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.

Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications.

As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. As a major port of entry, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness of inhaled medications. In addition, a drug's efficacy may be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat.

Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications.

Research in the area of pulmonary drug delivery has gathered momentum in the last several years, with increased interest in using the lung as a means of delivering drugs systemically. Advances in device technology have led to the development of more efficient delivery systems capable of delivering larger doses and finer particles into the lung. As more efficient pulmonary delivery devices and sophisticated formulations become available, physicians and health professionals will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung's clearance mechanisms and be retained within the lung for longer periods. It is now recognized that it is not enough just to have inhalation therapy available for prescribing; physicians and other healthcare providers need a basic understanding of aerosol science, inhaled formulations, delivery devices, and bioequivalence of products to prescribe these therapies optimally.

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.

Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia.

Intranasal instillation techniques are used to deliver various substances to the upper and lower respiratory tract (URT and LRT) in mice. Here, we quantify the relative distribution achieved with intranasal delivery of a nonabsorbable tracer, (99m)Tc-labeled sulfide-colloid. Relative distribution was determined by killing mice after instillation and quantifying the radioactivity in dissected tissues using gamma scintigraphy. A significant effect of delivery volume on relative distribution was observed when animals were killed 5 min after instillation delivered under gas anesthesia. With a delivery volume of 5 microl, no radiation was detected in the LRT; this increased to a maximum of 55.7 +/- 2.5% distribution to the LRT when 50 microl were delivered. The majority of radiation not detected in the LRT was found in the URT. Over the course of the following 1 h, radiation in the LRT remained constant, while that in the URT decreased and appeared in the gastrointestinal tract. Instillation of 25 microl into anesthetized mice resulted in 30.1 +/- 6.9% distribution to the LRT, while only 5.3 +/- 1.5% (P < 0.05) of the same volume was detected in the LRT of awake mice. Varying the body position of mice did not affect relative distribution. When using intranasal instillation, the relative distribution between the URT and LRT and the gastrointestinal tract is heavily influenced by delivery volume and level of anesthesia.

Therapeutic equivalence of three metered-dose inhalers containing salbutamol (Albuterol) in protecting against methacholine-induced bronchoconstriction in children with asthma.

Many pharmaceutical companies sell salbutamol in metered-dose inhalers (MDI) for the treatment of asthma. However, the therapeutic equivalence of the more recently released generic products has not been compared with the original patented product in children. Twenty children with mild to moderate asthma, presently asymptomatic and with normal lung function, were randomly allocated to receive 200 microg of inhaled salbutamol (Albuterol) from three MDIs prepared by different manufacturers: the original Glaxo product and two generic products. The three drug formulations and placebo were given 10 min before a methacholine challenge test to determine the degree of protection provided against methacholine-induced bronchoconstriction (MIB) by each salbutamol aerosol. Tests were performed on 4 consecutive days. Doubling concentrations of methacholine were inhaled until the forced expired volume in 1 sec (FEV(1)) decreased by 20% from its baseline value. Compared to placebo, all patients increased significantly the provocation concentration that decreased FEV(1) by 20% (PC(20)) by more than one doubling concentration after inhaling each of the three salbutamol aerosols. The effectiveness was not significantly different between medications (P = 0.8). There was a small but significant difference among MDIs in aerosol particle size and total and fine-particle dose released per actuation. However, no relation was found between aerosol particle size or released dose and the protective effect. This study shows that the three tested brands of salbutamol MDI protected asthmatic children equally from MIB. When prescribing these salbutamol MDIs to prevent symptoms triggered by nonspecific stimuli in asthmatic children, the selection may be based on cost-benefit criteria.

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.

Delivery of salbutamol pressurized metered-dose inhaler administered via small-volume spacer devices in intubated, spontaneously breathing rabbits.

Little is known about the ability of small-volume valved spacer devices to deliver a significant amount of an aerosolized drug to the lungs of babies. This study compared the in vitro delivery of salbutamol administered via Aerochamber-Infant (145 mL), Babyhaler (350 mL), and metallic NES-spacer (250 mL), as well as the in vivo delivery using an animal model. The lung deposition study of technetium-99m-labeled salbutamol was conducted in six anesthetized, intubated (3.0-mm endotracheal tube simulating oropharyngeal deposition), spontaneously breathing New Zealand White rabbits, a model for 3-kg babies. Each rabbit was studied on three separate occasions, once with each spacer device. The amount of radioactivity deposited in the spacer device, the endotracheal tube, the lungs, or the body was measured by a gamma camera and expressed as a percentage of the emitted labeled dose. The emitted dose and particle size distribution of salbutamol via the three spacer devices were measured using unit dose sampling tubes and an eight-stage Anderson cascade impactor, respectively. The results were compared by ANOVA or Student-Newman-Keuls test when indicated. In vitro, the NES-spacer and Babyhaler were equivalent for delivering particles <5.8 microm in diameter (NES-spacer = Babyhaler > Aerochamber-Infant; p < 0.05). In vivo, the lung and body deposition was low with all spacer devices (range: 0.52-5.40% of the delivered dose) but greater with the NES-spacer than with the Aerochamber-Infant or the Babyhaler (5.40 +/- 2.40%, 2.91 +/- 0.86%, 0.52 +/- 0.46%, respectively; p = 0.002). These results suggest the metal-valved spacer device may be preferable for delivering pressurized aerosols to spontaneously breathing infants.

