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1. Suckling piglets submitted to creep feeding management from 5 days-old showed optimal performance and exploratory behaviour

Author

Agnol, J. D., primary, Meneghetti, F., additional, Gaggini, T. S., additional, Rodrigues, G. A., additional, Genova, J. L., additional, Carvalho, P. L. O., additional, Carvalho, S. T., additional, Costa, L. B., additional, Paiano, D., additional, Saraiva, A., additional, Eyng, C., additional, and Oliveira, N. T. E., additional

Published
2024
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4. Elagolix analogues as potential new GnRH antagonists

Author

Ciceri, S., Colombo, D., Fassi, E., Ferraboschi, P., Grazioso, G., Grisenti, P., and Meneghetti, F.

Subjects
Elagolix, GnRH antagonist, Atropisomerism, Settore BIO/10 - Biochimica, Settore CHIM/06 - Chimica Organica, Settore CHIM/08 - Chimica Farmaceutica
Published
2022

7. Suckling piglets submitted to creep feeding management from 5 days-old showed optimal performance and exploratory behaviour.

Author

Agnol, J. D., Meneghetti, F., Gaggini, T. S., Rodrigues, G. A., Genova, J. L., Carvalho, P. L. O., Carvalho, S. T., Costa, L. B., Paiano, D., Saraiva, A., Eyng, C., and Oliveira, N. T. E.

Subjects
*PIGLETS, *SWINE breeding, *ANIMAL weaning, *BODY weight, *AMYLASES
Abstract

This study aimed to assess the effects of starting creep feeding at different ages on performance, behaviour, haematological, and biochemical parameters in piglets. A total of 138 piglets (1.34 ± 0.25 kg, n = 13 sows), weaned at 21 d-old, were assigned to treatments using a completely randomized design. The litter was divided into two groups: seven litters (n = 80 piglets) were subjected to creep feeding on the fifth day of age (creep 5) and five litters (n = 58 piglets), on the tenth day of age (creep 10). Piglets were weighed at birth, weaning, and after the first week in the nursery. Piglet behaviour was evaluated daily for 15 min until day 20. Blood was collected on day 13, at weaning, and at the end of the first week in the nursery. There was no difference in body weight in the suckling phase, but piglets fed Creep 5 showed greater body weight gain in the first nursery week. The Creep 5 group had lower feed leftovers during the five days of evaluation of feed intake. There were no differences in haematological parameters and amylase concentration; however, the piglets spent more time lying down, sucking, and massaging the udder. On day 8, the piglets in the Creep 5 group showed a higher frequency of exploratory behaviour. In conclusion, piglets fed Creep 5 had optimal performance after weaning and improved feed intake capacity by displaying more exploratory behaviour than Creep 10. Creep management did not alter haematological and biochemical parameters. [ABSTRACT FROM AUTHOR]

Published
2023
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23. Cascade Reaction by Chemo- and Biocatalytic Approaches to Obtain Chiral Hydroxy Ketones and anti 1,3-Diols

Author

Gandolfi R., Facchetti G., Christodoulou M. S., Fuse' M., Meneghetti F., Rimoldi I., Gandolfi, R., Facchetti, G., Christodoulou, M. S., Fuse', M., Meneghetti, F., and Rimoldi, I.

Subjects
Settore CHIM/03 - Chimica Generale e Inorganica, biocatalysis, borylation, copper, biocatalysi, Settore CHIM/11 - Chimica e Biotecnologia delle Fermentazioni, reduction, Settore CHIM/06 - Chimica Organica, yeast, Settore CHIM/08 - Chimica Farmaceutica, Settore CHIM/02 - Chimica Fisica
Abstract

A chemo- and biocatalytic cascade approach was applied for the stereoselective synthesis of hydroxy ketones and the corresponding 1,3-diols. A new class of tridentate N,N,O ligands was used with copper(II) complexes for the asymmetric β-borylation of α,β-unsaturated compounds. The complex containing ligand L5 emerged as the best performer, and it gave the organoborane derivatives with good ee values. The corresponding keto–alcohol compounds were then bioreduced by yeasts. The biotransformation set up with Rhodotorula rubra allowed (R)-keto–alcohols and (S,S)-diols to be obtained with up to 99 % ee and up to 99 % de in favor of the anti enantiomers.

