Impact of downstream processing on crystal quality during the precipitation of a pharmaceutical product

In pharmaceutical industries, active pharmaceutical ingredients (API) are made of crystals whose properties must be controlled because they influence the end-use properties of the drug. Even if crystal quality is mainly determined during the precipitation step, downstream processing also has an influence. In this study, the influence of washing on the crystal size and shape was analyzed. For the API being considered, different impurities have to be removed from the final suspension by filter cake washing. The efficiency of the washing steps was measured by different types of characterization on the solid phase (differential scanning calorimetry, scanning electron microscopy, and size distribution) and on the remaining filtrate (concentration of impurities). A second component also coprecipitates with the API. A specific study has been carried out on the withdrawal of this by-product and on its impact on the evolution of the crystalline form during washing steps. It was found that three filter cake washings allow us to remove all the impurities and to obtain a pure crystalline form

Influence of pH, Temperature and Impurities on the Solubility of an Active Pharmaceutical Ingredient (API)

Solubility, which defines the liquid /solid equilibrium, is a key parameter to control a crystallization process. This work is focused on the effects of pH, temperature and impurities on the aqueous solubility of an Active Pharmaceutical Ingredient (API).As the API is a weak acid (pKa = 3.7), its solubility increases with the pH. On the basis of the experimental curve of solubility, a model was defined to fit the evolution of the solubility as a function of pH. In the case of this compound, studies revealed a weak influence of the temperature in comparison with the pH. So, the solubility of the compound is slightly impacted by the temperature.Some experiments were carried out in order to compare the solubility of the API, at the same pH and temperature, for different concentrations of impurities found in the process. The results revealed a solubility increase in presence of acetic acid and a high solubility decrease in presence of sodium chloride. By carrying out experiments on common ions salts, the anion chloride Cl- has been identified as the cause of the solubility decrease

Characterization of the conglomerate form of acetyl-dl-leucine by thermal analysis and solubility measurements

Starting from a mixture of enantiomers in solution, crystallization can generate different types of crystals. In order to determine which type of crystal is obtained in the case of acetylleucine, an active pharmaceutical ingredient (API), analytical methods have been used to partially elucidate the binary and ternary phase diagrams of the system composed of the two enantiomers and water.The melting temperature phase diagram of this compound has been obtained by using differential scanning calorimetry (DSC) analyzes. The results show that it is characteristic of a conglomerate. This mode of crystallization has also been confirmed by X-ray powder diffraction analysis. Solubility measurements of enantiomerical mixtures in water enabled the determination of the ternary diagram of solubility. The empiric Meyerhoffer double solubility rule has been modified, due to the characterization of interactions between enantiomers

Medicosocial outcome after admission in post-intensive care unit at PRM St-Hélier, Rennes

IntroductionPost-Intensive Care Units (PICU) are PRM structures aiming to start the appropriated rehabilitative care as early as possible even though persistent complex medical issues.ObjectiveTo assess medicosocial outcomes of patients away from their admission in PICU.MethodsA retrospective descriptive study that included 81 consecutive patients (mean age 51 years) admitted from 2008 to 2012 in the PICU of Pôle St-Helier Rennes based on called semi-structured interviews between March 2014 and March 2015. Exhaustive data (only 4 lost, 5%) by the patient himself and/or a member of family on autonomy, place of life, structures since the release and reintegration, of patients for 85% of them brain damaged.ResultsThere is 29% (21/77) of death (post-exit life: 1,6 years±1.18). Eighty percent live at home (46/56) of which only 5 without family environment, 10% (5/56) in medicosocial structures (foster or nursing homes…), 10% in hospital (hospital at home, persistent vegetative units…). Fourteen percent (8/56) are completely autonomous and work, all with adaptations. Twenty-three percent (13/56) had a significant dependence for activities of daily life and instrumental ones. Forty percent (22/56) have no hobby. Use of different downstream structures, long-term readaptative monitoring, legal and families’ feelings were also analyzed.Discussion and ConclusionMedical and social outcome of patients in the aftermath of a stay in PICU is disparate, depending on the pathology involved, but also the pre-social situation that seems to be the main predictor of returning home. Most patients have regained a relatively large autonomy for the daily life activities but are embarrassed to complex instrumental activities impeding social inclusion. These results are consistent with those of the literature on head trauma patients but no other study has focused for the moment on the specific population of patients admitted to the PICU. We see the value of such early rehabilitative care units with a real impact on the subsequent independence and opportunities back home

