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Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development.

Long-term outcomes after lung transplantation remain poor mainly to the development of bronchiolitis obliterans syndrome (BOS). Currently, treatment options for BOS are very limited. Strategies to prevent and treat this complication include the use of aerosolized therapy with only cyclosporine used in patients to date. We describe the use of aerosolized tacrolimus in a lung transplant recipient with BOS. The patient demonstrated clinical improvement in functional capacity and oxygenation while receiving tacrolimus by nebulization. Further research is needed to study whether aerosolized tacrolimus is beneficial in lung transplant recipients with BOS.

STUDY OBJECTIVES:
The aim of this study was to determine the effects of an antibiotic strategy with intravenous (IV) continuous infusion of a β-lactam (CIBL) antibiotic and high-dose extended-interval (HDEI) tobramycin upon outcomes in patients with cystic fibrosis (CF) requiring invasive mechanical ventilation (IMV) for acute respiratory failure.

DESIGN:
The study was a retrospective review from June 1, 2006, to December 1, 2010, of patients at a university hospital with an adult CF center.

RESULTS:
The study population included adult CF patients requiring IMV. A total of 15 hospitalizations with IMV episodes were reviewed, involving 10 adult (31.4 ± 11.1 years) CF patients with end-stage lung disease (FEV(1) = 23.6 ± 7.8% predicted) and malnutrition (body mass index = 20.5 ± 3.1). Each patient survived to discharge and to follow-up 6 months later without the need for lung transplantation during the study period.

CONCLUSIONS:
A novel antibiotic strategy with a CIBL antibiotic and HDEI tobramycin improved survival in a small cohort of critically ill CF patients with end-stage lung disease and malnutrition requiring IMV.

The technical advances in microscopy imaging techniques have been applied to assess the fate of drugs for researching respiratory drug delivery in ex vivo and in vivo experiments. Recent developments in optical imaging (confocal microscopy, multi-photon microscopy, fluorescence imaging (FLI) and bioluminescence imaging (BLI)), and in non-optical imaging (magnetic resonance imaging (MRI), computing tomography (CT), positron-emission tomography (PET) and single-photon-emission computed tomography (SPECT)) are presented with their derivative medical devices. Novel microscopy have been utilized to address many biological questions in basic research and are becoming powerful clinical tools for non-invasive objective diagnosis, guided treatment, and monitoring therapies. The goal of this paper is to present recent advances in microscopy imaging techniques and to discuss their novel applications in respiratory drug delivery imaging.

The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres composed of poly-lactic-co-glycolic acid (PLGA) following a single intramuscular depot injection. The serum octreotide levels of three Oakwood Laboratories formulations and one Sandostatin LAR(®) formulation were compared. Three formulations of octreotide acetate-loaded PLGA microspheres were prepared by a solvent extraction and evaporation procedure using PLGA polymers with different molecular weights. The in vivo drug release study was conducted in male Sprague-Dawley rats. Blood samples were taken at predetermined time points for up to 70 days. Drug serum concentrations were quantified using a radioimmunoassay procedure consisting of radiolabeled octreotide. The three octreotide PLGA microsphere formulations and Sandostatin LAR(®) all showed a two-phase drug release profile (i.e., bimodal). The peak serum drug concentration of octreotide was reached in 30 min for all formulations followed by a decline after 6 h. Following this initial burst and decline, a second-release phase occurred after 3 days. This second-release phase exhibited sustained-release behavior, as the drug serum levels were discernible between days 7 and 42. Using pharmacokinetic computer simulations, it was estimated that the steady-state octreotide serum drug levels would be predicted to fall in the range of 40-130 pg/10 μL and 20-100 pg/10 μL following repeat dosing of the Oakwood formulations and Sandostatin LAR(®) every 28 days and every 42 days at a dose of 3 mg/rat, respectively.

Novel advanced spray-dried inhalable trehalose microparticulate/nanoparticulate powders with low water content were successfully produced by organic solution advanced spray drying from dilute solution under various spray-drying conditions. Laser diffraction was used to determine the volumetric particle size and size distribution. Particle morphology and surface morphology was imaged and examined by scanning electron microscopy. Hot-stage microscopy was used to visualize the presence/absence of birefringency before and following particle engineering design pharmaceutical processing, as well as phase transition behavior upon heating. Water content in the solid state was quantified by Karl Fisher (KF) coulometric titration. Solid-state phase transitions and degree of molecular order were examined by differential scanning calorimetry (DSC) and powder X-ray diffraction, respectively. Scanning electron microscopy showed a correlation between particle morphology, surface morphology, and spray drying pump rate. All advanced spray-dried microparticulate/nanoparticulate trehalose powders were in the respirable size range and exhibited a unimodal distribution. All spray-dried powders had very low water content, as quantified by KF. The absence of crystallinity in spray-dried particles was reflected in the powder X-ray diffractograms and confirmed by thermal analysis. DSC thermal analysis indicated that the novel advanced spray-dried inhalable trehalose microparticles and nanoparticles exhibited a clear glass transition (T(g)). This is consistent with the formation of the amorphous glassy state. Spray-dried amorphous glassy trehalose inhalable microparticles and nanoparticles exhibited vapor-induced (lyotropic) phase transitions with varying levels of relative humidity as measured by gravimetric vapor sorption at 25°C and 37°C.

