133 results on '"Puccini, Paola"'
Search Results
102. Synthesis of glycose carbamides and evaluation of the induction of erythroid differentiation of human erythroleukemic K562 cells
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Landi, Martina, Catelani, Giorgio, D’Andrea, Felicia, Ghidini, Eleonora, Amari, Gabriele, Puccini, Paola, Bianchi, Nicoletta, Gambari, Roberto, Landi, Martina, Catelani, Giorgio, D’Andrea, Felicia, Ghidini, Eleonora, Amari, Gabriele, Puccini, Paola, Bianchi, Nicoletta, and Gambari, Roberto
- Abstract
SUMMARY A series of carbamides derived from 1,2:5,6-di-O-isopropylidene-D-gluco- (1) and D-allofuranose (3) as well as their 5,6-O-deprotected analogues (2 and 4) and methyl 3,4-O-isopropylidene-alfa- and beta-D-galactopyranosides (5 and 6) have been prepared in order to evaluate their ability to induce erythroid differentiation of human erythroleukemic K562 cells. Twenty out of 51 carbamides tested exhibit an appreciable activity as inducers of erythroid differentiation and have been fully characterized and described.
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- 2009
103. Du conte oral au conte écrit : une diachronie du fantastique québécois
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Puccini, Paola
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- 1998
104. Human macrophage differentiation induces OCTN2–mediated L-carnitine transport through stimulation of mTOR–STAT3 axis
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Ingoglia, Filippo, Visigalli, Rossana, Rotoli, Bianca Maria, Barilli, Amelia, Riccardi, Benedetta, Puccini, Paola, Milioli, Marco, Di Lascia, Maria, Bernuzzi, Gino, and Dall’Asta, Valeria
- Abstract
Monocyte-to-macrophages differentiation associates with upregulation of carnitine transport due to mTOR-dependent activation of STAT3. l-Carnitine, in addition to playing a fundamental role in the ß-oxidation of fatty acids, has been recently identified as a modulator of immune function, although the mechanisms that underlie this role remain to be clarified. In this study, we addressed the modulation of l-carnitine transport and expression of related transporters during differentiation of human monocytes to macrophages. Whereas monocytes display a modest uptake of l-carnitine, GM-CSF–induced differentiation massively increased the saturable Na+-dependent uptake of l-carnitine. Kinetic and inhibition analyses demonstrate that in macrophage l-carnitine transport is mediated by a high-affinity component (Km~4 µM) that is identifiable with the operation of OCTN2 transporter and a low-affinity component (Km> 10 mM) that is identifiable with system A for neutral amino acids. Consistently, both SLC22A5/OCTN2 and SLC38A2/SNAT2 are induced during the differentiation of monocytes to macrophages at gene and protein levels. Elucidation of GM-CSF signaling demonstrates that the cytokine causes the activation of mTOR kinase, leading to the phosphorylation and activation of STAT3, which, in turn, is responsible for OCTN2 transcription. SLC22A5/OCTN2 therefore emerges as a novel member of the set of genes markers of macrophage differentiation.
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- 2017
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105. Le rapport entre les langues dans l’œuvre de Félix Pécaut : de la langue maternelle à la langue de l’idéal, en passant par la langue nationale
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Puccini, Paola, primary
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- 2009
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106. Le fonctionnement du mot « francophonie » dans la revue Esprit, novembre 1962 : à la recherche d’une définition
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Puccini, Paola, primary
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- 2008
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107. In vitro and in vivo metabolism of CHF 6001, a selective phosphodiesterase (PDE4) inhibitor.
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Cenacchi, Valentina, Battaglia, Rosangela, Cinato, Flavio, Riccardi, Benedetta, Spinabelli, Daniele, Brogin, Giandomenico, Puccini, Paola, and Pezzetta, Daniele
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PHOSPHODIESTERASE inhibitors ,MICROSOMES ,LIVER cells ,HYDROLYSIS ,MOIETIES (Chemistry) - Abstract
1. The metabolism of CHF 6001, a novel PDE4 inhibitor, was determined in vitro in mouse, rat, dog, monkey and human microsomes and hepatocytes and in vivo in plasma, urine, feces and bile of rats after intravenous and intratracheal administration. 2. The behavior of CHF 6001 in microsomes and hepatocytes changed across species. CYP3A4/5 isoenzymes were identified to be the primary enzymes responsible for the metabolism of CHF 6001 in human liver microsomes. 3. In the rat, CHF 6001 was found extensively metabolized in urine, feces and bile, but not in plasma, where CHF 6001 was the main compound present. The metabolite profiles were different in the four biological matrices from both qualitative and quantitative point of view. 4. CHF 6001 was metabolized through hydrolysis with the formation of the alcohol CHF 5956, loss of a chlorine atom, loss of the N-oxide, hydroxylation, loss of the cyclopropylmethyl group in the alcohol moiety, conjugation with glucuronic acid, glutathione and cysteine-glycine. 5. The major metabolite present in the bile was isolated and characterized by nuclear magnetic resonance analysis. It derived from CHF 6001 through contraction of the pyridine- N-oxide ring to N-hydroxy pyrrole and conjugation with glucuronic acid. [ABSTRACT FROM AUTHOR]
