Effect of terbutaline on mucociliary clearance in asthmatic and healthy subjects after inhalation from a pressurised inhaler and a dry powder inhaler.

BACKGROUND: beta Agonists have been shown to increase mucociliary clearance in some studies but not all. Whether the formulation of beta agonists affects mucociliary clearance is not known but may be important as the use of dry powder inhalers increases. METHODS: The effect of different methods of administration of inhaled terbutaline on mucociliary clearance and forced expiratory volume in one second (FEV1) was assessed in 10 patients with asthma and 10 healthy subjects. Terbutaline (1 mg) was administered through a metered dose inhaler with a spacer (Nebuhaler) or a dry powder inhaler (Turbuhaler), or both treatments were given, in a four way double blind, double dummy trial. Mucociliary clearance was measured by bronchoscintigraphy. RESULTS: Clearance of radioactivity from the lobar bronchi increased in the asthmatic patients by a median of 32% after terbutaline was given by metered dose inhaler and 55% after a combined dose of 2 mg from both inhalers (1 mg from each) compared with placebo but by only 9% after 1 mg of terbutaline was given by a dry powder inhaler. In the healthy subjects mucociliary clearance increased by 51% when terbutaline was given by a dry powder inhaler, by 66% when given by a metered dose inhaler, and by 66% when given by both inhalers combined. The effect of terbutaline on FEV1 was the same with each of the inhalers. CONCLUSION: Despite similar changes in FEV1 with the two formulations terbutaline increased mucociliary clearance significantly in asthmatic and healthy subjects when inhaled from a metered dose inhaler whereas when it was inhaled from a dry powder inhaler its effect was significant only in healthy subjects. The reason for the difference in asthmatic subjects is unclear, but may be associated with differences in the deposition of terbutaline.     

Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurised metered dose inhaler, as a dry powder, and as a nebulised solution.

The lung dose and deposition patterns of drug delivered by dry powder inhaler are not known. The effects of inhaling 400 micrograms salbutamol delivered by dry powder inhaler (two 200 micrograms salbutamol Rotacaps), by pressurised metered dose inhaler, and by Acorn nebuliser were studied in nine subjects with chronic stable asthma. Technetium-99m labelled Teflon particles were mixed with micronised salbutamol in the pressurised metered dose inhaler and in the capsules; technetium-99m labelled human serum albumin was mixed with the salbutamol solution for the nebuliser study. The pressurised metered dose inhaler deposited 11.2% (SEM 0.8%) of the dose within the lungs; this was significantly more than the dose deposited by the dry powder inhaler (9.1% (0.6%], but did not differ significantly from the dose delivered by the nebuliser (9.9% (0.7%]. Distribution within the peripheral third of the lung was significantly greater with the nebuliser than with the other two systems; FEV1 improved to a significantly greater extent after inhalation of 400 micrograms salbutamol from the pressurised metered dose inhaler (35.6% from baseline) than from the nebuliser (25.8%) or dry powder inhaler (25.2%). Thus after inhalation of similar doses of salbutamol a larger proportion of drug was deposited within the lungs when it was inhaled from a metered dose inhaler than from a dry powder system; the nebuliser achieved the greatest peripheral deposition. The bronchodilator response seems to depend on the amount of drug within the lungs rather than its pattern of distribution.     

Effect of a volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from a metered dose inhaler and dry powder inhaler.

