Terahertz pulsed spectroscopy as a new tool for measuring the structuring effect of solutes on water.

Absorption spectra of aqueous solution of ''chaotropes'' (structure maker) and ''kosmotropes'' (structure breaker) have been recorded in the mid-infrared (MIR) and terahertz (THz) spectral region. A different impact of the two groups of solutes on the absorption spectrum of water was found in the recorded THz spectra. A concentration-dependent increased absorption across the investigated THz spectral region (0.04-2 THz, 1.3-66 cm(-1), respectively) has been recorded for all studied chaotropic solutions, whereas the opposite has been obtained for kosmotrope containing solutions. In the case of ionic solutes a further increase in absorption towards higher frequencies was measured. The distinction between chaotrope and kosmotrope solutes was, as expected, also possible in the MIR spectral region. Depending on the structure-forming effect of the solute the OH stretch vibration of the water (around 3400 cm(-1)) was slightly shifted. A red shift has been observed for solution of kosmotropes, whereas a blue shift was observed in the case of solutions containing chaotropes. Compared to the MIR spectral region the structure influencing effect of solutes can be more efficiently studied in the THz spectral region, which provides information from interactions between neighboring water molecules.

Asthma medications and their potential adverse effects in the elderly: recommendations for prescribing.

The incidence of drug-induced adverse effects is likely to increase as a result of advanced age and exposure of elderly patients to polypharmacy. Therefore, pharmacological therapy of asthma and chronic obstructive pulmonary disease (COPD) in the elderly patient can be potentially hazardous. beta(2)-agonists, administered as therapy for asthma and COPD, have recognised systemic sequelae, such as hypokalaemia and chronotropic effects, which may be life-threatening in susceptible patients. Adverse effects such as hypokalaemia can be aggravated by concomitant treatment with other drugs promoting potassium loss including diuretics, corticosteroids and theophyllines. In addition, relatively minor adverse events associated with the administration of beta(2)-agonists, such as tremor and blood pressure changes, may be of significance to the elderly patient leading to impairment in the quality of life. However, long-term treatment with beta(2)-agonists may reduce the incidence of drug-induced adverse effects as a result of beta-receptor subsensitivity. Oral and inhaled corticosteroids have been used for the treatment of acute asthma and COPD in the elderly patient. Long-term treatment with oral corticosteroids can result in serious systemic adverse effects such as suppressed adrenal function, bone loss, skin thinning and cataract formation. In contrast to beta(2)-agonists, oral corticosteroids can upregulate beta(2)-adrenoceptors and thereby potentiate the systemic sequelae of beta(2)-agonists. Hence, oral corticosteroids should be administered with caution for as short a duration as possible. Inhaled corticosteroids appear to be relatively well tolerated when administered at doses below approximately 1000 microg. However, larger doses of inhaled corticosteroids may affect hypothalamic-pituitary-adrenal function and bone turnover. In the case of inhaled corticosteroids, spacer devices, often used in older patients who cannot operate metered dose inhalers, can potentiate the systemic sequelae of both corticosteroids and beta(2)-agonists. The use of theophyllines in the treatment of COPD or chronic asthma is controversial. Theophyllines have a wide adverse effect profile and are prone to drug-drug interactions. The adverse effects may be mild or life threatening and include nausea and vomiting or sinus and supraventricular tachycardias. Therefore, theophyllines should be prescribed with extreme caution to elderly patients with asthma or COPD. In contrast, inhaled anticholinergic drugs such as ipratropium bromide and oxitropium bromide are generally safe in elderly patients and have useful bronchodilator function. Commonly reported adverse effects are an unpleasant taste and dryness of the mouth. When used as first-line therapy, anticholinergic drugs may optimise the bronchodilator effects of low-dose inhaled beta(2)-agonists in patients with chronic airflow obstruction, and hence obviate the need for higher doses.

Large-volume, coolable spectroscopic cell for aerosol studies.

