mild asthma: effect on peripheral blood phagocyte function and cytokine levels.

beta 2-Adrenergic agonists are widely prescribed for the symptomatic relief of asthma, but are not thought to alter the underlying pathogenesis. However, it has been suggested that salmeterol, a new beta-agonist with prolonged bronchodilatory action, may have anti-inflammatory properties. A double-blind crossover study of 4 weeks of inhaled salmeterol versus placebo was performed using a chemiluminescence assay to measure peripheral phagocyte function before and after each treatment period. Circulating cytokines [interleukin-1 beta (IL1 beta), IL4, IL6, IL2 receptor (IL2R)] were also measured. Although salmeterol caused a significant improvement in spirometry, there was no apparent modulation of phagocyte or cytokine activity. No evidence was obtained to support a clinically significant anti-inflammatory action of salmeterol.

The enlarged carotid body of the chronically hypoxic and chronically hypoxic and hypercapnic rat: a morphometric analysis.

Rats were subjected to chronic hypoxia (10% O2) or hypoxia and hypercapnia (10% O2 + 4% CO2) for 3-4 weeks and their carotid bodies (twenty-three from twenty rats) were compared with those of litter-mate controls. Both chronic exposures, which simulated high altitude or chronic lung disease, caused a 4-10-fold increase in carotid body volume. The larger increases were attributed to higher fixation-perfusion pressures. The organs were fixed by perfusion with glutaraldehyde. Semi-thin (1 micron) sections for light microscopy and ultra-thin sections for electron microscopy were cut at regular intervals and were examined by stereological techniques to determine the nature of the enlargement. The proportion occupied by blood vessels was much increased in both chronic hypoxia and hypoxia plus hypercapnia; the endothelium appeared stretched with conspicuous fenestrations. There were increased numbers of endothelial cells which suggested new growth as well as stretching of endothelium and the mean transectional area of the vessels was increased. The mean surface area of blood vessels per unit area of carotid body was unaltered but the total surface area of blood vessels in the whole carotid body was greatly increased. Both the Type 1 cell nucleus and cytoplasm were increased in size. The proportion nucleus/cytoplasm was unaltered in hypoxia but reduced in hypoxia plus hypercapnia. There were fewer Type 1 cell nuclei per unit area but the estimated total number of Type 1 cell nuclei per carotid body was increased 2-4-fold; this was interpreted as Type 1 cell hyperplasia. Some of the dense-cored vesicles in Type 1 cells were enlarged with eccentric dense cores but their number per unit area of cytoplasm was decreased. Their mean size was not significantly altered. However, the total number of vesicles per carotid body was presumed to be increased because their decreased density in the cell was offset by a greater increase in total Type 1 cell volume. The harmonic and arithmetic mean distances between endothelium and the boundary of glomus tissue were significantly reduced. The harmonic mean distance is an indication of the diffusion distance for gases to and from blood and glomus tissue. The arithmetic mean distance is a measure of the amount of tissue in between. The significance of the vascular enlargement and hyperplasia and the Type 1 cell hyperplasia cannot be assessed at present. We do not know if enlargement is associated with the same, greater, or lesser activity of the organ for a given stimulus.

Subsensitivity of beta-adrenoceptor responses in asthmatic patients taking regular low dose inhaled salbutamol.

Tremor (Tr), chronotropic (HR) and metabolic (K, Glu) responses to cumulative doses of inhaled salbutamol (100 micrograms to 4000 micrograms) were compared in an age and sex matched group of 7 normal (N) and asthmatic (A) subjects. Comparison of regression lines between groups showed differences in HR and K. This was also reflected in attenuation of maximum responses in group A, for HR and K. These results show subsensitivity of chronotropic and hypokalaemic responses in patients with asthma, which may reflect tachyphylaxis from the effects of long term inhaled salbutamol therapy.

Comparison of the effects of prolonged treatment with low and high doses of inhaled terbutaline on beta-adrenoceptor responsiveness in patients with chronic obstructive pulmonary disease.

