RESUMO
OBJECTIVE: To investigate the efficacy and safety of nebulized poractant alfa (at 200 and 400 mg/kg doses) delivered in combination with nasal continuous positive airway pressure compared with nasal continuous positive airway pressure alone in premature infants with diagnosed respiratory distress syndrome. STUDY DESIGN: This randomized, controlled, multinational study was conducted in infants at 280/7 to 326/7 weeks of gestation. The primary outcome was the incidence of respiratory failure in the first 72 hours of life, defined as needing endotracheal surfactant and/or mechanical ventilation owing to prespecified criteria. Secondary outcomes included the time to respiratory failure in the first 72 hours, duration of ventilation, mortality, incidence of bronchopulmonary dysplasia, and major associated neonatal comorbidities. In addition, the safety and tolerability of the treatments were assessed reporting the number and percentage of infants with treatment-emergent adverse events and adverse drug reactions during nebulization. RESULTS: In total, 129 infants were randomized. No significant differences were observed for the primary outcome: 24 (57%), 20 (49%), and 25 (58%) infants received endotracheal surfactant and/or mechanical ventilation within 72 hours in the poractant alfa 200 mg/kg, poractant alfa 400 mg/kg, and nasal continuous positive airway pressure groups, respectively. Similarly, secondary respiratory outcomes did not differ among groups. Enrollment was halted early owing to a change in the benefit-risk balance of the intervention. Nebulized poractant alfa was well-tolerated and safe, and no serious adverse events were related to the study treatment. CONCLUSIONS: The intervention did not decrease the likelihood of respiratory failure within the first 72 hours of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03235986.
Assuntos
Doenças do Prematuro , Surfactantes Pulmonares , Síndrome do Desconforto Respiratório do Recém-Nascido , Insuficiência Respiratória , Produtos Biológicos , Pressão Positiva Contínua nas Vias Aéreas , Humanos , Recém-Nascido , Doenças do Prematuro/epidemiologia , Fosfolipídeos , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologia , Insuficiência Respiratória/tratamento farmacológico , Tensoativos/uso terapêuticoRESUMO
PURPOSE: The objective of this study was to incorporate a passive cyclic loading strategy into the infant air-jet dry powder inhaler (DPI) in a manner that provides high efficiency aerosol lung delivery and is insensitive to powder mass loadings and the presence of downstream pulmonary mechanics. METHODS: Four unique air-jet DPIs were initially compared and the best performing passive design (PD) was selected for sensitivity analyses. A single preterm in vitro nose-throat (NT) model, air source, and nasal interface were utilized throughout. While the majority of analyses were evaluated with a model spray-dried excipient enhanced growth (EEG) formulation, performance of a Surfactant-EEG formulation was also explored for the lead DPI design. RESULTS: Two devices, PD-2 and PD-3, evaluated in the preterm model achieved an estimated lung delivery efficiency of 60% with the model EEG formulation, and were not sensitive to the loaded dose (10-30 mg of powder). The PD-3 device was also unaffected by the presence of downstream pulmonary mechanics (infant lung model) and had only a minor sensitivity to tripling the volume of the powder reservoir. When using the Surfactant-EEG formulation, increasing the actuation flow rate from 1.7 to 4.0 L/min improved lung delivery by nearly 10%. CONCLUSIONS: The infant air-jet DPI platform was successfully modified with a passive cyclic loading strategy and capable of providing an estimated > 60% lung delivery efficiency of a model spray-dried formulation with negligible sensitivity to powder mass loading in the range of 10-30 mg and could be scaled to deliver much higher doses.