STUDY OBJECTIVES:
The aim of this study was to determine if electrocardiographically synchronized, prospectively triggered multidetector row computed tomography (ECG-MDR-CT) angiography of the aorta can accurately predict the location of ectopic bronchial arteries in patients with cystic fibrosis (CF) with massive hemoptysis prior to bronchial artery embolization (BAE).

DESIGN AND SETTING:
The study was a prospective, observational study from September 1, 2009 to June 30, 2011, conducted at a university hospital with an adult CF center.

PATIENTS:
The study included adult CF patients with massive hemoptysis.

RESULTS:
A total of four adult patients (mean [± SD] age = 31.5 ± 7.9 years) with CF and massive hemoptysis underwent ECG-MDR-CT angiography. The location of the bleeding source was predicted in each case based on lung pathology observed on ECG-MDR-CT angiography. All four patients eventually required BAE without the need for conventional aortograms since the locations of the bronchial arteries were determined prior to the procedure. Review of lung pathology and arterial networks from the ECG-MDR-CT angiography data limited the number of selective catheterizations necessary to complete the procedures. BAE resulted in complete resolution of hemoptysis in three patients and successful mitigation of the bleeding in the fourth patient until lung transplantation was performed 1 week later.

CONCLUSIONS:
ECG-MDR-CT angiography accurately depicted bronchial artery anatomy in CF patients with massive hemoptysis and provided excellent preprocedural planning for BAE. The information provided by ECG-MDR-CT angiography of the aorta prior to conventional angiography decreased the BAE radiation dose and contrast volume and likely reduced table time.

OBJECTIVES:
Heart and lung transplant recipients are at risk for invasive fungal infections. This study evaluated the affect of single-agent antifungal prophylaxis with itraconazole on the rate of fungal infections after heart or lung transplant.

MATERIALS AND METHODS:
An observational, retrospective study was performed to evaluate the rate of fungal infections in heart and lung transplant recipients at the University of Kentucky Medical Center over 4.5 years who received itraconazole as a single therapy prophylaxis.

RESULTS:
Eighty-three recipients (42 heart, 41 lung) had an overall fungal infection incidence of 16.9% (14/83), while the incidence was 11.9% for heart recipients (5/42), and 22.0% for lung recipients (9/41).

CONCLUSIONS:
Single-agent use with itraconazole in heart or lung transplant recipients did not affect the rate of fungal infection as compared with previous reports. The incidence of fungal infection increased significantly within 3 months after escalation of immunosuppressant for treatment of acute rejection.

Co-encapsulated doxorubicin (DOX) and curcumin (CUR) in poly(butyl cyanoacrylate) nanoparticles (PBCA-NPs) were prepared with emulsion polymerization and interfacial polymerization. The mean particle size and mean zeta potential of CUR-DOX-PBCA-NPs were 133 ± 5.34 nm in diameter and +32.23 ± 4.56 mV, respectively. The entrapment efficiencies of doxorubicin and curcumin were 49.98 ± 3.32% and 94.52 ± 3.14%, respectively. Anticancer activities and reversal efficacy of the formulations and various combination approaches were assessed using 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide assay and western blotting. The results showed that the dual-agent loaded PBCA-NPs system had the similar cytotoxicity to co-administration of two single-agent loaded PBCA-NPs (DOX-PBCA-NPs+CUR-PBCA-NPs), which was slightly higher than that of the free drug combination (DOX+CUR) and one free drug/another agent loaded PBCA-NPs combination (DOX+CUR-PBCA-NPs or CUR+DOX-PBCA-NPs). The simultaneous administration of doxorubicin and curcumin achieved the highest reversal efficacy and down-regulation of P-glycoprotein in MCF-7/ADR cell lines, an MCF-7 breast carcer cell line resistant to adriamycin. Multidrug resistance can be enhanced by combination delivery of encapsulated cytotoxic drugs and reversal agents.

