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Anatomical and physiological changes alter airflow characteristics and aerosol distribution in the developing lung. Correlation between age and aerosol dosimetry is needed, specifically because youth are more susceptible to medication side effects. In this study, we estimate aerosol dosages (particle diameters of 1, 3, and 5 μ m) in a 3 month-old infant, a 6 year-old child, and a 36 year-old adult by performing whole lung subject-specific particle simulations throughout respiration. For 3 μ m diameter particles we estimate total deposition as 88, 73, and 66 % and the conducting versus respiratory deposition ratios as 4.0, 0.5, and 0.4 for the infant, child, and adult, respectively. Due to their lower tidal volumes and functional residual capacities the deposited mass is smaller while the tissue concentrations are larger in the infant and child subjects, compared to the adult. Furthermore, we find that dose cannot be predicted by simply scaling by tidal volumes. These results highlight the need for additional clinical and computational studies that investigate the efficiency of treatment, while optimizing dosage levels in order to alleviate side effects, in youth. [ABSTRACT FROM AUTHOR]

Purpose: Despite being the most prominent dosage form for topical ocular delivery, eye-drops have several well-recognized drawbacks. Addressing these limitations, in this work we introduce a novel method to accurately deliver ophthalmic medications to the surface of the eye at relatively low volume and low velocity. By aerosolizing a medicament and dispensing it in the form of a toroidal vortex, commonly known as a 'smoke ring', several major drawbacks associated with topical drug delivery can be avoided. Methods: A device capable of emitting a toroidal vortex was developed such that actuation force and aerosol loading could be modulated. Different solution formulations were tested for deposited dose on an in vitro eye. Results: It was found that the dose delivered to the surface of an in vitro eye was directly proportional to the velocity and the size of the droplets emitted from the device. With a dilute solution formulation (0.05% fluorescein sodium), doses could be reproducibly deposited by actuating the device at different velocities (from ~5 ng to ~18 ng per actuation). While a more concentrated solution of 0.5% fluorescein sodium, between 20 ng and 160 ng could be deposited depending on selected actuation velocity. And with the highest concentration, 5% fluorescein sodium, 1.15 +/− 0.075 μg was deposited. It was also shown that the amount of drug deposited onto the eye surface could be modulated by modulating the chamber fill time. Conclusion: Precise toroidal vortex based aerosol delivery may facilitate optimized administration of medicines to the surface of the eye. [ABSTRACT FROM AUTHOR]

Precise determination of concentration of gases, such as NO, in urban atmosphere is crucial in studying chemical reactions leading to secondary pollutants. In this study, a novel and sensitive yet simple and cost effective spectrometer was developed where two laser wavelengths and two parallel identical optical cavities were used. Monitoring of NO even in the presence of aerosol spectral interference was demonstrated. The intensity transmitted through one cavity, evacuated to 0.1 mbar, was designated as the reference signal ( I ) while that through the other cavity, sampling air at atmospheric pressure, was designated as sample signal ( I). Quasi-simultaneous measurements of these I and I were done for both laser wavelengths sequentially: one at 406.4 nm near the peak of the largest electronic transition of NO and the other at 446.9 nm, away from the peak yet exhibiting significant absorption. The addition of the second wavelength where NO has absorption was to ascertain the presence of aerosol scattering and compensate for it. Aerosol extinctions at both operating wavelengths were assumed to be the same, their ratio taken as unity for simplicity, and aerosol light extinction was retrieved. The spectrometer with average sampling interval of 5 s exhibited detection sensitivity of low parts per billion concentrations. [ABSTRACT FROM AUTHOR]

Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach delivering intraperitoneal chemotherapy by means of a pressurized aerosol. This study was conducted to evaluate the distribution pattern of doxorubicin in the abdominal cavity after PIPAC in a postmortem swine model. Methods: Doxorubicin was aerosolized through a Micropump© (MIP) into the peritoneal cavity of two swines at a pressure of 12 mm Hg CO and 32 °C. To measure the distribution of the drug, 9 different positions within the abdominal cavity were sampled. In-tissue doxorubicin penetration was evaluated using fluorescence microscopy on frozen thin sections. Results: A maximum of drug penetration was observed in the area around the MIP. The penetration in the small intestine reached a depth of 349 ± 65 µm. Penetration depth in the right upper abdomen and left upper abdomen were 349 ± 65 and 140 µm ± 26 µm, respectively. Distant areas to the MIP showed variable penetration rates between 50 and 150 µm. Conclusions: Doxorubicin reached all areas within the peritoneum. Highest penetration rates were measured in the area around the Micropump. Further studies are warranted to evaluate and optimize the distribution and penetration of cytotoxic agent into the tissue after PIPAC. [ABSTRACT FROM AUTHOR]

Oxygen therapy can be delivered using low-flow, intermediate-flow (air entrainment mask), or high-flow devices. Low/intermediate-flow oxygen devices have several drawbacks that cause critically ill patients discomfort and translate into suboptimal clinical results. These include limitation of the FiO2 (due to the high inspiratory flow often observed in patients with respiratory failure), and insufficient humidification and warming of the inspired gas. High-flow nasal cannula oxygenation (HFNCO) delivers oxygen flow rates of up to 60 L/min and over the last decade its effect on clinical outcomes has widely been evaluated, such as in the improvement of respiratory distress, the need for intubation, and mortality. Mechanisms of action of HFNCO are complex and not limited to the increased oxygen flow rate. The main aim of this review is to guide clinicians towards evidence-based clinical practice guidelines. It summarizes current knowledge about HFNCO use in ICU patients and the potential areas of uncertainties. For instance, it has been recently suggested that HFNCO could improve the outcome of patients with hypoxemic acute respiratory failure. In other settings, research is ongoing and additional evidence is needed. For instance, if intubation is required, studies suggest that HFNCO may help to improve preoxygenation and can be used after extubation. Likewise, HFNCO might be used in obese patients, or to prevent respiratory deterioration in hypoxemic patients requiring bronchoscopy, or for the delivery of aerosol therapy. However, areas for which conclusive data exist are limited and interventions using standardized HFNCO protocols, comparators, and relevant clinical outcomes are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Enhancement of intranasal sinus deposition involves nebulization of a drug superimposed by an acoustic airflow. We investigated the impact of fixed frequency versus frequency sweep acoustic airflow on the improvement of aerosolized drug penetration into maxillary sinuses. Methods: Fixed frequency and frequency sweep acoustic airflow were generated using a nebulizing system of variable frequency. The effect of sweep cycle and intensity variation was studied on the intranasal sinus deposition. We used a nasal replica created from CT scans using 3D printing. Sodium fluoride and gentamicin were chosen as markers. Results: Studies performed using fixed frequency acoustic airflow showed that each of maxillary sinuses of the nasal replica required specific frequency for the optimal aerosol deposition. Intranasal sinus drug deposition experiments under the effect of the frequency sweep acoustic airflow showed an optimal aerosol deposition into both maxillary sinus of the nasal replica. Studies on the effect of the duration of the sweep cycle showed that the shorter the cycle the better the deposition. Conclusions: We demonstrate the benefit of frequency sweep acoustic airflow on drug deposition into maxillary sinuses. However further in vivo studies have to be conducted since delivery rates cannot be obviously determined from a nasal replica. [ABSTRACT FROM AUTHOR]

