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Metered-dose inhaler add-on devices: an in vitro evaluation of the BronchoAir inhaler and several spacer devices.

Spacer devices minimize the drug deposition in the oropharyngeal region as they retain between 30% and 50% of the nominal drug dose. Additionally, they should increase the fine particle fraction of the emitted aerosol. A new effort to increase the lung deposition was the design of a new actuator, the BronchoAir inhaler, (BronchoAir Medizintechnik GmbH, Munich, Germany). This study was carried out to evaluate the usefulness of this new actuator device by comparing its fine particle fraction with that emitted with the standard actuators and with spacer devices. The fine particle fraction's of commercially available metered dose inhalers (MDIs) marketed with specific spacers were determined using a multistage liquid impinger (MSLI). The effect of the BronchoAir inhaler on fine particle fractions was quite dependent on the formulation causing a decrease as great as 43% with Beclomet forte (beclomethasone-17, 21-dipropionate [BDP]) and an increase as great as 35% with Arubendol (salbutamol) but causing a difference of less than 20% with the other six tested formulations. Deposition in the upper stages of the impinger was sometimes higher than it was for the standard actuator. Spacer devices decreased the deposition in the upper stages of the impinger significantly, and in some cases, the fine particle fractions were also decreased. Varying the spacer design showed the superiority of large-volume open spacers compared with spacers with other designs.

Bronchodilator Agents↗

Characterization of a microprocessor-controlled tubular multiple metered dose inhaler aerosol generator for inhalation exposures of pharmaceuticals.

A microprocessor-controlled tubular multiple metered dose inhaler (MDI) aerosol generator was constructed for the delivery of pharmaceutical aerosols to inhalation chambers. The MDIs were mounted in four cassettes containing one to four MDIs on a stepped end plate. The MDIs in each cassette were pneumatically activated at intervals that were controlled by the microprocessor. The cassettes permitted easy replacement of each set of MDIs with a fresh set of MDIs whenever necessary. Aerosol concentration was controlled by varying the number of active MDIs in each cassette and the frequency of activations per minute of each row. Aerosol from the MDIs flowed along the long axis of the tube, which provided a path length sufficient to diminish impaction losses. Using a light-scattering device to monitor the aerosol concentration, the pulsatile output from the MDIs in the cassettes was demonstrated to be adequately damped out provided that the dilution/mixing/aging chamber exceeded 3 ft in length. The tube diameter selected was the minimum compatible with mounting the required number of MDIs so that the linear velocity of the aerosol was adequate to efficiently transport the aerosol out of the dilution chamber. Aerosol concentration and particle size data were recorded for a nose-only rodent exposure chamber. Reproducible aerosol concentrations ranging from 0.03 to 0.6 mg/L were generated. Particle sizes ranged from 2- to 3-microm mass median aerodynamic diameter. Thus, the aerosol generated was within the size range suitable for inhalation exposures.

Aerosols↗

Relationship between IgG1 and IgG4 antibodies to foods and the development of IgE antibodies to inhalant allergens. II. Increased levels of IgG antibodies to foods in children who subsequently develop IgE antibodies to inhalant allergens.

In the present investigation we have tested the hypothesis that children with a high IgG antibody response to foods have an increased risk of developing IgE antibodies to inhalant allergens. Sera from 106 children with an increased risk of developing IgE-mediated allergy were analysed. During the follow-up, in 54 of these children IgE antibodies to inhalant allergens appeared. A positive/negative IgG1 and IgG4 anti-food score was determined as described previously: sera from age-clustered unselected children were tested for the levels of IgG1 and IgG4 antibodies to common foods. For each IgG RAST and each age group, the 75-percentile was chosen as cut-off value. Each antibody level was thus converted into a positive (higher than the 75-percentile of the age group) or negative value. The number of positive tests was used as the score. High-risk children with a high IgG1 anti-food score more often developed inhalant-specific IgE antibodies than high-risk children with low IgG1 titres: 50% of the children with a high IgG1 anti-food score developed IgE antibodies to grass pollen. Fifty per cent of the children with a high and 14% of the children with a low IgG1 anti-food score developed IgE antibodies to cat dander. For the prediction of the development of IgE anti-mite (house dust mite), the IgG4 anti-food scores appeared less useful than the IgG1 anti-food scores; 46% of the IgG4 high responders versus 22% of the IgG4 low responders acquired IgE anti-mite, whereas for IgG1 these percentages were 73 and 19, respectively.

