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The increasing use of hexavalent chromium (Cr(VI)) has exposed large populations to this environmental and occupational carcinogenic agent. Therefore, researchers have been interested in removing this substance through adsorbents. This study aimed to investigate the efficiency of natural zeolite in the direct adsorption of Cr(VI) from airflow and its adsorption modeling. In this study, a nebulizer device produced the Cr(VI) mist. The efficiency of natural zeolite in Cr(VI) adsorption from airflow, modeling of fixed column adsorption, and the effective parameters on adsorption efficiency including the initial concentration of chromium, airflow rate, and adsorption bed depth were studied. To facilitate the prediction of the performance of natural zeolite’s adsorption column, Yoon–Nelson, Thomas, BDST, and Buhart–Adams models were used. The results showed that the adsorption capacity diminished with increased airflow rate and initial concentration, while it increased with elevated height of the adsorption bed. Yoon–Nelson, Thomas, and BDST models corresponded to experimental data with a correlation coefficient of 0.9933, but the information of the Buhart–Adams model had a lower correlation coefficient (around 0.6677). In conclusion, natural zeolite can be used as an efficient low-cost adsorbent for directly Cr(VI) removing from the airflow in a fixed bed column. [ABSTRACT FROM AUTHOR]

Capillary electrophoresis (CE) is a powerful and sensitive tool for speciation analysis when combined with inductively coupled plasma mass spectrometry (ICP-MS); however, the performance of this technique can be limited by the nature of pneumatic nebulizers. This study compares two commercially available pneumatic nebulizers to a newly introduced vibrating capillary nebulizer (VCN) for on-line coupling of CE with ICP-MS. The VCN is a low-cost, non-pneumatic nebulizer that is based on the design of capillary vibrating sharp-edge spray ionization. As a piezoelectrically driven nebulization source, the VCN creates an aerosol independent of gas flows and does not produce a low-pressure region at the nebulizer orifice. To compare the systems, we performed replicate analyses of sulfate in river water with each nebulizer and the same CE and ICP-MS instruments and determined the figures of merit of each setup. With the CE-VCN-ICP-MS setup, we achieved around 2–4 times lower sensitivity compared to the commercial setups. However, the VCN-based setup provided lower noise levels and better linear correlation from the analysis of calibration standards, which resulted in indistinguishable LOD and LOQ values from the in-house-built VCN-based and commercial setups for CE-ICP-MS analysis. The VCN is found to have the highest baseline stability with a standard deviation of 3500 cts s−1, corresponding to an RSD of 2.7%. High reproducibility is found with the VCN with a peak area RSD of 4.1% between 3 replicate measurements. [ABSTRACT FROM AUTHOR]

Background: The administration technique for inhaled drug delivery during invasive ventilation remains debated. This study aimed to compare in vivo and in vitro the deposition of a radiolabeled aerosol generated through four configurations during invasive ventilation, including setups optimizing drug delivery. Methods: Thirty-one intubated postoperative neurosurgery patients with healthy lungs were randomly assigned to four configurations of aerosol delivery using a vibrating-mesh nebulizer and specific ventilator settings: (1) a specific circuit for aerosol therapy (SCAT) with the nebulizer placed at 30 cm of the wye, (2) a heated-humidified circuit switched off 30 min before the nebulization or (3) left on with the nebulizer at the inlet of the heated-humidifier, (4) a conventional circuit with the nebulizer placed between the heat and moisture exchanger filter and the endotracheal tube. Aerosol deposition was analyzed using planar scintigraphy. Results: A two to three times greater lung delivery was measured in the SCAT group, reaching 19.7% (14.0–24.5) of the nominal dose in comparison to the three other groups (p < 0.01). Around 50 to 60% of lung doses reached the outer region of both lungs in all groups. Drug doses in inner and outer lung regions were significantly increased in the SCAT group (p < 0.01), except for the outer right lung region in the fourth group due to preferential drug trickling from the endotracheal tube and the trachea to the right bronchi. Similar lung delivery was observed whether the heated humidifier was switched off or left on. Inhaled doses measured in vitro correlated with lung doses (R = 0.768, p < 0.001). Conclusion: Optimizing the administration technique enables a significant increase in inhaled drug delivery to the lungs, including peripheral airways. Before adapting mechanical ventilation, studies are required to continue this optimization and to assess its impact on drug delivery and patient outcome in comparison to more usual settings. [ABSTRACT FROM AUTHOR]

Recently, many preclinical and clinical studies have been conducted on the delivery of therapeutic antibodies to the lungs using nebulizers, but standard treatment guidelines have not yet been established. Our objective was to compare nebulization performance according to the low temperature and concentration of immunoglobulin G (IgG) solutions in different types of nebulizers, and to evaluate the stability of IgG aerosols and the amount delivered to the lungs. The output rate of the mesh nebulizers decreased according to the low temperature and high concentration of IgG solution, whereas the jet nebulizer was unaffected by the temperature and concentration of IgG. An impedance change of the piezoelectric vibrating element in the mesh nebulizers was observed because of the lower temperature and higher viscosity of IgG solution. This affected the resonance frequency of the piezoelectric element and lowered the output rate of the mesh nebulizers. Aggregation assays using a fluorescent probe revealed aggregates in IgG aerosols from all nebulizers. The delivered dose of IgG to the lungs in mice was highest at 95 ng/mL in the jet nebulizer with the smallest droplet size. Evaluation of the performance of IgG solution delivered to the lungs by three types of nebulizers could provide valuable parameter information for determination on dose of therapeutic antibody by nebulizers. [ABSTRACT FROM AUTHOR]