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- 2015
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108. P1-055: Substrate selectivity of three novel γ-secretase modulators analyzed by target gene expression profiling
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Moretto, Nadia, primary, Grassi, Francesca, additional, Imbimbo, Bruno P., additional, Villetti, Gino, additional, Riccardi, Benedetta, additional, Puccini, Paola, additional, and Ottonello, Simone, additional
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- 2006
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109. Synthesis and Biological Activity of Flurbiprofen Analogues as Selective Inhibitors of β-Amyloid1-42 Secretion
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Peretto, Ilaria, primary, Radaelli, Stefano, additional, Parini, Carlo, additional, Zandi, Michele, additional, Raveglia, Luca F., additional, Dondio, Giulio, additional, Fontanella, Laura, additional, Misiano, Paola, additional, Bigogno, Chiara, additional, Rizzi, Andrea, additional, Riccardi, Benedetta, additional, Biscaioli, Marcello, additional, Marchetti, Silvia, additional, Puccini, Paola, additional, Catinella, Silvia, additional, Rondelli, Ivano, additional, Cenacchi, Valentina, additional, Bolzoni, Pier Tonino, additional, Caruso, Paola, additional, Villetti, Gino, additional, Facchinetti, Fabrizio, additional, Del Giudice, Elda, additional, Moretto, Nadia, additional, and Imbimbo, Bruno P., additional
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- 2005
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110. High Throughput Screening of β-Amyloid Secretion Inhibitors Using Homogenous Time-Resolved Fluorescence
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Albrecht, Hugo, primary, Zbinden, Peter, additional, Rizzi, Andrea, additional, Villetti, Gino, additional, Riccardi, Benedetta, additional, Puccini, Paola, additional, Catinella, Silvia, additional, and Imbimbo, Bruno, additional
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- 2004
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111. P4-342 High throughput screening of β-amyloid secretion inhibitors using homogenous time-resolved fluorescence
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Imbimbo, Bruno P., primary, Albrecht, Hugo, additional, Zbinden, Peter, additional, Rizzi, Andrea, additional, Villetti, Ginno, additional, Riccardi, Benedetta, additional, Puccini, Paola, additional, and Catinella, Silvia, additional
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- 2004
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112. O3-06-05 New flurbiprofen analogues, devoid of cyclooxygenase activity, selectively lower β-amyloid1–42 secretion
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Imbimbo, Bruno P., primary, Peretto, Ilaria, additional, Radaelli, Stefano, additional, Parini, Carlo, additional, Raveglia, Luca, additional, Villetti, Gino, additional, Rizzi, Andrea, additional, Ghirardi, Silvia, additional, Riccardi, Benedetta, additional, Marchetti, Silvia, additional, Puccini, Paola, additional, Catinella, Silvia, additional, Rondelli, Ivano, additional, and Volta, Roberta, additional
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- 2004
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113. Characterization of Ganstigmine metabolites in hepatocytes by low- and high-resolution mass spectrometry coupled with liquid chromatography
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Pelizzi, Nicola, primary, Puccini, Paola, additional, Riccardi, Benedetta, additional, Acerbi, Daniela, additional, and Catinella, Silvia, additional
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- 2003
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114. Optimization of M3Antagonist–PDE4 Inhibitor (MAPI) Dual Pharmacology Molecules for the Treatment of COPD
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Rizzi, Andrea, Amari, Gabriele, Pivetti, Fausto, Delcanale, Maurizio, Amadei, Francesco, Pappani, Alice, Fornasari, Luca, Villetti, Gino, Marchini, Gessica, Pisano, Anna Rita, Pitozzi, Vanessa, Pittelli, Maria Gloria, Trevisani, Marcello, Salvadori, Michela, Cenacchi, Valentina, Fioni, Alessandro, Puccini, Paola, Civelli, Maurizio, Patacchini, Riccardo, Baker-Glenn, Charles, Van de Poël, Hervé, Blackaby, Wesley, Nash, Kevin, and Armani, Elisabetta
- Abstract
Aiming at the inhaled treatment of pulmonary diseases, the optimization process of the previously reported MAPI compound 92ais herein described. The project was focused on overcoming the chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats in order to be confident in a clinical effect without having to overdose at one of the biological targets. The chemical strategy was based on fine-tuning of the substitution pattern in the muscarinic and PDE4 structural portions of the dual pharmacology compounds, also making use of the analysis of a proprietary crystal structure in the PDE4 catalytic site. Compound 10fwas identified as a chemically stable, potent, and in vivobalanced MAPI lead compound, as assessed in bronchoconstriction and inflammation assays in rats after intratracheal administration. After the in-depth investigation of the pharmacological and solid-state profile, 10fproved to be safe and suitable for development.
