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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.

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., Competing Interests: GP, DS, SG, CP, and GN are all employees of Chiesi Farmaceutici S.p.A. KB has received honoraria and/or research funding from Alexion, Astellas, Bristol-Myers Squibb, Chiesi, Fresenius, Hansa, Hexal, Merck, Novartis, Otsuka, Pfizer, Roche, Sandoz, Siemens, and Veloxis Pharmaceuticals. UM received participation fees from Chiesi for scientific advisory boards. LR has been an advisor for Hansa and Biotest; has received speaker fees from Astellas, Novartis, Chiesi and Bristol-Myers Squibb; and has received grants from Chugai, Terumo and HemaT. GP, who is now an employee of Chiesi Farmaceutici S.p.A., worked at Dipartimento di Medicina e Chirurgia, UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy at the time of the study and received consulting fees from Chiesi for work as a medical research physician for the present study. OW has received research grants for clinical studies, speaker's fees, honoraria, and travel expenses from Amgen, Astellas, Bristol-Myers Squibb, Chiesi, Hexal, Janssen-Cilag, MSD, Novartis, Pfizer, Roche, and Sanofi. DS received consulting fees from Chiesi for work as a clinical study manager for the present study. NK has received speaker fees and participated in advisory boards for Abbvie, Amgen, Astellas, Chiesi, Fresnius Medical Care, Gilead, Merck Sharp and Dohme, Neovii, Novartis, Roche, Sanofi, and Shire. MB has received funds for travel from Astellas and Chiesi. JP has received consulting fees from Chiesi. DK has received honoraria from Chiesi and Astellas. TW has received honoraria from Chiesi and Therakos/Mallinckrodt, and research funding from Astellas, Chiesi, Neovii, Novartis, Sandoz, Sanofi, and Teva. AG-D has received travel grants, speaker fees, and/or advisory board honoraria from Alexion, Chiesi, MSD and Novartis, and has participated in clinical trials sponsored by Alexion, Astellas, Chiesi and Novartis. LW had received research funding from Chiesi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study (ClinicalTrials.gov, NCT02432833) was funded by Chiesi Farmaceutici SpA. The funder was involved in study design, collection, analysis and interpretation of data. All co-authors have contributed substantially to the analyses and interpretation of the data, and have provided important intellectual input and approval of the final version of the manuscript. Fishawack Inc. has received funding by Chiesi Farmaceutici SpA to provide medical writing support., (Copyright © 2022 Budde, Rostaing, Maggiore, Piotti, Surace, Geraci, Procaccianti, Nicolini, Witzke, Kamar, Albano, Büchler, Pascual, Gutiérrez-Dalmau, Kuypers, Wekerle, Głyda, Carmellini, Tisone, Midtvedt, Wennberg and Grinyó.)

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 FEV 1 . 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 FEV 1 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.

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.

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.

Objective: To assess the efficacy and safety of high-flow nasal oxygen (HFNO) therapy in patients undergoing rapid sequence intubation (RSI) for emergency abdominal surgery., Methods: HFNO of 60 L.min -1 at an inspiratory oxygen fraction of 1 was delivered 4 min before laryngoscopy and maintained until the patient was intubated, and correct intubation was verified by the appearance of the end-tidal CO 2 (EtCO 2 ) waveform. Transcutaneous oxygenation (SpO 2 ), heart rate and non-invasive mean arterial pressure were monitored at baseline (T0), after 4 min on HFNO (T1) and at the time of laryngoscopy (T2) and endotracheal intubation (ETI) (T3). An SpO 2 of <3% from baseline was recorded at any sampled time. The value of EtCO 2 at T3 was registered after two mechanical breaths. The apnoea time was defined as the time from the end of propofol injection to ETI. RSI was performed with propofol, fentanyl and rocuronium., Results: Forty-five patients were enrolled. SpO 2 levels showed a statistically significant increase at T1, T2 and T3 compared with those at T0 (p<0.05); median SpO 2 % (interquartile range) was 97% (range, 96%-99%) at T0, 99% (range, 99%-100%) at T1, 99% (range, 99%-100%) at T2 and 99% (range, 99%-100%) at T3. Minimal SpO 2 was 96%; no patient showed an SpO 2 of <3% from baseline; mean EtCO 2 at the time of ETI was 36±4 mmHg. Maximum apnoea time was 12 min., Conclusion: HFNO is an effective and safe technique for pre-oxygenation in patients undergoing rapid sequence induction of general anaesthesia for emergency surgery., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

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.