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PubMed1998

Surface-modified antiasthmatic dry powder aerosols inhaled intratracheally reduce the pharmacologically effective dose.

PURPOSE: The aim of this study was to construct a reliable dry powder inhalation (DPI) testing system for use in guinea pigs. Using this system, we were able to demonstrate the superiority of pulmonary administration of hydrophilically surface-modified pranlukast hydrate powder (SM-DP) over IV and PO administration as reflected in improved pharmacological action. Our ultimate aim is the development of an ideal treatment system for bronchial asthma involving topical administration to the lung. METHODS: The reliability of the present DPI system was validated by continuously monitoring the concentration and particle size distribution of aerosols generated with an ambient particulate monitor and an Andersen air sampler, respectively. The pharmacological effect of SM-DP intratracheally administered to guinea pig was investigated by measuring the degree of bronchoconstriction and microvascular leakage induced by leukotriene D4. RESULTS: The mass concentration of aerosols generated by the DPI system was stable and the mass median aerodynamic diameter of aerosols insufflated from the respirator of the DPI system ranged from 1.4 to 1.7 microm, within respirable limits. Inhibition of bronchoconstriction and airway microvascular leakage induced by leukotriene D4 was achieved successfully with a dramatically lower dose of DP, or a further lower dose of SM-DP, comparable with that of the drug solution injected intravenously. The plasma pranlukast hydrate level with SM-DP at 50% inhibition of bronchoconstriction and airway microvascular leakage was reduced to 1/10 or less that following IV and PO administration. CONCLUSIONS: The hydrophilically surface-modified pranlukast hydrate powders were ideally aerosolized by the present DPI system, and were uniformly deposited in the lung lobes after inhalation. The pulmonary administration system with SM-DP is strongly recommended as an ideal system for the treatment of bronchial asthma in order to avoid systemic side-effects due to a dramatically reduced ED50, comparable with or lower than IV, and the low plasma concentration of drug, 1/12 or less than that following IV and PO administration.

Administration, Inhalation↗
PubMed1989

Optimized inhalation aerosols. I. The effects of spherical baffle size and position upon the output of several pressurized nonaqueous suspension formulations.

Baffles contained in conventional actuators may be a convenient alternative to some of the extension devices used presently with metered-dose inhalers (MDIs). Actuators were modified to determine whether baffles could be used to decrease the output of large "nonrespirable" droplets. These actuators were tested using a series of nonaqueous suspension aerosols containing 0.1 to 2.0% micronized disodium fluorescein (DF) as the model drug, stabilized by sorbitan trioleate in a constant blend of fluorocarbons 11, 12, and 114. A 25-microliter metering volume was used throughout. Aerosol output was characterized by cascade impaction. Baffle size and position had pronounced effects on actuator retention and aerosol output. Increasing baffle size resulted in increased retention in the actuator. The total output of the MDI in the "respirable" range (aerodynamic diameter, Dae, less than 5.5 microns) was greater in the unbaffled actuator than in all baffled actuators. However, all baffles increased the respirable fraction (DF with Dae less than 5.5 microns: total DF leaving the actuator), R, when compared to their unbaffled controls. For example, for a 0.1% DF, 0.14% surfactant formulation, R was increased from 0.40 (unbaffled) to 0.71 by incorporation of a 0.6-cm-diameter sphere 1.3 cm from the jet of the actuator. In these cases, aerosol segregation occurred due to droplet inertia in the high velocity gas flows. Increasing the respirable fraction at the expense of the total respirable output may obviate undesirable clinical effects.

Aerosols↗
PubMed2003

On the horizontal homogeneity of mass-related aerosol properties.