Published
2018

27. Ureido-Pyridazinone Derivatives: Insights into the Structural and Conformational Properties for STAT3 Inhibition

Author

Meneghetti, F, Villa, S, Masciocchi, D, Barlocco, D, Toma, L, Han, D, Kwon, B, Ogo, N, Asai, A, Legnani, L, Gelain, A, Meneghetti F., Villa S., Masciocchi D., Barlocco D., Toma L., Han D. -C., Kwon B. -M., Ogo N., Asai A., Legnani L., Gelain A., Meneghetti, F, Villa, S, Masciocchi, D, Barlocco, D, Toma, L, Han, D, Kwon, B, Ogo, N, Asai, A, Legnani, L, Gelain, A, Meneghetti F., Villa S., Masciocchi D., Barlocco D., Toma L., Han D. -C., Kwon B. -M., Ogo N., Asai A., Legnani L., and Gelain A.

Abstract

Three new ureido-pyridazinone derivatives, which are structurally related to the known STAT3 inhibitor AVS-0288, were designed by taking into account the structure-activity relationships determined for several ureido-oxadiazole derivatives previously studied by our group. Their synthesis was first attempted through suitable 5-aminopyridazinone intermediates (6a and 6b), which molecular structures were confirmed by means of X-ray diffraction data on 6a. Amine functionalization was unsuccessful, therefore, an alternative method was devised. Dual-luciferase and AlphaScreen-based assays were used to test their activity. The obtained data were rationalized on the basis of a modeling study, which focused our attention on the geometrical preferences of the ureido moiety. Computational results seem to indicate that both the 1,2,5-oxadiazole ring and the extended ZZ arrangement are essential and probably act in a synergistic way to confer significant activity against STAT3.

Published
2015

29. Crystallographic spectroscopic and theoretical investigation on the efficiently separated 21R and 21S-diastereoisomers of Argatroban

Author

Ferraboschi, P, Colombo, D, Legnani, L, Toma, L, Grisenti, P, Vistoli, G, Meneghetti, F, Ferraboschi P., Colombo D., LEGNANI, LAURA, TOMA, LUCIO, Grisenti P., Vistoli G., Meneghetti F., Ferraboschi, P, Colombo, D, Legnani, L, Toma, L, Grisenti, P, Vistoli, G, Meneghetti, F, Ferraboschi P., Colombo D., LEGNANI, LAURA, TOMA, LUCIO, Grisenti P., Vistoli G., and Meneghetti F.

Abstract

Argatroban (I), a potent noncovalent reversible thrombin inhibitor, is used as an anticoagulant for the parenteral treatment of heparin-induced thrombocytopenia (HIT) patients. By virtue of its pharmacological properties and the well-balanced risks and benefits, argatroban is now emerging as a clinically relevant antithrombotic agent. The availability of this drug as a mixture of 21R and 21S-diastereoisomers, in a ratio of roughly 64:36, prompted us to design an efficient separation setup of the two epimers. We pursued our efforts on their detailed structural analysis with the aim of understanding their different activity and aqueous solubility. These investigations were accompanied by a modeling study of the two diastereoisomers, with particular attention on the easy interconverting half-chair of the tetrahydroquinoline system and its preferred conformation, which is determined by the configuration at C21. These results, together with the analysis of their physicochemical profiles, provide new useful information for the development of the individual diastereoisomers.

