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Nanoparticles are extensively studied for drug delivery and are proving to be effective in drug delivery and the diagnostic field. Drug delivery to lungs has its advantages over other routes of administration. Inhalable powders consisting of nanoparticles are gaining much interest in respiratory research and clinical therapy. Particle engineering technique is a key factor to develop inhalable formulations that can successfully deliver drug with improved therapeutic effect and enhanced targeting. Inhalable nanoparticles in the solid-state dry powders for targeted pulmonary delivery offer unique advantages and are an exciting new area of research. Nasal delivery of inhalable nanoparticulate powders is gaining research attention recently, particularly in vaccine applications, systemic drug delivery in the treatment of pain, and non-invasive brain targeting. Fundamental aspects and recent advancements along with future prospects of inhalable powders consisting of nanoparticles in the solid-state for respiratory delivery are presented.

Targeted pulmonary delivery facilitates the direct application of bioactive materials to the lungs in a controlled manner and provides an exciting platform for targeting magnetic nanoparticles (MNPs) to the lungs. Iron oxide MNPs remotely heat in the presence of an alternating magnetic field (AMF) providing unique opportunities for therapeutic applications such as hyperthermia. In this study, spray drying was used to formulate magnetic nanocomposite microparticles ("MnMs") consisting of iron oxide MNPs and d-mannitol. The physicochemical properties of these MnMs were evaluated and the in vitro aerosol dispersion performance of the dry powders was measured by the Next Generation Impactor(®). For all powders, the mass median aerosol diameter (MMAD) was <5μm and deposition patterns revealed that MnMs could deposit throughout the lungs. Heating studies with a custom AMF showed that MNPs retain excellent thermal properties after spray drying into composite dry powders, with specific absorption ratios (SAR)>200W/g, and in vitro studies on a human lung cell line indicated moderate cytotoxicity of these materials. These inhalable composites present a class of materials with many potential applications and pose a promising approach for thermal treatment of the lungs through targeted pulmonary administration of MNPs.

LTx in children with CF remains controversial. The UNOS database was queried from 1987 to 2013 for CF patients <18 yr of age at time of transplant. PCHR model was used to quantify hazard of mortality. 489 recipients were included in the survival analysis. The hazard function of post-transplant mortality was plotted over attained age to identify age window of highest risk, which was 16-20 yr. Unadjusted PCHR model revealed ages immediately after the high-risk window were characterized by lower hazard of mortality (HR = 0.472; 95% CI = 0.302, 0.738; p = 0.001). After adjusting for potential confounders, the decline in mortality hazard immediately after the high-risk window remained statistically significant (HR = 0.394; 95% CI: 0.211, 0.737; p = 0.004). Hazard of mortality in children with CF after LTx was highest between 16 and 20 yr of attained age and declined thereafter.

Introduction: The number of pulmonary diseases that are effectively treated by aerosolized medicine continues to grow. Areas covered: These diseases include chronic obstructive pulmonary disease (COPD), lung inflammatory diseases (e.g., asthma) and pulmonary infections. Dry powder inhalers (DPIs) exhibit many unique advantages that have contributed to the incredible growth in the number of DPI pharmaceutical products. To improve the performance, there are a relatively large number of DPI devices available for different inhalable powder formulations. The relationship between formulation and inhaler device features on performance of the drug-device combination product is critical. Aerosol medicine products are drug-device combination products. Device design and compatibility with the formulation are key drug-device combination product aspects in delivering drugs to the lungs as inhaled powders. In addition to discussing pulmonary diseases, this review discusses DPI devices, respirable powder formulation and their interactions in the context of currently marketed DPI products used in the treatment of COPD, asthma and pulmonary infections. Expert opinion: There is a growing line of product options available for patients in choosing inhalers for treatment of respiratory diseases. Looking ahead, combining nanotechnology with optimized DPI formulation and enhancing device design presents a promising future for DPI development.