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- 2023
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115. Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β2Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases
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Carzaniga, Laura, Linney, Ian D., Rizzi, Andrea, Delcanale, Maurizio, Schmidt, Wolfgang, Knight, Christopher K., Pastore, Fiorella, Miglietta, Daniela, Carnini, Chiara, Cesari, Nicola, Riccardi, Benedetta, Mileo, Valentina, Venturi, Luca, Moretti, Elisa, Blackaby, Wesley P., Patacchini, Riccardo, Accetta, Alessandro, Biagetti, Matteo, Bassani, Franco, Tondelli, Marina, Murgo, Annalisa, Battipaglia, Loredana, Villetti, Gino, Puccini, Paola, Catinella, Silvia, Civelli, Maurizio, and Rancati, Fabio
- Abstract
The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and β2agonists (MABAs) promises to be an excellent opportunity to reduce formulation issues and boost efficacy through cross-talk and allosteric interactions. Herein, we report the results of our drug discovery campaign aimed at improving the therapeutic index of a previous MABA series by exploiting the super soft-drug concept. The incorporation of a metabolic liability, stable at the site of administration but undergoing rapid systemic metabolism, to generate poorly active and quickly eliminated fragments was pursued. Our SAR studies yielded MABA 29, which demonstrated a balanced in vivo profile up to 24 h, high instability in plasma and the liver, as well as sustained exposure in the lung. In vitro safety and non-GLP toxicity studies supported the nomination of 29(CHF-6366) as a clinical candidate, attesting to the successful development of a novel super-soft MABA compound.
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- 2022
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116. O3-06-05 New flurbiprofen analogues, devoid of cyclooxygenase activity, selectively lower β-amyloid 1–42 secretion
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Imbimbo, Bruno P., Peretto, Ilaria, Radaelli, Stefano, Parini, Carlo, Raveglia, Luca, Villetti, Gino, Rizzi, Andrea, Ghirardi, Silvia, Riccardi, Benedetta, Marchetti, Silvia, Puccini, Paola, Catinella, Silvia, Rondelli, Ivano, and Volta, Roberta
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- 2004
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117. In vitro and in vivo profiling of CHF5022 and CHF5074: Two β-amyloid1–42 lowering agents
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Imbimbo, Bruno P., Del Giudice, Elda, Cenacchi, Valentina, Volta, Roberta, Villetti, Gino, Facchinetti, Fabrizio, Riccardi, Benedetta, Puccini, Paola, Moretto, Nadia, Grassi, Francesca, Ottonello, Simone, and Leon, Alberta
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NONSTEROIDAL anti-inflammatory agents , *ANALGESICS , *BIPHENYL compounds , *CELL culture - Abstract
Abstract: Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may delay or prevent the onset of Alzheimer''s disease (AD). A subset of NSAIDs, including flurbiprofen, has been shown to selectively inhibit the production of β-amyloid1–42 (Aβ42), independently from their cyclooxygenase (COX) inhibiting activity. We evaluated the in vitro and in vivo profiles of CHF5022 and CHF5074, two flurbiprofen analogues. The in vitro Aβ inhibiting activity was evaluated in a human neuroglioma cell line (H4) carrying the double Swedish mutation (K595N/M596L) of the human amyloid precursor protein (APPsw). The in vitro anti-COX activity was evaluated using human recombinant enzymes isolated from transfected Sf-9 cells. The in vivo pharmacokinetic and pharmacodynamic profiles of the two compounds were evaluated in young APPsw transgenic mice (Tg2576) after oral gavage (100 or 300mgkg−1 day−1 for 4–5 days) and after medicated diet (375ppm for 4 weeks). R-Flurbiprofen was used as comparator. In vitro, CHF5022 and CHF5074 were found to be 3- and 7-fold more potent than R-flurbiprofen in inhibiting Aβ42 secretion (IC50s of 92, 40 and 268μM, respectively). Differently from R-flurbiprofen, CHF5022 and CHF5074 did not affect COX-1 (at 100μM) and COX-2 (at 300μM) activity. Similarly to R-flurbiprofen, no significant alteration in the expression profile of a subset of Notch intracellular domain-responsive genes was observed with either CHF5022 or CHF5074. In Tg2576 mice, CHF5022 was well tolerated when administered by oral gavage (100mgkg−1 day−1 for 5 days) or by medicated diet (56mg kg−1 day−1 for 4 weeks). R-Flurbiprofen was poorly tolerated in the diet (32mgkg−1 day−1) with 55% of the animals dying during the first week of treatment. After 4–5 days of oral gavage, CHF5022 and CHF5074 plasma and brain levels at 3h were found to increase with the dose, leading to brain concentrations of about 10% and 5% of the corresponding plasma concentrations, respectively. In animals fed for 4 weeks with compound-supplemented diet, mean plasma (580μM) and brain (20μМ) concentrations of CHF5022 were 8 and 15 times higher than those of R-flurbiprofen. Plasma Aβ42 concentration was dose-dependently decreased by CHF5022 and CHF5074. Brain Aβ levels (formic acid-extractable) were not significantly affected by either compound, although Aβ42 levels tended to inversely correlate (P =0.105) with CHF5022 concentration in the brain. CHF5022 and CHF5074 thus appear to have a promising in vitro and in vivo profile. This warrants further evaluation of their long-term effects on Aβ brain pathology. [Copyright &y& Elsevier]
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- 2007
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118. Analisi metaforica e stilistica dei corpora in prospettiva contrastiva: idee per stimolare la consapevolezza (inter)linguistica in classe
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Ferrari, Federica, Johnson, Jane Helen, Ivancic, Barbara, Puccini, Paola, Rodrigo Mora, Maria José, Turci, Monica, Ferrari, Federica, and Johnson, Jane Helen
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Metafora, stilistica dei corpora, didattica della traduzione - Abstract
