Inhalation of macrolides: a novel approach to treatment of pulmonary infections.

Systemic antibiotic treatment is established for many pulmonary diseases, e.g., cystic fibrosis (CF), bronchiectasis and chronic obstructive pulmonary disease (COPD) where recurrent bacterial infections cause a progressive decline in lung function. In the last decades inhalative administration of antibiotics was introduced into clinical routine, especially tobramycin, colistin, and aztreonam for treatment of CF and bronchiectasis. Even though they are important in systemic treatment of these diseases due to their antimicrobial spectrum and anti-inflammatory and immunomodulatory properties, macrolides (e.g., azithromycin, clarithromycin, erythromycin, and telithromycin) up to now are not administered by inhalation. The number of in vitro aerosol studies and in vivo inhalation studies is also sparse. We analyzed publications on preparation and administration of macrolide aerosols available in PUBMED focusing on recent publications. Studies with solutions and dry powder aerosols were published. Publications investigating physicochemical properties of aerosols demonstrated that macrolide aerosols may serve for inhalation and will achieve sufficient lung deposition and that the bitter taste can be masked. In vivo studies in rats demonstrated high concentrations and areas under the curve sufficient for antimicrobial treatment in alveolar macrophages and epithelial lining fluid without lung toxicity. The obtained data demonstrate the feasibility of macrolide inhalation which should be further investigated.

Treatment of systemic diseases by inhalation of biomolecule aerosols.

Clinical experience since many years has shown that aerosol inhalation is an established route for the treatment of pulmonary diseases. In contrast, treatment of systemic diseases by means of aerosol inhalation is a novel therapeutic approach. This was caused for a long time by a lack of accuracy, efficiency, and reproducibility of the administered drug doses due to a poor knowledge of the physiological background of aerosol inhalation, an insufficient inhaler technology as well as a suboptimal breathing procedure. However, these problems have been solved in the last years and nowadays modern aerosol delivery systems allow the production of an aerosol with a defined and optimised particle size combined with an optimized breathing maneuver and optimization of the efficacy of the technology. Clinical studies demonstrated that only a small number of morphological factors (e.g., exogen allergic alveolitis, active sarcoidosis, active smoking) influence alveolar drug deposition and the inhaled systematically active compounds caused no relevant allergic reactions even after inhalation for longer time periods. Up to now, most data are available for the inhalation of insulin which has been introduced in clinical treatment for a short time. However, a lot of other molecules have been tested in aerosol inhalation studies. This review describes some examples other than insulin in the field of inhalant treatment of systemic diseases.

Novel devices for individualized controlled inhalation can optimize aerosol therapy in efficacy, patient care and power of clinical trials.

In the treatment of pulmonary diseases the inhalation of aerosols plays a key role - it is the preferred route of drug delivery in asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. But, in contrast to oral and intravenous administration drug delivery to the lungs is controlled by additional parameters. Beside its pharmacology the active agent is furthermore determined by its aerosol characteristics as particle diameter, particle density, hygroscopicity and electrical charge. The patient related factors like age and stage of pulmonary disease will be additionally affected by the individual breathing pattern and morphometry of the lower airways. A number of these parameters with essential impact on the pulmonary drug deposition can be influenced by the performance of the inhalation system. Therefore, the optimization of nebulisation technology was a major part of aerosol science in the last decade. At this time the control of inspiration volume and air flow as well as the administration of a defined aerosol bolus was in the main focus. Up to date a more efficient and a more targeted pulmonary drug deposition - e.g., in the alveoli - will be provided by novel devices which also allow shorter treatment times and a better reproducibility of the administered lung doses. By such means of precise dosing and drug targeting the efficacy of inhalation therapy can be upgraded, e.g., the continuous inhalation of budesonide in asthma. From a patients' perspective an optimized inhalation manoeuvre means less side effects, e.g., in cystic fibrosis therapy the reduced oropharyngeal tobramycin exposure causes fewer bronchial irritations. Respecting to shorter treatment times also, this result in an improved quality of life and compliance. For clinical trials the scaling down of dose variability in combination with enhanced pulmonary deposition reduces the number of patients to be included and the requirement of pharmaceutical compounds. This review summarises principles and advances of individualised controlled inhalation (ICI) as offered by the AKITA inhalation system.