We have constructed a coolable spectroscopic cell for characterizing the physical and chemical properties of simulated atmospheric aerosol particles. The cell is designed for experiments in which the refractive indices, freezing temperatures, and the phase and chemical composition of a wide range of aerosol types are measured. The relatively large volume (0.075 m(3)) of the cell reduces wall-aerosol interactions and allows the aerosol residence time to exceed 2 h. The cell has been optically interfaced to Fourier-transform spectrometers to record broadband infrared, visible, and ultraviolet extinction spectra of aerosol particles and gas-phase components over a range of temperatures (180-300 K). The data generated with the cell have applications in remote sensing, radiative transfer models, heterogeneous atmospheric chemistry, and pollution studies.

Infrared and visible fourier-transform spectra of sulfuric-acid-water aerosols at 230 and 294 K.

The extinction spectra of aqueous sulfuric acid aerosols fully covering the mid-IR to visible regions from 750 to 23,000 cm(-1) (13.9-0.4 microm) have been measured in the laboratory with a Fourier-transform spectrometer. Both large and small aerosol particles with compositions of approximately 60-70-wt. % H(2)SO(4) were generated and their spectra recorded at 230 and 294 K. The spectra were fitted to a model incorporating room-temperature refractive-index data [Appl. Opt. 14, 208 (1975)] and Mie theory calculations to characterize the composition and size distributions of the aerosol samples.

Sensitivity of the cough reflex in young and elderly subjects.

OBJECTIVE: To compare the sensitivity of the cough reflex--which is said to be normal in elderly people--in elderly and young subjects. SUBJECTS: 20 elderly (14 female) subjects, mean (SEM) age 83 (1) years and 20 young (nine female) subjects, mean (SEM) age 27 (1) years, who were all non-smokers. None of the subjects was taking antitussive drugs and none suffered from clinically evident lung, cardiac or neurological disease. Five elderly subjects were unable to perform adequate spirometry and were excluded from analysis. DESIGN AND OUTCOME MEASURES: Each subject inhaled 10 ml of nebulized distilled water and isotonic saline (as placebo) for 30 s, 10 min apart in a randomized double-blind crossover fashion. The cough frequency induced with each treatment was recorded on a click counter. RESULTS: Cough frequency on inhaling distilled water was significantly lower in the elderly group than in the younger group, with a difference of 9.53 (95% confidence intervals: 3.63, 15.4; P < 0.001). None of the subjects coughed when inhaling placebo solution, resulting in significant differences in cough frequencies between distilled water and placebo of 5.87 (2.82, 8.92; P < 0.05) for the elderly group and 15.4 (11.0, 19.8; P < 0.0005) for the younger group. CONCLUSIONS: The sensitivity of the cough reflex appears to be significantly reduced in elderly subjects. This may increase the risk of aspiration and bronchopulmonary infection in old age, even in the absence of respiratory disease.

Self-funding and community care admissions to nursing homes in Aberdeen.

OBJECTIVE: Admissions to nursing homes are an essential component of community care following the Community Care Act reforms. The present study sought to evaluate recent admissions from the community or hospital to private nursing homes in Aberdeen, in order to assess care management in operation and to determine whether admission criteria or access are influenced by funding. DESIGN AND SUBJECTS: A census of admissions to 11 private nursing homes within Aberdeen City boundary was performed over a nine-month period (April 1994 to January 1995), one year after the NHS and Community Care Act reforms had been implemented. One hundred and nineteen residents (102 females), means (SEM) age, 83(1) years range 64-98 years, admitted from the community or hospital since 1 April 1994, were included. For each resident an evaluation of Barthel Index, Abbreviated Mental Test Score (AMTS), source of funding (Local Authority Funding (LAF) or private) and appropriateness of placement was made. RESULTS: Twenty-seven residents were admitted from home, 77 from hospital and 15 from residential or nursing homes. 58% (69 residents) were funded by LAF and 42% (50 residents) were funded privately. Barthel scores as mean (SEM): 10.7 (0.72) vs 14.1 (0.55), p < 0.001, were significantly higher in the privately funded group. 68.1% (81 residents) were considered to be appropriately placed. However, a significantly higher proportion of those with LAF funding were appropriately placed: (number of residents); 53 vs 28, p = 0.016. CONCLUSIONS: It would appear that there is a selection in favour of privately funded residents with a lower level of dependency. If resources are limited this could disadvantage more dependent patients in hospital who merit institutional care but require Local Authority funding support.

Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients.

BACKGROUND: There is controversy as to the role of long acting beta 2 agonists such as eformoterol and, in particular, whether bronchodilator tolerance occurs during continuous therapy. The purpose of this study was to extend previous observations of bronchodilator subsensitivity with metered dose eformoterol aerosol in order to assess whether tolerance also occurs with a dry powder formulation of the same drug. METHODS: Sixteen asthmatic patients of mean age 33 (range 18-53) years and FEV1 (% predicted) of 64 (3)%, of whom 13 were receiving inhaled corticosteroids, received regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily (without beta 2 agonists) given concurrently for four weeks in a randomised double blind cross-over design. An initial two week run-in was used when beta 2 agonists were withdrawn and substituted with ipratropium bromide. Dose-response curves to eformoterol (cumulative dose 6-102 micrograms) for airways and systemic beta 2 responses were constructed at the end of each treatment period. RESULTS: Baseline values for airways and systemic responses were similar. The peak delta FEV1 response from the dose-response curve (as change from baseline) and the delta response for FEV1 and FEF25-75 at six hours after the last dose were attenuated after eformoterol compared with placebo: peak delta FEV1 response 1.001 with placebo v 0.841 with eformoterol (95% CI 0.04 to 0.28); at six hours 0.931 with placebo v 0.581 with eformoterol (95% CI 0.20 to 0.50); and for delta FEF25-75 at six hours 1.29 1/s with placebo v 0.87 1/s with eformoterol (95% CI 0.15 to 0.69). Morning peak expiratory flow rate was significantly improved during treatment with eformoterol (451 1/min) compared with placebo (399 1/min) (95% CI 21 to 82). Systemic beta 2 responses were blunted after eformoterol, together with a reduction in lymphocyte beta 2 receptor binding density. CONCLUSIONS: Regular twice daily eformoterol dry powder may produce bronchodilator subsensitivity in terms of both peak and duration of response to cumulative repeated doses of eformoterol. Systemic beta 2-mediated adverse effects also showed tolerance, which was mirrored by downregulation of lymphocyte beta 2 adrenoceptors.

Comparison of the relative airways and systemic potencies of inhaled fenoterol and salbutamol in asthmatic patients.

BACKGROUND: There is controversy as to the relative safety of fenoterol and salbutamol. No differences have been found in the relative cardiac beta 1/beta 2 receptor activity of inhaled fenoterol and salbutamol in normal subjects. These initial findings have been extended by comparing the respective potencies of equivalent doses by weight of fenoterol and salbutamol in asthmatic subjects, in terms of airways and systemic responses. METHODS: Eighteen asthmatic patients of mean (SD) age 40 (14) years and a forced expiratory volume in one second (FEV1)% predicted of 56 (14)% (1.97 (0.66)1) were randomised to inhale fenoterol (100 micrograms/puff or 200 micrograms/puff), salbutamol, or placebo (100 micrograms/puff or 200 micrograms/puff) on three separate days. Dose-response curves were constructed using cumulative doses of 100 micrograms, 200 micrograms, 400 micrograms, 1000 micrograms, 2000 micrograms, and 4000 micrograms, and airways and systemic responses were measured 20 minutes after each dose with 40 minute increments. Dose ratios for the relative potency of fenoterol versus salbutamol were calculated from the dose-response curves using regression analysis of parallel slopes. RESULTS: There was no difference in bronchodilator potency between fenoterol and salbutamol (as median dose ratio): FEV1 1.1 (95% CI 0.4 to 4.6). In contrast, dose ratios for systemic responses showed that fenoterol was more potent than salbutamol: serum potassium 3.7 (95% CI 2.0 to 6.0), tremor 5.7 (95% CI 1.4 to 10.2), heart rate 1.6 (95% CI 1.0 to 2.3). At a conventional dose of 200 micrograms the only difference in response between the two drugs was observed for tremor (as mean difference): 0.23 log units (95% CI 0.06 to 0.41 log units). CONCLUSIONS: There was no difference in the bronchodilator potency between fenoterol and salbutamol on a microgram equivalent basis. In contrast, systemic potency was greater with fenoterol, although this difference was not clinically relevant at conventional dosages up to 200 micrograms.

