Differential Performance and Lung Deposition of Levofloxacin with Different Nebulisers Used in Cystic Fibrosis.

We compared the performance and levofloxacin (Quinsair) lung deposition of three nebulisers commonly used in CF (I-Neb Advance, eFlow rapid, and LC Plus) with the approved nebuliser Zirela. The delivered dose, delivery rate, and aerosol particle size distribution (APSD) for each device were determined using the methods described in the Pharmacopeia. High-resolution computed tomography scans obtained from seven adult patients with mild CF were used to generate computer-aided, three-dimensional models of their airway tree to assess lung deposition using functional respiratory imaging (FRI). The eFlow rapid and the LC Plus showed poor delivery efficiencies due to their high residual volumes. The I-Neb, which only delivers aerosols during the inspiratory phase, achieved the highest aerosol delivery efficiency. However, the I-Neb showed the largest particle size and lowest delivery rate (2.9 mg/min), which were respectively associated with a high extrathoracic deposition and extremely long nebulisation times (>20 min). Zirela showed the best performance considering delivery efficiency (159.6 mg out of a nominal dose of 240 mg), delivery rate (43.5 mg/min), and lung deposition (20% of the nominal dose), requiring less than 5 min to deliver a full dose of levofloxacin. The present study supports the use of drug-specific nebulisers and discourages the off-label use of general-purpose devices with the present levofloxacin formulation since subtherapeutic lung doses and long nebulisation times may compromise treatment efficacy and adherence.

Prolonged-Release Once-Daily Formulation of Tacrolimus Versus Standard-of-Care Tacrolimus in de novo Kidney Transplant Patients Across Europe.

Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed. Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201). Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile. Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02432833.

Deposition of Inhaled Levofloxacin in Cystic Fibrosis Lungs Assessed by Functional Respiratory Imaging.

Pulmonary infections caused by Pseudomonas aeruginosa (PA) represent the leading cause of pulmonary morbidity in adults with cystic fibrosis (CF). In addition to tobramycin, colistin, and aztreonam, levofloxacin has been approved in Europe to treat PA infections. Nevertheless, no lung deposition data on inhaled levofloxacin are yet available. We conducted a Functional Respiratory Imaging (FRI) study to predict the lung deposition of levofloxacin in the lungs of patients with CF. Three-dimensional airway models were digitally reconstructed from twenty high-resolution computed tomography scans obtained from historical patients' records. Levofloxacin aerosols generated with the corresponding approved nebuliser were characterised according to pharmacopeia. The obtained data were used to inform a computational fluid dynamics simulation of levofloxacin lung deposition using breathing patterns averaged from actual CF patients' spirometry data. Levofloxacin deposition in the lung periphery was significantly reduced by breathing patterns with low inspiratory times and high inspiratory flow rates. The intrathoracic levofloxacin deposition percentages for moderate and mild CF lungs were, respectively, 37.0% ± 13.6 and 39.5% ± 12.9 of the nominal dose. A significant albeit modest correlation was found between the central-to-peripheral deposition (C/P) ratio of levofloxacin and FEV1. FRI analysis also detected structural differences between mild and moderate CF airways. FRI revealed a significant intrathoracic deposition of levofloxacin aerosols, which distributed preferentially to the lower lung lobes, with an influence of the deterioration of FEV1 on the C/P ratio. The three-dimensional rendering of CF airways also detected structural differences between the airways of patients with mild and moderate CF.

Management of chronic Pseudomonas aeruginosa infection with inhaled levofloxacin in people with cystic fibrosis.