La metafora concettuale (Lakoff 2003 [1980], 1993), applicata all’analisi linguistica – (Steen 1999; Ferrari 2007, 2013) offre uno strumento prezioso per l’analisi e la comprensione del testo, a livello micro e macro-analitico. In prospettiva traduttiva, attraverso l’osservazione delle differenze nella resa linguistica e concettuale di certe aree testuali (prospettiva contrastiva), l’analisi metaforica può aprire nuovi orizzonti multiculturali di lettura e nuove modalità per ‘aprire’ il testo in senso critico, così come per affrontare aree problematiche di traduzione, promuovendo allo stesso tempo la consapevolezza (inter)linguistica. Lo scopo di questo capitolo è di associare la stilistica dei corpora all’analisi della metafora, anche in prospettiva traduttiva, per fornire un modello di analisi del testo letterario atto a stimolare la consapevolezza linguistica nello studente di lingua inglese. Partiamo da un precedente case study (Johnson 2014) sull’applicazione della linguistica dei corpora (es. Mahlberg 2009) per esaminare lo stile letterario individuale di Grazia Deledda (Johnson 2009). Da questo studio emerge l’importanza del linguaggio figurativo nelle sue opere, in particolare la metonimia delle parti del corpo, e la similitudine, così fornendo conferma e estensione a precedenti studi senza l’utilizzo dei corpora (per esempio Miccinesi 1975). Tipicamente associato con gli stati d’anima e le emozioni dei protagonisti (vedi anche Johnson 2010), tale linguaggio figurativo si colloca spesso insieme ad espressioni metaforiche referenti agli elementi ed al paesaggio naturale (vedi anche Massaiu 1972; Scrivano 1990). Con lo scopo di ampliare gli studi precedenti, il presente lavoro utilizza alcuni strumenti tipici della linguistica dei corpora come punto di partenza per poi esaminare la portata metaforica di certe frasi chiave. Il nostro obiettivo qui è di combinare la stilistica dei corpora (“Corpus Stylistics” – CS) e l’analisi della metafora in uno schema operativo coerente con particolare attenzione all’aspetto visivo (“Image Rendering” – IR). Lo schema (CS&IR) prevede: 1) estrazione di parole/frasi chiave e lettura preliminare 2) analisi metaforico-visiva e lettura analitica e contrastiva del Testo di Partenza e del Testo di Arrivo con possibile sviluppo anche in 3) prospettiva trans-culturale. Questo schema può fungere da modello applicativo in classe per stimolare la consapevolezza linguistica e offrire attività finalizzate anche all’acquisizione di competenze pratiche di traduzione. Tra queste è previsto anche il riferimento a traduzioni selezionate per discuterne alcune problematicità per i traduttori così come le peculiarità concettuali anche in prospettiva contrastiva. Conceptual metaphor (Lakoff 2003 [1980], 1993), applied to the text (Steen 1999; Ferrari 2007, 2013) provides a precious tool for analysis and text comprehension, at a micro as well as macro-textual level. In a translation perspective, through observing differences in the linguistic and conceptual rendering of certain textual areas (contrastive perspective), metaphor analysis can open up new multicultural horizons of reading, and questioning the text, as well as addressing problematic areas of translation, and fostering language awareness. The focus of this paper is to explore how corpus stylistics and metaphor analysis within a translation perspective may be combined to provide a consistent analytical framework of the literary text for awareness-raising in the student of English. Previous research into Grazia Deledda’s authorial style (Johnson 2009) using corpus stylistics techniques (eg. Mahlberg 2009) showed that figurative language was prominent in her work, particularly body part metonymy, and simile (Johnson 2014), confirming and extending previous non-corpus-based studies (eg. Miccinesi 1975). Typically used in conjunction with the moods and emotions of the characters (see also Johnson 2010), such figurative language often occurred in juxtaposition with metaphorical expressions connected with the elements and the natural landscape (see also Massaiu 1972; Scrivano 1990). With a view to extending the previous studies, this study applies additional corpus tools such as Wmatrix (Rayson 2008) to further explore the metaphorical usage of certain key phrases. Our aim here is to combine keywords/phrases and metaphor into a consistent methodological framework – 1) keywords/phrases extraction and preliminary reading 2) metaphor analysis and analytical reading also in a 3) contrastive cultural perspective - and provide a template for language awareness-raising practices in the classroom, while making reference to selected translations in order to discuss problematic issues these raise for translators, as well as conceptual peculiarities also in a contrastive perspective.
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- 2018
119. Repenser la ville du dedans. Le bien-être en ville : espaces urbains, langues, cultures et sociétés
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P. Puccini, Paola Puccini, Dino Gavinelli, Paolo Molinari, Marco Alberio, Diane-Gabrielle Tremblay, Maurizio Bergamaschi, Harold Bérubé, Anna Giaufret, Jean-François Plamondon, Sophie Bienvenu, Cristiano Felice, Sherry Simon et Gerardo Acerenza., P.PUCCINI, I.KIROUAC MASSICOTTE, and Puccini, Paola
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Langue, Littérature, Québec, interdisciplinarité - Abstract
By adopting various perspectives from different fields (linguistics, translatology, discourse analysis, literary studies, sociology, urbanism, study of the landscape, geography, history, etc.) and using current theoretical approaches, the participants turned their attention on the well-being in the city. The contributions have exceeded the medico-social approach implied in the title of the conference and in which we evaluate carefully a politicʼs effect on the citizensʼ well-being. We examined the subject matter on the angle of the identity paradigms. We think that the study of the living together implies to analyse as well the constitutive paradigms of identity, encountered by an individual facing linguistic, cultural and social differences that enrich and animate the society. This work includes contributions from Paola Puccini, Dino Gavinelli, Paolo Molinari, Marco Alberio, Diane-Gabrielle Tremblay, Maurizio Bergamaschi, Harold Bérubé, Anna Giaufret, Jean-François Plamondon, Sophie Bienvenu, Cristiano Felice, Sherry Simon and Gerardo Acerenza.
