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[Scintigraphic assessment of pulmonary deposition of pentamidine administered by aerosol].

Isotopic techniques enable to determine the best conditions to aerosolize pentamidine as a preventive treatment of pneumocystis. An original labelling technique of pentamidine isethionate has led into a feasibility study of pentamidine scintigraphy in the monkey, and then to a clinical study. A tracer dose of 2 mg of pentamidine isethionate was diluted into 200 mg of pentamidine mesylate. An ultrasonic nebulizer (TV 6000) and a jet nebulizer (Venticis II) were first compared in four baboons. With the two nebulisers the curves of pulmonary kinetic activity showed a peak 10-15 minutes after the beginning of inhalation and then a plateau. With the ultrasonic TV6000 the pulmonary dose was on average 0.8 mg or 0.4% of the pentamidine aerosolized and the gastric contamination 3.1%. With the Venticis II compressed air apparatus the amount of pentamidine delivered to the deep lung was a mean of 4.2 mg or 2.1% of the aerosolized dose whereas the gastric contamination was only 0.5%. The delivery of the aerosol by the ultrasonic inhaler TV 6000 was then compared with two compressed air inhalers Venticis II and Respirgard II in four patients infected with HIV virus who were submitted to a preventative therapy against pneumocystis. With the ultrasonic TV 6000 the pulmonary dose was 0.8 mg or 0.3%-0.5% of the dose of pentamidine aerosolized and the digestive contamination was 3.1%. The performance of the two compressed air nebulizers Venticis II and Respirgard II were similar. The amount of pentamidine delivered to the deep lung was respectively 12 and 14 mg or 6 and 8% of the dose of pentamidine aerosolized and the digestive activity was 0.2%.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗

Sterilization efficacy of ultraviolet irradiation on microbial aerosols under dynamic airflow by experimental air conditioning systems.

In order to know the sterilization efficacy of ultraviolet irradiation on microbial aerosols, the size and the weight of the aerosol particles were evaluated, and these were irradiated under dynamic air flow created by an experimental air conditioning system. The experimental apparatus consisted of a high efficiency particulate air (HEPA) filter, an aerosol generator, spiral UV lamps placed around a quart glass tube, an Andersen air sampler and a vacuum pump. They were connected serially by stainless steel ducts (85 mm in diameter, 8m in length). Six types of microbial aerosols generated from an ultrasonic nebulizer were irradiated by UV rays (wavelength 254nm, mean density 9400 microW/cm2). Their irradiation time ranged from 1.0 to 0.0625 seconds. The microbial aerosols were collected onto the trypticase soy agar (TSA) medium in the Andersen air sampler. After incubation, the number of colony forming units (CFU) were counted, and converted to particle counts. The diameter of microbial aerosol particles calculated by their log normal distribution were found to match the diameter of a single bacteria cell measured by a microscope. The sterilization efficacy of UV in standard airflow conditions (0.5 sec. irradiation) were found to be over 99.5% in Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens, Bacillus subtilis (vegetative cell) and Bacillus subtilis (spore) and 67% in Aspergillus niger (conidium). In A. niger, which was the most resistant microbe to UV irradiation, the efficacy rose up to 79% when irradiated for 1.0 sec., and it was observed that the growth speed of the colonies was slower than that of the controls. It was thought that UV rays caused some damage to the proliferation of A. niger cells.

Aerosols↗

Treatment of steroid-dependent asthma with triamcinolone acetonide aerosol.

Corticosteroids, originally developed as topical agents, have proved effective in aerosol form in the treatment of asthma. Of 33 chronic bronchial asthmatic patients dependent on oral corticosteroids, 16 were randomly selected for treatment with triamcinolone acetonide aerosol and 17 for treatment with triamcinolone acetonide aerosol and 17 for treatment with placebo to determine the effectiveness of the active drug and the feasibility of eliminating or reducing oral steroids. Aerosol dosages of 800 g daily continued for 12 weeks. The patients improved about 30, 50 and 60% in mean FVC, FEV1, and FEF25 75, respectively. Their mean oral steroid dose dropped 77%, with 13 of the 16 discontinuing oral steroids entirely, and their asthma symptoms decreased about 30%. Placebo patients showed minimal or no improvement in these areas. The clinical results indicated that 14 of 16 active aerosol and 4 of 17 placebo aerosol patients improved over baseline. No side effects or fungal infections appeared and only two patients experienced oral-steroid withdrawal symptoms.