BACKGROUND: High doses of inhaled corticosteroids are absorbed systemically and may cause long term side effects. As rinsing the mouth out after use and inhaling through a spacing device may reduce systemic absorption this has been further investigated. METHODS: Three crossover studies were carried out to assess the effect of budesonide given by dry powder inhaler (Turbuhaler) with and without mouth rinsing and beclomethasone dipropionate given by metered dose inhaler with or without a spacing device (Volumatic) on serum cortisol concentrations and urinary cortisol excretion in patients with asthma taking an inhaled corticosteroid. Each treatment period was two weeks with in a two week washout period. Serum cortisol concentrations at 0800 hours on day 14 and the 24 hour urinary excretion of cortisol were measured. In study 1 24 patients taking beclomethasone dipropionate 500 micrograms twice a day inhaled with (n = 10) or without (n = 14) a Volumatic spacing device were switched to a budesonide dry powder inhaler, 600 micrograms to be taken twice a day without mouth rinsing. In study 2 10 patients took budesonide 800 micrograms twice a day with and without mouth rinsing and without swallowing the rinsing water. In study 3 17 patients took budesonide 800 micrograms twice daily with mouth rinsing and beclomethasone dipropionate 500 micrograms twice daily with the spacing device and mouth rinsing. RESULTS: In study 1 no difference was seen between budesonide without mouth rinsing and beclomethasone dipropionate without a spacer: beclomethasone with spacer caused less suppression of cortisol (mean (SD) serum cortisol concentration: beclomethasone and spacer 487(148), budesonide 368(145) nmol/l). In study 2 mouth rinsing caused less suppression of morning serum cortisol concentrations (rinsing 440(63), no rinsing 375(56) nmol/1). In study 3 there was no difference in serum or urinary cortisol concentrations between twice daily beclomethasone dipropionate 500 micrograms inhaled by Volumatic spacer or budesonide by Turbuhaler 800 micrograms twice daily, both with mouth rinsing. Individual serum cortisol values were within the normal range in all patients except one in study 1. CONCLUSION: Systemic absorption of a corticosteroid inhaled from a metered dose inhaler is reduced by using a spacing device and that from a dry powder inhaler by mouth rinsing.     

Aerosol deposition in the human lung following administration from a microprocessor controlled pressurised metered dose inhaler.

BACKGROUND--Gamma scintigraphy was employed to assess the deposition of aerosols emitted from a pressurised metered dose inhaler (MDI) contained in a microprocessor controlled device (SmartMist), a system which analyses an inspiratory flow profile and automatically actuates the MDI when predefined conditions of flow rate and cumulative inspired volume coincide. METHODS--Micronised salbutamol particles contained in a commercial MDI (Ventolin) were labelled with 99m-technetium using a method validated by the determination of (1) aerosol size characteristics of the drug and radiotracer following actuation into an eight stage cascade impactor and (2) shot potencies of these non-volatile components as a function of actuation number. Using nine healthy volunteers in a randomised factorial interaction design the effect of inspiratory flow rate (slow, 30 l/min; medium, 90 l/min; fast, 270 l/min) combined with cumulative inspired volume (early, 300 ml; late, 3000 ml) was determined on total and regional aerosol lung deposition using the technique of gamma scintigraphy. RESULTS--The SmartMist firing at the medium/early setting (medium flow and early in the cumulative inspired volume) resulted in the highest lung deposition at 18.6 (1.42)%. The slow/early setting gave the second highest deposition at 14.1 (2.06)% with the fast/late setting resulting in the lowest (7.6 (1.15)%). Peripheral lung deposition obtained for the medium/early (9.1 (0.9)%) and slow/early (7.5 (1.06)%) settings were equivalent but higher than those obtained with the other treatments. This reflected the lower total lung deposition at these other settings as no difference in regional deposition, expressed as a volume corrected central zone:peripheral zone ratio, was apparent for all modes of inhalation studied. CONCLUSIONS--The SmartMist device allowed reproducible actuation of an MDI at a preprogrammed point during inspiration. The extent of aerosol deposition in the lung is affected by a change in firing point and is promoted by an inhaled flow rate of up to 90 l/min-that is, the slow and medium setting used in these studies.     

Domiciliary comparison of terbutaline treatment by metered dose inhaler with and without conical spacer in severe and moderately severe chronic asthma.