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25 years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effectiveness of nebulized magnesium sulfate in treating persistent pulmonary hypertension of newborn (PPHN). Methods: Twenty-eight mechanically ventilated term neonates with severe PPHN were randomized into two groups: NebMag group (n = 14), who receiving nebulized isotonic magnesium (1024 mg/h), and IVMag group (n = 14), who received intravenous magnesium (200 mg/kg over 30 min, followed by 50 mg/kg/h). The study time frame was 24 h. Outcome measures were the changes in oxygenation index (OI), mean arterial blood pressure (MABP), vasoactive inotropic score (VIS), and serum magnesium level. Results: Baseline demographic, ventilatory, and hemodynamic characteristics were comparable between the two groups. At the end of the study, the OI decreased by 44.3% in the NebMag group compared with 35.3% in the IVMag group (mean difference −3.14; 95%CI −5.08, −1.19; p 0.003). The NebMag group had a higher MABP (mean difference 2.29 mmHg; 95% CI 1.80, 2.77; p 0.000) and lower VIS (mean difference −14.64; 95% CI −16.52, −12.77; p 0.000) at the 24-h study time point. The increase in serum magnesium level, measured at 12-h study time point, was lower in the NebMag group (mean difference −2.26 mmol/L; 95% CI −2.58, −1.96; p 0.000). Conclusion: Nebulized magnesium sulfate may be an effective therapeutic modality for neonates with severe PPHN on mechanical ventilation, but this should be confirmed by larger studies. Retrospectively registered at www.clinicaltrials.gov (identifier: NCT04328636). [ABSTRACT FROM AUTHOR]

Background: Inspired air is heated and humidified in the nose before it reaches lower airways. This mechanism is bypassed during tracheostomy, directly exposing the airways to colder and drier air from the environment, known to negatively affect mucociliary transport; however, little is known about how quickly mucociliary transport deteriorates. This study determines the short-term effect of flowing room air and nebulized hypertonic saline and mannitol on mucociliary transport in the trachea. In an ovine perfused in vitro tracheal model (N = 9) the epithelium was exposed to 25 L/min of flow, heated to lamb body temperature (38 °C) and fully saturated with water vapor as the control, followed by either room air (22 °C and 50% relative humidity) or nebulized solutions of NaCl 7% and mannitol 20% up to 1 min for a short duration, until mucociliary transport had visually changed. Mucus transport velocity (MTV) and cilia beat frequency (CBF) were continuously measured with video-microscopy. Results: Exposing the tracheal epithelium to air heated to body temperature and fully humidified had stable MTV 9.5 ± 1.1 mm/min and CBF 13.4 ± 0.6 Hz. When exposed to flow of room air, MTV slowed down to 0.1 ± 0.1 mm/min in 2.0 ± 0.4 s followed by a decrease in CBF to 6.7 ± 1.9 Hz, after 2.3 ± 0.8 s. Both MTV and CBF recovered to their initial state when heated and humidified air-flow was re-introduced. Exposing the tracheal epithelium to nebulized hypertonic saline and nebulized mannitol for 1 min increased MTV without a subsequent increase in CBF. Conclusions: This study demonstrates mucociliary transport can deteriorate within seconds of exposing the tracheal epithelium to flowing room air and increase rapidly when exposed to nebulized hypertonic solutions. The reduction in MTV precedes slowing of CBF with room air and MTV increases without a subsequent increase in CBF during the nebulization. Their relationship is non-linear and a minimum CBF of approximately 6 Hz is required for MTV > 0, while MTV can reach 10.9 mm/min without CBF increasing. Clinically these findings indicate a potential rapid detrimental effect of breathing with non-humidified air via bypassed upper airways and the short-term effects of nebulized osmotic agents that increase MTV. [ABSTRACT FROM AUTHOR]

