Acquired resistance to macrolides in from cystic fibrosis patients.

Cystic fibrosis (CF) patients receive chronic treatment with macrolides for their antivirulence and anti-inflammatory properties. We, however, previously showed that , considered as naturally resistant to macrolides, becomes susceptible when tested in a eukaryotic medium rather than a conventional broth.We therefore looked for specific macrolide resistance determinants in 333 CF isolates from four European CF centres in comparison with 48 isolates from patients suffering from hospital-acquired pneumonia (HAP).

Antimicrobial Susceptibility of Pseudomonas aeruginosa Isolated from Cystic Fibrosis Patients in Northern Europe.

Pseudomonas aeruginosa is a major cause of morbidity and mortality in cystic fibrosis patients. This study compared the antimicrobial susceptibilities of 153 P. aeruginosa isolates from the United Kingdom (UK) (n = 58), Belgium (n = 44), and Germany (n = 51) collected from 118 patients during routine visits over the period from 2006 to 2012.

A Randomised, Cross-Over Study to Estimate the Influence of Food on the 25-Hydroxyvitamin D₃ Serum Level after Vitamin D₃ Supplementation.

Vitamin D₃ is known to be liposoluble and its release could be a factor limiting the rate of absorption. It was presumed that the presence of fat could favor absorption of vitamin D₃. However, as bioavailability is related not only to the active molecules but also to the formulations and excipients used, the optimization of the pharmaceutical form of vitamin D₃ is also important.

Budesonide/salmeterol in fixed-dose combination for the treatment of asthma.

Fixed dose combinations (FDC) of inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) are well established in asthma treatment. The budesonide/salmeterol (B/S) FDC is now about to reach the market. It is provided as powder in hard capsules of two strengths: 120/20μg and 240/20μg when expressed as delivered doses, equivalent to 150/25μg and 300/25μg when expressed as nominal doses.

A Randomized, Double-Blind, Parallel Study to Evaluate the Dose-Response of Three Different Vitamin D Treatment Schemes on the 25-Hydroxyvitamin D Serum Concentration in Patients with Vitamin D Deficiency.

Many people worldwide are vitamin D (VTD) deficient or insufficient, and there is still no consensus on the dose of VTD that should be administered to achieve a 25(OH)D concentration of 20 or 30 ng/mL. In this study, we aimed to determine an adapted supplementation of VTD able to quickly and safely increase the vitamin D status of healthy adults with low 25(OH)D. One hundred and fifty (150) subjects were randomized into three groups, each to receive, orally, a loading dose of 50,000, 100,000 or 200,000 IU of VTD3 at Week 0, followed by 25,000, 50,000 or 100,000 IU at Week 4 and Week 8.

Efficacy and safety of a 12-week therapy with a new formulation of fluticasone propionate at doses of 125 and 250 μg administered through a new generation cyclohaler twice daily, in comparison to fluticasone propionate 500 μg dry powder inhaler twice daily in patients with moderate asthma.

Introduction: Inhaled fluticasone is used in the treatment of chronic bronchial asthma. Its high efficacy and good safety profile have been proven by clinical trials and observations. Its unique pharmacokinetic properties make it distinguishable from other drugs from this group.

Carrier-free combination for dry powder inhalation of antibiotics in the treatment of lung infections in cystic fibrosis.

The aim of the study was to develop an efficient combination antibiotic formulation containing tobramycin and clarithromycin as a dry powder for inhalation. A carrier-free formulation of the two drugs was produced by spray-drying and characterised for its aerodynamic behaviour by impaction tests with an NGI and release profiles. The particle size distribution, morphological evaluation and crystallinity state were determined by laser diffraction, scanning electron microscopy and powder X-ray diffraction, respectively.

New co-spray-dried tobramycin nanoparticles-clarithromycin inhaled powder systems for lung infection therapy in cystic fibrosis patients.