We studied the mass-related aerosol properties, simultaneously at two sites at the urban roof top level in the same city. No systematic influence of the wind vector on the difference in the aerosol concentrations between the two locations could be found. These results are compared with results from a second, similar experiment over a larger distance including one urban and one rural site. Surprisingly, we could not detect a tendency which would indicate that sampling air at distance in the order of 1 km would be less affected by the heterogeneity than sampling distanced in the order of 10 km apart. On the contrary, the results suggest that mass-related properties at two sites in the same city are not necessarily more similar than at an urban and a rural site outside the city. These results stress the limited horizontal homogeneity of urban atmospheric aerosol. As a conclusion it is suggested that single-site measurements of mass-related aerosol properties should be considered to be representative for an area smaller than 1 km2 on size.

Aerosols↗
PubMed2003

Evaluation of an aerosolized selective COX-2 inhibitor as a potentiator of doxorubicin in a non-small-cell lung cancer cell line.

PURPOSE: To evaluate the in vitro effects of an aerosolized cyclooxygenase-2 (COX-2) inhibitor, nimesulide, on the cytotoxicity and apoptotic response of doxorubicin against the human lung adenocarcinoma cell line A549. METHODS: Nimesulide was formulated into a metered dose inhaler (MDI) formulation and characterized for aerodynamic particle size and medication delivery. The in vitro cytotoxicity of nimesulide-MDI in the presence or absence of doxorubicin was assessed by using the six-stage viable impactor by an already standardized method. Induction of apoptosis in A549 cells by nimesulide (nonaerosolized or aerosolized) in combination with doxorubicin was evaluated by established techniques such as caspase-3 estimation and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. Finally, to understand the mechanism of action, the influence of different treatments on the expression of COX-2 and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in A549 cells was studied by immunoblotting. RESULTS: The nimesulide-MDI formulation had a mass median aerodynamic diameter (MMAD) of 1.1 microm, (GSD = 2.8) and a medication delivery of 51 microg/shot. Nimesulide-MDI (40 shots) in combination with doxorubicin (0.01 microg/ml) had a cell kill of more than 60% as determined by in vitro cytotoxicity assay. The specific caspase-3 activity in A549 cells treated with nimesulide (40 microg/ml) and doxorubicin (0.25 microg/ml) in combination was 3 and 5 times higher than doxorubicin and nimesulide, respectively. Further, TUNEL staining showed apoptosis in over 30% of A549 cells treated with aerosolized nimesulide and doxorubicin combination vs. negligible as seen in cells treated individually. The expression of COX-2 was not altered in control or treatments, whereas PPAR-gamma was expressed only in the combination treatment. CONCLUSION: Our results indicate that aerosolized nimesulide significantly enhances doxorubicin activity against A549 cells, and the enhanced cytotoxicity was probably mediated via a COX-2-independent mechanism.

Aerosols↗
PubMed2004

LIDAR measurements of the vertical aerosol profile and optical depth during the ACE-Asia 2001 IOP, at Gosan, Jeju Island, Korea.

In order to investigate the characteristic of optical properties of Asian dust particles, the atmospheric aerosol vertical profile was measured with the multi-wavelength LIDAR system, at the Gosan super site (33 degrees 17'N, 126 degrees 10'E) in Jeju Island, Korea, during the ACE-Asia intensive observation period, 11 March-4 May 2001. An air mass backward trajectory analysis, using Hysplit-4, was carried out to track the aerosol plume, with high mass loading, from the Chinese desert regions during the period of Asian dust storm events. Vertical atmospheric aerosol profiles on three major Asian dust storm event days, 22 March and 13 and 26 April 2001, have been analyzed. The LIDAR-derived aerosol optical depth values were compared with those measured by a collocated sunphotometer.

Aerosols↗
PubMed2002

Marine aerosol formation from biogenic iodine emissions.

