The sedative effect of intranasal administration of medetomidine using a mucosal atomization device in Japanese White rabbits.

To prevent aspiration in Japanese White (JW) rabbits, the maximum single volume of medetomidine administered intranasally is 0.3 mL per nostril using a mucosal atomization device (MAD). This study aimed to examine the sedative effect of intranasal administration of medetomidine using MAD in eight healthy female JW rabbits. Each rabbit received intranasal atomization (INA) of saline (Control treatment) along with three doses of 1 mg/mL medetomidine (0.3 mL to one nostril [MED0.3 treatment]; 0.3 mL each to both nostrils [MED0.6 treatment]; 0.3 mL twice to both nostrils [MED1.2 treatment]), with a washout period of at least 7 days between treatments. The actual doses of medetomidine were 82 (75-84) µg/kg (median [25th-75th percentile]), 163 (156-168) µg/kg, and 323 (295-343) µg/kg for the MED0.3, MED0.6, and MED1.2 treatments, respectively. A medetomidine-dose dependent sedative effect was detected, and the loss of righting reflex (LRR) was achieved in one rabbit at 18 min, seven rabbits at 11 (9-18) min, and eight rabbits at 7 (4-18) min after the MED0.3, MED0.6, and MED1.2 treatments, respectively. The LRR was maintained for 63 (29-71) min and 83 (68-101) min after the MED0.6 and MED1.2 treatments, respectively. Additionally, the INA of medetomidine produced a significant dose-dependent cardiorespiratory depression including a decrease in pulse rate, respiratory rate, percutaneous oxygen saturation, and arterial partial pressure of oxygen, and an increase in arterial partial pressure of carbon dioxide in the rabbits.

Avaliação da efetividade da esterilização por luz ultravioleta em aerossóis contaminados por Sars-Cov-2 / Evaluation of the effectiveness of ultraviolet light sterilization in aerosols contaminated by Sars-Cov-2 / Evaluación de la eficacia de la esterilización por luz ultravioleta en aerosoles contaminados por Sars-Cov-2

O contato direto e a disseminação aérea são os principais mecanismos de transmissão do SARS-CoV-2. Uma abordagem direta para limitar as transmissões virais no ar é inativá-las dentro de um curto período de tempo após sua produção é a luz ultravioleta C (UVC). Neste sentido, o objetivo do presente estudo foi de avaliar a efetividade do uso de luz ultravioleta na esterilização de aerossóis contaminados pelo SARS-CoV-2. Para o estudo foram analisados todos os pacientes que estavam internados na enfermaria COVID com resultados dos swabs positivos. O paciente escolhido para o estudo encontrava-se com resultado positivo e com 8 dias de sintomas. As medições de contaminação da deposição de aerossol na mesa de tomografia foram realizadas em triplicatas, utilizando swabs estéreis com meio de transporte viral. O paciente foi mantido sozinho dentro desta sala por 30 minutos produzindo aerossóis para que pudesse ocorrer contaminação do ar. Após, foram realizadas as medições utilizando a exposição à luz ultravioleta C, coletada nos minutos 0, 5, 10, 15, 30, 60, 120 e 180, após o paciente ter deixado a sala de tomografia. Esta sequência de medições foi realizada por 6 dias, sendo o primeiro dia sem a exposição da luz UVC e 5 dias com a exposição da luz UVC. Após a coleta dos dados, foi realizada a análise dos swabs para os resultados através do método RT-PCR. Os resultados encontrados das coletas desde o tempo 0 até 180 minutos foram negativos para os 6 dias de estudo. Os resultados dos swabs do paciente seguiram positivos do primeiro até o último dia de estudo. Sendo assim, conclui-se a efetividade da utilização da luz ultravioleta como uma forma de descontaminação, juntamente com a ação antimicrobiana do desinfetante, pois a ausência do vírus vivo evidencia a importância de cuidados de higienização para evitar a reincidência da contaminação após a limpeza.

