In vitro performance testing of the novel Medspray wet aerosol inhaler based on the principle of Rayleigh break-up.
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ABSTRACT:
SUBMITTER: de Boer AH
PROVIDER: S-EPMC2292500 | biostudies-other | 2008 May
REPOSITORIES: biostudies-other
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Project description:PurposeThe Respimat is a handheld, propellant-free, soft-mist inhaler. Observations by patients and physicians prompted development of an improved second-generation Respimat inhaler. Human-factor studies assessing the usability of the new inhaler and in vitro assessment of aerosol performance are important to demonstrate functionality of the updated inhaler.MethodsStudies were performed to assess any possible impact of the reusable Respimat inhaler design on aerosol performance (delivered dose [DD] and fine-particle dose [FPD]) and iteratively assess and improve usability of the new design. The tiotropium-olodaterol inhalation solution for Respimat was used as a model. The DD and FPD of the reusable Respimat inhaler (across multiple cartridges) and the disposable Respimat inhaler were determined by laser diffraction and with an alternative Andersen cascade impactor. Usability was measured across three studies involving health care professionals and patients with diagnoses of COPD, asthma, or combined disease (with and without experience with the Respimat inhaler). These studies measured performance of handling tasks and collected subjective feedback directly related to the inhaler's new or altered features, which fed into optimization of the inhaler.ResultsDDs of tiotropium and olodaterol were stable up to 15 cartridges and consistently within the upper and lower limits of the disposable Respimat inhaler. The FPD was also found to be batch-consistent over the cartridges and comparable with the reference. The usability of the reusable Respimat inhaler compared with the disposable inhaler was improved in terms of assembly and daily use. Cartridge exchange was rated as intuitive and easy to very easy.ConclusionThe new reusable Respimat is a medical inhaler developed with enhanced features that meets health care professionals' and patients' needs. Drug delivery across multiple cartridges is not affected by the design. Compared with the original disposable inhaler, the usability of the reusable inhaler has been improved, and cartridge exchange was rated as easy to perform. The reusable Respimat provides greater convenience for patients vs the disposable inhaler, with reduced environmental impact.
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Project description:The effectiveness of metered-dose inhalers (MDIs) in delivering medication to the lungs highly depends on its correct usage technique. Current guidelines state optimal technique for high lung deposition should include a slow inhalation (>5 seconds) at an inspiratory flow rate of 30?L/min and inhaler actuation at the start of inhalation. However, these recommendations were based on clinical studies using CFC (chlorofluorocarbon)-MDIs and in vitro studies of HFA (hydrofluoroalkane)-MDIs using idealized MDI techniques of uniform inhalation and actuation, disregarding the nonuniform techniques of actual patients.To better understand the effects of time-varying MDI usage parameters on lung deposition of aerosol delivered by an HFA-MDI, we conducted an in vitro study modeled on real-life variable inspiratory flow and actuation techniques recorded from 15 subjects with asthma/chronic obstructive pulmonary disease (COPD). We developed a model representing the time-varying inspiratory flow waveforms and actuation timings based on 43 MDI techniques recorded from patients. Furthermore, we constructed an in vitro experimental setup using a mouth-throat cast, programmable MDI actuator, and breath simulator to evaluate lung deposition for the MDI techniques derived from our model.High inspiratory flow rates, 60-90?L/min, consistently resulted in high in vitro lung deposition (>40%) of aerosol (albuterol delivered from Ventolin HFA-MDI) compared to 30?L/min when MDI actuation occurred in the first half of inhalation. Also, positive coordination resulted in higher in vitro lung deposition compared with negative or zero coordination (actuating before or at the start of inspiration). Furthermore, variation in coordination affected lung deposition more significantly (23%) than flow rate or duration of inspiration (?5%).In an in vitro experimental model based on inhalation data from patients with asthma and COPD, we demonstrated that aerosol lung deposition emitted from Ventolin HFA-MDI is most optimal for MDI actuation in the first half of inspiration at high flow rates (60-90?L/min).