Administration, Oral↗

[Fundamental investigations for the deposition of aerosols from radioactive solutions in the upper and lower airways (author's transl)].

By means of 99mtechnetium diphosphonate and a scintillation camera we measured the deposition of aerosols. During normal breathing rhythm and without leading the aerosol by valves the retention in the lower airways was on an average of 5.6%, that is 0.07 ml/min. By installation of suitable valves for in- and expiration and mouth tubes, deep and complete expiration with breath holding the retention of the aerosol increases to 17.3-13.8% (0.22-0.17 ml/min); with normal breathing the deposition was only 9%. In the upper airways we found the following deposition rates: Nose/hypopharynx (inhalation via mask) 2.6%; Mouth and pharynx (after rinsing) 1.6%; Larynx 0.1%. A considerable part remains in the inhalation system; by special variations we were able to reduce this portion of the aerosol. After inhaling electro-aerosols (4 kv) the deposition in the lungs was 5.6%; the more the charge was reduced the more the deposition of the aerosol in the lung increased.

Aerosols↗

Respiratory disease in calves produced with aerosols of parainfluenza-3 virus and Pasteurella haemolytica.

In four experiments, 22 calves were exposed to aerosols of parainfluenza-3 virus, followed by Pasteurella haemolytica at intervals of three to 13 days. The purpose of each experiment was to study viral-bacterial interactions in the respiratory tracts. Two experiments, in which the viral aerosols were diluted by the addition of air, produced sporadic temperature elevations while two experiments with undiluted viral aerosols produced consistent temperature elevations. Diluted viral aerosols produced lobular sized lesions in the lungs and hemagglutinating inhibition antibodies in sera, whilst undiluted aerosols produced a synergistic effect in the form of purulent pneumonia in ten of 14 calves when the interval between viral and bacterial aerosols was from three to ten days. Histopathological changes attributable to the virus only were seen in all experiments, and the histopathological changes due to mixed infection of parainfluenza-3 virus and P. haemolytica are described in detail. This is the first report of extensive purulent pneumonia in calves after parainfluenza-3 virus and P. haemolytica exposure. This was achieved using much smaller inocula than in experiments previously reported.

Aerosols↗

Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone.

To determine whether cough and bronchoconstriction result from alterations in the osmolarity or alterations in the ion concentration of inhaled aerosols and to determine if the specific ions in the aerosol are important, we had 9 subjects with mild asthma inhale various solutions while we recorded cough and measured specific airway resistance. To evaluate the effects of altering osmolarity and ion concentration separately, we administered aerosols of hypo-osmolar distilled water (0 mosm), iso-osmolar sodium chloride (308 mosm), iso-osmolar dextrose in water (308 mosm), hyperosmolar sodium chloride (1,232 mosm), and a hyperosmolar solution of dextrose and sodium chloride (1,232 mosm). To evaluate cough without bronchoconstriction, we had the subjects inhale metaproterenol before inhaling the same aerosols. To determine whether the absence of a specific ion was important in causing cough or bronchoconstriction, we had the subjects inhale iso-osmolar solutions of sodium bromide, sodium gluconate, and lysine monohydrochloride. We found that alteration in osmolarity away from iso-osmolarity of inhaled aerosols is a stimulus for bronchoconstriction in subjects with mild asthma. Absence of ions in the presence of iso-osmolarity is not a stimulus for bronchoconstriction, but the absence of a permeant anion is a stimulus for cough. Thus, we found that the responses of cough and bronchoconstriction to inhaled aerosols can be separated.

Adult↗

Cool and heated aerosol and the measurement of oral temperature.