Published
2013

30. Synthesis structure-activity relationships and stereochemical investigations of new tricyclic pyridazinone derivatives as potential STAT3 inhibitors

Author

Masciocchi, D, Gelain, A, Porta, F, Meneghetti, F, Pedretti, A, Celentano, C, Barlocco, D, Legnani, L, Toma, L, Kwon, B, Asai, A, Villa, S, Masciocchi D., Gelain A., Porta F., Meneghetti F., Pedretti A, Celentano C., Barlocco D., LEGNANI, LAURA, TOMA, LUCIO, Kwon B.M., Asai A., Villa S., Masciocchi, D, Gelain, A, Porta, F, Meneghetti, F, Pedretti, A, Celentano, C, Barlocco, D, Legnani, L, Toma, L, Kwon, B, Asai, A, Villa, S, Masciocchi D., Gelain A., Porta F., Meneghetti F., Pedretti A, Celentano C., Barlocco D., LEGNANI, LAURA, TOMA, LUCIO, Kwon B.M., Asai A., and Villa S.

Abstract

Through a cell-based biological screening, the benzocinnolinone derivative (±)-2c was identified as a promising STAT3 inhibitor. Since SAR studies on a series of compounds structurally related to (±)-2c (1c, 2a-p, 3c, 4c, 6) showed that the latter had the most significant inhibitory activity, we investigated in depth its essential structural features. In particular, enantiomeric separation was performed, and the absolute configuration of the stereoisomers was assigned by theoretical and crystallographic studies. The biological evaluation highlighted that (S)-(-)-2c is twice as potent as (R)-(+)-2c.

Published
2013

31. Antiretroviral genotypic resistance in plasma RNA and whole blood DNA in HIV-1 infected patients failing HAART

Author

Saracino, A, Gianotti, N, Marangi, M, Cibelli, Dc, Galli, A, Punzi, G, Monno, L, Lazzarin, A, Angarano, G, Dini, M, Del Gobbo, R, Montroni, M, Butini, L, Scalise, G, Ancarani, F, Di Cesare, S, Giacometti, A, Biglino, A, Degioanni, M, Paoloni, M, Mariani, R, Calella, G, Pastore, G, Ladisa, N, Mennea, G, Gritti, Fm, Fasullo, G, Chiodo, F, Borderi, M, Carosi, Giampiero, Castelli, Francesco, Torti, Carlo, Uccelli, C, Rizzardini, G, Visoná, R, Salvo, A, Averna, A, Russo, R, Celesia, Bm, Cosentino, S, Rinaldi, E, Pusterla, L, Carnevale, G, Mondello, P, Petrini, C, Ghinelli, F, Sighinolfi, L, Mazzotta, F, Lo Caputo, S, Pierotti, P, Leoncini, F, Sterrantino, Gk, Corsi, P, Pompei, Ag, Di Toro MT, Purificato, F, Indiveri, F, Setti, M, Murdaca, G, Iannessi, A, Cellini, A, Mariani, A, Scasso, A, De Gennaro, M, Chiodera, A, Castelli, P, Maltempo, K, Mongolo, G, Caggese, L, Schlacht, I, Cargnel, A, Atzori, C, Micheli, V, Moroni, M, Bini, T, Marcatto, I, Chiesa, E, Vigevani, G, Argenteri, B, Capetti, A, Esposito, R, Guaraldi, G, Seghetto, B, Chirianni, A, Gargiulo, M, Abrescia, N, D'Abbraccio, M, Busto, T, Marchitelli, C, Santirocchi, M, Abbadessa, V, Mancuso, S, Meneghetti, F, Pranzetti, M, Ferrari, C, Pizzaferri, P, Stagni, G, Di Candilo, F, Petrelli, E, Balducci, M, Menichetti, F, Polidori, M, Tascini, C, Di Carlo, A, Palamara, G, Antinori, A, Liuzzi, G, Aiuti, F, Mezzaroma, I, Pinter, E, Barbone, B, Vullo, V, Massetti, P, Dell'Isola, S, Mura, Ms, Mannazzu, M, Delias, R, Di Giammartino, D, Tarquini, P, Marranconi, F, Ferretto, R, Caramello, P, Orofino, Gc, Cimino, T, Bramato, C, Di Perri, G, Sinicco, A, Zeme, D, Bonora, S, Trentini, L, Soranzo, Ml, Macor, A, Salassa, B, Branz, F, Delle Foglie, P, Vaglia, A, Rossi, Mc, Ciccone, L, Panzolli, L, Grossi, P, Giola, M, Raise, E, Narne, E, Poggio, A, Demin, F, Mondino, V, Serpelloni, G, Malena, M, Bosco, O., Saracino, A, Gianotti, N, Marangi, M, Cibelli, D, Galli, A, Punzi, G, Monno, L, Lazzarin, A, Angarano, G, and Mancuso, S