The formation of marine aerosols and cloud condensation nuclei--from which marine clouds originate--depends ultimately on the availability of new, nanometre-scale particles in the marine boundary layer. Because marine aerosols and clouds scatter incoming radiation and contribute a cooling effect to the Earth's radiation budget, new particle production is important in climate regulation. It has been suggested that sulphuric acid derived from the oxidation of dimethyl sulphide is responsible for the production of marine aerosols and cloud condensation nuclei. It was accordingly proposed that algae producing dimethyl sulphide play a role in climate regulation, but this has been difficult to prove and, consequently, the processes controlling marine particle formation remains largely undetermined. Here, using smog chamber experiments under coastal atmospheric conditions, we demonstrate that new particles can form from condensable iodine-containing vapours, which are the photolysis products of biogenic iodocarbons emitted from marine algae. Moreover, we illustrate, using aerosol formation models, that concentrations of condensable iodine-containing vapours over the open ocean are sufficient to influence marine particle formation. We suggest therefore that marine iodocarbon emissions have a potentially significant effect on global radiative forcing.

Aerosols↗
PubMed2000

Microbial aerosols in general dental practice.

OBJECTIVE: To measure the concentration of microbial aerosols in general dental practices and to use this information to carry out quantitative microbiological risk assessments. METHODOLOGY: Microbial air sampling was carried out continuously during 12 treatment sessions in 6 general dental practices in the South West of England. RESULTS: The microbial aerosol concentration in treatment rooms was generally less than 10(3) colony forming units per cubic metre of air (cfu x m(-3)). However, in 6 out of the 12 visits, at least one peak concentration with much higher numbers of bacteria was detected. The peak concentrations were associated with increased recoveries of presumptive oral streptococci suggesting these aerosols originated from the mouths of patients. These aerosol peaks dissipated within 30 minutes and no dissemination into waiting areas was detected. The peak concentrations were associated with mechanical scaling procedures (47% of procedures giving rise to a peak) and to a lesser extent by cavity preparation (11%). No aerosolised blood was detected. CONCLUSIONS: The data have been used to generate a framework for quantifying risk of exposure of staff to aerosolised microbial pathogens in general dental practice. For example, dentists and their assistants may have a slightly higher risk of exposure to Mycobacterium tuberculosis than the general public. The use of face seal masks that have been shown to protect against aerosolised micro-organisms may reduce this exposure.

Aerosols↗
PubMed2001

Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI-p53 complexes.

Lung metastases are a frequent complication of osteosarcoma and a treatment that would reduce the severity of this complication would be of great benefit to patients. We have used a formulation consisting of polyethyleneimine (PEI) and a p53 gene administered in aerosol to treat established lung micrometastases as a model of human osteosarcoma in nude mice. The SAOS-LM6 cell line, a metastatic derivative of the p53 null SAOS-2 line, expresses high levels of p53 protein after in vitro transfection with PEI-p53 complexes as determined by ELISA, and transfection with both p53wt and the p53 variant, p53-CD(1-366) in vitro, results in a marked inhibition of SAOS-LM6 cell proliferation. Aerosol delivery of plasmid DNA containing either the p53 gene or a p53-CD(1-366) variant gene formulated with PEI to mice resulted in highly significant reductions in the numbers and size of tumors (P<.001), the total number of tumor foci in the lungs (P<.001) and the size of individual tumor nodules in treated animals compared to untreated, PEI only-treated and PEI-CAT-treated control animals. The different tissues examined did not reveal any signs of toxicity or inflammation after repeated exposure to PEI-DNA. The aerosol delivery of PEI-based formulations of p53 or synthetic p53 variant genes represents a promising new strategy for the treatment of established human osteosarcoma lung metastases. The noninvasive nature of aerosol delivery coupled with low toxicity also make this therapeutic approach potentially appropriate for combination therapy with either radio- or chemotherapy.

Administration, Inhalation↗
PubMedDate not supplied

The role of condensation and coagulation in aerosol monitoring.

