Anti-inflammatory effects of once daily low dose inhaled ciclesonide in mild to moderate asthmatic patients.

BACKGROUND: Ciclesonide exhibits clinical efficacy at 160 microg (ex-actuator) once daily but the anti-inflammatory effects at this dose are not known. We wished to know whether 4 weeks therapy with ciclesonide pMDI 160 microg once daily in the morning exhibited significant anti-inflammatory effects. METHODS: Seventeen patients with mild persistent asthma (FEV(1) 3.35 l) were recruited into a double-blind placebo-controlled randomized crossover study. Measurements were made after ciclesonide and placebo treatment as well as after run-in and washout periods, for adenosine monophosphate (AMP) bronchial challenge (primary variable), exhaled nitric oxide (NO) and induced sputum (in a subgroup). RESULTS: The mean (SEM) AMP bronchial challenge PC(20) following ciclesonide (140 (63) mg/ml) was significantly (P < 0.001) increased compared with placebo (17 (8) mg/ml), run-in (13 (5) mg/ml) and washout (9 (3) mg/ml) periods. This amounted to an eightfold (CI: 5.3-12.0) for ciclesonide vs placebo. Likewise, there were significant improvements in exhaled NO levels and a significant reduction in induced sputum eosinophil cell counts. CONCLUSION: We have shown that inhaled ciclesonide given at 160 microg once daily in the morning exhibits significant anti-inflammatory effects that are in keeping with the previously described clinical effects.

Uptake of 18fluorodeoxyglucose in the cystic fibrosis lung: a measure of lung inflammation?

Positron emission tomography is a three-dimensional imaging technique that measures physiological effects, including metabolism. 18Fluorodeoxyglucose has been extensively used as a tracer of cellular energy metabolism in the brain and in tumour detection. As neutrophils utilise glucose as an energy source during their respiratory burst, it was hypothesised that 18fluorodeoxyglucose uptake, by these cells, could be interpreted as a measure of neutrophil activation in cystic fibrosis (CF). Ten adult CF patients were given a bolus intravenous injection of 18fluorodeoxyglucose, followed by a 90-min dynamic mid-lung acquisition scan. Right-lung 18fluorodeoxyglucose uptake was assessed using a Patlak plot and values were converted to glucose utilisation. Three clinically inactive pulmonary sarcoidosis patients served as controls. From the 10 CF patients with baseline sputum neutrophils of 14 x 10(6) cells x mL(-1) who were investigated, seven were found to have sputum at a normal or slightly depressed glucose utilisation rate (mean 1.33 micromol x g(-1) x h(-1)) compared with a mean of 2.82 micromol x g(-1) x h(-1) for the sarcoidosis patients. In eight patients, receiving inhaled tobramycin therapy, no change in lung glucose utilisation or sputum neutrophil counts were found. Despite high-sputum neutrophil levels, lung glucose utilisation was not elevated in patients with cystic fibrosis.

Sputum induction: effect of nebulizer output and inhalation time on cell counts and fluid-phase measures.

BACKGROUND: A knowledge of the factors that can affect induced sputum results is essential in order to standardize the procedure. OBJECTIVE: We investigated the influence of nebulizer output on sputum cell counts and fluid phase measurements at increasing times of sputum induction. METHODS: Eighteen adults with stable asthma inhaled an aerosol of 3% hypertonic saline to induce sputum after 7, 14 and 21 min on 2 days separated by 48 h. On one day, in random order, the ultrasonic nebulizer used had a relatively low output of 0.87 mL/min (particle size 5.58 microm mass median aerodynamic diameter, MMAD) and, on the other, a higher output of 1.90 mL/min (particle size 4.14 microm MMAD). The sputum was selected from each expectorate and examined blind to the induction procedures. RESULTS: With both nebulizers, the 14- and 21-min samples were lower in weight, neutrophils, eosinophils, eosinophil cationic protein (ECP) and interleukin (IL)-8 and higher in macrophages. The higher output nebulizer induced sputum with higher cell viability and lower ECP and IL-8. CONCLUSION: The results identify that the volume of hypertonic saline inhaled in sputum induction influences the fluid-phase measurements. The duration of induction does alter the cell counts and suggests that the later expectorated sputum samples originate from more peripheral airways. The results draw attention to the need to standardize the volume and time of nebulization to accurately interpret and compare results.

Lung models: strengths and limitations.