Elastomeric cardiopatch scaffold for myocardial repair and ventricular support

[EN] OBJECTIVES: Prevention of postischaemic ventricular dilatation progressing towards pathological remodelling is necessary to decrease ventricular wall deterioration. Myocardial tissue engineering may play a therapeutic role due to its capacity to replace the extracellular matrix, thereby creating niches for cell homing. In this experimental animal study, a biomimetic cardiopatch was created with elastomeric scaffolds and nanotechnologies. METHODS: In an experimental animal study in 18 sheep, a cardiopatch was created with adipose tissue-derived progenitor cells seeded into an engineered bioimplant consisting of 3-dimensional bioabsorbable polycaprolactone scaffolds filled with a peptide hydrogel (PuraMatrix (TM)). This patch was then transplanted to cover infarcted myocardium. Non-absorbable poly(ethyl) acrylate polymer scaffolds were used as controls. RESULTS: Fifteen sheep were followed with ultrasound scans at 6 months, including echocardiography scans, tissue Doppler and spectral flow analysis and speckle-tracking imaging, which showed a reduction in longitudinal left ventricular deformation in the cardiopatch-treated group. Magnetic resonance imaging (late gadolinium enhancement) showed reduction of infarct size relative to left ventricular mass in the cardiopatch group versus the controls. Histopathological analysis at 6 months showed that the cardiopatch was fully anchored and integrated to the infarct area with minimal fibrosis interface, thereby promoting angiogenesis and migration of adipose tissue-derived progenitor cells to surrounding tissues. CONCLUSIONS: This study shows the feasibility and effectiveness of a cardiopatch grafted onto myocardial infarction scars in an experimental animal model. This treatment decreased fibrosis, limited infarct scar expansion and reduced postischaemic ventricular deformity. A capillary network developed between our scaffold and the heart. The elastomeric cardiopatch seems to have a positive impact on ventricular remodelling and performance in patients with heart failure.The RECATABI Project (Regeneration of Cardiac Tissue Assisted by Bioactive Implants) was financially supported by the 7th Framework Programme (FP7) of the European Commission. Project ID: 229239. Funded under FP7-NMP and the European Regional Development Fund (FEDER Spain).Chachques, JC.; Lila, N.; Soler Botija, C.; Martínez-Ramos, C.; Vallés Lluch, A.; Autret, G.; Perier, M.... (2020). Elastomeric cardiopatch scaffold for myocardial repair and ventricular support. European Journal of Cardio-Thoracic Surgery. 57(3):545-555. https://doi.org/10.1093/ejcts/ezz252S545555573Madonna, R., Van Laake, L. W., Botker, H. E., Davidson, S. M., De Caterina, R., Engel, F. B., … Sluijter, J. P. G. (2019). ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure. Cardiovascular Research, 115(3), 488-500. doi:10.1093/cvr/cvz010Nielsen, S. H., Mouton, A. J., DeLeon-Pennell, K. Y., Genovese, F., Karsdal, M., & Lindsey, M. L. (2019). Understanding cardiac extracellular matrix remodeling to develop biomarkers of myocardial infarction outcomes. Matrix Biology, 75-76, 43-57. doi:10.1016/j.matbio.2017.12.001Spinale, F. G., Frangogiannis, N. G., Hinz, B., Holmes, J. W., Kassiri, Z., & Lindsey, M. L. (2016). Crossing Into the Next Frontier of Cardiac Extracellular Matrix Research. Circulation Research, 119(10), 1040-1045. doi:10.1161/circresaha.116.309916Chachques, J. C., Pradas, M. M., Bayes-Genis, A., & Semino, C. (2013). Creating the bioartificial myocardium for cardiac repair: challenges and clinical targets. Expert Review of Cardiovascular Therapy, 11(12), 1701-1711. doi:10.1586/14779072.2013.854165Bayés-Genís, A., Gálvez-Montón, C., & Roura, S. (2016). Cardiac Tissue Engineering. Journal of the American College of Cardiology, 68(7), 724-726. doi:10.1016/j.jacc.2016.05.055Shafy, A., Fink, T., Zachar, V., Lila, N., Carpentier, A., & Chachques, J. C. (2012). Development of cardiac support bioprostheses for ventricular restoration and myocardial regeneration. European Journal of Cardio-Thoracic Surgery, 43(6), 1211-1219. doi:10.1093/ejcts/ezs480Castells-Sala, C., Recha-Sancho, L., Llucià-Valldeperas, A., Soler-Botija, C., Bayes-Genis, A., & Semino, C. E. (2016). Three-Dimensional Cultures of Human Subcutaneous Adipose Tissue-Derived Progenitor Cells Based on RAD16-I Self-Assembling Peptide. Tissue Engineering Part C: