P. Diot

What the pulmonary specialist should know about the new inhalation therapies

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patients inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

Comorbidities of COPD.

By 2020, chronic obstructive pulmonary disease (COPD) will be the third cause of mortality. Extrapulmonary comorbidities influence the prognosis of patients with COPD. Tobacco smoking is a common risk factor for many comorbidities, including coronary heart disease, heart failure and lung cancer. Comorbidities such as pulmonary artery disease and malnutrition are directly caused by COPD, whereas others, such as systemic venous thromboembolism, anxiety, depression, osteoporosis, obesity, metabolic syndrome, diabetes, sleep disturbance and anaemia, have no evident physiopathological relationship with COPD. The common ground between most of these extrapulmonary manifestations is chronic systemic inflammation. All of these diseases potentiate the morbidity of COPD, leading to increased hospitalisations and healthcare costs. They can frequently cause death, independently of respiratory failure. Comorbidities make the management of COPD difficult and need to be evaluated and treated adequately.

Systemic sclerosis and occupational risk factors: a case–control study

Aims: A case–control study was carried out between 1998 and 2000 to investigate the relation between systemic sclerosis and occupational exposure. Methods: Eighty cases of systemic sclerosis admitted consecutively to the Department of Internal Medicine at the University Hospital of Tours from 1998 to 2000 were included. For each case, two age, gender, and smoking habits matched controls hospitalised during the same period in the same department were selected. A committee of experts was set up retrospectively to assess occupational exposure. Exposure to silica dust and organic solvents (such as trichlorethylene and other chlorinated solvents, and benzene and other aromatic solvents) was investigated using semiquantitative estimates of exposure. An exposure score was calculated for each subject based on probability, intensity, daily frequency, and duration of exposure for each period of employment. The final cumulative exposure score was obtained, taking into account all periods of employment. Results: Significant associations with SS were observed for crystalline silica, trichlorethylene, chlorinated solvents, toluene, aromatic solvents, ketones, white spirit, epoxy resins, and welding fumes. Risk of SS was significantly associated with a high final cumulative exposure score of occupational exposure to crystalline silica, trichlorethylene, chlorinated solvents, welding fumes, and any types of solvents. Conclusion: Results confirm the influence of occupational risk factors in the occurrence of SS in both men and women. The link is not only with silica but also with other compounds such as solvents.

Aerosol Deposition in Neonatal Ventilation

Lung deposition of inhaled drugs in ventilated neonates has been studied in models of questionable relevance. With conventional nebulizers, pulmonary deposition has been limited to 1% of the total dose. The objective of this study was to assess lung delivery of aerosols in a model of neonatal ventilation using a conventional and novel electronic micropump nebulizer. Aerosol deposition studies with 99mTc diethylenetriamine pentaacetate (99mTc-DTPA) were performed in four macaques (2.6 kg) that were ventilated through a 3.0-mm endotracheal tube (with neonatal settings (peak inspiratory pressure 12–14 mbar, positive end-expiratory pressure 2 mbar, I/E ratio 1/2, respiratory rate 40/min), comparing a jet-nebulizer MistyNeb (3-mL charge, 4.8 μm), an electronic micropump nebulizer operating continuously [Aeroneb Professional Nebulizer (APN-C); 0.5-mL charge, 4.6 μm], and another synchronized with inspiration [Aeroneb Professional Nebulizer Synchronized (APN-S); 0.5-mL charge, 2.8 μm]. The amount of radioactivity deposited into lungs and connections and remaining in the nebulizer was measured by a gamma counter. Despite similar amounts of 99mTc-DTPA in the respiratory circuit with all nebulizers, both APN-S and APN-C delivered more drug to the lungs than MistyNeb (14.0, 12.6, and 0.5% in terms of percentage of nebulizer charge, respectively; p = 0.006). Duration of delivery was shorter with APN-C than with the two other nebulizers (2 versus 6 and 10 min for the APN-S and the MistyNeb, respectively; p < 0.001). Electronic micropump nebulizers are more efficient to administer aerosols in an animal model of ventilated neonates. Availability of Aerogens electronic micropump nebulizers offers new opportunities to study clinical efficacy and risks of aerosol therapy in ventilated neonates.