The most widely used particle dosimetry models are those proposed by the National Council on Radiation Protection, International Commission for Radiological Protection, and the Netherlands National Institute of Public Health and the Environment (the RIVM model). Those models have inherent problems that may be regarded as serious drawbacks: for example, they are not physiologically realistic. They ignore the presence and commensurate effects of naturally occurring structural elements of lungs (eg, cartilaginous rings, carinal ridges), which have been demonstrated to affect the motion of inhaled air. Most importantly, the surface structures have been shown to influence the trajectories of inhaled particles transported by air streams. Thus, the model presented herein by Martonen et al may be perhaps the most appropriate for human lung dosimetry. In its present form, the model's major "strengths" are that it could be used for diverse purposes in medical research and practice, including: to target the delivery of drugs for diseases of the respiratory tract (eg, cystic fibrosis, asthma, bronchogenic carcinoma); to selectively deposit drugs for systemic distribution (eg, insulin); to design clinical studies; to interpret scintigraphy data from human subject exposures; to determine laboratory conditions for animal testing (ie, extrapolation modeling); and to aid in aerosolized drug delivery to children (pediatric medicine). Based on our research, we have found very good agreement between the predictions of our model and the experimental data of Heyder et al, and therefore advocate its use in the clinical arena. In closing, we would note that for the simulations reported herein the data entered into our computer program were the actual conditions of the Heyder et al experiments. However, the deposition model is more versatile and can simulate many aerosol therapy scenarios. For example, the core model has many computer subroutines that can be enlisted to simulate the effects of aerosol polydispersity, aerosol hygroscopicity, patient ventilation, patient lung morphology, patient age, and patient airway disease.

A randomized controlled trial on the effect of inhaled corticosteroids on airways inflammation in adult cigarette smokers.

STUDY OBJECTIVE: To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers. DESIGN: This was a randomized, placebo-controlled, double-blinded clinical trial. SETTING: The subjects were recruited from the community by advertising. PARTICIPANTS: Seventy-one adults with a > or = 5 pack-year history who were current smokers, had a normal FEV1, and produced sputum daily. INTERVENTION: Sixty subjects were randomized to receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total dosage, 1,000 microg/d) using a metered-dose aerosol inhaler with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28 days. MEASUREMENTS AND RESULTS: Eleven subjects were not randomized because of poor compliance. The primary outcome was fractional airway neutrophilia, as assessed by a differential cell count of sputum. Additional outcome measures were spirometry, measurement of airway responsiveness by methacholine challenge, and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid. There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment. CONCLUSIONS: With normal spirometry, we found no benefit of treatment with inhaled BDP, 1,000 microg/d, on noninvasive measures of airways inflammation in adult smokers. This indicates that cigarette smoke-induced inflammation in its early stages (before a demonstrable airflow obstruction) is not steroid sensitive. This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids.

Nicotine microaerosol inhaler.

OBJECTIVE: To measure the droplet size distribution of a nicotine pressurized metered-dose inhaler using a nicotine in ethanol solution formulation with hydrofluoroalkane as propellant. MATERIALS AND METHODS: Sizing was performed at room temperature by multistage liquid impinger and quartz crystal impactor. RESULTS: The mass median aerodynamic diameter of the nicotine aerosol produced was measured at 1.6 mm by multistage liquid impinger and 1.5 mm by quartz crystal impactor. CONCLUSIONS: The inhaler formulation used produces a microaerosol of sufficiently fine droplet size that mimics the puff-by-puff pulmonary arterial bolus nicotine delivery of tobacco smoke. The absence of combustion products such as heat, carcinogens and carbon monoxide permits safer nicotine delivery via the inhaler than is possible via smoked tobacco.

Pulmonary deposition of salbutamol aerosol delivered by metered dose inhaler, jet nebulizer, and ultrasonic nebulizer in mechanically ventilated rabbits.

The deposition efficiency of three methods of aerosol delivery of salbutamol into lungs of ventilated rabbits was compared: 1) metered dose inhaler (MDI) with holding chamber (HC), 2) jet nebulizer (JN), and 3) ultrasonic (US) nebulizer. The latter system was tested using two different sized medication reservoirs, a large (20 mL) cup (US20) and a small (10 mL) cup (US10). After delivery of technetium-99m-labeled salbutamol aerosol, deposition in the lungs, trachea, and ventilator circuit were estimated by a gamma counter. Total pulmonary deposition [mean(SEM)] as a percentage of the prescribed drug was: MDI + HC 0.22(0.05)%; JN 0.48(0.05)%; US20 0.90(0.13)%; US10 3.05(0.49)%. Only the deposition from the US10 was statistically significantly higher than the other modes (p < 0.05). Dynamic scintigraphy showed that, among the nebulizers, the US10 continued to deliver medication for longer than either the JN or the US20. We conclude that the US10 appears to be more efficient in delivering aerosol to the lung in this rabbit model and merits further evaluation for clinical efficiency.