The bronchodilator response to cumulative doses of terbutaline administered by metered dose inhaler with and without a conical spacer device and by Acorn nebuliser has been compared in groups of patients with chronic severe and moderately severe asthma. After laboratory studies the patients undertook a randomised domiciliary crossover comparison of bronchodilator response to terbutaline given by metered dose inhaler with and without a spacer device, during which the severity of asthma was assessed by thrice daily recordings of peak expiratory flow (PEF) and symptom score. Improvement in FEV1 produced in the laboratory by the metered dose inhaler with spacer device was significantly greater than by metered dose inhaler alone (p less than 0.001) and similar to that from the nebuliser in both asthmatic groups throughout a range of terbutaline doses. In the domiciliary comparison mean midday and evening PEF rates were significantly higher with the use of the spacer device both in those with severe (p less than 0.01) and in those with moderately severe (p less than 0.05) asthma, and mean morning PEF was significantly higher in the severe group (p less than 0.05). The spacer device also produced a significant improvement in symptom score in both the severe and the moderately severe groups (p less than 0.05). Regular domiciliary use of the spacer device with the metered dose inhaler improves bronchodilator response, particularly in patients with chronic severe asthma, and may be a useful alternative to nebuliser treatment.     

Effect of an extension tube on the bronchodilator efficacy of terbutaline delivered from a metered dose inhaler.

A double-blind within-patient investigation was performed to determine whether the interposition of an extension tube (10 cm length X 3.2 cm diameter) between a metered dose inhaler and the mouth alters the bronchodilator efficacy of terbutaline sulphate. On two consecutive study days 14 adult patients with stable reversible airways obstruction inhaled a cumulative dose of 500 micrograms of terbutaline which was delivered from a metered dose inhaler with or without the extension tube attached and received placebo in a similar manner. The drug was inhaled in doses of 125, 125, and 250 micrograms at 20 minutes intervals. The following measurements were made: forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), thoracic gas volume (TGV), and specific airways conductance (sGaw). These were done immediately before and at five and 15 minute intervals after each dose, and were repeated 90, 120, 180, 240, and 300 minutes after the first inhalation of terbutaline. Administration of terbutaline with and without an extension tube achieved significant bronchodilation at all dose levels in all respiratory variables (p < 0.001). There was no statistically significant difference in FEV1, FVC, PEFR, and sGaw values at any time or dose level with either method of administration. The use of the extension tube did not impair the efficacy or duration of action of inhaled terbutaline.     

Delivery of propellant soluble drug from a metered dose inhaler.

The deposition of particulate suspensions delivered from a metered dose inhaler has been investigated extensively. The distribution of propellant, delivered from a metered dose inhaler, was studied by radiolabelling it with technetium-99m hexamethylpropyleneamine oxime. Andersen sampler measurements indicated that half of the dose was associated with particles in the size range 0.5-5 microns diameter. The preparation was administered to healthy subjects by inhalation and deposition was monitored with a gamma camera. Each lung image was divided into an inner, mid, and peripheral zone. The effects on deposition of varying the size of the delivery orifice (0.46, 0.61, and 0.76 mm internal diameters) and the effect of attaching a spacer were assessed. Lung deposition was independent of the orifice size within the actuator. Without the spacer the average dose deposited in the lungs was 39%, with 15% penetrating into the peripheral part of the lungs. Attachment of the spacer to the mouth-piece increased the mean lung deposition to 57% and reduced oropharyngeal deposition. The study has shown that propellant soluble drugs can be delivered efficiently to the lungs from a metered dose inhaler.     

Factors affecting total and "respirable" dose delivered by a salbutamol metered dose inhaler.