Lipid nanocapsules: Ready-to-use nanovectors for the aerosol delivery of paclitaxel

Aerosol drug delivery permits the development of dose-intensification strategies in severe, malignant lung diseases. The aim of the study was to demonstrate that the encapsulation of paclitaxel in lipid nanocapsules (LNCs), a novel drug nanocarrier for lipophilic components, allows one to provide pulmonary drug delivery of paclitaxel by nebulisation, thereby allowing preclinical and clinical studies. LNC dispersions are made into aerosols with commercial nebulisers. The structure, drug payload and cytotoxicity of nebulised LNCs were compared to fresh LNCs. The results demonstrated that LNC dispersions could be made into aerosols by using mesh nebulisers without altering the LNC structure. Only eFlow rapid-produced aerosols are compatible with human use: the mean duration to nebulise 3 ml of LNC dispersion is less than 9 min, with an aerosol mass median aerodynamic diameter equal to 2.7+/-0.1 microm and a fine-particle fraction (between 1.0 and 5.0 microm) of 81.5+/-3.1%. No modifications of drug payload or cytotoxicity effects of paclitaxel-loaded LNC (PTX-LNC) were observed. In order to carry out preclinical studies, a scaled-up LNC formulation protocol was used. Chemical parameters, such as acidity and osmolarity, were optimised, and a storage procedure for PTX-LNC batches was set-up. Animal studies are now needed to determine the tolerance and therapeutic potential of LNC dispersion aerosols.

Influence of DNA on the Activities and Inhibition of Neutrophil Serine Proteases in Cystic Fibrosis Sputum

Uncontrolled proteolysis by neutrophil serine proteases (NSPs) in lung secretions is a hallmark of cystic fibrosis (CF). We have shown that the active neutrophil elastase, protease 3, and cathepsin G in CF sputum resist inhibition in part by exogenous protease inhibitors. This resistance may be due to their binding to neutrophil extracellular traps (NETs) secreted by the activated neutrophils in CF sputum and to genomic DNA released from senescent and dead neutrophils. Treating CF sputum with DNase dramatically increases its elastase activity, which can then be stoichiometrically inhibited by exogenous elastase inhibitors. However, DNase treatment does not increase the activities of protease 3 and cathepsin G, indicating their different distribution and/or binding in CF sputum. Purified blood neutrophils secrete NETs when stimulated by the opportunistic CF bacteria Pseudomonas aeruginosa and Staphylococcus aureus. The activities of the three proteases were unchanged in these conditions, but subsequent DNase treatment produced a dramatic increase in all three proteolytic activities. Neutrophils activated with a calcium ionophore did not secrete NETs but released huge amounts of active proteases whose activities were not modified by DNase. We conclude that NETs are reservoirs of active proteases that protect them from inhibition and maintain them in a rapidly mobilizable status. Combining the effects of protease inhibitors with that of DNA-degrading agents could counter the deleterious proteolytic effects of NSPs in CF lung secretions.

Deposition of amphotericin B aerosols in pulmonary aspergilloma

The aim of the present study was to characterize amphotericin B aerosols nebulized by ultrasonic and jet nebulizers and to study their deposition and pharmacokinetics in patients with pulmonary mycetoma. The aerodynamic behaviour and pulmonary deposition of amphotericin B particles were measured using a direct isotopic method based on stable labelling of the drug with 99mTc. Each nebulizer was bench tested for inhaled mass and particle size distribution. Three patients suffering from pulmonary aspergilloma were enrolled for a 4 week clinical study. They received 5 mg of amphotericin B daily delivered by either Fisoneb or DP100 (ultrasonic) or Respirgard II (jet) nebulizers. Deposition of radiolabelled amphotericin B was measured once with each nebulizer using a gamma-camera. In two patients, amphotericin B serum concentration was monitored over a 330 min period after the nebulization had been completed. Inhaled masses of the three nebulizers, assessed as % of labelled drug caught in inspiratory filter in duplicate experiments, were: 5.8 and 3.6% for Respirgard II; 26.5 and 28.3% with Fisoneb; 5.9 and 6.3% for DP100. Mass median aerodynamic diameter (mean +/- SD) results were: 0.28 +/- 0.04 micron with Respirgard II; 4.82 +/- 0.78 microns with Fisoneb; and 2.27 +/- 1.14 microns with DP100. Because of larger particles and significantly greater inhaled mass, Fisoneb delivered more amphotericin B to the central airways, the lung periphery and in the mycetoma lung regions. Amphotericin B serum concentrations correlated with pulmonary deposition and remained below 25 ng.mL-1. No untoward effects were reported by the patients during the 4 week trial.(ABSTRACT TRUNCATED AT 250 WORDS)