Methods, 22(2), 113-124. doi:10.1089/ten.tec.2015.0270Martínez-Ramos, C., Rodríguez-Pérez, E., Garnes, M. P., Chachques, J. C., Moratal, D., Vallés-Lluch, A., & Monleón Pradas, M. (2014). Design and Assembly Procedures for Large-Sized Biohybrid Scaffolds as Patches for Myocardial Infarct. Tissue Engineering Part C: Methods, 20(10), 817-827. doi:10.1089/ten.tec.2013.0489Biswas, M., Sudhakar, S., Nanda, N. C., Buckberg, G., Pradhan, M., Roomi, A. U., … Houle, H. (2013). Two- and Three-Dimensional Speckle Tracking Echocardiography: Clinical Applications and Future Directions. Echocardiography, 30(1), 88-105. doi:10.1111/echo.12079Dorsey, S. M., McGarvey, J. R., Wang, H., Nikou, A., Arama, L., Koomalsingh, K. J., … Burdick, J. A. (2015). MRI evaluation of injectable hyaluronic acid-based hydrogel therapy to limit ventricular remodeling after myocardial infarction. Biomaterials, 69, 65-75. doi:10.1016/j.biomaterials.2015.08.011Chachques, J. C. (2009). Cellular cardiac regenerative therapy in which patients? Expert Review of Cardiovascular Therapy, 7(8), 911-919. doi:10.1586/erc.09.84Chachques, J. (1997). Dynamic cardiomyoplasty: clinical follow-up at 12 years. European Journal of Cardio-Thoracic Surgery, 12(4), 560-568. doi:10.1016/s1010-7940(97)00214-5Varela, C. E., Fan, Y., & Roche, E. T. (2019). Optimizing Epicardial Restraint and Reinforcement Following Myocardial Infarction: Moving Towards Localized, Biomimetic, and Multitherapeutic Options. Biomimetics, 4(1), 7. doi:10.3390/biomimetics4010007Van den Borne, S. W. M., Cleutjens, J. P. M., Hanemaaijer, R., Creemers, E. E., Smits, J. F. M., Daemen, M. J. A. P., & Blankesteijn, W. M. (2009). Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction. Cardiovascular Pathology, 18(1), 37-43. doi:10.1016/j.carpath.2007.12.012Ducharme, A., Frantz, S., Aikawa, M., Rabkin, E., Lindsey, M., Rohde, L. E., … Lee, R. T. (2000). Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. Journal of Clinical Investigation, 106(1), 55-62. doi:10.1172/jci8768Sieminski, A. L., Semino, C. E., Gong, H., & Kamm, R. D. (2008). Primary sequence of ionic self-assembling peptide gels affects endothelial cell adhesion and capillary morphogenesis. Journal of Biomedical Materials Research Part A, 87A(2), 494-504. doi:10.1002/jbm.a.31785Bagó, J. R., Soler-Botija, C., Casaní, L., Aguilar, E., Alieva, M., Rubio, N., … Blanco, J. (2013). Bioluminescence imaging of cardiomyogenic and vascular differentiation of cardiac and subcutaneous adipose tissue-derived progenitor cells in fibrin patches in a myocardium infarct model. International Journal of Cardiology, 169(4), 288-295. doi:10.1016/j.ijcard.2013.09.013Chachques, J. C., Trainini, J. C., Lago, N., Cortes-Morichetti, M., Schussler, O., & Carpentier, A. (2008). Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Trial): Clinical Feasibility Study. The Annals of Thoracic Surgery, 85(3), 901-908. doi:10.1016/j.athoracsur.2007.10.052Lee, H., Ahn, S., Bonassar, L. J., & Kim, G. (2012). Cell(MC3T3-E1)-Printed Poly(ϵ-caprolactone)/Alginate Hybrid Scaffolds for Tissue Regeneration. Macromolecular Rapid Communications, 34(2), 142-149. doi:10.1002/marc.201200524Strub, M., Van Bellinghen, X., Fioretti, F., Bornert, F., Benkirane-Jessel, N., Idoux-Gillet, Y., … Clauss, F. (2018). Maxillary Bone Regeneration Based on Nanoreservoirs Functionalizedε-Polycaprolactone Biomembranes in a Mouse Model of Jaw Bone Lesion. BioMed Research International, 2018, 1-12. doi:10.1155/2018/7380389Rohman, G., Huot, S., Vilas-Boas, M., Radu-Bostan, G., Castner, D. G., & Migonney, V. (2015). The grafting of a thin layer of poly(sodium styrene sulfonate) onto poly(ε-caprolactone) surface can enhance fibroblast behavior. Journal of Materials Science: Materials in Medicine, 26(7). doi:10.1007/s10856-015-5539-7Spadaccio, C., Nappi, F., De Marco, F., Sedati, P., Taffon, C., Nenna, A., … Rainer, A. (2017). Implantation of a Poly-l-Lactide GCSF-Functionalized Scaffold in a Model of Chronic Myocardial Infarction. Journal of Cardiovascular Translational Research, 10(1), 47-65. doi:10.1007/s12265-016-9718-9Monnet, E., & Chachques, J. C. (2005). Animal Models of Heart Failure: What Is New? The Annals of Thoracic Surgery, 79(4), 1445-1453. doi:10.1016/j.athoracsur.2004.04.002Bellin, G., Gardin, C., Ferroni, L., Chachques, J., Rogante, M., Mitrečić, D., … Zavan, B. (2019). Exosome in Cardiovascular Diseases: A Complex World Full of Hope. Cells, 8(2), 166. doi:10.3390/cells802016