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- 2017
120. Autotraduction et reconfiguration identitaire. Marco Micone, Madeleine Blais-Dahlem et Patrice Desbiens
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P. Puccini and Puccini, Paola
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Autotraduzione ,Québec, Canada francofono, identità - Abstract
La monografia verte sull'autotraduzione come forma di riconfigurazione identitaria. Da Marco Micone a Patrice Desbien , passando per Madeleine Blais-Dahlem, l'autrice segue il filo rosso della ricerca del sè attraverso il passaggio interlinguistico. Un approccio traduttologico è affiancato ad un approccio antropologico per dimostrare che attraverso l'autotraduzione questi tre diversi autori canadesi compione una quete che è di ogni uomo.
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- 2017
121. Introduction: langue et pouvoir
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P. Puccini, I. Kirouac Massicotte, P.PUCCINI, I. KIROUAC MASSICOTTE, Puccini, Paola, and KIROUAC MASSICOTTE, Isabelle
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Langue, Québec, identité, minorité - Abstract
Language is obviously a power issue; at first political, but it is also symbolic and economic. We wanted to bring to light the problematics that reunite language and power, or better still languages and powers, thematic with which we were dealing during this day that has rallied linguists and literature specialists. In the context in which we were interested, that of Québec and francophone Canada, the link between language and power is so strong that it leads to the creation of neologisms, as Langagement, invented by Lise Gauvin to illustrate that Québecʼ engaged literature (even all Québecʼ literature) goes together with the issue of language. In these conference proceedings, we take as examples many discursive spaces, such as literature, dictionaries and the social discourse, fields where we can identify the strong relationship between language and power. With the contributions of Paola Puccini, Wim Remysen, Cristina Brancaglion, Nadine Vincent, Annette Boudreau, Isabelle Kirouac Massicotte and Marco Modenesi.
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- 2017
122. Harmoniae belli: les sonorités de la guerre dans l'oeuvre de Louis-Ferdinand Céline
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Trovato, Loredana, Puccini Paola, Regattin Fabio, and Trovato, Loredana
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interjection ,Louis-Ferdinand Céline ,onomatopée ,guerre - Abstract
L'articolo analizza le onomatopee presenti nell'opera di Louis-Ferdinand Céline, rilevandone il ruolo fondamentale nel costruire la "chronique du réel". Viene così dimostrato come l'intera opera del controverso scrittore francese possa essere definita una "oto-fiction".
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- 2013
123. O3-06-05 New flurbiprofen analogues, devoid of cyclooxygenase activity, selectively lower β-amyloid1–42 secretion
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Imbimbo, Bruno P., Peretto, Ilaria, Radaelli, Stefano, Parini, Carlo, Raveglia, Luca, Villetti, Gino, Rizzi, Andrea, Ghirardi, Silvia, Riccardi, Benedetta, Marchetti, Silvia, Puccini, Paola, Catinella, Silvia, Rondelli, Ivano, and Volta, Roberta
- Published
- 2004
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124. Comparison of Formoterol, Glycopyrrolate, and Beclomethasone Dipropionate Pharmacokinetic Profile after Inhaled Administration as pMDI Using HFA134a or HFA152a Propellant: Preclinical Assessment of Drug Exposure in Sprague-Dawley Rat Model.
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Fioni A, Brogin G, Puccini P, Allen AD, Miglietta D, Cuoghi E, Zambelli E, and Battipaglia L
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Background: A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate is approved in some geographic areas as pressurized metered dose inhaler (pMDI) formulation for the treatment of asthma and chronic obstructive pulmonary disease. Current pMDIs use hydrofluoroalkanes (HFAs) as a propellant, such as 1,1,1,2-tetrafluoroethane (HFA134a), that have a high global warming potential (GWP), but their use is being progressively lowered to reduce impact on climate. One option to reduce the carbon footprint of the pMDI products while preserving pMDIs as a therapeutic option is reformulating the current pMDIs using low GWP propellants, such as 1,1-difluoroethane (HFA152a). Nevertheless, pharmaceutical, clinical, and regulatory challenges need to be considered when reformulating a pMDI. A nonclinical study in rodents has been performed to support the formulation work and optimize the design of the bioequivalence study in humans. Methods: A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate (BDP) as pMDI with the two propellants HFA134a or HFA152a was administered by inhalation to Sprague-Dawley rats, using inhalation tower, to assess the impact of the propellant on the PK profile of the active components. After administration, serial blood samples were taken from each rat, and plasma aliquots were analyzed by HPLC-MS/MS. Results: Inhalation administration to rats of the fixed triple combination as pMDI showed similar PK profile for formoterol, glycopyrrolate, and BDP with the two propellants. Exposure parameters C
max and AUClast of the three active ingredients were compared, showing no statistically significant differences in the systemic exposure between the two treatment groups. Higher interanimal variability was observed for the metabolite beclomethasone 17-monopropionate, likely due to individual differences in the metabolite generation. Conclusions: Considering these data, it was possible to conclude that replacing propellant HFA134a with HFA152a in a newly developed formulation had no significant impact on the plasmatic PK profile of formoterol, glycopyrrolate, and BDP in rats after inhalation administration using inhalation towers.- Published
- 2024
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125. Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and β 2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.