BACKGROUND--Many factors contribute to the high variability of doses delivered to the lungs of patients using metered dose inhalers (MDIs). Relatively little attention has been paid to the contribution to this variability of the way in which the MDI is handled before the inhalation manoeuvre. Instruction leaflets often recommend procedures at odds with those used for in vitro testing of the device. The standard protocol for in vitro assessment of salbutamol MDIs involves shaking the MDI vigorously for 30 seconds and wasting the first two actuations. Subsequent actuations are introduced into the testing device at five second intervals. Patient instructions do not include a recommendation to waste the first two actuations and recommend a delay of one minute between actuations. A series of experiments was performed to determine whether such differences might be important. METHODS--The total and "respirable" doses delivered by a salbutamol MDI (Ventolin, Allen & Hanburys) under various conditions were assessed with a multistage liquid impinger. The quantity of drug deposited on each stage was measured by an ultraviolet spectrophotometric method. The effect on the delivered dose of not shaking the canister, not wasting the first two doses, waiting 30 seconds between actuations, and using multiple rapid actuations was assessed by comparing the results with those obtained using the standard in vitro testing protocol. RESULTS--Compared with a standard protocol, it was found that not shaking the MDI before use reduced the total and "respirable" dose by 25.5% and 35.7%, respectively. The dose delivered when actuating the MDI at 30 second intervals was no different from that when intervals was no different from that when intervals of five seconds were used. Two actuations separated by one second had no effect on the total dose but reduced the "respirable" dose by 15.8%, while four rapid actuations reduced the total and "respirable" doses by 8.2% and 18.2%, respectively. Storing the MDI stem down reduced the total and "respirable" dose delivered in the first actuation by 25.0% and 23.3% despite shaking the MDI before use. CONCLUSIONS--MDIs containing drug in suspension must be shaken before use to resuspend the drug contained in the MDI, but shaking does not alter the composition of the suspension in the metering chamber and hence the dose in the first actuation remains low. Very rapid actuations can reduce the dose delivered per actuation, but salbutamol MDIs can be actuated immediately after a 10 second breath holding pause without affecting the dose delivered.     

Foreign body aspiration following unconventional use of a metered dose inhaler

PURPOSE: Aspiration of a foreign body may be life-threatening. This report describes laryngeal obstruction after inhalation of a piece of a Turbuhaler which resulted from a patient tampering with the device. CLINICAL FEATURES: A 27-yr-old man disassembled a Turbuhaler and inadvertently aspirated a plastic dispensing medication disc (22 mm diameter) while attempting to inhale the remnant terbutaline sulfate which accumulated on it. Although the patient was hoarse, he was not in acute respiratory distress. X-ray revealed the disc lodged in the larynx below the vocal cords. The patient was immediately transferred to an operating theatre, and a drying agent (glycopyrrolate), judicious sedation (midazolam and fentanyl) and O2 were administered. The airway was anesthetized with lidocaine 4% delivered using high-flow O2 through an atomizer. Direct laryngoscopy revealed a partially obstructed view of the disc lodged distal to the vocal cords which was inaccessible for retrieval. Loss of consciousness was subsequently induced by spontaneous mask ventilation with sevoflurane (in O2). The airway was visualized using a suspension laryngoscope and the foreign body was removed with grasping forceps. The patient was awakened, transferred to the ICU and given 4 mg decadron i.v. every eight hours (two doses). Laryngoscopy prior to discharge indicated good mobility of the vocal cords and normal glottic structure. CONCLUSION: Aspiration of a foreign body is a potentially life-threatening situation requiring coordination between anesthesiologist, surgeon, and nursing staff. Anesthetic goals include avoidance of upper airway obstruction and maintenance of adequate ventilation while the foreign body is retrieved. Provisions must be made for tracheostomy if these goals cannot be realized.     

Comparative dose-response study of three anticholinergic agents and fenoterol using a metered dose inhaler in patients with chronic obstructive pulmonary disease.