Eleven patients with chronic obstructive pulmonary disease (age, 61 +/- 2 yr; FEV1, 1.36 +/- 0.24 L, 46 +/- 7% predicted) were given 4 wk of treatment with either a conventional low dose of inhaled terbutaline (LDT), 500 micrograms four times a day, or a high dose of inhaled terbutaline (HDT), 2,000 micrograms four times a day, delivered by a spacer. A randomized double-blind crossover design was used with 2-wk run-in and washout periods, when ipratropium bromide was substituted for inhaled beta-agonists. Dose response curves (DRC) to cumulative doubling doses of inhaled terbutaline (125 to 4,000 micrograms) were constructed after each treatment period, and baseline spirometry, finger tremor (Tr), plasma potassium (K), plasma cAMP, and ECG (HR and T wave) were measured at each dose step of the DRC. Daily PEFR measurements (A.M. and P.M.) and Holter ECG were performed during run-in and treatment periods. Baseline values for FEV1 were not significantly different during run-in, treatment, or washout periods. There were dose-related increases in FEV1 (p less than 0.0001) with no significant differences between DRC after treatment with HDT compared with those with LDT: delta FEV1 max, 0.46 +/- 0.14 L, 15.5 +/- 3.7% predicted (HDT); 0.50 +/- 0.11 L, 16.0 +/- 3.1% predicted (LDT). There were also no differences between DRC for delta FVC: 1.08 +/- 0.22 L, 31.1 +/- 5.4% predicted (HDT); 0.99 +/- 0.14 L, 28.5 +/- 3.8% predicted (LDT). There were no significant changes in K or HR in response to cumulative doses of terbutaline after either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Problems with asthma following treatment of thyrotoxicosis.

We describe two cases of asthma associated with concomitant thyrotoxicosis where initial improvement followed antithyroid treatment. Relapse of asthma on thyroxine replacement was accompanied by subclinical hyperthyroidism with elevated levels of triiodothyronine. This emphasizes the need to follow up asthmatic patients closely for biochemical relapse following treatment of thyrotoxicosis.

Shrinking lungs, diaphragmatic dysfunction, and systemic lupus erythematosus.

One of the more unusual respiratory manifestations of systemic lupus erythematosus is "shrinking lungs." We report a patient with this syndrome and provide evidence for this being due to diaphragm dysfunction. Significant improvement occurred after albuterol therapy, providing new possibilities in the treatment of this syndrome. This is the first report in humans supporting animal work demonstrating that beta-agonists can improve diaphragmatic performance.

Effect of salmeterol on polymorphonuclear leukocyte (PMNL) chemiluminescence in vitro.

Although beta-agonists remain an important aspect of the treatment of asthma, their role has recently been questioned. Salmeterol has recently been developed as a beta-agonist with prolonged bronchodilator action. Using lucigenin-enhanced chemiluminescence, we have shown that salmeterol inhibits this aspect of phagocyte function in vitro in a concentration-dependent manner. However, salmeterol differs from classical beta 2-agonists in that at concentrations between 10(-5) and 10(-3) mol/L, its effects on phagocytes cannot be completely reversed by washing the cells or by propranolol. The effects on phagocytes may not therefore be explicable on the basis of beta-adrenergic mechanisms alone.

Asymmetric interactions between phosphorylation pathways regulating ciliary beat frequency in human nasal respiratory epithelium in vitro.

1. The effects of the sequential stimulation of ciliary beat frequency (CBF) via two different phosphorylation cascades (dependent on protein kinase A (PKA) and calmodulin, respectively) were determined using video microscopy applied to a perfused preparation of human nasal respiratory epithelium in vitro. Dibutyryl cyclic AMP (db-cAMP) (10(-3) M) was used to stimulate PKA and the calcium ionophore 4-Br-A23187 (10(-5) M) was used to stimulate calmodulin-dependent phosphorylation. 2. Perfusion with db-cAMP (10(-3) M) alone showed an early rise in CBF (15.0 +/- 4%, mean +/- S.E.M., P < 0.05) by 10 min which remained elevated for 35 min; in contrast, the highest CBF response to 4-Br-A23187 (10(-5) M) alone was not achieved until 35 min (16.1 +/- 1.8%, P < 0.05). 3. When a db-cAMP stimulus was applied to cells which had been pre-incubated with 4-Br-A23187 for 30 min, a further rise in CBF (maximal at 20 min, 14.3 +/- 2%, P < 0.05) was observed. Reversing the sequence of perfusions, cells pre-incubated with db-cAMP showed no further rise in response to stimulation with 4-Br-A23187. 4. We hypothesized that PKA inhibited the response to the 4-Br-A23187. This notion was supported by the restoration of the CBF response (22.8 +/- 4%, P < 0.05) to 4-Br-A23187 when the cells were pre-incubated with the protein kinase inhibitor 1-(5-isoquinolinyl-sulphonyl)-2-methylpiperazine (10(-3) M), before the sequential perfusions with db-cAMP and 4-Br-A23187. We conclude that the A23187-dependent pathway, which regulates intrinsic CBF, is inhibited by db-cAMP but not vice versa.