Introduction: Personalized therapy for patients with COPD requires appropriate choice of drug and delivery device. Inhalers and nebulizers vary in their drug delivery characteristics, particularly the need for passive or active patient inhalation for appropriate drug dispersal and delivery. In this in vitro analysis, we assessed the aerosol performance and drug delivery of two long-acting muscarinic antagonists, glycopyrrolate (GLY; 25 µg solution; 1 ml) and tiotropium (TIO; 18 µg powder) through their respective delivery systems: the eFlow® Closed System (CS) vibrating membrane nebulizer and the HandiHaler® dry-powder inhaler (DPI). Methods: The aerosol performances of the eFlow® CS nebulizer and the HandiHaler® were determined using the Next Generation cascade Impactor. The delivered dose of GLY and TIO was determined using different breathing patterns, which varied in tidal volume and peak inspiratory flow rate, respectively, to simulate breathing conditions ranging from normal to severe obstruction. Results: Aerodynamic particle analysis showed generally similar mass median aerodynamic diameter (MMAD, range, 3.6–4.6 µm) and fine particle fraction (FPF, range, 48.2%–63.7%) with GLY delivered using the eFlow® CS nebulizer under all breathing patterns tested. TIO, delivered via the HandiHaler®, showed variations in MMAD (range, 3.8–5.8 µm) and FPF (range, 16.1%–32.4%) under different inspiratory flow rates. The majority of GLY was deposited in stages 2–5 of the impactor, which corresponds with particle sizes in the respirable range (< 5 µm), whereas a large proportion of TIO was deposited in the throat/mouthpiece pre-separator, irrespective of test conditions. The median residual dose of GLY with eFlow® CS was notably lower compared to that of TIO with HandiHaler® (2.4%–4.4% vs. 40%–67%, respectively). Conclusions: These simulation results highlight the different deposition patterns generated by a DPI device and a vibrating membrane nebulizer, which may help inform device selection and treatment decision in COPD management. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to develop novel paclitaxel-loaded proliposome tablet formulations for pulmonary drug delivery. Method: Proliposome powder formulations (i.e. F1 – F27) were prepared employing Lactose monohydrate (LMH), Microcrystalline cellulose (MCC) or Starch as a carbohydrate carriers and Soya phosphatidylcholine (SPC), Hydrogenated soya phosphatidylcholine (HSPC) or Dimyristoly phosphatidylcholine (DMPC) as a phospholipid. Proliposome powder formulations were prepared in 1:5, 1:15 or 1:25 w/w lipid phase to carrier ratio (lipid phase; comprising of phospholipid and cholesterol in 1:1 M ratio) and Paclitaxel (PTX) was used as model anticancer drug. Results: Based on flowability studies, out of 27 formulations; F3, F6, and F9 formulations were selected as they exhibited an excellent angle of repose (AOR) (17.24 ± 0.43, 16.41 ± 0.52 and 15.16 ± 0.72°), comparatively lower size of vesicles (i.e. 5.35 ± 0.76, 6.27 ± 0.59 and 5.43 ± 0.68 μm) and good compressibility index (14.81 ± 0.36, 15.01 ± 0.35 and 14.56 ± 0.14) via Carr's index. The selected formulations were reduced into Nano (N) vesicles via probe sonication, followed by spray drying (SD) to get a dry powder of these formulations as F3SDN, F6SDN and F9SDN, and gave high yield (>53%) and exhibited poor to very poor compressibility index values via Carr's Index. Post tablet manufacturing, F3 tablets formulation showed uniform weight uniformity (129.40 ± 3.85 mg), good crushing strength (14.08 ± 1.95 N), precise tablet thickness (2.33 ± 0.51 mm) and a short disintegration time of 14.35 ± 0.56 min, passing all quality control tests in accordance with British Pharmacopeia (BP). Upon nebulization of F3 tablets formulation, Ultrasonic nebulizer showed better nebulization time (8.75 ± 0.86 min) and high output rate (421.06 ± 7.19 mg/min) when compared to Vibrating mesh nebulizer. PTX-loaded F3 tablet formulations were identified as toxic (60% cell viability) to cancer MRC-5 SV2 cell lines while safe to normal MRC-5 cell lines. Conclusion: Overall, in this study LMH was identified as a superior carbohydrate carrier for proliposome tablet manufacturing in a 1:25 w/w lipid to carrier ratio for in-vitro nebulization via Ultrasonic nebulizer. [ABSTRACT FROM AUTHOR]

The mainstay treatment of pulmonary disorders lies around the direct drug targeting to the lungs using a nebulizer, metered-dose inhaler, or dry powder inhaler. Only few inhalers are available in the market that could be used for inhalational drug delivery in rodents. However, the available rodent inhalers invariably require high cost and maintenance, which limits their use at laboratory scale. The present work, therefore, was undertaken to develop a simple, reliable, and cost-effective nose-only inhalation chamber with holding capacity of three mice at a time. The nebulized air passes directly and continuously from the central chamber to mouthpiece and maintains an aerosol cloud for rodents to inhale. Laser diffraction analysis indicated volume mean diameter of 4.02 ± 0.30 μm, and the next-generation impactor studies, however, revealed mean mass aerodynamic diameter of 3.40 ± 0.27 μm, respectively. An amount of 2.05 ± 0.20 mg of voriconazole (VRC) was available for inhalation at each delivery port of the inhaler. In vivo studies indicated the deposition of 76.12 ± 19.50 μg of VRC in the mice lungs when nebulized for a period of 20 min. Overall, the developed nose-only inhalation chamber offers a reliable means of generating aerosols and successfully exposing mice to nebulization. [ABSTRACT FROM AUTHOR]

The purpose of the study was to analyze the effectiveness of adding nebulized antibiotics to systemic antimicrobials in critically ill patients with respiratory tract infections (pneumonia or tracheobronchitis) and the effect on renal function. A retrospective observational cohort study including critically ill patients with respiratory tract infections during a 2-year period was conducted. Intervention group included patients that received nebulized and systemic antimicrobials. Patients in the control group received only systemic antimicrobials. Clinical resolution was the primary endpoint. Secondary outcomes included change in fever, inflammatory parameters, and creatinine clearance; length of hospital stay, systemic therapy, and mechanical ventilation; hospital readmission; and mortality. Regression models were performed to estimate the effect of nebulized antibiotics on outcome variables adjusted by potential confounders. A total of 136 patients were included (93 in control group and 43 in intervention group). The intervention group had higher odds of clinical resolution (adjusted odds ratio (OR): 7.1; 95% confidence interval (95% CI): 1.2, 43.3). Nebulized antibiotic therapy was independently associated with reduction in procalcitonin (adjusted OR: 12.4; 95% CI: 1.4, 109.7). There were no significant differences in the rest of the secondary outcomes or in creatinine clearance reduction. Adding nebulized antibiotics for the management of respiratory tract infections has a positive impact on clinical resolution without increasing the risk of renal toxicity. [ABSTRACT FROM AUTHOR]

Targeted drug delivery is an impressive topic that attracted the attention of many scientists in various scientific communities. Magnetic drug targeting is one of the targeted drug delivery techniques, which uses the magnetic field to externally control the magnetic drug particles. In this study, we aim to assess the magnetic drug delivery to the human respiratory system using a new aerosolization technique driven by surface acoustic waves (SAWs) into a realistic lung model geometrically reconstructed using computed tomography scan images. To achieve this aim, a simulation study using computational fluid-particle dynamics considering the Lagrangian approach for particle tracking is carried out. An external magnetic field was applied to govern the Magnetit (Fe3O4) particles as the magnetic drug career. The drug particles were assumed to be spherical and inert. The effects of magnetic field intensity, magnetic source position, and SAW injection position were examined for a light breathing condition (Q = 15 L/min). Given the realistic geometry of the respiratory system and its complexity, the airflow patterns vary as it penetrates deeper into the lung and experiences many irregularities, and bending deflections exist in the airways model. High-inertia particles tend to deposit at locations where the geometry experiences a significant reduction in cross section. Our results show that the magnetic field highly affects the particle deposition efficiency for fourfold. However, the magnet and SAW injection positions have a low impact on the deposition efficiency of drug particles. [ABSTRACT FROM AUTHOR]