Direct contact and aerial dissemination are the main transmission mechanisms of SARS-CoV-2. A direct approach to limiting airborne viral transmissions is to inactivate them within a short period of time after their production is ultraviolet C (UVC) light. In this sense, the objective of the present study was to evaluate the effectiveness of using ultraviolet light in the sterilization of aerosols contaminated by SARS-CoV-2. For the study, all patients who were admitted to the COVID ward with positive swab results were analyzed. The patient chosen for the study had a positive result and had had 8 days of symptoms. Measurements of contamination from aerosol deposition on the CT table were performed in triplicate, using sterile swabs with viral transport medium. The patient was kept alone inside this room for 30 minutes, producing aerosols so that air contamination could occur. Afterwards, measurements were performed using exposure to ultraviolet C light, collected at 0, 5, 10, 15, 30, 60, 120 and 180 minutes, after the patient had left the tomography room. This sequence of measurements was carried out in 6 days, the first day being without exposure to UVC light and 5 days with exposure to UVC light. After data collection, swab analysis was performed for the results using the RT-PCR method. The results found for collections from time 0 to 180 minutes were negative for the 6 days of study. The patient's swab results were positive from the first to the last day of the study. Thus, the effectiveness of using ultraviolet light as a form of decontamination is concluded, along with the antimicrobial action of the disinfectant, as the absence of the live virus highlights the importance of hygiene care to prevent the recurrence of contamination after cleaning.

El contacto directo y el contagio por vía aérea son los principales mecanismos de transmisión del SRAS-CoV-2. Un enfoque directo para limitar las transmisiones virales en el aire es inactivarlas en un corto período de tiempo después de su producción es la luz ultravioleta C (UVC). En este sentido, el objetivo del presente estudio fue evaluar la eficacia del uso de la luz ultravioleta en la esterilización de aerosoles contaminados con el SARS-CoV-2. Se analizaron todos los pacientes ingresados en la sala COVID con resultados positivos de los hisopos. El paciente elegido para el estudio era positivo y llevaba 8 días con síntomas. Las mediciones de la contaminación por deposición de aerosoles en la mesa de TC se realizaron por triplicado utilizando hisopos estériles con medio de transporte viral. El paciente se mantuvo solo dentro de esta habitación durante 30 minutos produciendo aerosoles para que se produjera la contaminación del aire. A continuación, se realizaron mediciones mediante la exposición a la luz ultravioleta C, recogidas a los 0, 5, 10, 15, 30, 60, 120 y 180 minutos después de que el paciente saliera de la sala de tomografía. Esta secuencia de mediciones se realizó durante 6 días, el primer día sin exposición a la luz UVC y 5 días con exposición a la luz UVC. Tras la recogida de datos, se realizó el análisis de los hisopos para obtener los resultados mediante el método RT-PCR. Los resultados encontrados en las recolecciones desde el tiempo 0 hasta los 180 minutos fueron negativos para los 6 días de estudio. Los resultados de los hisopos de los pacientes siguieron siendo positivos desde el primer hasta el último día del estudio. Así, se concluye la eficacia del uso de la luz ultravioleta como forma de descontaminación, junto con la acción antimicrobiana del desinfectante, ya que la ausencia de virus vivos pone de manifiesto la importancia de los cuidados higiénicos para evitar la reaparición de la contaminación tras la limpieza.

Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans.

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.

Aerosol release, distribution, and prevention during aerosol therapy: a simulated model for infection control.

Aerosol therapy is used to deliver medical therapeutics directly to the airways to treat respiratory conditions. A potential consequence of this form of treatment is the release of fugitive aerosols, both patient derived and medical, into the environment and the subsequent exposure of caregivers and bystanders to potential viral infections. This study examined the release of these fugitive aerosols during a standard aerosol therapy to a simulated adult patient. An aerosol holding chamber and mouthpiece were connected to a representative head model and breathing simulator. A combination of laser and Schlieren imaging was used to non-invasively visualize the release and dispersion of fugitive aerosol particles. Time-varying aerosol particle number concentrations and size distributions were measured with optical particle sizers at clinically relevant positions to the simulated patient. The influence of breathing pattern, normal and distressed, supplemental air flow, at 0.2 and 6 LPM, and the addition of a bacterial filter to the exhalation port of the mouthpiece were assessed. Images showed large quantities of fugitive aerosols emitted from the unfiltered mouthpiece. The images and particle counter data show that the addition of a bacterial filter limited the release of these fugitive aerosols, with the peak fugitive aerosol concentrations decreasing by 47.3-83.3%, depending on distance from the simulated patient. The addition of a bacterial filter to the mouthpiece significantly reduces the levels of fugitive aerosols emitted during a simulated aerosol therapy, p≤ .05, and would greatly aid in reducing healthcare worker and bystander exposure to potentially harmful fugitive aerosols.