Subjects
Anti-HIV Agents, DNA Mutational Analysis, Molecular Sequence Data, Proviral DNA, HIV Infections, HAART failure, medicine.disease_cause, DNA Mutational Analysi, chemistry.chemical_compound, HIV Protease, Proviruses, Antiretroviral Therapy, Highly Active, Virology, Drug Resistance, Viral, medicine, Humans, Multicenter Studies as Topic, HIV Infection, Treatment Failure, Genotyping, Randomized Controlled Trials as Topic, COLD-PCR, Mutation, Plasma RNA, biology, Proviruse, Sequence Analysis, RNA, Anti-HIV Agent, RNA, Sequence Analysis, DNA, biology.organism_classification, HIV Reverse Transcriptase, Reverse transcriptase, Antiretroviral genotypic resistance, Infectious Diseases, chemistry, DNA, Viral, Lentivirus, Immunology, HIV-1, RNA, Viral, DNA, antiretroviral genotypic resistance, haart failure, hiv-1, plasma rna, proviral dna, Human
Abstract

The extent to which HIV-1 proviral DNA mutations cause clinically relevant antiretroviral resistance is still controversial. Paired plasma HIV-1 RNA and whole blood DNA were compared in patients failing HAART to investigate if the additional knowledge of archived mutations could improve the selection of potentially active drugs. Seventy-three HIV-1-infected patients with first/second HAART failure were studied before starting a new regimen based on RNA genotyping. Follow-up data after a 12-week therapy were available. DNA genotyping was retrospectively performed on stored whole blood samples and mutational profiles were compared to those from RNA. The mean number of IAS pol mutations was significantly higher in RNA (4.45 ± 2.76) than in DNA (2.88 ± 2.47) (P < 0.001). DNA genotyping provided a 6% increase in detection of resistance-associated mutations. Among 64/73 patients showing discordant DNA/RNA profiles, 54 (84%) also differed for predicted active drugs. 16/73 (22%) patients had ≥1 mutation revealed by DNA genotyping alone, probably affecting therapy success in 2/16. However, neither RNA/DNA discordance nor detection of isolated DNA mutations were statistically associated with outcome. In conclusion, plasma RNA remains the elective choice for HIV genotyping in patients with therapy failure, even if the detection of proviral resistance-associated mutations, not simultaneously found in RNA, is a frequent event. Therefore, in some cases DNA plus RNA genotyping might assist in choosing more accurately subsequent antiretroviral regimens. © 2008 Wiley-Liss, Inc.

Published
2008
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32. Unexpected synthesis by a non-classical Pschorr reaction of 3,5-dimethyl-1-phenyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, with binding affinity for the central benzodiazepine receptor

Author

MAGGIO, Benedetta, RAFFA, Demetrio, DAIDONE, Giuseppe, Meneghetti, F, Maggio, B, Raffa, D, Meneghetti, F, and Daidone, G

Subjects
Pschorr, Sandmeyer reactions, 1,4-pyrazolyl transfer, fused pyrazoles, quinolines, 1,5-hydrogen transfer, Settore CHIM/08 - Chimica Farmaceutica
Abstract

The reaction of the diazonium salt 12 derived from N-(2-aminophenyl)-N,3-dimethyl-1-phenyl-1H-pyrazole-5-carboxamide with copper sulfate and sodium chloride in the presence of ascorbic acid afforded the unexpected products 3,5-dimethyl-1-phenyl-1,5-dihydro-4H-pyrazolo[4,3-c]¬quinolin-4-one (17) and N-methyl-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)aniline (19), accompanied by N-(2-chlorophenyl)-N,3-dimethyl-1-phenyl-1H-pyrazole-5-carboxamide (18). Products 17 and 19 are formed via a non-classical Pschorr reaction. The formation of 17 represents an alternative to the literature synthesis of this biologically active compound. The molecular structure of 18 was confirmed by single-crystal X-ray analysis.