We derive general-purpose mathematical model for pollution concentration studies. The model is based on the aerosol general dynamic equation (GDE). It accounts for aerosol processes like coagulation and growth by deposition and is therefore suited for suspended-particle monitoring. Our model is validated by controlled experiments done using standard aerosol monitoring devices that measure PM10, particle cross section, particle-bound polycyclic aromatic hydrocarbons (PPAHs) and number concentration, showing an excellent agreement with the experimental data in a 77-m(3) room with a time sequence of cigarettes smoked. As an example of an application, we calculated the mean PPAH emission rate in environmental tobacco smoke (ETS) for a "smolder-smoked" cigarette and found it to be 8 ng/s for a total emission of 5.28 microg per cigarette. The results show that real aerosol dynamics should be taken into account when monitoring suspended particles.

Aerosols↗
PubMed1994

Measurement of fine aerosols in workplaces. A review.

The fine aerosol fractions of interest in occupational health are those associated with the regional deposition of inhaled aerosols in the different parts of the human respiratory tract. The recent recommendations of the International Standards Organization, the American Conference of Governmental Industrial Hygienists and the Comité Europeén de Normalisation define the thoracic fraction (inhaled particles which penetrate into the lung) and the respirable fraction (inhaled particles which penetrate further into the alveolar region). Based on the results of inhalation experiments with humans, conventional curves for these fractions are proposed, which provide 'yardsticks' for health-related sampling devices. Samplers for the respirable fraction have been in existence since the early 1950s, and a fairly large range of acceptable instrumentation is available commercially. Recently, however, attention has been drawn to the effect of even small departures from the 'target' curve on the respirable mass sampled. This suggests the need for additional criteria for sampler acceptability, based on sampled mass in addition to particle size selectivity. Samplers for the thoracic fraction may be based on similar physical concepts to those for respirable aerosol. In addition, versatile devices capable of providing information about more than one fraction simultaneously are being proposed and are finding increasing use as investigative tools for industrial hygienists. Finally, measurement of fine fibrous aerosols is recognized as a special case, and so is treated separately.

Aerosols↗
PubMed1994

Strategies for the simultaneous collection of vapours and aerosols with emphasis on isocyanate sampling.

Workplace air frequently contains hazardous substances that may be present as vapours or as aerosols with a wide range of particle sizes. Depending upon a chemical species' volatility and use, it may be present in significant amounts in both the vapour and particulate phases. Unfortunately, the mechanisms by which vapours and particles are removed from an air stream during pumped sampling are substantially different. Collection of vapour molecules relies on their diffusion to a surface during their residence time in a sampler. Once in contact with a surface, vapour molecules are trapped either by adsorption onto a solid surface, absorption by a liquid, or by reaction with the medium or chemicals in the medium. Aerosol particles are most frequently collected by filtration or inertial impaction. However, if it is necessary to collect both phases simultaneously, a sampler with two stages is generally required. The exact nature of the sampler depends upon the size of the aerosol particles and the physical and chemical characteristics of the species of interest. A number of recent projects undertaken by researchers at the National Institute for Occupational Safety and Health have dealt with development of sampling and analytical methods for compounds present in workplace air as both vapour and aerosol particles. One strategy invoked in several instances consisted of a filter for particle collection followed by an appropriate second stage for vapour collection. For organophosphorus pesticides, the second stage was a sorbent tube. For gaseous hydrogen fluoride, it was an alkaline-impregnated back-up pad. For formaldehyde, the second stage was an impinger containing an aqueous solution of sodium hydrogensulfite.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed2004

Correlations in the chemical composition of rural background atmospheric aerosol in the UK determined in real time using time-of-flight mass spectrometry.

