Electrochemical Method for the Design of New Possible Gadolinium-Based Contrast Agents.

Magnetic resonance imaging (MRI) is a technique that employs strong magnetic fields and radio frequencies to generate detailed images of the body's interior. In oncology patients, gadolinium-based contrast agents (GBCAs) are frequently administered to enhance the visualization of tumors. Those contrast agents are gadolinium chelates, characterized by high stability that prevents the release of the toxic gadolinium ion into the body.

Enabling amidation in water: micellar catalysis approach for sustainable synthesis of iopamidol.

Micellar catalysis is becoming an increasingly versatile tool to carry out a wide range of organic transformations using water as the reaction medium. The approach was recently found to be effective also in the case of water sensitive organics such as acyl chlorides. This finding is of great relevance for the manufacturing of challenging substrates such as the known iodinated contrast agent iopamidol, requiring the use of aprotic dipolar solvents (DMF, NMP, DMAc) in the key amidation step of an acyl dichloride intermediate with serinol.

A serendipitous one-pot synthesis of the octahydro-2-pyrazino[1,2-]pyrazine core.

An unexpected nitro group displacement during a nitro-Mannich reaction led to the one-pot formation of the octahydro-2-pyrazino[1,2-]pyrazine core, representing the shortest access to date to this pharmacologically relevant heterobicyclic system. A mechanistic hypothesis is suggested and supported by specific experiments and HRMS analysis of reaction mixtures.

TRASUTA: The Effect of the Structural Rigidity of a Mesocyclic AAZTA-like Chelating Agent on the Thermodynamic, Kinetic, and Structural Properties of Some Divalent Metal and Ga Complexes.

Mesocyclic chelating agents such as AAZTA and its derivatives have been recently reported to overcome the relatively low thermodynamic stability of metal complexes of acyclic chelating agents and the slow complexation kinetics of macrocyclic chelating agents. This work reports the preparation of a spirobicyclic hexadentate AAZTA-like chelating agent (TRASUTA) and the investigation of the thermodynamic, kinetic, and structural properties of the corresponding chelates with the PET-relevant Ga and selected metal ions. A combination of analytical techniques allowed identification of a coordination isomerization process, involving the coordinating side arms and the inversion of a nitrogen atom and leading to lower thermodynamic and kinetic inertness with respect to mononuclear mesocyclic analogues.

A look at the past to draw lessons for the future: how the case of an urgent ICU transfer taught us to always be ready with a plan B.

Objective: The urgent transfer of an intensive care unit (ICU) is particularly challenging because it carries a high clinical and infectious risk and is a critical node in a hospital's patient flow. In early 2017, exceptional rainfall damaged the roof of the tertiary hospital in Udine, necessitating the relocation of one of the three ICUs for six months. We decided to assess the impact of this transfer on quality of care and patient safety using a set of indicators, primarily considering the incidence of healthcare-associated infections (HAIs) and mortality rates.

Improved synthesis of DA364, an NIR fluorescence RGD probe targeting αβ integrin.

Optical imaging (OI) is gaining increasing attention in medicine as a non-invasive diagnostic imaging technology and as a useful tool for image-guided surgery. OI exploits the light emitted in the near-infrared region by fluorescent molecules able to penetrate living tissues. Cyanines are an important class of fluorescent molecules and by their conjugation to peptides it is possible to achieve optical imaging of tumours by selective targeting.

Supramolecular adducts between macrocyclic Gd(iii) complexes and polyaromatic systems: a route to enhance the relaxivity through the formation of hydrophobic interactions.

The of reversible binding interactions between the hydrophobic region of macrocyclic GBCAs (Gadolinium Based Contrast Agents) and SO /OH containing pyrene derivatives provides new insights for pursuing relaxivity enhancements of this class of MRI contrast agents. The strong binding affinity allows attaining relaxation enhancements up to 50% at pyrene/GBCA ratios of 3 : 1. High resolution NMR spectra of the Yb-HPDO3A/pyrene system fully support the formation of a supramolecular adduct based on the set-up of hydrophobic interactions.

H-Bonding and intramolecular catalysis of proton exchange affect the CEST properties of Eu complexes with HP-DO3A-like ligands.

Eu(HP-DO3A) is present in solution as a mixture of two diastereoisomers whose alcoholic groups are the source of the mobile protons for the CEST effect. The exchange is base catalyzed. Two novel Eu complexes of HP-DO3A-like ligands containing an amino or a carboxylate functionality in the proximity of the -OH groups showed the occurrence of intramolecular catalysis of the prototropic exchange.

PIDAZTA: Structurally Constrained Chelators for the Efficient Formation of Stable Gallium-68 Complexes at Physiological pH.