Published
2014

33. Complete Characterization of the 3D Properties of the CCR5 Antagonist Vicriviroc through DFT Calculations, NMR Spectroscopy, and X-ray Analysis

Author

Legnani, L, Colombo, D, Villa, S, Meneghetti, F, Castellano, C, Gelain, A, Marinone, F, Toma, L, LEGNANI, LAURA, Colombo D., Villa S., Meneghetti F., Castellano C., Gelain A., MARINONE, FRANCA, TOMA, LUCIO, Legnani, L, Colombo, D, Villa, S, Meneghetti, F, Castellano, C, Gelain, A, Marinone, F, Toma, L, LEGNANI, LAURA, Colombo D., Villa S., Meneghetti F., Castellano C., Gelain A., MARINONE, FRANCA, and TOMA, LUCIO

Abstract

Vicriviroc is a piperazine-based CCR5 receptor antagonist, with better oral availability, potency, safety, and pharmacological properties than those of its precursor SCH-C, but whose development has been stopped. A full evaluation of the 3D properties of vicriviroc was carried out in order to achieve a complete knowledge of its conformational behavior and, consequently, to identify the parameters necessary to design new, possibly better, analogs. The theoretical study was performed at the B3LYP/6-31G(d) level of calculations. Particular attention was focused on the arrangement at the planar amido function and the conformational preferences of the piperazine and piperidine rings. Several conformational families, characterized by different through-space contacts and comparable energy values, were located and confirmed by high-field NMR spectroscopy. Two distinct series of signals, originating from the barrier to rotation of the amido function, were observed in the NMR spectrum. Moreover, a NOESY experiment provided evidence for all the close contacts present assuring the coexistence, in solution, of numerous conformations in equilibrium, characterized by different chair geometries of the heterocyclic rings. A complete modeling study of vicriviroc was carried out by using theoretical calculations, and the results were confirmed through a NOESY experiment. Several populated conformations were identified originating from the amido group arrangement as well as chair inversion at the piperazine and piperidine rings and rotations around the bond connecting them.

Published
2012

34. Crystallographic, spectroscopic, and theoretical investigation of the efficiently separated 21R and 21S-diastereoisomers of argatroban

Author

Ferraboschi P., Colombo D., LEGNANI, LAURA, TOMA, LUCIO, Grisenti P., Vistoli G., Meneghetti F., Ferraboschi, P, Colombo, D, Legnani, L, Toma, L, Grisenti, P, Vistoli, G, and Meneghetti, F

Subjects
Models, Molecular, Sulfonamides, Magnetic Resonance Spectroscopy, solubility, structure-activity relationship, Stereoisomerism, Arginine, Crystallography, X-Ray, computational chemistry, Pipecolic Acids, argatroban, Thermodynamics, Computer Simulation, direct thrombin inhibitor
Abstract

Argatroban (I), a potent noncovalent reversible thrombin inhibitor, is used as an anticoagulant for the parenteral treatment of heparin-induced thrombocytopenia (HIT) patients. By virtue of its pharmacological properties and the well-balanced risks and benefits, argatroban is now emerging as a clinically relevant antithrombotic agent. The availability of this drug as a mixture of 21R and 21S-diastereoisomers, in a ratio of roughly 64:36, prompted us to design an efficient separation setup of the two epimers. We pursued our efforts on their detailed structural analysis with the aim of understanding their different activity and aqueous solubility. These investigations were accompanied by a modeling study of the two diastereoisomers, with particular attention on the easy interconverting half-chair of the tetrahydroquinoline system and its preferred conformation, which is determined by the configuration at C21. These results, together with the analysis of their physicochemical profiles, provide new useful information for the development of the individual diastereoisomers.