Introduction: The use of concurrent aerosol delivery during high-flow nasal therapy (HFNT) may be exploited to facilitate the delivery of a variety of prescribed medications for inhalation. Until now, a systematic approach to determine the conditions required to yield an optimal emitted dose has not been reported. The aim of this study was to establish the effects of gas flow rate, input droplet size, and nebulizer position on the amount of aerosol exiting the nasal cannula during HFNT and thus becoming available for inhalation.Methods: Testing was completed according to a factorial statistical design of experiments (DOE) approach. Emitted dose was characterized with a vibrating mesh nebulizer (Aerogen Solo, Aerogen Ltd) for an adult model of HFNT at three clinically relevant gas flow rates, using three nebulizers producing varying input droplet sizes and placed at two different nebulizer positions.Results: Increasing the gas flow rate significantly lowered the emitted dose, with a dose of 7.10% obtained at 10 LPM, 2.67% at 25 LPM, and 1.30% at 40 LPM (p < 0.0001). There was a significant difference in emitted dose between nebulizers with different input droplet sizes, with increasing input droplet size associated with a reduced emitted dose (6.11% with an input droplet size of 3.22 µm, 2.76% with 4.05 µm, and 2.38% with 4.88 µm, p  = 0.0002, Pearson’s r = − 0.2871). In addition, the droplet size exiting the nasal cannula interface was lower than that produced by the aerosol generator for all devices under test. Positioning the nebulizer immediately after the humidification chamber yielded a marginally greater emitted dose (3.79%) than when the nebulizer was placed immediately upstream of the nasal cannula (3.39%). Flow rate, input droplet size, and nebulizer position were at the 0.10 level of significance, indicating that all three factors had significant effects on emitted dose. According to the DOE model, flow rate had the greatest influence on emitted dose, followed by input droplet size and then nebulizer position.Conclusion: Our findings indicate that in order to optimize the amount of aerosol exiting the nasal cannula interface during HFNT, it is necessary for gas flow rate to be low and the input droplet size to be small, while the nebulizer should be positioned immediately after the humidification chamber.Funding: Aerogen Limited. [ABSTRACT FROM AUTHOR]

Administration of drug in the form of particles through inhalation is generally preferable in the treatment of respiratory disorders. Conventional inhalation therapy devices such as inhalers and nebulizers, nevertheless, suffer from low delivery efficiencies, wherein only a small fraction of the inhaled drug reaches the lower respiratory tract. This is primarily because these devices are not able to produce a sufficiently fine drug mist that has aerodynamic diameters on the order of a few microns. This study employs computational fluid dynamics to investigate the transport and deposition of the drug particles produced by a new aerosolization technique driven by surface acoustic waves (SAWs) into an in silico lung model geometrically reconstructed using computed tomography scanning. The particles generated by the SAW are released in different locations in a spacer chamber attached to a lung model extending from the mouth to the 6th generation of the lung bronchial tree. An Eulerian approach is used to solve the Navier-Stokes equations that govern the airflow within the respiratory tract, and a Lagrangian approach is adopted to track the particles, which are assumed to be spherical and inert. Due to the complexity of the lung geometry, the airflow patterns vary as it penetrates deeper into the lung. High inertia particles tend to deposit at locations where the geometry experiences a significant reduction in cross section. Our findings, nevertheless, show that the injection location can influence the delivery efficiency: Injection points close to the spacer centerline result in deeper penetration into the lung. Additionally, we found that the ratio of drug particles entering the right lung is significantly higher than the left lung, independent of the injection location. This is in good agreement with this fact that the most of airflow enters to the right lobes. [ABSTRACT FROM AUTHOR]

This review describes beneficial effects and adverse events of various intranasal medications in treating rhinosinusitis. Application of intranasal steroids has been described in treating all subtypes of adult rhinosinusitis, but reports are limited in pediatrics and mostly in acute pediatric subgroups resulted in benefits While saline irrigation is effective for patients with chronic rhinosinusitis without polyps and in pediatric acute rhinosinusitis, there is no evidence yet for saline drips and sprays. Application of intranasal antifungals and nasal irrigation with surfactant brings more harm than benefits. There is no evidence supporting the use of intranasal antibiotics. We also review influence of devices, methods, and patient head position on nasal and paranasal sinus drug delivery. [ABSTRACT FROM AUTHOR]

Introduction: Nebulizers used to deliver aerosol during non-invasive mechanical ventilation (NIV) have many types, each type has many different designs. This study aimed to determine the effect of nebulizer deign on aerosol delivery in NIV. Methods: Different designs of jet nebulizer (JN) and vibrating mesh nebulizer (VMN) were tested by placing 1 ml of salbutamol in a nebulizer chamber operated in an in vitro NIV setting using a breathing simulator with adult settings (inhalation-exhalation ratio 1:3, 15 breaths/min and tidal volume 500 ml) and mechanical ventilator (MV) set at spontaneous mode with a peak inspiratory pressure of 20 cm HO and a peak expiratory pressure of 5 cm HO. Inhalation filters were placed before the breathing simulator to collect emitted aerosol (inhalable dose). Also, amounts of drug left in nebulizer chamber (residual dose) were collected and analyzed for salbutamol content. Statistical data analysis and modeling was performed on the results. Results: The vibrating mesh nebulizer delivered significantly higher inhalable doses and lower residual dose compared to JN ( p < 0.001). Inhalable doses of salbutamol and residual dose differed significantly ( p < 0.05) for different designs of JN. Delivery via VMN was not affected by the difference in designs. Data modeling showed no change by changing VMN type but changing JN type resulted in a sharp change in the inhaled and residual doses. Conclusions: Nebulizer design has a great role in efficacy of JN but not VMN and different types of JN should not considered interchanges without dose adjustment. Modeling can optimize these results for better aerosol delivery. [ABSTRACT FROM AUTHOR]