Purpose: Unlike in the outpatient setting, delivery of aerosols to critically ill patients may be considered complex, particularly in ventilated patients, and benefits remain to be proven. Many factors influence aerosol delivery and recommendations exist, but little is known about knowledge translation into clinical practice.Methods: Two-week cross-sectional study to assess the prevalence of aerosol therapy in 81 intensive and intermediate care units in 22 countries. All aerosols delivered to patients breathing spontaneously, ventilated invasively or noninvasively (NIV) were recorded, and drugs, devices, ventilator settings, circuit set-up, humidification and side effects were noted.Results: A total of 9714 aerosols were administered to 678 of the 2808 admitted patients (24 %, CI95 22-26 %), whereas only 271 patients (10 %) were taking inhaled medication before admission. There were large variations among centers, from 0 to 57 %. Among intubated patients 22 % (n = 262) received aerosols, and 50 % (n = 149) of patients undergoing NIV, predominantly (75 %) inbetween NIV sessions. Bronchodilators (n = 7960) and corticosteroids (n = 1233) were the most frequently delivered drugs (88 % overall), predominantly but not exclusively (49 %) administered to patients with chronic airway disease. An anti-infectious drug was aerosolized 509 times (5 % of all aerosols) for nosocomial infections. Jet-nebulizers were the most frequently used device (56 %), followed by metered dose inhalers (23 %). Only 106 (<1 %) mild side effects were observed, despite frequent suboptimal set-ups such as an external gas supply of jet nebulizers for intubated patients.Conclusions: Aerosol therapy concerns every fourth critically ill patient and one-fifth of ventilated patients. [ABSTRACT FROM AUTHOR]

The administration of drugs to neonates poses significant challenges. The aim of this review was to provide insight into some of these challenges and resolutions that may be encountered with several of the most commonly used routes of administration and dosage forms in neonatal care, including oral, parenteral, transdermal, intrapulmonary, and rectal. Important considerations include fluctuations in stomach pH hours to years after birth, the logistics of setting up an intravenous infusion, the need for reduced particle size for aerosol delivery to the developing neonatal lung, and variation in perirectal venous drainage. Additionally, some of the recently developed technologies for use in neonatal care are described. While the understanding of neonatal drug delivery has advanced over the past several decades, there is still a deficiency of technologies and formulations developed specifically for this population. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficiency of a new technique for delivering aerosols to intubated infants that employs a new Y-connector, access port administration of a dry powder, and excipient enhanced growth (EEG) formulation particles that change size in the airways. Methods: A previously developed CFD model combined with algebraic correlations were used to predict delivery system and lung deposition of typical nebulized droplets (MMAD = 4.9 μm) and EEG dry powder aerosols. The delivery system consisted of a Y-connector [commercial (CM); streamlined (SL); or streamlined with access port (SL-port)] attached to a 4-mm diameter endotracheal tube leading to the airways of a 6-month-old infant. Results: Compared to the CM device and nebulized aerosol, the EEG approach with an initial 0.9 μm aerosol combined with the SL and SL-port geometries reduced device depositional losses by factors of 3-fold and >10-fold, respectively. With EEG powder aerosols, the SL geometry provided the maximum tracheobronchial deposition fraction (55.7%), whereas the SL-port geometry provided the maximum alveolar (67.6%) and total lung (95.7%) deposition fractions, respectively. Conclusions: Provided the aerosol can be administered in the first portion of the inspiration cycle, the proposed new method can significantly improve the deposition of pharmaceutical aerosols in the lungs of intubated infants. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the novel application of nano X-ray computed tomography (NanoXCT) for visualizing and quantifying the internal structures of pharmaceutical particles. Methods: An Xradia NanoXCT-100, which produces ultra high-resolution and non-destructive imaging that can be reconstructed in three-dimensions (3D), was used to characterize several pharmaceutical particles. Depending on the particle size of the sample, NanoXCT was operated in Zernike Phase Contrast (ZPC) mode using either: 1) large field of view (LFOV), which has a two-dimensional (2D) spatial resolution of 172 nm; or 2) high resolution (HRES) that has a resolution of 43.7 nm. Various pharmaceutical particles with different physicochemical properties were investigated, including raw (2-hydroxypropyl)-beta-cyclodextrin (HβCD), poly (lactic-co-glycolic) acid (PLGA) microparticles, and spray-dried particles that included smooth and nanomatrix bovine serum albumin (BSA), lipid-based carriers, and mannitol. Results: Both raw HβCD and PLGA microparticles had a network of voids, whereas spray-dried smooth BSA and mannitol generally had a single void. Lipid-based carriers and nanomatrix BSA particles resulted in low quality images due to high noise-to-signal ratio. The quantitative capabilities of NanoXCT were also demonstrated where spray-dried mannitol was found to have an average void volume of 0.117 ± 0.247 μm and average void-to-material percentage of 3.5%. The single PLGA particle had values of 1993 μm and 59.3%, respectively. Conclusions: This study reports the first series of non-destructive 3D visualizations of inhalable pharmaceutical particles. Overall, NanoXCT presents a powerful tool to dissect and observe the interior of pharmaceutical particles, including those of a respirable size. [ABSTRACT FROM AUTHOR]

This study investigated the ability of aerosolized bovine lactoferrin (bLF) to protect the lungs from injury induced by chronic hyperoxia. Female CD-1 mice were exposed to hyperoxia (FiO = 80 %) for 7 days to induce lung injury and fibrosis. The therapeutic effects of bLF, administered via an aerosol delivery system, on the chronic lung injury induced by this period of hyperoxia were measured by bronchoalveolar lavage, lung histology, cell apoptosis, and inflammatory cytokines in the lung tissues. After exposure to hyperoxia for 7 days, the survival of the mice was significantly decreased to 20 %. The protective effects of bLF against hyperoxia were further confirmed by significant reductions in lung edema, total cell numbers in bronchoalveolar lavage fluid, inflammatory cytokines (IL-1β and IL-6), pulmonary fibrosis, and apoptotic DNA fragmentation. The aerosolized bLF protected the mice from oxygen toxicity and increased the survival fraction to 66.7 % in the hyperoxic model. The results support the use of an aerosol therapy with bLF in intensive care units to reduce oxidative injury in patients with severe hypoxemic respiratory failure or chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Purpose: Improvement of clinical outcome in patients with sinuses disorders involves targeting delivery of nebulized drug into the maxillary sinuses. We investigated the impact of nebulization conditions (with and without 100 Hz acoustic airflow), particle size (9.9 μm, 2.8 μm, 550 nm and 230 nm) and breathing pattern (nasal vs. no nasal breathing) on enhancement of aerosol delivery into the sinuses using a realistic nasal replica developed by our team. Methods: After segmentation of the airways by means of high-resolution computed tomography scans, a well-characterized nasal replica was created using a rapid prototyping technology. A total of 168 intrasinus aerosol depositions were performed with changes of aerosol particle size and breathing patterns under different nebulization conditions using gentamicin as a marker. Results: The results demonstrate that the fraction of aerosol deposited in the maxillary sinuses is enhanced by use of submicrometric aerosols, e.g. 8.155 ± 1.476 mg/L of gentamicin in the left maxillary sinus for the 2.8 μm particles vs. 2.056 ± 0.0474 for the 550 nm particles. Utilization of 100-Hz acoustic airflow nebulization also produced a 2- to 3-fold increase in drug deposition in the maxillary sinuses (e.g. 8.155 ± 1.476 vs. 3.990 ± 1.690 for the 2.8 μm particles). Conclusions: Our study clearly shows that optimum deposition was achieved using submicrometric particles and 100-Hz acoustic airflow nebulization with no nasal breathing. It is hoped that our new respiratory nasal replica will greatly facilitate the development of more effective delivery systems in the future. [ABSTRACT FROM AUTHOR]

Purpose: Deposition of drug emitted from two commercially available inhalers was measured in an in vitro child oral airway model and compared to existing in vivo data to examine the ability of the child model to replicate in vivo deposition. Methods: In vitro deposition of drug from a QVAR® pressurized metered dose inhaler (pMDI) and Pulmicort® Turbuhaler® dry powder inhaler (DPI) in an Idealized Child Throat () and downstream filter was measured using UV spectroscopy and simulated realistic breathing profiles. Potential effects of ambient relative humidity ranging from 10% to 90% on deposition were also considered. Results: In vitro QVAR pMDI deposition in the idealized mouth-throat at 50% RH (39.2 ± 2.3% of delivered dose) compared well ( p > 0.05) with in vivo extrathoracic deposition in asthmatic children age 8 to 14 (45.8 ± 12.3%). In vitro Turbuhaler DPI deposition in the idealized mouth-throat at 50% RH (69.0 ± 1.5%) matched in vivo extrathoracic deposition ( p > 0.05) in 6 to 16 year old children with cystic fibrosis (70.4 ± 21.2%). The effects of ambient humidity were found to be insignificant for Turbuhaler and minor for QVAR. Conclusions: The Idealized Child Throat successfully mimics in vivo deposition data in school age children for the inhalers tested, and may provide a standard platform for optimizing pediatric treatment with inhaled pharmaceutical aerosols. [ABSTRACT FROM AUTHOR]