Efficiency of aerosol medication delivery from a metered dose inhaler versus jet nebulizer in infants with bronchopulmonary dysplasia.

The best means for optimal delivery of drugs into lungs of infants with bronchopulmonary dysplasia (BPD) is uncertain. We aimed to measure radio-aerosol deposition of salbutamol by jet nebulizer and metered dose inhalers (MDI) in ventilated and non-ventilated BPD infants. In a randomized, crossover sequence, salbutamol lung deposition was measured using an MDI (2 puffs or 200 micrograms) or sidestream jet nebulizer (5 minutes of nebulization with 100 micrograms/kg) in 10 ventilated (mean birthweight, 1,101 g) and 13 non-ventilated (mean birthweight, 1,093 g) prematurely born infants. Non-ventilated infants inhaled aerosol through a face mask, connected to a nebulizer or an MDI and spacer (Aerochamber). Ventilated infants received aerosol from an MDI + MV15 Aerochamber or a nebulizer inserted in the ventilator circuit. Lung deposition by both methods was low: mean (SEM) from the MDI was 0.67 (0.17)% of the actuated dose, and from the nebulizer it was 1.74 (0.21)% and 0.28 (0.04)% of the nebulized and initial reservoir doses, respectively. Corresponding figures for the ventilated infants were 0.98 (0.19)% from the MDI and 0.95 (0.23)% and 0.22 (0.08)% from the nebulizer. In both groups, and for both methods of delivery, there was marked inter-subject variability in lung deposition and a tendency for the aerosol to be distributed to the central lung regions.

Ciliary function, cell viability, and in vitro effect of ribavirin on nasal epithelial cells in acute rhinorrhea.

Nasal epithelial (NE) cells were collected from the nasopharynx of 25 individuals with symptomatic colds and 27 healthy volunteers (controls), and ciliary beat frequency (CBF) was assessed by microscopy employing video motion analysis techniques. Baseline CBF was statistically significantly elevated in the group with colds compared to the control group (14.6 +/- 1.5 Hz [mean +/- SD] vs 13.8 +/- 0.9 Hz; p = 0.02). After four days of incubation in culture, there was a significant decrease in the CBF in both groups, with a change from baseline of 1.9 Hz for the cold group, compared to 1.0 Hz for the control group (p = 0.0001). The in vitro addition of ribavirin at 500 micrograms/ml to NE cells from individuals with colds preserved the viability of the cells and maintained the CBF at baseline values. Twenty-four (96 percent) of 25 ribavirin-treated specimens from the cold group survived for four days in culture, compared with 17 (68 percent) of 25 untreated cold specimens. In addition, the ribavirin-treated cells had a mean CBF of 14.2 +/- 1.3 Hz, compared with 12.7 +/- 1.9 Hz for the untreated cell samples (p = 0.0005). Ribavirin had no effect on NE cells from the control group. These results suggest that ribavirin in a concentration of 500 micrograms/ml may have some benefit in the treatment of acute rhinorrhea.

Ventilation scanning with technetium labeled aerosols. DTPA or sulfur colloid?

We have compared the distribution in the lungs of submicronic aerosols of either Tc-99m sulfur colloid or Tc-99m DTPA immediately after inhalation with the distribution 20 minutes later in 83 patients. Thirty-two of the 83 patients were active smokers. Of the 28 smokers who received Tc-99m DTPA aerosol, the total lung count fell by a mean of 27 +/- 14% between the 0 and 20 minute image. Eleven of these patients also had a major change in distribution of isotope during this time. In the nonsmoking patients total lung counts from Tc-99m DTPA fell by only 16 +/- 8% and none had a major change in distribution pattern. None of the smoking or non-smoking patients who received Tc-99m sulfur colloid had a significant change in count rate or distribution pattern over 20 minutes. The effects on the ventilation images of these rapid changes in count rate and distribution pattern after Tc-99m DTPA aerosol can be minimized by completing the ventilation study as quickly as possible after inhaling Tc-99m DTPA or by using a nondiffusible agent such as Tc-99m sulfur colloid.