Allergens↗

A double-blind comparison between a new multidose powder inhaler (Turbuhaler) and metered dose inhaler in children with asthma.

Turbuhaler is a ready-loaded multiple dose inhaler which does not require co-ordination between release of dose and inhalation. 57 children with asthma participated in this clinical trial to compare the clinical effect and acceptance of terbutaline sulphate via Turbuhaler with that of metered dose inhaler (MDI). The trial consisted of two parts. In the first part of the study, which made use of a double-blind cross-over design, the clinical effect and number of treatment occasions with Turbuhaler were compared with those of MDI. In the second part, which was open, all patients were treated with Turbuhaler for 2 weeks. At the end of this period the patients were asked to make a subjective assessment of effect and to state their preference. There was no difference in clinical effect and number of treatment occasions between Turbuhaler and MDI. A majority of the patients thought Turbuhaler had the best effect and was easy to use.

Adolescent↗

Easyhaler, a novel multiple dose powder inhaler: clinically equivalent to salbutamol metered dose inhaler and easier to use.

Twenty-one adult asthmatic patients participated in a trial to compare the clinical equivalence of a single dose of salbutamol inhaled either from a novel multiple dose powder inhaler (MDPI), Easyhaler, or from a conventional metered dose inhaler (MDI). The trial was carried out as a randomized, double-blind, crossover study. The study involved 2 study days with a 6-hour follow-up period of spirometric indices. In addition, blood pressure and heart rate were measured immediately before each lung function test. Our data indicate that salbutamol treatment with the MDPI achieves values which are equivalent to those achieved with the conventional pressurized MDI as regards improving pulmonary function and tolerability. The mean maximum forced expiratory volume in 1 s (FEV1) after the powder dose was 2.44 +/- 0.96 liters and after the aerosol dose 2.45 +/- 0.93 liters. The mean area under the curve of absolute FEV1 values was 822 +/- 340 and 829 +/- 335, respectively. The mean percent change from the baseline in FEV1, forced vital capacity and peak expiratory flow following administration of the preparations was of equal magnitude in both cases. The treatments tested had no effect on blood pressure or heart rate and were well tolerated. A further important finding was that most patients found the MDPI easier or no more difficult to use than the conventional MDI and this probably facilitates the transition from pressurized MDIs to the novel MDPI.

Adult↗

Occupational asthma due to inhalation of chloramine-T. I. Clinical observations and inhalation-provocation studies.

Respiratory symptoms developed in 5 patients who were exposed to chloramine-T, a potent disinfectant used in cleaning butcheries, kitchens, and operating theaters. Skin tests, performed in 4 patients, showed an immediate type of wheal and flare reaction followed by a late-type infiltrative reaction. In 3 patients, inhalation tests with chloramine-T were done. 1 patient showed asthmatic bronchial obstruction, immediately after inhalation, followed by a late-type asthmatic reaction after some hours. 2 patients only exhibited late-type reactions, 4-8 h after challenge. The late bronchial response lasted for several hours or even days and was accompanied by leukocytosis in all 3 patients and a slight fever in 1 patient. No evidence of alveolar involvement appeared. Pre-challenge inhalation of cromoglycate in 1 patient ameliorated the late response considerably.

Administration, Intranasal↗

Therapeutic equivalence of Spiros dry powder inhaler and Ventolin metered dose inhaler. A bioassay using methacholine.

Because chlorofluorocarbons (CFCs) contribute to depletion of stratospheric ozone, CFC-containing metered-dose inhalers (MDIs) such as Ventolin and Proventil are being phased out of production. In terms of delivery of albuterol to the lungs, we compared an alternative delivery system, the Spiros dry-powder inhaler (DPI), with Ventolin, using a methacholine challenge-based clinical bioassay. Twenty-four adults and adolescents with asthma completed this double-blind, four-period crossover study. Doses evaluated were one and three actuations each of Spiros and Ventolin (90- and 270-microgram albuterol base). A methacholine challenge (Cockcroft method) was initiated 3 h before and 0.25 h after albuterol. Predose PC(20)FEV(1) values were not significantly different between study days. Postdose PC(20)FEV(1) results met standard bioassay study validity criteria: i.e., a significant dose-response relationship was present (p = 0.0002); tests for deviation from parallelism and overlap of dose-response curves were nonsignificant (p = 0.08, 0.69). By using Finney 2-by-2 bioassay analysis, we estimate that each Spiros actuation delivers 1.12 times as much albuterol to the airways as one Ventolin actuation (90% confidence interval, 0.68 to 1.94). There were no significant differences in markers of systemic effects (vital signs, potassium, and blood glucose concentrations). We conclude that Spiros and Ventolin inhalers deliver comparable quantities of albuterol to the airways.