Nebuliser performance, pharmacokinetics, airways and systemic effects of salbutamol given via a novel nebuliser delivery system ("Ventstream").

BACKGROUND: Currently available nebulisers are inefficient and show variable aerosol deposition in the lung owing to the differences in the particle size generated. The aim of this study was to compare systemic absorption and bronchodilator effects of salbutamol given via a novel ("Ventstream") and a conventional ("Hudson Updraft II") nebuliser system, having initially evaluated the performance of both nebulisers in vitro. The "Ventstream" nebuliser uses a one way valve system to provide an additional inspiratory side flow to match aerosol delivery with tidal volume. METHODS: Nebuliser output and particle distribution from 10 Ventstream and 10 Hudson nebulisers were compared in vitro. Eight asthmatic patients, FEV1 55(2)% predicted, were then randomised to receive salbutamol via Ventstream or Hudson nebulisers on separate days. On each day cumulative doses of inhaled salbutamol were given: 1.25 mg, 2.5 mg (1.25 + 1.25 mg), and 5.0 mg (2.5 + 2.5 mg). Airways responses, systemic responses, and plasma salbutamol concentrations were measured at each dose and for up to 240 minutes after the final dose. RESULTS: The in vitro comparison showed a greater respirable fraction with a higher percentage volume of particles < 5 microns in diameter using Ventstream than Hudson nebulisers (mean (95% CI) for difference): 25.4% (95% CI 22.4% to 28.3%), and a higher aerosol rate of output: 0.08 g/min (95% CI 0.05 to 0.11 g/min). At the 5.0 mg dose the Ventstream produced a twofold greater concentration of plasma salbutamol than the Hudson nebuliser (AUC0-240): 392.1 ng/ml.min (95% CI 240.6 to 543.6 ng/ml.min). There was a higher AUC0-240 for PEFR with the Ventstream than with the Hudson nebuliser: 74.161 x 10(2) (95% CI 39.50 to 108.821 x 10(2). For FEV1 and FEV25-75 there was a difference in the peak response between the 5.0 mg and 2.5 mg doses with the Ventstream only. Extrapulmonary beta 2 responses were greater with the Ventstream than with the Hudson at 2.5 mg and 5.0 mg doses, although the differences did not appear to be clinically relevant. CONCLUSIONS: The Ventstream produced a twofold increase in the delivery of salbutamol to the lung compared with the Hudson nebuliser, and there was an associated increase in systemic beta 2 responses with an improvement in some parameters of bronchodilator efficacy. As a consequence of improved delivery with the Ventstream, it may be possible to halve the drug dose to produce similar bronchodilator efficacy at reduced cost. Further studies are required to evaluate the value of the Ventstream for delivery of nebulised antibiotics and corticosteroids.

Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma.