The aim of the study was to produce easily dispersible and porous agglomerates of tobramycin nanoparticles surrounded by a matrix composed of amorphous clarithromycin. Nanoparticles of tobramycin with a median particle size of about 400 nm were produced by high-pressure homogenisation. The results from the spray-dried powders showed that the presence of these nanoparticles enhanced powder dispersion during inhalation.

Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention.

Three Itraconazole (ITZ) dry powders for inhalation (DPI) were prepared by spray-drying a mannitol solution in which the ITZ was in suspension (F1) or was in solution without (F2) or with phospholipid (PL) (F3). These powders were endotracheally insufflated in vivo at a single dose of 0.5mg/kg for pharmacokinetic profile (lung and plasma concentration) determination in ICR CD-1 mice.

New inhalation-optimized itraconazole nanoparticle-based dry powders for the treatment of invasive pulmonary aspergillosis.

Purpose: Itraconazole (ITZ) dry powders for inhalation (DPI) composed of nanoparticles (NP) embedded in carrier microparticles were prepared and characterized.

Methods: DPIs were initially produced by reducing the ITZ particle size to the nanometer range using high-pressure homogenization with tocopherol polyethylene 1000 succinate (TPGS, 10% w/w ITZ) as a stabilizer. The optimized nanosuspension and the initial microsuspension were then spray-dried with different proportions of or in the absence of mannitol and/or sodium taurocholate.

New respirable and fast dissolving itraconazole dry powder composition for the treatment of invasive pulmonary aspergillosis.

Purpose: Novel itraconazole (ITZ)-based dry powders for inhalation (DPI) were optimized for aerodynamic and dissolution properties and contained excipients that are acceptable for inhalation.

Methods: The DPI were produced by spray drying solutions. The drug content, crystallinity state, and morphological evaluation of the dry powders were determined by high performance liquid chromatography, powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, respectively.

Increased susceptibility of Pseudomonas aeruginosa to macrolides and ketolides in eukaryotic cell culture media and biological fluids due to decreased expression of oprM and increased outer-membrane permeability.

Background: Macrolides show high minimum inhibitory concentrations (MICs) against Pseudomonas aeruginosa when tested in recommended media (cation-adjusted Muller-Hinton broth [CA-MHB]). Nevertheless, azithromycin is successfully used in cystic fibrosis patients, supposedly because of "nonantibiotic effects."

Methods: CA-MHB and Roswell Park Memorial Institute (RPMI) 1640 medium (used for growing eukaryotic cells) were compared for measuring azithromycin MICs (with or without Phe-Arg-β-naphthylamide [PAβN], an efflux inhibitor), [(14)C]-clarithromycin accumulation, azithromycin-induced protein synthesis inhibition, oprM (encoding the outer-membrane protein coupled with MexAB and MexXY efflux systems) expression, outer-membrane permeability (tested with 1-N-phenylnaphthylamine and nitrocefin), and synergy (determined by checkerboard assay) between azithromycin and outer-membrane disrupting agents.

In vitro and in vivo evaluation of a dry powder endotracheal insufflator device for use in dose-dependent preclinical studies in mice.

The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering.

Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties.

The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties.

Safety of a fixed-dose combination of fenofibrate/pravastatin 160 mg/40 mg in patients with mixed hyperlipidaemia: a pooled analysis from a database of clinical trials.

Background: Fenofibrate can be prescribed concomitantly with an HMG-CoA reductase inhibitor (statin) to improve achievement of lipid goals in patients with atherogenic mixed hyperlipidaemia. However, some safety concerns, particularly an increased risk of myopathy, have been reported when these drugs are taken together.

Objective: The aim of this analysis was to assess the general safety and tolerability of a fenofibrate/pravastatin (FF/PRA) 160 mg/40 mg fixed-dose combination (FDC) capsule based on a pooled database of phase III clinical trials in patients with mixed hyperlipidaemia.

Efficacy of the combination of tobramycin and a macrolide in an in vitro Pseudomonas aeruginosa mature biofilm model.

Respiratory disease is the main cause of morbidity and mortality in patients with cystic fibrosis (CF). In particular, patients suffer from chronic infection due to biofilm formation by opportunistic Pseudomonas aeruginosa (32). Therefore, there is an urgent need to develop alternative ways to treat biofilm-associated clinical infections.