Purpose: To describe the practice, knowledge and beliefs about aerosol therapy during mechanical ventilation in an international sample of physicians working in intensive care units (ICU). Methods: A self-administered survey was emailed to physicians who worked regularly in ICUs. The physicians were identified from the databases of the European and French societies of intensive care medicine and the REVA network. Results: Of the 1,192 responses (15 % response rate), 854 were analyzed. Of the respondents, who represented 611 departments in 70 countries, 99 % reported using aerosol therapy during mechanical ventilation (including non-invasive), 43 % exclusively used nebulizers and 55 % also used metered dose inhalers. Nebulization relied on jet, ultrasonic and vibrating mesh nebulizers (55 %, 44 % and 14 % of respondents, respectively). Bronchodilators and steroids were the most frequently delivered drugs, and 80 % of respondents had a positive opinion concerning nebulized colistin and 30 % reported the use of nebulized antibiotics at least every other month. During nebulization, ventilator settings were never changed by 77 % of respondents, 65 % reported placing a filter on the expiratory limb, and of these 28 % never changed it. Only 22 % of respondents using heated humidifiers reported turning them off during nebulization. Specific knowledge about droplet size and nebulization yield was poor. A majority of respondents (87 %) thought that ultrasonic nebulizers outperform jet nebulizers, while 69 % had no opinion concerning mesh nebulizers. Conclusions: Aerosol therapy during mechanical ventilation is used by over 95 % of intensivists, mostly for bronchodilator and steroid administration, but also frequently for antibiotics. The current scientific knowledge about optimal implementation seemed infrequently applied, suggesting the need for educational programs and research focusing on a better bench-to-bedside transfer of knowledge. [ABSTRACT FROM AUTHOR]

Conventional radiotherapy or chemotherapy for the long-term survival of patients with lung cancer is still difficult for treatment in metastatic and advanced tumors. Therefore, the safe and effective approaches to the treatment of lung cancer are needed. In this study, the effect of delivered eukaryotic translation initiation factor 4E (elF4E)-binding protein 1 (4E-BP1) on lung cancer progression was evaluated. Recombinant adeno-associated virus (rAAV)-M3/4E-BP1 was delivered into 6-week-old K-rasLA1 lung cancer model mice through a nose-only inhalation system twice a week for 4 weeks. Long-term repeated delivery of 4E-BP1 effectively reduced tumor progression in the lungs of K-rasLA1 mice. Reduction of elF4E by overexpression of 4E-BP1 resulted in suppression of cap-dependent protein expression of basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF). In addition, delivered 4E-BP1 inhibited the proliferation of lung cancer cells in K-rasLA1 mice model. Our results suggest that long-term repeated viral delivery of 4E-BP1 may provide a useful tool for designing lung cancer treatment. [ABSTRACT FROM AUTHOR]

Indacaterol inhalation powder (Onbrez® Breezhaler®) is a long-acting, selective ß2-adrenoceptor agonist that is indicated for the maintenance bronchodilator treat-ment of airflow obstruction in adults with chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of indacaterol 150 and 300 pg once daily in adults with moderate to severe COPD, as well as reviewing indacaterol's pharmacological properties and results of a cost-utility analysis. Indacaterol has a fast onset of action after the first dose and is effective over 24 hours, allowing for once-daily administration. In short-term trials (≤21 days) in patients with COPD, once-daily indacaterol 150 or 300 μg significantly improved lung function, exercise endurance and lung hyperinflation relative to placebo. In large, longer-term clinical studies (12 weeks to 1 year) in patients with moderate to severe COPD, once-daily indacaterol 150 or 300 μg improved lung function (primary endpoint) significantly more than placebo, and improvements were significantly greater than twice-daily formoterol 12μg or salmeterol 50 μg, and noninferior to once-daily tiotropium bromide 18μg (all agents were ad-ministered via inhalation). Overall, indacaterol improved dyspnoea, use of rescue medication and general health status significantly more than placebo, salmeterol or tiotropium bromide, and the degree of improvement in these endpoints was similar to or greater than that achieved with formoterol. Improvements were sustained over the long term (1 year), with no evidence of tolerance. Combination therapy with indacaterol plus tiotropium bromide improved lung function, dyspnoea, rescue medication use and general health status significantly more than tiotropium bromide alone in patients with moderate to severe COPD. Indacaterol is generally well tolerated when used alone or in combination with tiotropium bromide in patients with COPD and has not been associated with any safety issues. The most common adverse event in clinical trials was COPD worsen-ing, which occurred more commonly with placebo than indacaterol. Indacaterol was not associated with an increased risk of cardiovascular adverse events. In a cost-utility analysis from a German healthcare payer perspective, once-daily indacaterol 150μg was dominant (i.e. more effective with lower total costs) to once-daily tiotropium bromide 18pg and twice-daily salmeterol 50 μg in the treatment of patients with COPD. In conclusion, indacaterol provides a valuable option for the maintenance treatment of adults with COPD. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a respiratory syndrome affecting more than 80 million people worldwide and is estimated to become the third-leading cause of death worldwide by 2030. A standard-of-care ap-proach to COPD treatment is multifaceted, including pharmacological and non-pharmacological therapies, yet the optimum combination among many bronchodilator possibilities remains unclear. We discuss the evidence for ef-fectiveness of combination bronchodilator and inhaled corticosteroid ther-apy in affecting the minimal clinically important difference for these agents in COPD. We propose an approach to the rational use of these combinations that favours the combination of long-acting β-adrenergic agents with long-acting anticholinergic agents in lieu of any other bronchodilators whenever possible. We suggest that, to better detect effects of disease modification in COPD, future studies of combination bronchodilator effectiveness should emphasize endpoints other than short-term change in post-bronchodilator forced expiratory volume in 1 second (FEV1). [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a highly heterogeneous, progressive inflammatory disease that imposes considerable economic and health-care burdens on society, with the disease predicted to remain a leading cause of mor-bidity and mortality worldwide in the future. Current pharmacological treatment can improve symptoms of the disease, but not progression. Global Initiative for Chronic Obstructive Lung Disease guidelines recommend that patients with moderate COPD should use one or more long-acting bronchodilators (e.g. a long-acting ß2-agonist) as required and, for those with severe and very severe disease who are experiencing repeated COPD exacerbations, an inhaled corticosteroid should be added as required. Budesonide/formoterol Turbuhaler® (Symbicort® Turbuhaler®) is a dry powder inhaler (DPI) that combines these two classes of drugs in a single inhaler, thereby making administration easier and more convenient. Budesonide/formoterol Turbuhaler® (delivered dose 320 μg/9 μg) is recommended for the symptomatic treatment of adult patients with severe COPD (forced expiratory volume in 1 second <50% of predicted value) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodi-lators. This article reviews the pharmacological properties and clinical use of budeso-nide/formoterol Turbuhaler® in adult patients with moderate to severe COPD. Budesonide/formoterol Turbuhaler® (320 μg/9 μg twice daily) was effective and well tolerated in adult patients with moderate to severe COPD participating in large, multicentre trials of up to 12 months' duration. Budesonide/formoterol Turbuhaler® improved lung function, exacerbation rates, COPD symptom scores and health status from baseline to a significantly greater extent than placebo and, in general, than the individual monotherapies in these trials. Moreover, as re-flected in the faster onset of action of formoterol than salmeterol, budesonide/ formoterol Turbuhaler® was more effective than salmeterol/fluticasone propio-nate DPI at improving the patient's ability to perform morning activities in a short-term study. In the 12-week CLIMB trial, adding budesonide/formoterol Turbuhaler® to inhaled tiotropium bromide therapy was significantly more effec-tive than adding placebo to tiotropium bromide therapy. Thus, inhaled budesonide/ formoterol, either alone or as add-on therapy to other medications, continues to be a useful option for the management of COPD. [ABSTRACT FROM AUTHOR]

