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In vitro comparison of beclomethasone and salbutamol metered-dose inhaler aerosols inhaled during pediatric tidal breathing from four valved holding chambers.

STUDY OBJECTIVES: To determine the amount of salbutamol or beclomethasone delivered from metered-dose inhalers (MDIs) in particle sizes appropriate for inhalational treatment with four common holding chambers (AeroChamber, OptiChamber, Space Chamber, E-Z Spacer) when used under simulated pediatric tidal breathing conditions. DESIGN: Five devices of each type were tested with salbutamol (100 microg, Glaxo-Wellcome) and beclomethasone (50 microg, Glaxo-Wellcome) MDIs. Each device was connected to face replicas representative of 7-month-old (infant), 2-year-old (toddler), and 4-year-old (child) children and aerosol inhaled into a cascade impactor (Anderson) using a valve system and simulated tidal breathing patterns representative of children of these ages. MEASUREMENTS AND RESULTS: Amounts of drug inhaled in fine particles varied significantly between devices and ages (p < 0.01), eg, for beclomethasone, from 4 microg (infant, Space Chamber) to 8 microg (toddler, OptiChamber), and for salbutamol, from 18 to 36 microg. The AeroChamber and OptiChamber behaved quite similarly, delivering more drug in the fine particles than the other two devices, and having insignificant variations in these amounts with age (p > 0.05). CONCLUSIONS: Amounts of drug inhaled in fine particles during pediatric tidal breathing from valved holding chambers are dependent on the holding chamber model, the drug used, and the breathing pattern, although dependence on the breathing pattern is relatively small for some of the devices tested.

Administration, Inhalation↗

Extrafine beclomethasone dipropionate breath-actuated inhaler (400 micrograms/day) versus budesonide dry powder inhaler (800 micrograms/day) in asthma.

Hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol breath-actuated inhaler (Qvar Autohaler; BDP-AH) provides an alternative to chlorofluorocarbon metered dose inhalers or dry powder inhalers (DPIs). The aim of this six-week, open-label study was to determine whether BDP-AH demonstrates equivalent asthma control to twice the dose of budesonide (BUD)-DPI (Pulmicort Turbuhaler). Adults with symptomatic asthma inadequately controlled on BUD-DPI 400 micrograms/day and beta-agonist were enrolled. Patients (n = 193) were randomised to receive 400 micrograms/day BDP-AH (n = 98) (two puffs of 100 micrograms/actuation inhaler twice daily) or 800 micrograms/day BUD-DPI (n = 95) (two puffs of 200 micrograms/actuation inhaler twice daily). Both groups showed a statistically significant change from baseline in morning (a.m.) peak expiratory flow (PEF) at weeks 5-6 (p < 0.01), indicating study treatment improved a.m. PEF over prestudy 400 micrograms/day BUD. Changes from baseline in a.m. PEF at weeks 5-6 were 15.9 l/min for BDP-AH and 14.2 l/min for BUD-DPI; the groups were statistically equivalent (90% CI -7.02-10.44; p < -0.001 [equivalence = within +/- 25 l/min]). Other efficacy assessments (evening PEF, FEV1, asthma symptoms, beta-agonist use) confirmed the treatments were clinically equivalent. Thirty-nine (40%) patients on BDP-AH and 35 (37%) on BUD-DPI experienced at least one adverse event (p = 0.767). Four (4%) patients on BDP-AH and 3 (3%) on BUD-DPI reported increased asthma symptoms. BDP-AH at half the daily dose provided equivalent asthma control to BUD-DPI; both treatments were well tolerated.

Administration, Inhalation↗

Acute resistant asthma caused by excessive beta-2-adrenoceptor agonist inhalation and reversed by inhalation of beclomethasone.

With the aim of devising an improved beta 2-agonist treatment regimen for patients presenting with acute severe resistant asthma, a double-blind, placebo-controlled randomised study of the effect of fenoterol and beclomethasone inhalations was done in 40 patients. Fenoterol inhalations had minimal effect in acute resistant asthma, but significant improvement was obtained when beclomethasone inhalations were given before fenoterol inhalations. Sequential beclomethasone and fenoterol inhalations can therefore be used as a preliminary emergency treatment for these patients.

Administration, Inhalation↗

[Comparison of the bronchodilator effect of salbutamol between pressure metered dosed inhaler and dry powder inhaler in patients with stable bronchial asthma].