Aerosols and devices.

The success of aerosol therapy depends upon the delivery of ample amounts of the drug to appropriate sites in the lung with minimal side effects. Successful aerosol therapy delivery systems must provide sufficient respirable particles or droplets, with minimal loss of the drug. Ultimately, the patient must be able to use the device easily, maintain it, and derive clinical benefit from the drug delivered from the system.

Delivery of HFA and CFC salbutamol from spacer devices used in infancy.

The aim of the study was to compare the in vitro delivery of four salbutamol pressurized metered-dose inhalers (pMDIs) via the three spacer devices commonly used in European infants: Aerochamber-Infant, Babyhaler, and metallic NES-spacer. Emitted dose (ED) and fine particle dose (FPD, particles<5.8 microm) of each combination of spacer device and pMDI (chlorofluorocarbon-based Ventoline, Eolène, Spréor, and hydrofluoroalkane-based Airomir were measured respectively using unit dose sampling tubes (n=30 per combination) and an 8-stage cascade impactor (n=6 per group). The results were compared by analysis of variance and the Student-Newman-Keuls method. ED of Airomir was always greater than for Ventoline (P<0.05). FPD obtained with Ventoline was the lowest, with Eolène>Airomir=Spréor>Ventoline (P<0.05). Only Airomir produced a similar FPD with all three spacer devices. Chlorofluorocarbon-salbutamol pMDIs are not generics when used with spacer devices. The three spacer devices may be used interchangeably with Airomir.

Measuring total and regional lung deposition using inhaled radiotracers.

The delivery of an inhaled drug to the lungs can be measured by adding a gamma-emitting radiotracer to the formulation and using two-dimensional planar imaging or three-dimensional single photon emission computerized tomography (SPECT) to provide detailed information on lung deposition. The isotope most commonly used is the low energy (140 KeV) isotope, 99m technetium. Radiolabeling techniques have been successfully developed for use with nebulizers, pressurized metered dose inhalers (pMDIs), and dry powder inhaler formulations (DPI), and to investigate drug delivery to the respiratory tract for a variety of drug formulations and patient populations. However, for pMDIs and DPIs, the radiotracer is usually only physically associated with, rather than chemically bound, to the drug. Therefore, once deposited, the radiotracer may disassociate from the drug and cannot be used to track its subsequent fate; however, incorporation of a radiotracer directly into the drug molecule can overcome this. By using positron emitters such as 11carbon or 18fluorine it is possible to generate three-dimensional images of the drug in the lung using positron emission tomography (PET) scanning, which has a higher resolution and is more accurate than SPECT. Labeling drugs with PET emitters is more complex as the drug molecule must first be synthesized to contain the radioactive isotope before the drug is formulated for the inhaler. As with gamma-scintigraphy, PET scanning can be used to investigate physiological changes in the lung following therapeutic intervention, but as biological radiotracers are used, functional images (i.e., of the drug's uptake and metabolism) can also be obtained.

Influence of inspiratory flow rate, particle size, and airway caliber on aerosolized drug delivery to the lung.

A number of studies in the literature support the use of fine aerosols of drug, inhaled at low IFRs to target peripheral airways, with the objective of improving clinical responses to inhaled therapy (Fig. 8). Attempts have been made to separate response due to changes in total administered dose or the surface concentration of the dose from response due to changes in site of deposition--both are affected by the particle size of the aerosol, with IFR additionally influencing the latter. The tools for measuring dose and distribution have improved over the last 10-15 years, and thus we should expect greater accuracy in these measurements for assessing drug delivery to the lung. There are still issues, though, in producing radiolabeled (99m)technetium aerosols that are precise markers for the pharmaceutical product being tested and in quantitating absolute doses deposited in the lung. PET isotopes may provide the means for directly labelling a drug and perhaps can offer an alternative for making these measurements in the future, but deposition measurements should not be used in isolation; protocols should incorporate clinical tests to provide parallel therapeutic data in response to inhalation of the drug by the various patient populations being studied.

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.

Safety and efficiency of metered dose inhaler delivery of salbutamol in the intubated rabbit.

