Due to the insufficient Cu+ accumulation, Cu+ efflux mechanism, and highly immunosuppressive tumor microenvironment (TME) in lung metastasis, the cuproptosis efficacy is limited. Herein, an inhalable nanodevice (CLDCu) is constructed to successfully overcome the drawbacks of cuproptosis. CLDCu consists of a Cu2+-chitosan shell and low molecular weight heparin-tocopherol succinate (LMWH-TOS, LT) core with disulfiram (DSF) loading. The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions (63.6%) with 56.5 times higher than intravenous injection. Within tumor cells, the mild acidity triggers the co-release of DSF and Cu2+, thus generating bis(diethyldithiocarbamate)-copper (CuET) to block Cu+ efflux protein ATP7B and forming toxic Cu+, leading to enhanced cuproptosis. Meanwhile, the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes (STING) pathway, which significantly potentiates dendritic cells (DCs) maturation, as wells as evokes innate and adaptive immunity. In lung metastatic mice model, CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration. Moreover, CLDCu combined with anti-programmed cell death protein ligand-1 antibody (aPD-L1) provokes stronger antitumor immunity. Therefore, nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.

Pulmonary fibrosis (PF) is a chronic, progressive, and fatal lung disease with a high mortality rate. Nintedanib, as a multi-tyrosine kinase inhibitor, is widely used as the first line drug for PF patients. However, only nintedanib oral formulations are used currently in clinic and show a low drug selectivity, significant first-pass effect and low bioavailability with 4.7%, thus limiting the clinical outcome of nintedanib. In this study, nintedanib was prepared in the form of nintedanib nanocrystalline (Nib-NC) and then encapsulated with hyaluronic acid (HA) to construct a nanocrystalline-in-adhesive delivery system Nib-NC@HA with high drug loading efficacy and pulmonary bio-adhesive properties, which could avoid the first-pass effects, increase the bioavailability and reduce the systemic side effects of nintedanib. After inhalation administration of Nib-NC@HA, due to the bio-adhesive properties of HA, Nib-NC@HA could prolong the retention time of drug in the lungs and inhibit the expression of inflammation associated factors such as IL-6, IL-1β and TNF-α in lung tissue, reduce the release of pro-fibrotic growth factor, and improve the lung function, thus showing enhanced anti-fibrotic effect than Nib-NC. The results suggested that Nib-NC@HA is an efficient and optimal targeted bio-adhesive delivery system for the lungs to treat pulmonary fibrosis.

OBJECTIVE: To identify the administration characteristics and connection methods of bronchodilators by pressurized inhalers to the ventilatory circuit of patients under invasive mechanical ventilation.
METHODS: A scope review was conducted following the PRISMA for Scoping Review, using the PubMed, Embase Elsevier, Cochrane Library, and Lilacs databases without language restrictions, up to July 2023. Eligible sources included reviews and consensuses (based on clinical studies), experimental and observational studies involving adult patients admitted to the intensive care unit and undergoing invasive mechanical ventilation, regardless of the underlying condition, who used bronchodilator drugs contained in pressurized inhalers. Information regarding inhalation technique, pressurized inhalers connection mode to the circuit, and patient care were collected by 2 researchers independently, with discrepancies resolved by a third reviewer. Studies involving bronchodilators combined with other pharmacological classes in the same device, as well as reviews containing preclinical studies, were excluded.
RESULTS: In total, 23 publications were included, comprising 19 clinical trials and 4 non-randomized experimental studies. Salbutamol (albuterol) was the bronchodilator of study in the majority of the articles (n=18), and the spacer device was the most commonly used to connect the pressurized inhaler to the circuit (n=15), followed by an in-line adapter (n=3), and a direct-acting device without chamber (n=3). Concerning the pressurized inhaler placement in the circuit, 18 studies positioned it in the inspiratory limb, and 19 studies synchronized the jet actuation with the start of the inspiratory phase. Agitation of the pressurized inhaler before each actuation, waiting time between actuations, airway suction before administration, and semi-recumbent patient positioning were the most commonly described measures across the studies.
CONCLUSIONS: This review provided insights into the aspects related to inhalation technique in mechanically ventilated patients, as well as the most prevalent findings and the existing gaps in knowledge regarding bronchodilator administration in this context. The evidence indicates the need for further research on this subject.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a triterpenoid with multiple biological effects, such as anti-inflammatory and anti-fibrotic properties. Herein, inhalable milk-derived extracellular vesicles (mEVs) encapsulating GA (mEVs@GA) were screened and evaluated for IPF treatment. The results indicated that the loading efficiency of GA in mEVs@GA was 8.65%. Therapeutic effects of inhalable mEVs@GA were investigated in vitro and in vivo. The mEVs@GA demonstrated superior anti-inflammatory effects on LPS-stimulated MHS cells. Furthermore, repeated noninvasive inhalation delivery of mEVs@GA in bleomycin-induced IPF mice could decrease the levels of transforming growth factors β1 (TGF-β1), Smad3 and inflammatory cytokines IL-6, IL-1β and TNF-α. The mEVs@GA effectively diminished the development of fibrosis and improved pulmonary function in the IPF mice model at a quarter of the dose compared with the pirfenidone oral administration group. Additionally, compared to pirfenidone-loaded mEVs, mEVs@GA demonstrated superior efficacy at the same drug concentration in the pharmacodynamic study. Overall, inhaled mEVs@GA have the potential to serve as an effective therapeutic option in the treatment of IPF.