An aerosol time-of-flight mass spectrometer (ATOFMS) was used to determine, in real time, the size and chemical composition of individual particles in the atmosphere at the remote inland site of Eskdalemuir, Scotland. A total of 51,980 particles, in the size range 0.3-7.4 microm, were detected between the 25th and 30th June 2001. Rapid changes in the number density, size and chemical composition of the atmospheric aerosol were observed. These changes are attributed to two distinct types of air mass; a polluted air mass that had passed over the British mainland before reaching Eskdalemuir, interposed between two cleaner air masses that had arrived directly from the sea. Such changes in the background aerosol could clearly be very important to studies of urban aerosols and attempts at source apportionment. The results of an objective method of data analysis are presented. Correlations were sought between the occurrence of: lithium, potassium, rubidium, caesium, beryllium, strontium, barium, ammonium, amines, nitrate, nitrite, boron, mercury, sulfate, phosphate, fluorine, chlorine, bromine, iodine and carbon (both elemental and organic hydrocarbon) in both fine (d < 2.5 microm) and coarse (d > 2.5 microm) particle fractions. Several previously unreported correlations were observed, for instance between the elements lithium, beryllium and boron. The results suggest that about 2 in 3 of all fine particles (by number rather than by mass), and 1 in 2 of all coarse particles containing carbon, consisted of elemental carbon rather than organic hydrocarbon (although a bias in the sensitivity of the ATOFMS could have affected these numbers). The ratio of the number of coarse particles containing nitrate anions to the number of particles containing chloride anions exceeded unity when the air mass had travelled over the British mainland. The analysis also illustrates that an air mass of marine origin that had travelled slowly over agricultural land can accumulate amines and ammonium.

Aerosols↗
PubMed2005

Secondary organic aerosols from anthropogenic and biogenic precursors.

Secondary organic aerosol (SOA) formation from the photooxidation of an anthropogenic (1,3,5-trimethylbenzene) and a biogenic (alpha-pinene) precursor was investigated at the new PSI smog chamber. The chemistry of the gas phase was followed by proton transfer reaction mass spectrometry, while the aerosol chemistry was investigated with aerosol mass spectrometry, ion chromatography, laser desorption ionization mass spectrometry, and infrared spectroscopy, along with volatility and hygroscopicity studies. Evidence for oligomer formation for SOA from both precursors was given by an increasing abundance of compounds with a high molecular weight (up to 1000 Da) and by an increasing thermal stability with increasing aging time. The results were compared to data obtained from ambient aerosol samples, revealing a number of similar features.

Aerosols↗
PubMed2005

Measuring rates of reaction in supercooled organic particles with implications for atmospheric aerosol.

The kinetics of heterogeneous reactions involving supercooled organic droplets is reported for the first time. Reactions between ozone and internally-mixed sub-micrometre particles containing an unsaturated alkenoic acid, oleic acid, and an n-alkanoic acid, myristic acid, were studied as a simple model for the oxidation of meat-cooking aerosol. The reactions were followed by monitoring the rate of oleic acid loss using an Aerosol CIMS (chemical ionization mass spectrometry) instrument for real-time particle analysis. Evidence of as much as 32 degrees C supercooling at room temperature was observed depending on particle composition. FTIR spectra of the aerosol also demonstrate features indicative of supercooling. Particles in which crystallization was induced by cooling below room temperature demonstrated decreased reactivity by a factor of 12 compared to supercooled particles of the same composition. This drastic difference in reactivity could have significant implications for the lifetimes of reactive species in ambient aerosol as well as for the accurate source apportionment of particulate matter.

Aerosols↗
PubMed1991

Variability in the measurement of nebulized aerosol deposition in man.

