Sustainable approaches for drug repurposing in rare diseases: recommendations from the IRDiRC Task Force

Drug repurposing represents a real opportunity to address unmet needs and improve the lives of rare disease patients. It is often presented as a faster, safer and cheaper path for bringing drugs into new indications. However, several economic, regulatory and scientific barriers can impede the successful repurposing of drugs for rare diseases. The International Rare Diseases Research Consortium (IRDiRC) set up the Task Force on Sustainable Models in Drug Repurposing with the objective of identifying key factors for achieving sustainable repurposing approaches in rare diseases. In order to help inform expert opinion, the Task Force investigated six cases of medicinal products repurposed into new rare indications and four cases of ongoing development programs. A questionnaire addressing the major steps of the repurposing approach was developed by the Task Force and sent to contact points of the organizations. In addition, interviews were conducted with the relevant organization representatives to conduct a deeper dive into the sustainability of the repurposing approach for each of the selected cases. Based on the collective experience of the members of the Task Force and the output from the questionnaires/interviews, we have identified ten key factors that should be considered by those embarking on repurposing projects. These factors include the identification of unmet patient needs and partnership with patients, collection of evidence concerning disease prevalence, patient numbers, drug pharmacology and disease etiology, drug industrial property status, off-label or compounding use, data from past clinical studies and needs for extended non-clinical and clinical studies. The development of a collaborative funding framework and early discussion with regulators and payers are additional factors to implement early in the development of sustainable drug repurposing projects

Evidence for a More Disrupted Immune-Endocrine Relation and Cortisol Immunologic Influences in the Context of Tuberculosis and Type 2 Diabetes Comorbidity

Pulmonary tuberculosis (PTB), caused by Mycobacterium tuberculosis (Mtb), is a major health problem worldwide, further aggravated by the convergence of type 2 diabetes mellitus (DM) which constitutes an important risk factor for TB development. The worse scenario of patients with PTB and DM may be partly related to a more unbalanced defensive response. As such, newly diagnosed PTB patients with DM (TB+DM, n = 11) or not (TB, n = 21), as well as DM (n = 18) patients and pair matched controls (Co, n = 22), were investigated for the circulating immuno-endocrine-metabolic profile (ELISA), along with studies in peripheral blood mononuclear cells (PBMC) analyzing transcript expression (RT-qPCR) of mediators involved in glucocorticoid functionality. Given the hyperglycemic/hypercortisolemic scenario of TB+DM patients, PBMC were also exposed to stress-related cortisol concentrations (0.1 and 1 μM) and supraphysiologic glucose doses (10, 20, and 40 mM) and assessed for the specific response against Mtb stimulation (lymphoproliferation, -thymidine incorporation-, and cytokine production -bead-cytometry). All TB patients displayed increased plasma amounts of cortisol, growth hormone -hGH-, and proinflammatory mediators. In turn, TB+DM showed even higher levels of interferon gamma -IFN-γ- and hGH (vs. TB), or IL-6, C reactive protein, cortisol and hGH (vs. DM). Both DM groups had equally augmented values of IL-10. All TB patients showed decreased dehydroepiandrosterone- sulfate concentrations, even more in TB+DM cases. Leptin was also decreased in both TB cases, particularly in the TB group, revealing a lower body mass index, as well. Unlike PBMC from TB cases showing a decreased relationship between the glucocorticoids receptor (GR) isoforms (GRα/GRβ; functional isoform/negative isoform), cells from TB+DM patients had no changes in this regard, along with an increased expression of 11-beta hydroxysteroid dehydrogenase type-1, the enzyme facilitating intracellular cortisone to cortisol conversion. TB+DM patients also showed an increased Mtb antigen-driven lymphoproliferation. Compared to TB, DM and HCo counterparts, PBMC from TB+DM patients had a biased Th1 response to Mtb stimulation (increased IL-2 and IFN-γ production), even when exposed to inhibitory cortisol doses. TB+DM patients show a more unbalanced immuno-endocrine relationship, respect the non-diabetic counterparts, with a relative deficiency of cortisol immunomodulatory influences, despite their more favorable microenvironment for cortisol-mediated immune effects.Fil: Fernández, Rocío del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Díaz, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bongiovanni, Bettina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Gallucci, Georgina Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bértola, Diego. Universidad Nacional de Rosario; ArgentinaFil: Gardeñez, Walter. Universidad Nacional de Rosario; ArgentinaFil: Lioi, Susana. Hospital Provincial del Centenario; ArgentinaFil: Bertolin, Yésica. Hospital Provincial del Centenario; ArgentinaFil: Galliano, Romina. Hospital Provincial del Centenario; ArgentinaFil: Bay, Maria Luisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: D'attilio, Luciano David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; Argentin