The past five decades have witnessed remarkable advancements in the field of inhaled medicines targeting the lungs for respiratory disease treatment. As a non-invasive drug delivery route, inhalation therapy offers numerous benefits to respiratory patients, including rapid and targeted exposure at specific sites, quick onset of action, bypassing first-pass metabolism, and beyond. Understanding the characteristics of pulmonary drug transporters and metabolizing enzymes is crucial for comprehending efficient drug exposure and clearance processes within the lungs. These processes are intricately linked to both local and systemic pharmacokinetics and pharmacodynamics of drugs. This review aims to provide a comprehensive overview of the literature on lung transporters and metabolizing enzymes while exploring their roles in exogenous and endogenous substance disposition. Additionally, we identify and discuss the principal challenges in this area of research, providing a foundation for future investigations aimed at optimizing inhaled drug administration. Moving forward, it is imperative that future research endeavors to focus on refining and validating in vitro and ex vivo models to more accurately mimic the human respiratory system. Such advancements will enhance our understanding of drug processing in different pathological states and facilitate the discovery of novel approaches for investigating lung-specific drug transporters and metabolizing enzymes. This deeper insight will be crucial in developing more effective and targeted therapies for respiratory diseases, ultimately leading to improved patient outcomes.

The formulation of microparticles composed of a mixture of carriers represents an innovative approach for lung drug delivery of dry powder. The carriers used can significantly influence the properties of the microparticles, such as size, shape, surface area, hygroscopicity, or aggregation, thus improving the aerosolization of the drugs after inhalation. The properties mentioned above are crucial for effective  pulmonary  therapy. The  combination of carriers of a carbohydrate nature and gelling agents is advantageous for controlled drug release. The experimental work aimed to prepare by spray drying and subsequently evaluate ten batches of microparticles composed of sugar-based carriers (mannitol, maltodextrin, dextran) and gelling polymers (chitosan, chondroitin sulfate) and to select a suitable combination for follow-up experimental work aimed at drug incorporation into the microparticle matrix. The most suitable parameters were exhibited by batches whose aerodynamic diameter was close to 5 µm, particles prepared from a combination of mannitol and dextran, chitosan and chondroitin, or maltodextrin and chondroitin. These batches also showed the highest fine particle fraction value (> 43%). From a processability point of view, the batch with maltodextrin and chondroitin is preferable due to the lower viscosity of the dispersion and the more regular shape of the final microparticles.

The formulation of microparticles composed of a mixture of carriers represents an innovative approach for lung drug delivery of dry powder. The carriers used can significantly influence the properties of the microparticles, such as size, shape, surface area, hygroscopicity, or aggregation, thus improving the aerosolization of the drugs after inhalation. The properties mentioned above are crucial for effective  pulmonary  therapy. The  combination of carriers of a carbohydrate nature and gelling agents is advantageous for controlled drug release. The experimental work aimed to prepare by spray drying and subsequently evaluate ten batches of microparticles composed of sugar-based carriers (mannitol, maltodextrin, dextran) and gelling polymers (chitosan, chondroitin sulfate) and to select a suitable combination for follow-up experimental work aimed at drug incorporation into the microparticle matrix. The most suitable parameters were exhibited by batches whose aerodynamic diameter was close to 5 µm, particles prepared from a combination of mannitol and dextran, chitosan and chondroitin, or maltodextrin and chondroitin. These batches also showed the highest fine particle fraction value (> 43%). From a processability point of view, the batch with maltodextrin and chondroitin is preferable due to the lower viscosity of the dispersion and the more regular shape of the final microparticles.