Exploring Insulin Production Following Alveolar Islet Transplantation (AIT).

Recent studies have demonstrated the feasibility of islet implantation into the alveoli. However, until today, there are no data on islet behavior and morphology at their transplant site. This study is the first to investigate islet distribution as well insulin production at the implant site. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized into the lung using an endoscopic spray-catheter. Lung tissue was explanted and bronchial airways were surgically isolated and connected to a perfusor. Correct implantation was confirmed via histology. The purpose of using this new lung perfusion model was to measure static as well as dynamic insulin excretions following glucose stimulation. Alveolar islet implantation was confirmed after aerosolization. Over 82% of islets were correctly implanted into the intra-alveolar space. The medium contact area to the alveolar surface was estimated at 60 +/- 3% of the total islet surface. The new constructed lung perfusion model was technically feasible. Following static glucose stimulation, insulin secretion was detected, and dynamic glucose stimulation revealed a biphasic insulin secretion capacity during perfusion. Our data indicate that islets secrete insulin following implantation into the alveoli and display an adapted response to dynamic changes in glucose. These preliminary results are encouraging and mark a first step toward endoscopically assisted islet implantation in the lung.

Spray-freeze-dried inhalable composite microparticles containing nanoparticles of combinational drugs for potential treatment of lung infections caused by Pseudomonas aeruginosa.

The multi-drug resistance of Pseudomonas aeruginosa is an overwhelming cause of terminal and persistent lung infections in cystic fibrosis (CF) patients. Antimicrobial synergy has been shown for colistin and ivacaftor, and our study designed a relatively high drug-loading dry powder inhaler formulation containing nanoparticles of ivacaftor and colistin. The ivacaftor-colistin nanosuspensions (Iva-Col-NPs) were prepared by the anti-solvent method with different stabilizers. Based on the aggregation data, the formulation 7 (F7) with DSPG-PEG-OMe as the stabilizer was selected for further studies. The F7 consisted of ivacaftor, colistin and DSPG-PEG-OMe with a mass ratio of 1:1:1. The F7 powder formulation was developed using the ultrasonic spray-freeze-drying method and exhibited a rough surface with relatively high fine particle fraction values of 61.4 ± 3.4% for ivacaftor and 63.3 ± 3.3% for colistin, as well as superior emitted dose of 97.8 ± 0.3% for ivacaftor and 97.6 ± 0.5% for colistin. The F7 showed very significant dissolution improvement for poorly water soluble ivacaftor than the physical mixture. Incorporating two drugs in a single microparticle with synchronized dissolution and superior aerosol performance will maximize the synergy and bioactivity of those two drugs. Minimal cytotoxicity in Calu-3 human lung epithelial cells and enhanced antimicrobial activity against colistin-resistant P. aeruginosa suggested that our formulation has potential to improve the treatment of CF patients with lung infections.

Assessment of in vitro kinetics and biological impact of nebulized trehalose on human bronchial epithelium.

