The Inhalation Characteristics of Patients When They Use Different Dry Powder Inhalers

Background: The characteristics of each inhalation maneuver when patients use dry powder inhalers (DPIs) are important, because they control the quality of the emitted dose. Methods: We have measured the inhalation profiles of asthmatic children [CHILD; n=16, mean forced expiratory volume in 1 sec (FEV1) 79% predicted], asthmatic adults (ADULT; n=53, mean predicted FEV1 72%), and chronic obstructive pulmonary disease (COPD; n=29, mean predicted FEV1 42%) patients when they inhaled through an Aerolizer, Diskus, Turbuhaler, and Easyhaler using their “real-life” DPI inhalation technique. These are low-, medium-, medium/high-, and high-resistance DPIs, respectively. The inhalation flow against time was recorded to provide the peak inhalation flow (PIF; in L/min), the maximum pressure change (ΔP; in kPa), acceleration rates (ACCEL; in kPa/sec), time to maximum inhalation, the length of each inhalation (in sec), and the inhalation volume (IV; in liters) of each inhalation maneuver. Results: PIF, ΔP, and ACCEL values were consistent with the order of the inhaler's resistance. For each device, the inhalation characteristics were in the order ADULT>COPD>CHILD for PIF, ΔP, and ACCEL (p4 L and ΔP >4 kPa. Conclusion: The large variability of these inhalation characteristics and their range highlights that if inhalation profiles were used with compendial in vitro dose emission measurements, then the results would provide useful information about the dose patients inhale during routine use. The inhalation characteristics highlight that adults with asthma have greater inspiratory capacity than patients with COPD, whereas children with asthma have the lowest. The significance of the inhaled volume to empty doses from each device requires investigation

Inhalation characteristics of asthma patients, COPD patients and healthy volunteers with the Spiromax® and Turbuhaler® devices: a randomised, cross-over study.

BACKGROUND: Spiromax® is a novel dry-powder inhaler containing formulations of budesonide plus formoterol (BF). The device is intended to provide dose equivalence with enhanced user-friendliness compared to BF Turbuhaler® in asthma and chronic obstructive pulmonary disease (COPD). The present study was performed to compare inhalation parameters with empty versions of the two devices, and to investigate the effects of enhanced training designed to encourage faster inhalation. METHODS: This randomised, open-label, cross-over study included children with asthma (n = 23), adolescents with asthma (n = 27), adults with asthma (n = 50), adults with COPD (n = 50) and healthy adult volunteers (n = 50). Inhalation manoeuvres were recorded with each device after training with the patient information leaflet (PIL) and after enhanced training using an In-Check Dial device. RESULTS: After PIL training, peak inspiratory flow (PIF), maximum change in pressure (∆P) and the inhalation volume (IV) were significantly higher with Spiromax than with the Turbuhaler device (p values were at least <0.05 in all patient groups). After enhanced training, numerically or significantly higher values for PIF, ∆P, IV and acceleration remained with Spiromax versus Turbuhaler, except for ∆P in COPD patients. After PIL training, one adult asthma patient and one COPD patient inhaled <30 L/min through the Spiromax compared to one adult asthma patient and five COPD patients with the Turbuhaler. All patients achieved PIF values of at least 30 L/min after enhanced training. CONCLUSIONS: The two inhalers have similar resistance so inhalation flows and pressure changes would be expected to be similar. The higher flow-related values noted for Spiromax versus Turbuhaler after PIL training suggest that Spiromax might have human factor advantages in real-world use. After enhanced training, the flow-related differences between devices persisted; increased flow rates were achieved with both devices, and all patients achieved the minimal flow required for adequate drug delivery. Enhanced training could be useful, especially in COPD patients

Gastroprotective effects and metabolomic profiling of Chasteberry fruits against indomethacin-induced gastric injury in rats