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Project description:Ultra-bright femtosecond X-ray pulses generated by X-ray free-electron lasers (XFELs) can be used to image high-resolution structures without the need for crystallization. For this approach, aerosol injection has been a successful method to deliver 70-2000?nm particles into the XFEL beam efficiently and at low noise. Improving the technique of aerosol sample delivery and extending it to single proteins necessitates quantitative aerosol diagnostics. Here a lab-based technique is introduced for Rayleigh-scattering microscopy allowing us to track and size aerosolized particles down to 40?nm in diameter as they exit the injector. This technique was used to characterize the 'Uppsala injector', which is a pioneering and frequently used aerosol sample injector for XFEL single-particle imaging. The particle-beam focus, particle velocities, particle density and injection yield were measured at different operating conditions. It is also shown how high particle densities and good injection yields can be reached for large particles (100-500?nm). It is found that with decreasing particle size, particle densities and injection yields deteriorate, indicating the need for different injection strategies to extend XFEL imaging to smaller targets, such as single proteins. This work demonstrates the power of Rayleigh-scattering microscopy for studying focused aerosol beams quantitatively. It lays the foundation for lab-based injector development and online injection diagnostics for XFEL research. In the future, the technique may also find application in other fields that employ focused aerosol beams, such as mass spectrometry, particle deposition, fuel injection and three-dimensional printing techniques.
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Project description:The AKP (Anna Karenina principle), which refers to observations inspired by the opening line of Leo Tolstoy's Anna Karenina, "all happy families are all alike; each unhappy family is unhappy in its own way," predicts that all "healthy" microbiomes are alike and each disease-associated microbiome is "sick" in its own way in human microbiome-associated diseases (MADs). The AKP hypothesis predicts the rise of heterogeneity/stochasticity in human microbiomes associated with dysbiosis due to MADs. We used the beta-diversity in Hill numbers and stochasticity analysis to detect AKP and anti-AKP effects. We tested the AKP with 27 human MAD studies and discovered that the AKP, anti-AKP, and non-AKP effects were exhibited in approximately 50%, 25%, and 25% of the MAD cases, respectively. Mechanistically, AKP effects are primarily influenced by highly dominant microbial species and less influenced by rare species. In contrast, all species appear to play equal roles in influencing anti-AKP effects.
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Project description:Determining whether magma fragments during eruption remains a seminal challenge in volcanology. There is a robust paradigm for fragmentation of high viscosity, silicic magmas, however little is known about the fragmentation behaviour of lower viscosity systems-the most abundant form of volcanism on Earth and on other planetary bodies and satellites. Here we provide a quantitative model, based on experiments, for the non-brittle, fluid dynamic induced fragmentation of low viscosity melts. We define the conditions under which extensional thinning or liquid break-up can be expected. We show that break-up, both in our experiments and natural eruptions, occurs by both viscous and capillary instabilities operating on contrasting timescales. These timescales are used to produce a universal break-up criterion valid for low viscosity melts such as basalt, kimberlite and carbonatite. Lastly, we relate these break-up instabilities to changes in eruptive behaviour, the associated natural hazard and ultimately the deposits formed.
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Project description:Asthma management guidelines recommend adding a long-acting ?2-agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12-80?years) prescribed step-up therapy as a ?50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point in comparisons of cohorts matched for asthma severity and control during the baseline year. After 1:2 cohort matching, the increased extrafine ICS versus separate ICS+LABA cohorts included 3232 and 6464 patients, respectively, and the fine-particle ICS/LABA FDC versus separate ICS+LABA cohorts included 7529 and 15?058 patients, respectively (overall mean age 42?years; 61-62% females). Over one outcome year, adjusted OR (95% CI) for achieving asthma control were 1.25 (1.13-1.38) for increased ICS versus separate ICS+LABA and 1.06 (1.05-1.09) for ICS/LABA FDC versus separate ICS+LABA. For patients with asthma, increased dose of extrafine-particle ICS, or add-on LABA via ICS/LABA combination inhaler, is associated with significantly better outcomes than ICS+LABA via separate inhalers.