Assuntos
Inaladores de Pó Seco , Excipientes , Recém-Nascido , Humanos , Lactente , Pós , Desenho de Equipamento , Tamanho da Partícula , Administração por Inalação , Aerossóis , TensoativosRESUMO
The objective of this study was to characterize the effects of multiple nasal prong interface configurations on nasal depositional loss of pharmaceutical aerosols in a preterm infant nose-throat (NT) airway model. Benchmark in vitro experiments were performed in which a spray-dried powder formulation was delivered to a new preterm NT model with a positive-pressure infant air-jet dry powder inhaler using single- and dual-prong interfaces. These results were used to develop and validate a computational fluid dynamics (CFD) model of aerosol transport and deposition in the NT geometry. The validated CFD model was then used to explore the NT depositional characteristic of multiple prong types and configurations. The CFD model highlighted a turbulent jet effect emanating from the prong(s). Analysis of NT aerosol deposition efficiency curves for a characteristic particle size and delivery flowrate (3 µm and 1.4 L/min (LPM)) revealed little difference in NT aerosol deposition fraction (DF) across the prong insertion depths of 2-5 mm (DF = 16-24%) with the exception of a single prong with 5-mm insertion (DF = 36%). Dual prongs provided a modest reduction in deposition vs. a single aerosol delivery prong at the same flow for insertion depths < 5 mm. The presence of the prongs increased nasal depositional loss by absolute differences in the range of 20-70% compared with existing correlations for ambient aerosols. In conclusion, the use of nasal prongs was shown to have a significant impact on infant NT aerosol depositional loss prompting the need for prong design alterations to improve lung delivery efficiency.
Assuntos
Inaladores de Pó Seco , Recém-Nascido Prematuro , Administração por Inalação , Aerossóis , Inaladores de Pó Seco/métodos , Desenho de Equipamento , Humanos , Lactente , Recém-Nascido , Sprays Nasais , Tamanho da Partícula , PósRESUMO
The objective of this study was to develop a new heated dryer system (HDS) for high efficiency lung delivery of nebulized aerosol and demonstrate performance with realistic in vitro testing for trans-nasal aerosol administration simultaneously with high-flow nasal cannula (HFNC) therapy and separately for direct oral inhalation (OI) of the aerosol. With the HDS-HFNC and HDS-OI platforms, new active synchronization control routines were developed to sense subject inhalation and coordinate drug aerosol delivery. In vitro experiments were conducted to predict regional drug loss and lung delivery efficiency in systems that included the HDS with various patient interfaces, realistic airway models, and simulated breathing waveforms. For the HDS-HFNC platform and a repeating breathing waveform, total system loss was < 10%, extrathoracic deposition was approximately 6%, and best-case lung delivery efficiency was 75-78% of nebulized dose. Inclusion of randomized breathing with the HFNC system decreased lung delivery efficiency by ~ 10% and had no impact on nasal depositional loss. For the HDS-OI platform and best-case mouthpiece, total system loss was < 8%, extrathoracic deposition was < 1%, and lung delivery efficiency was > 90% of nebulized dose. Normal vs. deep randomized oral inhalation had little impact on performance of the HDS-OI platform and environmental aerosol loss was negligible. In conclusion, both platforms demonstrated the potential for high efficiency lung delivery of the aerosol with the HDS-OI platform having the added advantages of nearly eliminating extrathoracic deposition, being insensitive to breathing waveform, and preventing environmental aerosol loss.
Assuntos
Temperatura Alta , Sprays Nasais , Humanos , Aerossóis , Administração Intranasal , PulmãoRESUMO
Delivery of medications to preterm neonates receiving non-invasive ventilation (NIV) represents one of the most challenging scenarios for aerosol medicine. This challenge is highlighted by the undersized anatomy and the complex (patho)physiological characteristics of the lungs in such infants. Key physiological restraints include low lung volumes, low compliance, and irregular respiratory rates, which significantly reduce lung deposition. Such factors are inherent to premature birth and thus can be regarded to as the intrinsic factors that affect lung deposition. However, there are a number of extrinsic factors that also impact lung deposition: such factors include the choice of aerosol generator and its configuration within the ventilation circuit, the drug formulation, the aerosol particle size distribution, the choice of NIV type, and the patient interface between the delivery system and the patient. Together, these extrinsic factors provide an opportunity to optimize the lung deposition of therapeutic aerosols and, ultimately, the efficacy of the therapy.In this review, we first provide a comprehensive characterization of both the intrinsic and extrinsic factors affecting lung deposition in premature infants, followed by a revision of the clinical attempts to deliver therapeutic aerosols to premature neonates during NIV, which are almost exclusively related to the non-invasive delivery of surfactant aerosols. In this review, we provide clues to the interpretation of existing experimental and clinical data on neonatal aerosol delivery and we also describe a frame of measurable variables and available tools, including in vitro and in vivo models, that should be considered when developing a drug for inhalation in this important but under-served patient population.