Purpose: Despite the advances in asthma therapeutics, there are few data on the use and determinants of anti-asthmatic drugs in the general population of children. This study describes the use of asthma medications among children in the general population and in children with current asthma, living in a large urban center in Brazil. Methods: A population-based cross-sectional survey, aimed at analyzing asthma determinants, was conducted with 1,382 children aged 4-11 years, between February and May 2006, in Salvador, Brazil. At baseline, an extensive questionnaire was applied, including questions about the use of asthma medications in the last 12 months. Results: In all studied children ( n = 1,382) aged 4-11 years, oral beta2-agonists were the drugs most frequently used (9.8%), followed by short-acting inhaled beta2-agonists (4.3%) and systemic corticosteroids (1.6%). Anti-asthmatic drug use was higher among males than females, and it significantly decreased with age in both genders. A total of 312 children (22.6%) reported current asthma, and 62% of them were not being treated with any anti-asthmatic drugs. Of all those who reported following a certain type of treatment, 20% used oral beta2-agonists alone; 6.1%, short-acting inhaled beta2-agonists alone; and 4.8%, a combination of both drugs. Anti-asthmatic drug use did not differ according to socioeconomic status, except for the use of inhaled beta2-agonists and systemic corticosteroids. Conclusions: An overwhelming majority of asthmatic children were not using long-term medications for asthma, in particular inhaled corticosteroids, regardless of the severity of their disease. This result points to the deficiencies of the Brazilian public health system in recognizing this important pharmacological need for child care and thereby limiting the access of these children to a group of efficacious, available, and low risk therapeutic medications. [ABSTRACT FROM AUTHOR]

Therapeutic aerosol bioengineering (TAB) of Mycobacterium tuberculosis ( MTb) therapies using inhalable microparticles offers a unique opportunity to target drugs to the site of infection in the alveolar macrophages, thereby increasing dosing in the lungs and limiting systemic exposure to often toxic drugs. Previous work by us used sophisticated, high content analysis to design the optimal poly(lactide-co-glycolic) acid (PLGA) microparticle for delivery of drugs to alveolar macrophages. Herein, we applied this technology to three different anti- MTb drugs. These formulations were then tested for encapsulation efficiency, drug-release, in vitro killing against MTb and aerosol performance. Methods for encapsulating each of the drugs in the PLGA microparticles were successfully developed and found to be capable of controlling the release of the drug for up to 4 days. The efficacy of each of the encapsulated anti- MTb drugs was maintained and in some cases enhanced post-encapsulation. A method of processing these drug-loaded microparticles for inhalation using standard dry powder inhaler devices was successfully developed that enabled a very high respirable dose of the drug to be delivered from a simple dry powder inhaler device. Overall, TAB offers unique opportunities to more effectively treat MTb with many potential clinical and economic benefits resulting. [ABSTRACT FROM AUTHOR]

We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients. [ABSTRACT FROM AUTHOR]

Large surveillance studies or phase IV clinical studies of long-acting β-agonists (LABA) compared with placebo in asthma patients using variable (from nil to regular) doses of inhaled corticosteroids (ICS) have raised the issue of mortality risk in patients with asthma taking regular LABA. There have been a number of meta-analyses and systematic reviews that have examined the risk of LABA in asthma patients, and the general conclusion is that LABA added to ICS reduces asthma-related hospitalizations compared with ICS alone and there is no statistical increase in mortality. However. LABA without ICS do increase mortality risk in asthma. All reviews and analyses show a greater number of LABA deaths, but not all are statistically significant. A recent meta-analysis found LABA with concomitant ICS had a higher mortality rate in asthma than ICS alone. The flaw in the study is the higher doses of ICS in the control arms, but the implicit message remains: the essential need for enough ICS to control airway inflammation. We suggest that the pragmatic solution is to have LABA only available in the same device as ICS for asthma treatment. We do not think that a study comparing the safety of LABA plus ICS versus ICS alone in asthma is necessary. If such a study is conducted, the measurement of morbidity from increased doses of ICS is an essential design consideration. Furthermore, the critical focus in asthma management should not be forgotten--education of health professionals and the community of the critical role of ICS, and the need for good communication between health professionals and the asthma patient to facilitate good asthma control. The same arguments apply to the asthma-with- chronic obstructive pulmonary disease overlap syndrome in older patients. There is an urgent need to provide medical practitioners with the capability to diagnose the overlap syndrome. [ABSTRACT FROM AUTHOR]

Purpose: This study compares the in vivo relative lung bioavailability of Hydrofluoroalkane (HFA) Seretide delivered via unprimed and unwashed Aerochamber Plus (AP) or Volumatic (VM) spacers, a integrated breath-actuated vortex Synchro-Breathe (SB) device and an Evohaler pMDI (EH) device using adrenal suppression and early fall in serum potassium (K) as surrogates for respirable dose. Methods: Seventeen healthy volunteers completed this randomised double-blind, double-dummy crossover study. Single doses of placebo/Seretide 250 (total dose ex valve fluticasone 2000 mcg/salmeterol 200 mcg) were administered via the devices. Overnight urinary cortisol/creatinine (OUCC) and serum K were measured at baseline and after each dose. Results: Significant suppression of OUCC and K occurred from baseline with the SB, AP and VM but not with the EH devices. The geometric mean fold suppression (95% confidence interval, p) was: EH, 1.59 (0.80-3.14, p = 0.40); AP, 4.26 (3.01-6.02, p < 0.001); VM, 3.11 (1.99-4.78, p < 0. 001); SB, 3.29 (2.04-5.24, p < 0.001). For K, the arithmetic mean fall (mmol/l) (95% confidence interval; p) was: EH, −0.10 (−0.25-0.05, p = 0.18); AP, −0.23 (−0.41 to −0.04, p = 0.02); VM, −0.22 (−0.44 to −0.01, p = 0.04); SB, −0.28 (−0.42 to −0.13, p = 0.001). Conclusions: The breath-actuated SB device was comparable to 'out of the box' small and large volume spacers and produced similar improvements in relative systemic lung bioavailability for fluticasone and salmeterol. [ABSTRACT FROM AUTHOR]

There are several aerosolized drugs which have been used in the treatment of neonatal respiratory illnesses, such as bronchodilators, diuretics, and surfactants. Preclinical in vitro and in vivo studies identified a number of variables that affect aerosol efficiency, including particle size, aerosol flows, nebulizer choice, and placement. Nevertheless, an optimized aerosol drug delivery system for mechanically ventilated infants still does not exist. Increasing interest in this form of drug delivery requires more controlled and focused research of drug/device combinations appropriate for the neonatal population. In the present article, we review the research that has been conducted thus far and discuss the next steps in developing the optimal aerosol delivery system for use in mechanically ventilated neonates. [ABSTRACT FROM AUTHOR]

Aztreonam lysine for inhalation solution (AZLI) is a new option for the treatment of Pseudomonas aeruginosa lung infection in patients with cystic fibrosis. When compared with placebo in clinical trials, AZLI improved respiratory symptoms, pulmonary function and sputum P. aeruginosa density, delayed the time to need for inhaled or intravenous antipseudomonal anti-bacterials when used after a course of tobramycin inhalation solution, and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Multilayer argon plasma coagulation (APC) is a new effective method for the treatment of genital warts. We assessed the generation of aerosols containing human papilloma virus (HPV) DNA during treatment of genital warts with multilayer APC and with CO laser ablation. Surveillance petri dishes, swabs from the glasses and nasolabial folds of the operating physician, and swabs taken from the suction units used during CO laser ablation were tested by HPV PCR. HPV DNA corresponding to patient derived HPV types of genital warts was not found in any of the petri dishes and swabs obtained during APC treatment. HPV DNA was detected in none of the petri dishes obtained during CO laser treatment, but in suction filters. In conclusion, both CO laser ablation with plume suction and APC treatment seem to have a low risk of HPV contamination of the operation room. [ABSTRACT FROM AUTHOR]

The article discusses a randomized trial investigating the effect of inhaled hypertonic saline on the hospital admission rate in children with viral bronchiolitis. The objective of the study included determining whether 3% hypertonic saline (HS) reduced admission to hospital in ambulatory children with moderately severe viral bronchiolitis, comparing changes in respiratory scores before and after treatment, and assessing the need for unscheduled medical intervention within seven days.