Introduction: Many devices (e.g., nebulizers and spacers) are used to deliver aerosol in a non-invasive ventilation circuit (NIV) without any special recommendation. The aim of the present work was to compare the doses delivered from seven different aerosol delivery systems when placed in the NIV using automatic continuous positive airway pressure (Auto-CPAP). Methods: Three spacers and three vibrating mesh nebulizers were compared to a Sidestream jet nebulizer (SIDE). Each device was placed proximal to a breathing simulator in a standard NIV circuit with a 500 ml tidal volume, 15 breaths/min and a 1:3 inspiratory-expiratory ratio. Two ml of salbutamol solution containing 10,000 μg was nebulized using Aerogen Pro (PRO), Aerogen Solo (SOLO), NIVO and SIDE. Twelve metered dose inhaler doses, containing 100 μg salbutamol each, were delivered using AeroChamber MV (AC), AeroChamber Vent (VC) and AeroChamber Mini (MC). Total emitted dose (TED) and its percentage were determined. Aerodynamic droplet characteristics were measured using cooled Andersen Cascade Impactor. Results: The vibrating mesh nebulizers used had significantly more ( p < 0.001) TED compared to the jet nebulizer. The spacers used had higher TED % ( p < 0.001) compared to the nebulizers. The fine particle fraction of SIDE was the highest ( p = 0.021) and mass median aerodynamic diameter of the spacers was the smallest ( p = 0.001). The fine particle dose from vibrating mesh nebulizers was the greatest ( p = 0.02). Conclusions: Aerosol delivery in Auto-CPAP NIV is feasible; however, aerosol delivery method should be chosen or substituted with care. 2 mg delivered from a spacer would be equivalent to 3 mg nebulized from a vibrating mesh nebulizer and 5 mg nebulized from a Sidestream. [ABSTRACT FROM AUTHOR]

We compared survival of bone marrow mesenchymal stem cells after compressor, ultrasound, and mesh nebulization of the cell suspension over 10 min. Viability of stromal cells was best preserved after compressor nebulization (72%). Cell survival after ultrasonic nebulization was significantly lower (20%). After mesh nebulization, no live cells were found. Thus, compressor nebulization is the most preferable method of the production of cell aerosol for their delivery to the lower respiratory tract. [ABSTRACT FROM AUTHOR]

Invasive pulmonary aspergillosis (IPA) is a fungal infection that is seen with particular frequency in immunocompromised patients, and associated with high rates of mortality. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole have become accepted as first- and second-line therapy, respectively. However, triazoles are associated with issues of oral bioavailability, high liver metabolism, and/or drug-drug interactions, increasing the variability of systemic concentrations. As a way to overcome these issues, inhalation appears to be a promising route for delivery of triazoles for prophylactic or curative therapy in IPA. Indeed, pulmonary drug delivery drastically increases the drug in situ while decreasing the systemic exposure, thereby limiting drug metabolization, side effects, and drug-drug interactions. The development of triazoles for inhalation has focused on voriconazole and itraconazole, drugs which are both highly permeable but with significant different solubility. In this review, we describe the most advanced and promising pharmaceutical developments for voriconazole and itraconazole. [ABSTRACT FROM AUTHOR]

Inhaled pharmaceuticals are formulated and delivered differently according to the therapeutic indication. However, specific device-formulation coupling is often fickle, and new medications or indications also demand new strategies. The discontinuation of chlorofluorocarbon propellants has seen replacement of older metered dose inhalers with dry powder inhaler formulations. High-dose dry powder inhalers are increasingly seen as an alternative dosage form for nebulised medications. In other cases, new medications have completely bypassed conventional inhalers and been formulated for use with unique inhalers such as the Staccato® device. Among these different devices, integration of software and electronic assistance has become a shared trend. This review covers recent device and formulation advances that are forming the current landscape of inhaled therapeutics. [ABSTRACT FROM AUTHOR]

Purpose: Intranasal deposition of aerosols is often studied using in vitro nasal cavity models. However, the relevance of these models to predict in vivo human deposition has not been validated. This study compared in vivo nasal aerosol deposition and in vitro deposition in a human plastinated head model (NC1) and its replica constructed from CT-scan (NC2). Methods: Two nebulizers (Atomisor Sonique® and Easynose®) were used to administer a 5.6 μm aerosol of Tc-DTPA to seven healthy volunteers and to the nasal models. Aerosol deposition was quantified by γ-scintigraphy in the nasal, upper nasal cavity and maxillary sinus (MS) regions. The distribution of aerosol deposition was determined along three nasal cavity axes (x, y and z). Results: There was no significant difference regarding aerosol deposition between the volunteers and NC1. Aerosol deposition was significantly lower in NC2 than in volunteers regarding nasal region ( p < 0.05) but was similar for the upper nasal cavity and MS regions. Mean aerosol distribution for NC1 came within the standard deviation (SD) of in vivo distribution, whereas that of NC2 was outside the in vivo SD for x and y axes. Conclusions: In conclusion, nasal models can be used to predict aerosol deposition produced by nebulizers, but their performance depends on their design. [ABSTRACT FROM AUTHOR]