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Broncodilatadores/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nebulizadores e Vaporizadores , Ventilação não Invasiva/métodos , Nascimento Prematuro/tratamento farmacológico , Mecânica Respiratória/efeitos dos fármacos , Administração por Inalação , Aerossóis , Sistemas de Liberação de Medicamentos/instrumentação , Humanos , Recém-Nascido , Ventilação não Invasiva/instrumentação , Nascimento Prematuro/diagnóstico , Nascimento Prematuro/fisiopatologia , Mecânica Respiratória/fisiologiaRESUMO
PURPOSE: In order to improve the delivery of dry powder aerosol formulations to the lungs of infants, this study implemented an infant air-jet platform and explored the effects of different air sources, flow rates, and pulmonary mechanics on aerosolization performance and aerosol delivery through a preterm nose-throat (NT) in vitro model. METHODS: The infant air-jet platform was actuated with a positive-pressure air source that delivered the aerosol and provided a full inhalation breath. Three different air sources were developed to provide highly controllable positive-pressure air actuations (using actuation volumes of ~10 mL for the preterm model). While providing different flow waveform shapes, the three air sources were calibrated to produce the same flow rate magnitude (Q90: 90th percentile of flow rate). Multiple air-jet DPI designs were coupled with the air sources and evaluated with a model spray-dried excipient enhanced growth formulation. RESULTS: Compared to other designs, the D1-Single air-jet DPI provided improved performance with low variability across all three air sources. With the tested D1-Single air-jet and Timer air source, reducing the flow rate from 4 to 1.7 L/min marginally decreased the aerosol size and significantly increased the lung delivery efficiency above 50% of the loaded dose. These results were not impacted by the presence of downstream pulmonary mechanics (resistance and compliance model). CONCLUSIONS: The selected design was capable of providing an estimated >50% lung delivery efficiency of a model spray-dried formulation and was not influenced by the air source, thereby enabling greater flexibility for platform deployment in different environments.
Assuntos
Química Farmacêutica/métodos , Inaladores de Pó Seco/métodos , Pós/química , Administração por Inalação , Aerossóis/química , Desenho de Equipamento/métodos , Excipientes/química , Humanos , Lactente , Pulmão/metabolismo , Nariz/efeitos dos fármacos , Tamanho da PartículaRESUMO
There is a clear need for low-cost, self-applied, long-lasting approaches to prevent human immunodeficiency virus (HIV) infection in both men and women, even with the advent of pre-exposure prophylaxis (PrEP). Broadly neutralizing antibodies represent an option to improve HIV prophylaxis, but intravenous delivery, cold-chain stability requirements, low cervicovaginal concentrations, and cost may preclude their use. Here, we present an approach to express the anti-GP120 broadly neutralizing antibody PGT121 in the primary site of inoculation, the female reproductive tract, using synthetic mRNA. Expression is achieved through aerosol delivery of unformulated mRNA in water. We demonstrated high levels of antibody expression for over 28 days with a single mRNA administration in the reproductive tract of sheep. In rhesus macaques, neutralizing antibody titers in secretions developed within 4 h and simian-HIV (SHIV) infection of ex vivo explants was prevented. Persistence of PGT121 in vaginal secretions and epithelium was achieved through the incorporation of a glycosylphosphatidylinositol (GPI) anchor into the heavy chain of the antibody. Overall, we present a new paradigm to deliver neutralizing antibodies to the female reproductive tract for the prevention of HIV infections.