The objective was to determine if the plasma concentrations of salbutamol, obtained during inhalation treatment of infantile acute asthma, are influenced by age range and by the aerosol system used. A randomized clinical trial was conducted in 46 children (1–5 years of age) with a diagnosis of acute asthma crisis, established in an emergency room pediatric service. Twenty-five children received salbutamol using a pressurized metered-dose inhaler with spacer (50 µg/kg), and 21 children received salbutamol by nebulization (150 µg/kg),three times during a 1-h period. At the end of the treatment, one blood sample was drawn and the plasma was stored for later determination of salbutamol concentration (liquid chromatography). Salbutamol plasma concentrations were compared in two age groups (≤2 years and >2 years of age). The type of device used (pressurized metered-dose inhaler or nebulizer) and the need of hospitalization were also tested. The Mann-Whitney U test was used with the level of significance set at 5% ( P < 0.05). No differences were detected regarding either the aerosol delivery system used or the need for hospitalization in relation to the plasma concentrations of salbutamol. However, higher plasma levels were found in patients >2 years vs patients ≤2 years [median (IQR): 9.40 (6.32–18.22) vs. 4.65 (2.77–10.10) ng/mL], demonstrating a significance difference ( P = 0.05). Salbutamol plasma concentrations were influenced by age group of the patients submitted to inhalation therapy, even with doses adjusted for body weight. After correcting for the differences in the biovailabilities of the delivery systems, the concentrations were independent of the aerosol delivery device used. [ABSTRACT FROM AUTHOR]

The analgesic activities of nanoaerosols of the nonsteroidal anti-inflammatory drugs indomethacin, butadion, and diclofenac were studied. It was found that nanoaerosol delivery of these drugs gave analgesic activities that were comparable to those of oral delivery 5 - 8 min after administration at doses that were 3 - 5 orders of magnitude lower. [ABSTRACT FROM AUTHOR]

The Wilms' tumor gene 1 (WT1) is a universal tumor antigen and consequently a good therapeutic target for the development of gene therapy strategies. Earlier, we reported the in vitro efficacy of WT1 RNAi in the inhibition of B16F10 murine melanoma cell line growth. In this study, we used an aerosol system to deliver WT1 RNAi complexes, polyethyleneimine (PEI)–WT1-1 or PEI–WT1-2, to the lungs of mice with B16F10 lung metastasis. This treatment produced a statistically significant (P=0.020) reduction in the number and size of lung tumor foci, resulting in decreased lung weight and tumor index in treated mice compared with controls. The WT1 RNAi treatment also reduced the number and size of tumor blood vessels, suggesting decreased angiogenesis. Furthermore, the treated lung tissue showed cells in the tumor infiltrations undergoing apoptosis and elevated expression of the proapoptotic genes Bcl-xS and Bax, suggesting an activation of the intrinsic apoptotic pathway. Overall, WT1-1 treatment prolonged the mean survival time of tumor-bearing mice in comparison with the control and WT1-2-treated mice. Our data show that WT1 gene silencing in vivo by aerosol delivery of PEI–WT1 RNAi complexes is an effective therapeutic strategy for the treatment of lung metastases. [ABSTRACT FROM AUTHOR]

Salmeterol/fluticasone propionate (Seretide/Advair Diskus® [dry powder inhaler] or Seretide/Advair® inhalation aerosol [metered-dose inhaler]) is a fixed-dose combination inhalation agent containing a long-acting b2-adrenoceptor agonist (LABA) plus a corticosteroid. In patients with symptomatic asthma, twice-daily salmeterol/fluticasone propionate maintenance therapy improves lung function and asthma symptoms to a greater extent than monotherapy with inhaled corticosteroids (ICS), such as fluticasone propionate, oral montelukast with or without fluticasone propionate, or sustained-release theophylline plus fluticasone propionate. The greater efficacy achieved with salmeterol/fluticasone propionate versus fluticasone propionate alone was sustained for 1 year in a well designed trial. Salmeterol/fluticasone propionate is also associated with a corticosteroid-sparing effect. Results of studies comparing fixed dosages of salmeterol/fluticasone propionate with formoterol/budesonide in adults and adolescents are equivocal. Twicedaily salmeterol/fluticasone propionate is associated with clinically meaningful improvements from baseline in health-related quality of life (HR-QOL), and improvements were greater than those reported with fluticasone propionate alone. Salmeterol/fluticasone propionate is generally well tolerated in adults, adolescents and children aged 4-11 years, and the fixed-combination inhaler ensures the appropriate use of a LABA in combination with an ICS. In cost-utility analyses in patients with uncontrolled asthma, salmeterol/fluticasone propionate compares favourably with fluticasone propionate alone or oral montelukast. Thus, salmeterol/fluticasone propionate provides an effective, well tolerated and costeffective option for maintenance treatment in patients with asthma. Salmeterol is a selective LABA, which causes bronchodilation and inhibition of the release of hypersensitivity mediators from mast cells. The corticosteroid fluticasone propionate inhibits eosinophil activation and the subsequent release of inflammatory mediators. Coadministration of inhaled salmeterol and fluticasone propionate produce similar effects to those observed when the two agents are administered separately, and in vitro studies suggest beneficial additive or synergistic effects. The pharmacokinetics of concomitant salmeterol and fluticasone propionate are generally similar to those recorded following individual administration, with no systemic pharmacokinetic interaction.… [ABSTRACT FROM AUTHOR]

Abstract Purpose  Tobramycin microparticulate powders containing the hydrophobic adjunct sodium stearate were studied for their use as pulmonary formulations in dry powder inhalers. Methods  Spray-dried powders were characterized in terms of particle size distribution, morphology, crystallinity, drug dissolution rate, toxicity on epithelial lung cells and aerosol efficiency. Results  The presence of the sodium stearate had a direct influence on the aerosol performance of tobramycin spray-dried powders. Powders containing 1% w/w sodium stearate had fine particle fraction FPF of 84.3 ± 2.0% compared to 27.1 ± 1.9% for powders containing no adjunct. This was attributed to the accumulation of sodium stearate at the particle surface. Powders with higher sodium stearate concentrations (2% w/w) showed significantly lower FPF (66.4 ± 0.9%) and less accumulation of sodium stearate at the particle surface. This was attributed to the formation of adjunct micelles, which remained internalised in the particle structure due to their reduced tropism toward the drying drop surface and molecular mobility. Preliminary analysis of the toxicity effect of sodium stearate on A549 cell lines showed that the adjunct, in the concentration used, had no effect on cell viability over a 24-h period compared to particles of pure tobramycin. Conclusions  Tobramycin pulmonary powders with low level of sodium stearate, presenting high respiration performances and no overt toxicity on lung cells, could be used to improve therapeutic outcomes of patient with Cystic Fibrosis (CF). [ABSTRACT FROM AUTHOR]

The article presents a study on the production of nanoaerosols of sparingly water-soluble drugs. It develops an inhaler based on a thermal condensation-type that generates nanoparticles of drugs at a high concentration with a high stability. The anti-inflammatory properties of indomethacin was also studied to clarify the possibility of decreasing the therapeutic dose for inhalation administration. Result shows that the indomethacin aerosol is more efficient than the traditional oral delivery.