Two structurally constrained chelators based on a fused bicyclic scaffold, 4-amino-4-methylperhydro-pyrido[1,2-a][1,4]diazepin-N,N',N'-triacetic acids [(4R*,10aS*)-PIDAZTA (L1) and (4R*,10aR*)-PIDAZTA (L2)], were designed for the preparation of Ga -based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected [Ga(L2)OH] species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of Ga into the cavity of L2.

[Pharmaceutical prescription of proton pump inhibitors and ranitidine in the general population living in the area of the Healthcare Authority and University of Udine (Friuli Venezia Giulia, Northeastern Italy)].

Objectives: to describe the use of proton pump inhibitors (PPI) and ranitidine in the general population living in the area of the Healthcare Authority and University of Udine (Friuli Venezia Giulia, Northeastern Italy) and to evaluate whether there are any cases of co-prescription of medications in those classes.

Design: analysis of health-related administrative databases (list of potential healthcare beneficiaries, prescriptions of medications, exemption from medical charges because of chronic conditions, list of general practitioners).

Setting And Participants: population of the Italian area of the Healthcare Authority and University of Udine (approximately 250,000 inhabitants) ≥1 year of age as of January 1st, 2016.

Exploring the intramolecular catalysis of the proton exchange process to modulate the relaxivity of Gd(iii)-complexes of HP-DO3A-like ligands.

The Gd(iii)-complexes of three novel HP-DO3A-like ligands have been investigated to assess the relationship between relaxometry and intramolecular catalysis of the proton exchange. The structures of these ligands differ from the parent HP-DO3A because the methyl group of the hydroxy-propyl arm has been replaced by -Ph-OH, -Ph-NH2 and -Ph-COOH, respectively. The phenol, amine and carboxylate functionalities display an intramolecular H-bonding with the coordinated hydroxyl moiety that affects either the pK values of the involved functionalities and the rate of the proton exchange process.

Exploiting the Proton Exchange as an Additional Route to Enhance the Relaxivity of Paramagnetic MRI Contrast Agents.

The relaxivity of Gd(HP-DO3A) was studied as a function of pH and buffer composition in order to identify the main factors of the observed relaxation enhancement due to the exchange of the coordinated hydroxyl proton. It was established that the paramagnetic relaxation time, T, of the coordinated hydroxyl proton is about 50% shorter than that of the protons in the coordinated water molecule. The control of the p K of the coordinated alcoholic -OH moiety in the ligand is fundamental to utilize the proton exchange enhanced relaxivity under physio/pathologic conditions.

Synthesis, Characterization, and Biodistribution of a Dinuclear Gadolinium Complex with Improved Properties as a Blood Pool MRI Agent.

A dinuclear gadolinium(III) chelate containing two moieties of diethylenetriaminepentaacetic acid (DTPA), covalently conjugated to an analogue of deoxycholic acid, was synthesized and thoroughly characterized. A full relaxometric analysis was carried out, consisting of 1) the acquisition of nuclear magnetic resonance dispersion (NMRD) profiles in various media; 2) the study of binding affinity to serum albumin; 3) the measurement of O transverse relaxation rate versus temperature, and 4) a transmetallation assay. In vivo biodistribution MRI studies at 1 T and blood pharmacokinetics assays were carried out in comparison with Gd-DTPA (Magnevist) and gadocoletic acid trisodium salt (B22956/1), two well-known Gd complexes that share the same chelating cage and the same deoxycholic acid residue of the Gd complex investigated herein ((GdDTPA) -Chol).

Development and validation of a new HPLC-MS method for meglumine impurity profiling.

We report a new High Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) method to rapidly detect and quantify meglumine by-products (specifically reducing sugar(s) and nitrogen impurities) that could be present in the meglumine samples. Meglumine is a secondary amine obtained from glucose and it is an excipient used as counter-ion in several pharmaceutical formulations, especially when the concentration of the active pharmaceutical ingredient (API) is so high that the sodium is not a suitable option. Moreover, the increased use of meglumine is related to its ability to improve solubility in aqueous solutions due to the presence of a large number of hydroxyl groups.

Opening of a respiratory intermediate care unit in a general hospital: impact on mortality and other outcomes.

Background: Respiratory intermediate care units (RICUs) are specialized areas aimed at optimizing the cost-benefit ratio of care. No data exist about the impact of opening a RICU on hospital outcomes.

Objectives: We wondered if opening a RICU may improve the outcomes of patients with acute respiratory failure (ARF), acute exacerbation of chronic obstructive pulmonary disease (AECOPD), or community-acquired pneumonia (CAP).

In Vivo MR Imaging of Fibrin in a Neuroblastoma Tumor Model by Means of a Targeting Gd-Containing Peptide.