This study investigated the establishment of a data base for use when assessing body temperature in patients receiving aerosol therapy by face mask. Thirty subjects participated in two different treatment situations. Baseline temperature recordings were taken while subjects had heated aerosol administered through a standard face mask. Temperature recordings were repeated at one-minute and five-minute intervals after the mask was removed. Temperature recordings were repeated using cool aerosol treatments. An electronic thermometer was used for sublingual temperature recordings, and a polygraph with preamplifier and thermocouple interface was used to record changes in air temperature at the portal entry of the face mask. Constant monitoring of controlled ranges of aerosol temperature at the portal entry site allowed comparison of data during treatment. Significant effects were reported for both the cool and heated aerosol treatments. A comparison of mean baseline temperature with temperatures obtained at the measurement intervals yielded no change greater than three-tenths degree centigrade. This investigation suggested that a statistically significant change in oral temperature with treatments took place but there is relatively little clinically significant change in oral temperature due to aerosol temperature's influence.

Adult↗

Clinical ventilation imaging with In-113m aerosol: a comparison with Kr-81m.

Following routine ventilation (Kr-81m)/perfusion (Tc-99m) scanning, we obtained aerosol ventilation scans using a solution of In-113m albumin and a settling-bag system. The large-volume settling bag reduces deposition of particles in the large airway by removing large droplets. The patient inhales the aerosol with 5-10 min of tidal breathing, then lung scans are obtained on a gamma camera. The energy of In-113m allows the ventilation scanning to be performed after Tc-99m perfusion scanning. Semiquantitative scoring of regional ventilation showed a close correlation (r = 0.97) between Kr-81m and In-113m aerosol ventilation scans. The aerosol technique gave a slight underestimation of ventilation compared with Kr-81m. This is explained by a slightly reduced penetration of particles to the periphery of the lung in patients with severe obstructive airways disease. In all cases, however, the aerosol did visualize all ventilated regions. The results indicate that this readily available aerosol technique can be useful for clinical ventilation imaging in multiple views.

Adult↗

Inhalation lung imaging with radioactive aerosols and gases.

Krypton lung-imaging is considered the ventilation procedure of choice when it is available. Aerosol and krypton wash-in images both reveal regional abnormalities of ventilation, but the aerosol images also disclose evidence of major airways disease. Xenon wash-out images are probably the most sensitive indicators of regional abnormalities of ventilation and/or small airways obstruction, whereas xenon wash-in images are far less sensitive and may be frequently misinterpreted. The Tc-DTPA aerosol inhalation procedure is perferred over xenon and krypton ventilation imaging for routine use immediately after a perfusion examination in pulmonary embolism suspects. This combined method provides the referring physician with the necessary diagnostic information quickly and with around-the-clock availability. In our opinion, this new aerosol procedure deserves wider application in the diagnosis and management of pulmonary disease. Lung imaging procedures, performed after th inhalation of 99mTechnetium labeled aerosols, 133Xenon and and 81mKrypton gases, were used to visualize the sites of airway obstruction and regional abnormalities of ventilatory function in normal volunteers, patients with obstructive airway disease and pulmonary embolism suspects. This chapter presents intercomparisons of these three methods regarding their functional significance, diagnostic merits, and limitations. A new nebulizer-radioaerosol delivery system is described. Test agent kits are inexpensive and readily available for on site assembly. Currently, we consider radioaerosol imaging in multiple views as more informative and suitable for routine use than xenon methods to detect regional abnormalities of the airways and ventilatory function. The krypton procedure is preferred in pulmonary embolism suspects because it requires far less patient cooperation than the xenon and aerosol methods and the lung images disclose regional ventilatory impairment quickly and accurately. However, krypton gas is cyclotron-produced and not yet commercially available.

Adolescent↗

A metal aerosol holding chamber devised for young children with asthma.

The low tidal volume and flow in preschool children may reduce the efficiency of aerosol delivery from a pressurized metered-dose inhaler (pMDI) through a traditional holding chamber. A prototype small-volume steel holding chamber with two one-way valves was devised to prolong aerosol availability in the chamber and to ensure unidirectional airflow. Dead space between the valves was minimized to less than 2 ml. The dose-delivery and rate of passive disappearance of a budesonide pMDI aerosol were compared between this prototype and the large-volume, single-valved plastic Nebuhaler, in 164 asthmatic children less than 8 yrs of age. In vitro, the half life of aerosol disappearance in the steel prototype and the plastic Nebuhaler was > 30 s and 9 s, respectively. In vivo, the prototype delivered an age-independent mean dose of 38% of the nominal dose, and the Nebuhaler delivered an age-dependent mean dose, ranging from 42% of the nominal dose in children > or = 4 yrs to 19% of the nominal dose in infants. We conclude that the use of plastic for holding chambers may influence dose-delivery, and single-valve control may cause age-dependent dose-delivery. Reproducible age-independent drug-delivery may be achieved by pMDI aerosol inhaled through a small-volume metal holding chamber with separate inlet and outlet valves and minimized dead space. This holding chamber would improve the possibilities of aerosol therapy for young children.