Planck intermediate results. XXIII. Galactic plane emission components derived from Planck with ancillary data

Planck data when combined with ancillary data provide a unique opportunity to separate the diffuse emission components of the inner Galaxy. The purpose of the paper is to elucidate the morphology of the various emission components in the strong star-formation region lying inside the solar radius and to clarify the relationship between the various components. The region of the Galactic plane covered is l = 300\ub0 \u2192 0\ub0 \u2192 60\ub0 wherestar-formation is highest and the emission is strong enough to make meaningful component separation. The latitude widths in this longitude range lie between 1 and 2, which correspond to FWHM z-widths of 100-200 pc at a typical distance of 6 kpc. The four emission components studied here are synchrotron, free-free, anomalous microwave emission (AME), and thermal (vibrational) dust emission. These components are identified by constructing spectral energy distributions (SEDs) at positions along the Galactic plane using the wide frequency coverage of Planck (28.4-857GHz) in combination with low-frequency radio data at 0.408-2.3 GHz plus WMAP data at 23-94 GHz, along with far-infrared (FIR) data from COBE-DIRBE and IRAS. The free-free component is determined from radio recombination line (RRL) data. AME is found to be comparable in brightness to the free-free emission on the Galactic plane in the frequency range 20-40 GHz with a width in latitude similar to that of the thermal dust; it comprises 45 \ub1 1% of the total 28.4 GHz emission in the longitude range l = 300\ub0 \u2192 0\ub0 \u2192 60\ub0. The free-free component is the narrowest, reflecting the fact that it is produced by current star-formation as traced by the narrow distribution of OB stars. It is the dominant emission on the plane between 60 and 100 GHz. RRLs from this ionized gas are used to assess its distance, leading to a free-free z-width of FWHM 48 100 pc. The narrow synchrotron component has a low-frequency brightness spectral index \u3b2synch 48 -2.7 that is similar to the broad synchrotron component indicating that they are both populated by the cosmic ray electrons of the same spectral index. The width of this narrow synchrotron component is significantly larger than that of the other three components, suggesting that it is generated in an assembly of older supernova remnants that have expanded to sizes of order 150 pc in 3 7 105 yr; pulsars of a similar age have a similar spread in latitude. The thermal dust is identified in the SEDs with average parameters of Tdust = 20.4 \ub1 0.4 K, \u3b2FIR = 1.94 \ub1 0.03 (> 353 GHz), and \u3b2mm = 1.67 \ub1 0.02 (< 353 GHz). The latitude distributions of gamma-rays, CO, and the emission in high-frequency Planck bands have similar widths, showing that they are all indicators of the total gaseous matter on the plane in the inner Galaxy. \ua9 ESO, 2015

Low‐cost Photoactive Hybrid Materials: From Green Synthesis to Multi‐technique Analytical Characterization

Low-cost photoactive hybrid materials for light management, based on neutral organic molecules intercalated into saponite, were prepared by facile green methods and characterized. TPBI (2-(2'-tosylaminophenyl)benzimidazole) was chosen as an organic host dye, envisioning its application as a downconverter in silicon or dye-sensitized photovoltaic modules. Mixed with a cationic surfactant, the neutral molecule was intercalated with a sort of "trojan horse" approach by an easy, almost solvent-free method, thus limiting its aggregation. The obtained material was characterized by combining spectroscopic, diffractometric, and microscopic techniques. Moreover, the intercalation of the dye, the species present in the interlayer, their stability and mutual interactions were assessed by TGA-GC-MS. We obtained a material containing a fluorescent dye in the solid state and stabilized by intercalation and dispersion into saponite. At last, this material was used to prepare a photoactive polymer by melt blending, obtaining materials with the desired optical properties, with Stokes shifts larger than 100 nm and an emission yield above 50%