The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for development of novel options. Aerosol gene delivery may provide the alternative for safe and effective treatment for lung cancer. Therefore, current study was performed to elucidate the potential effects of C-terminal modulator protein (CTMP) via aerosol on lung tumorigenesis. Lentiviral vector-CTMP was delivered into K-ras null lung cancer mice through the nose-only inhalation system for 30 min. After 48 h, the potential effects of CTMP on Akt1-related signals and cell cycle regulation in the lungs were evaluated by western blot, immunohistochemistry and zymography. Lentivirus-based CTMP delivery inhibited the Akt1 activity through selective suppression of Akt1 phosphorylation at Ser473. Aerosol delivery of CTMP inhibited proteins important for Akt1 signals, cell cycle and tumor metastasis in lungs of K-ras null mice. Together, our results suggest that lentivirus-mediated aerosol delivery of CTMP may be compatible with noninvasive in vivo gene therapy. Our results emphasize the importance of noninvasive-targeted delivery of CTMP for lung cancer therapy in the future. While the studies are conducted in mice, it is envisioned that noninvasive targeting the specific genes responsible for cancer progression is an attractive strategy for effective anticancer therapeutics.Gene Therapy (2007) 14, 1721–1730; doi:10.1038/sj.gt.3303042; published online 25 October 2007 [ABSTRACT FROM AUTHOR]

Background and objectives: To compare in vitro characteristics and pharmacokinetics of Bramitob®, a preservative-free tobramycin solution for nebulization, and Tobi® in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa infection. Methods: In vitro characteristics of Bramitob® and Tobi® were evaluated using Pari TurboBoy™/LC Plus® and the Systam 290 LS™ nebulizers. In the randomized, double-blind, two-way crossover pharmacokinetic study, 11 patients with CF received a single nebulized dose (300mg) of Bramitob® or Tobi®, separated by a 7-day washout period. Plasma and sputum tobramycin concentrations were measured immediately before and over 24 hours after administration. Results: Bramitob® and Tobi® performed alike during nebulization. The fine particle fraction was 33–37% and the mass median aerodynamic diameter was <5μm. Nine patients completed the pharmacokinetic study. Tobramycin plasma profiles after administration of Bramitob® or Tobi® were similar, with a peak at 90 and 72 minutes after inhalation of Bramitob® and Tobi®, respectively. The elimination half-life was ∼5 hours for both products. The relative bioavailability of Bramitob® to Tobi® was 1.01, indicating comparable systemic exposure. Peak sputum concentration of tobramycin was 816 ± 681 μg/g for Tobi® and 1289 ± 851 μg/g for Bramitob® and was >400 μg/g (threshold sufficient for an antibacterial effect against P. aeruginosa) in 5 out of 9 patients receiving Tobi® and 8 out of 9 patients receiving Bramitob®. All adverse events were considered mild and judged not related to the study drugs. Conclusions: In vitro performance of Bramitob® was similar when nebulized with Pari TurboBoy™/LC Plus® and Systam 290 LS™ nebulizers and comparable to that of Tobi®. The systemic bioavailability of tobramycin was similar after administration of either Bramitob® or Tobi®; however, in sputum samples the tobramycin peak concentration was slightly greater after administration of Bramitob® than after Tobi®. [ABSTRACT FROM AUTHOR]

Objective: We set out to investigate whether the nebulized and inhaled specific caspase-1 inhibitor Ac-YVAD-CHO has the potential to attenuate the pulmonary and systemic release of the caspase-1-dependent cytokines interleukin-1 beta (IL-1 beta) and interleukin-18 (IL-18) as well as their downstream enzymes iNOS and COX-2 in rat experimental endotoxaemia.Design and Setting: Controlled, randomized animal study in a university research facility.Subject: Male Sprague-Dawley rats (n=32) were randomly treated as follows: Inhaled Ac-YVAD-CHO was administered in eight rats at a inhaled total dosage of 5 mg and in eight rats at a inhaled total dose of 0.5 mg before infusion of lipopolysaccharide (LPS; 5 mg/kg, i.v.). Eight animals received LPS only. Eight animals served as controls without endotoxaemia.Measurements and Results: After 4h of endotoxaemia, levels of IL-1 beta, IL-18 and TNF-alpha in plasma and bronchoalveolar fluid (BALF) were analyzed. Nitric oxide (NO) release from alveolar macrophages was measured by Griess assay. Amounts of iNOS protein in alveolar macrophages and COX-2 protein in lung homogenates were determined by Western blotting. Significant reductions in release of IL-1 beta (-58%, p<0.05) and IL-18 (-51%, p<0.05) in plasma and IL-1 beta (-59%, p<0.05) in BALF were found in animals pretreated with inhaled caspase-1 inhibitor compared with animals without therapy. Expression of iNOS in alveolar macrophages and COX-2 in lung tissue was concurrently decreased in the treatment groups compared with control animals.Conclusions: Our data demonstrate that administration of the caspase-1 inhibitor Ac-YVAD-CHO by inhalation is able to reduce the pulmonary and systemic release of proinflammatory mediators in rat endotoxaemia. These results further underscore that inhalation may constitute an effective route of anti-inflammatory drug administration, beneficial in the clinical setting of ARDS. [ABSTRACT FROM AUTHOR]

We describe the development of an aerosol system for topical gene delivery to the lungs of C57BL/6 mice. This system is based on the combination of the commercial cationic lipid Lipofectin with a novel amphiphilic triblock copolymer, poly(p-dioxanone-co-L-lactide)-block-poly(ethylene glycol) (PPDO/PLLA-b-PEG, and abbreviated in the text as polymeric micelles). After optimizing conditions for DNA delivery to the lungs of mice using the combination of polymeric micelles with Lipofectin and LacZ DNA, we used the Lipofectin/polymeric micelle system to deliver the tumor suppressor gene PTEN to the lungs of C57BL/6 mice bearing the B16-F10 melanoma. Lipofectin/PTEN/polymeric micelles significantly improved gene expression of PTEN in the lungs of mice with no evidence of cell toxicity or acute inflammation. Importantly, lung metastasis, as measured by lung weight, was significantly reduced (P<0.001), as were total tumor foci in the lungs (P<0.001) and size of individual tumor nodules in animals treated with Lipofectin/PTEN/polymeric micelles compared with control animals. Survival time was also extended. These results suggest that the Lipofectin/polymeric micelle system is appropriate for enhancing gene delivery in vivo and that it can be applied as a non-invasive gene therapy for lung cancer.Gene Therapy (2007) 14, 476–483. doi:10.1038/sj.gt.3302876; published online 23 November 2006 [ABSTRACT FROM AUTHOR]

Aerosolised administration of antibacterials remains theoretically attractive for the prevention and treatment of hospital-acquired pneumonia (HAP) because of the ability to generate high drug concentrations at the site of infection. There is renewed interest in this area because of the shortcomings of current therapies and increasing multidrug resistance in Gram-negative organisms. Clinical trials of aerosolised or endotracheally administered antibacterials for HAP prevention have generally been positive; however, early trials were hampered by the development of resistance related to indiscriminate use. More recent trials have shown efficacy at HAP prevention without adverse effects on microflora as a result of more limited usage. However, prophylactic aerosolised antibacterials still need to be studied in large randomised trials before they could enter widespread use. The treatment of HAP with aerosolised antibacterials has mostly been reported in case series without control groups. Both early reports with aminoglycosides and the more recent use of colistin have reported very good response rates; even with organisms such as Pseudomonas aeruginosa and Acinetobacter baumannii. Aerosolised antibacterials were almost always added to intravenous therapy. On the basis of these reports, the current HAP guidelines allow the addition of aerosolised antibacterials in selected patients with multidrug-resistant organisms. This seems to be a reasonable recommendation until large trials are performed. Overall, toxicity was relatively low in the publications reviewed. Aerosolised drug administration in mechanically ventilated patients requires attention to a number of factors in order to maximise drug deposition in the lung. [ABSTRACT FROM AUTHOR]