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Carzaniga L, Linney ID, Rizzi A, Schmidt W, Knight CK, Mileo V, Amadei F, Pastore F, Miglietta D, Cesari N, Riccardi B, Mazzucato R, Ghidini E, Blackaby WP, Patacchini R, Battipaglia L, Villetti G, Puccini P, Catinella S, Civelli M, and Rancati F
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- Animals, Humans, Administration, Inhalation, Rats, Drug Discovery, Structure-Activity Relationship, Male, Pulmonary Disease, Chronic Obstructive drug therapy, Muscarinic Antagonists pharmacokinetics, Muscarinic Antagonists pharmacology, Muscarinic Antagonists chemistry, Muscarinic Antagonists chemical synthesis, Muscarinic Antagonists therapeutic use, Muscarinic Antagonists administration & dosage, Adrenergic beta-2 Receptor Agonists pharmacokinetics, Adrenergic beta-2 Receptor Agonists pharmacology, Adrenergic beta-2 Receptor Agonists chemistry, Adrenergic beta-2 Receptor Agonists administration & dosage
- Abstract
Clinical guidelines for COPD and asthma recommend inhaled β-adrenergic agonists, muscarinic antagonists, and, for frequent exacerbators, inhaled corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist and β
2 agonist) concept has the potential to simplify this complexity while increasing the efficacy of both pharmacologies. In this article, we report the outcome of our solid-state driven back-up program that led to the discovery of the MABA compound CHF-6550 . A soft drug approach was applied, aiming at high plasma protein binding and high hepatic clearance, concurrently with an early stage assessment of crystallinity through a dedicated experimental workflow. A new chemotype was identified, the diphenyl hydroxyacetic esters, able to generate crystalline material. Among this class, CHF-6550 demonstrated in vivo efficacy, suitability for dry powder inhaler development, favorable pharmacokinetics, and safety in preclinical settings and was selected as a back-up candidate, fulfilling the desired pharmacological and solid-state profile.- Published
- 2024
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126. Optimization of M 3 Antagonist-PDE4 Inhibitor (MAPI) Dual Pharmacology Molecules for the Treatment of COPD.
- Author
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Rizzi A, Amari G, Pivetti F, Delcanale M, Amadei F, Pappani A, Fornasari L, Villetti G, Marchini G, Pisano AR, Pitozzi V, Pittelli MG, Trevisani M, Salvadori M, Cenacchi V, Fioni A, Puccini P, Civelli M, Patacchini R, Baker-Glenn C, Van de Poël H, Blackaby W, Nash K, and Armani E
- Subjects
- Rats, Animals, Bronchodilator Agents pharmacology, Bronchodilator Agents therapeutic use, Anti-Inflammatory Agents pharmacology, Phosphodiesterase 4 Inhibitors pharmacology, Phosphodiesterase 4 Inhibitors therapeutic use, Pulmonary Disease, Chronic Obstructive drug therapy
- Abstract
Aiming at the inhaled treatment of pulmonary diseases, the optimization process of the previously reported MAPI compound 92a is herein described. The project was focused on overcoming the chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats in order to be confident in a clinical effect without having to overdose at one of the biological targets. The chemical strategy was based on fine-tuning of the substitution pattern in the muscarinic and PDE4 structural portions of the dual pharmacology compounds, also making use of the analysis of a proprietary crystal structure in the PDE4 catalytic site. Compound 10f was identified as a chemically stable, potent, and in vivo balanced MAPI lead compound, as assessed in bronchoconstriction and inflammation assays in rats after intratracheal administration. After the in-depth investigation of the pharmacological and solid-state profile, 10f proved to be safe and suitable for development.
- Published
- 2023
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- View/download PDF
127. ADME properties of CHF6366, a novel bi-functional M3 muscarinic receptor antagonist and ß 2 adrenoceptor agonist (MABA) radiolabelled at both functional moieties.