Lung epithelial permeability: relation to nonspecific airway responsiveness.

Lung epithelial permeability was measured in five normal, five asthmatic, and five smoking subjects by quantifying removal from the lung and accumulation in the blood of an inhaled radiolabeled low-molecular-weight substance, technetium-99m-labeled diethyleneaminepentaacetate (99mTc-DTPA). Measurements on 2 control days were highly reproducible. Nonspecific bronchial responsiveness to histamine was determined in all subjects on a 3rd day, and the results were expressed as the provocation concentration producing a fall in forced expiratory volume in 1 s of 20% (PC20 histamine). Lung epithelial permeability was similar for the normal and asthmatic subjects. However, smokers had greatly increased permeability when compared with the other two groups. The responsiveness to histamine was increased in the asthmatics but within the normal range for normal subjects and smokers. No relationship was established between increased epithelial permeability and increased responsiveness to histamine. Results indicate that increased permeability of the epithelial lining of the bronchi is not a dominant factor in the increased nonspecific responsiveness to histamine observed in asthma.

[Ventilation scintigraphy of the lung with 99mTc-DTPA or with 99mTc-sulfur colloid?]. / Ventilationsszintigraphie der Lunge mit 99mTc-DTPA oder mit 99mTc-Schwefelkolloid?

Ventilation scintigraphy of the lung, obtained with sufficiently small 99mTc-labelled aerosol particles, provides an image of ventilation distribution that is acceptable in clinical routine. Whether 99mTc-DTPA or 99mTc-sulfur colloid is more suitable as a carrier was studied in 6 smokers and 8 non-smokers with chronic obstructive pulmonary disease. 99mTc-sulfur colloid was not absorbed by the bronchial mucosa and therefore appears to be an almost ideal agent. In contrast, 99mTc-DTPA was absorbed by the bronchial mucosa in all smoking patients more rapidly and inhomogenously than in non-smokers. The quantitative and qualitative comparison of the two dorsal ventilation scans taken both immediately after inhalation and 20 min later, showed in all 6 smoking patients after 20 min significant differences which influenced the diagnosis result. 99mTC-DTPA is therefore not recommended for use in ventilation lung scintigraphy, especially in smoking patients.

Effect of TLV levels of SO2 and H2 SO4 on bronchial clearance in exercising man.

Pulmonary mucociliary function was assessed following exposure to industrial threshold limit values (TLV) of sulfur dioxide (5 ppm) SO2) and sulphuric acid mist (1 mg/m3 H2SO4). Bronchial clearance was measured in two sets of ten healthy exercising non-smoking adults under control and exposure conditions. A 99mTc-albumen saline aerosol (MMD 3 micrometer) was inhaled as a bolus in late inspiration under controlled conditions to produce reproducible deposition in large airways. Lung retention of radioactivity was quantified using a gamma camera and computer analysis. Clearance was significantly faster (P less than .05) on exposure to both SO2 and H2SO4 compared to control values. Maximum mid-expiratory flow rates (MMFR) were significantly reduced (P less than .01) on exposure to SO2 (mean decrease 8.5%), but only slightly reduced for H2SO4 (1.4%). The speeding in clearance was probably an irritant response in both cases. For SO2 the response appeared predominantly reflex, while H2SO4 showed evidence of a direct effect.

Aerosol penetrance: a sensitive index of peripheral airways obstruction.

Early injury of the small airways has been demonstrated in asymptomatic smokers. Ventilatory tests including the maximum midexpiratory flow rate and closing volume have been useful in clinical detection of small airways disease in symptomatic subjects. In the present study, airway "obstruction" was assessed aerodynamically by gamma camera measurements of chest radioactivity following the inhalation of 131I-labeled aerosol (aerodynamic mass median diameter 3 mum). Studies were performed in normal subjects, asymptomatic smokers, and patients with chronic obstructive lung disease. An aerosol penetrance index (AeP) was devised from determinations which involved 1) an analysis of central (inner zone) and peripheral (outer zone) deposition of aerosol in the lung and 2) a ratio of initial counts to 24-h counts in the periphery (outer zone) of the lung. AeP values were 41.5 +/- 11.5 for the normal group, 20.9 +/- 7.6 for the smoker group, and 10.6 +/- 5.2 for the subjects with chronic obstructive airway disease. AeP was significantly reduced in the smokers indicating that the AeP is a sensitive index of early peripheral airways obstruction.