Purpose??The aim of this study was to kinetically and dynamically analyzein vitrocytotoxicity as an index of skin irritation by use of a three-dimensional cultured human skin model and to compare thein vitroassay data with data from living animals.Methods??A cationic surfactant, cetylpyridinium chloride (CPC), was selected as a model irritant. Living skin equivalent-high (LSE-high) and hairless mice were used for thein vitroandin vivotests, respectively. Skin irritation dermatodynamics was evaluated by calorimetric thiazoyl blue (MTT) conversion assay both forin vitroandin vivotests, whereas dermatokinetics of CPC in LSE-high and mouse skin were evaluated using HPLC.Results??The time course of cell viability in the skin after application of CPC to intact skin was distinctly different from that of stratum-corneum-stripped skin in both LSE-high and hairless mice. Biphasic behavior characterized by two first-order rates with an inflection time point was observed in intact skin, whereas cell viability monoexponentially decreased immediately after CPC application in stripped skin. The time courses of cell viability in the skin and dermatodynamics were closely related to that of dermatokinetics of CPC.Conclusion??The present study demonstrates that thein vitrocytotoxic profile was similar to thein vivocytotoxicity test and that dermatodynamics was related to dermatokinetics of CPC. [ABSTRACT FROM AUTHOR]

Aim: To characterize gemcitabine aerosol, its in vitro activity against lung cancer cells, its deposition, and tolerance in a non-human primate model. Methods: In vitro cytotoxicity of nebulized gemcitabine against NCI-H460 and A549 lung cancer cells was tested using a growth inhibition assay and compared with non-nebulized gemcitabine. The (99m)Tc-DTPA-radiolabeled gemcitabine aerosol was characterized by cascade impaction and the gemcitabine mass/(99m)Tc activity relationship was established for further quantitative nuclear imaging. Nine weekly inhalations at a target dose of 1 mg/kg body weight of gemcitabine were performed in three baboons using dynamic scintigraphic acquisitions for continuous monitoring of gemcitabine delivery during inhalation. Gemcitabine plasma concentrations were measured during the first inhalation. Results: Growth inhibition assays for both NCI-H460 and A549 cells did not differ between nebulized and non-nebulized gemcitabine. Aerosol characterization showed a particle mass median aerodynamic diameter of 3.7+/-0.8 microm and a linear relationship between gemcitabine mass (y) and (99m)Tc activity (x) (y=0.82x - 10(-5), R (2)=0.88). No toxicity was observed after nine weekly inhalations of a mean dose of gemcitabine of 11.1 mg (88% of the target dose) as assessed from scintigraphic data. A dose-dependent peak plasma concentration of gemcitabine (20-74 ng/ml) was observed by the tenth minute of inhalation. Conclusions: We have characterized a gemcitabine aerosol suitable for intrathoracic airway deposition and demonstrated that jet nebulization does not alter the cytotoxic properties of the drug. In a primate model, we have developed a scintigraphic procedure for the monitoring of aerosol deposition, and we have demonstrated the safety of nine weekly aerosol administrations of gemcitabine. [ABSTRACT FROM AUTHOR]

A new nebulizer system is described that extends the analytical capability of the inductively coupled plasma technique to include the simultaneous determination of two elements Sb and Sn (hydride-forming), with two conventional elements, V and Zn. The main advantage of this system is its simultaneous determination of elements that form volatile hydrides and elements that do not, without any instrumental changes. Optimization of reaction and instrumental conditions was performed to characterize the new system. The performance of the new nebulizer system was evaluated by studying the effect of some transition metals (Ni, Cu, Co, and Fe, 1–1000 mg L−1) on the Sb, Sn, V, and Zn emission signals (1 mg L−1). Interferences from transition metal ions were found to be insignificant for determination of the four elements in presence of L-cysteine. Long-term and short-term stability was also evaluated. The precision, expressed as RSD for 15 replicate measurements was 0.7% for Sb, 1.7% for Sn, 2.5% for V, and 2.3% for Zn at 200 μg L−1 of each analyte. The detection limits obtained were 0.52, 1.3, 3.2, and 4.7 μg L−1 for Sb, Sn, V, and Zn, respectively. Spike and recovery experiments were performed on the NIST 1643c trace metals in water standard reference material and results were in agreement with the certified values. [ABSTRACT FROM AUTHOR]

Purpose. To investigate the feasibility of using the Aerosol Solvent Extraction System (ASES) to produce fine powders of recombinant human deoxyribonuclease (rhDNase), lysozyme-lactose and rhDNaselactose powders from aqueous based solutions. Methods. The ASES technique using high pressure carbon dioxide modified with ethanol or ethanol and triethylamine was used for the generation of rhDNase powders and protein-lactose powders from aqueous based solutions. Particle size, morphology, size distributions, crystallinity, and powder aerosol performance were measured. The biochemical integrity of the processed rhDNase was assessed by testing the monomer content and the degree of deamidation. Results. RhDNase precipitated as spherical particles in the size range between 50 and 500 nm. The primary nano-sized particles were agglomerated to micron-sized clumps of particles during the precipitation process. The median particle size and the fine particle fraction were functions of the operating temperature and the nozzle system used. RhDNase was substantially denatured in the ASES process using carbon dioxide modified with ethanol as anti-solvent. However almost complete recovery of the monomer was achieved using carbon dioxide modified with ethanol-triethylamine as an anti-solvent. Lysozyme-lactose and rhDNase-lactose powders were also precipitated as agglomerated spheres using the ASES process. The powders were amorphous except for those with lactose content higher than 45%. Conclusions. Micron-sized particles of rhDNase suitable for inhalation delivery were generated from aqueous based solutions using the modified ASES technique. The biochemical integrity of the rhDNase powder is a function of the antisolvent and the operating temperature. KEY WORDS: ASES; rhDNase; micronization; aerosol delivery; SCF. [ABSTRACT FROM AUTHOR]

Published data indicate that metered-dose inhalers (MDIs) in combination with a holding chamber (spacer) device are at least as effective and safe as nebulisers in the administration of short-acting bronchodilator therapy to children with asthma. In addition, spacer devices offer a number of advantages over nebulisers including lower cost, greater ease and speed of use, and lack of need for electricity or hospital gas wall outlets. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of inspiratory time and inspiratory flow pattern on albuterol delivery by aerosol during mechanical ventilation.Design: A ventilator was connected to a lung model and set to deliver a tidal volume of 0.6 l, PEEP 5 cmH(2)O, and respiratory rate of 15/min. We evaluated inspiratory times of 1 and 2 s, lung mechanics of 0.05 l/cmH(2)O compliance and 50 cmH(2)O/l/s resistance, or 0.02 l/cmH(2)O compliance and 5 cmH(2)O/l/s resistance, and three inspiratory flow patterns (constant flow volume-controlled ventilation, descending ramp flow volume-controlled ventilation, and pressure-controlled ventilation). Albuterol was delivered into the ventilator circuit by a nebulizer containing 5 mg (4 ml) albuterol or a pMDI and spacer (four actuations; 360 micro g). A filter between the Y-piece and the lung model collected the aerosol, which was analyzed for albuterol by spectrophotometry.Results: For the nebulizer there were significant differences in albuterol delivered for inspiratory time, flow pattern, and lung mechanics. For the pMDI there were no significant differences for the amount of albuterol delivered for inspiratory time, flow pattern, or lung mechanics.Conclusions: Albuterol delivery by nebulizer is affected by inspiratory time and inspiratory flow pattern. When a pMDI is used, the amount of albuterol delivered is not affected by inspiratory flow pattern or inspiratory time. [ABSTRACT FROM AUTHOR]

Computer simulations of airflow patterns within the human upper respiratory tract (URT) are presented. The URT model includes airways of the head (nasal and oral), throat (pharyngeal and laryngeal), and lungs (trachea and main bronchi). The head and throat morphology was based on a cast of a medical school teaching model; tracheobronchial airways were defined mathematically. A body-fitted three-dimensional curvilinear grid system and a multiblock method were employed to graphically represent the surface geometries of the respective airways and to generate the corresponding mesh for computational fluid dynamics simulations. Our results suggest that for a prescribed phase of breath (i.e., inspiration or expiration), convective respiratory airflow patterns are highly dependent on flow rate values. Moreover, velocity profiles were quite different during inhalation and exhalation, both in terms of the sizes, strengths, and locations of localized features such as recirculation zones and air jets. Pressure losses during inhalation were 30–35% higher than for exhalation and were proportional to the square of the flow rate. Because particles are entrained and transported within airstreams, these results may have important applications to the targeted delivery of inhaled drugs. [ABSTRACT FROM AUTHOR]