Administration, Inhalation↗

Frequency of voice problems and cough in patients using pressurized aerosol inhaled steroid preparations.

The aim of the study was to assess the prevalence of throat and voice symptoms in asthma patients using pressurized aerosol, metered-dose, inhaled corticosteroid preparations. A questionnaire was administered to hospital out-patients in an asthma clinic and to a control group attending a diabetic clinic. Two hundred and fifty five consecutive out-patients using pressurized aerosol inhaled corticosteroids and 100 controls were surveyed. One hundred and forty seven (58%) patients taking inhaled steroids reported voice dysphonia or throat symptoms compared with 13% of control patients. Women admitted to symptoms more frequently than men. Throat symptoms were more prevalent in patients using higher doses of inhaled steroid. Aerosol inhaler-induced cough was reported by 87 (34%) patients. Local side-effects were equally prevalent both with beclomethasone dipropionate and budesonide aerosol inhalers. The use of a large volume spacing device with either steroid aerosol did not appear to protect against these symptoms. Local side-effects are common in asthmatics taking pressurized aerosol, metered-dose, inhaled steroids.

Aerosols↗

[Assessment of pulmonary aerosol deposition and epithelial permeability in 99mTc-DTPA inhalation scintigram].

The degree of lung injury in bronchiolo-alveolar lesions may be quantitated from the pulmonary epithelial permeability estimated by 99mTc-DTPA (diethylene triamine penta acetate) aerosol inhalation scintigram. However, significant aerosol deposition sometimes occurs in the central airways and obscures the permeability change in the lung periphery. The radioaerosol deposition pattern and its effect on assessing the pulmonary epithelial permeability was studied. 99mTc-DTPA aerosol scintigraphy was performed in 47 patients with pulmonary fibrosis (PF), 12 patients with chronic obstructive pulmonary diseases (COPD), and 27 non-smoking and 17 smoking healthy volunteers. The scintigraphic images of the lungs were classified into 4 grades, 0; homogeneous distribution, 1; patchy distribution, 2; hot spots with partial defect, and 3; hot spots with little deposition in the lung field. The rate constant was used as a parameter for the permeability. The smokers and patients with PF showed increased kep values of 2.36 +/- 1.21%/min (mean +/- SD) and 2.49 +/- 1.29%/min as compared with the nonsmokers with 0.94 +/- 0.27%/min, respectively. The nonsmokers, smokers and 36 patients with PF were classified as deposition grade 0 or 1, suggesting good aerosol penetration to the lung periphery. All patients with COPD showed either grade 2 or 3 deposition. Aerosol deposition in the central airways can cause underestimation of the permeability because of the thicker lining layer in the bronchus than in the alveolus. In conclusion, the aerosol deposition pattern should be analyzed when the method is applied clinically to assess the permeability of the bronchiolo-alveolar epithelium.

Adult↗

[Pulmonary deposition of colistin aerosols in cystic fibrosis. Comparison of an ultrasonic nebulizer and a pneumatic nebulizer].