Adolescent↗

[Investigations on airborne microorganisms in animal stables. 3: Relationship between inhalable endotoxin, inhalable dust and airborne bacteria in a hen house].

The relationship between inhalable endotoxin, inhalable dust and airborne bacteria was studied in a hen house. Neither the concentration of inhalable dust nor the concentration of airborne bacteria are suitable to reflect the concentration of airborne endotoxin. Furthermore it was found that the endotoxic activity can persist over a long period of time in dust samples. Therefore an accumulation of endotoxin in different environments is possible. Airborne endotoxin seems to be a suitable marker to characterize exposure to airborne organic dust, since this toxin is responsible for different respiratory diseases (e.g. toxic pneumonitis, airway obstructions) and the toxic activity of endotoxin in dust samples is known to persist for a long time.

Air↗

[New technics for producing inhalation aerosols--initial experiences and results with the piezoelectric inhalation device].

In the treatment of chronic obstructive airway diseases, the inhalative application of medicaments with a bronchodilatory effect is given preference throughout the world. In addition to inhalation solutions and powder capsules, so-called metered-dose aerosols have formed an established part of the treatment plan for approximately 30 years now. With the piezoelectric inhalation device, a fully portable ultrasonic atomiser that is small enough to fit within the pocket, has been developed for the first time. In this device, the piezoelectric effect is utilised to produced, pressure-free, microfine aerosols. Within it, an accurately metered volume containing the therapeutic dose is applied to an atomising element oscillating in the ultrasonic range. The particle spectrum generated with the piezo-system corresponds, in terms of size, to that of metered aerosol devices, and the mean particle diameter is approximately 2.1 microns. The atomisation process takes approximately one second.

Aerosols↗

Bronchodilator effects of a fenoterol metered dose inhaler and fenoterol powder in asthmatics with poor inhaler technique.

Thirty-seven per cent of 204 consecutive asthmatic patients using metered dose inhalers (MDI) regularly had faulty inhaler technique. Twenty patients with poor technique volunteered for bronchomotor tests. The bronchodilator effects of 0.2 mg of fenoterol in MDI form, 0.2 mg of fenoterol in powder form and a placebo powder were compared. Mean peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) values after 0.2 mg of fenoterol in MDI form were only slightly different from those after placebo. Inhalation of 0.2 mg of fenoterol powder was, however, followed by a highly significant (p less than 0.001) increase in measured expiratory indices. PEF and FEV1 values were significantly higher after fenoterol powder than after fenoterol in MDI form (PEF, p less than 0.01 at 5 min, p less than 0.001 at 15 min, and p less than 0.05 at 60 min, FEV1, p less than 0.01 1 h after drug administration). Poor MDI technique can severely impair the effect of bronchodilator drugs. Use of a bronchodilator in powder form is more reliable in these patients.

Adolescent↗

The use of methacholine inhalation, methacholine skin testing, distilled water inhalation challenge and eosinophil counts in the evaluation of patients presenting with cough and/or nonwheezing dyspnea.

Twenty-four patients presenting with cough and/or nonwheezing dyspnea were evaluated with methacholine inhalation challenge (MC), distilled water inhalation challenge (DC), intracutaneous tests to varying concentrations of methacholine, total eosinophil counts (TEC), sinus and chest x-rays. We found a statistically significant difference (P less than .005) in the mean TEC in those patients with a positive MC test and those with a negative test. Hyperreactivity of the airways to methacholine in asthmatics is not found in the skin. Distilled water inhalation did not serve to substitute for MC as a test of hyperreactive airways. The TEC is an excellent screening test as a predictor of patients with cough or dyspnea who have hyperreactive airways.

Adolescent↗

The duration of protection from exercise-induced asthma by inhaled salbutamol, and a comparison with inhaled reproterol.

beta-Adrenergic bronchodilators can prevent the development of exercise-induced asthma (EIA). To investigate the duration of this effect, we determined the time at which the protective effect of salbutamol diminished significantly in six subjects. All had stable asthma known to be triggered by exercise. Following a control exercise test, identical tests were repeated weekly at various times (1-6 hours) after inhalation of 200 micrograms of salbutamol. Significant protection (less than 75%) was lost in two subjects at 2 hours, in two at 4 hours and in two at 6 hours. A further exercise test was performed after inhalation of 1 mg of reproterol, at the time when salbutamol no longer afforded significant protection. There was a significantly smaller fall in peak expiratory flow rate after exercise (P less than 0.01) with reproterol than with salbutamol, at the same time after inhalation. There was no relationship between the degree or duration of protection from EIA and the bronchodilator effect of the drugs, the age and sex of the subjects, the length of asthma history or severity of base-line EIA, except perhaps the requirement for regular treatment with a steroid aerosol or sodium cromoglycate.

