A study was carried out to investigate the predictive value of 81-metastable-krypton (81mKr) distribution, high-size 99-metastable-technetium (99mTc) aerosol deposition and low-size 99mTc aerosol (Technegas) deposition on the pulmonary ventilation evaluated by 133-xenon (133Xe) lung scintigraphy, and to assess the correlation between the 81mKr distribution, the 99mTc aerosols deposition, and the respiratory parameters of patients with chronic obstructive pulmonary disease (COPD). Twenty COPD patients were included. The 81mKr, 133Xe, and 99mTc aerosol lung scintigraphies were successively carried out. The 81mKr distribution and 99mTc deposition were compared to the 133Xe distribution at equilibrium and to the 133Xe clearance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 81mKr and Technegas lung scintigraphies to detect alterations in ventilation revealed by 133Xe were defined. The 81mKr distribution and 99mTc deposition according to respiratory parameters were described using a principal component analysis. Compared to 133Xe distribution, a significantly higher distribution of 81mKr in the upper parts of the lungs in the more severe patients (p = 0.05), a significantly higher deposition of Technegas in the lower parts of the lungs (p = 0.0008), and a significantly higher deposition in the central parts of the high-size 99mTc aerosol were observed (p = 0.0001). The PPV and the NPV were, respectively, 0.54 and 0.58 for 81mKr and 0.54 and 0.55 for Technegas. There was a significant negative correlation between 81mKr distribution and 133Xe clearance (p = 0.0001) between Technegas deposition and 133Xe clearance (p = 0.0007), and between 99mTc diethylene-triamino-penta-acetate (DTPA) deposition and 133Xe clearance (p = 0.001). Both the 81mKr peripheral distribution and Technegas peripheral deposition correlated negatively with increased obstruction, as measured by forced expiratory volume in 1 sec (FEV1). Peripheral deposition of the high-size 99mTc aerosol deposition correlated with the inspiration/expiration time ratio. In conclusion, 81mKr and 99mTc aerosols' lung scintigraphies do not reflect exactly the pulmonary ventilation as measured by 133Xe scintigraphy.

The purpose of this research was to evaluate the safety of pulmonary administration of gemcitabine and to determine the maximum tolerated dose by weekly pulmonary administrations in an animal model. Five groups of eight Wistar rats received gemcitabine at doses of 2, 4, 6, or 8 mg/kg or the vehicle solution by endotracheal spray with scintigraphic imaging of lung deposition. In order to document the safety of digestive exposure, five groups of eight rats received gemcitabine at the same dosages or the vehicle solution by gavage. Nine weekly sessions were planned, and blood cell counts and histological examinations were performed in live animals at day 64. Scintigraphic imaging confirmed pulmonary deposition in 310 of 316 spray administrations (98%) with homogeneous pattern of deposition. The maximum tolerated dose of gemcitabine by pulmonary administration was 4 mg/kg. At this dosage, administered once a week for 9 consecutive weeks, there were no chemotherapy-related deaths and no clinical, histological, or hematological signs of toxicity except for a decrease in platelet and red blood cell counts, with no clinical significance. The toxicity of gemcitabine was higher via oral than lung delivery in terms of weight loss and white blood cell toxicity at dosages of 2, 4, and 6 mg/kg. Pulmonary administration of gemcitabine is safe in rats at a maximum tolerated dose of 4 mg/kg once a week for 9 weeks. At an equivalent dosage, the toxicity of gemcitabine is lower by lung than oral administration.

To evaluate the effectiveness of morphine aerosols in the treatment of dyspnoea in the palliative care of patients with lung cancer.During a randomised, double blind, cross-over study 12 patients receiving palliative care for lung cancer and suffering from dyspnoea despite conventional treatments were given, for two periods of 48 hours separated by a 24 hour wash-out period, 4 mls of morphine sulphate and 4 mls of normal saline 4 hourly by a jet nebuliser. Before and after each nebulisation respiratory rate and capillary oxygen saturation were measured and dyspnoea was quantified with the aid of a visual analogue scale by the patient and various other observers (doctors, students, nurses, care assistants and physiotherapists).The aerosols of normal saline and morphine produced the same improvements in the dyspnoea scores independently of the mass nebulised. Furthermore the nebulisations did not produce any significant change in respiratory rate or oxygen saturation.The fact that both aerosols lead to a similar improvement in dyspnoea scores suggests that humidification of the airways rather than a pharmacological action may be beneficial in the treatment of dyspnoea in terminally ill patients.

