Aromatic ionene topology and counterion-tuned gelation of acidic aqueous solutions

Unusual gelation of acidic solutions was achieved using polycations bearing quaternary ammonium moieties. These ionene polymers are based on a disubstituted phenylene dibenzamide core, which allows the construction of different topomers (i.e. ortho-1, meta-2 and para-3). The topology of the polymers was found to play a key role on their aggregation behaviour both in pure water and in a variety of aqueous acidic solutions leading to the formation of stable acidic gels. Specifically, ortho-1 showed superior gelation ability than the analogues meta-2 and para-3 in numerous solutions of different pH and ionic strengths. Lower critical gelation concentrations, higher gel-to-sol transition temperatures and faster gelation were usually observed for ortho-1 regardless the solvent system. Detailed computational molecular dynamic simulations revealed a major role of the counterion (Cl-) and specific polymer¿polymer interactions. In particular, hydrogen bonds, N–H¿p interactions and intramolecular p–p stacking networks are distinctive in ortho-1. In addition, counterions located at internal hydration regions also affect to such polymer¿polymer interactions, acting as binders and, therefore, providing additional stability.Peer ReviewedPostprint (published version

Freigabe: 05.05.2018 Synthesis, characterization and application of smart materials based on low-molecular-weight compounds and polymers

Chapter A: Introduction on supramolecular gels and application of gels in drug release The first section (chapter B1) presents the transfer of a concept which is originally used for the design of new drug molecules, to the rational development of new gelator compounds, namely the isosteric replacement. Here the substitution of the amide function in N stearoyl-L-glutamic acid (C18-Glu) (see Fig. 48) – a compound which is known to be able to act as gelator for several solvents – was replaced by a 1,4-di¬subs¬tituted 1,2,3-triazole unit (click-Glu) and a sulfonamide (sulfo-Glu), respect¬ive¬ly. In both cases the total number of C atoms has formally been kept intact.In terms of gelation of a range of different organic solvents, as well as water, it was found that click-Glu revealed superior features with respect to the CGC, Tgel and mechanical stability in polar protic solvents, whereas sulfo-Glu exhibited improved properties in non-polar solvents and C18-Glu showed in average values between those of click-Glu and sulfo-Glu. But not only the characterization of the gel material itself was described but also the successful application of hydrogels derived from all three glutamic acid derivatives as carriers of several hydrophilic and hydrophobic drugs and the subsequent release over a period up to two weeks could be demonstrated which revealed the influence of the functional group in the respective gelator molecules on the release rate of the drugs. Chapter B2 describes the application of hydrogels, derived from glycyrrhizic acid ammonium salt, as drug depot. Glycyrrhizic acid ammonium salt is a salt of glycyrrhizin, a natural compound which can be extracted from the licorice root. It exhibits an excellent biocompatibility, which is why it was chosen for the formulation and drug release study of three anti-cancer agents of different hydrophilicity. The influence of drug inherent hydrophilicity as well as the pH and nature of the release medium on the drug diffusion rate was investigated. In good agreement with previous publications, more hydrophobic compounds were found to tend to a slower diffusion into the release medium as they experience a greater retention from the gel environment. In terms of pH of surrounding medium, the release into more basic solutions was found to be faster as high pH values seemed to destabilize the integrity of the gel network. However the nature of the release buffer (e.g. organic or inorganic) also played an important role, which makes a forecast of the release kinetics, depending on the pH difficult and therefor demonstrates the limitations of in vitro drug delivery experiments. Nevertheless, preliminary release studies provide important information necessary for the design of in vivo experiments. A formamidine based low molecular weight compound and its gelation properties are presented in chapter B3. The amphiphilic molecule consists of a long chain containing 16 carbon atoms and an acetyl L-phenyl alanine connected via a formamidine group.This molecule is able to form gels in a variety of different organic solvents as well as two ionic liquids and water. It was found that ultrasonication of an isotropic solution of the gelator led to superior materials in comparison to gels prepared by the classical heating and spontaneous cooling of gelator solution. Furthermore temperature controlled 1H-NMR reveled the