PURPOSE: The aim of the present study was to evaluate in vivo and in vitro beta 2-adrenoceptor responsiveness after chronic inhaled therapy with the long-acting beta 2-agonist eformoterol or placebo, given twice daily, in patients with mild to moderate asthma. PATIENTS AND METHODS: Seven asthmatic patients, age 34 +/- 5 years were evaluated. Mean forced expiratory volume in 1 second (FEV1) (% predicted) at entry was 58 +/- 5%. After at least 2 weeks run-in without beta 2-agonist therapy, patients were randomized to receive regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily given by metered-dose inhaler for 4 weeks, in a double-blind, crossover design. Dose-response curves (DRC) to eformoterol (cumulative dose 6 micrograms to 126 micrograms) for airways and systemic beta 2-responses were constructed at the end of each treatment period. Responses were measured at baseline, 30 minutes after each dose, and for 6 hours after the last dose. In addition, in vitro parameters of lymphocyte beta 2-receptor function were evaluated prior to the DRC after each treatment period. RESULTS: There was a nonsignificant trend towards higher baseline values after eformoterol compared with placebo for FEV1: 0.16 L (95% CI -0.04 to 0.36) and forced expiratory flow (FEF25-75): 0.27 L/sec (95% CI -0.08 to 0.62). The peak bronchodilator response from the DRC and response 6 hours after the last dose were both significantly (P < 0.05) attenuated after chronic therapy with eformoterol compared with placebo. The mean differences between eformoterol and placebo for delta FEV1 were as follows: peak: 0.26 L (95% CI 0.09 to 0.43), and at 6 hours: 0.39 L (95% CI 0.20 to 0.58). Corresponding values for delta FEF25-75 were as follows: peak: 0.41 L/sec (95% CI 0.10 to 0.71), 6 hours 0.52 L/sec (95% CI 0.22 to 0.82). Systemic responses were likewise significantly blunted after eformoterol treatment compared with placebo. There was also subsensitivity of lymphocyte beta 2-adrenoceptor function after treatment with eformoterol compared with placebo. CONCLUSIONS: Our results suggest that chronic therapy with eformoterol produces (1) tachyphylaxis to its bronchodilator response, which was greatest at 6 hours after the last dose, (2) tachyphylaxis of extrapulmonary beta 2-mediated responses, and (3) subsensitivity of in vitro beta 2-adrenoceptor function.

Influence of sex-steroid hormones on the regulation of lymphocyte beta 2-adrenoceptors during the menstrual cycle.

1. Up to 40% of female asthmatic subjects suffer a premenstrual deterioration in their condition which may be ameliorated by progesterone supplementation, although the mechanism responsible for this phenomenon is not understood. In vitro studies have shown that female sex-steroid hormones potentiate the bronchorelaxant effect of isoprenaline, whilst in vivo it has been shown that females exhibit greater sensitivity of systemic beta 2-adrenoceptor responses. 2. The aim of the present study was to determine whether cyclical alterations in beta 2-adrenoceptor expression, occurring under the influence of ovarian sex-steroid hormones, may offer an explanation for these findings. In vitro parameters of lymphocyte beta 2-adrenoceptor function were investigated in nine normal female subjects (aged 24 +/- 2 years) during the follicular (day 2-4) and luteal (day 21-23) phases of their menstrual cycle, and results were compared with those of nine age-matched healthy male controls studied at the same time intervals. 3. In female subjects there were significant increases in serum concentrations of oestradiol (3.3-fold) and progesterone (10.6-fold) between the follicular and luteal phases of the menstrual cycle, whereas no changes occurred in males. 4. In females during the luteal phase, the increase in sex-steroid hormones was mirrored by an increase in lymphocyte beta 2-adrenoceptor density (Bmax) and in maximal cyclic AMP response to isoprenaline (Emax), which were significantly higher than in male subjects. Mean differences (95% CI) between male and female subjects on visit 2 were 1.09 (0.49 to 1.69) fmol/10(6) cells (P = 0.001) for Bmax, and 3.42 (0.80 to 6.04) pmol/10(6) cells (P = 0.02) for Emax.(ABSTRACT TRUNCATED AT 250 WORDS)

Extrapulmonary beta 2-responses to intravenous salbutamol during the menstrual cycle.