Trehalose is added in drug formulations to act as fillers or improve aerosolization performance. Its characteristics as a carrier molecule have been explored; however, the fate of trehalose in human airway tissues has not been thoroughly investigated. Here, we investigated the fate of nebulized trehalose using in vitro human air-liquid bronchial epithelial cultures. First, a tracing experiment was conducted using 13C12-trehalose; we measured trehalose distribution in different culture compartments (apical surface liquid, epithelial culture, and basal side medium) at various time points following acute exposure to 13C12-labeled trehalose. We found that 13C12-trehalose was metabolized into 13C6-glucose. The data was then used to model the kinetics of trehalose disappearance from the apical surface of bronchial cultures. Secondly, we evaluated the potential adverse effects of nebulized trehalose on the bronchial cultures after they were acutely exposed to nebulized trehalose up to a level just below its solubility limit (50 g/100 g water). We assessed the ciliary beating frequency and histological characteristics. We found that nebulized trehalose did not lead to marked alteration in ciliary beating frequency and morphology of the epithelial cultures. The in vitro testing approach used here may enable the early selection of excipients for future development of inhalation products.

In vitro-in vivo correlation of cascade impactor data for orally inhaled pharmaceutical aerosols.

In vitro-in vivo correlation is the establishment of a predictive relationship between in vitro and in vivo data. In the context of cascade impactor results of orally inhaled pharmaceutical aerosols, this involves the linking of parameters such as the emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter to in vivo lung deposition from scintigraphy data. If the dissolution and absorption processes after deposition are adequately understood, the correlation may be extended to the pharmacokinetics and pharmacodynamics of the delivered drugs. Correlation of impactor data to lung deposition is a relatively new research area that has been gaining recent interest. Although few in number, experiments and meta-analyses have been conducted to examine such correlations. An artificial neural network approach has also been employed to analyse the complex relationships between multiple factors and responses. However, much research is needed to generate more data to obtain robust correlations. These predictive models will be useful in improving the efficiency in product development by reducing the need of expensive and lengthy clinical trials.

Pulmonary in vitro instruments for the replacement of animal experiments.

Advanced in vitro systems often combine a mechanical-physical instrument with a biological component e.g. cell culture models. For testing of aerosols, it is of advantage to consider aerosol behavior, particle deposition and lung region specific cell lines. Although there are many good reviews on the selection of cell cultures, articles on instruments are rare. This article focuses on the development of in vitro instruments targeting the exposure of aerosols on cell cultures. In this context, guidelines for toxicity investigation are taken into account as the aim of new methods must be the prediction of human relevant data and the replacement of existing animal experiments. We provide an overview on development history of research-based instruments from a pharmaceutical point of view. The standardized commercial devices resulting from the research-based instruments are presented and the future perspectives on pulmonary in vitro devices are discussed.

An in vitro visual study of fugitive aerosols released during aerosol therapy to an invasively ventilated simulated patient.

COVID-19 can cause serious respiratory complications resulting in the need for invasive ventilatory support and concurrent aerosol therapy. Aerosol therapy is considered a high risk procedure for the transmission of patient derived infectious aerosol droplets. Critical-care workers are considered to be at a high risk of inhaling such infectious droplets. The objective of this work was to use noninvasive optical methods to visualize the potential release of aerosol droplets during aerosol therapy in a model of an invasively ventilated adult patient. The noninvasive Schlieren imaging technique was used to visualize the movement of air and aerosol. Three different aerosol delivery devices: (i) a pressurized metered dose inhaler (pMDI), (ii) a compressed air driven jet nebulizer (JN), and (iii) a vibrating mesh nebulizer (VMN), were used to deliver an aerosolized therapeutic at two different positions: (i) on the inspiratory limb at the wye and (ii) on the patient side of the wye, between the wye and endotracheal tube, to a simulated intubated adult patient. Irrespective of position, there was a significant release of air and aerosol from the ventilator circuit during aerosol delivery with the pMDI and the compressed air driven JN. There was no such release when aerosol therapy was delivered with a closed-circuit VMN. Selection of aerosol delivery device is a major determining factor in the release of infectious patient derived bioaerosol from an invasively mechanically ventilated patient receiving aerosol therapy.

In vitro and ex vivo models in inhalation biopharmaceutical research - advances, challenges and future perspectives.