OBJECTIVE: To determine the safety and efficiency of metered dose inhaler salbutamol delivered to the intubated rabbit. DESIGN: Prospective, comparative, five-group laboratory investigation. SETTING: Animal laboratory, Department of Nuclear Medicine. SUBJECTS: A total of 30 adult, anesthetized New Zealand White rabbits. INTERVENTIONS: Three groups of rabbits underwent tracheal intubation through a tracheostomy and received 5 puffs of 99mTcO4 salbutamol delivered at the elbow connector (group 1) or via a catheter with its distal tip positioned at the midpoint (group 2) or bevel of the endotracheal tube (group 3). No intervention was provided for the rabbits in the fourth group. A fifth group underwent tracheal intubation through the mouth and received salbutamol (5 puffs) delivered at the bevel of the endotracheal tube. MEASUREMENTS: Delivery efficiency was expressed as the ratio of radioactivity emitted from lungs and trachea to the total radioactivity of the administered dose. Histopathologic injury scores were assigned to each trachea or lung specimen. MAIN RESULTS: Delivery efficiency was 30 times greater in groups 3 and 5 (full catheter) than in group 1 (elbow). The injury scores were similar in all groups. CONCLUSION: We conclude that the increased efficiency obtained by administration of metered dose inhaler salbutamol at the distal tip of endotracheal tube is not necessarily associated with increased epithelial injury.

Emitted doses of salbutamol pressurized metered-dose inhaler from five different plastic spacer devices.

In a recent clinical study we have demonstrated that the bronchodilator effect of 200 microg salbutamol (Ventoline) was spacer device-dependent in 100 tested asthmatic children, with the Babyhaler providing greater efficacy for improving peak expiratory flow rate compared to Aeroscopic, Nebuhaler, Aerochamber and Volumatic. The aim of this present study was to correlate our clinical results to in vitro determinations of the emitted dose (ED) of Ventoline administered via these five different plastic spacer devices. ED was determined from the mean of single doses collected in unit dose sampling tubes using a constant suction flow of 28.3 L/min. Three pressurized metered-dose inhalers and three sets of spacer devices were used to obtain a total of 30 measurements per group. Inter-group results were compared by RM-ANOVA or Student-Newman-Keuls method when indicated. Babyhaler delivered significantly (P < 0.05) more salbutamol than Nebuhaler, Aerochamber and Aeroscopic (mean +/- standard deviation: 63.6 +/- 2.9 microg/100 microg actuation for Babyhaler vs. 59.4 +/- 8.6 for Nebuhaler, 50.8 +/- 5.0 for Aerochamber and 47.5 + 2.5 for Aeroscopic). The ED from Volumatic (61.5 +/- 7.9 microg/100 microg actuation) was similar to that from the Babyhaler. The variability in the ED was greatest with the large volume spacers. Despite a greater ED from the Babyhaler, in vitro results do not fully explain the in vivo results. However, the previously described clinical improvement seen with the Babyhaler may be due to the quantitatively different aerosol production in a more 'useful' size range, as well as the different breathing patterns of the children tested. The results of this present study question the relevance of mouthpiece filter collection studies using a constant sampling in predicting clinical or physiological outcomes.

New delivery systems and propellants.

The removal of chlorofluorocarbon (CFC) propellants from industrial and household products has been agreed to by over 165 countries of which more than 135 are developing countries. The timetable for this process is outlined in the Montreal Protocol on Substances that Deplete the Ozone Layer document and in several subsequent amendments. Pressured metered dose inhalers (pMDIs) for medical use have been granted temporary exemptions until replacement formulations, providing the same medication via the same route, and with the same efficacy and safety profiles, are approved for human use. Hydrofluoroalkanes (HFAs) are the alternative propellants for CFCs-12 and -114. Their potential for damage to the ozone layer is nonexistent, and while they are greenhouse gases, their global warming potential is a fraction (one-tenth) of that of CFCs. Replacement formulations for almost all inhalant respiratory medications have been or are being produced and tested; in Canada, it is anticipated that the transition to these HFA or CFC-free pMDIs will be complete by the year 2005. Initially, an HFA pMDI was to be equivalent to the CFC pMDI being replaced, in terms of aerosol properties and effective clinical dose. However, this will not necessarily be the situation, particularly for some corticosteroid products. Currently, only one CFC-free formulation is available in Canada - Airomir, a HFA salbutamol pMDI. This paper discusses the in vitro aerosol characteristics, in vivo deposition and clinical data for several HFA pMDIs for which there are data available in the literature. Alternative delivery systems to the pMDI, namely, dry powder inhalers and nebulizers, are briefly reviewed.

Estimation of pulmonary deposition of aerosol using gamma scintigraphy.

Following delivery of technetium 99m-labeled aerosols through a ventilator circuit, the amount of radioactivity in the lungs of 58 ventilated rabbits was estimated first by gamma scintigraphy via gamma camera and later by direct counting of the excised lungs (n = 116 specimens) with a gamma counter. The in situ radioactivity measured via scintigraphy was closely correlated with the gamma counter ex vivo tissue counts of the radioactivity (R2 = 0.997, P < 0.001). Overall, gamma scintigraphy gave slightly lower values of activity than the tissue counts from the gamma counter, but the limits of agreement between the two measurements were narrow enough for us to consider that the tissue and scintigraphy methods were in agreement. We conclude that gamma scintigraphy provides a convenient and noninvasive means for the accurate estimation of aerosol deposition in the lungs of small animals and possibly in small infants.