EPI-hNE4, a Proteolysis-Resistant Inhibitor of Human Neutrophil Elastase and Potential Anti-Inflammatory Drug for Treating Cystic Fibrosis

EPI-hNE4 (depelstat) is a potent inhibitor of human neutrophil elastase derived from human inter-α-trypsin inhibitor and designed to control the excess proteolytic activity in the sputum of cystic fibrosis patients. We analyzed its resistance to the proteolysis it is likely to encounter at inflammatory sites in vivo. EPI-hNE4 resisted hydrolysis by neutrophil matrix metalloproteases (MMPs) and serine proteases that are released from activated neutrophils in inflammatory lung secretions, including MMP-8 and MMP-9, and the elastase-related protease 3 and cathepsin G. It also resisted degradation by epithelial lung cell MMP-7 but was broken down by the Pseudomonas aeruginosa metalloelastase pseudolysin, when used in a purified system, but not when this protease competed with equimolar amounts of neutrophil elastase. We also investigated the inhibitory properties of EPI-hNE4 at the surface of purified blood neutrophils and in the sputum of cystic fibrosis patients where neutrophil elastase is in both a soluble and a gel phase. The elastase at the neutrophil surface was fully inhibited by EPI-hNE4 and formed soluble complexes. The elastase in cystic fibrosis sputum supernatants was inhibited by stoichiometric amounts of EPI-hNE4, allowing titration of the protease. But the percentage of inhibition in whole sputum homogenates varied from 50 to 100%, depending on the sample tested. EPI-hNE4 was rapidly cleaved by the digestive protease pepsin in vitro. Therefore, EPI-hNE4 seems to be an elastase inhibitor suitable for use in aerosols to treat patients with cystic fibrosis.

Validation of laser diffraction method as a substitute for cascade impaction in the European Project for a Nebulizer Standard.

The project for a European standard testing procedure to characterize nebulizers in terms of particle size distribution has been based on using the Andersen-Marple personal cascade impactor model 298 (A-MPCI) with a sodium fluoride reference solution. In the present study methods based on laser diffraction (Mastersizer-X) and time-of-flight (TOF)(APS) and another cascade impactor (GS1-CI) were compared with the A-MPCI. Two types of nebulizer (Pari LC+ and Microneb) were tested with all apparatuses, and a third type of nebulizer (NL9) was tested with the A-MPCI and Mastersizer-X. Nebulizers were charged with a solution of sodium fluoride in conditions reproducing the European Committee for Normalization (CEN) protocol. There was no difference between the Mastersizer-X and the A-MPCI or between the GS1-CI and the A-MPCI in terms of mass median aerodynamic diameter (MMAD). Comparison between the APS and the A-MPCI showed a significant difference with the Microneb. The geometric standard deviations (GSD) obtained with the A-MPCI were on average 10% greater than GSD obtained with the other apparatuses, but the differences were not statistically significant. We conclude that laser diffraction can be used for particle size distribution in the context of the European standard, and that the Mastersizer-X is particularly interesting for industrial practice in view of its simplicity and robustness.

Aerosolized Gemcitabine in Patients with Carcinoma of the Lung: Feasibility and Safety Study

BACKGROUND We investigated the biodistribution, pharmacokinetics, safety profile, and feasibility of aerosolized gemcitabine (GCB) in patients with lung carcinoma. METHOD Eleven patients with carcinoma localized in the lungs were studied in a dose escalation study of aerosolized GCB administered 1 day/week for 9 consecutive weeks. Safety data, scintigraphic assessment of the delivered dose and pharmacokinetic monitoring were analyzed. Patients were treated with doses of between 1 mg/kg and 4 mg/kg (dose in the nebulizer), using a new inhaler device (Aeroneb Pro with an Idehaler Chamber). RESULTS AND CONCLUSIONS The total dose of GCB delivered to the patients lung was 42±16% of the initial amount of dose in the nebulizer. Safety data showed no hematologic toxicity, nephrotoxicity or neurotoxicity. At 4 mg/kg, one patient experienced grade 4 pulmonary toxicity (bronchospasm), which was the dose-limiting toxicity. Grade 2 and 3 toxic effects included fatigue, vomiting, dyspnea, and cough. Overall response: minor response in one patient, stable disease in four patients, progressive disease in four patients. Pharmacokinetic data showed very low plasma GCB levels. Maximal plasma concentration was observed at the end of nebulization. Aerosolized gemcitabin was safe, with minimal toxicity, for patients with lung carcinoma.