Oral inhalation results in pulmonary drug targeting and thereby reduces systemic side effects, making it the preferred means of drug delivery for the treatment of respiratory disorders such as asthma, chronic obstructive pulmonary disease or cystic fibrosis. In addition, the high alveolar surface area, relatively low enzymatic activity and rich blood supply of the distal airspaces offer a promising pathway to the systemic circulation. This is particularly advantageous when a rapid onset of pharmacological action is desired or when the drug is suffering from stability issues or poor biopharmaceutical performance following oral administration. Several cell and tissue-based in vitro and ex vivo models have been developed over the years, with the intention to realistically mimic pulmonary biological barriers. It is the aim of this review to critically discuss the available models regarding their advantages and limitations and to elaborate further which biopharmaceutical questions can and cannot be answered using the existing models.

Robustness of aerosol delivery of amikacin liposome inhalation suspension using the eFlow® Technology.

The purpose of these studies was to understand the effect on product performance of batch-to-batch variability in both the amikacin liposome inhalation suspension (ALIS) formulation and its delivery device, the Lamira® nebulizer system, designed and manufactured by PARI (PARI Pharma GmbH, Munich, Germany). Three batches of ALIS spanning a range of lipid concentrations (43, 48 and 54 mg/mL) were tested with nine PARI inhalation devices that varied within the production process of the vibrating membrane with respect to hole geometry. Three hole geometry clusters were built including a geometry close to the mean geometry (median) and two geometries deviating from the mean geometry with smaller (smaller) and larger (larger) holes. The output parameters included the nebulization rate, the aerosol droplet size distribution, the liposome vesicle size post-nebulization, and the fraction of amikacin that remained encapsulated post-nebulization. Across the 27 experimental combinations of three formulation batches and nine devices, the nebulization time varied between 12 and 15 min with the fastest nebulization rate occurring with the combination of low lipid concentration and larger hole geometry (0.68 g/min) and the slowest nebulization rate occurring with the combination of high lipid concentration and the smaller hole geometry (0.59 g/min). The mean liposome vesicle size post-nebulization ranged from 269 to 296 nm across all experimental combinations which was unchanged from the control samples (276-292 nm). While all three batches contained > 99% encapsulated amikacin prior to nebulization, the nebulization process resulted in a consistent generation of ~ 35% unencapsulated amikacin (range: 33.8% to 37.6%). There was no statistically significant difference in the generated aerosol particle size distributions. The mass median aerodynamic diameters (MMAD) ranged from 4.78 µm to 4.98 µm, the geometric standard deviations (GSD) ranged from 1.61 to 1.66, and the aerosol fine particle fraction (FPF < 5 µm) ranged from 50.3 to 53.5%. The emitted dose (ED) of amikacin ranged from 473 to 523 mg (80.2 to 89.3% of loaded dose (LD)) and the fine particle dose (FPD < 5 µm) ranged from 244 to 278 mg (41.4 to 47.1% of label claim (LC)). In conclusion, while variations in the lipid concentration of the ALIS formulation and the device hole geometry had a small but significant impact on nebulization time, the critical aerosol performance parameters were maintained and remained within acceptable limits.

Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections in Syrian hamsters at ultra-low doses.

Globally, there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss and substantially reduces viral burdens in both lower and upper airways compared to control. Aerosol delivery of PiN-21 facilitates deposition throughout the respiratory tract and dose minimization to 0.2 mg/kg. Inhalation treatment quickly reverses animals' weight loss after infection, decreases lung viral titers by 6 logs leading to drastically mitigated lung pathology, and prevents viral pneumonia. Combined with the marked stability and low production cost, this innovative therapy may provide a convenient and cost-effective option to mitigate the ongoing pandemic.

Assessment of workplace environmental contamination and occupational exposure to cisplatin and doxorubicin aerosols during electrostatic pressurized intraperitoneal aerosol chemotherapy.