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Anticorpos Amplamente Neutralizantes/imunologia , Expressão Gênica , Anticorpos Anti-HIV/imunologia , Mucosa/imunologia , Mucosa/metabolismo , RNA Mensageiro/administração & dosagem , Vagina , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Aerossóis , Animais , Chlorocebus aethiops , Feminino , Imunofluorescência , Infecções por HIV/imunologia , HIV-1/imunologia , Camundongos , Testes de Neutralização , RNA Mensageiro/síntese química , Ovinos , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Vagina/imunologia , Vagina/metabolismo , Células VeroRESUMO
While dry powder aerosol formulations offer a number of advantages, their use in children is often limited due to poor lung delivery efficiency and difficulties with consistent dry powder inhaler (DPI) usage. Both of these challenges can be attributed to the typical use of adult devices in pediatric subjects and a lack of pediatric-specific DPI development. In contrast, a number of technologies have recently been developed or progressed that can substantially improve the efficiency and reproducibility of DPI use in children including: (i) nose-to-lung administration with small particles, (ii) active positive-pressure devices, (iii) structures to reduce turbulence and jet momentum, and (iv) highly dispersible excipient enhanced growth particle formulations. In this study, these technologies and their recent development are first reviewed in depth. A case study is then considered in which these technologies are simultaneously applied in order to enable the nose-to-lung administration of dry powder aerosol to children with cystic fibrosis (CF). Using a combination of computational fluid dynamics (CFD) analysis and realistic in vitro experiments, device performance, aerosol size increases and lung delivery efficiency are considered for pediatric-CF subjects in the age ranges of 2-3, 5-6 and 9-10 years old. Results indicate that a new 3D rod array structure significantly improves performance of a nasal cannula reducing interface loss by a factor of 1.5-fold and produces a device emitted mass median aerodynamic diameter (MMAD) of 1.67 µm. For all ages considered, approximately 70% of the loaded dose reaches the lower lung beyond the lobar bronchi. Moreover, significant and rapid size increase of the aerosol is observed beyond the larynx and illustrates the potential for targeting lower airway deposition. In conclusion, concurrent CFD and realistic in vitro analysis indicates that a combination of multiple new technologies can be implemented to overcome obstacles that currently limit the use of DPIs in children as young as two years of age.
RESUMO
Respiratory disease is the leading cause of death in children under the age of 5 years old. Currently available treatments for paediatric respiratory diseases including bronchopulmonary dysplasia, asthma, cystic fibrosis and interstitial lung disease may ameliorate symptoms but do not offer a cure. Cellular therapy may offer a potential cure for these diseases, preventing disease progression into adulthood. Induced pluripotent stem cells, mesenchymal stromal cells and their secretome have shown great potential in preclinical models of lung disease, targeting the major pathological features of the disease. Current research and clinical trials are focused on the adult population. For cellular therapies to progress from preclinical studies to use in the clinic, optimal cell type dosage and delivery methods need to be established and confirmed. Direct delivery of these therapies to the lung as aerosols would allow for lower doses with a higher target efficiency whilst avoiding potential effect of systemic delivery. There is a clear need for research to progress into the clinic for the treatment of paediatric respiratory disease. Whilst research in the adult population forms a basis for the paediatric population, varying disease pathology and anatomical differences in paediatric patients means a paediatric-centric approach must be taken.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Doenças Respiratórias/terapia , Criança , Humanos , Doenças Respiratórias/patologiaRESUMO
PURPOSE: The objective of this study was to optimize nose-to-lung aerosol delivery in an adult upper airway model using computational fluid dynamics (CFD) simulations in order to guide subsequent human subject aerosol delivery experiments. METHODS: A CFD model was developed that included a new high-flow nasal cannula (HFNC) and pharmaceutical aerosol delivery unit, nasal cannula interface, and adult upper airway geometry. Aerosol deposition predictions in the system were validated with existing and new experimental results. The validated CFD model was then used to explore aerosol delivery parameters related to synchronizing aerosol generation with inhalation and inhalation flow rate. RESULTS: The low volume of the new HFNC unit minimized aerosol transit time (0.2 s) and aerosol bolus spread (0.1 s) enabling effective synchronization of aerosol generation with inhalation. For aerosol delivery correctly synchronized with inhalation, a small particle excipient-enhanced growth delivery strategy reduced nasal cannula and nasal depositional losses each by an order of magnitude and enabled ~80% of the nebulized dose to reach the lungs. Surprisingly, nasal deposition was not sensitive to inhalation flow rate due to use of a nasal cannula interface with co-flow inhaled air and the small initial particle size. CONCLUSIONS: The combination of correct aerosol synchronization and small particle size enabled high efficiency nose-to-lung aerosol delivery in adults, which was not sensitive to inhalation flow rate.