Published
2013

36. Synthesis and anticancer activity of 3-amino-N-phenyl-1H-indazole-1-carboxamide and 1-(1H)indazol-3-yl-3-phenylureido derivatives

Author

RAFFA, Demetrio, MAGGIO, Benedetta, CASCIOFERRO, Stella Maria, RAIMONDI, Maria Valeria, SCHILLACI, Domenico, DAIDONE, Giuseppe, PLESCIA, Salvatore, DI CRISTINA, Antonietta, GRIMAUDO, Stefania, GALLO G, MENEGHETTI F, BOMBIERI G, TOLOMEO M, RAFFA D, MAGGIO B, CASCIOFERRO S, RAIMONDI V, SCHILLACI D, GALLO G, DAIDONE G, PLESCIA S, MENEGHETTI F, BOMBIERI G, TOLOMEO M, DI CRISTINA A, and GRIMAUDO S

Published
2007

39. European Confederation of Medical Mycology (ECMM) prospective survey of cryptococcosis: Report from Italy

Author

Viviani, Ma, Antinori, S, Cogliati, M, Esposto, Mc, Pinsi, G, Casari, S, Bergamasco, A, De Santis Ml, Ghirga, P, Bonaccorso, C, Jacchetti, G, Niero, F, Ammassari, A, Morace, G, Ossi, C, Montagna, Mt, Angarano, G, Farina, C, Maggiolo, F, Moroni, M, Pierdomenico, S, Michelone, G, Cavanna, C, Viti, F, Carli, T, Barchiesi, F, Agrappi, C, Mena, M, Giola, M, Lombardi, G, Tinelli, M, Ceraminiello, A, Codeluppi, M, Casolari, C, Foresti, S, Bramati, S, Ruggieri, A, Caggese, L, Astolfi, A, Bonora, S, Scotton, Pg, Rigoli, R, Angioni, G, Meneghetti, F, Nullg, Nulldi Perri, UBERTI FOPPA, CATERINA, Viviani, Ma, Antinori, S, Cogliati, M, Esposto, Mc, Pinsi, G, Casari, S, Bergamasco, A, De Santis, Ml, Ghirga, P, Bonaccorso, C, Jacchetti, G, Niero, F, Ammassari, A, Morace, G, UBERTI FOPPA, Caterina, Ossi, C, Montagna, Mt, Angarano, G, Farina, C, Maggiolo, F, Moroni, M, Pierdomenico, S, Michelone, G, Cavanna, C, Viti, F, Carli, T, Barchiesi, F, Agrappi, C, Mena, M, Giola, M, Lombardi, G, Tinelli, M, Ceraminiello, A, Codeluppi, M, Casolari, C, Foresti, S, Bramati, S, Ruggieri, A, Caggese, L, Astolfi, A, Bonora, S, Scotton, Pg, Rigoli, R, Angioni, G, Meneghetti, F, and Nullg, Nulldi Perri

Abstract

Italy is one of the countries participating in a prospective epidemiological survey of cryptococcosis set up in July 1997 by the European Confederation of Medical Mycology (ECMM). Over a 30-month period 156 cases, all caused by Cryptococcus neoformans var. neoformans, were reported by 29 hospitals in 9 regions. An ECMM questionnaire was used to report the clinical presentation and the diagnostic and treatment approach used. Cryptococcosis was associated with HIV infection in 147 cases and was considered indicative of AIDS in 65%. The estimated incidence in the Lombardy region was 0.85/100 in the AIDS population. One isolate from each of 129 patients was serotyped and genotyped. PCR fingerprinting using the primer (GACA)(4) proved to be a more reproducible typing method than the slide agglutination test. Genotypes VN1 (serotype D), VN6 (serotype A) and VN3-VN4 (serotype AD hybrid strains) occurred in Italy at similar levels nationwide, but VN1 (D) was prevalent in the North. In vitro resistance to antifungals was uncommon.