Extrapulmonary beta 2-adrenoceptor mediated responses to salbutamol were evaluated in 9 healthy female subjects during the follicular (day 2-4, Visit 1) and luteal (day 21-23, Visit 2) phases of the menstrual cycle, and were compared with those of 9 age-matched male controls. At each visit, salbutamol was given by intravenous infusion for 30 minutes at a dose of 0.2 mg.kg-1.min-1. Plasma salbutamol concentration and responses in heart rate (HR), finger tremor (Tr), Q-T interval (Q-Tc), serum potassium (K), serum insulin (Ins) and serum glucose (Glu) were measured at baseline and at 10, 20 and 30 minutes after commencing the infusion. Comparisons were made between sexes and between visits for peak responses calculated as percentage change from baseline. Mean plasma salbutamol concentration (ng.ml-1) were not significantly different between males and females on Visit 1: 6.9 (95% CI 6.01, 7.82) vs 7.3 (95% CI 6.4, 8.3), or on Visit 2: 6.9 (95% CI 6.0, 7.8) vs 7.2 (95% CI 6.3, 8.1). On Visit 1, significantly greater responses were demonstrated in females, compared with males for K (as mean difference): 6 (95% CI 1, 11)%, Tr: 17 (95% CI 1, 33)%, Q-Tc: 8 (95% CI 2, 14)% and Ins: 276 (95% CI 71, 481)%. In addition, a significantly greater response was demonstrated in females on Visit 1 compared with males on Visit 2 for HR (as mean difference): 32 (95% CI 1, 63)%, and for Ins: 262 (95% CI 57, 467)%. Thus, despite no difference in plasma salbutamol concentrations, female subjects exhibited greater responsiveness to salbutamol compared with males during the follicular phase of the menstrual cycle. This suggests that in vivo, females have enhanced sensitivity of extrapulmonary beta 2-adrenoceptors.

Beta-adrenoceptor subtypes mediating the airways response to BRL 35135 in man.

1 The purpose of the study was to assess the bronchorelaxant effects of the beta3-adrenoceptor agonist BRL 35135 in normal human airways. 2 Eight healthy male subjects were studied, having previously demonstrated airways responsiveness to inhaled salbutamol 200 microg, with a group mean (+/- s.e. mean) fall in airways resistance (Raw), from baseline, of 37 +/- 5%. 3 Subjects attended the laboratory on 3 separate days, having fasted and taken placebo (PL) or nadolol 20 mg (N20), 2 h previously. 4 After 30 min rest, baseline measurements of Raw, serum potassium, glucose and free fatty acid were performed before subjects were given single oral doses of BRL 35135 8 mg (BRL) or placebo BRL. Measurements were repeated 60 min after the BRL or placebo BRL were given. 5 There was a significant (P < 0.05) fall in Raw (% change from baseline, as means and 95% CI) with PL/BRL: -32(-18, -46), compared with either PL/PL: -8(5, -21), or N20/BRL: -11(2, -24). There was no significant difference between PL/PL and N20/BRL. 6 A similar pattern to Raw was observed for both of the beta2-mediated metabolic responses which were also antagonised by nadolol. For the potassium response (mmol l(-1)), there was a significant (P < 0.05) difference between PL/BRL: -0.50(-0.31, -0.69), in comparison with either PL/PL: 0.08(-0.11, 0.27) or N20/BRL: 0.09(-0.10, 0.28), but values for PL/PL and N20/BRL were not significantly different. In contrast, with the free fatty acid response (nmol 1(-1)), the increase seen with N20/BRL: 85(1.0, 171.0) was significantly (P < 0.05) different from PL/PL: 3.7(-82.3, 89.8), but was not different from PL/BRL: 132.5(46.5, 218.5). 7 In conclusion, BRL 35135 produced airways, potassium and glucose responses which were antagonised by nadolol, whereas the lipolysis response was not. This suggests that there are not functional beta3-adrenoceptors in human airways.

Bronchodilator reversibility to low and high doses of terbutaline and ipratropium bromide in patients with chronic obstructive pulmonary disease.

