Journal of Aerosol Medicine and Pulmonary Drug Delivery最新文献

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

Background: A pressurized metered dose inhaler combined with a valved holding chamber (pMDI+VHC) is used to prevent upper airway complications and improve the efficiency of inhaled drug delivery; however, the aerodynamic behavior of the released particles has not been well investigated. This study aimed at clarifying the particle release profiles of a VHC using simplified laser photometry. Methods: An inhalation simulator comprised a computer-controlled pump and a valve system that withdrew aerosol from a pMDI+VHC using a jump-up flow profile. A red laser illuminated the particles leaving VHC and evaluated the intensity of the light reflected by the released particles. Results: The data suggested that the output (OPT) from the laser reflection system represented particle concentration rather than particle mass, and the latter was calculated as OPT × instantaneous withdrawn flow (WF). Summation of OPT hyperbolically decreased with flow increment, whereas summation of OPT × instantaneous flow was not influenced by WF strength. Particle release trajectories consisted of three phases, namely increment with a parabolic curve, flat, and decrement with exponential decay phases. The flat phase appeared exclusively at low-flow withdrawal. These particle release profiles suggest the importance of early phase inhalation. The hyperbolic relationship between WF and particle release time revealed the minimal required withdrawal time at an individual withdrawal strength. Conclusions: The particle release mass was calculated as laser photometric output × instantaneous flow. Simulation of the released particles suggested the importance of early phase inhalation and predicted the minimally required withdrawal time from a pMDI+VHC.

Nanopharmaceuticals represent a group of nanoparticles engineered for medical purposes. Nowadays, nanotechnology offers several possibilities to improve the safety and efficacy of medicines by designing advanced carrier systems which have been found to offer particular advantages when formulated in the nanoscale. Some of the initially marketed nano-formulations already demonstrate advantages over conventional formulations. Innovative delivery systems offer the possibility to not only control drug release but also to overcome biological barriers. For the translation of new drug products from bench to bedside, however, it is pivotal to test and prove their safety. This is of course also true for nanopharmaceuticals, where in particular the biocompatibility and also the clearance/biodegradation of the carrier material after drug delivery has to be demonstrated. The pulmonary route offers some great opportunities for noninvasive drug delivery but also implicates peculiar challenges. Advanced aerosol formulations with innovative drug carriers have already contributed to the significant progress of inhalation therapy. However, in spite of the large alveolar epithelial surface area, the respiratory tract still features diverse efficient biological barriers, primarily designed by nature to protect the human body against inhaled pollutants and pathogens. Only a thorough understanding of particle-lung interactions will allow the rational design of novel nanopharmaceuticals capable of overcoming these barriers, while of course always keeping in mind the strict demands for their safety. While the recent resurrection of inhaled insulin has already confirmed the potential of the pulmonary route for systemic delivery of biopharmaceuticals, inhaled nanopharmaceuticals, currently under investigation, promise to improve also local therapies like anti-infectives.

Background: This study examined the effect of age and head position on total and regional deposition of aerosol delivered by a mucosal atomization device (MAD™) in three-dimensional (3D) models of the intranasal airways of an 18-, 5-, and 2-year-old human. Models consisted of four pieces: anterior nose and nasal cavity that was divided horizontally into upper, middle, and lower thirds. Methods: Models were tested six times at supine, supine with head backward at 45° (supine45), and sitting with head backward at 45° (sitting45). The MAD delivered saline/fluorescein aerosol into model nostrils, during static airflow. Model pieces were tested for fluorescence using a fluorometer, and deposition calculated as percent fluorescence per piece relative to its reference. Total deposition (four pieces combined) and regional deposition (four pieces separately) were calculated. Results: Age and head position had little effect on total deposition. In contrast, deposition in the upper and middle third supine45 and in the lower third sitting45 was significantly different in the 2-year-old model, compared with the two older models. In addition, some head positions significantly increased deposition in the upper, middle, and lower thirds within each model, compared with other positions. Upper deposition was significantly greater at supine45, compared with sitting45 (18-year-old) and supine45, compared with supine and sitting45 (5-year-old). Middle deposition was significantly greater at supine and supine45, compared with sitting45 (2-year-old). Lower deposition was significantly greater at sitting45, compared with supine45 (18-year-old); supine and sitting45, compared with supine45 (5-year-old); and sitting45, compared with supine45 and supine (2-year-old). Conclusions: Age and head position significantly affected regional deposition of aerosol delivered by the MAD in these 3D models. Such models might be used to study other methods for targeting intranasal regions with aerosolized medications in children and adults.