OBJECTIVE:To evaluate the effectiveness of morphine aerosols in the treatment of dyspnoea in the palliative care of patients with lung cancer.MATERIALS AND METHODS:During a randomised, double blind, cross-over study 12 patients receiving palliative care for lung cancer and suffering from dyspnoea despite conventional treatments were given, for two periods of 48 hours separated by a 24 hour wash-out period, 4 mls of morphine sulphate and 4 mls of normal saline 4 hourly by a jet nebuliser. Before and after each nebulisation respiratory rate and capillary oxygen saturation were measured and dyspnoea was quantified with the aid of a visual analogue scale by the patient and various other observers (doctors, students, nurses, care assistants and physiotherapists).RESULTS:The aerosols of normal saline and morphine produced the same improvements in the dyspnoea scores independently of the mass nebulised. Furthermore the nebulisations did not produce any significant change in respiratory rate or oxygen saturation.CONCLUSION:The fact that both aerosols lead to a similar improvement in dyspnoea scores suggests that humidification of the airways rather than a pharmacological action may be beneficial in the treatment of dyspnoea in terminally ill patients.

Fixed-combination drug products (FCDPs) for patients with type 2 diabetes mellitus (T2DM) may show efficacy comparable to their individual components (ICs) while improving adherence to treatment. This study evaluated the bioequivalence and safety of 2 dapagliflozin/saxagliptin/metformin extended-release (XR) FCDPs relative to their ICs: saxagliptin and dapagliflozin/metformin XR.This randomized, open-label, single-dose, single-center crossover study was conducted in 84 healthy subjects aged 18–55 years. The primary objective was to evaluate the fed-state bioequivalence of a dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP and a dapagliflozin 10-mg/saxagliptin 5-mg/metformin 1000-mg XR FCDP relative to the ICs. Secondary objectives included the evaluation of the effect of food on the pharmacokinetic (PK) parameters of saxagliptin, dapagliflozin, and metformin in both FCDPs and characterization of the PK parameters of the active metabolite of saxagliptin, 5-hydroxy saxagliptin, in healthy subjects. PK parameters (AUC0–∞, AUC0–t, and Cmax) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The Cmax and AUC0–t of the study drugs were compared between female and male subjects to assess sex differences in exposure. Safety and tolerability of both FCDPs and ICs were also assessed with adverse events, vital signs (systolic and diastolic blood pressures and pulse rate), 12-lead ECG, physical examinations, and laboratory assessments.Both dapagliflozin/saxagliptin/metformin XR FCDPs were bioequivalent to their ICs. For the dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP, the 90% CI for the geometric mean ratio of dapagliflozin Cmax was slightly above the 80%–125% bioequivalence limit, which is unlikely to be clinically relevant. Food delayed the absorption of the study drugs in both FCDPs, which is unlikely to have a clinically relevant impact on efficacy. In both cohorts, exposure was higher in female subjects compared with male subjects, potentially due to the lower body weight of the female subjects. The safety profile and tolerability of the FCDPs were similar to those of their ICs, and no deaths or serious adverse events were reported.These data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.

Le contrôle local reste un défi majeur dans le traitement à visée curative des carcinomes bronchiques à petites cellules localisés au thorax. Malgré le développement des polychimiothérapies, la radiothérapie médiastinopulmonaire est indispensable à l'obtention du contrôle local et d'une survie à long terme. Le contrôle local est d'autant meilleur que la dose totale est élevée et l'irradiation accélérée. La survie est plus longue si l'irradiation thoracique est précoce. La radiothérapie peut être délivrée de première intention en même temps qu'une chimiothérapie par étoposide et cisplatine. Les résultats obtenus avec cette chimioradiothérapie semblent meilleurs si la radiothérapie est hyperfractionnée et accélérée, quoique la toxicité aiguë, en premier lieu œsophagienne, soit augmentée. L'administration alternée de la radiothérapie et de la chimiothérapie est cependant souvent préconisée, car elle permet de délivrer précocement l'irradiation thoracique sans diminuer les doses de cytostatiques; l'intensité de dose est en effet un facteur pronostique significatif de la survie. C'est probablement l'évaluation des effets tardifs qui permettra de définir le schéma optimal d'association de la radiothérapie thoracique et de la chimiothérapie.Local control remains a major challenge in the treatment of limited small-cell lung cancer. In spite of the use of polychemotherapy, mediastinal irradiation is still necessary as regards local control and long-term survival. A high total dose and accelerated radiation improves local control, and survival time is increased by early mediastinal irradiation. Radiotherapy can be administered concomitantly with chemotherapy (etoposide and cisplatin) from the beginning. Optimal results seem to be obtained with hyperfractionated and accelerated irradiation, although there is a resulting increase in acute toxicity, primarily oesophageal. Alternating the radio and chemotherapy schedule is often used as a treatment procedure, as it permits early mediastinal irradiation without a reduction in the dose of cytostatics. Dose intensity is in fact a significant prognostic factor in survival. It is probably through the evaluation of late effects that a definition can be made of the optimal schedule for combined mediastinal radiotherapy and chemotherapy in the treatment of limited small-cell lung cancer.