Rationale: Impact of pulmonary hypertension (PH) on survival in cystic fibrosis (CF) remains unclear. Objectives: To determine influence of PH on survival in the CF population. Methods: The UNOS database was queried from 1987 to 2013 to identify first-time lung transplant candidates who were tracked from wait list entry date until death or censoring to determine influence of PH. Using right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mmHg and severe ≥ 35 mmHg. Measurements and Main Results: Of 2781 CF patients, 2100 were used for univariate analysis, 764 for Kaplan-Meier (KM) survival function, 687 for multivariate Cox models, and 576 (mild PH) and 132 (severe PH) for propensity score matching, respectively. Univariate analysis with KM functions found significant differences in survival for mild PH (HR = 1.747, 95% CI: 1.387, 2.201, p < 0.001) and severe PH (HR = 2.299, 95% CI: 1.639, 3.225, p < 0.001). Further assessment by multivariate Cox models identified significant risk for death for mild PH (HR = 1.757, 95% CI: 1.367, 2.258, p < 0.001) and severe PH (HR = 2.284, 95% CI: 1.596, 3.268, p < 0.001). Propensity score matching confirmed the risk for death for mild PH (HR = 1.919, 95% CI: 1.290, 2.85, p = 0.001) and severe PH (HR = 4.167, 95% CI: 1.709, 10.157, p = 0.002). Conclusions: The manifestation of PH is associated with significantly increased risk for death in CF patients with advanced lung disease.

Inhalable lung surfactant-based carriers composed of synthetic phospholipids, dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG), along with paclitaxel (PTX), were designed and optimized as respirable dry powders using organic solution co-spray-drying particle engineering design. These materials can be used to deliver and treat a wide variety of pulmonary diseases with this current work focusing on lung cancer. In particular, this is the first time dry powder lung surfactant-based particles have been developed and characterized for this purpose. Comprehensive physicochemical characterization was carried out to analyze the particle morphology, surface structure, solid-state transitions, amorphous character, residual water content, and phospholipid bilayer structure. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy. PTX loading was high, as quantified using UV-VIS spectroscopy, and sustained PTX release was measured over weeks. In vitro cellular characterization on lung cancer cells demonstrated the enhanced chemotherapeutic cytotoxic activity of paclitaxel from co-spray-dried DPPC/DPPG (co-SD DPPC/DPPG) lung surfactant-based carrier particles and the cytotoxicity of the particles via pulmonary cell viability analysis, fluorescent microscopy imaging, and transepithelial electrical resistance (TEER) testing at air-interface conditions. In vitro aerosol performance using a Next Generation Impactor™ (NGI™) showed measurable powder deposition on all stages of the NGI and was relatively high on the lower stages (nanometer aerodynamic size). Aerosol dispersion analysis of these high-performing DPIs showed mass median diameters (MMADs) that ranged from 1.9 to 2.3 μm with excellent aerosol dispersion performance as exemplified by high values of emitted dose, fine particle fractions, and respirable fractions.