BACKGROUND: Electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC) is a novel approach for intraperitoneal drug delivery. As ePIPAC using cisplatin and doxorubicin is performed in an operating room, the challenge is to safely deliver the chemotherapeutic aerosol intraperitoneally while preventing exposure to healthcare workers. The objective of this study was to describe cisplatin and doxorubicin workplace environmental contamination and healthcare worker exposure during ePIPAC. METHODS: Antineoplastic drugs concentrations of cisplatin and doxorubicin were measured in wipe samples from the operating room, and urine samples were collected from healthcare workers. The air samples were collected in order to detect Cisplatin contamination. Cisplatin was analysed by inductively coupled plasma-mass spectrometry and doxorubicin by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: No trace of cisplatin was found in the air. Cisplatin and doxorubicin were detected on the operating room floor, surfaces, devices and personal protective equipment even after a cleaning protocol. No traces of cisplatin or doxorubicin were found in the urine samples. CONCLUSION: In this study, no internal contamination was found in the ePIPAC surgical team even after implementing two successive ePIPAC procedures. These results showed the effectiveness of the individual and collective protective measures applied. However, the cleaning procedure during ePIPAC should be respected to limit environmental exposure to chemotherapy to cisplatin and doxorubicin during ePIPAC.

Infant rhesus macaques as a non-human primate model of Bordetella pertussis infection.

BACKGROUND: The prevalent resurgence of pertussis has recently become a critical public health problem worldwide. To understand pertussis pathogenesis and the host response to both the pathogen and vaccines, a suitable pertussis animal model, particularly a non-human primate model, is necessary. Recently, a non-human primate pertussis model was successfully established with baboons. Rhesus macaques have been shown to be ideal animal models for several infectious diseases, but a model of infectious pertussis has not been established in these organisms. Studies on rhesus macaque models of pertussis were performed in the 1920s-1930s, but limited experimental details are available. Recent monkey pertussis models have not been successful because the typical clinical symptoms and transmission have not been achieved. METHODS: In the present study, infant rhesus macaques were challenged with Bordetella pertussis (B.p) using an aerosol method to evaluate the feasibility of this system as an animal model of pertussis. RESULTS: Upon aerosol infection, monkeys infected with the recently clinically isolated B.p strain 2016-CY-41 developed the typical whooping cough, leukocytosis, bacteria-positive nasopharyngeal wash (NPW), and interanimal transmission of pertussis. Both systemic and mucosal humoral responses were induced by B.p. CONCLUSION: These results demonstrate that a model of pertussis was successfully established in infant rhesus macaques. This model provides a valuable platform for research on pertussis pathogenesis and evaluation of vaccine candidates.

The combination of an innovative dry powder for inhalation and a standard cisplatin-based chemotherapy in view of therapeutic intensification against lung tumours.

Cisplatin is one of the most commonly used chemotherapy in lung cancer despite its high nephrotoxicity leading to an administration only every 3-4 weeks. This study is the first report of a preclinical investigation of therapeutic intensification combining a cisplatin dry powder for inhalation (CIS-DPI) with an intravenous (iv) cisplatin-based treatment. CIS-DPI with 50% cisplatin content (CIS-DPI-50) was developed using lipid excipients through scalable processes (high-speed and high-pressure homogenization and spray-drying). CIS-DPI-50 showed good aerodynamic performance (fine particle fraction of ~ 55% and a mass median aerodynamic particle size of ~ 2 µm) and a seven-fold increase and decrease in Cmax in the lungs and in plasma, respectively, in comparison with an iv cisplatin solution (CIS-iv) in healthy mice. Finally, the addition of CIS-DPI-50 to the standard cisplatin/paclitaxel iv doublet increased the response rate (67% vs 50%), decreased the tumour growth and prolonged the median survival (31 vs 21 days), compared to the iv doublet in the M109 lung carcinoma model tending to demonstrate a therapeutic intensification of cisplatin.

The Clinical Practice and Best Aerosol Delivery Location in Intubated and Mechanically Ventilated Patients: A Randomized Clinical Trial.

