National reflection on organs-on-chip for drug development: New regulatory challenges.

Organs-on-chip (OoC) are innovative and promising in vitro models, particularly in the process of developing new drugs, to improve predictivity of preclinical studies in humans. However, a lack of regulatory consensus on acceptance criteria and standards around these technologies currently hinders their adoption and implementation by end-users. A reflection has been conducted at the National Agency for Medicines and Health products safety (ANSM) in order to address this issue, which has gained momentum at the international level in recent years. If the subject of OoC is of international interest, France is also in the process of structuring an OoC network, in order to best support the emergence of this new technological innovation. Focusing on liver-on-a-chip, the authors drafted a first list of regulatory requirements to help standardize these devices and their use. Technological and biological relevance of liver-on-a-chip was also evaluated, in comparison with current in vitro and in vivo models, based on the available literature. The authors offer an analysis of the current scientific and regulatory situation, highlighting the key regulatory issues for the future.

Development of a drug delivery system for efficient alveolar delivery of a neutralizing monoclonal antibody to treat pulmonary intoxication to ricin.

The high toxicity of ricin and its ease of production have made it a major bioterrorism threat worldwide. There is however no efficient and approved treatment for poisoning by ricin inhalation, although there have been major improvements in diagnosis and therapeutic strategies. We describe the development of an anti-ricin neutralizing monoclonal antibody (IgG 43RCA-G1) and a device for its rapid and effective delivery into the lungs for an application in humans. The antibody is a full-length IgG and binds to the ricin A-chain subunit with a high affinity (KD=53pM). Local administration of the antibody into the respiratory tract of mice 6h after pulmonary ricin intoxication allowed the rescue of 100% of intoxicated animals. Specific operational constraints and aerosolization stresses, resulting in protein aggregation and loss of activity, were overcome by formulating the drug as a dry-powder that is solubilized extemporaneously in a stabilizing solution to be nebulized. Inhalation studies in mice showed that this formulation of IgG 43RCA-G1 did not induce pulmonary inflammation. A mesh nebulizer was customized to improve IgG 43RCA-G1 deposition into the alveolar region of human lungs, where ricin aerosol particles mostly accumulate. The drug delivery system also comprises a semi-automatic reconstitution system to facilitate its use and a specific holding chamber to maximize aerosol delivery deep into the lung. In vivo studies in monkeys showed that drug delivery with the device resulted in a high concentration of IgG 43RCA-G1 in the airways for at least 6h after local deposition, which is consistent with the therapeutic window and limited passage into the bloodstream.

Evaluation of lung tolerance of ethanol, propylene glycol, and sorbitan monooleate as solvents in medical aerosols.

BACKGROUND: Aerosol therapy is an expanding technique allowing administration of drugs acting locally in the bronchial tree and lungs or acting systemically after absorption through the respiratory tract. However, the choice of solvents and adjuvants is a critical step in the formulation process of new drugs. Pulmonary tolerance of ethanol, propylene glycol and sorbitan ester was evaluated in a rat model of intratracheal administration using a Microsprayer in a 4-day toxicity study. METHODS: Four groups of Sprague-Dawley rats (11 rats per group, n = 44) have received, on 4 consecutive days 150 microL of solutions containing the solvents, by intratracheal route using a IA-1B-2 inches-Microsprayer (PennCentury, Philadelphia, PA). Once a day, the rats received deionized water (control) or ethanol 10% or propylene glycol 30% or sorbitan monooleate 10%. All rats were sacrificed 24 h after the fourth administration. Biochemical analysis on bronchoalveolar lavage (BAL) fluid was performed on seven rats per group. The respiratory tract of the remaining four rats/group was examined histologically. RESULTS: Biochemistry and histopathology findings demonstrated that under the conditions tested, deionized water, 10% ethanol, and 30% propylene glycol were tolerated in a qualitatively similar way presenting limited cellular reaction. In contrast, 10% sorbitan monooleate produced an accumulation of foamy macrophages in the lungs and a higher degree of inflammation. In addition, animals in this group showed higher polymorphonuclear neutrophil recruitment and total proteins levels in BAL fluid. CONCLUSION: The overall results recommended ranking the vehicles according to the degree of inflammation which was induced: deionized water <10% ethanol < or =30% propylene glycol <10% Tween 80.

Pharmacologie de l'infinitesimal: application aux dilutions homeopathiques / Infinitesimal pharmacology: application to homeopatics dilutions

Apres avoir rappele les grands principes sur lesquels s'appuie l'Homeopathie, les autres axent leur reflexion sur l'activite des hautes dilutions au-dela du nombre d'AVOGADRO. A partir d'experiences realisees tant in vitro qu'in vivo et sur des modeles vegetaux ou animaux, les principes de similitude et d'infinitesimal sont illustres et analyses. Les auteurs insistent notamment sur la necessite de reproduire les resultats et sur l'importance de parametres experimentaux pouvant moduler la reponse biologique. L'aspect clinique est egalement aborde a travers trois etudes. Les differentes theories emises pour tenter d'expliquer l'action de ces hautes dilutions sont evoquees; leur multiplicite indique qu'aucune d'elles n'apportent actuellement de reponse satisfaisante quant au support de l'activite

Environnement stress, anxiete et homeopathie / Environment stress, anxiety and homeopathy

Tout stress (exposition a une situation aversive, choc affectif, maladie intercurrente...) peut provoquer, chez l'homme comme chez l'animal, une rupture des relations de l'individu avec son environnement (inhibition, agressivite, desinteret...) pouvant avoir des repercussions sur l'ensemble des systemes d'integration (SNC, endocrinien, immunitaire). De plus, cet etat d'anxiete parait interferer... (AU)