A comparison of the effects of prednisolone and mianserin on ventilatory, exercise and psychometric parameters in patients with chronic obstructive pulmonary disease.

There is controversy as to whether effects on mood play a role in mediating the response to corticosteroids in chronic obstructive pulmonary disease (COPD). If alterations in mood are important, it is conceivable that psychotropic drugs such as mianserin might produce similar responses to prednisolone in patients with COPD. Twelve patients age 62.5 y, with FEV1 29% of predicted and < 15% reversibility to salbutamol completed a randomised, double-blind crossover study. After an initial three week placebo run-in period patients received three weeks of prednisolone 40 mg daily or mianserin 60-90 mg daily with an intervening three week placebo washout period. Full respiratory function tests, bicycle ergometry and 6 minute walks were performed before and after the run-in and at the end of each period. Psychological and functional assessments were also made at each visit. Prednisolone significantly increased FVC, maximum ventilation (VEmax) and maximum heart rate (HRmax) compared with placebo, with mean for the difference of 0.25 l, 2.56 l.min-1 and 12 beats.min-1 respectively. FVC, maximum oxygen uptake (VO2max) and HRmax were also significantly increased with prednisolone compared with mianserin. Anxiety scores were significantly lower with prednisolone compared with placebo. In contrast, mianserin had no significant effects on lung function, exercise or psychological parameters compared with placebo. The improvements in ventilation, exercise and anxiety scores following treatment with prednisolone were not reproduced by mianserin, suggesting that the effects of prednisolone in COPD are unlikely to be due to alterations in mood.

Beta-adrenoceptor responses to high doses of inhaled salbutamol in patients with bronchial asthma.

1. Fourteen asthmatics (mean +/- s.e. mean baseline FEV1 62 +/- 6% of predicted) were given cumulative doubling doses of salbutamol by metered-dose inhaler as follows: 100 micrograms, 200 micrograms, 500 micrograms, 1000 micrograms, 2000 micrograms, 4000 micrograms. 2. Airways, tremor, haemodynamic and cyclic AMP responses were measured at each dose increment (made every 20 min). 3. There was a linear log dose-response relationship for each airways parameter (FEV1, VC, sGaw, FEF 50%). The plateau in the dose-response curve was not reached within our dose range. These changes were also mirrored in cyclic AMP responses. 4. There was a wide range in maximum airways response expressed in terms of absolute increase over baseline (95% confidence intervals: delta FEV1 667-1483 ml; delta VC 689-1695 ml; delta sGaw 0.92-4.50 s-1 kPa-1; delta FEF 50% 0.94-2.15 l s-1). Patients with a lower baseline showed a greater response in terms of percent increase in FEV1 (r = -0.83, P less than 0.001). There was however, no correlation between baseline airway calibre and the dose required for maximum bronchodilatation. 5. There were objective increases (mean +/- s.e. mean) in both heart rate (maximum delta HR of 14 +/- 5 beats min-1 at 4000 micrograms) and tremor power (maximum delta Tr of 115 +/- 44% at 2000 micrograms). These were not dose limiting side-effects as subjective symptoms were infrequent at higher doses. 6. Higher than conventional doses of salbutamol given by metered-dose inhaler may produce a distinct improvement in airways response without significant side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Is fibreoptic bronchoscopy in patients with lung cancer and hepatic metastases potentially dangerous?

Plasma lignocaine levels were measured in 18 patients with lung cancer undergoing fibreoptic bronchoscopy to determine whether those with hepatic metastases and disturbed hepatic function were at special risk from lignocaine toxicity. Peak plasma lignocaine levels were in fact lower in six patients with hepatic metastases and deranged hepatic function tests than in the nine patients with no evidence of hepatic metastases or dysfunction (mean +/- SEM 1.89 +/- 0.2 mg/litre and 2.60 +/- 0.3 mg/litre respectively, P not significant). The peak plasma lignocaine level did not correlate with tests of liver function but did correlate with age. Using a total dose of lignocaine of less than 400 mg, plasma lignocaine levels remained below the toxic range in all patients. The peak plasma lignocaine level correlated significantly with the amount of drug administered directly into the bronchial tree (P less than 0.05) rather than total dose administered. Patients with hepatic metastases from lung cancer do not appear to be at an increased risk from the toxic effects of lignocaine topical anaesthesia if moderate doses are used.