Vitex agnus castus L. extract (VACE) was investigated for its gastroprotective properties and possible molecular mechanisms in rats. VACE (60 or 120 mg/kg) or Esomeprazole (20 mg/kg) were orally administered for 3 weeks before the induction of gastropathy using indomethacin (30 mg/kg, single oral dose). VACE ameliorated the indomethacin-induced gastric juice acidity and pathological changes. VACE significantly preserved GSH, SOD, NO and PGE2 contents, while decreased lipid-peroxide, TNF-α and MPO contents. Moreover, VACE downregulated NF-κB1, COX-2, Caspase-3 and upregulated Bcl-2 and HSP-70 expression. Ultra-high-performance liquid chromatography (UPLC) coupled with quadrupole high-resolution time of flight mass spectrometry (qTOF-MS) enabled the tentative identification of 87 compounds allocated in seven main classes including flavonoids, glycosylated iridoid and labdane diterpenes. Notably, different agnuside derivatives and diterpenoids were reported in VACE for the first time. In conclusion, VACE contains an arsenal of bioactive metabolites which may exhibit gastroprotection by inhibiting inflammation, oxidative stress, and apoptosis

Advances in three-dimensional rapid prototyping of microfluidic devices for biological applications

The capability of 3D printing technologies for direct production of complex 3D structures in a single step has recently attracted an ever increasing interest within the field of microfluidics. Recently, ultrafast lasers have also allowed developing new methods for production of internal microfluidic channels within the bulk of glass and polymer materials by direct internal 3D laser writing. This review critically summarizes the latest advances in the production of microfluidic 3D structures by using 3D printing technologies and direct internal 3D laser writing fabrication methods. Current applications of these rapid prototyped microfluidic platforms in biology will be also discussed. These include imaging of cells and living organisms, electrochemical detection of viruses and neurotransmitters, and studies in drug transport and induced-release of adenosine triphosphate from erythrocytes

Supercooled liquid water cloud observed, analysed, and modelled at the top of the planetary boundary layer above Dome C, Antarctica

Abstract. A comprehensive analysis of the water budget over the Dome C (Concordia, Antarctica) station has been performed during the austral summer 2018–2019 as part of the Year of Polar Prediction (YOPP) international campaign. Thin (∼100 m deep) supercooled liquid water (SLW) clouds have been detected and analysed using remotely sensed observations at the station (tropospheric depolarization lidar, the H2O Antarctica Microwave Stratospheric and Tropospheric Radiometer (HAMSTRAD), net surface radiation from the Baseline Surface Radiation Network (BSRN)), radiosondes, and satellite observations (CALIOP, Cloud-Aerosol LIdar with Orthogonal Polarization/CALIPSO, Cloud Aerosol Lidar and Infrared Pathfinder Satellite Observations) combined with a specific configuration of the numerical weather prediction model: ARPEGE-SH (Action de Recherche Petite Echelle Grande Echelle – Southern Hemisphere). The analysis shows that SLW clouds were present from November to March, with the greatest frequency occurring in December and January when ∼50 % of the days in summer time exhibited SLW clouds for at least 1 h. Two case studies are used to illustrate this phenomenon. On 24 December 2018, the atmospheric planetary boundary layer (PBL) evolved following a typical diurnal variation, which is to say with a warm and dry mixing layer at local noon thicker than the cold and dry stable layer at local midnight. Our study showed that the SLW clouds were observed at Dome C within the entrainment and the capping inversion zones at the top of the PBL. ARPEGE-SH was not able to correctly estimate the ratio between liquid and solid water inside the clouds with the liquid water path (LWP) strongly underestimated by a factor of 1000 compared to observations. The lack of simulated SLW in the model impacted the net surface radiation that was 20–30 W m−2 higher in the BSRN observations than in the ARPEGE-SH calculations, mainly attributable to the BSRN longwave downward surface radiation being 50 W m−2 greater than that of ARPEGE-SH. The second case study took place on 20 December 2018, when a warm and wet episode impacted the PBL with no clear diurnal cycle of the PBL top. SLW cloud appearance within the entrainment and capping inversion zones coincided with the warm and wet event. The amount of liquid water measured by HAMSTRAD was ∼20 times greater in this perturbed PBL than in the typical PBL. Since ARPEGE-SH was not able to accurately reproduce these SLW clouds, the discrepancy between the observed and calculated net surface radiation was even greater than in the typical PBL case, reaching +50 W m−2, mainly attributable to the downwelling longwave surface radiation from BSRN being 100 W m−2 greater than that of ARPEGE-SH. The model was then run with a new partition function favouring liquid water for temperatures below −20 down to −40 ∘C. In this test mode, ARPEGE-SH has been able to generate SLW clouds with modelled LWP and net surface radiation consistent with observations during the typical case, whereas, during the perturbed case, the modelled LWP was 10 times less than the observations and the modelled net surface radiation remained lower than the observations by ∼50 W m−2. Accurately modelling the presence of SLW clouds appears crucial to correctly simulate the surface energy budget over the Antarctic Plateau