Assuntos
Administração Intranasal/instrumentação , Administração Intranasal/métodos , Aerossóis/administração & dosagem , Simulação por Computador , Hidrodinâmica , Administração por Inalação , Adulto , Broncodilatadores/administração & dosagem , Sistemas de Liberação de Medicamentos , Desenho de Equipamento , Humanos , Pulmão , Sprays Nasais , Nariz , Tamanho da PartículaRESUMO
PURPOSE: To determine the predictive power of computational fluid dynamics (CFD)-based dispersion parameters in the development of a new inline DPI that is actuated with low volumes of air. METHODS: Four new versions of a dose aerosolization and containment (DAC)-unit DPI were created with varying inlet and outlet orifice sizes and analyzed with results from five previous designs. A concurrent in vitro and CFD analysis was conducted to predict the emitted dose (ED; as a % of loaded dose) and aerosol mass median aerodynamic diameter (MMAD) produced by each device when actuated with 10 ml air bursts. CFD simulations of device operation were used to predict flow field and particle-based dispersion parameters. RESULTS: Comparisons of experimental and CFD results indicated that multiple flow field and particle-based dispersion parameters could be used to predict ED (minimum RMS Error = 4.9%) and MMAD (minimum RMS Error = 0.04 µm) to a high degree of accuracy. Based on experiments, the best overall device produced mean (standard deviation; SD) ED = 82.9(4.3)% and mean MMAD (SD) = 1.73(0.07)µm, which were in close agreement with the CFD predictions. CONCLUSIONS: A unique relationship was identified in the DAC-unit DPI in which reducing turbulence also reduced the MMAD.
Assuntos
Simulação por Computador , Inaladores de Pó Seco/instrumentação , Hidrodinâmica , Administração por Inalação , Aerossóis/química , Ar , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/instrumentação , Desenho de Equipamento/instrumentação , Humanos , Modelos Biológicos , Tamanho da Partícula , Pós/administração & dosagemRESUMO
The reprogramming of the epigenome through silencing of genes and microRNAs by cytosine DNA methylation and chromatin remodeling is critical for the initiation and progression of lung cancer through affecting all major cell regulatory pathways. Importantly, the fact that epigenetic reprogramming is reversible by pharmacological agents has opened new avenues for clinical intervention. This review focuses on the tremendous progress made in elucidating genes and microRNAs that are epigenetically silenced in lung cancer and highlights how loss of function impacts cell phenotype and major signaling pathways. The article describes the utility of (a) an in vitro model using hTERT/Cdk4 immortalized human bronchial epithelial cell lines to identify genes and microRNAs silenced during premalignancy and (b) an in vivo orthotopic nude rat lung cancer model to evaluate response to epigenetic therapy. New insights regarding the advantage of aerosol delivery of demethylating agents and the concept of priming tumors for subsequent therapy are presented and discussed.
Assuntos
Epigênese Genética/genética , Epigênese Genética/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatologia , Animais , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Metilação de DNA/genética , Metilação de DNA/fisiologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica/fisiologia , Humanos , Técnicas In Vitro , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/fisiologia , Fenótipo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/fisiopatologia , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/fisiologia , RatosRESUMO
Middle East respiratory syndrome coronavirus (MERS-CoV) induces severe aggravating respiratory failure in infected patients, frequently resulting in mechanical ventilation. As limited therapeutic antibody is accumulated in lung tissue following systemic administration, inhalation is newly recognized as an alternative, possibly better, route of therapeutic antibody for pulmonary diseases. The nebulization process, however, generates diverse physiological stresses, and thus, the therapeutic antibody must be resistant to these stresses, remain stable, and form minimal aggregates. We first isolated a MERS-CoV neutralizing antibody that is reactive to the receptor-binding domain (RBD) of spike (S) glycoprotein. To increase stability, we introduced mutations into the complementarity-determining regions (CDRs) of the antibody. In the HCDRs (excluding HCDR3) in this clone, two hydrophobic residues were replaced with Glu, two residues were replaced with Asp, and four residues were replaced with positively charged amino acids. In LCDRs, only two Leu residues were replaced with Val. These modifications successfully generated a clone with significantly greater stability and equivalent reactivity and neutralizing activity following nebulization compared to the original clone. In summary, we generated a MERS-CoV neutralizing human antibody that is reactive to recombinant MERS-CoV S RBD protein for delivery via a pulmonary route by introducing stabilizing mutations into five CDRs.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Regiões Determinantes de Complementaridade/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Administração por Inalação , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/genética , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/genética , Chlorocebus aethiops , Regiões Determinantes de Complementaridade/genética , Humanos , Células VeroRESUMO