Background: Two significant limitations of intraperitoneal drug therapy are limited drug distribution and poor penetration into peritoneal nodules. A possible solution is the application of the so-called 'therapeutic pneumoperitoneum,' taking advantage of the gaseous nature and the pressure of capnoperitoneum during laparoscopy. Our objective was to develop a device able to apply such therapeutic pneumoperitoneum. Methods: The technology presented here is a spraying device and can be introduced through a trocar. It is driven by mechanical pressure and consists of an injector, a line, and a nozzle. An in vivo experimental study was performed in five pigs. A transvaginal cholecystectomy was performed. At the end of the procedure, a standard dose of methylene blue was sprayed/infused into the abdominal cavity for 30 min (4 test animals w/therapeutic pneumoperitoneum (12 mmHg CO) and 1 control animal w/conventional lavage (2 l intra-abdominal volume with extracorporeal circulation)). At the end of the procedure, all animals were autopsied and the peritoneum was analyzed. Outcome criteria were: (1) drug distribution (as assessed by the stained peritoneal surface at autopsy), and (2) diffusion into the peritoneum (presence or not of macroscopic staining of the outer aspect of the peritoneum immediately after surgery). Results: Stained peritoneal surface was larger after aerosol application compared with peritoneal lavage, and staining more intense. Hidden peritoneal surfaces and the anterior abdominal wall were stained only in the aerosol group. In contrast to peritoneal lavage, the outer aspect of peritoneal membrane was immediately stained after pressurized spraying. Conclusions: This device and the related approach significantly improve both distribution and penetration of a test substance into the peritoneal cavity in a large animal model. This might be a significant progress in treating intraperitoneal disease, in particular peritoneal carcinomatosis. [ABSTRACT FROM AUTHOR]

Background: Peritoneal carcinomatosis is an unmet medical need. Laparoscopy offers a unique opportunity to control and to steer the operating environment during surgery by loading carbon dioxide with a therapeutic substance and creating the so-called therapeutic capnoperitoneum. We have treated a human sample of peritoneal carcinomatosis from an endometrial adenocarcinoma ex vivo just after surgery. Methods: A nontoxic therapeutic agent (Dbait) was aerosolized into a box containing diseased human peritoneum under a pressure of 12 mmHg CO. Dbait (noncoding DNA fragments) acts through jamming DNA damage sensing and signaling, ultimately inhibiting DNA repair system of cancer cells. Dbait were coupled to cholesterol molecules to facilitate intracellular uptake, and to Cyanine (Cy5) to allow detection by fluorescence. In a control experiment, the same solution was applied to the other half of the sample using conventional lavage. Results: Physical results revealed fluorescence within the tumor up to 1 mm depth in the therapeutic capnoperitoneum sample and no uptake in the lavage sample. Biological results showed intranuclear phosphorylation of H2AX in the nebulized sample and no activity in the lavage sample. Importantly, tumor nodules showed more activity than the neighbor, normal peritoneum. Detection of histone gamma-H2AX (phosphorylated H2AX) reveals activation of DNA-dependent protein kinase (DNA-PK) by Dbait, which has been shown to be the key step for sensitization to genotoxic therapy. Conclusions: Dbait are taken up by cancer cells and have a biological activity up to 1 mm depth. Nebulization of the molecule is significantly more effective than conventional lavage. This proof of principle supports the need for clinical studies applying therapeutic capnoperitoneum together with Dbait for treating peritoneal carcinomatosis. [ABSTRACT FROM AUTHOR]

Ventilator-associated pneumonia (VAP) remains a leading cause of morbidity and mortality in mechanically-ventilated patients in the Intensive Care Unit (ICU). Ventilator-associated tracheobronchitis (VAT) was previously believed to be an intermediate stage between colonization of the lower respiratory tract and VAP. More recent data, however, suggest that VAT may be a separate entity that increases morbidity and mortality, independently of the occurrence of VAP. Some, but not all, patients with VAT progress to develop VAP. Although inhaled antibiotics alone could be effective for the treatment of VAP, the current consensus of opinion favors their role as adjuncts to systemic antimicrobial therapy for VAP. Inhaled antibiotics are increasingly employed for salvage therapy in patients with VAP due to multi-drug resistant Gram-negative bacteria. In contrast to VAP, VAT could be effectively treated with inhaled antibiotic therapy alone or in combination with systemic antimicrobials. [ABSTRACT FROM AUTHOR]

The aim of this work was to evaluate the in vitro performance of a nebulized nanoemulsion formulation which had been optimised previously. To do so, a transparent nanoemulsion preparation containing 1.5 mg/ml of budesonide was prepared and diluted to achieve concentrations of 250 and 500 μg/ml budesonide. The in vitro characteristics of the diluted nanoemulsions were then compared with the commercially available suspension of budesonide (Pulmicort Respules®) when nebulized using a jet and a vibrating mesh nebulizer. A smaller MMAD with improved aerosol output was observed in the nanoemulsion preparations compared with the corresponding suspension formulations indicating an improved in vitro performance for the nanoemulsion-based preparations. [ABSTRACT FROM AUTHOR]

Pharmaceutical aerosols have been targeted to the lungs for the treatment of asthma and pulmonary infectious diseases successfully. Micafungin (Astellas Pharma US, Deerfield, IL, USA) has been shown to be an effective antifungal agent when administrated intravenously. Pulmonary delivery of micafungin has not previously been reported. In the present pilot study, we characterize the performance of two nebulizers and their potential for delivering micafungin to the lungs as well as the use of multivariate data analysis for mass distribution profile comparison. The concentration of micafungin sodium increased by 21% when delivered by the Acorn II nebulizer and by 20% when delivered by the LC Plus nebulizer, respectively, from the first to the second sampling period. The Acorn II nebulizer delivered a fine particle fraction FPF5.8 (%<5.8 μm) of 92.5 ± 0.8 and FPF3.3 (%<3.3 μm) of 82.3 ± 2.1 during the first sampling period. For the LC Plus nebulizer, FPF5.8 was 92.3 ± 0.1 and FPF3.3 was 67.0 ± 0.7 during the first sampling period. The mass median aerodynamic diameter (MMAD) increased from 1.67 ± 0.05 to 1.77 ± 0.04 μm (Acorn II nebulizer) and from 2.09 ± 0.01 to 2.20 ± 0.01 μm (Pari LC Plus nebulizer) from the first to the second sampling periods. These changes in MMAD were statistically significant by paired t test. Multivariate data analysis showed that this could be explained systematically by greater drug deposition on stages with larger cutoff sizes and reduced drug deposition on stages with smaller cutoff sizes rather than multimodal deposition or other anomalies in size distribution. [ABSTRACT FROM AUTHOR]