Purpose: A magnetic resonance imaging contrast agent based on a tetrameric Gd-DTPA-like system linked to a fibrin-targeting peptide (Gd-F) has been designed for in vivo tumor characterization.

Procedures: Gd-F was synthesized following Fmoc-SPPS strategy. Binding was measured using soluble fibrin DD(E) fragment and a dried fibrin assay.

AMPED: a new platform for picolinate based luminescent lanthanide chelates.

The synthesis of a new nonacoordinating ligand based on an AMPED (6-amino-6-methylperhydro-1,4-diazepine) scaffold functionalized by three picolinate (6-carboxy-2-methylpyridine) arms is described. Coordination of lanthanide cations (Ln = Eu and Tb) was investigated by spectrophotometric titrations monitored by UV-Vis absorption and steady-state emission spectroscopy, showing the formation of [LnL] complexes in aqueous solutions. The corresponding Eu and Tb complexes were isolated and characterized, and their spectroscopic properties (luminescence quantum yields, excited state lifetimes) were determined in buffered water (TRIS/HCl, pH 7.

An enzymatic approach to bifunctional chelating agents.

Bifunctional chelating agents (BFCAs) combine the complexing properties of a multidentate ligand with the presence of a free reactive functional group, mainly devoted to conjugation purposes. Indeed, products obtained by conjugation of a BFCA to a biomolecule and coordination of a suitable metal ion are widely applied in medicine nowadays as diagnostic and therapeutic agents. BFCAs are generally prepared through multi-step syntheses and with extensive application of protection-deprotection strategies, due to the large number of functional groups involved.

Vitamin K antagonists in patients with nonvalvular atrial fibrillation: appropriateness and quality of treatment in an Italian cohort.

Background: Vitamin K antagonists (VKA) are highly recommended in patients with atrial fibrillation for their efficacy in preventing stroke. However, there is a lack of data on oral anticoagulation (OAC) with VKA overall treatment (i.e.

Synthesis of Gd and (68)Ga complexes in conjugation with a conformationally optimized RGD sequence as potential MRI and PET tumor-imaging probes.

We report the synthesis of novel chelates of Gd and (68)Ga with DPTA, DOTA, HP-DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents were appropriately conjugated, prior to metal complexation, with DB58, an RGD peptidomimetic, conformationally constrained on an azabicycloalkane scaffold and endowed with high affinity for integrin α(ν)β(3) . Because α(ν)β(3) is involved in neo-angiogenesis in solid tumors and is also directly expressed in cancer cells (e.

The synthesis and application of polyamino polycarboxylic bifunctional chelating agents.

Bifunctional chelating agents (BFCAs) are molecules which contain two different moieties: a strong metal chelating unit and a reactive functional group. The latter is directed to react with amines, thiols, alcohols or other reactive molecules to form stable covalent bonds while the chelating moiety is able to strongly coordinate a metal ion. In this way, it is possible to label a molecule of interest (e.

Stevens rearrangement as a tool for the structural modification of polyaminopolycarboxylic ligands.

Polyaminopolycarboxylic acids are a well known class of ligands employed for metal ion complexation. Despite the large commercial availability, reports of their use as substrates for direct structural modifications are rare. Herein we report a simple and efficient protocol for the preparation of substituted polyaminopolycarboxylic ligands relying on a one-pot N-alkylation-Stevens rearrangement cascade.

[Indications for cardiology consultation and management of cardiac patients who will undergo surgical or endoscopic procedures: the proposal of the University Hospital of Trieste, Italy].

The number of patients affected by cardiovascular disease admitted to internal medicine and geriatric wards is expanding due to the increasing prevalence of cardiovascular disease in the ageing population. This contributes to a growing demand for cardiology consult visits, with requests for perioperative risk stratification for non-cardiac surgery or endoscopy, and general clinical management. This document was jointly drafted by the Cardiology and Anesthesiology departments, medical and surgical departments, and endoscopy services of the Azienda Ospedaliero-Universitaria "Ospedali Riuniti" in Trieste (Italy).

Relative survival in dilated cardiomyopathy: a stratification study of long-term outcome to evaluate life insurance cover.

Objectives: The aim of this study was to compare mortality of dilated cardiomyopathy (DCM) patients with the mortality in the background Italian population, taking into account demographic characteristics and clinical stratification of long-term outcome, ie, "reverse remodelling" within the first 2 years of follow-up.

Background: DCM is a myocardial disease, characterized by left and/or right ventricular dilation and dysfunction and poor outcome. Evidence-based treatment with ACE inhibitors, beta-blockers and, in the last decade, implantable cardioverter defibrillators have been demonstrated to improve significantly heart failure symptoms and prognosis.