Therapeutic liposomal powders (i.e., lipospheres and proliposomes) for dry powder inhalation aerosol delivery, formulated with phospholipids similar to endogenous lung surfactant, offer unique opportunities in pulmonary nanomedicine while offering controlled release and enhanced stability. Many pulmonary diseases such as lung cancer, tuberculosis (TB), cystic fibrosis (CF), bacterial and fungal lung infections, asthma, and chronic obstructive pulmonary disease (COPD) could greatly benefit from this type of pulmonary nanomedicine approach that can be delivered in a targeted manner by dry powder inhalers (DPIs). These delivery systems may require smaller doses for efficacy, exhibit reduced toxicity, fewer side effects, controlled drug release over a prolonged time period, and increased formulation stability as inhaled powders. This state-of-the-art review presents these novel aspects in depth.

Airway complications occur frequently after lung transplantation. Bronchial stenosis is the most frequently encountered complication with the most severe form of that being the vanishing bronchus intermedius syndrome (VBIS). This rare disorder has never been reported in the pediatric population. This is the first report of VBIS in a pediatric patient, specifically a 16-yr-old male patient with cystic fibrosis whose course was complicated by a lower airway infection with Aspergillus fumigatus. The VBIS responded to bronchoscopic balloon dilation and placement of an airway stent.

Bronchiolitis obliterans syndrome (BOS) can have either an acute or chronic onset with an abrupt or insidious course. The diagnosis is typically achieved by physiological criteria with development of a sustained decline in expiratory flow rates for at least 3 weeks. We review the rapid development of acute BOS and bronchiectasis after respiratory syncytial virus infection in a lung transplant recipient, who had been doing well with normal pulmonary function for 3 years after lung transplantation.

The aims of this study were to examine the phase behavior of itraconazole-phenol mixtures and assess the feasibility of topical formulations of itraconazole using eutectic mixture systems. Itraconazole-phenol eutectic mixtures were characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, (1)H-nuclear magnetic resonance, and powder X-ray diffractometry. The skin permeation rates of itraconazole-phenol eutectic formulations were determined using Franz diffusion cells fitted with excised hairless mouse skins. Itraconazole can form eutectic compounds with phenol, and the hydrogen-bonding interactions between the carbonyl group in the itraconazole and hydroxyl group in phenol play a major role in itraconazole-phenol eutectic formation. Despite its high molecular weight and hydrophobicity, the drug (i.e., itraconazole) can be permeated through excised hairless mouse skins from itraconazole-phenol eutectic formulations. The findings of this study emphasize the capabilities of the topical application of itraconazole via external preparations.

BACKGROUND:
Lipid-laden macrophage (LLM) index could be potentially useful in assessing gastroesophageal (GE) reflux and aspiration after lung transplantation (LT) in patients with cystic fibrosis (CF).

METHODS:
A retrospective review of CF patients undergoing LT and/or laparoscopic Nissen fundoplication (LNF) from January 1, 2009, to December 31, 2011, was performed.

RESULTS:
Seventeen CF patients (nine women), mean (± SD) age 27.9 ± 7.5 yr, underwent LT with mean (± SD) pre-transplant FEV(1) of 20.9 ± 5.0% predicted. Seventy percentage (12/17) of patients underwent LNF without complications within 1-2 wk of LT. After LT, but prior to antireflux surgery, there was no significant difference in the mean (± SD) baseline LLM index (154 ± 41 vs. 146 ± 51, p = NS) between patients who were to undergo LNF and patients who did not. After LNF, a significant reduction in the mean (± SD) LLM index occurred following the procedure (154 ± 41-74 ± 54, p < 0.0001) while each patient reported resolution of symptoms of GE reflux, whereas 40% (2/5) undergoing only medical treatment reported resolution of symptoms.

CONCLUSIONS:
Significant reduction in the LLM index occurred after LNF in CF patients after LT that correlated with resolution of clinical symptoms of GE reflux.

Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray-drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan® software and were determined to be 600 nm to 1.2 μm in diameter, which is optimal for deep-lung alveolar penetration. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were performed to analyze solid-state transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers in the solid state of the particles. The residual water content of the particles was very low, as quantified analytically via Karl Fischer titration. The composition of the particles was confirmed using attenuated total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and confocal Raman microscopy (CRM), and chemical imaging confirmed the chemical homogeneity of the particles. The dry powder aerosol dispersion properties were evaluated using the Next Generation Impactor™ (NGI™) coupled with the HandiHaler® dry powder inhaler device, where the mass median aerodynamic diameter from 2.6 to 4.3 μm with excellent aerosol dispersion performance, as exemplified by high values of emitted dose, fine particle fraction, and respirable fraction. Overall, it was determined that the pump rates defined in the spray-drying process had a significant effect on the solid-state particle properties and that a higher pump rate produced the most optimal system. Advanced dry powder inhalers of inhalable lipopolymers for targeted dry powder inhalation delivery were successfully achieved.

The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.

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.

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.

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

MATERIALS AND METHODS:
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.

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

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.

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