1,720,971 research outputs found
Synthesis, biological activity and SARs of new heteroaryl-substituted isonipecotanilide inhibitors of the blood coagulation factors
No full textStructure and Thermal Stability of Two Estetrol Solvates
Full text linkTwo solvates of estetrol have been isolated and characterized by SCXRD and PXRD as well as by thermal analyses, morphology and spectroscopy. Estetrol monohydrate (Estetrol.H2O, S.G. P1, Z = 12) contains 12 molecules in its asymmetric unit with very subtle conformational differences with one another but reveals an intricate network made of intermolecular H-bonds established with the neighbour estetrol molecules and with crystallization water. Each molecule of estetrol methanol hemisolvate (Estetrol.0.5CH(3)OH, S.G. C2, Z = 4) establishes six O-H horizontal ellipsis O bonds with six different neighbours and additional H-bonds with methanol. In both structures, estetrol molecules are organized in a head-to-tail arrangement that favours the formation of O-H horizontal ellipsis O interactions. The increased thermal stability of Estetrol.0.5CH3OH crystals with respect to Estetrol.H2O can be correlated to the strengthened network of H-bonds
Novel factor Xa inhibitors: a patent review
No full textIMPORTANCE OF THE FIELD:
New oral anticoagulants with favorable safety profiles and fixed doses are required for the management of thromboembolism and stroke prevention in patients with atrial fibrillation. Among them, fXa inhibitors (the so-called xabans) are attractive options that can overcome limitations (e.g., bleeding) of the current oral antithrombotic therapy. The rational design of small-molecule direct fXa inhibitors, whose importance is testified by the growing number of publications and patents recently registered, has been fully supported by the X-ray crystallography of enzyme-ligand complexes.
AREAS COVERED IN THIS REVIEW:
Pubmed, SciFinder Scholar, ISI web of knowledge(SM), http://ep.espacenet.com/ and Google websites were used as the main sources for literature retrieving, and > 100 patents filed between 2006 and April 2009, reviewed and discussed herein, highlight the variety among the P1 and P4 moieties on suitable scaffolds.
WHAT THE READER WILL GAIN:
The replacement of the benzamidine P1 moiety, which characterizes the first generation, with less basic bioisosteric or nonpolar neutral P1 groups led to the disclosure of numerous fXa inhibitors with high potency, selectivity and oral bioavailability. Novel selective fXa inhibitors with stable pharmacokinetics, better therapeutic windows and ease-of-use than the existing anticoagulants are currently under advanced stage clinical trials.
TAKE-HOME MESSAGE:
Available data from Phase II and Phase III studies reflect the drive towards fXa inhibitors as potentially more effective and safer antithrombotic drugs. Their development is expected to address two major needs for anticoagulation, namely safety and ease-of-use, and to significantly affect the anticoagulant market
Lead optimization studies, synthesis and biological evaluation of new isonipecotamide-based orally active thrombin inhibitors
No full textCurrent anticoagulant therapy of venous thromboembolism (VTE) is based on
parenterally administered heparins and orally administered vitamin K antagonists
(e.g., warfarin), but narrow therapeutic window and side effects, such as bleeding,
diet and genetic makeup influence, are associated with their use [1]. Recently, key
serine proteases of the blood coagulation cascade, such as thrombin (thr) and factor
Xa (fXa), have emerged as promising targets for anticoagulants, and indeed several
direct inhibitors of thr (e.g., argatroban, dabigatran) and fXa (e.g., rivaroxaban,
apixaban) have been introduced in therapy or in advanced clinical trials [2,3].
Some years ago we investigated the isonipecotanilide scaffold for new thr/fXa
inhibitors [4]. Further optimization studies led us to develop new benzyloxy
derivatives of N-(phenyl)-1-(pyridin-4-yl)piperidine-4-carboxamide, one of them
(i.e., the 3-F analog, see below) showing low nanomolar Ki (thr) value, high
selectivity against other serine proteases and good anticoagulant activity as
measured by the activated partial thromboplastin time (aPTT) test. Physicochemical profiles of the newly synthesized compounds were assessed and
their potential oral bioavailability estimated, by measuring effective permeability
coefficients using PAMPA (Parallel Artificial Membrane Permeability Assay)
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Cistopessi e TVT come terapia del prolasso associato ad incontinenza urinaria da sforzo manifesta o latente. Prime valutazioni
No full textVariations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Impact of 68Ga-DOTATOC PET/CT in comparison to 111In-Octreotide SPECT/CT in management of neuro-endocrine tumors: A case report
Full text linkRationale:In the diagnostics of neuroendocrine tumors (NETs), scintigraphy and Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) with 111Indium-Octreotide occupy a prominent place.The introduction in clinical practice of 68Gallium-labelled somatostatin analogues (DOTA-TOC, DOTA-TATE, DOTA-NOC) for Positron Emission Tomography/Computed Tomography (PET/CT), significantly improved NETs diagnostics due to greater sensitivity and improved lesion detection in addition to better patient convenience and decreased radiation dose.Patient concerns:We report a case of a patient who was diagnosed with a neuroendocrine tumor of the ileocecal valve.Diagnoses:Diagnosis was made by ultrasonography, CT, and colonoscopy. Hystology after surgery was G2 NET of ileo-cecal valve. Restaging was carried out by 111In-Octreotide SPECT/CT and, 1 month later, by 68Ga-DOTATOC PET/CT. 18F-FDG PET/C was also carried out.Interventions:68Ga-DOTATOC PET/CT showed larger disease that modified disease management from surgery to medical treatment.Outcomes:After an initial improvement in the patient clinical condition, the tumor caused a worsening with the appearance of ascites.Lessons:68Ga-DOTA-conjugate PET/CT is appropriate in low and intermediate NET (Ki67 index respectively ≤3% and 3%-20%) characterized by better survival and better response after Peptide Receptor Radionuclide Therapy.18F-FDG is mostly useful in high grade (G3) of disease, so that 68Ga-DOTA-conjugate SUV and 18F-FDG SUV have an opposite trend in relation to the tumor grade. 68Ga-DOTATOC PET/CT changes, as in our case, therapeutic management in about 40% of cases
Beta-d-Glucosyl Conjugates of Highly Potent Inhibitors of Blood Coagulation Factor Xa Bearing 2-Chorothiophene as a P1 Motif.
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