The objective of this study was to optimize the performance of a high-efficiency pediatric inhaler, referred to as the pediatric air-jet DPI, using computational fluid dynamics (CFD) simulations with supporting experimental analysis of aerosol formation. The pediatric air-jet DPI forms an internal flow pathway consisting of an inlet jet of high-speed air, capsule chamber containing a powder formulation, and outlet orifice. Instead of simulating full breakup of the powder bed to an aerosol in this complex flow system, which is computationally expensive, flow-field-based dispersion parameters were sought that correlated with experimentally determined aerosolization metrics. For the pediatric air-jet DPI configuration that was considered, mass median aerodynamic diameter (MMAD) directly correlated with input turbulent kinetic energy normalized by actuation pressure and flow kinetic energy. Emitted dose (ED) correlated best with input flow rate multiplied by the ratio of capillary diameters. Based on these dispersion parameters, an automated CFD process was used over multiple iterations of over 100 designs to identify optimal inlet and outlet capillary diameters, which affected system performance in complex and unexpected ways. Experimental verification of the optimized designs indicated an MMAD < 1.6 µm and an ED > 90% of loaded dose. While extrathoracic depositional loss will be determined in future studies, at an operating flow rate of 15 L/min, it is expected that pediatric mouth-throat or even nose-throat aerosol deposition fractions will be below 10% and potentially less than 5% representing a significant improvement in the delivery efficiency of dry powder pharmaceutical aerosols to children.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Inaladores de Pó Seco/métodos , Desenho de Equipamento/métodos , Hidrodinâmica , Administração por Inalação , Aerossóis , Criança , Sistemas de Liberação de Medicamentos/normas , Inaladores de Pó Seco/normas , Desenho de Equipamento/normas , Humanos , Tamanho da Partícula , PósRESUMO
BACKGROUND: Preservative-free tobramycin is commonly used as aerosolized therapy for ventilator associated pneumonia. The comparative delivery profile of the formulations of two different concentrations (100â¯mg/ml and 40â¯mg/ml) is unknown. This study aims to evaluate the aerosol characteristics of these tobramycin formulations in a simulated adult mechanical ventilation model. METHODS: Simulated adult mechanical ventilation set up and optimal settings were used in the study. Inhaled mass study was performed using bacterial/viral filters at the tip of the tracheal tube and in the expiratory limb of circuit. Laser diffractometer was used for characterising particle size distribution. The physicochemical characteristics of the formulations were described and nebulization characteristics compared using two airways, an endotracheal tube (ET) and a tracheostomy tube (TT). For each type of tube, three internal tube diameters were studied, 7â¯mm, 8â¯mm and 9â¯mm. RESULTS: The lung dose was significantly higher for 100â¯mg/ml solution (mean 121.3â¯mg vs 41.3â¯mg). Viscosity was different (2.11cp vs 1.58cp) for 100â¯mg/ml vs 40â¯mg/ml respectively but surface tension was similar. For tobramycin 100â¯mg/ml vs 40â¯mg/ml, the volume median diameter (2.02 vs 1.9⯵m) was comparable. The fine particle fraction (98.5 vs 85.4%) was higher and geometric standard deviation (1.36 vs 1.62⯵m) was significantly lower for 100â¯mg/ml concentration. Nebulization duration was longer for 100â¯mg/ml solution (16.9 vs 10.1â¯min). The inhaled dose percent was similar (30%) but the exhaled dose was higher for 100â¯mg/ml solution (18.9 vs 10.4%). The differences in results were non-significant for type of tube or size except for a small but statistically significant reduction in inhaled mass with TT compared to ET (0.06%). CONCLUSION: Aerosolized tobramycin 100â¯mg/ml solution delivered higher lung dose compared to tobramycin 40â¯mg/ml solution. Tracheal tube type or size did not influence the aerosol characteristics and delivery parameters.