1. This study was performed to determine the variability of two different scintigraphic methods of measuring pulmonary aerosol deposition, and to examine nebulizer particle size and drug output as potential sources of this variability. 2. A radioaerosol was produced from a 3 ml solution of 99mTc-labelled colloidal human serum albumin (0.05 mg, 37 MBq) using a standard jet nebulizer and air compressor. This was inhaled on three separate occasions by nine healthy male subjects. One one of these occasions, a further inhalation was performed to assess immediate repeatability using increased 99mTc activity (92 MBq). 3. Intrapulmonary aerosol deposition was measured with a gamma-camera and was corrected for tissue attenuation and geometric distribution by using two different methods. 4. Estimated mean pulmonary deposition was 4.3% of the nebulizer dose using a lung phantom correction method, and 6.1% using a tissue attenuation method. For these two methods respectively variability between subjects (coefficient of variation) was 54 and 47%. For both methods, within-subject variability (coefficient of variation) was 37% between occasions and 23% within occasions. 5. The particle-size output of several nebulizers was highly reproducible (coefficient of variation less than 4%), but the nebulizer mass and radionuclide output of two nebulizers was more variable (coefficient of variation 5-19%), and appeared to be an important contributor to the variability in pulmonary aerosol deposition. 6. The data presented here for pulmonary deposition, used with appropriate power statistics formulae, can be used to estimate the sample sizes required for comparative studies of lung aerosol deposition.

Aerosols↗
PubMed1999

Systemic availability of budesonide after nasal administration of three different formulations: pressurized aerosol, aqueous pump spray, and powder.

AIMS: The present study was undertaken to determine the absolute systemic availability of budesonide from three different devices for nasal administration: pressurized aerosol, aqueous pump spray, and powder. METHODS: Sixteen healthy, non-smoking, volunteers participated in this open, randomized, and crossover study. All subjects received budesonide as an intravenous dose of 400 microg, and as three, single-dose, intranasal administrations: pressurized aerosol 800 microg, aqueous pump spray 400 microg, and powder 800 microg. Blood was sampled for 10 h after each administration and budesonide was assayed in plasma by liquid chromatography plus mass spectrometry. RESULTS: The mean [95% CI] systemic availability of budesonide with reference to the metered dose was: 13 [10; 15]%, 29 [23; 37]%, and 20 [16; 23]%, and the maximum plasma concentration (Cmax) was attained at (tmax) 2.0, 0.7, and 0.4 h after administration for the pressurized aerosol, aqueous pump spray, and powder, respectively. CONCLUSIONS: The uptake of budesonide was more rapid and more complete, and the systemic availability of the drug was significantly higher from the aqueous pump spray and powder than from the pressurized aerosol.

Administration, Intranasal↗
PubMed2000

Survival of mycobacterial species in aerosols generated from artificial saliva.

Tuberculosis is transmitted primarily by the aerosol route and the aim of this study was to measure the ability of pathogenic mycobacteria to survive in aerosols generated from artificial saliva. Aerosols of Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium tuberculosis were generated and maintained in air under controlled conditions using a Henderson apparatus and a rotating drum. There were no differences in aerosol survival between the three species, and all had a poor survival rate over a period of 1 h. These data confirm epidemiological studies that close and prolonged contact with a TB patient is required for transmission of infection.

Aerosols↗
PubMed1999

Activity of aerosol thiamphenicol glycinate acetylcysteinate in a mouse model of S. pyogenes pneumonia.

Thiamphenicol glycinate acetylcysteinate (TGA, CAS 20192-91-0) is a water soluble ester of thiamphenicol (TAP) that allows a rapid utilization by the systemic route but also a direct local action when used as aerosol. To assess the efficacy of aerosolized TGA in the treatment of experimental pneumonia in mice, we compared its in vivo activity with that of thiamphenicol glycinate hydrochloride (TG), erythromycin (ERT) and amoxicillin (AMX), the last two compounds being more active in vitro than TAP. TGA, administered by aerosol route, showed better efficacy than the aerosolized TG, particularly as far as survival rate is concerned, and was significantly more potent than ERT and similar to AMX either administered by oral route. No significantly different therapeutic efficacy was observed when TGA was parenterally administered. The rapid release, at the site of infection, of TAP and N-acetylcysteine and the favourable pharmacokinetic properties of TGA accounted in large part for its high therapeutic efficacy against Streptococcus pyogenes pneumonia.

Acetylcysteine↗