Ultra-Small Superparamagnetic Iron-Oxide Nanoparticles Exert Different Effects on Erythrocytes in Normotensive and Hypertensive Rats

We determined erythrocyte physiological and biochemical properties after the single and repeated administration of ultra-small superparamagnetic iron-oxide nanoparticles (USPIONs) in normotensive Wistar–Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Polyethylene glycol-coated USPIONs (transmission electron microscope detected a mean size of ~30 nm and hydrodynamic size ~51 nm) were intravenously administered to rats either in one infusion at nominal dose 1 mg Fe/kg or in two infusions (administered with a difference of 24 h) at nominal dose 2 mg Fe/kg. Results showed that USPIONs did not deteriorate erythrocyte deformability, nitric oxide production, and osmotic resistance in both experimental settings. Both the single and repeated USPION administration elevated erythrocyte deformability in WKY. However, this effect was not present in SHR; deformability in USPION-treated SHR was significantly lower than in USPION-treated WKY. Nitric oxide production by erythrocytes was increased after a single USPION treatment in WKY, so it can be associated with improvement in erythrocyte deformability. Using biomagnetometry, we revealed significantly lower amounts of USPION-originated iron in erythrocytes in SHR compared with WKY. We found a much faster elimination of USPIONs from erythrocytes in hypertensive rats compared with the normotensive ones, which might be relevant for clinical practice in hypertensive patients undergoing clinical examination with the use of iron-oxide nanoparticles.

Automated Filling Equipment Allows Increase in the Maximum Dose to Be Filled in the Cyclops® High Dose Dry Powder Inhalation Device While Maintaining Dispersibility

In recent years there has been increasing interest in the pulmonary delivery of high dose dry powder drugs, such as antibiotics. Drugs in this class need to be dosed in doses far over 2.5 mg, and the use of excipients should therefore be minimized. To our knowledge, the effect of the automatic filling of high dose drug formulations on the maximum dose that can be filled in powder inhalers, and on the dispersion behavior of the powder, have not been described so far. In this study, we aimed to investigate these effects after filling with an Omnidose, a vacuum drum filler. Furthermore, the precision and accuracy of the filling process were investigated. Two formulations were used—an isoniazid formulation we reported previously and an amikacin formulation. Both formulations could be precisely and accurately dosed in a vacuum pressure range of 200 to 600 mbar. No change in dispersion was seen after automatic filling. Retention was decreased, with an optimum vacuum pressure range found from 400 to 600 mbar. The nominal dose for amikacin was 57 mg, which resulted in a fine particle dose of 47.26 ± 1.72 mg. The nominal dose for isoniazid could be increased to 150 mg, resulting in a fine particle dose of 107.35 ± 13.52 mg. These findings may contribute to the understanding of the upscaling of high dose dry powder inhalation products.

Extended Pharmacopeial Characterization of Surfactant Aerosols Generated by a Customized eFlow Neos Nebulizer Delivered through Neonatal Nasal Prongs

The delivery of nebulized medications to preterm infants during Non-Invasive Ventilation (NIV) remains an unmet clinical need. In this regard, the effective delivery of nebulized surfactant has been particularly investigated in preclinical and clinical studies. In this work, we investigated the feasibility of delivering nebulized surfactant through various commercially available nasal prong types. We first performed a compendial characterization of surfactant aerosols generated by the eFlow Neos nebulizer, customized to be used in neonates, determining the amount of surfactant delivered by the device as well as the aerodynamic characteristics of surfactant aerosols. Additionally, we extended the compendial characterization by testing the effect of different nasal prong types on the estimated lung dose using a realistic Continuous Positive Airway Pressure (CPAP) circuit that included a cast of the upper airways of a preterm neonate. The compendial characterization of surfactant aerosols delivered through different nasal prongs achieved relatively high delivered surfactant doses (in the range 63–74% of the nominal dose), with aerodynamic characteristics displaying mass median aerodynamic diameters ranging between 2.52 and 2.81 µm. Nevertheless, when using a representative in vitro setup mimicking NIV in a clinical setting, significant differences were observed in terms of the estimated lung dose accounting for up to two-fold differences (from 10% to 20% estimated lung deposition of the nominal dose) depending on the chosen nasal prong type. Considering that surfactant lung deposition rates are correlated with therapeutic efficacy, this study points out the relevance of choosing the appropriate NIV interface to maximize the lung dose of nebulized medications.