People with cystic fibrosis (CF) are highly susceptible to bacterial infections of the airways. By adulthood, chronic Pseudomonas aeruginosa (Pa) is the most prevalent infective organism and is difficult to eradicate owing to its adaptation to the CF lung microenvironment. Long-term suppressive treatment with inhaled antimicrobials is the standard care for reducing exacerbation frequency, improving quality of life and increasing measures of lung function. Levofloxacin (a fluoroquinolone antimicrobial) has been approved as an inhaled solution in Europe and Canada, for the treatment of adults with CF with chronic P. aeruginosa pulmonary infections. Here, we review the clinical principles relating to the use of inhaled antimicrobials and inhaled levofloxacin for the management of P. aeruginosa infections in patients with CF.

Effect of Concentration/Dose Ratio in De Novo Kidney Transplant Recipients Receiving LCP-Tacrolimus or Immediate-Release Tacrolimus: Post Hoc Analysis of a Phase 3 Clinical Trial.

BACKGROUND A previous phase 3 clinical trial in de novo adult kidney transplant recipients (NCT01187953) compared the efficacy and safety of once-daily LCP-tacrolimus (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). However, whether the rate of tacrolimus metabolism affects outcomes between LCPT and IR-Tac was not examined. MATERIAL AND METHODS Patients were initiated on 0.17 mg/kg/day LCPT or 0.1 mg/kg/day IR-Tac, with doses adjusted over time to maintain target therapeutic trough concentrations. This post hoc analysis examined dosing trends, relative efficacy, and safety of LCPT (n=247) and IR-Tac (n=249) in slow, intermediate, and rapid metabolizers as defined by concentration/dose ratios at day 30. RESULTS For all metabolizer subgroups, minimum target tacrolimus trough concentrations were obtained more rapidly with LCPT than with IR-Tac. Slow metabolizers were more likely to exceed target trough concentrations with LCPT, while rapid metabolizers were more likely to fall below target trough concentrations with IR-Tac. Regardless of metabolizer status, significant differences were not detected between LCPT and IR-Tac for treatment failure, death, graft failure, biopsy-proven acute rejection, estimated glomerular filtration rate, or other clinical outcomes. CONCLUSIONS Although within metabolizer subgroups, attainment of target trough concentrations in the first week differed between LCPT and IR-Tac, these results suggest that, regardless of metabolizer phenotype, clinical outcomes do not differ between these formulations when dose adjustments are made.

Whole genome analysis and microRNAs regulation in HepG2 cells exposed to cadmium.

Cadmium (Cd) is a metal known to be toxic and carcinogenic, but its mechanism of action remains to be fully elucidated. We investigated the gene expression modulation in the human hepatoma cell line HepG2 after exposure to 2 µM and 10 µM Cd using an Agilent microarray. Furthermore, we evaluated the microRNA modulation after exposure to 10 µM Cd with a Low Density Array. At the low concentration only eleven genes belonging to the metallothionein familiy were regulated. At the higher concentration the pathway enrichment analysis for the 536 up-regulated genes showed a large number of pathways related to cancer, whereas the 424 down-regulated genes were enriched on pathways correlated to liver function. A large percentage of modified microRNAs belonged to the let-7 family, which is considered to have oncosuppressor functions. Several pathways connected to cancer were regulated at the transcription level, and miRNAs had a potential impact on the modulation of this regulation.

The cell transformation assay: toward a statistical classification of mixed and intermediate foci images.

The human carcinogenicity evaluation of chemicals has a great impact on public health. In vitro methods, such as the cell transformation assay (CTA), allow for a fast and reliable assessment of the carcinogenic potential of a chemical compound in comparison with the standard two-year bioassay. The scoring and classification of foci in selected cell lines is performed, after staining, by light microscopy. Foci can be separated into three classes: type I, which are scored as non-transformed, and types II and III that are considered to include fully transformed foci. However, in a number of cases, even an expert is uncertain about the attribution of a focus to a given class, due to its mixed or intermediate nature. Here, we suggest a simple approach to classifying mixed or intermediate foci by exploiting the quantitative information available from images, which is captured by statistical descriptors. A quantitative index is proposed, to describe the degree of dissimilarity of mixed and intermediate images to the three well-distinguished classes.