participation of H-bonding, π - π-stacking, as well as van-der-Waals interactions in the gelation process. Moreover the temperature controlled turning on/off of birefringence of a gel in MeCN could be demonstrated, which constitutes an important property for potential applications in optical devices. Unfortunately this gelator, as well as its hydrogel was found to be toxic, which is why this material could not be used for drug delivery studies. The second half, chapter C of this thesis describes the synthesis of different ionene polymers as well as various applications. In chapter C1 the antimicrobial and hemolytic activity of ionenes (Fig. 51) was investigated. The majority of the polymers showed antimicrobial activity against the Gram-negative bacterium Escherichia coli, with minimum inhibition concentration values affected by both the topology of the polymer and the nature of the diamine linker. Most polymers revealed to be harmless towards red blood cells and therefor show a low hemolytic activity. In general, DABCO containing polymers exhibited the lowest antimicrobial and the highest hemolytic activities. In contrast, meta-ionenes showed the best antimicrobial and lowest hemolytic activity, which makes them promising candidates for potential antimicrobial applications. In chapter C2 cationic vesicles derived from ionene polymers with alternating α,ω-tertiary diamine linker (ortho-DABCO, -C2 and -C6, see Fig. 51) and the non-ionic surfactant polysorbate 80 are presented. These vesicles were used in different formulations for the transfection of oligonucleotide single strands which are comple-mentary to Renilla luciferase mRNA. Formulations based on ortho-DABCO and -C2 were found to be non-toxic but those with ortho-C6 showed critical cell viabilities at higher ionene concentrations. When testing the efficiencies of the cationic vesicles to silence the activity of Renilla luciferase, those formulations with DABCO-ionene showed no efficacy. On the contrast, C2- and C6-ionene derived formulations (at non-toxic ionene concentrations) could reduce the luciferase activity by 48 and 38%, respectively. The use of these formulations might be an interesting alternative to current transfection agents. Last but not least in chapter C3 ionenes with DABCO-linker were found to be able to gel water and acidic solutions. Here the topology, the substitution pattern (ortho-, meta- or para-) at the central benzene of the ionenes, was found to play an highly important role for the gelation properties. Ortho-DABCO showed superior gelation ability compared to the analogues meta-DABCO and para-DABCO in solutions of different pH and ionic strengths. Atomistic MD simulations have allowed to conclude that the distinctive properties of ortho-DABCO are due to the formation of specific polymer ··· polymer interactions (i.e. hydrogen bonds, N–H ··· π and intra-molecular π – π stacking), which are facilitated by the binder effect of Cl- counterions. Polymer ··· polymer interactions are more abundant in ortho-DABCO than in meta-DABCO and para-DABCO which is responsible for the superior gelation of ortho-DABCO

A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19

Background: current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking. Methods: we conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days. Results: the analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported. Conclusions: postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.)

A Selective HDAC 1/2 Inhibitor Modulates Chromatin and Gene Expression in Brain and Alters Mouse Behavior in Two Mood-Related Tests

Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary – albeit often ineffective – treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.Stanley Medical Research InstituteNational Institutes of Health (U.S.) (R01DA028301)National Institutes of Health (U.S.) (R01DA030321

ICO-ICS Praxis para el tratamiento médico y con irradiación del mieloma múltiple

Tractament mèdic; Tractament amb irradiació; Mieloma múltipleMedical treatment; Irradiation treatment; Multiple myelomaTratamiento médico; Tratamiento con irradiación; Mieloma múltipleEl mieloma múltiple (MM) és una neoplàsia de cèl·lules plasmàtiques que representa al voltant de l’1% del total de neoplàsies i el 10% de les neoplàsies hematològiques. Té una incidència aproximada de 4-5 nous casos/100.000 habitants/any i presenta una incidència màxima entre els 70 i 75 anys d’edat. Un 35% dels afectats té menys de 65 anys. Els objectius d'aquesta guia són: desenvolupar i difondre la ICO-ICSPraxi per al tractament del mieloma múltiple; disminuir la variabilitat terapèutica entre els pacients tractats en els diferents centres d’aquesta institució; implementar i avaluar els resultats de la terapèutica en els pacients amb mieloma múltiple tractats d’acord amb les recomanacions d’aquesta guia

Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial

No effective treatments for coronavirus disease 2019 (COVID-19) exist. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be efficacious for outpatients with COVID-19.The authors thank Gerard Carot-Sans, PhD, for providing medical writing support during the revisions of the subsequent drafts of the manuscript; the personnel from the Fights Aids and Infectious Diseases Foundation for their support in administration, human resources and supply chain management; Eric Ubals (Pierce AB) and Òscar Palao (Opentic) for website and database management; Óscar Camps and OpenArms nongovernmental organization for nursing home operations; and Anna Valentí and the Hospital Germans Trias i Pujol Human Resources Department for telephone monitoring. We thank Consorci Sanitari del Maresme, Centre Sociosanitari El Carme, l'Hospital General de Granollers and occupational hazards department of Hospital Germans Trias i Pujol for their contribution with patient enrollment. We are very grateful to Marc Clotet and Natalia Sánchez who coordinated the JoEmCorono crowd-funding campaign. We thank the Hospital Germans Trias Pujol Institutional Review Board and the Spanish Agency of Medicines and Medical Devices for their prompt action for consideration and approvals to the protocol. Financial support. This work was mainly supported by the crowd-funding campaign JoEmCorono (https://www.yomecorono.com/) with contributions from more than 72 000 citizens and corporations. The study also received financial support from Laboratorios Rubió, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, and Generalitat de Catalunya. Laboratorios Rubió also contributed to the study with the required doses of hydroxychloroquine (Dolquine®). Foundation Dorneur partly funded lab equipment at Irsi-Caixa.Peer reviewe

Measurement of shoulder abduction angles in dogs: an ex vivo study of accuracy and repeatability

OBJECTIVE: The aim of this study was to determine the accuracy and repeatability of the shoulder abduction test and to assess the effect of transection of the medial shoulder support structures in canine cadavers. MATERIALS AND METHODS: The shoulder abduction angle was measured by three separate observers, both with the shoulder extended and at a neutral angle. Shoulder abduction was then measured, using craniocaudal fluoroscopic images. Arthroscopy was performed in all shoulder joints, with the medial support structures transected in one shoulder of each dog. The three observers again measured shoulder abduction angles in all dogs. Shoulder abduction was measured again using fluoroscopy. Accuracy and repeatability of the abduction test were assessed using linear mixed models. RESULTS: All three observers had different measured abduction angles when compared with fluoroscopy ( < 0.01); however, the experienced surgeon had an error of only 2.9°. Inter-observer repeatability was poor, with all three observers having different abduction measurements ( < 0.001). Intra-observer repeatability, however, indicated no differences on repeated measurements ( = 0.26). Placing the shoulder at a neutral standing angle, and transection of support structures caused an average increase in abduction by 8.2° ( < 0.001) and 4.4° respectively. CONCLUSION: Significant variation exists between observers performing this test, increased accuracy seen in the more experienced observer. Shoulder flexion angle can significantly affect measured abduction angles

Concurs adequació nau central Fabra i Coats

Projecte presentat al Contracte de Serveis pel “Projecte bàsic i executiu, Direcció d’obra i estudi de Seguretat i Salut de les obres d’adequació de la nau central del recinte de Fabra i Coats per a contenidor de producció cultural

Concurs adequació nau central Fabra i Coats

Projecte presentat al Contracte de Serveis pel “Projecte bàsic i executiu, Direcció d’obra i estudi de Seguretat i Salut de les obres d’adequació de la nau central del recinte de Fabra i Coats per a contenidor de producció cultural”No es va saber la valoració exactePostprint (published version

Oficines Heineken

Primer premiAward-winningPostprint (published version