Dry powder inhalation aerosols of antibiotic drugs (a first-line aminoglycoside, tobramycin, and a first-line macrolide, azithromycin) and a sugar alcohol mucolytic agent (mannitol) as co-spray dried (co-SD) particles at various molar ratios of drug:mannitol were successfully produced by organic solution advanced co-spray drying from dilute solute concentration. These microparticulate/nanoparticulate aerosols consisting of various antibiotic drug:mannitol molar ratios were rationally designed with a narrow and unimodal primary particle size distribution, spherical particle shape, relatively smooth particle surface, and very low residual water content to minimize the interparticulate interactions and enhance in vitro aerosolization. These microparticulate/nanoparticulate inhalation powders were high-performing aerosols as reflected in the aerosol dispersion performance parameters of emitted dose, fine particle fraction (FPF), respirable fraction (RF), and mass median aerodynamic diameter (MMAD). The glass transition temperature (Tg ) values were significantly above room temperature, which indicated that the co-SD powders were all in the amorphous glassy state. The Tg values for co-SD tobramycin:mannitol powders were significantly lower than those for co-SD azithromycin:mannitol powders. The interplay between aerosol dispersion performance parameters and Tg was modeled where higher Tg values (i.e., more ordered glass) were correlated with higher values in FPF and RF and lower values in MMAD. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Abstract Background: The purpose was to design and characterize inhalable microparticulate/nanoparticulate dry powders of mannitol with essential particle properties for targeted dry powder delivery for cystic fibrosis mucolytic treatment by dilute organic solution spray drying, and, in addition, to tailor and correlate aerosol dispersion performance delivered as dry powder inhalers based on spray-drying conditions and solid-state physicochemical properties. Methods: Organic solution advanced spray drying from dilute solution followed by comprehensive solid-state physicochemical characterization and in vitro dry powder aerosolization were used. Results: The particle size distribution of the spray-dried (SD) powders was narrow, unimodal, and in the range of ∼500 nm to 2.0 μm. The particles possessed spherical particle morphology, relatively smooth surface morphology, low water content and vapor sorption (crystallization occurred at exposure above 65% relative humidity), and retention of crystallinity by polymorphic interconversion. The emitted dose, fine particle fraction (FPF), and respirable fraction (RF) were all relatively high. The mass median aerodynamic diameters were below 4 μm for all SD mannitol aerosols. Conclusion: The in vitro aerosol deposition stage patterns could be tailored based on spray-drying pump rate. Positive linear correlation was observed between both FPF and RF values with spray-drying pump rates. The interplay between various spray-drying conditions, particle physicochemical properties, and aerosol dispersion performance was observed and examined, which enabled tailoring and modeling of high aerosol deposition patterns.

Neurotoxicity is a significant complication of calcineurin inhibitor use, and posterior reversible encephalopathy syndrome has been reported. Limited data exist on the use of alternative immunosuppression regimens in the management of posterior reversible encephalopathy syndrome in transplant recipients.

We present the immunosuppression management strategy of a girl who underwent bilateral transplantation for cystic fibrosis 6 months earlier, then suddenly developed a grand mal seizure due to posterior reversible encephalopathy syndrome diagnosed by magnetic resonance imaging of the brain. In an effort to reduce her tacrolimus dose, an alternative immunosuppressant regimen combining tacrolimus and sirolimus was used.

After the modification of her immunosuppressant regimen, there was rapid clinical improvement with no further seizures. Her brain findings had resolved on magnetic resonance imaging 2 months later. Over the next 6 months, allograft function remained stable and surveillance transbronchial biopsies found no allograft rejection on the combined sirolimus and tacrolimus therapy.

Tacrolimus-associated neurotoxicity resolved in a lung transplant recipient with a combined tacrolimus and sirolimus regimen. This combined therapy appears to be an effective alternative for lung transplant recipients that allow them to receive the benefits of both drugs but at lower doses, which reduces the risk for adverse effects.

The purpose of this study was to systematically design pure antibiotic drug dry powder inhalers (DPIs) for targeted antibiotic pulmonary delivery in the treatment of pulmonary infections and comprehensively correlate the physicochemical properties in the solid-state and spray-drying conditions effects on aerosol dispersion performance as dry powder inhalers (DPIs). The two rationally chosen model antibiotic drugs, tobramycin (TOB) and azithromycin (AZI), represent two different antibiotic drug classes of aminoglycosides and macrolides, respectively. The particle size distributions were narrow, unimodal, and in the microparticulate/nanoparticulate size range. The SD particles possessed relatively spherical particle morphology, smooth surface morphology, low residual water content, and the absence of long-range molecular order. The emitted dose (ED%), fine particle fraction (FPF%) and respirable fraction (RF%) were all excellent. The MMAD values were in the inhalable range (<10μm) with smaller MMAD values for SD AZI powders in contrast to SD TOB powders. Positive linear correlations were observed between the aerosol dispersion performance parameter of FPF with increasing spray-drying pump rates and also with the difference between thermal parameters expressed as Tg-To (i.e. the difference between the glass transition temperature and outlet temperature) for SD AZI powders. The aerosol dispersion performance for SD TOB appeared to be influenced by its high water vapor sorption behavior (hygroscopicity) and the ratio of pump rate/To. Aerosol dispersion performance of SD powders were distinct for both antibiotic drug aerosol systems and also between different pump rates for each system.