Particle clearance from the airways of subjects with bronchial hyperresponsiveness and with chronic obstructive pulmonary disease.

The aim of this study was to determine particle clearance and retention from non-alveolated airways of 14 healthy subjects (HS), 10 subjects with asymptomatic bronchial hyperresponsiveness (BHR), and 23 patients with chronic obstructive pulmonary disease (COPD). Monodisperse iron oxide particles of 1.6 micro m geometric and 3.5 micro m aerodynamic diameter labeled with (99m)Tc were delivered to the airways by inspiration of small aerosol boli into shallow volumetric lung depths. In each subject the penetration front depth of the aerosol boli was adjusted to 55% of the Fowler dead space of the airways. Particle deposition was enhanced by about 7 seconds of breath-holding after bolus inhalation. Retention of the particles in the airways during the 48 hours after their administration was assessed by measuring the decline in lung activity with a sensitive gamma counter. Particle deposition was not significantly different among study groups. Twenty-four hour particle retention in the airways was not different among study groups. Sixty-one percent of the particles were retained at 24 hours in HS, 58% in BHR, and 64% in COPD. However, subjects with BHR showed accelerated mucociliary clearance compared to healthy subjects, whereas clearance was retarded in COPD patients. This long-term particle retention in the airways has to be taken into account in aerosol toxicology risk assessment and aerosol therapy dose evaluation.

[Perspectives in the inhalative administration of drugs]. / Perspektiven in der Inhalationstherapie.

Administration of drugs via the inhalation route will find new indications in the therapy for lung diseases. Furthermore, aerosolised drugs are of increasing interest for systemic treatment. The inhalation of antibiotics is already a well established therapy in cystic fibrosis. In bronchiectasis, severe COPD with bacterial airway colonisation and in mechanically ventilated patients, aerosolised aminoglycosides may provide benefit. Substitution of alpha1-antitrypsin in lung emphysema via inhalation seems to be superior to the intravenous administration. Inhaled insulin has currently been withdrawn from the market in spite of being approved by FDA and EMEA. However, intensive scientific research is still ongoing and many clinical studies are underway in the field of the inhalation of insulin, heparins and other systemic treatments.

Systemic treatment by inhalation of macromolecules--principles, problems, and examples.

Aerosol inhalation is an established route of medical administration for the treatment of pulmonary diseases. In contrast, aerosol inhalation for treatment of systemic diseases is a novel therapeutic approach. Clinical use of the latter therapy for many years has been limited by the lack of accuracy, efficiency, and reproducibility of the administered doses. Usually, only a small fraction of inhaled drug reached the target region within the lungs. Further problems were the risk of potential allergic reactions in the respiratory tract and a potential variability of drug absorption from the alveoli into the circulation. These problems have been solved in the last years by modern aerosol delivery systems allowing the production of an aerosol with a defined and optimised aerosol particle size combined with an optimized breathing maneuver and optimization of the efficacy of the technology. Furthermore, there were no observations of relevant allergic reactions after inhalation of systemically active drugs in numerous studies. Studies demonstrated that only a small number of morphological factors influence alveolar drug deposition (e.g., exogen allergic alveolitis, active sarcoidosis, active smoking). In consequence, an increasing number of studies investigated the systemic effect of inhaled high molecular weight substances (e.g., insulin, heparin, interleukin-2) and demonstrated that controlled aerosol therapy may serve as a non-invasive alternative for drug application by means of a syringe. Our review briefly summarizes the mechanisms for pulmonary absorption of macromolecules and gives an overview on prior research in the field of inhalant treatment of systemic diseases.

Inhaled insulin--does it become reality?