The objective of this study was to quantify the deposition in the lung of a Colistine aerosol generated using a pneumatic nebuliser (Pari LL(R) equipped with a Pari Master, Pari, Germany) and to compare this with the results obtained with an ultrasonic nebuliser (DP100, DP Medical, France) in four subjects suffering from cystic fibrosis being colonised with Pseudomonas aeruginosa. To quantify the pulmonary deposition of the aerosols we have used an indirect isotopic method which consists in assimilating the kinetics of the molecules studied with a serum albumin tagged with Technetium 99m (Tc99mm) and added to a preparation of Colistine. We have previously verified that the addition of a radioactive tracer does not change the normal distribution or dynamics of the medication within the aerosol and the radioactive counter linked to the tracer reflects the mass of the medicament. The pulmonary deposition was expressed as a percentage of the nebuliser dose. A regional analysis of the deposition (central, peripheral, superior and inferior) was carried out and in central deposition compared to the periphery (C/P) and superior compared to inferior (S/I) were calculated. With the DP100 nebuliser the pulmonary deposition of the aerosol was very reproducible from one patient to another, varying only between 9.5 to 14 percent of the nebuliser dose. With the Pari LL the fraction deposited varied more from one patient to another from 5.6 to 27% of the nebuliser dose. In three of four patients, the pulmonary deposition was superior or equal to that obtained with the ultrasonic nebuliser. The patients whose pulmonary deposition was inferior, using the pneumatic nebuliser, was the youngest in the group and co-ordinately poorly the triggering of the nebuliser with the beginning of inspiration. With the two nebulisers, the pulmonary deposition of Colisitine was very heterogeneous throughout the pulmonary parenchyma. The mean of the ratio C/P and S/I obtained in all four patients was identical (1.35 an 0.86 respectively), indicating a deposition of the aerosol which was predominantly central and inferior but was distributed equally in the peripheral parts of the lung. Pneumatic nebulisers offer a reliable alternative notably for domiciliary treatment for Colistine aerosols in patients suffering from cystic fibrosis. In younger patients who have not yet acquired good motor co-ordination, nebulisers which function continuously or are triggered by inspiration seem to be the preferred choice.

Administration, Inhalation↗

Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation.

Inhalation of nitric oxide (NO) causes selective pulmonary vasodilation, but demands continuous supply of the gaseous agent. We investigated the suitability of aerosolization of NO-donor drugs for achieving sustained reduction of pulmonary vascular tone. In buffer-perfused rabbit lungs, stable pulmonary hypertension was achieved by continuous infusion of the thromboxane-analogue U46619. The NO-donor drugs molsidomine, 3-morpholinosydnone-imine (SIN-1), sodium nitroprusside (SNP) and glyceryl-trinitrate reduced the pulmonary hypertension in a dose-dependent fashion, whether admixed to the perfusate or inhaled as alveolar-accessible aerosol particles (aerosolization time 3-6 min), with an efficiency ranking of SNP > SIN-1 >> molsidomine and glyceryl-trinitrate. Notably, nearly identical dose-response curves were obtained when corresponding molar quantities of the most potent agents, SNP and SIN-1, were applied either via transbronchial or via intravascular routes, with respect to rapidity of onset, extent (pressure reduction to near baseline) and duration (>90 min) of vasorelaxation. Appearance of sydnonimines in the perfusate after aerosolization and reduction of SIN-1 efficacy when nebulized in nonrecirculatingly perfused lungs demonstrated substantial entry of this prodrug into the vascular space after alveolar deposition. In contrast, undiminished vasodilatory efficacy of aerosolized SNP under conditions of non-recirculating perfusion suggested predominant efficacy via local NO release for this agent. We conclude that short aerosolization maneuvers of NO-donor drugs are suitable to achieve dose-dependent, extensive and sustained vasodilation in the pulmonary circulation, thus offering a new therapeutic approach in pulmonary hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

Protection against influenza infection by cytokine-enhanced aerosol genetic immunization.

BACKGROUND: Conventional vaccine development for newly emerging pandemic influenza virus strains would likely take too long to prevent devastating global morbidity and mortality. If DNA vaccines can be distributed and delivered efficiently, genetic immunization could be an attractive solution to this problem, since plasmid DNA is stable, easily engineered to encode new protein antigens, and able to be quickly produced in large quantities. METHODS: We compared two novel genetic immunization methods in a mouse model of influenza to evaluate protective effects: aerosol delivery of polyethylenimine (PEI)-complexed hemagglutinin (HA)-expressing plasmid and intravenous (IV) delivery of the plasmid complexed with macroaggregated albumin/PEI. Serial serum samples were obtained for assay of neutralizing antibodies against HA. Mice were then challenged in the airway with influenza virus, and production of infectious virus in the lungs was titered. RESULTS: Most mice immunized with HA plasmid alone by aerosol and all mice immunized IV developed protective immune responses, whereas none administered control plasmid were protected. Aerosol co-administration of HA plasmid with plasmids encoding the cytokines interleukin 12 (IL12) and granulocyte-macrophage colony stimulating factor (GM-CSF) markedly increased neutralizing antibody responses, so that all aerosol immunized mice were protected from high level virus proliferation. CONCLUSIONS: Cytokine-enhanced aerosol delivery of plasmid vaccines can elicit robust protective immune responses against influenza. Thus, aerosol delivery has the potential to address the need for rapid widespread immunization against new influenza virus strains, and may have applications for other infectious and toxic disease processes.