- Author
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Ghiglieri A, Messina M, Cenacchi V, Piutti C, Cinato F, Brogin G, and Puccini P
- Subjects
- Feces, Glucuronides, Carbamates, Receptors, Adrenergic, Administration, Oral, Body Fluids
- Abstract
CHF6366, a dual action β
2 -receptor agonist and M3-muscarinic receptor antagonist developed for chronic obstructive pulmonary disease (COPD) was [14 C]-radiolabelled on the two different functional moieties of the molecule (either aminobutanolic or carbamate) to characterise its ADME profile following intravenous (IV), intratracheal (IT) and oral (PO) administration.A very low oral bioavailability and a good balance between absorption and lung retention after IT administration were observed, together with a rapid distribution throughout the body and a complete metabolic transformation of the parent drug without relevant gender difference.CHF6366 was observed fully hydrolysed to alcohol (CHF6387) and carboxylic acid (CHF6361) in plasma and urine after IV and IT administration, and mainly unchanged in faeces only after oral administration. An important number of metabolites containing aminobutanolic moiety was excreted via urine, whereas carbamate-containing derivatives were excreted mainly by bile.The major metabolic routes of the alcoholic moiety (CHF6387) included isomerisation (Ma7), conjugation with glucuronic acid and dehydrogenation, while the carboxylic acid moiety (CHF6361) was mainly metabolised through oxidation, glucuronide conjugation and, in both pathways, combinations of those metabolic reactions.No major differences arose also from in vitro metabolism profiles investigated using liver microsomes and hepatocytes of different species.- Published
- 2023
- Full Text
- View/download PDF
128. Lymph-vascular Space Involvement and/or p53 Overexpression Correlated With the Clinical Outcome of Early-stage Endometrial Cancer Patients Treated With Adjuvant Vaginal Brachytherapy.
- Author
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Laliscia C, Gadducci A, Coccia N, Mattioni R, Fuentes T, Caretto M, Pistolesi S, Puccini P, Perrone F, Morganti R, and Paiar F
- Subjects
- Female, Humans, Iridium Radioisotopes, Tumor Suppressor Protein p53, Lymph Node Excision, Neoplasm Recurrence, Local pathology, Hysterectomy, Neoplasm Staging, Retrospective Studies, Brachytherapy, Endometrial Neoplasms radiotherapy, Endometrial Neoplasms surgery, Carcinoma, Endometrioid pathology
- Abstract
Background/aim: The majority of patients with endometrial cancer (EC) are diagnosed at an early stage and undergo primary surgery, followed by observation or adjuvant therapy according to risk factors on surgical samples. The objective of this study was to assess the correlation between a risk profile represented by the presence of substantial lymph-vascular space involvement (LVSI) and/or p53 overexpression and the clinical outcome of patients with early-stage endometrial cancer (EC) who received adjuvant vaginal brachytherapy (BT)., Patients and Methods: This investigation assessed 79 patients who underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic and/o aortic lymphadenectomy or sentinel lymph node biopsy followed by hypofractionated (HDR)-vaginal BT, using 192Ir source, for stage I-II endometrioid (n=70) or non-endometrioid (n=9) EC. Thirty-four patients (43.0%) were considered to have an unfavorable risk profile defined by the presence of substantial LVSI and /or p53 overexpression., Results: Five-year disease-free survival (DFS) and five-year overall survival (OS) were 93.7% and 95%, respectively. There was a significant correlation between unfavorable risk-profile and pelvic recurrence rate (p=0.002) and distant recurrence rate (p=0.017). Patients with abnormal p53 had a higher risk of local relapse (p=0.041). Substantial LVSI was strongly associated with pelvic recurrence (p=0.001) and distant metastasis (p<0.001)., Conclusion: The presence of substantial LVSI and/or p53 overexpression strictly correlated with poor outcome of patients with early-stage EC and should be taken into consideration for better planning adjuvant treatment in this clinical setting., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2023
- Full Text
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129. Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β 2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.
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Carzaniga L, Linney ID, Rizzi A, Delcanale M, Schmidt W, Knight CK, Pastore F, Miglietta D, Carnini C, Cesari N, Riccardi B, Mileo V, Venturi L, Moretti E, Blackaby WP, Patacchini R, Accetta A, Biagetti M, Bassani F, Tondelli M, Murgo A, Battipaglia L, Villetti G, Puccini P, Catinella S, Civelli M, and Rancati F
- Subjects
- Administration, Inhalation, Adrenergic beta-2 Receptor Agonists pharmacology, Adrenergic beta-2 Receptor Agonists therapeutic use, Bronchodilator Agents therapeutic use, Drug Discovery, Humans, Lung, Muscarinic Antagonists pharmacology, Muscarinic Antagonists therapeutic use, Pulmonary Disease, Chronic Obstructive drug therapy
- Abstract
The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and β
2 agonists (MABAs) promises to be an excellent opportunity to reduce formulation issues and boost efficacy through cross-talk and allosteric interactions. Herein, we report the results of our drug discovery campaign aimed at improving the therapeutic index of a previous MABA series by exploiting the super soft-drug concept. The incorporation of a metabolic liability, stable at the site of administration but undergoing rapid systemic metabolism, to generate poorly active and quickly eliminated fragments was pursued. Our SAR studies yielded MABA 29 , which demonstrated a balanced in vivo profile up to 24 h, high instability in plasma and the liver, as well as sustained exposure in the lung. In vitro safety and non-GLP toxicity studies supported the nomination of 29 (CHF-6366) as a clinical candidate, attesting to the successful development of a novel super-soft MABA compound.- Published
- 2022
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130. Discovery of M 3 Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease.