BACKGROUND: There is uncertainty regarding the use of monotherapy or combination therapy with beta 2 agonists and anticholinergic drugs in patients with chronic obstructive pulmonary disease (COPD). The measurement of forced expiratory volume in one second (FEV1) or relaxed vital capacity (RVC) in the assessment of reversibility in these patients has also caused considerable debate. METHODS: Twenty seven patients with COPD were evaluated on two occasions. Patients received the following treatments in sequence: (sequence 1) low dose terbutaline 500 micrograms, high dose terbutaline 5000 micrograms, low dose ipratropium 40 micrograms, high dose ipratropium 200 micrograms; (sequence 2) low dose ipratropium 40 micrograms, high dose ipratropium 200 micrograms, low dose terbutaline 500 micrograms, high dose terbutaline 5000 micrograms. RVC, FEV1 and FVC were measured at baseline and 30 minutes after successive treatments. RESULTS: Values for FEV1 at baseline on the first and second study days were not significantly different: 0.90 (0.87-0.93) 1 v 0.90 (0.87-0.93) 1. Likewise, baseline values for RVC and FVC were not different. The number of patients showing a greater than 330 ml overall improvement in RVC was 20 of 27 for sequence 1 and 22 of 27 for sequence 2; similar trends were observed for FEV1 and FVC. For all three parameters there was a significant difference between mean responses to low and high doses of terbutaline when the latter was given as the first drug in sequence 1. When ipratropium was given first in sequence 2 there was, however, no significant improvement with high dose terbutaline over and above the response to low dose terbutaline. The latter effect was more noticeable with RVC than with either FEV1 or FVC. The total bronchodilator response at the end of each sequence was similar whether ipratropium was given first or second. CONCLUSIONS: The measurement of RVC, FEV1, and FVC were equally effective at picking up those patients who had a significant overall bronchodilator response to combined therapy with inhaled beta 2 agonist and anticholinergic medication. There was no significant benefit of adding a higher dose of terbutaline when ipratropium bromide had been given previously, particularly when using RVC as the parameter of response.

Comparison of the extrapulmonary beta2-adrenoceptor responses and pharmacokinetics of salbutamol given by standard metered dose-inhaler and modified actuator device.

1. Ten healthy subjects were randomised to inhale salbutamol via a standard metered-dose inhaler (MDI), or via a modified metered-dose actuator device (MA). Previously published radiolabelled aerosol data had shown that the MA device produced a lower aerosol velocity, reduced oropharyngeal deposition, but with unchanged pulmonary deposition. 2. Dose-response curves (DRC) were constructed with the following cumulative doses of salbutamol: 200 microg, 600 microg (200 microg + 400 microg), 1400 microg (600microg + 800 microg) ad 2600 microg (1400 + 1200 microg). Dose increments were made every 30 min and measurements of extrapulmonary beta2-adrenoceptor responses were performed 20 min after each dose. In addition, plasma salbutamol concentrations were also measured immediately before and for up to 60 min after the last dose. 3. Baseline values were not significantly different between the two study days for any of the measured parameters. 4. Cmax (ng ml(-1)) for plasma salbutamol (as means and 95% CI for difference between MA and MDI) was: 2.0 (0.3-3.7), P = 0.03. Values for t(max) (min), median and range: MA 5 (5-10) vs MDI 5 (5-10); and AUC 0-60, (ng ml(-1) min, mean and 95% CI for difference between MA and MDI): 69 (-5-143), were not significantly different between the two devices. 5. There was a significant (P < 0.01) left shift in the DRC with the MA device compared with the MDI, for hypokalaemic, finger tremor, chronotropic and electrocardiographic (Twave, Q-Tc) responses to salbutamol. Values for the hypokalaemic response (mmol l(-1)) at 2600 microg were (as change from baseline, means and 95% CI for difference between MA and MDI): 0.23 (0.10-0.36). 6. Thus, the MA device produced greater systemic absorption of salbutamol, and associated extrapulmonary beta2-adrenoceptor responses compared with a standard MDI. These results, therefore, suggest that data from radiolabelled aerosol deposition studies may not predict the systemic absorption of inhaled beta2-adrenoceptor agonists.

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)

Single dosing comparison of the relative cardiac beta 1/beta 2 activity of inhaled fenoterol and salbutamol in normal subjects.