Adolescent↗

Clinical equivalence of a novel multiple dose powder inhaler versus a conventional metered dose inhaler on bronchodilating effects of salbutamol.

In this study the bronchodilating effect of salbutamol (CAS 18559-94-9) after administration a single-dose (100 micrograms) from a novel multiple dose powder inhaler (MDPI; Easyhaler) and from a conventional metered dose inhaler (MDI) was compared. Forty adult asthmatic patients participated in a double-blind, randomized, cross-over, multicenter study with double-dummy technique. The study comprised two study days with a 4-h follow-up period of spirometric indices and measurements of blood pressure and heart rate. Both the powder and aerosol treatments caused a clear increase in spirometric parameters. The mean (SD) maximum forced exspiratory volume in one second (FEV1) after powder delivery was 2.82 (1.13) l and after aerosol 2.77 (1.03) l. The mean percentual change from the baseline in FEV1 was equal after both preparations. The mean area under the curve (AUC) of the absolute FEV1 values was 616 (264) and 609 (240) l x min after the powder and aerosol delivery, respectively. The treatments had no clinically significant effects on blood pressure or heart rate and were equally well tolerated. Thus the clinical effects indicate therapeutical bioequivalence of the powder and aerosol treatments. Furthermore, most patients found the handling of the MDPI device easier than or equal to that of the conventional MDI, which in all probability increase the patient compliance, which is one of the corner stones in the inhalation therapy of bronchial asthma.

Adolescent↗

[Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma].

The anti-asthmatic effect of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 micrograms/day. The trial was designed as a randomized, double-blind, parallel-group study in several European countries. 69 patients were treated for 6 weeks with theophylline plus BDP 400 micrograms/day, compared to 64 patients treated with BDP 800 micrograms/day. The mean +/- SD serum theophylline concentration was 10.1 +/- 4.2 mg/l. Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow rate (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p < 0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p < 0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 micrograms/day and beclomethasone dipropionate 800 micrograms/day in patients whose asthma is not controlled on beclomethasone dipropionate 400 micrograms/d. The results support the use of theophylline as steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.

Adolescent↗

Mosquito coil smoke inhalation toxicity. Part II: subchronic nose-only inhalation study in rats.

This paper addresses the results of a subchronic inhalation study in rats exposed to the smoke of burning mosquito coils manufactured in Indonesia. The objective of the study was a comparative assessment of different mosquito coils, including a blank coil, utilizing the OECD No. 413 testing paradigm, however, with the focus on hazard identification at a single maximum tolerated exposure concentration rather than concentration-response. Groups of rats were nose-only exposed 6 h a day, 5 days a week for 13 weeks to an average particulate concentration of 30 mg m(-3) from either blank coils or coils that contain the insecticidal ingredient transfluthrin. Nose-only air-exposed rats served as a control. A range of markers of exposure have been characterized to define the most critical exposure metrics with regard to total suspended particulate matter (TSP) and potentially noxious volatile products of combustion. During the course of the exposure period the smoke-exposed rats showed clinical signs suggestive of acute upper respiratory tract sensory irritation. Body weights were mildly affected in the male rats, but food and water consumption were indistinguishable amongst the groups. Carboxyhemoglobin concentrations were approximately 11% throughout the exposure period in smoke exposed rats. Hematology, clinical pathology and urinalysis as well as the analysis of organ weights and histopathology of extrapulmonary organs and the lung did not reveal any evidence of adverse systemic or local effects, whereas in the anterior region of the nasal passages, and to some extent also in the larynx, irritant-related changes typical for water-soluble upper respiratory irritants were found. Markers of pulmonary inflammation or increased phagocytosis and lysosomal activity in bronchoalveolar lavage were indistinguishable amongst the groups. gamma-Glutamyltranspeptidase was significantly increased in the smoke exposure groups, which is taken as indirect evidence of an adaptive upregulation of the pulmonary antioxidant glutathione. In rats exposed to mosquito coil smoke containing transfluthrin, a somewhat increased frequency of alveolar macrophages with foamy appearance was identified through cytodifferentiation but not histopathology compared with the blank coil. From the specific staining of intracellular phospholipids, the notion is supported that this equivocal finding is probably related to an increased uptake of modified pulmonary surfactant rather than increased engulfment of insoluble particulate matter since pigmentation or clustering or intra-alveolar cells did not occur. The results of this subchronic inhalation study support the conclusion that smoke from burning mosquito coils in concentrations high enough to elicit acute upper respiratory tract irritation due to the presence of common wood-combustion products (such as aliphatic aldehydes) did not cause any adverse effect in the lower respiratory tract or any other extrapulmonary organ. The most critical mode of action is related to acute and readily perceivable sensory irritation. The concentration tested was estimated to be well above that occurring under more realistic exposure conditions. Therefore, overnight exposure to the smoke from burning mosquito coils (manufactured in Indonesia) is unlikely to be associated with any unreasonable health risk.