Recently, dry powder inhaler (DPI) was more available than pressure metered dosed inhaler (pMDI) for the inhalation therapy of the respiratory disease. But there are differences in the lung deposition of the drug in these devices. We investigated the bronchodilator effect of salbutamol inhalation with two device, pMDI and Tubuhaler on the stable 8 asthmatic patients. The time course of FEV1 had a no significant difference between two devices. DeltaAUC (=difference between area under the curve for time course of increase in FEV1 via pMDI and via DPI) and Deltamax FEV1 (=difference between maximum increases in FEV1 following inhalation of salbutamol via pMDI and DPI) were defined as the index of difference of bronchodilator effect between the two devices. PMDI was more effective on improving the pulmonary function in subjects with severely decreased FEV1 and FEV1% than DPI. These results may reflect the correlation of inspiratory flow rate and drug deposition. PMDI is still useful on the part of asthmatic patients with decreased pulmonary function.

Adult↗

Inhalation of pertechnegas: similar clearance from the lungs to that of inhaled pertechnetate aerosol.

It has been reported that the inhalation of pertechnegas (TGO3) generated under an atmosphere of 3% oxygen (O2) in argon (Ar) instead of 100% Ar without O2 in the technegas generator, offers a simple but accurate quantification of clearance from the lungs, permitting it to be used in place of 99Tcm-diethylenetriamine pentaacetic acid (DTPA). The disappearance from the lungs of inhaled TGO3 was so similar to that of inhaled pertechnetate aerosol (TcO4) in this study, that there was neither a statistically significant difference in the clearance half-time (t1/2), nor a difference in the lung images between them. Neither TGO3 nor TcO4 inhalation could distinguish smokers from non-smokers using t1/2. When inhaled, TGO3 appears to behave in a similar manner to TcO4 in the lungs and hence cannot be used in place of 99Tcm-DTPA in clinical practice.

Administration, Inhalation↗

Nasal distribution of budesonide inhaled via a powder inhaler.

The distribution pattern of budesonide in the nasal passages and lungs was investigated in 10 healthy subjects after nasal inhalation. The subjects inhaled drug powder, radiolabelled with 99mTc, at maximum flow rate (46.3 +/- 6.8 l/min) and at 29.9 +/- 2.5 l/min via Turbuhaler. At both flows, the majority of the dose was deposited in the anterior part of the nasal cavity on a single, rather localized area, but some particles also penetrated more posteriorly into the main nasal passages and to the lungs. At maximum flow rate the nasal deposition was 65.2% (range 39.5-84.1%) and the lung deposition 4.7% (range 1.4-9.3%) of the metered dose, and at 30 l/min, the nasal deposition was 67.6% (range 49.7-81.6%) and the lung deposition was 4.2% (range 1.7-7.9%). A large fraction of the metered dose was deposited in the nasal adaptor of the inhaler during the administration (mean values 29 and 28%, for the two inhalation flows). Of the dose actually reaching the subject, 91 and 93% (mean values) was deposited in the nose. There were no statistically significant differences in distribution pattern between the two inhalation flows.

Administration, Inhalation↗

Standardization of inhalation provocation tests: influence of nebulizer output, particle size, and method of inhalation.

Standardization of inhalation tests requires a knowledge of factors that will affect the response. We measured the output and particle size of six types of nebulizers used for inhalation tests. Output varied considerably between nebulizers of different types (0.12 to 1.59 ml/min) and to a lesser extent between nebulizers of the same type. Particle size varied between 0.8 and 5.2 micrometer aerodynamic mass median diameter (AMMD). The influence of these two properties on bronchial response to inhaled methacholine was examined. Nebulizer output but not particle size (between 1.3 and 3.6 micrometer AMMD) altered the response. We also examined the effect of change in inspiratory time during inhalation from residual volume to total lung capacity on lung deposition of radiolabeled aerosol and on the provocative concentration of histamine required to reduce the 1-sec forced expiratory volume (FEV1) by 20% (PC20). A reduction in inspiratory time from 8 to 2 sec resulted in a lower total lung dose, relatively more aerosol deposited in central airways, and a higher PC20. The results emphasize the importance of keeping nebulizer output and pattern of breathing constant when performing inhalation provocation tests if consistent results are to be obtained.

Aerosols↗

Addition of inhaled salmeterol to inhaled corticosteroids in patients with poorly controlled nocturnal asthma.