Contribution à l'étude de la virulence de Listeria monocytogenes

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

L'Information financière en crise : Comptabilité et Captialisme

Enron, Andersen, Parmalat : des entreprises majeures ont disparu brutalement à la suite de la révélation de manipulations financières. La comptabilité ne peut plus être considérée comme une science exacte, et la crise de confiance s’installe au cœur même du fonctionnement des marchés. En saisir les causes et les enjeux est aujourd’hui indispensable. Ce livre part d’un constat : les règles comptables ne sont pas neutres, elles sont à la fois un miroir et un élément structurant de notre système économique. S’adressant à la fois au public éclairé et aux praticiens, multipliant les exemples et les cas concrets, il donne à chacun les clés pour comprendre le nouveau monde de l'information financière. La montée en puissance et l’internationalisation des marchés de capitaux bouleversent les équilibres traditionnels entre entreprises, auditeurs, investisseurs et puissance publique. En analysant ces mouvements sous le prisme de l’information financière, les auteurs apportent une perspective inédite à la réflexion sur la transformation du capitalisme

Smoke and Mirrors, Inc. Accounting for Capitalism

Enron, Arthur Andersen, Parmalat, AIG: business headlines over the last few years have stimulated worldwide interest in accounting responsibilities and standards. Smoke and Mirrors, Inc., is a remarkable introduction to contemporary accounting and its central importance for the operation of modern capitalism. Nicolas Véron, Matthieu Autret, and Alfred Galichon show how accounting always mirrored the features of contemporaneous financial systems, while remaining intrinsically subject to judgment and uncertainty and thus leaving scope for manipulation that can convert a rotten balance sheet into a picture of robust financial health. Beginning with the story of the fictional company Smoke & Mirrors Inc., Véron and his coauthors provide a brief history of accounting's emergence and its key concepts and practices. They then shift their focus to the political economy of the various actors involved in the preparation, auditing, and use of financial information and the new challenges facing regulators as capital markets spread across national boundaries. The authors challenge widespread beliefs that accounting practices are neutral and involve the mere reporting of objective data. They trace how different accounting standards, which alter the calculus of what counts as a "fair representation" of business dealings, can change economic behavior. Along the way they provide numerous examples and case studies, including a detailed account of the tricks with which Enron cooked its books. For students of corporate finance, practicing accountants and businesspeople, and general readers who have followed a seemingly endless parade of financial scandals with disbelief, Smoke and Mirrors, Inc., provides a clear and concise overview of the use and abuse of accounting and of the underlying changes in today's capital markets.