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Respiração Artificial/instrumentação , Respiração Artificial/métodos , Tobramicina/análise , Ventiladores Mecânicos , Aerossóis , Desenho de Equipamento , Humanos , Intubação Intratraqueal/instrumentação , Modelos Teóricos , Nebulizadores e Vaporizadores , Tamanho da Partícula , Tobramicina/administração & dosagem , Tobramicina/químicaRESUMO
BACKGROUND: Research on the effect of nebulizer location on aerosol delivery during noninvasive ventilation has reached inconsistent conclusions. OBJECTIVE: To investigate the effects of nebulizer position on aerosol delivery efficiency and ventilator performance during noninvasive ventilation. METHODS: The Active Servo Lung 5000 respiratory simulation system (ASL5000) was used to simulate a COPD patient. The noninvasive ventilator was set to the spontaneous breathing mode. Six nebulizer positions, 2 exhalation valve types (single-arch exhalation port and whisper swivel), 4 combinations of inspiratory and expiratory pressure, and 2 respiratory rates were used. RESULTS: Significant differences between nebulizer positions existed in aerosol delivery (p < 0.05). Aerosol delivery efficiency was lower for nebulizer locations on either side of the exhalation valve and next to the ventilator outlet. When the nebulizer was located between the exhalation valve and the simulated lung, increased inspiratory pressure increased and increased expiratory pressure decreased delivery efficiency (both p < 0.05). When the nebulization device was located between the exhalation valve and the ventilator, no obvious trend was observed. Compared to baseline, nebulization lowered the air leakage volume displayed on the ventilator. There were no differences in ventilator performance between different nebulizer positions. CONCLUSIONS: The closer the nebulizer was to the exhalation valves or ventilator, the lower the aerosol delivery efficiency. Nebulizer position had little clinically significant effect on ventilator performance.
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Aerossóis/administração & dosagem , Nebulizadores e Vaporizadores , Respiração com Pressão PositivaRESUMO
Rifapentine is an anti-tuberculosis (anti-TB) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. We have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. The delivery of crystalline particles to the lungs may promote inflammation. This in vivo study characterizes the inflammatory response caused by pulmonary deposition of the rifapentine particles. The rifapentine powder was delivered to BALB/c mice by intratracheal insufflation at a dose of 20 mg/kg. The inflammatory response in the lungs and bronchoalveolar lavage (BAL) was examined at 12 h, 24 h, and 7 days post-treatment by flow cytometry and histopathology. At 12 and 24 h post-treatment, there was a significant influx of neutrophils into the lungs, and this returned to normal by day 7. A significant recruitment of macrophages occurred in the BAL at 24 h. Consistent with these findings, histopathological analysis demonstrated pulmonary vascular congestion and significant macrophage recruitment at 12 and 24 h post-treatment. In conclusion, the pulmonary delivery of crystalline rifapentine caused a transient neutrophil-associated inflammatory response in the lungs that resolved over 7 days. This observation may limit pulmonary delivery of rifapentine to once a week at a dose of 20 mg/kg or less. The effectiveness of weekly dosing with inhalable rifapentine will be assessed in murine Mycobacterium tuberculosis infection.
Assuntos
Pneumonia/induzido quimicamente , Rifampina/análogos & derivados , Administração por Inalação , Animais , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/efeitos adversos , Feminino , Meia-Vida , Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pós/administração & dosagem , Pós/efeitos adversos , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Tuberculose/tratamento farmacológicoRESUMO
PURPOSE: To compare in vivo the total and regional pulmonary deposition of aerosol particles generated by a new system combining a vibrating-mesh nebulizer with a specific valved holding chamber and constant-output jet nebulizer connected to a corrugated tube. METHODS: Cross-over study comparing aerosol delivery to the lungs using two nebulizers in 6 healthy male subjects: a vibrating-mesh nebulizer combined with a valved holding chamber (Aerogen Ultra®, Aerogen Ltd., Galway, Ireland) and a jet nebulizer connected to a corrugated tube (Opti-Mist Plus Nebulizer®, ConvaTec, Bridgewater, NJ). Nebulizers were filled with diethylenetriaminepentaacetic acid labelled with technetium-99 m (99mTc-DTPA, 2 mCi/4 mL). Pulmonary deposition of 99mTc-DTPA was measured by single-photon emission computed tomography combined with a low dose CT-scan (SPECT-CT). RESULTS: Pulmonary aerosol deposition from SPECT-CT analysis was six times increased with the vibrating-mesh nebulizer as compared to the jet nebulizer (34.1 ± 6.0% versus 5.2 ± 1.1%, p < 0.001). However, aerosol penetration expressed as the three-dimensional normalized ratio of the outer and the inner regions of the lungs was similar between both nebulizers. CONCLUSIONS: This study demonstrated the high superiority of the new system combining a vibrating-mesh nebulizer with a valved holding chamber to deliver nebulized particles into the lungs as comparted to a constant-output jet nebulizer with a corrugated tube.