The aim of this study was to design and develop respirable antibiotics moxifloxacin (MOXI) hydrochloride and ofloxacin (OFLX) microparticles and nanoparticles, and multifunctional antibiotics particles with or without lung surfactant 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced by advanced spray-drying particle engineering from an organic solution in closed mode (no water) from dilute solution. Scanning electron microscopy indicated that these particles had both optimal particle morphology and surface morphology, and the particle size distributions were suitable for pulmonary delivery. Comprehensive and systematic physicochemical characterization and in vitro aerosol dispersion performance revealed significant differences between these two fluoroquinolone antibiotics following spray drying as drug aerosols and as cospray-dried antibiotic drug: DPPC aerosols. Fourier transform infrared spectroscopy and confocal Raman microspectroscopy were employed to probe composition and interactions in the solid state. Spray-dried MOXI was rendered noncrystalline (amorphous) following organic solution advanced spray drying. This was in contrast to spray-dried OFLX, which retained partial crystallinity, as did OFLX:DPPC powders at certain compositions. Aerosol dispersion performance was conducted using inertial impaction with a dry powder inhaler device approved for human use. The present study demonstrates that the use of DPPC offers improved aerosol delivery of MOXI as cospray-dried microparticulate/nanoparticulate powders, whereas residual partial crystallinity influenced aerosol dispersion of OFLX and most of the compositions of OFLX:DPPC inhalation powders.

ABSTRACT Background: Venovenous (VV) extracorporeal membrane oxygenation (ECMO) applied through a single site with a bicaval dual-lumen (BCDL) catheter is a growing method of treatment of acute respiratory failure, thus animal models for research purposes are needed. We describe a rapid technique for the placement of the BCDL catheter for single-site VV ECMO in swine. Design: Prior to the application of single-site VV ECMO model with common crossbred piglets, BCDL catheters were placed using anatomical landmarks. Transthoracic echocardiography (TTE) with color Doppler was used to determine catheter placement. Final determination of catheter placement was confirmed by necropsy. Arterial blood gas and hemodynamic parameters were recorded at baseline and then hourly. The values are mean ± SD. Results: Using anatomical landmarks by positioning the BCDL catheter tip approximately 6.5 cm distal to the tip of the manubrium, cannulation was easily accomplished in five piglets with no positional adjustments of the catheter required. Cannula placement was confirmed with both TTE color Doppler and necropsy. Respiratory support was achieved with baseline and hourly measurements of pH 7.45 ± 0.03, 7.44 ± 0.07, 7.46 ± 0.05, 7.47 ± 0.06 (p = NS); PO2 86 ± 30 mmHg, 98 ± 30 mmHg, 94 ± 40 mmHg, and 79 ± 30 mmHg (p = NS); and PCO2 43 ± 3 mmHg, 44 ± 8 mmHg, 38 ± 5 mmHg, and 40 ± 4 mmHg (p = NS). Conclusions: Using anatomical landmarks for the placement of the BCDL catheter was rapid and effective in a swine model of VV ECMO, resulting in improved time efficiency for research.

No abstract given.