To compare the efficiency of an Aeroneb Pro vibrating plate and an Atomisor MegaHertz ultrasonic nebulizer for providing ceftazidime distal lung deposition. In vitro experiments. One gram of cetazidime was nebulized in respiratory circuits and mass median aerodynamic diameter of particles generated by ultrasonic and vibrating plate nebulizers was compared using a laser velocimeter. In vivo experiments. Lung tissue concentrations and extrapulmonary depositions were measured in ten anesthetized ventilated piglets with healthy lungs that received 1 g of ceftazidime by nebulization with either an ultrasonic ( n = 5), or a vibrating plate ( n = 5) nebulizer. A two-bed Experimental Intensive Care Unit of a University School of Medicine. Following sacrifice, 5 subpleural specimens were sampled in dependent and nondependent lung regions for measuring ceftazidime lung tissue concentrations by high-performance liquid chromatography. Mass median aerodynamic diameters generated by both nebulizers were similar with more than 95% of the particles between 0.5 and 5 μm. Lung tissue concentrations were 553 ± 123 [95% confidence interval: 514–638] μg g−1 using ultrasonic nebulizer, and 452 ± 172 [95% confidence interval: 376–528] μg g−1 using vibrating plate nebulizers (NS). Extrapulmonary depositions were, respectively, of 38 ± 5% (ultrasonic) and 34 ± 4% (vibrating plate) (NS). Vibrating plate nebulizer is comparable to ultrasonic nebulizers for ceftazidime nebulization. It may represent a new attractive technology for inhaled antibiotic therapy. [ABSTRACT FROM AUTHOR]

Although laparoscopic surgery is known to cause less postoperative pain when compared to laparotomy, some patients still suffer from excessive pain, especially during the first stages of recovery. The purpose of our study was to assess the effect of intraperitoneal nebulization of lidocaine during gynecological laparoscopic procedures on perioperative pain. The study was a prospective, randomized, double-blinded, placebo-controlled trial (Canadian task force classification I) that included 23 patients who underwent outpatient gynecological laparoscopic procedures. Patients were randomly assigned either to a study group that received 5 mg/kg of lidocaine intraperitonealy during surgery (n=15) or to a control group that received sterile water in the same manner (n=8). The fluid was infuslated along with the CO2 through a Insuflow® device. All patients received the same anesthetic technique. Intraoperative pain as assessed by changes in the vital signs was treated with fentanyl. Postoperative pain was evaluated according to postoperative opioid requirements and by the Visual Analogue Scale (VAS) at 15 min, 1 h and 24 h postoperatively. The VAS score was found to be lower for the study group 1 h after surgery (p=0.023). There was no difference in the VAS scores at 15 min (p=0.9) and 24 h (p=0.11) after surgery. A correlation analysis showed no association between the amount of lidocaine insufflated and the severity of the postoperative pain. There was no difference in terms of fentanyl administration during surgery or opioid consumption following surgery between the groups. We concluded that continuous intraperitoneal insuflation of lidocaine using an Insuflow® device may significantly reduce pain in the initial stage of postoperative recovery. [ABSTRACT FROM AUTHOR]

The purpose of this article is to catalogue in a systematic way the available information about factors that may influence the outcome and variability of cascade impactor (CI) measurements of pharmaceutical aerosols for inhalation, such as those obtained from metered dose inhalers (MDIs), dry powder inhalers (DPIs) or products for nebulization; and to suggest ways to minimize the influence of such factors. To accomplish this task, the authors constructed a cause-and-effect Ishikawa diagram for a CI measurement and considered the influence of each root cause based on industry experience and thorough literature review. The results illustrate the intricate network of underlying causes of CI variability, with the potential for several multi-way statistical interactions. It was also found that significantly more quantitative information exists about impactor-related causes than about operator-derived influences, the contribution of drug assay methodology and product-related causes, suggesting a need for further research in those areas. The understanding and awareness of all these factors should aid in the development of optimized CI methods and appropriate quality control measures for aerodynamic particle size distribution (APSD) of pharmaceutical aerosols, in line with the current regulatory initiatives involving quality-by-design (QbD). [ABSTRACT FROM AUTHOR]

Background: Peritoneal involvement is a significant issue in the treatment of gastrointestinal malignancies. Current statistics indicate that after surgical intervention, up to 20% of patients will present with locoregional metastasis. The ability to inhibit initial tumor adhesion to the mesothelial lining of the peritoneum may be considered critical in the inhibition of tumor development. This article describes, the use of a novel nebulizer system capable of delivering high-concentration, low-dose therapeutics to the peritoneal cavity.Methods: For this study, 30 male WAG rats were inoculated with CC531 colorectal tumor cells. The rats were randomized into three groups: control group (n = 10), heparin-treated group (n = 10), and high-molecular-weight hyaluronan-treated group (n = 10). A peritoneal cancer index was used to determine tumor burden at 15 days. Analysis of variance (ANOVA) was used to compare multiple group means.Results: Nebulization therapy was performed without any complication in the cohort. Heparin inhibited macroscopic intraperitoneal tumor growth completely (p = 0.0001) without affecting tumor cell viability. The introduction of hyaluronan attenuated both tumor size and distribution, was compared with the control group (p = 0.002).Conclusion: Nebulized heparin and hyaluronic acid using a novel nebulization technique attenuates peritoneal tumor growth after laparoscopic surgery. The technique itself is easy to use and safe. [ABSTRACT FROM AUTHOR]