Nebulization is a useful administration route in cystic fibrosis (CF) as it delivers antibiotics directly to the endobronchial site of infection and is associated with decreased toxicity because of limited systemic absorption. It is assumed that the concentration of antibiotics in bronchial secretions should be as high as 10 times the minimum inhibiting concentration to allow penetration of antibiotics into biofilms, suppress inhibitory factors and promote bactericidal effectiveness. However, effective aerosol delivery is compromised by nebulizers with limited capacity to produce particles of a size in the respirable range. Three antibiotics are commonly used for inhalation: tobramycin, amikacin and colistin (colomycin). Placebo-controlled studies evaluating antibiotic aerosol maintenance in stable patients chronically infected with Pseudomonas aeruginosa indicate a significant improvement of lung function and a reduction of the number of hospital admissions for an acute exacerbation of CF. TOBI is a recently marketed preservative- and sulfate-free formula of tobramycin, specially designed for diffusion in the bronchioles and optimal tolerance. A wide-scope study involving 520 patients compared TOBI (300mg twice daily; n = 258) with placebo (n = 262) for three 28-day cycles with each cycle separated by a 28-day period of no treatment. Respiratory function was significantly improved as early as in the second week and remained so for the rest of the trial even during periods without aerosol treatment. There was also a parallel decrease in the relative risk of hospitalization, the number of days of hospitalization and the number of days on intravenous antipyocyanic treatment. Toxicity studies carried out so far have shown no renal or ototoxicity with nebulized tobramycin. Introduction or selection of resistant bacteria is relatively rare but remains a matter of concern. Aerosol maintenance treatment with an appropriate antibiotic in a high enough dosage can be recommended for patients with CF who are chronically infected with P. aeruginosa. [ABSTRACT FROM AUTHOR]

Computer simulations of airflow and particle-transport phenomena within the human respiratory system have important applications to aerosol therapy (e.g., the targeted delivery of inhaled drugs) and inhalation toxicology (e.g., the risk assessment of air pollutants). A detailed description of airway morphology is necessary for these simulations to accurately reflect conditions in vivo. Therefore, a three-dimensional (3D) physiologically realistic computer model of the human upper-respiratory tract (URT) has been developed. The URT morphological model consists of the extrathoracic (ET) region (nasal, oral, pharyngeal, and laryngeal passages) and upper airways (trachea and main bronchi) of the lung. The computer representation evolved from a silicone rubber impression of a medical school teaching model of the human head and throat. A mold of this ET system was sliced into 2-mm serial sections, scanned, and digitized. Numerical grids, for use in future computational fluid dynamics (CFD) simulations, were generated for each slice using commercially available software (CFX-F3D), AEA Technology, Harwell, UK. The meshed sections were subsequently aligned and connected to be consistent with the anatomical model. Finally, a 3D curvilinear grid and a multiblock method were employed to generate the complete computational mesh defined by the cross-sections. The computer reconstruction of the trachea and main bronchi was based on data from the literature (cited herein). The final unified 3D computer model may have significant applications to aerosol medicine and inhalation toxicology, and serve as a cornerstone for computer simulations of air flow and particle-transport processes in the human respiratory system. [ABSTRACT FROM AUTHOR]

Computer simulations were conducted to describe drug particle motion in human lung bifurcations with tumors. The computations used FIDAP with a Cray T90 supercomputer. The objective was to better understand particle behavior as affected by particle characteristics, airflow conditions, and disease-modified airway geometries. The results indicated that increases in particle sizes, breathing intensities and tumor sizes could enhance drug deposition on the tumors. The modeling suggested that targeted drug delivery could be achieved by regulating breathing parameters and designing (selecting physical features of) aerosolized drugs. We present the theoretical work as a step towards improving aerosol therapy protocols. Since modeling describes factors affecting dose, it is complementary to considerations of the molecular aspects of drug formulation and pharmacokinetics. [ABSTRACT FROM AUTHOR]

The corticosteroid budesonide is a 1:1 racemic mixture of 2 epimers, (22R)- and (22S)-, and is available in 3 different inhaled formulations for the management of asthma: a pressurised metered dose inhaler (pMDI), a dry powder inhaler (DPI) and a solution for nebulised therapy. Inhaled corticosteroids such as budesonide reach the systemic circulation either by direct absorption through the lungs (a route that is much more important than previously recognised) or via gastrointestinal absorption of drug that is inadvertently swallowed. Although the pharmacokinetics of budesonide have been extensively investigated following oral and intravenous administration, relatively few studies have defined the systemic disposition of budesonide after inhalation. Drug deposition in the lungs depends on the inhaler device: 15% of the metered dose of budesonide reached the lung with a pMDI compared with 32% with a breath-actuated DPI. In patients with asthma (n = 38) receiving different doses of budesonide by DPI (Turbuhaler), the pharmacokinetic parameters peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were dose-dependent after both single dose and repeat dose (3 weeks) administration: time to Cmax (tmax) was short (0.28 to 0.40 hours) and the elimination half-life approximately 3 hours. Both AUC and Cmax were linearly related to budesonide dose. In a small group of healthy male volunteers (n = 9), the pharmacokinetics of budesonide 1,600 microg twice daily via pMDI were assessed on the fifth day of administration. Mean model-independent parameters for (22R)-budesonide were as follows: Cmax 1.8 microg/L, tmax 0.46 hours, elimination half-life 2.3 hours and oral clearance 163 L/h, and there were no enantiomer-specific differences in drug disposition. Budesonide undergoes fatty acid conjugation within the lung, but very limited pharmacokinetic data are available to define the pulmonary absorption characteristics. There is evidence from a population analysis that the pulmonary absorption of budesonide is prolonged and shows wide interindividual variation. Further pharmacokinetic studies are required to define the time-course of budesonide absorption through the lung in specific patient groups, and to investigate the effect of new inhaler devices (especially chlorofluorocarbon-free pMDIs) on the pharmacokinetic profile and systemic drug exposure. [ABSTRACT FROM AUTHOR]

Background: Short courses of oral prednisolone are used as rescue therapy for severe asthma exacerbations. This study compares nebulised budesonide or oral prednisolone, both followed by budesonide Turbohaler®, as a treatment for severe asthma exacerbations, in the absence of life-threatening features. Patients and Methods: Thirteen adults admitted to hospital were randomised to receive either nebulised budesonide (4mg 8-hourly) for 48 to 72 hours followed by budesonide Turbohaler (1600µg twice daily for 7 days, then 800µg twice daily for 21 days) for 28 days or prednisolone (40mg daily) for 9 to 11 days followed by budesonide Turbohaler (800µg twice daily) for 21 days. The primary efficacy variable was the change from baseline at 48 hours in forced expiratory volume in 1 second (FEV). Secondary efficacy variables included an assessment of symptom severity (0 = none, 1 = mild, 2 = moderate, 3 = severe). Results: Difficulties were experienced with patient recruitment in the emergency setting. The results presented are from an incomplete study. Change in FEV from baseline to 48 hours was not statistically significantly different between the groups (the study was underpowered to detect a difference in change in FEV, as the power to detect a prespecified difference between groups was 18%). Nebulised budesonide significantly reduced the severity of wheeze after 24 hours compared with prednisolone [estimate of treatment effect = -0.95; 95% confidence intervals (CI) = -1.76 to -0.15; p = 0.0336 between groups] and 48 hours (estimate of treatment effect = -0.79; 95% CI = -1.42 to -0.15; p = 0.0326 between groups). Conclusion: While oral prednisolone or intravenous hydrocortisone, oxygen and bronchodilators are the mainstay of acute management in severe asthma, the results of this study suggest that nebulised budesonide may assist in regaining control of symptoms during exacerbations of asthma. [ABSTRACT FROM AUTHOR]