The effect of adding inhaled salmeterol to inhaled corticosteroids was studied in patients with poorly controlled nocturnal asthma. In a double-blind, cross-over study, 20 patients were randomized to receive either salmeterol 50 micrograms twice daily or placebo via a Diskhaler after a 1-week run-in period. After 4 weeks of treatment, patients were subsequently crossed over to receive the other treatment for a further 4 weeks with a 2-week wash-out period in between. The response to treatment was assessed by peak expiratory flow rates (PEF) measured in the morning and evening, symptom scores of asthma, number of bronchodilators used, forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) at regular intervals. Patients' preference for the Diskhaler or metered-dose inhaler was assessed at the last visit. The results showed that morning PEF was significantly higher while on salmeterol than on placebo (296.9 +/- 70.2 vs 274.6 +/- 77.4 L/min). Evening PEF showed a trend towards a higher value while on salmeterol than on placebo (321.1 +/- 73.4 vs 288.7 +/- 79.4 L/min), but the difference was not significant. There was no statistically significant improvement in symptom scores, number of rescue bronchodilators used and FEV1 or FVC between the two treatment groups. The occurrence of side effects in terms of tremors and palpitations between treatment and placebo were similar. There were more patients who preferred Diskhaler to metered-dose inhaler (70% vs 30%). We conclude that salmeterol 50 micrograms twice daily produces significant improvement in morning PEF and is well tolerated in patients with nocturnal asthma. Diskhaler is a device which is easy to use and preferred to a metered-dose inhaler.

Adult↗

Therapeutic equivalence of inhaled beclomethasone dipropionate with CFC and non-CFC (HFA 134a) propellants both delivered via the Easibreathe inhaler for the treatment of paediatric asthma.

Chlorofluorocarbon (CFC)-containing inhalers for use in the treatment of asthma are to be phased out under the terms of the Montreal Protocol (1). In this multi-centre, randomized, double-blind study, the therapeutic equivalence of two formulations of beclomethasone dipropionate (BDP) containing CFC or non-CFC (HFA134a) propellant, both delivered via the Easibreathe (Norton Healthcare Ltd, London, U.K.) inhaler, was determined in 229 asthmatic children. Each child received 100 microg doses of BDP (containing either CFC or HFA propellant) twice daily for 12 weeks. Both CFC and HFA formulations produced statistically and clinically significant improvements in patient's lung function and symptom scores when administered via the Easibreathe inhaler. The improvements in mean morning peak expiratory flow (PEF) were 41 l min(-1) and 34 l min(-1) for the BDP-HFA and BDP-CFC products respectively (P<0.001) and for mean evening PEF the improvements were 38 l min(-1) and 38 l min(-1), respectively (P<0.001). Similar findings were demonstrated for the other efficacy parameters. The two formulations were statistically equivalent with respect to efficacy. For mean morning PEF the estimated treatment difference (BDP-CFC/BDP-HFA ratio) was 102.6% (95% CI 99.1, 106.2). Similar equivalence was shown for the other efficacy parameters. Both products were well tolerated, with no difference in the adverse event profiles, effects on 24 h urinary cortisol or Candida colonisation. This study demonstrates that the new formulation of BDP with HFA-134a propellant is equivalent to and directly substitutable for BDP with the older CFC propellant in a dose for dose manner. This should enable a seamless transition from one product to the other when CFC containing products are eventually phased out. In addition this study has also shown that the Easibreathe inhaler is an effective delivery system for use with inhaled products for the treatment of asthma in children.

Aerosol Propellants↗

A comparison of terbutaline inhaled by Turbuhaler and by a chlorofluorocarbon (CFC) inhaler in children with exercise-induced asthma.

The present study compared the bronchodilating effect of inhalation from the Turbuhaler (0.5 mg terbutaline x 2) with the effect of inhalation from the chlorofluorocarbon (CFC) inhaler (0.25 mg terbutaline x 4) in children aged 9-17 years with reproducible, exercise-induced asthma (EIA). The treatments were given on two occasions, 5 min apart (terbutaline 0.5 mg + 0.5 mg). The study was performed as a double-blind, double-dummy, and placebo-controlled trial in 12 asthmatic children. The study was conducted on three separate days. The bronchoconstriction was induced by steady running on a treadmill. Forced expiratory volume in 1 s (FEV1.0), vital capacity (VC), and volume of trapped gas (VTG) were measured before and after the exercise test and after treatment. The study showed that the same amount of terbutaline inhaled from the Turbuhaler or from a CFC inhaler is equally effective for reversing EIA, and that the Turbuhaler is possibly more effective for treating spasm in small airways.

