Search

International audience; Background and purpose: Pseudomonas aeruginosa is a main cause of ventilator-associated pneumonia (VAP) with drug-resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of pneumonia caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized-phage therapy.Experimental approach: (i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled-phage therapy was evaluated in pigs, which were anesthetized, mechanically ventilated and infected with P. aeruginosa.Key results: By selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5 Log reduction, p

La mise sur le marché de biosimilaires requiert une démonstration stricte de la similarité avec l’anticorps de référence, au travers d’études précliniques et cliniques. Cet article synthétise l’ensemble des analyses physicochimiques et fonctionnelles mises en œuvre in vitro, préalables à la réalisation d’études cliniques. Pour chaque caractéristique critique de l’anticorps, nous avons détaillé les techniques analytiques communément employées, leur principe de fonctionnement, ainsi que le type d’informations que ces techniques permettent d’obtenir.

During the 2018 European Respiratory Society (ERS) International Congress in Paris the author of the best abstract from every assembly was awarded (based on the highest average score from the abstract reviewers for an author under 40 years of age). Best-abstract awardees were invited to write a short summary of their Congress experience and view on the evolving field of research of their respective assembly. The purpose of this article is to give the readers a fast overview of some of the Congress highlights and to give the stage to the young and promising best-abstract awardees, as they are the future of the ERS., A summary of the ERS International Congress 2018 from the best-abstract awardees for each ERS Assembly and their views on the evolving field of research of their respective Assemblies http://ow.ly/c0eq30ntKuw

International audience; Nonclinical studies are fundamental for the development of inhaled drugs, as for any drug product, and for successful translation to clinical practice. They include in silico, in vitro, ex vivo and in vivo studies and are intended to provide a comprehensive understanding of the inhaled drug beneficial and detrimental effects. To date, animal models cannot be circumvented during drug development programs, acting as surrogates of humans to predict inhaled drug response, fate and toxicity. Herein, we review the animal models used during the different development stages of inhaled pharmaceuticals and biopharmaceuticals, highlighting their strengths and limitations.

International audience; Inhaled protein therapeutics meet a growing interest for the treatment of respiratory diseases. In liquid aerosols, proteins face stresses that may generate instabilities, such as physicochemical denaturations, aggregation and loss of activity. Monitoring protein stability is thus crucial but implies collection of aerosol droplets before analysis. Many aerosol collection methods may be used, still their interference on protein stability is unknown. In this study, we compared the impact of six aerosol samplers on the stability of a model monoclonal antibody (Ig1), aerosolized with a mesh nebulizer. Ig1 stability was assessed for aggregation and biological activity. The six aerosol samplers generated distinct aggregation profiles for Ig1 at all size scales; counts of micron-sized particles varied by a factor of 100. The heterogeneity did not impact Ig1 activity, which was not significantly changed after nebulization. To extrapolate these results, we evaluated the impact of two samplers on three other proteins. Depending on the protein, samplers gave discordant aggregation and/or activity profiles, sometimes in the reverse trend as compared to Ig1. In conclusion, aerosol samplers interfere with protein stability; this impact depends both on the samplers and the protein, highlighting the importance of using the same collection device throughout the aerosol development process

Pseudomonas aeruginosa (Psa) lung infections are increasingly difficult to treat due to evolving antibiotic resistance; bacteriophages (phages) are part of the foreseen complementary/alternative therapies. In this study, we developed a phage cocktail for airways delivery and assessed its preclinical efficacy and resistance to aerosolization. A phage cocktail was tested against the 43-strain Psa reference panel published in 2013. Its efficacy was assessed in vivo in a murine model of acute Psa lung infection, obtained by pulmonary inoculation. Two hours post-infection, the phage cocktail was delivered by the pulmonary route; the therapeutic response was monitored by animal survival and lung bacterial count. Finally, phage suspension was aerosolized with 4 different nebulizers; aerosolized phage viability was assessed after aerosol collection. The phage cocktail displayed 95% efficacy in vitro on the reference panel. After pulmonary administration in infected mice, it allowed 90% survival at 48h (vs 0% in untreated animals) and a drop in bacterial lung count. The aerosolization study showed that mesh nebulization was the less deleterious to phages, with 33.4% viability vs 29.6% and 7.7% for ultrasonic and jet-nebulization, respectively. Transmission electron microscopy analysis of phage suspensions before and after nebulization revealed that phage titer loss was caused by mechanical disruption of capsids and tails. To conclude, we developed a phage cocktail efficient against Psa, both in vitro and in vivo. Besides, its nebulization was associated with 1/3 phage viability, allowing a high dose of phages to be delivered. Optimization of the drug and device may help in improving phage stability.