Air Pollutants↗

The assessment of the systemic effects of inhaled glucocorticosteroids. The effects of inhaled budesonide vs oral prednisolone on calcium metabolism.

In a randomized, double-blind crossover study, the effects of 0.8, 1.6 and 3.2 mg/day inhaled budesonide and 5, 10 and 20 mg/day oral prednisolone on mineral metabolism were compared. Twelve healthy subjects (4 m, 8 f) were treated for 1 week at each dosage level, the graduated dosages being given in ascending order. Budesonide and prednisolone were given twice daily and once daily, respectively, which reflects the schedules common in clinical practice. Serum calcium and the regulatory hormones of calcium metabolism (parathyroid hormone, vitamin D metabolites and calcitonin) were not changed either by prednisolone or budesonide. Prednisolone significantly increased 24 h and 08.00 h fasting urinary calcium excretion and decreased renal calcium reabsorption, while budesonide had little or no effect on urinary calcium loss and increased renal reabsorption at the highest dose level. Both drugs significantly increased renal phosphate reabsorption and serum phosphate levels, but prednisolone caused greater increases than budesonide. In conclusion, during short-term treatment with the dosages used, inhaled budesonide had less effect on calcium and phosphate metabolism than oral prednisolone, and so it may have a lesser action on the skeleton of the type contributing to osteoporosis during long-term treatment.

Administration, Inhalation↗

Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide.

OBJECTIVE: To determine whether inhalation of nitric oxide (INO) can increase the frequency of reversal of acute lung injury (ALI) in nitric oxide (NO) responders. DESIGN: Prospective, open, randomised, multicentre, parallel group phase III trial. SETTING: General ICUs in 43 university and regional hospitals in Europe. PATIENTS: Two hundred and sixty-eight adult patients with early ALI. INTERVENTIONS: NO responders were patients whose PaO(2) increased by more than 20 % when receiving 0, 2, 10 and 40 ppm of INO for 10 min within 96 h of study entry. Responders were randomly allocated to conventional treatment with or without INO. INO, 1-40 ppm, was given at the lowest effective dose for up to 30 days or until an end point was reached. The primary end point was reversal of ALI. Clinical outcome parameters and safety were assessed in all patients. RESULTS: Two hundred and sixty-eight patients were recruited, of which 180 were randomised NO responders. Frequency of reversal of ALI was no different in INO patients (61 %) and controls (54 %; p > 0.2). Development of severe respiratory failure was lower in the INO (2.2 % ) than controls (10.3 %; p < 0.05). The mortality at 30 days was 44 % for INO patients, 40 % for control patients (p > 0.2 vs INO) and 45 % in non-responders. CONCLUSIONS: Improvement of oxygenation by INO did not increase the frequency of reversal of ALI. Use of inhaled NO in early ALI did not alter mortality although it did reduce the frequency of severe respiratory failure in patients developing severe hypoxaemia.

Administration, Inhalation↗

Short-term crocidolite inhalation studies in mice: validation of an inhalation chamber.

A nose-only inhalation chamber is described: this chamber being computer automated has been particularly designed for mice on which it was validated using a crocidolite aerosol at a nominal concentration of 13.6 mg/m3, 6 h/day during 5 days. A month later the mice showed typical inflammatory bronchoalveolar liquids with many polynucleated or activated macrophages and asbestos bodies. The burden of crocidolite fibers ranged from 345,000 to 1,300,000 fibers per mg of dried lung. This study demonstrates that during the month that followed a short-term mice exposure to crocidolite fibers, the inflammatory response was still persistent. These toxicological endpoints validate the nose-only inhalation chamber to be useful for common or transgenic mice.

Administration, Inhalation↗