BACKGROUND: The aim of the present study was to compare the dose related effects of fenoterol and salbutamol on cardiac beta 1 and beta 2 receptors using the beta 1 selective antagonist atenolol, in order to dissect out relative beta 1/beta 2 mediated responses. METHODS: Fourteen normal volunteers were randomised to receive pretreatment with either atenolol 25 mg or placebo, followed by inhaled fenoterol or salbutamol in equal doses by weight (cumulative doses of 1 mg and 4 mg). Measurements were made 30 minutes after inhaling each dose of beta 2 agonist. Values (mean and 95% CI) were expressed as a change from baseline. RESULTS: At 4 mg fenoterol produced equivalent falls in serum potassium and increases in tremor to salbutamol. The mean (95% CI) increase in heart rate (beats/min) with fenoterol at 4 mg after placebo was 47 (41-53) and after atenolol was 34 (28-40), with values for salbutamol being 46 (40-52) after placebo and 30 (24-36) after atenolol. The inotropic response (stroke distance) after atenolol at the 4 mg dose was 5.0 (3.9-6.1) cm for fenoterol and 4.7 (3.5-5.9) cm for salbutamol. There were no significant differences in heart rate or stroke distance response between the two drugs after either placebo or atenolol. Furthermore, ECG effects (Q-Tc and T wave) of fenoterol and salbutamol were comparable at both doses. CONCLUSIONS: These results show that there is no difference in the respective chronotropic or inotropic activities of fenoterol and salbutamol on cardiac beta 1 or beta 2 receptors when given at higher than conventional doses.

Comparison of parameters of in vitro lymphocyte beta 2-adrenoceptor function in normal and asthmatic subjects.

There is conflicting data in the literature as to whether subsensitivity of in-vivo beta 2-adrenoceptor (beta 2-AR) responses in patients with asthma is due to an endogenous defect of beta 2-AR or an effect of exogenous beta 2-agonist therapy. The purpose of the study was to compare in-vitro parameters of lymphocyte beta 2-AR function in eight age and sex matched normal [FEV1, 98 (2)% predicted] volunteers and asthmatic [FEV1, 60 (5)% predicted] subjects. The asthmatic group were washed out for 4 weeks by substituting inhaled beta 2-agonist therapy with ipratropium bromide, in order to exclude possible exogenous effects of beta 2-agonist exposure. Receptor binding affinity (Kd) and density (Bmax) were evaluated using (-)125I-iodocyanopindolol and maximal cAMP response (Emax) was assayed following stimulation with isoprenaline (10(-4) M). No significant differences were found between the normal and asthmatic group for Kd (pmol.l-1): 9.65 vs 10.2, Bmax (fmol/10(6) cells): 1.9 vs 1.6, or Emax (pmol/10(6) cells): 4.24 vs 4.85. Thus, parameters of beta 2-AR function are unaltered in asthmatic patients who have not been exposed to beta 2-agonists, suggesting that asthma is not associated with an endogenous defect of beta 2-AR.

The effects of frusemide and triamterene on the hypokalaemic and electrocardiographic responses to inhaled terbutaline.

Fifteen normal volunteers were given 5000 micrograms inhaled terbutaline following three separate 4 day oral treatment periods with placebo, frusemide 40 mg, and frusemide 40 mg plus triamterene 50 mg. Serum potassium (K), and electrocardiographic (ECG) responses were measured after 30 min rest and 30 min after inhalation of terbutaline. Frusemide produced significant hypokalaemia compared with placebo (means and 95% CI): 3.58 mmol l-1 (3.5-3.66) vs 3.88 mmol l-1 (3.8-3.96) (P less than 0.001), and this effect was significantly attenuated by the addition of triamterene: 3.80 mmol l-1 (3.72-3.88) (P less than 0.05). Terbutaline alone also caused significant hypokalaemia: from 3.88 mmol l-1 (3.8-3.96) to 3.35 mmol l-1 (3.24-3.46) (P less than 0.001), and a lower absolute level of K was seen when combined with frusemide: 3.13 mmol l-1 (3.02-3.24) (P less than 0.05). The addition of triamterene conferred no significant protection against the combined hypokalaemia: 3.29 mmol l-1 (3.18-3.4). Changes in T wave amplitude during the study periods showed a similar pattern of response to the hypokalaemic effects. These results show that the hypokalaemic response to terbutaline was additive to that of frusemide, and that triamterene attenuated the hypokalaemic response to frusemide, but not terbutaline.