Adolescent↗

Inhaled drug delivery: a practical guide to prescribing inhaler devices.

Direct delivery of medication to the target organ results in a high ratio of local to systemic bioavailability and has made aerosol delivery of respiratory medication the route of choice for the treatment of obstructive lung diseases. The most commonly prescribed device is the pressurized metered dose inhaler (pMDI); its major drawback is the requirement that inspiration and actuation of the device be well coordinated. Other requirements for effective drug delivery include an optimal inspiratory flow, a full inspiration from functional residual capacity and a breath hold of at least 6 s. Available pMDIs are to be gradually phased out due to their use of atmospheric ozone-depleting chlorofluorocarbons (CFCs) as propellants. Newer pMDI devices using non-CFC propellants are available; preliminary experience suggests these devices greatly increase systemic bioavailability of inhaled corticosteroids. The newer multidose dry powder inhalation devices (DPIs) are breath actuated, thus facilitating coordination with inspiration, and contain fewer ingredients. Furthermore, drug delivery is adequate even at low inspired flows, making their use appropriate in almost all situations. Equivalence of dosing among different devices for inhaled corticosteroids will remain imprecise, requiring the physician to adjust the dose of medication to the lowest dose that provides adequate control of asthma. Asthma education will be needed to instruct patients on the effective use of the numerous inhalation devices available.

Anti-Asthmatic Agents↗

Standardization of inhalation provocation tests: two techniques of aerosol generation and inhalation compared.

Comparison of methods of aerosol generation and inhalation is required to improve standardization of inhalation provocation tests. We compared two widely used methods in 10 asthmatics, by measuring the dose and distribution of radiolabeled aerosol deposited in the throat and lung, and the provocation concentration of inhaled histamine required to reduce the FEV1 by 20% (PC20). In one method, aerosol was generated by a DeVilbiss 646 nebulizer attached to a dosimeter, and was inhaled by 5 inspiratory capacity breaths. The measurements with each method were repeated once to determine the reproducibility of results. Both methods deposited the same dose in the lung, but the distribution of the dose was different; the dosimeter method deposited more aerosol in the throat and central airways. The PC20 obtained with each method was the same. The reproducibility of all measurements in the same subject was similar. The lung dose deposited by each method in different subjects varied to the same degree. The results indicated that the bronchial response to inhaled histamine can be measured as reliably using a nebulizer and tidal breathing as by a more complex dose-metering device. They also suggested that, when the methods are regulated as described, the PC20 will have the same clinical significance.

Adolescent↗

Salmeterol administration by metered-dose inhaler alone vs metered-dose inhaler plus valved holding chamber.

STUDY OBJECTIVE: To determine whether a spacer device designed as a valved holding chamber with a flow signal increases the efficacy of the long-acting beta(2)-agonist, salmeterol, in patients who use incorrect technique with metered-dose inhaler (MDI) alone. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: University hospital outpatient rooms. PATIENTS: Twenty adult outpatients with stable persistent asthma, receiving a daily anti-inflammatory drug. INTERVENTIONS: Patients were randomized to either salmeterol MDI (incorrect use: 1 s after actuating MDI, inhale rapidly) and placebo plus spacer (correct use: inhale slowly as MDI is actuated, continue to inhale slowly and deeply) or placebo MDI (incorrect use) and salmeterol plus spacer (correct use). The following week, patients received the opposite treatment. The dose was two puffs from each device on each treatment day; each puff was separated by 1 min. MEASUREMENTS AND RESULTS: After baseline peak expiratory flow (PEF), salmeterol was administered and serial PEF determined (0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h). Administration of salmeterol MDI plus spacer resulted in significantly greater increases in PEF from baseline vs MDI at 4 h (44 L/min vs 10 L/min; p < 0.01) and 6 h (49 L/min vs 24 L/min; p < 0.05). Both methods of administration were equally well tolerated. CONCLUSION: We conclude that patients who have poor timing and rapid inhalation with salmeterol MDI alone will have greater increases in PEF at 4 h and 6 h and no additional side effects if the dose is administered with a valved holding chamber that is used correctly. Further study is needed regarding other errors in MDI technique with salmeterol.

Adult↗

[Experimental studies of long-term aerosol inhalation. Inhalation chambers and their operation characteristics (author's transl)].