BACKGROUND--Inhaled anticholinergics and beta agonists are widely used in the treatment of patients with chronic obstructive pulmonary disease (COPD). However, dosage requirements have not been thoroughly evaluated and comparative dose-response data for these agents are limited. METHODS--Twenty men with stable COPD of mean (SD) age 69.4 (5.8) years and FEV1 0.93 (0.38) litres were studied in randomised, double blind, crossover, placebo controlled experiments. All of the patients received two, four, eight, and 16 puffs of ipratropium bromide (20 micrograms/puff), flutropium bromide (30 micrograms/puff), oxitropium bromide (100 micrograms/puff), fenoterol (200 micrograms/puff), or placebo in random order on five separate days. Doses were administered by a metered dose inhaler at intervals of 60 minutes to give cumulative doses of two, six, 14, and 30 puffs. Five mg of nebulised salbutamol was administered 60 minutes after the patient had received the final 16 puffs of each regimen. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), heart rate, and blood pressure were measured five minutes before each treatment and 30 minutes after treatment with nebulised salbutamol. RESULTS--FEV1 and FVC reached a plateau after administration of a cumulative dose of 14 puffs of ipratropium bromide (280 micrograms) or flutropium bromide (420 micrograms), and after six puffs of oxitropium bromide (600 micrograms). There were no differences with respect to maximum increases in FEV1 and FVC amongst the three anticholinergic agents. However, after six puffs oxitropium bromide produced a greater increase in FEV1 than either ipratropium bromide or flutropium bromide. Fenoterol caused a greater increase in both FEV1 and FVC than the three anticholinergic agents after six puffs, as well as a greater increase in pulse rate. Oxitropium bromide produced a greater increase in pulse rate than the other anticholinergics after 14 puffs. The incidence of side effects was dose-related and notable adverse effects were reported after 30 puffs of ipratropium bromide, 14 puffs of oxitropium bromide, and two puffs of fenoterol. CONCLUSIONS--Oxitropium bromide produced a greater bronchodilator effect than either ipratropium bromide or flutropium bromide when used at doses of less than six puffs, without apparent side effects. There were, however, no differences in maximal response between these drugs. Fenoterol may have a greater peak bronchodilator effect than the anticholinergic agents but it causes more adverse effects, even at lower doses. Depending upon the balance between efficacy and side effects, oxitropium bromide may be preferred in the treatment of patients with COPD.     

Improvement of drug delivery with a breath actuated pressurised aerosol for patients with poor inhaler technique.

BACKGROUND The metered dose inhaler is difficult to use correctly, synchronising actuation with inhalation being the most important problem. A breath actuated pressurised inhaler, designed to help patients with poor inhaler technique, was compared with a conventional metered dose inhaler in terms of aerosol deposition and bronchodilator response. METHODS Radioaerosol deposition and bronchodilator response to 100 micrograms salbutamol were measured in 18 asthmatic patients, who inhaled from a conventional metered dose inhaler by their own chosen metered dose inhaler technique, from a conventional metered dose inhaler by a taught metered dose inhaler technique, and from a breath actuated pressured inhaler (Autohaler). RESULTS In the 10 patients who could coordinate actuation and inhalation of the inhaler on their own deposition of aerosol in the lungs and bronchodilator response were equivalent on the three study days. By contrast, in the eight patients who could not coordinate the mean (SEM) percentage of the dose deposited in the lungs with their own inhaler technique (7.2% (3.4%] was substantial lower than those attained by the taught metered dose inhaler technique (22.8% (2.5%] and by Autohaler (20.8% (1.7%]. CONCLUSION Although of little additional benefit to asthmatic patients with good coordination, the Autohaler is potentially a valuable aid to those with poor coordination, and should be considered in preference to a conventional metered dose inhaler in any patient whose inhaler technique is not known to be satisfactory.     

Time course and duration of bronchodilatation with formoterol dry powder in patients with stable asthma.

BACKGROUND--Formoterol, a new beta 2 agonist, is long and fast acting when given as an aerosol. The aim was to determine the onset and duration of bronchodilatation with formoterol as a dry powder compared with salbutamol dry powder and with placebo. METHODS--Fifteen patients with stable asthma with a reversibility of 15% or more participated in a double blind, within patient study. On five different days the patients received formoterol 6 micrograms, 12 micrograms, or 24 micrograms, salbutamol 400 micrograms, or placebo in random order. Forced expiratory volume in one second (FEV1) was measured 10 minutes before, 30 minutes after, and then every hour for up to 12 hours after treatment. Specific airway resistance (sRaw) and specific airway conductance (sGaw) were measured immediately before and one, three, five, 10, 15, and 30 minutes after treatment. RESULTS--Formoterol 12 micrograms and 24 micrograms caused bronchodilatation as rapidly as salbutamol 400 micrograms. Peak values were not significantly different in the active treatments. The duration of action, calculated as median time with 20% or more of the maximum achieved increase in FEV1, was sustained for 9 hours and 16 minutes with salbutamol 400 micrograms, for 9 hours and 45 minutes with formoterol 6 micrograms, for 11 hours and 22 minutes with formoterol 12 micrograms, and for 11 hours and 42 minutes with formoterol 24 micrograms. CONCLUSIONS--Formoterol as a dry powder at doses of 12 micrograms and 24 micrograms produces a rapid onset of action and has a bronchodilator effect comparable with salbutamol 400 micrograms as a dry powder. The bronchodilatation was sustained for 11-12 hours. Formoterol 6 micrograms caused similar bronchodilatation but more slowly and for a shorter time.     