The aim of this paper was to investigate the effect of carboxymethyl chitosan anti-adhesion solution on prevention of postsurgical adhesion. Forty adult male Wistar rats were randomly divided into three groups: 0.9 % normal saline solution (group A), hyaluronic acid gels (group B) and carboxymethyl chitosan anti-adhesion solution (group C). The animals were treated with normal saline, hyaluronic acid gels or carboxymethyl chitosan anti-adhesion solution at the time of surgery. After 2 or 3 weeks, the degree of adhesions and histological effects were determined. The adhesions in groups B and C were significantly decreased, and the levels of TGF-β1 and hydroxyproline in group C were significantly lower than that in group A (P < 0.05). The histopathology in group C showed fewer inflammatory cells and fibroblasts. Carboxymethyl chitosan anti-adhesion solution can effectively prevent postoperative adhesion which is a promising drug delivery system in the context of postsurgical anti-adhesion.

Although pulmonary arterial hypertension (PAH) is a potential co-morbidity in cystic fibrosis (CF), right heart catheterization (RHC) is not commonly performed in this patient population until referral for lung transplantation.

An non-randomized observational pilot study was performed after an exercise protocol with an upright stationary bicycle was added to RHC performed in patients with CF undergoing evaluation for lung transplantation (LT).

Twelve consecutive patients with advanced lung disease due to CF referred for LT completed RHC with exercise protocol. Transthoracic echocardiography (TTE) prior to the RHC did not identify evidence of PAH or significant structural abnormalities; right and left ventricular systolic function were normal. non-randomized RHC in this same cohort found 75% (9/12) had PAH with an elevation of the mean pulmonary artery pressure (PAP) at rest with a mean (±SD) of 27.8 ± 4.9 mmHg that significantly increased during exercise to 47.2 ± 5.4 mmHg, p = 0.0025. For the last 6 patients, pulmonary vascular resistance was calculated during exercise, with a significant increase from 3.15 ± 0.3 to 12.8 ± 0.6 Wood Units (p = 0.0313) comparing measurements at rest to exercise.

RHC at rest and during exercise was safely and effectively performed in patients with CF referred for LT. Furthermore, central hemodynamic measurements found significant worsening of PAH during exercise in a small cohort of CF patients with advanced lung disease.

Respirable microparticles/nanoparticles of the antibiotics vancomycin (VCM) and clarithromycin (CLM) were successfully designed and developed by novel organic solution advanced spray drying from methanol solution. Formulation optimization was achieved through statistical experimental design of pump feeding rates of 25% (Low P), 50% (Medium P) and 75% (High P). Systematic and comprehensive physicochemical characterization and imaging were carried out using scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Karl Fischer titration (KFT), laser size diffraction (LSD), gravimetric vapor sorption (GVS), confocal Raman microscopy (CRM) and spectroscopy for chemical imaging mapping. These novel spray-dried (SD) microparticulate/nanoparticulate dry powders displayed excellent aerosol dispersion performance as dry powder inhalers (DPIs) with high values in emitted dose (ED), respirable fraction (RF), and fine particle fraction (FPF). VCM DPIs displayed better aerosol dispersion performance compared to CLM DPIs which was related to differences in the physicochemical and particle properties of VCM and CLM. In addition, organic solution advanced co-spray drying particle engineering design was employed to successfully produce co-spray-dried (co-SD) multifunctional microparticulate/nanoparticulate aerosol powder formulations of VCM and CLM with the essential lung surfactant phospholipid, dipalmitoylphosphatidylcholine (DPPC), for controlled release pulmonary nanomedicine delivery as inhalable dry powder aerosols. Formulation optimization was achieved through statistical experimental design of molar ratios of co-SD VCM:DPPC and co-SD CLM:DPPC. XRPD and DSC confirmed that the phospholipid bilayer structure in the solid-state was preserved following spray drying. Co-SD VCM:DPPC and co-SD CLM:DPPC dry powder aerosols demonstrated controlled release of antibiotic drug that was fitted to various controlled release mathematical fitting models. The Korsmeyer-Peppas model described the best data fit for all powders suggesting super case-II transport mechanism of controlled release. Excellent aerosol dispersion performance for all co-SD microparticulate/nanoparticulate DPIs was higher than the SD antibiotic drugs suggesting that DPPC acts as an aerosol performance enhancer for these antibiotic aerosol dry powders. Co-SD VCM:DPPC DPIs had higher aerosol dispersion parameters compared to co-SD CLM:DPPC which was related to differences in the physicochemical properties of VCM and CLM.