We assessed the effects of inhalation administration of lavender essential oil (LEO) either once (L1) or twice (L2) a day on animal welfare indicators, carcass and meat quality of Italian heavy pigs. Pigs (n = 108) were allotted to three experimental groups (control -C-, L1 and L2) and lavender was administered, via a vaporizer device, to the treated groups during the entire fattening-finishing period (79-160 kg BW). Tail lesion severity was reduced in L1 at the end of the trial compared to the other groups (p < 0.05). Body lesion counts, however, were higher in L2 than in C (p < 0.05), resulting in a more severe overall damage classification (p < 0.01). At slaughter, no differences were observed in carcass traits or blood stress indicators, only minor differences were observed in meat quality, and no LEO residual was found in fat or lean tissues, highlighting the preserved suitability of thighs for the dry curing process. While it was not possible to conclude on the ability to improve animal welfare of vaporized LEO in this production phase, the absence of adverse effects on meat quality and the discrepancies observed regarding the body lesions in L1 and L2 make further studies on behavioral aspects and the method of administration (route, frequency) of the product desirable.

Inhalation administration of dry powder particles is a common application route to achieve local and systemic drug effects. For pulmonary diseases, the deposition of drugs at the site of action is desirable. Thus, the parameters of the inhaled particles, especially their size, shape, or aerosolization, are essential for effective treatment. Suitable parameters can be achieved by choice of preparation method or excipients (carriers, porogens, or aerosolizing agents). This experiment aimed to prepare 11 batches of powder mixtures by spray drying, which differed in the carrier used and the amount of leucine or porogen. The aim was to optimize the formulation for drug binding concerning the requirements for pulmonary administration. The prepared particles were evaluated in terms of morphology, flow properties, porosity, and geometric and aerodynamic diameter. It was found that with increasing concentration of leucine, the bulk density of the particles decreased while the FPF value increased. Similarly, there was a decrease in MMAD. The batch containing 15% leucine was the most suitable. In determining the optimum porogen concentration for mannitol particles, the batch with its 1% gave the best results due to its adequate particle size compared to the other batches (MMAD 5.92 ± 1.32 μm), suitable porosity, and particle morphology. Thus, to formulate drug-loaded particles, it would be advisable to reduce the aerodynamic diameter of the particles, e.g., by spray drying process parameters.

Inhaled corticosteroids (ICSs) are a fundamental pillar of most regimens for long-term control of persistent asthma. Poor adherence to ICS medication is a common problem in the asthma population that can lead to poor asthma control. We hypothesized that conducting a follow-up telephone call after general pediatric clinic visits for asthma would improve refill persistence.
We conducted a prospective cohort analysis of pediatric and young adult subjects followed in our pediatric primary care clinic for asthma on ICS medication found to have poor ICS refill persistence. This cohort received a follow-up telephone outreach call 5-8 weeks after the clinic visit. The primary outcome measure was refill persistence with regard to ICS therapy.
There were 289 subjects who met the inclusion criteria and did not meet any exclusion criteria for the study (n = 131 in the primary cohort, n = 158 in the post-COVID cohort). The mean ICS refill persistence increased significantly for subjects in the primary cohort (39.4 ± 30.8% post intervention vs 32.4 ± 19.7% pre intervention) (P = .02) but not in the post-COVID cohort (36.4 ± 25.6% post intervention vs 38.9 ± 21.0% pre intervention) (P = .26). There was not a statistically significant change in hospitalizations after the intervention in either the primary or the post-COVID cohorts (P = .08 and .07, respectively). Systemic corticosteroid courses and emergency department visits decreased significantly post intervention (P = .01 and P = .004, respectively) in the primary group but not in the post-COVID group (P = .75 and P = .16, respectively).
These results suggest that telephone outreach after out-patient clinic visits for asthma may have short-term benefit in ICS refill persistence; however, the effect size was small.