Background: Inhalation and deposition of particles in human airways have attracted considerable attention due to importance of particulate pollutants, transmission of infectious diseases, and therapeutic delivery of drugs at targeted areas. We summarize current state-of-the art research in particle deposition on airway surface liquid (ASL) influenced by mucociliary clearance (MCC) by identifying areas that need further investigation. Methodology: We aim to review focus on governing and constitutive equations describing MCC geometry followed by description of mathematical modeling of ciliary forces, mucus rheology properties, and numerical approaches to solve modified time-dependent Navier-Stokes equations. We also review mathematical modeling of particle deposition in ASL influenced by MCC, particle transport in ASL in terms of Eulerian and Lagrangian approaches, and discuss the corresponding mass transport issues in this layer. Whenever required, numerical predictions are contrasted with the pertinent experimental data. Results: Results indicate that mean mucus and periciliary liquid velocities are strongly influenced by mucus rheological characteristics as well as ciliary abnormalities. However, most of the currently available literature on mucus fiber spacing, ciliary beat frequency, and particle surface chemistry is based on particle deposition on ASL by considering a fixed value of ASL velocity. The effects of real ASL flow regimes on particle deposition in this layer are limited. In addition, no other study is available on modeling nonhomogeneous and viscoelastic characteristics of mucus layer on ASL drug delivery. Conclusion: Simplification of assumptions on governing equations of drug delivery in ASL influenced by MCC leads to imposing some limitations on numerical results.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition, characterized by diffuse inflammatory lung injury. Since the coronavirus disease 2019 (COVID-19) pandemic spread worldwide, the most common cause of ARDS has been the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Both the COVID-19-associated ARDS and the ARDS related to other causes-also defined as classical ARDS-are burdened by high mortality and morbidity. For these reasons, effective therapeutic interventions are urgently needed. Among them, inhaled nitric oxide (iNO) has been studied in patients with ARDS since 1993 and it is currently under investigation. In this review, we aim at describing the biological and pharmacological rationale of iNO treatment in ARDS by elucidating similarities and differences between classical and COVID-19 ARDS. Thereafter, we present the available evidence on the use of iNO in clinical practice in both types of respiratory failure. Overall, iNO seems a promising agent as it could improve the ventilation/perfusion mismatch, gas exchange impairment, and right ventricular failure, which are reported in ARDS. In addition, iNO may act as a viricidal agent and prevent lung hyperinflammation and thrombosis of the pulmonary vasculature in the specific setting of COVID-19 ARDS. However, the current evidence on the effects of iNO on outcomes is limited and clinical studies are yet to demonstrate any survival benefit by administering iNO in ARDS.

Background: Aerosol therapies with vented facemasks are considered a risk for nosocomial transmission of viruses such as severe acute respiratory syndrome coronavirus 2. The transmission risk can be decreased by minimizing aerosol leakage and filtering the exhaled air. Objective: In this study, we determined which closed facemask designs show the least leakage. Methods: Smoke leakage was quantified during in- and exhalation in a closed system with expiration filter for three infant, six child, and six adult facemasks (three times each mask), using age-appropriate anatomical face models and breathing patterns. To assess leakage, smoke release was recorded and cumulative average pixel intensity (cAPI) was calculated. Results: In the adult group, aircushion edges resulted in less leakage than soft edges (cAPI: 407 ± 250 vs. 774 ± 152) (p = 0.004). The Intersurgical^® Economy 5 mask (cAPI: 146 ± 87) also released less smoke than the Intersurgical^® Clearlite 5 (cAPI: 748 ± 68) mask with the same size, but different geometry and edge type (p-value <0.05). Moreover, mask size had an effect, as there was a difference between Intersurgical^® Economy 4 (cAPI: 708 ± 346) and 5, which have the same geometry but a different size (p-value <0.05). Finally, repositioning masks increased the standard deviations. Mask leakage was not dependent on breathing patterns within the child group. Conclusions: Mask leakage can be minimized by using a closed system with a well-fitting mask that is appropriately positioned. To decrease leakage, and therewith minimize potential viral transmission, selecting a well-fitting mask with an aircushion edge is to be recommended.