Pulmonary inhalation chemotherapeutic drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. Inhalable particles are advantageous in their ability to deliver drug deep in the lung by utilizing optimally sized particles and higher local drug dose delivery. In this work, spray-dried and co-spray dried inhalable lung surfactant-mimic PEGylated lipopolymers as microparticulate/nanoparticulate dry powders containing paclitaxel were rationally designed via organic solution advanced spray drying (no water) in closed-mode from dilute concentration feed solution. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) with varying PEG chain length were mixed with varying amounts of paclitaxel in methanol to produce co-spray dried microparticles and nanoparticles. Scanning electron microscopy showed the spherical particle morphology of the inhalable particles. Thermal analysis and X-ray powder diffraction confirmed the retention of the phospholipid bilayer structure in the solid-state following spray drying, the degree of solid-state molecular order, and solid-state phase transition behavior. The residual water content of the particles was very low as quantified analytically Karl Fisher titration. The amount of paclitaxel loaded into the particles was quantified which indicated high encapsulation efficiencies (43-99%). Dry powder aerosol dispersion performance was measured in vitro using the Next Generation Impactor (NGI) coupled with the Handihaler dry powder inhaler device and showed mass median aerodynamic diameters in the range of 3.4-7 μm. These results demonstrate that this novel microparticulate/nanoparticulate chemotherapeutic PEGylated phospholipid dry powder inhalation aerosol platform has great potential in lung cancer drug delivery.

Antisynthetase Syndrome is associated with interstitial lung disease in adult patients, but this has not been described in children.

A 13-year-old with interstitial lung disease due to Antisynthetase Syndrome and pulmonary arterial hypertension underwent emergent bilateral lung transplantation after a rapid clinical decline.

We present the clinical, radiographic, and histological findings of a child with interstitial lung disease due to Antisynthetase Syndrome.

In this systematic and comprehensive study, inhalation powders of the polypeptide immunosuppressant drug - cyclosporine A - for lung delivery as dry powder inhalers (DPIs) were successfully designed, developed, and optimized. Several spray drying pump rates were rationally chosen. Comprehensive physicochemical characterization and imaging was carried out using scanning electron microscopy, hot-stage microscopy, differential scanning calorimetry, powder X-ray diffraction, Karl Fischer titration, laser size diffraction, and gravimetric vapor sorption. Aerosol dispersion performance was conducted using a next generation impactor with a Food and Drug Administration-approved DPI device. These DPIs displayed excellent aerosol dispersion performance with high values in emitted dose, respirable fraction, and fine particle fraction. In addition, novel multifunctional inhalation aerosol powder formulations of cyclosporine A with lung surfactant-mimic phospholipids were also successfully designed and developed by advanced organic solution cospray drying in closed mode. The lung surfactantmimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-snglycero- 3-(phosphor-rac-1-glycerol). These cyclosporine A lung surfactant-mimic aerosol powder formulations were comprehensively characterized. Powder X-ray diffraction and differential scanning calorimetry confirmed that the phospholipid bilayer structure in the solid state was preserved following advanced organic solution spray drying in closed mode. These novel multifunctional inhalation powders were optimized for DPI delivery with excellent aerosol dispersion performance and high aerosol performance parameters.

Extracorporeal membrane oxygenation (ECMO) is an established therapy for primary graft dysfunction (PGD) in adults after lung transplant, while venovenous (VV) ECMO is an evolving therapy that can bridge patients to lung transplantation. This report describes a case of relatively quick improvement of grade 3 PGD, based on the PaO2/FIO2 (P/F) ratio, in a 17-year-old patient with cystic fibrosis who was bridged to lung transplantation with ambulatory VV ECMO and then received support with VV ECMO as a protective strategy during the initial phases of PGD after lung transplantation.