This randomized clinical trial (RCT) is aimed at exploring the best nebulizer position for aerosol delivery within the mechanical ventilation (MV) circuitry. This study enrolled 75 intubated and MV patients with respiratory failure and randomly divided them into three groups. The nebulizer position of patients in group A was between the tracheal tube and Y-piece. For group B, the nebulizer was placed at the inspiratory limb near the ventilator water cup (80 cm away from the Y-piece). For group C, the nebulizer was placed between the ventilator inlet and the heated humidifier. An indirect competitive enzyme-linked immunosorbent assay (ELISA) was used to measure salbutamol drug concentrations in serum and urine. The serum and urine salbutamol concentrations of the three groups were the highest in group B, followed by group C, and the lowest in group A. Serum and urine salbutamol concentrations significantly differed among the three groups (P < 0.05). It was found that the drug was statistically significant between group differences for groups B and A (P = 0.001; P = 0.002, respectively) for both serum and urine salbutamol concentrations. There were no significant differences observed among the other groups. It was found that the drug concentrations were the highest when the nebulizer was placed 80 cm away from the Y-piece, while the location between the tracheal tube and the Y-piece with the higher frequency of nebulizer placement was the location with the lowest drug concentration.

Inhalation dosimetry of nasally inhaled respiratory aerosols in the human respiratory tract with locally remodeled conducting lungs.

Objective: Respiratory diseases are often accompanied by alterations to airway morphology. However, inhalation dosimetry data in remodeled airways are scarce due to the challenges in reconstructing diseased respiratory morphologies. This study aims to study the airway remodeling effects on the inhalation dosimetry of nasally inhaled nanoparticles in a nose-lung geometry that extends to G9 (ninth generation).Materials and methods: Statistical shape modeling was used to develop four diseased lung models with varying levels of bronchiolar dilation/constriction in the left-lower (LL) lobe (i.e. M1-M4). Respiratory airflow and particle deposition were simulated using a low Reynolds number k-ω turbulence model and a Lagrangian tracking approach.Results: Significant discrepancies were observed in the flow partitions between the left and right lungs, as well as between the lower and upper lobes of the left lung, which changed by 10-fold between the most dilated and constricted models.Much lower doses were predicted on the surface of the constricted LL bronchioles G4-G9, as well as into the peripheral airways beyond G9 of the LL lung. However, the LL lobar remodeling had little effect on the dosimetry in the nasopharynx, as well as on the total dosimetry in the nose-lung geometry (up to G9).Conclusion: It is suggested that airway remodeling may pose a higher viral infection risk to the host by redistributing the inhaled viruses to healthy lung lobes. Airway remodeling effects should also be considered in the treatment planning of inhalation therapies, not only because of the dosimetry variation from altered lung morphology but also its evolution as the disease progresses.

Performance of Low Air Volume Dry Powder Inhalers (LV-DPI) when Aerosolizing Excipient Enhanced Growth (EEG) Surfactant Powder Formulations.

Efficient delivery of dry powder aerosols dispersed with low volumes of air is challenging. This study aims to develop an efficient dry powder inhaler (DPI) capable of delivering spray-dried Survanta-EEG powders (3-10 mg) with a low volume (3 mL) of dispersion air. A series of iterative design modifications were made to a base low air volume actuated DPI. The modifications included the replacement of the original capsule chamber with an integral dose containment chamber, alteration of the entrainment air flow path through the device (from single-sided (SS) to straight through (ST)), change in the number of air inlet holes (from one to three), varying the outlet delivery tube length (45, 55, and 90 mm) and internal diameter (0.60, 0.89, and 1.17 mm). The modified devices were evaluated by determining the influence of the modifications and powder fill mass on aerosol performance of spray-dried Survanta-EEG powders. The optimal DPI was also evaluated for its ability to aerosolize a micronized powder. The optimized dose containment unit DPI had a 0.21 mL powder chamber, ST airflow path, three-0.60 mm air inlet holes, and 90 mm outlet delivery tube with 0.89 mm internal diameter. The powder dispersion characteristics of the optimal device were independent of fill mass with good powder emptying in one 3 mL actuation. At 10 mg fill mass, this device had an emitted mass of 5.3 mg with an aerosol Dv50 of 2.7 µm. After three 3 mL actuations, >85% of the spray-dried powder was emitted from the device. The emitted mass of the optimal device with micronized albuterol sulfate was >72% of the nominal fill mass of 10 mg in one 3 mL actuation. Design optimization produced a DPI capable of efficient performance with a dispersion air volume of 3 mL to aerosolize Survanta-EEG powders.