Subthreshold dynamics of the neural membrane potential driven by stochastic synaptic input

In the cerebral cortex, neurons are subject to a continuous bombardment of synaptic inputs originating from the network's background activity. This leads to ongoing, mostly subthreshold membrane dynamics that depends on the statistics of the background activity and of the synapses made on a neuron. Subthreshold membrane polarization is, in turn, a potent modulator of neural responses. The present paper analyzes the subthreshold dynamics of the neural membrane potential driven by synaptic inputs of stationary statistics. Synaptic inputs are considered in linear interaction. The analysis identifies regimes of input statistics which give rise to stationary, fluctuating, oscillatory, and unstable dynamics. In particular, I show that (i) mere noise inputs can drive the membrane potential into sustained, quasiperiodic oscillations (noise-driven oscillations), in the absence of a stimulus-derived, intraneural, or network pacemaker; (ii) adding hyperpolarizing to depolarizing synaptic input can increase neural activity (hyperpolarization-induced activity), in the absence of hyperpolarization-activated currents

Study of the Emitted Dose After Two Separate Inhalations at Different Inhalation Flow Rates and Volumes and an Assessment of Aerodynamic Characteristics of Indacaterol Onbrez Breezhaler® 150 and 300 μg

Onbrez Breezhaler® is a low-resistance capsule-based device that was developed to deliver indacaterol maleate. The study was designed to investigate the effects of both maximum flow rate (MIF) and inhalation volume (Vin) on the dose emission of indacaterol 150 and 300 μg dose strengths after one and two inhalations using dose unit sampling apparatus (DUSA) as well as to study the aerodynamic characteristics of indacaterol Breezhaler® using the Andersen cascade impactor (ACI) at a different set of MIF and Vin. Indacaterol 150 and 300 μg contain equal amounts of lactose per carrier. However, 150 μg has the smallest carrier size. The particle size distribution (PSD) of indacaterol DPI formulations 150 and 300 μg showed that the density of fine particles increased with the increase of the primary pressure. For both strengths (150 μg and 300 μg), ED1 increased and ED2 decreased when the inhalation flow rate and inhaled volume increased. The reduction in ED1 and subsequent increase in ED2 was such that when the Vin is greater than 1 L, then 60 L/min could be regarded as the minimum MIF. The Breezhaler was effective in producing respirable particles with an MMAD ≤5 μm irrespective of the inhalation flow rate, but the mass fraction of particles with an aerodynamic diameter <3 μm is more pronounced between 60 and 90 L/min. The dose emission of indacaterol was comparable for both dose strengths 150 and 300 μg. These in vitro results suggest that a minimum MIF of 60 L/min is required during routine use of Onbrez Breezhaler®, and confirm the good practice to make two separate inhalations from the same dose

Simple model for 1/f noise

We present a simple stochastic mechanism which generates pulse trains exhibiting a power law distribution of the pulse intervals and a $1/f^\alpha$ power spectrum over several decades at low frequencies with $\alpha$ close to one. The essential ingredient of our model is a fluctuating threshold which performs a Brownian motion. Whenever an increasing potential $V(t)$ hits the threshold, $V(t)$ is reset to the origin and a pulse is emitted. We show that if $V(t)$ increases linearly in time, the pulse intervals can be approximated by a random walk with multiplicative noise. Our model agrees with recent experiments in neurobiology and explains the high interpulse interval variability and the occurrence of $1/f^\alpha$ noise observed in cortical neurons and earthquake data.Comment: 4 pages, 4 figure

Dysplasia epiphysealis hemimelica of the talus

Dysplasia epiphysealis hemimelica is a rare developmental disorder with unknown etiology affecting epiphysis in childhood. The lesion is an osteochondroma arising from the epiphysis and increasing in size until skeletal maturity is reached. Surgical treatment is mandatory when symptoms such as pain, joint impingement or deformation are present, and yields good results when the mass is juxtaarticular or extraarticular. In those cases where articular symptoms are not present and only mass evolution is observed, surgical treatment is not recommended before skeletal maturity has been reached. A case of DEH located in the talus and successfully treated with surgery is presented