The object of this study was to evaluate in vitro the influence of various ventilatory parameters on the delivery of synchronized nebulization of terbutaline during mechanical ventilation and to determine a semiempirical model to control the quantity of aerosol delivered into the patient's lung. An ATOMISOR NL9 M jet nebulizer (La Diffusion Technique Francaise, France) was filled with terbutaline (Bricanyl, Astra-Zeneca, Sweden) and connected to the inspiratory line of a Horus ventilator (Taema, France). Nebulization was synchronized with the inspiratory phase. We assessed at the end of the endotracheal tube the quantity of terbutaline (terbutaline mass output) and the volume median diameter (VMD) by diffraction-laser method. There was a negative correlation between terbutaline mass output and inspiratory air flow ( r =-0.95, p <0.0001) and between VMD and inspiratory air flow ( r =-0.96, p <0.0001). Moreover, positive end-expiratory pressure levels between 0 cm and 8 cm of water did not significantly change the terbutaline output mass ( p =0.22). Total nebulization time and terbutaline mass output calculated by the mathematical model showed good agreement with experimental data. In conclusion, our semiempirical model allows calculation of the duration of the nebulization required to deliver a given mass of terbutaline into patient lungs. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of inspiratory time and inspiratory flow pattern on albuterol delivery by aerosol during mechanical ventilation.Design: A ventilator was connected to a lung model and set to deliver a tidal volume of 0.6 l, PEEP 5 cmH(2)O, and respiratory rate of 15/min. We evaluated inspiratory times of 1 and 2 s, lung mechanics of 0.05 l/cmH(2)O compliance and 50 cmH(2)O/l/s resistance, or 0.02 l/cmH(2)O compliance and 5 cmH(2)O/l/s resistance, and three inspiratory flow patterns (constant flow volume-controlled ventilation, descending ramp flow volume-controlled ventilation, and pressure-controlled ventilation). Albuterol was delivered into the ventilator circuit by a nebulizer containing 5 mg (4 ml) albuterol or a pMDI and spacer (four actuations; 360 micro g). A filter between the Y-piece and the lung model collected the aerosol, which was analyzed for albuterol by spectrophotometry.Results: For the nebulizer there were significant differences in albuterol delivered for inspiratory time, flow pattern, and lung mechanics. For the pMDI there were no significant differences for the amount of albuterol delivered for inspiratory time, flow pattern, or lung mechanics.Conclusions: Albuterol delivery by nebulizer is affected by inspiratory time and inspiratory flow pattern. When a pMDI is used, the amount of albuterol delivered is not affected by inspiratory flow pattern or inspiratory time. [ABSTRACT FROM AUTHOR]

α -antitrypsin (AAT) deficiency is a genetic disease in which low serum and lung levels of the antiprotease AAT cause a deficiency of the anti-elastase defensive screen of the lower respiratory tract such that neutrophil elastase is free to degrade the connective tissue of the lung, eventually resulting in emphysema. Intravenous AAT infusion therapy restores lung levels of AAT, but is inefficient, costly and a demanding form of therapy. As an alternative, we evaluated aerosol delivery of human plasma AAT (pAAT) and recombinant DNA-produced AAT (rAAT), as a means of providing anti-elastase protection to the lower respiratory tract. In vitro studies demonstrated that both pAAT and rAAT can be aerosolized into droplets suitable for alveolar deposition without loss of antiprotease activity. When administered by aerosol to individuals with AAT deficiency, pAAT and rAAT each significantly raised lung epithelial lining fluid levels of AAT and anti-neutrophil elastase capacity, with the likelihood that twice daily administration of 100 mg of either form would result in normalization of lung anti-elastase defenses at the alveolar surface. Studies in sheep further demonstrated that the aerosolized pAAT and rAAT were each able to pass through alveolar epithelium and gain access to the interstitial compartment of the lung, thus increasing anti-elastase defenses of the lung intersitium. Therapy was safe and well tolerated in all cases. Aerosol therapy with pAAT or rAAT is a safe, feasible, and likely a biochemically efficacious alternative to intravenous AAT augmentation therapy and merits further long-term studies for clinical therapy. [ABSTRACT FROM AUTHOR]

Pneumocystis carinii pneumonia (PCP) is the most common presenting symptom in patients with the acquired immunodeficiency syndrome (AIDS). Clinical trials have shown that inhaled pentamidine, delivered by nebulizer, is an effective prophylaxis for PCP in high-risk patients, and can be used to treat mild to moderate episodes. Side effects are minor, in marked contrast to the parenteral route of administration. The choice of nebulizer system will determine both alveolar delivery of pentamidine and the incidence of cough related to deposition of droplets on large conducting airways. Radioaerosol studies have suggested that optimum nebulizer systems for inhaled pentamidine deliver the majority of the aerosol mass in droplets smaller than 2 µm diameter, ideal for alveolar penetration. [ABSTRACT FROM AUTHOR]

We have studied the cardiovascular effects of inhaled adenosine in healthy subjects. Adenosine at a concentration of 5 mg·ml is absorbed and produces an increase in heart rate of 6-7 beats per min, blood pressure and skin temperature being unaltered. The rise in heart rate is less than that seen with an infusion of a comparable dose and is unlikely to be adequate for therapeutic termination of supraventricular tachycardia. Higher doses are limited by the poor solubility of adenosine. Inhalation as a method of delivering adenosine has possibilities as an alternative route of administration, but some practical problems remain to be overcome. [ABSTRACT FROM AUTHOR]