In Vitro Performance of an Investigational Vibrating-Membrane Nebulizer with Surfactant under Simulated, Non-Invasive Neonatal Ventilation Conditions: Influence of Continuous Positive Airway Pressure Interface and Nebulizer Positioning on the Lung Dose

Non-invasive delivery of nebulized surfactant has been a long-pursued goal in neonatology. Our aim was to evaluate the performance of an investigational vibrating-membrane nebulizer in a realistic non-invasive neonatal ventilation circuit with different configurations. Surfactant (aerosols were generated with a nebulizer in a set-up composed of a continuous positive airway pressure (CPAP) generator with a humidifier, a cast of the upper airway of a preterm infant (PrINT), and a breath simulator with a neonatal breathing pattern. The lung dose (LD), defined as the amount of surfactant collected in a filter placed at the distal end of the PrINT cast, was determined after placing the nebulizer at different locations of the circuit and using either infant nasal mask or nasal prongs as CPAP interfaces. The LD after delivering a range of nominal surfactant doses (100–600 mg/kg) was also investigated. Surfactant aerosol particle size distribution was determined by laser diffraction. Irrespective of the CPAP interface used, about 14% of the nominal dose (200 mg/kg) reached the LD filter. However, placing the nebulizer between the Y-piece and the CPAP interface significantly increased the LD compared with placing it 7 cm before the Y-piece, in the inspiratory limb. (14% ± 2.8 vs. 2.3% ± 0.8, nominal dose of 200 mg/kg). The customized eFlow Neos showed a constant aerosol generation rate and a mass median diameter of 2.7 μm after delivering high surfactant doses (600 mg/kg). The customized eFlow Neos nebulizer showed a constant performance even after nebulizing high doses of undiluted surfactant. Placing the nebulizer between the Y-piece and the CPAP interface achieves the highest LD under non-invasive ventilation conditions.

Impact of the content of alcohol in petroleum on the level of an unsupercharged engine’s noise

The results of the studies conducted on the chassis dynamometer for a vehicle powered with a spark-ignition engine are presented in the study. The tested vehicle was equipped with an unsupercharged engine. There was tested the noise level of the engine powered with ethyl alcohol at variable settings of the fuel injection. In the course of the tests, the dose of fuel was increased within the range from the manufacturer’s settings respectively by: 5%, 10%, 20% 30% and 50% of the nominal dose, and the ignition advance angle with reference to manufacturer’s settings was increased respectively by 00 and 30 . It was found, that the noise level for the engine powered with ethanol decreases together with the increase of the fuel’s dose, (up to about 110% of the nominal dose), and then increases. At the same time, the increase of the noise level for the increased value of the ignition advance angle was found.

Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis

ABSTRACTPatients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0−24) were 109.49, 97.86, 145.33, and 207.04 μg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 μg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.)

Biofortification of maize with micronutrients by Spirulina

The aim of the present work was to examine the effect of the application of Spirulina platensis post-extraction residues enriched with Zn(II), Mn(II), Cu(II) via biosorption as micronutrient fertilizer for the biofortification of maize grains with micronutrients in field tests. As a nominal dose 2.5 kg ha-1 of zinc, 1.0 kg ha-1 of manganese and 0.5 kg ha-1 of copper were applied. The preparation was applied also in higher doses (150%, 200%) to investigate agronomic biofortification of maize grains.In field trials, obtained grain yield (7.2 Mg ha-1 for Spirulina 100%) was higher than in control group (6.2 Mg ha-1) and commercial reference product (6.6 Mg ha-1). For the same dose of micronutrients, their bioavailability was higher for bio-preparations than for reference fertilizer. The highest content of micronutrients delivered to plants (2.15 mg kg-1 – Cu, 7.07 mg kg-1 – Mn, 29.0 mg kg-1 – Zn) was observed for maize grains fertilized with preparation of Spirulina 150%, which signifies that biofortified maize grain was obtained. Corn grains biofortified with micronutrients can be used as staple food or feed preventing from micronutrient malnutrition. The application of micronutrient biocomponents based on Spirulina biomass allows to manufacture a valuable fertilizer with bioavailable micronutrients.

Biofortification of maize grains with micronutrients by enriched biomass of blackcurrant seeds

Effect of the application of blackcurrant seed post-extraction residues (BS) enriched via biosorption with Zn(II), Mn(II) and Cu(II) was examined in field tests on maize. As a nominal dose (100%), 2.5 kg of zinc, 1 kg of manganese and 0.5 kg of copper per hectare, were applied. The preparation was applied, also, in higher doses (150%, 200%).Crop yield and quality were assessed and multielemental analysis of grains was conducted. Grain yield obtained for maize treated with different doses of micronutrients (7.3 and 7.2 Mg ha-1 for BS 100% and BS 200%, respectively) was higher than in control group (6.2 Mg ha-1) and similar to a commercial reference product (7.1 Mg ha-1).Bioavailability of micronutrients from BS was shown to be higher than from reference commercial fertilizer. The highest content of micronutrients delivered to plants was observed for groups fertilized with BS in nominal dose of micronutrients (1.79, 7.08 and 28.55 mg kg-1 for Cu, Mn and Zn, respectively). The content of each micronutrient was 5.6% (Cu) 12.1% (Mn) and 12.6% (Zn) higher than in untreated group and 8.9% (Cu) 9.7% (Mn) and 8.7% (Zn) higher than commercial reference micronutrient fertilizer. New biocomponents are cheap and biodegradable carriers of nutrients which can be released in controlled way.