International audience; Respiratory diseases (RDs) constitute a major public health issue worldwide, and some RDs represent a significant unmet medical need. Inhaled protein therapeutics are now attracting increasing interest for the topical treatment of RDs, with one drug on the market and almost 20 others in clinical development. Here, we review advances in inhaled protein therapeutics and comment on the development strategies that can be considered. To date, the transformation of a therapeutic protein into an inhalable drug has often been performed on a case-by-case basis by taking account of specific protein-, inhaler-, and patient-related factors. A rational design process for both the drug formulation and the delivery deviceis crucial for maintaining the protein’s integrity and optimizing deposition in the lung, which in turn are decisive for clinically successful aerosol therapy. Despite significant advances in this field, there are still a number of outstanding questions about the stability of nebulized proteins and the consequences of nebulization on the biological activity, safety and pharmacokinetics of these innovative therapeutics. A better understanding of these parameters should promote the implementation of more rational development strategies, and thus accelerate progression towards clinical applications

The annual "LabEx MAbImprove Industrial Workshops" are primarily intended to provide a comprehensive view about topics of interest for the pharmaceutical industry to scientists involved in research on therapeutic antibodies. The third workshop in this series, held July 2, 2015 in Tours, was dedicated to the optimization of delivery, namely all processes leading monoclonal antibodies to reach their target site. The commonly used intravenous (IV) route, although advantageous in terms of pharmacokinetics and pharmacodynamics, presents some disadvantages in terms of patients' convenience, therapeutic target access or treatment cost. Such problems led pharmaceutical companies to consider more straightforward and patient-friendly administration routes, bringing the need for specific formulations adapted to the specific inherent physicochemical challenges. In this context, the workshop provided an overview of these advances and opened discussion on new administration routes and formulation development. In the first session, the opportunities and challenges of 3 main routes of administration (IV, subcutaneous (SC), and pulmonary) were discussed, integrating protein stability issues. The next session was dedicated to medical devices intended for SC and pulmonary administration. The last session focused on specific formulations for monoclonal antibodies, particularly to successfully protect antibodies upon aerosolization, to develop highly concentrated formulations for SC administration, and to use formulation as a mean to overcome the barriers to oral protein delivery. As in the previous editions, this workshop gathered people from the academic and industrial spheres and allowed rich debates and discussions.

Bacterial respiratory tract infections (RTIs) are increasingly difficult to treat due to evolving antibiotic resistance. In this context, bacteriophages (or phages) are part of the foreseen alternatives or combination therapies. Delivering phages through the airways seems more relevant to accumulate these natural antibacterial viruses in proximity to their bacterial host, within the infectious site. Areas covered: This review addresses the potential of phage therapy to treat RTIs and discusses preclinical and clinical results of phages administration in this context. Recent phage formulation and aerosolization attempts are also reviewed, raising technical challenges to achieve efficient pulmonary deposition via inhalation. Expert opinion: Overall, the inhalation of phages as antibacterial treatment seems both clinically relevant and technically feasible. Several crucial points still need to be investigated, such as phage product pharmacokinetics and immunogenicity. Furthermore, given phage-specific features, appropriate regulatory and manufacturing guidelines will need to be defined. Finally, randomized controlled clinical trials should be carried out to establish phage therapy's clinical positioning in the antimicrobial arsenal against RTIs.

Ambulatory oxygen therapy is sometimes needed when transferring inpatients. The prescribed administration rate must be maintained during the entire transit time. This implies that paramedical staff calculates the volume of gas remaining in the cylinder, based on the residual pressure displayed on the oxygen cylinders. This step carries a risk of errors and wastage. The objective of this study was to assess the impact of a digital autonomy display system on the use of oxygen cylinders at the hospital.: Two B5 oxygen cylinders (Air Liquide Santé France) were compared: Presence™ (regular manometer) and Takeo™ (digital display). This study was carried out in two wards; Presence™ cylinders were supplied for two months, and then Takeo™ cylinders for the next two months. For each period, we measured the turnover rates of the cylinders and their residual pressure. The economic impact of this change in practice was estimated by a cost study.: Use of Takeo™ cylinders resulted in a significant decrease in the turnover rate (69 % vs. 93 %,: A digital autonomy display increases the delivery performance of portable medicinal oxygen cylinders and generates an economic gain.