Published
2002

44. Utilizzo di test comportamentali con invertebrati marini per la valutazione tossicologica di sedimenti costieri

Author

Meneghetti F., Garaventa F. (*), Bon D., Di Fino A., Gambardella C., Faimaili M. (*), and Da Ros L. (**)

Subjects
end-point subletali, ecotossicologia, tossicità sedimenti
Abstract

Nell'ambito di un recente programma di ricerca finanziato dalla Regione Veneto e coordinato da ARPA Veneto-Osservatorio Alto Adriatico (93-T406-REL-G009, Intervento n.72-Campo Sperimentale in Mare), due nuovi test tossicologici di tipo comportamentale (il primo basato sulla valutazione delle caratteristiche del riaffossamento di molluschi bentonici della specieTapes philippinarum, il secondo sull'alterazione del nuoto larvale del crostaceo Balanus amphitrite) sono stati applicati sperimentalmente su 9 campioni di sedimento marino-costiero prelevati lungo la costa veneta. I risultati ottenuti, confrontati con le risposte di alcuni test tossicologici indicati dalla normativa per il monitoraggio marino-costiero (Microtox ®e inibizione della crescita algale di Dunaliella tertiolecta) e con la valutazione analitica del contenuto di numerosi contaminanti nei sedimenti, dimostrano come una batteria di saggi tossicologici che comprenda anche test innovativi sia lo strumento che meglio riesce ad evidenziare e discriminare la tossicità dei sedimenti

Published
2007

47. Determinants of virologic and immunologic outcomes in chronically HIV-infected subjects undergoing repeated treatment interruptions: The Istituto Superiore di Sanità-Pulsed Antiretroviral Therapy (ISS-PART) study

Author

Palmisano, L., Giuliano, M., Bucciardini, R., Fragola, V., Andreotti, M., Galluzzo, C. M., Pirillo, M. F., Weimer, L. E., Arcieri, R., Germinario, E. A. P., Amici, R., Mancini, M. G., D'Arminio Monforte, A., Castelli, F., Caramello, P., Vella, S., Abrescia, N., Figoni, M., Viglietti, R., Angarano, G., Saracino, A., Anselmo, M., Antinori, A., Sette, P., Zaccarelli, M., Liuzzi, G., Arlotti, M., Martelli, L. T., Ortolani, P., Bassetti, D., Di Biagio, A., Bisio, F., Bellissima, P., Branz, F., Dorigoni, N., Cadeo, G., Vangi, D., Bertelli, D., Bergamasco, A., Caggese, L., Volonterio, A., Orofino, G. C., Carosella, S., Gennero, L., Caremani, M., Tacconi, D., Carosi, G., Tomasoni, L., Patroni, A., Chiodo, F., Borderi, M., Calza, L., Gritti, F., Fasulo, G., Chirianni, A., Gargiulo, M., Colomba, A., Dalle Nogare, E. R., Di Lorenzo, F., Prestileo, T., Bini, T., Cicconi, P., De Lalla, F., Giordani, M. T., De Stefano, C., De Stefano, G., Delia, S., Ciardi, M., Di Perri, G., Sinicco, A., Sales, P., Dini, M., Simeone, M., Esposito, R., Guaraldi, G., Beghetto, B., Fatuzzo, F., La Rosa, R., Ferrari, C., Calzetti, C., Ferraro, T., Cosco, L., Ghinelli, F., Sighinolfi, L., Guadagnino, V., Caroleo, B., Izzi, A., Izzo, C., Franco, A., Lazzarin, A., Castagna, A., Fusetti, G., Leoncini, F., Pozzi, M., Sbaragli, S., Marzetti, M., Magnani, G., Bonazzi, L., Barchi, E., Zoboli, G., Pintus, A., Mandas, A., Soddu, M. L., Zucca, F., Mannucci, P. M., Gringeri, A., Marani Toro, G., Graziani, R. V., Consorti, A., Mazzotta, F., Di Pietro, M., Ble, C., Meneghetti, F., Sasset, L., Cattelan, A. M., Menichetti, F., Savalli, E., Mian, P., Pristera, R., Mignani, E., Artioli, S., Mura, M. S., Mannazzu, M., Narciso, P., Bellagamba, R., Orani, A., Perini, P., Ortona, L., De Luca, A., Murri, R., Pagano, G., Alessandrini, A., Paladini, A., Vinattieri, M. A., Carbonai, S., Pastore, G., Ladina, N., Tateo, M., Piersantelli, N., Penco, G., Petrelli, E., Balducci, M., Pippi, L., Gonnelli, A., Puppo, F., Murdaca, G., Raise, E., Pasquirucci, A., Riccio, G., Bartolacci, V., Carrega, G., Rizzardini, G., Migliorino, G., Russo, R., Casentino, S., Celesia, M., Soranzo, M. L., Macor, A., Salassa, B., Soscia, F., Roberti, L., Di Toro, M. T., Stagno, A., Beltrami, C., Suter, F., Maggiolo, F., Ripamonti, D., Tantimonaco, G., Grisorio, B., Tassara, A., Rossi, P., Tinelli, M., Regazzetti, A., Tirelli, U., Voltaggio, G., Cinelli, R., Toti, M., Baldari, M., Carli, T., Ricciardi, B., Trezzi, M., Vigevani, G. M., Capetti, A., Landonio, S., Vullo, V., Massetti, P., Zauli, T., and Casolari, S.