Comparison of inhaled and intravenous terbutaline in acute severe asthma.

In patients with acute severe asthma, 5 mg of terbutaline by inhalation and 500 microgram intravenously in divided doses both produced equally effective but not maximal bronchodilatation. There was no difference in the production of side-effects. These results support the view that inhaled therapy can be as effective in patients with acute severe asthma as injected treatment. In view of the risks of intravenous treatment, especially using high doses, inhaled bronchodilator therapy would seem advisable as initial treatment.     

Comparison of the systemic effects of fluticasone propionate and budesonide given by dry powder inhaler in healthy and asthmatic subjects

BACKGROUND: The potential for long term adverse effects from inhaled corticosteroids relates to their systemic absorption, usually assessed from proxy markers in short term studies. When fluticasone propionate and budesonide have been compared in this way the results have been inconsistent. To determine whether this is because of the subjects studied or the sensitivity of the systemic marker used, we have compared the effects of fluticasone propionate and budesonide in healthy and asthmatic subjects and investigated the effect of treatment on three systemic markers. METHODS: Forty six healthy subjects were randomised to receive inhaled fluticasone propionate 1500 microg/day (via an Accuhaler), budesonide 1600 microg/day (via a Turbuhaler), or placebo; 31 subjects with moderately severe asthma were randomised to receive the same doses of fluticasone propionate or budesonide but not placebo. Systemic effects in healthy and asthmatic subjects were compared after 7 days. Treatment was continued for another 21 days in the subjects with asthma when systemic effects and asthma control were assessed. RESULTS: At baseline healthy subjects had higher urinary levels of total cortisol metabolites (TCM) than subjects with asthma. After 7 days of treatment with fluticasone propionate urinary TCM levels in the healthy subjects were significantly lower than in the subjects with asthma (mean difference between groups 1663 microg/day, 95% CI 328 to 2938). This was not the case with budesonide, however, where urinary TCM levels in the healthy subjects remained above those in the asthmatic subjects (mean difference between groups 1210 microg/day, 95% CI -484 to 2904). Urinary TCM levels were considerably more sensitive to the effects of inhaled corticosteroids than morning serum cortisol or osteocalcin concentrations. Only budesonide reduced the serum level of osteocalcin. CONCLUSIONS: When given by dry powder inhaler for 7 days, fluticasone propionate 1500 microg/day has a greater effect on the hypothalamic-pituitary-adrenal axis in healthy subjects than in subjects with asthma, but this is not the case for budesonide 1600 microg/day. These findings, together with the differences in sensitivity between systemic markers, explain many of the discrepancies in the literature.     

In vitro assessment of drug delivery through an endotracheal tube using a dry powder inhaler delivery system.