Assuntos
Aerossóis/metabolismo , Pulmão/metabolismo , Administração por Inalação , Adulto , Aerossóis/administração & dosagem , Aerossóis/química , Estudos Cross-Over , Sistemas de Liberação de Medicamentos/métodos , Desenho de Equipamento/métodos , Voluntários Saudáveis , Humanos , Espaçadores de Inalação , Masculino , Nebulizadores e Vaporizadores , Tamanho da Partícula , Próteses e Implantes , Tecnécio/química , Tecnécio/metabolismo , Pentetato de Tecnécio Tc 99m/química , Pentetato de Tecnécio Tc 99m/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada por Raios X/métodosRESUMO
Pulmonary arterial hypertension (PAH) is an incurable cardiovascular disease characterized by high blood pressure in the arteries leading from the heart to the lungs. Over two million people in the USA are diagnosed with PAH annually and the typical survival rate is only 3 years after diagnosis. Current treatments are insufficient because of limited bioavailability, toxicity, and costs associated with approved therapeutics. Aerosol delivery of drugs is an attractive approach to treat respiratory diseases because it increases localized drug concentration while reducing systemic side effects. In this study, we developed phospholipid-based aerosol microparticles via spray drying consisting of the drug tacrolimus and the excipients dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol. The phospholipid-based spray-dried aerosol microparticles were shown to be smooth and spherical in size, ranging from 1 to 3 µm in diameter. The microparticles exhibited thermal stability and were amorphous after spray drying. Water content in the microparticles was under 10%, which will allow successful aerosol dispersion and long-term storage stability. In vitro aerosol dispersion showed that the microparticles could successfully deposit in the deep lung, as they exhibited favorable aerodynamic diameters and high fine particle fractions. In vitro dose-response analysis showed that TAC is nontoxic in the low concentrations that would be delivered to the lungs. Overall, this work shows that tacrolimus-loaded phospholipid-based microparticles can be successfully created with optimal physicochemical and toxicological characteristics.
Assuntos
Aerossóis/química , Descoberta de Drogas/métodos , Inaladores de Pó Seco/tendências , Microesferas , Fosfolipídeos/química , Células A549 , Administração por Inalação , Aerossóis/administração & dosagem , Aerossóis/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Inaladores de Pó Seco/métodos , Excipientes/administração & dosagem , Excipientes/química , Excipientes/metabolismo , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Tamanho da Partícula , Fosfolipídeos/administração & dosagem , Fosfolipídeos/metabolismo , Resultado do TratamentoRESUMO
Particles can be delivered to the respiratory tract of animals using various techniques. Inhalation mimics environmental exposure but requires large amounts of aerosolized NPs over a prolonged dosing time, varies in deposited dose among individual animals, and results in nasopharyngeal and fur particle deposition. Although less physiological, intratracheal (IT) instillation allows quick and precise dosing. Insufflation delivers particles in their dry form as an aerosol. We compared the distribution of neutron-activated 141CeO2 nanoparticles (5 mg/kg) in rats after (1) IT instillation, (2) left intrabronchial instillation, (3) microspraying of nanoceria suspension and (4) insufflation of nanoceria dry powder. Blood, tracheobronchial lymph nodes, liver, gastrointestinal tract, feces and urine were collected at 5 min and 24 h post-dosing. Excised lungs from each rat were dried at room temperature while inflated at a constant 30 cm water pressure. Dried lungs were then sliced into 50 pieces. The radioactivity of each lung piece and other organs was measured. The evenness index (EI) of each lung piece was calculated [EI = (µCi/mgpiece)/(µCi/mglung)]. The degree of EI value departure from 1.0 is a measure of deposition heterogeneity. We showed that the pulmonary distribution of nanoceria differs among modes of administration. Dosing by IT or microspraying resulted in similar spatial distribution. Insufflation resulted in significant deposition in the trachea and in more heterogeneous lung distribution. Our left intrabronchial instillation technique yielded a concentrated deposition into the left lung. We conclude that animal dosing techniques and devices result in varying patterns of particle deposition that will impact biokinetic and toxicity studies.