How to approach a Grätzel solar cell in a multivariate way

Nowadays, modern science proposes and optimizes new materials and technologies, whose characteristics and performances are governed by many factors. However, the scientific community rarely adopts multivariate strategies for the comprehension of what is proposed. As a striking example, a standard dye-sensitized solar cell (DSSC) is a typical complex system assembled with different and heterogeneous layers (FTO/nanocrystalline semiconductor/sensitizer/electrolyte/Pt-FTO), each one affected by intrinsic variability; moreover the layers influence each other and this increases the number of variables involved at the same time in the photoconversion process. Thousands of articles have been published to study a single parameter or component of DSSCs, but a comprehensive approach which considers all the experimental factors simultaneously has never adopted. In this work, we show how chemometric design of experiments (DoE) can be used for the formulation of UV-cured polymer electrolyte membranes, for the preparation of a cellulose-based gel-polymer electrolyte, for the proper sensitization of a ZnO photoanode and for the photostability optimization of a series of NIR dyes under different dipping conditions

Studies of the medicinal properties of total extract and different fractions of Ligaria cuneifolia (R. et P.) Tiegh (Loranthaceae)

Ligaria cuneifolia (Lc) (R. et P.) Tiegh. (Loranthaceae), popularmente conocida como “muérdago criollo”, “liga” o “liguilla”, es una especie hemiparásita, que se encuentra en el centro y norte de&nbsp;Argentina. En medicina tradicional es utilizada para disminuir la presión arterial y el colesterol. Basándonos en las observaciones empíricas, planteamos como objetivo demostrar científicamente que Ligaria cuneifolia tiene propiedades hipotensoras e hipocolesterolémicas. En ratas Wistar machos adultas alimentadas con dieta normal, enriquecida en colesterol y en hiperlipémicas (alimentadas con High Fat Diet), demostramos que el tratamiento por vía intraperitoneal con una fracción enriquecida en Proantocianidinas extraídas de Lc (PLc) produce disminución del 40% del colesterol plasmático (Co) debido al aumento de la velocidad de excreción biliar de sales biliares, así como disminución de triglicéridos y LDLCo, sin producir cambios en la fluidez de la sangre. Evaluamos el efecto vasoactivo de PLc in vitro en anillos de aorta aislada de ratas determinando su tensión isométrica, presentando efecto vasodilatador dependiente de endotelio, ya que la remoción mecánica del mismo anula completamente la relajación. El tratamiento con infusión de extracto liofilizado de hojas y tallos de Lc ingerida tres veces por semana durante dos meses por pacientes hipercolesterolémicos de ambos sexos (edad: 50 ± 15 años), permitió observar descenso en los niveles Co y LDLCo, sin mostrar alteraciones en la fluidez de la sangre ni en la funcion hepático. Conclusión: Ligaria cuneifolia sería una potencial herramienta en la prevención de enfermedades cardiovasculares, por disminuir el Colesterol plasmático y presentar un marcado efecto hipotensor.Ligaria cuneifolia (Lc) (R. et P.) Tiegh. (Loranthaceae), popularly known as “Creole mistletoe”, “league” or “liguilla”, is a hemiparasitic species, found in central and northern Argentina. In traditional medicine it is used to lower both blood pressure and cholesterol. Based on empirical observations, we set the objective of scientifically demonstrating that Ligaria cuneifolia has hypotensive and hypocholesterolemic properties. In adult male Wistar rats fed a normal diet, enriched in cholesterol and hyperlipemic (fed High Fat Diet), we demonstrated that treatment intraperitoneally with a fraction enriched in Proanthocyanidins extracted from Lc (PLc) produces a 40% decrease in cholesterol plasma (Co) due to an increase in the rate of biliary excretion of bile salts, as well as a decrease in triglycerides and LDLCo, without producing changes in blood fluidity. We evaluated the vasoactive effect of PLc in vitro in isolated rat aortic rings was evaluated by determining its isometric tension, presenting an endothelium-dependent vasodilator effect, since its mechanical removal completely cancels relaxation. Treatment with infusion of lyophilized extract of leaves and stems of Lc ingested three times a week for two months by hypercholesterolemic patients of both sexes (age: 50 ± 15 years), allowed to observe decrease in Cho and LDLCho levels, without showing alterations in blood fluidity or liver function. Conclusion: Ligaria cuneifolia is a potential tool in the prevention of cardiovascular diseases, as it reduces plasma cholesterol and has a marked hypotensive effect