After more than 80 years of history the American and European Drug Agencies (FDA and EMEA) approved the first pulmonary delivered version of insulin (Exubera) from Pfizer/Nektar early 2006. However, in October 2007, Pfizer announced it would be taking Exubera off the market, citing that the drug had failed to gain market acceptance. Since 1924 various attempts have been made to get away from injectable insulin. Three alternative delivery methods where always discussed: Delivery to the upper nasal airways or the deep lungs, and through the stomach. From these, the delivery through the deep lungs is the most promising, because the physiological barriers for the uptake are the smallest, the inspired aerosol is deposited on a large area and the absorption into the blood happens through the extremely thin alveolar membrane. However, there is concern about the long-term effects of inhaling a growth protein into the lungs. It was assumed that the large surface area over which the insulin is spread out would minimize negative effects. But recent news indicates that, at least in smokers, the bronchial tumour rate under inhaled insulin seems to be increased. These findings, despite the fact that they are not yet statistical significant and in no case found in a non-smoker, give additional arguments to stop marketing this approach. Several companies worked on providing inhalable insulin and the insulin powder inhalation system Exubera was the most advanced technology. Treatment has been approved for adults only and patients with pulmonary diseases (e.g., asthma, emphysema, COPD) and smokers (current smokers and individuals who recently quitted smoking) were excluded from this therapy. Pharmacokinetics and pharmacodynamics of Exubera are similar to those found with short-acting subcutaneous human insulin or insulin analogs. It is thus possible to use Exubera as a substitute for short-acting human insulin or insulin analogs. Typical side effects of inhaled insulin were coughing, shortness of breath, sore throat and dry mouth. Physical exercise increases the transport of inhaled insulin into the circulation and in consequence the likelihood of hypoglycemia. Other problems were the inability to deliver precise insulin doses, because the smallest blister pack available contained the equivalent of 3 U of regular insulin and this dose would make it difficult for many people using insulin to achieve accurate control, which is the real goal of any insulin therapy. For example, someone on 60 U of insulin per day would lower the blood glucose about 90 mg/dl (5 mmol) per 3 U pack, while someone on 30 U a day would drop 180 mg/dl (10 mmol) per pack. Precise control was not possible, especially compared with an insulin pump that can deliver one twentieth of a unit with precision. Another disadvantage was the size of the device. The Exubera inhaler, when closed, was about the size of a 200 ml water glass. It opened to about twice the size for delivery. To our information also other companies (Eli Lilly in cooperation with ALKERMES, Novo Nordisk (AERx, Liquid), Andaris (Powder)) stopped further development and it is unclear whether an inhaled form of insulin will ever be marketed, because of the problems that have occurred. Only Mannkind (Technosphere, Powder) is still working on a Phase III trial. However, our review will briefly summarize the experience regarding inhalant administration of insulin and will describe potential future developments for this type of therapy focussing on the lung.

Novel approaches to enhance pulmonary delivery of proteins and peptides.

In the last two decades, large efforts have been made to develop safe methods for the delivery of proteins and peptides via the lungs into blood circulation for treatment of systemic diseases. For this purpose, a number of biophysical and physiological parameters have to be considered, such as particle diameter, particle density, hygroscopicity, electrical charge, chemical properties of the substance and age, pulmonary diseases, breathing pattern, all of which affect the mechanisms of pulmonary drug deposition. Variations in these parameters result in a substantial change of particle deposition in the lung. For example, large particles (>10 microm) are not able to penetrate into the lung, because they are deposited by impaction in the upper respiratory tract. On the other hand, small particles (0.1-1.0 microm) are inspired into the alveoli but also expired without being deposited significantly. Particles of diameters 2-4 microm show the ideal pulmonary deposition behavior and are able to transport a substantial mass of pharmaceuticals into the lung. Modifications of breathing pattern allow an optimal particle deposition in the bronchial or the alveolar region. In addition, particle deposition in the alveolar region is the basis for treatment of systemic diseases by inhalant administration of drugs (e.g., insulin). This paper deals with the physical and physiological basics for inhalation therapy and demonstrates novel systems which were designed to optimize drug delivery into the lung periphery. The AKITA inhalation system is an example for a system that guides the patient through the inhalation maneuver and ensures an optimized particle deposition and a minimized intersubject variability.

Inhalation of tobramycin in patients with cystic fibrosis: comparison of two methods.