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Armani E, Rizzi A, Capaldi C, De Fanti R, Delcanale M, Villetti G, Marchini G, Pisano AR, Pitozzi V, Pittelli MG, Trevisani M, Salvadori M, Cenacchi V, Puccini P, Amadei F, Pappani A, Civelli M, Patacchini R, Baker-Glenn CAG, Van de Poël H, Blackaby WP, Nash K, and Amari G
- Subjects
- Animals, Dose-Response Relationship, Drug, Guinea Pigs, Male, Molecular Structure, Phosphodiesterase 4 Inhibitors chemistry, Pulmonary Disease, Chronic Obstructive metabolism, Rats, Rats, Inbred BN, Rats, Sprague-Dawley, Receptor, Muscarinic M3 metabolism, Structure-Activity Relationship, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Drug Discovery, Phosphodiesterase 4 Inhibitors pharmacology, Pulmonary Disease, Chronic Obstructive drug therapy, Receptor, Muscarinic M3 antagonists & inhibitors
- Abstract
In this paper, we report the discovery of dual M
3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.- Published
- 2021
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131. Dissecting the Pharmacodynamics and Pharmacokinetics of MSCs to Overcome Limitations in Their Clinical Translation.
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Salvadori M, Cesari N, Murgia A, Puccini P, Riccardi B, and Dominici M
- Abstract
Recently, mesenchymal stromal stem cells (MSCs) have been proposed as therapeutic agents because of their promising preclinical features and good safety profile. However, their introduction into clinical practice has been associated with a suboptimal therapeutic profile. In this review, we address the biodistribution of MSCs in preclinical studies with a focus on the current understanding of the pharmacodynamics (PD) and pharmacokinetics (PK) of MSCs as key aspects to overcome unsatisfactory clinical benefits of MSC application. Beginning with evidence of MSC biodistribution and highlighting PK and PD factors, a new PK-PD model is also proposed. According to this theory, MSCs and their released factors are key players in PK, and the efficacy biomarkers are considered relevant for PD in more predictive preclinical investigations. Accounting for the PK-PD relationship in MSC translational research and proposing new models combined with better biodistribution studies could allow realization of the promise of more robust MSC clinical translation.
- Published
- 2019
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132. Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion.
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Peretto I, Radaelli S, Parini C, Zandi M, Raveglia LF, Dondio G, Fontanella L, Misiano P, Bigogno C, Rizzi A, Riccardi B, Biscaioli M, Marchetti S, Puccini P, Catinella S, Rondelli I, Cenacchi V, Bolzoni PT, Caruso P, Villetti G, Facchinetti F, Del Giudice E, Moretto N, and Imbimbo BP
- Subjects
- Administration, Oral, Alzheimer Disease blood, Alzheimer Disease genetics, Amyloid beta-Peptides blood, Amyloid beta-Peptides metabolism, Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Blood-Brain Barrier metabolism, Caco-2 Cells, Cell Line, Tumor, Cell Membrane Permeability, Cyclooxygenase Inhibitors pharmacology, Flurbiprofen pharmacology, Glioma, Humans, Immunoassay, In Vitro Techniques, Injections, Intravenous, Mice, Mice, Transgenic, Peptide Fragments blood, Peptide Fragments metabolism, Rats, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Stereoisomerism, Structure-Activity Relationship, Amyloid beta-Peptides antagonists & inhibitors, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Flurbiprofen analogs & derivatives, Flurbiprofen chemical synthesis, Peptide Fragments antagonists & inhibitors
- Abstract
Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Abeta42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
- Published
- 2005
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133. High throughput screening of beta-amyloid secretion inhibitors using homogenous time-resolved fluorescence.
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Albrecht H, Zbinden P, Rizzi A, Villetti G, Riccardi B, Puccini P, Catinella S, and Imbimbo BP
- Subjects
- Antibodies, Monoclonal, Cells, Cultured, Chromatography, Liquid, Drug Evaluation, Preclinical, Enzyme-Linked Immunosorbent Assay, Fluorescent Dyes, Humans, Immunoassay, Mass Spectrometry, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides metabolism
- Abstract
A cell-based assay using homogeneous time-resolved fluorescence has been developed for high throughput screening of putative beta-amyloid (Abeta)production inhibitors. In this assay, total Abeta is detected by simply adding two commercially available antibody complexes. The first was a biotinylated monoclonal antibody (4G8), specifically recognizing an epitope comprising the residues 17-24 of the Abetapeptide, complexed with europium cryptate-streptavidin conjugate. The second was a polyclonal antibody (BioS-N), raised against the N-terminus of the Abeta peptide, complexed with an allophycocyanin-anti rabbit antibody conjugate. Binding of the two complexes to the Abeta peptide brought europium cryptate (fluorescence donor) and allophycocyanin (fluorescence acceptor) into close proximity, consequently a fluorescent resonance energy transfer signal was produced upon excitation at 337 nm. The resulting fluorescence signal (665 nm) was then detected using a Discovery or a ViewLux reader. Detection of Abeta by the proposed method is possible at concentrations of approximately 1 nM. The method was employed for the detection of Abeta secreted from a stable transfected human neuroglioma cell line (H4) overexpressing a mutated form of the human amyloid precursor protein (APP695NL) and developed for robotic automation. At optimized conditions, signal-to-background ratios exceeding 5 and Z' factors around 0.7 were achieved in a 384-well format. High throughput screening of 56,913 potential Abeta production inhibitors led to identification of new non-cytotoxic and cell permeable compounds with potencies in the submicromolar range.
- Published
- 2004
- Full Text
- View/download PDF
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