The aim of this study was to assess a residual gravimetric method based on weighing dry filters to measure the aerosol output of nebulizers. This residual gravimetric method was compared to assay methods based on spectrophotometric measurement of terbutaline (Bricanyl, Astra Zeneca, France), high-performance liquid chromatography (HPLC) measurement of tobramycin (Tobi, Chiron, U.S.A.), and electrochemical measurements of NaF (as defined by the European standard). Two breath-enhanced jet nebulizers, one standard jet nebulizer, and one ultrasonic nebulizer were tested. Output produced by the residual gravimetric method was calculated by weighing the filters both before and after aerosol collection and by filter drying corrected by the proportion of drug contained in total solute mass. Output produced by the electrochemical, spectrophotometric, and HPLC methods was determined after assaying the drug extraction filter. The results demonstrated a strong correlation between the residual gravimetric method (x axis) and assay methods (y axis) in terms of drug mass output (y = 1.00 x -0.02, r(2) = 0.99, n = 27). We conclude that a residual gravimetric method based on dry filters, when validated for a particular agent, is an accurate way of measuring aerosol output.

Objective To evaluate the effectiveness of morphine aerosols in the treatment of dyspnoea in the palliative care of patients with lung cancer.Materials and methods. During a randomised, double blind, cross-over study 12 patients receiving palliative care for lung cancer and suffering from dyspnoea despite conventional treatments were given, for two periods of 48 hours separated by a 24 hour wash-out period, 4 mls of morphine sulphate and 4 mls of normal saline 4 hourly by a jet nebuliser. Before and after each nebulisation respiratory rate and capillary oxygen saturation were measured and dyspnoea was quantified with the aid of a visual analogue scale by the patient and various other observers (doctors, students, nurses, care assistants and physiotherapists).Results The aerosols of normal saline and morphine produced the same improvements in the dyspnoea scores independently of the mass nebulised. Furthermore the nebulisations did not produce any significant change in respiratory rate or oxygen saturation.Conclusion The fact that both aerosols lead to a similar improvement in dyspnoea scores suggests that humidification of the airways rather than a pharmacological action may be beneficial in the treatment of dyspnoea in terminally ill patients.

The purpose of this study was to define nebulization conditions providing delivery of aerosols of EPI-hNE4, an inhibitor of human neutrophil elastase (HNE). EPI-hNE4 was nebulized with Pari LC Star and tested at three concentrations (2.5, 5, and 10 mg/mL). The inhaled mass was measured over 15 min. Particle size distribution was measured by cascade impaction. The effect was also tested of mixing EPI-hNE4 with a (99m)Tc human serum albumin (HSA) tracer on the aerodynamic properties of the aerosol. The inhibitory activity of EPI-hNE4 after nebulization was assessed on purified HNE. The inhaled mass was 32.3 +/- 3.5% (mean +/- SD) after 10 min and 44.2 +/- 3.8% (mean +/- SD) after 15 min. Mass median aerodynamic diameter ranged between 1.2 and 1.8 microm. The (99m)Tc HSA EPI-hNE4 aerosol was similar in terms of particle size distribution (y = 1.0338x - 0.003, r = 0.83). (99m)Tc activity was predictive of EPI-hNE4 mass distribution (y = 1.0278x - 1.6991, r = 0.89). The inhibitory capacity of aerosolized samples remained unchanged after up to 10 min of nebulization. EPI-hNE4 can be nebulized efficiently without decrease in its activity. Mixing this inhibitor with (99m)Tc HSA should allow quantification of its deposition in CF patients.

Background: The interpretation of 99mTc diethylenetriamine pentaacetate (99mTc DTPA) aerosol clearance is based on the hypothesis that the 99mTc-DTPA complex is not altered by the nebulization process. Objectives: To characterize (1) the radiochemical purity (RCP) of 99mTc-DTPA and the stability of labeling after jet nebulization, and (2) the particle size distribution of the aerosol. Methods: RCP and stability – the aerosol was driven by oxygen, captured on filters which were eluted and RCP was checked by thin layer chromatography. Particle size distribution – the aerosol was generated using dry air (50 psi) at three different flow rates, i.e. 3 (1 run), 6 (4 runs) and 9 l·min–1 (4 runs). The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (σg) were determined using a cascade impactor from the radioactivity counted on each stage. Results: The RCP was more than 95% in all cases. Mean MMAD (±SD) was 0.70 µm (±0.07) at 9 l·min–1, 0.93 µm (±0.05) at 6 l·min–1 (p < 0.05) and 1.50 µm at 3 l·min–1. Mean σg (±SD) was 2.02 (±0.08) at 9 l·min–1, 2.00 (±0.16) at 6 l·min–1 and 1.90 at 3 l·min–1. Conclusion: This study demonstrates (1) that the high RCP of 99mTc-DTPA is not affected by jet nebulization, even when using oxygen at a high flow rate, and (2) that when using a flow rate between 6 and 9 l·min–1, the MMAD remains optimal for peripheral lung deposition.

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.