Inhalant tobramycin is established in the treatment of cystic fibrosis patients. Conventional nebulizers require a large amount of the expensive compound, because only a small fraction is deposited in the targeted lung region. In contrast, techniques based on controlled inhalation allow a high and reproducible deposition of the drug in specific lung regions. In our study we compared the efficiency of two techniques based on conventional and controlled inhalation in 16 cystic fibrosis patients aged 13-39 years. Inhalations with the doses of tobramycin of 300 mg and 150 mg were performed twice daily for three days. The efficiency of the drug deposition was measured by the determination of its serum concentration 1 h after the end of the inhalation. The mean FEV1 value in our patients was 61% of predicted, range 36%-116%. There were no differences in tobramycin serum concentrations among the three study days in both methods (controlled inhalation: 0.983 +/-0.381(+/-SD) mg/l, 1.119+/-0.448 mg/l, 1.194+/-0.568 mg/l; conventional inhalation: 1.075+/-0.798 mg/l, 1.294 0.839 mg/l and 1.269+/-0.767 mg/l, on Day 1, Day 2, and Day 3, respectively). Even though the drug amount was double in the conventional technique, there was no significant difference in its overall serum concentration from the three study days (conventional inhalation: 1.210+/-0.783 mg/l, controlled inhalation: 1.092+/-0.461 mg/l). In addition, the coefficient of variation and the required inhalation time were shorter in controlled inhalation than in conventional inhalation (42% vs. 65% and 7-8 min vs. 20 min, respectively). Our data suggest that controlled inhalation can significantly reduce the amount of a drug required for therapy, the inhalation time required for drug deposition, and the variability of pulmonary dosage. It seems probable that controlled inhalation can improve the antibiotic prevention of pulmonary infection.

Optimum peripheral drug deposition in patients with cystic fibrosis.

In order to identify the optimum particle size and breathing pattern for high peripheral deposition of inhaled drugs in patients with cystic fibrosis, regional deposition in these patients was studied systematically as a function of particle size, inhalation volume and flow rate. Regional deposition was assessed using the single-breath regional deposition technique in which the concentration profile of inhaled and exhaled non-radioactive, monodisperse test particles is analyzed. Using this technique particle deposition within the functional dead space volume and peripherally can be assessed. Regional deposition was measured in 12 patients with cystic fibrosis using 2, 3, 4, and 5.5 microm particles, inhalation volumes of 500, 1000, 1500, and 2000 cm(3), and inhalation flow rates of 100, 250, 500, and 750 cm(3)/sec. Peripheral deposition was highest when 2-3-microm particles were inhaled with air-flow rates of 250-500 cm(3)/sec. With these parameters peripheral deposition increased with increasing inhalation volume and reached values of about 60% of the total drug inhaled. It has been shown that high peripheral drug deposition can be achieved in patients with CF when inhalations are performed using an optimized combination of particle size and breathing pattern.

[Inhaled antibiotic therapy in bronchiectasis?]. / Antimikrobielle Aerosoltherapie bei Bronchiektasen?

Antimicrobial therapy is an important aspect of disease management for patients with bronchiectasis. Delivery of an inhaled antibiotic is an appealing alternative to oral or intravenous administration because the antibiotic is delivered in high concentrations directly to the site of infection, eliminating the need for high systemic concentrations and reducing the risk of systemic toxicity. In recent controlled studies these potential benefits have been assessed in patients with bronchiectasis who became colonized by P. aeruginosa and the results support the use of nebulized antibiotics. In up to one-third of patients P. aeruginosa was eradicated from their sputum by inhaled antibiotic therapy and up to 62 % of patients showed improved medical condition. The further development of new aerosol devices supported by clinical testing will allow effective management of patients with bronchiectasis by an inhalation therapy that minimizes time constraints and drug loss which may improve health status and quality of life.

Inhalation of aerosolized vitamin a: reversibility of metaplasia and dysplasia of human respiratory epithelia -- a prospective pilot study.

The objective of this preliminary uncontrolled study was twofold: First, to assess the feasibility of retinyl palmitate inhalation and second, to analyze the changes of metaplastic lesions of the respiratory epithelium (metaplasia or dysplasia) following retinyl palmitate inhalation. The response to a daily dose of 18.000 I.U. retinyl palmitate by inhalation over a period of 3 month was assessed in 11 subjects (9 smokers, 2 ex-smokers). Using white-light bronchoscopy combined with autofluorescence bronchoscopy, bronchial biopsies were taken before and after a 3 month-period. The biopsy samples were evaluated blind by a referee lung pathologist. The overall response rate (remission or partial remission) was 56% (95% CI 0.30 0.79; p<0.05). These data suggest that inhalation of retinyl esters could be a promising therapeutical approach for chemoprevention of lung cancer. Vitamin A; chemoprevention; lung cancer; squamous metaplasia; dysplasia; retinoids

Impulse oscillometry in healthy nonsmokers and asymptomatic smokers: effects of bronchial challenge with methacholine.