BACKGROUND: Jet nubulisers and metered dose inhalers are widely used to deliver aerosolised drugs to the lungs of intubated patients in adult intensive care units. Drug delivery using these systems has been shown to be inefficient and both forms of delivery have the potential to induce paradoxical bronchoconstriction in patients with reactive airways disease. METHODS: Experiments were carried out to determine whether it was possible to deliver drug from a dry powder delivery system through an endotracheal tube. A 200 micrograms budesonide Turbohaler was enclosed in a chamber which allowed it to be inserted into a ventilator circuit. Experiments were performed with a multistage liquid impinger in which drug was drawn through the Turbohaler and endotracheal tube at 60 l/min providing an index of the maximum drug delivery achievable via this route. A second series of experiments was performed in which the Turbohaler was placed in a ventilator circuit using a Servo 900C volume cycled ventilator. Drug delivered from the Turbohaler during the inspiratory phase was collected on a filter placed between the end of a 9 mm endotracheal tube and a model lung. A tidal volume of 500 ml and inspiratory time of 0.5 seconds was used. Budesonide was assayed using an ultraviolet spectrophotometric assay. RESULTS: Thirty percent of the nominal dose passed through the endotracheal tube and was collected in the multistage liquid impinger. Mean drug delivery to the filter in the ventilator circuit was 20%. CONCLUSIONS: This in vitro study indicates that drugs from dry powder inhalers (in this case the Turbohaler) can be satisfactorily delivered through endotracheal tubes and that clinical evaluation of this technique is now indicated.     

Creatine kinase activity in patients with brittle asthma treated with long term subcutaneous terbutaline.

Infused beta 2 agonists have been shown to cause focal myocardial necrosis. Serum creatine kinase activity was compared in 13 patients with brittle asthma currently being treated with subcutaneous terbutaline and an age and sex matched control group of patients with moderate asthma having inhaled treatment only. The median serum total creatine kinase activity for patients receiving subcutaneous terbutaline (211 units/l) was greater than that for the control group (120 units/l). The cardiac specific isoenzyme component of creatine kinase was not raised in either group, and the electrocardiograms and serum aspartate aminotransferase activity were normal. Electromyograms in five patients receiving subcutaneous terbutaline with high creatine kinase activity showed changes consistent with myositis in two, one of whom was subsequently shown to have a metabolic myopathy, which is thought to be long standing. No pathological changes were seen in the myocardium at necropsy in a patient who died from an acute attack of asthma while taking subcutaneous terbutaline. These results suggest that the raised creatine kinase activity seen in patients receiving this treatment is unlikely to be myocardial in origin.     

Effect of sustained release terbutaline on symptoms and sleep quality in patients with nocturnal asthma.

The effect of an oral sustained release beta 2 agonist on symptoms, sleep quality, and peak flow rates has been studied in nine patients with nocturnal asthma. Patients received oral terbutaline 7.5 mg twice daily or placebo for seven days in a double blind crossover study and spent the last two nights of each limb in a sleep laboratory. Oral terbutaline improved morning peak flow (259 v 213 l min-1) and decreased nocturnal inhaler usage (1.3 v 1.9) with no alteration in sleep quality as assessed electroencephalographically. The study shows that oral sustained release terbutaline can be useful in the treatment of nocturnal asthma without impairment of sleep quality.     

Lung bioavailability of generic and innovator salbutamol metered dose inhalers.

BACKGROUND: The aim of this study was to determine whether significant differences exist in lung bioavailability between generic (Salamol, Salbulin) and innovator (Ventolin) formulations of inhaled salbutamol given by metered dose inhalers. METHODS: Ten healthy volunteers of mean age 20.5 years with a forced expiratory volume in one second (FEV1) of 112.1% predicted were studied in a randomised double blind single dosing crossover study. Salbutamol, 1200 micrograms, was given with mouth rinsing and lung bioavailability was assessed by measuring plasma salbutamol levels and urine excretion of salbutamol. RESULTS: No differences were seen between innovator and generic salbutamol metered dose inhalers in plasma salbutamol levels, urinary salbutamol excretion, or extrapulmonary beta 2 activity. The maximum plasma salbutamol concentration (mean Cmax) and time to maximum concentration (median Tmax) were: Ventolin (2.93 ng/ml, 10 minutes), Salbulin (3.01 ng/ml, 10 minutes), Salamol (3.33 ng/ml, 10 minutes). The geometric mean ratio and 95% confidence interval for Cmax were: Salbulin/Ventolin 1.02 (0.69 to 1.41) and Salamol/Ventolin 1.13 (0.94 to 1.35). CONCLUSIONS: No differences are apparent between the two generic and innovator formulations of salbutamol metered dose inhaler in terms of lung bioavailability.