Subjects
Adult, Male, medicine.medical_specialty, Anti-HIV Agents, medicine.medical_treatment, HIV Infections, Drug resistance, Drug Administration Schedule, law.invention, Randomized controlled trial, Drug Resistance, Multiple, Viral, law, Internal medicine, medicine, Humans, Pharmacology (medical), Protease inhibitor (pharmacology), Structured treatment interruptions, Chemotherapy, Reverse-transcriptase inhibitor, biology, business.industry, HIV, Middle Aged, biology.organism_classification, CD4 Lymphocyte Count, Clinical trial, Chronic infection, Regimen, Infectious Diseases, Immunology, Lentivirus, RNA, Viral, Female, business, medicine.drug
Abstract

Background: Factors influencing the outcome of structured treatment interruptions (STIs) in HIV chronic infection are not fully elucidated. Methods: In ISS-PART, 273 subjects were randomly assigned to arm A (137 assigned to continuous highly active antiretroviral therapy [HAART]) and arm B (136 assigned to 5 STIs of 1, 1, 2, 2, and 3 months'duration, each followed by 3 months of therapy). Main outcome measures were the proportion of subjects with a CD4 count >500 cells/mm 3 , the rate of virologic failure, and the emergence of resistance at 24 months. Results: The proportion of subjects with a CD4 count >500 cells/mm 3 was higher in arm A than in arm B (86.5% vs. 69.1%; P = 0.0075). Pre-HAART CD4 cell count and male gender were independent predictors of a CD4 count >500 cells/mm 3 in arm B. The overall risk of virologic failure was not increased in arm B; however, it was higher in the 38 subjects who had resistance mutations in the rebounding virus. Archived mutations at baseline and the use of a regimen that included an unboosted protease inhibitor (PI), compared with nonnucleoside reverse transcriptase inhibitor-based HAART, independently predicted the emergence of plasma mutations during STI (P = 0.002 for DNA mutations and P = 0.048 for PI-based HAART). Conclusions: Our results suggest that patients with preexisting mutations and treated with unboosted PI-based HAART should not be enrolled in studies of time-fixed treatment interruptions, being at higher risk of developing plasma mutations during STI and virologic failure at therapy reinstitution.

Published
2007

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