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Project description:ABSTRACT: The number of patients affected by chronic diseases with special vaccination needs is burgeoning. In this scenario, predictive markers of immunogenicity, as well as signatures of immune responses are typically missing even though it would especially improve the identification of personalized immunization practices in these populations. We aimed to develop a predictive score of immunogenicity to Influenza Trivalent Inactivated Vaccination (TIV) by applying deep machine learning algorithms using transcriptional data from sort-purified lymphocyte subsets after in vitro stimulation. Peripheral blood mononuclear cells (PBMCs) collected before TIV from 23 vertically HIV infected children under ART and virally controlled were stimulated in vitro with p09/H1N1 peptides (stim) or left unstimulated (med). A multiplexed-qPCR for 96 genes (Fluidigm, Biomark) was made on fixed numbers of 3 B cell subsets, 3 T cell subsets and total PBMCs. The ability to respond to TIV was assessed through hemagglutination Inhibition Assay (HIV) and ELIspot and patients were classified as Responders (R) and Non Responders (NR). A predictive modeling framework was applied to the data set in order to define genes and conditions with the higher predicted probability able to inform the final score. Twelve NR and 11 R were analyzed for gene expression differences in all subsets and 3 conditions (med, stim or Δ (stim-med). Differentially expressed genes between R and NR were selected and tested with the Adaptive Boosting Model to build a prediction score. The score obtained from subsets revealed the best prediction score from 46 genes from 5 different subsets and conditions. Calculating a combined score based on these 5 categories, we achieved a model accuracy of 95.6% and only one misclassified patient. In vitro stimulation, Cell sorting and RNA extraction. PBMC were thawed and cells were counted with Countess Automated Cell counter (Life technology). Cells were resuspended in complete RPMI medium at a concentration of 5 x 106 PBMCs/mL and left at 37°C for 16 hours in the presence or absence of of H1N1 A/California /09 HA peptides in a final concentration 20uL/mL. PMBCs were stained for surface markers, Vivid (Pacific Blue), CD10 (PECy7), CD20 (PE), CD27 (APC), IgD (FITC), CD21 (PECy5) for the B cell panel for 15 minutes and for CD3 (AmCyan), CD4 (PerCP Cy5.5), CD45RO (ECD), CCR7 (Alexa Fluor 700), and CXCR5 (Alexa Fluor 647) and a live/dead marker (ViViD; Molecular Probes) for the T cell panel for 15 minutes. Subsequently, stained PBMCs were washed twice in PBS, finally filtered with a 40 uM mesh and sorted by FACSAriaII (BD Biosciences). The purity of the sorted cell populations were typically >99%. All antibodies were previously titrated. Viable lymphocytes were identified as live dead amine dye negative (ViViD-) cells (Invitrogen). 500 live cells per B and T cell subset were sorted into tubes previously loaded with 9uL of PCR buffer (see also Figure 1 for gating strategy). After sorting, cells were immediately centrifuged (3000RPM for 3 minutes) and kept on ice. Samples were subsequently transferred in PCR tubes and 18 PCR cycles were performed on a C1000 Thermal Cycler (Bio Rad) with the following scheme (50°C for 20’, 95°C for 2’, 95°C 15’’, 60°C for 4’. Last step repeated 18 times). Cells were finally kept at -20 until further analysis. PCR buffer premix for cell sorting contained the following: Cells Direct Reaction mix 5uL, DEPC water 1,4, Superscript III + Taq 1ul, 0.2x diluted assay (96 primer mix) 2,5uL, Superasein 0,1uL. Multiplexed RT-PCR Previously amplified samples were loaded on a Fluidigm 96.96 standard chip following manufacturer’s instructions. Briefly, assay pre-mix was prepared 1:1 20X TaqMan Gene Expression Assay (Applied Biosystems) and Assay Loading Reagent (Fluidigm). The sample pre-mix was prepared with TaqMan Universal PCR Master Mix (2X)(Applied Biosystems), 20XGE Sample Loading Reagent (Fluidigm), and cDNA. Full list of the two panels of gene probes (B subsets and T subsets is shown in supplemental table 1 and 2). 5ul of Assay and Sample mix were loaded into the chip according to manufacturers instructions. Genes’ selection has been made according to previous analysis on RNA Sequencing on HIV infected children from a different cohort (data not shown), the literature and online gene banks and biological queries. Cycle threshold value (Ct) deriving from exported files was corrected according to number of cells sorted if lower than 500. Calculations were made following the expression 67,5 / 500 = Y / X where X is the number of cells sorted and Y is the cells equivalent cDNA of cell sorted. The dilution factor (n) was calculated as n= 67,5/Y, and base 2 log of n was subsequently subtracted to Ct value in order to get Corrected Cycle Threshold (c-Ct). Expression threshold (Et), which was used for the main analysis was finally obtained with 40-cCT. Once exported and corrected, data were analyzed through Fluidigm SingluaR (SingulaR analysis toolset 3.0) package, loaded on R (software R 3.0.2 GUI 1.62). As previously described (De Armas LR, 2017) gene expression differences between different groups within same subset and condition were used to identify Differentially Expressed Genes (DEGs). Alternatively, paired gene expression differences between stimulated (stim) and unstimulated samples (med) (stim-med) within the same subset were used to define Differentially Induced Genes (DIGs).
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