The clinical application of respiratory impedance measurements by oscillation techniques for monitoring bronchial challenge testing is hampered by the fact that data in healthy nonsmokers and asymptomatic smokers are very limited. The objective of this study was to analyze the changes in impedance to a methacholine provocation test in healthy nonsmokers and asymptomatic smokers, and to investigate whether smokers show a different response compared to nonsmokers. The response to methacholine challenge was assessed by impulse oscillometry (IOS) (resistance R and reactance X at 5, 10, 15, 20, 25, and 35 Hz) and spirometry (FEV1, MEF50) in 105 healthy subjects (55 nonsmokers: "NS"; 50 asymptomatic smokers: "S") in whom the provocation dose of 2.44 mg methacholine did not result in a fall of FEV1 below 20% predicted of the baseline value. The baseline reactance X values of S were significantly lower compared to NS from 10 to 35 Hz (p < or = 0.01), whereas S and NS did not differ in resistance R over the whole frequency spectrum from 5 to 35 Hz. S showed a significantly higher mean baseline resonant frequency X(f0); i.e., the frequency at which inertial forces are equal and opposite to elastic forces, compared to NS (NS: X(fo) = 10.8+/-2.9 Hz; S = 12.6+/-4.0 Hz, p = 0.01). In both groups methacholine challenge resulted in an increase in R (f) especially at 5 and 10 Hz, and a marked decrease in X(f) over the whole frequency spectrum. In S a significantly higher decrease of postchallenge X5Hz and X10Hz was measured compared to NS (NS: deltaX(5Hz) = -0.044+/-0.003; S: deltaX(5HZ) = -0.083+/-0.013; p = 0.0017. NS: deltaX(10Hz) = -0.050+/-0.001; S: deltaX(10Hz) = -0.082+/-0.017; p = 0.008). R and X at low frequencies showed a three to four times higher postchallenge reaction compared to FEV1. Pre- and postchallenge FEV1 did not correlate with resistance R (f) and reactance X(f) over the whole frequency spectrum. In S perchallenge X(f) values from 10 to 35 HZ were significantly lower, and postchallenge decrease of X5Hz and X10Hz values were significantly higher compared to that of NS, whereas pre- and postchallenge R(f) values were similar in both groups. These results can be explained by changes in the elastic properties of the lung induced by a diffuse subclinical respiratory bronchiolitis.

Increased fine particle deposition in women with asymptomatic nonspecific airway hyperresponsiveness.

Previous studies suggest that lung function tests using monodisperse aerosols can help to identify early stages of lung diseases. We investigated intrapulmonary particle loss and aerosol bolus dispersion-a marker of convective gas transport-in 32 women with asymptomatic nonspecific bronchial hyperresponsiveness (BHR) compared with 60 women without BHR. Deposition of inhaled particles (0.9 micrometer mass median aerodynamic diameter [MMAD]) was calculated from particle losses of inhaled aerosol boluses consisting of di-2-ethylhexyl sebacate droplets. Convective gas mixing was assessed by the aerosol bolus dispersion method. Women with BHR, nonsmokers as well as smokers, showed significantly increased deposition of aerosol particles (nonsmokers: 45.6 +/- 8.8%; smokers: 49.2 +/- 5.4%; mean +/- SD) compared with the control group of female nonsmokers without BHR (38.2 +/- 9.1%; mean +/- SD) (p < 0.01). Aerosol bolus dispersion values showed a trend for higher values in subjects with BHR (nonsmokers: 572 +/- 122 cm3; smokers: 587 +/- 85 cm3) compared with the control group (542 +/- 88 cm3) (p = 0.2). Also, the maximal expiratory flow at 25% vital capacity (MEF25) showed a trend for decreased values in nonsmokers with BHR compared with nonsmokers without BHR (64 +/- 16% of predicted versus 78 +/- 24% of predicted; p = 0.03). These results suggest that deposition of inhaled particles (0.9 micrometer MMAD) administered by the aerosol bolus technique is a sensitive index of peripheral lung injury that is usually not assessable by conventional methods.