The effect of combined tobramycin-clarithromycin on Mycobacterium tuberculosis isolates.

This study investigated the susceptibility of 25 Mycobacterium tuberculosis clinical isolates to tobramycin (TBM) and clarithromycin (CLM). The effect of the drugs administered together was examined for possible synergistic effect. The median minimum inhibitory concentration (MIC) for both drugs was 8 mug/ml.

Evaluation of long-term co-administration of tobramycin and clarithromycin in a mature biofilm model of cystic fibrosis clinical isolates of Pseudomonas aeruginosa.

Pseudomonas aeruginosa colonisation and chronic lung infection associated with biofilm formation is a major cause of morbidity and mortality in cystic fibrosis (CF) patients. There is thus an urgent need to develop alternative ways to treat biofilm-associated clinical infections. A kinetic study of twice-daily co-administration of the antibiotics tobramycin and clarithromycin was performed over 28 days on 12-day-old mature P.

Significance of the biopharmaceutical properties of tramadol sustained-release formulations for chrono-pharmacologically optimized treatment of pain from various sources.

Unlabelled: Tramadol is currently one of the most frequently used opioid analgesics in the world.

Objective: The objective of this study was to investigate the rate and extent of tramadol bioavailability following evening versus morning intake of an extended-release pellet system designed for once daily administration. Moreover, the suitability of the preparation for chrono-adjusted pharmacotherapy was to be investigated.

Effect of antibiotic co-administration on young and mature biofilms of cystic fibrosis clinical isolates: the importance of the biofilm model.

The prognosis of patients with cystic fibrosis (CF) has improved dramatically over the last three decades although the majority of patients still die in early adulthood. Infection with Pseudomonas aeruginosa has generally been associated with declining lung function and increased mortality in patients. This study aimed to investigate the in vitro activity of tobramycin/clarithromycin combination on biofilms of clinical isolates of P.

Preparation and characterization of spray-dried tobramycin powders containing nanoparticles for pulmonary delivery.

Using high-pressure homogenization and spray-drying techniques, novel formulations were developed for manufacturing dry powder for inhalation, composed of a mixture of micro- and nanoparticles in order to enhance lung deposition. Particle size analysis was performed by laser diffraction. Spray-drying was applied in order to retrieve nanoparticles in dried-powder state from tobramycin nanosuspensions.

Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa.

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy.

Spray-dried carrier-free dry powder tobramycin formulations with improved dispersion properties.

Tobramycin was spray dried at different temperatures from different water to isopropanol feed ratios (0:100-20:80) in order to obtain dry powder formulations for inhalation. The spray-dried powders were characterized for their physicochemical properties including crystallinity, morphology, density, water content, and particle size distribution using X-ray powder diffraction, scanning electron microscopy, tapped density measurements and laser diffraction. Aerosol performance was studied by dispersing the powders into a Multi-Stage Liquid Impinger with an Aerolizer device.

Evaluation and floating enhancement of levodopa sustained release floating minitablets coated with insoluble acrylic polymer.

This article describes the in vitro evaluation and the enhancement of the floating properties of coated sustained release (SR) minitablets (MTs). The evaluated system consisted of a 3-mm drug-containing gas-generating core prepared by melt granulation and subsequent compression, which was then coated with a flexible polymeric membrane. Eudragit RL30D and acetyl triethylcitrate were used as a film former and a plasticizer, respectively.

[Importance of the formulation for a chronopharmacologically optimised way of pain therapy. Results of a comparative bioavailability study of tramadol extended-release capsules after single-dose evening versus morning administration].

Unlabelled: Objective of this study was to investigate the rate and extent of tramadol bioavailability following evening versus morning administration.

Methods: The study was performed following an open, randomised, cross-over study-design. 18 male and female volunteers were enrolled into the study and treated with 200 mg tramadol extended-release capsules (T-long), which were to be taken either in the morning or in the evening.