In an attempt to develop the technique for long-term inhalation studies, a "multipurpose" inhalation system was devised. Using this system, an experimental model of the human polluted lung was successfully produced in rats after long lasting inhalation of heavy oil combustion products as a model aerosol. Facilities for concentration regulation of the particulated matter and the actual concentrations obtained throughout this experiment were described in the previous first report. In this second report, newly devised two types of inhalation chambers are described. One is a typical pyramidal type chamber of about 1 m3 with a newly devised exhaust orifice and another is an economical plane cubic type chamber of about 200l. Their operation characteristics, i.e., distribution of the particulated materials and maintenance of biological environment in the chamber were determined on a series of preliminary experiments under various air exchange rates. From the results routine performance discipline has been established. Data in the biological environment obtained from continuous operations of this inhalation system for over three years are also described. Occurrence of unfavorable respiratory infection was successfully avoided throughout those life long experiments, making the average life span and the main cause of the death of the animals satisfactorily acceptable.

Aerosols↗

Randomized comparison of a dry powder inhaler and metered dose inhaler with spacer in management of children with asthma.

OBJECTIVE: Comparison of the clinical efficacy of a transparent, DPI (transparent Rotahaler) with MDI and spacers in childhood asthma. DESIGN: Open, randomized, crossover trial. SETTINGS: Out patient clinic of a referral pediatric center. METHODS: Thirty (mean 6.1 +/-2.7 years) children with moderate persistent asthma were randomized to receive long-term medications by a DPI or a metered dose inhaler with spacer for six weeks and then crossed over to receive the same drugs for another period of six weeks after an initial run in period of one week for training in inhalation techniques. The preventative therapy consisted of inhaled Beclomethasone dipropionate (600 mcg/day) and Salbutamol as per requirement. The patients were monitored by a symptom diary, weekly PEFR, and PEFR variability by the parental record of PEFR measurements at home with Mini Wright s Peakflow meter in accordance with the Consensus guidelines. RESULTS: Comparisons made on weekly symptom scores, PEFR at interval visits, PEFR variability, additional beta sympathomimetic use and acute exacerbations of asthma did not reveal any statistically significant differences during the two treatment periods (>0.05). CONCLUSION: Metered dose inhaler and dry powder inhaler have equal efficacy in anti-inflammatory therapy of bronchial asthma in children.

Anti-Asthmatic Agents↗

Stability and performance characteristics of a budesonide powder for inhalation with a novel dry powder inhaler device.

The design and the functionality of an innovative, multidose dry powder inhaler for the topical administration of drugs to the lung are described. The integrated triple inhalation control system, combined with easy handling, should increase acceptance of the device by patients. In-vitro data on a 200-microgram dose of budesonide powder for inhalation have demonstrated the excellent performance and robustness of this pocket-sized, breath-actuated device. The inhaler was developed for a wide range of drugs, and its patented dispersion system can be used with pelletized pure drugs or powder blends. The multidose dry powder inhaler is already on the market for use with one of the key asthma drugs: budesonide (Budecort 200 Novolizer; Sofotec GmbH & Co. KG, Frankfurt, Germany).

Asthma↗

[The inhalation of beta stimulators. Effect of the inhaled aerosol deposited in the oropharynx and in the bronchial tree].

Inhaled aerosols are predominatly deposited in the oropharynx and only a minor portion penetrates into the sublaryngeal airways. The effectiveness of both components of an orciprenaline aerosol was tested in 12 asthmatics. For this purpose they were given an inhalation on one day and, on the next, the entire oropharynx was sprayed with the inhalant. Evaluation of the corresponding bronchodilator effects was based on repeated measurements of specific airway conductance. The results show that the inhalation is about 6 times as effective as the spray, and thus prove the superiority of inhalation therapy over oral or peroral medication with beta-stimulants in the treatment of bronchial asthma.

Adult↗

A cumulative dose response study for the comparison of the effect of inhalation of two dose sequences of fenoterol inhalation powder.

The effect of inhalation of two dose sequences of fenoterol inhalation powder were compared in a double-blind cumulative dose response investigation. Nine patients with stable asthma participated in the study. In dose sequence I, 50 + 50 + 100 + 200 micrograms of fenoterol powder were inhaled and in dose sequence II, 200 + 50 + 50 + 50 micrograms fenoterol inhalation powder. There was no significant difference in the effect on lung function or tremor at any point following the two methods of inhalation.

Dose-Response Relationship, Drug↗