Animals↗

Redesigned face mask improves "real life" aerosol delivery for Nebuchamber.

The currently available facemask interface for the Nebuchamber (N) valved-holding chamber (VHC) provides a very poor seal to the face, which, on average, decreases the aerosol dose and was previously shown to increase the variability of aerosol delivery. The efficiency of a redesigned mask (RD) for the Nebuchamber with a potentially better seal was compared to the standard mask (SM) supplied with the N in a randomized real-life crossover clinical trial. Twenty children (mean age, 26 +/- 10 months) were randomized to use the Nebuchamber for 1 week with the old mask and then for another week with the newer mask, and vice versa. Filters, changed daily, inserted between the mask and the VHC, trapped the delivered drug (budesonide). The dose of budesonide was quantified by high-performance liquid chromatography (HPLC). Use of the redesigned mask improved aerosol delivery to the filter by 30%, compared to the SM (mean 28.1 +/- 7.7% of nominal dose with RD vs. 21.6 +/- 9.6% with SM, P = 0.017). The relatively high within-subject variability in aerosol delivery (36-38%) did not change, however. Facemasks are arguably the most important determinants of aerosol delivery. The newly developed RD for the Nebuchamber proved to be considerably more efficient than the SM for aerosol delivery to young children. Patient-related factors may be more important with respect to the variability observed.

Asthma↗

Aerosol delivery in neonatal ventilator circuits: a rabbit lung model.

The benefits of inhaled therapy in ventilated neonates are recognized, but the reliability of drug delivery in nebulizer-ventilator circuits is uncertain. We quantified the effect of changing variables. Twenty-three freshly killed rabbits (1.15-1.9 kg) were ventilated via a tracheostomy by a pressure-limited, time-cycled ventilator (Neovent). A radioaerosol of 99Tcm pertechnetate from an Ultravent nebulizer (Mallinkrodt) was fed into the proximal ventilator tubing. Two 3-minute nebulizations at "standard settings" were followed by 2 at altered pressure, frequency, gas flow, I:E ratio, or position of the nebulizer in the circuit. Each nebulization was followed by a 3-minute gamma camera image and total deposited radioactivity was measured in excised lungs and trachea. Images demonstrated good peripheral aerosol deposition. At standard settings, lung deposition averaged 2.8% of the aerosol released. This was decreased markedly by reducing tidal volume (ventilator pressures) and residence time of aerosol (I:E ratio). Reduced gas flow decreased deposition slightly, presumably by increased particle size and marginally reduced tidal volume. Deposition did not change with increased frequency; increased minute ventilation was offset by decreased residence time of the aerosol. We conclude that the Ultravent nebulizer can be used to nebulize drugs in a standard neonatal circuit, although the dose delivered is small. Tidal volume and aerosol residence time are important determinants of aerosol delivery.

Animals↗

Aerosol administration of antibiotics.

Antibiotics can be aerosolized to the lower respiratory tract of patients with pulmonary infections. With attention to stability of the antibiotic, its ability to be aerosolized, and particle size of the aerosol, rational design of an antibiotic aerosol treatment regimen is possible. The choice of nebulizer for aerosol antibiotic administration depends not only on drug stability under the nebulization conditions, but practical considerations such as ease of use in the home and expense. In general, a greater volume of respirable aerosol is generated by an ultrasonic device in comparison to the jet nebulizers. Of the factors affecting antibiotic delivery to the lower respiratory tract, the patients and their disease are the most important. This patient effect is not directly amenable to medical intervention, but can be controlled through measurement of antibiotic concentrations in respiratory secretions, seeking a target estimated from the best available in vitro data.

Administration, Inhalation↗