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3. Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies

Author

Di Maio, Velia C., Cento, Valeria, Lenci, Ilaria, Aragri, Marianna, Rossi, Piera, Barbaliscia, Silvia, Melis, Michela, Verucchi, Gabriella, Magni, Carlo F., Teti, Elisabetta, Bertoli, Ada, Antonucci, Francescopaolo, Bellocchi, Maria C., Micheli, Valeria, Masetti, Chiara, Landonio, Simona, Francioso, Simona, Santopaolo, Francesco, Pellicelli, Adriano M., Calvaruso, Vincenza, Gianserra, Laura, Siciliano, Massimo, Romagnoli, Dante, Cozzolongo, Raffaele, Grieco, Antonio, Vecchiet, Jacopo, Morisco, Filomena, Merli, Manuela, Brancaccio, Giuseppina, Di Biagio, Antonio, Loggi, Elisabetta, Mastroianni, Claudio Maria, Pace Palitti, Valeria, Tarquini, Pierluigi, Puoti, Massimo, Taliani, Gloria, Sarmati, Loredana, Picciotto, Antonino, Vullo, Vincenzo, Caporaso, Nicola, Paoloni, Maurizio, Pasquazzi, Caterina, Rizzardini, Giuliano, Parruti, Giustino, Craxì, Antonio, Babudieri, Sergio, Andreoni, Massimo, Angelico, Mario, Perno, Carlo F., Ceccherini Silberstein, Francesca, Mariani, R., Iapadre, N., Grimaldi, A., Cozzolongo, R., Andreone, P., Verucchi, G., Menzaghi, B., Quirino, T., Pisani, V., Torti, MARIA CHIARA, Vecchiet, J., Bruzzone, B., De Maria, A., Marenco, S., Nicolini, L. A., Viscoli, C., Casinelli, K., Delle Monache, M., Lichtner, Miriam, Aghemo, A., Boccaccio, V., Bruno, S., Cerrone, M., Colombo, M., D'Arminio Monforte, A., Danieli, E., Donato, F., Gubertini, G., Lleo, A., Magni, C. F., Mancon, A., Monico, S., Niero, F., Russo, M. L., Gnocchi, M., Orro, A., Milanesi, L., Baldelli, E., Bertolotti, M., Borghi, V., Mussini, C., Brancaccio, G., Gaeta, G. B., Lembo, V., Sangiovanni, V., Di Marco, V., Mazzola, A., Petta, S., D'Amico, E., Cacciatore, P., Consorte, A., Pieri, A., Polilli, E., Sozio, F., Antenucci, F., Aragri, M., Baiocchi, L., Barbaliscia, S., Biliotti, Elisa, Biolato, M., Carioti, L., Ceccherini Silberstein, F., Cerasari, G., Cerva, C., Ciotti, M., D'Ambrosio, C., D'Ettorre, G., De Leonardis, F., De Sanctis, A., Di Maio, V. C., Di Paolo, D., Furlan, Caterina, Gallo, P., Gasbarrini, A., Giannelli, V., Grieco, S., Lambiase, L., Lattanzi, B., Lenci, I., Lula, R., Malagnino, V., Manuelli, M., Miglioresi, L., Milana, M., Moretti, A., Nosotti, L., Palazzo, Donatella, Pellicelli, A., Romano, M., Sarrecchia, C., Sforza, D., Sorbo, M. C., Spaziante, M., Svicher, V., Tisone, G., Vespasiani Gentilucci, U., D'Adamo, G., Mangia, A., Maida, I., Mura, M. S., Falconi, L., Di Giammartino, D., Di Maio, V., Cento, V., Lenci, I., Aragri, M., Rossi, P., Barbaliscia, S., Melis, M., Verucchi, G., Magni, C., Teti, E., Bertoli, A., Antonucci, F., Bellocchi, M., Micheli, V., Masetti, C., Landonio, S., Francioso, S., Santopaolo, F., Pellicelli, A., Calvaruso, V., Gianserra, L., Siciliano, M., Romagnoli, D., Cozzolongo, R., Grieco, A., Vecchiet, J., Morisco, F., Merli, M., Brancaccio, G., Di Biagio, A., Loggi, E., Mastroianni, C., Pace Palitti, V., Tarquini, P., Puoti, M., Taliani, G., Sarmati, L., Picciotto, A., Vullo, V., Caporaso, N., Paoloni, M., Pasquazzi, C., Rizzardini, G., Parruti, G., Craxã¬, A., Babudieri, S., Andreoni, M., Angelico, M., Perno, C., Ceccherini-Silberstein, F., Mariani, R., Iapadre, N., Grimaldi, A., Andreone, P., Menzaghi, B., Quirino, T., Pisani, V., Torti, C., Bruzzone, B., De Maria, A., Marenco, S., Nicolini, L., Viscoli, C., Casinelli, K., Delle Monache, M., Lichtner, M., Aghemo, A., Boccaccio, V., Bruno, S., Cerrone, M., Colombo, M., D'Arminio Monforte, A., Danieli, E., Donato, F., Gubertini, G., Lleo, A., Mancon, A., Monico, S., Niero, F., Russo, M., Gnocchi, M., Orro, A., Milanesi, L., Baldelli, E., Bertolotti, M., Borghi, V., Mussini, C., Gaeta, G., Lembo, V., Sangiovanni, V., DI MARCO, V., Mazzola, A., Petta, S., D'Amico, E., Cacciatore, P., Consorte, A., Pieri, A., Polilli, E., Sozio, F., Antenucci, F., Baiocchi, L., Biliotti, E., Biolato, M., Carioti, L., Cerasari, G., Cerva, C., Ciotti, M., D'Ambrosio, C., D'Ettorre, G., De Leonardis, F., De Sanctis, A., Di Paolo, D., Furlan, C., Gallo, P., Gasbarrini, A., Giannelli, V., Grieco, S., Lambiase, L., Lattanzi, B., Lula, R., Malagnino, V., Manuelli, M., Miglioresi, L., Milana, M., Moretti, A., Nosotti, L., Palazzo, D., Romano, M., Sarrecchia, C., Sforza, D., Sorbo, M., Spaziante, M., Svicher, V., Tisone, G., Vespasiani-Gentilucci, U., D'Adamo, G., Mangia, A., Maida, I., Mura, M., Falconi, L., Di Giammartino, D., Di Maio, V, Cento, V, Lenci, I, Aragri, M, Rossi, P, Barbaliscia, S, Melis, M, Verucchi, G, Magni, C, Teti, E, Bertoli, A, Antonucci, F, Bellocchi, M, Micheli, V, Masetti, C, Landonio, S, Francioso, S, Santopaolo, F, Pellicelli, A, Calvaruso, V, Gianserra, L, Siciliano, M, Romagnoli, D, Cozzolongo, R, Grieco, A, Morisco, F, Merli, M, Brancaccio, G, Di Biagio, A, Loggi, E, Mastroianni, C, Pace Palitti, V, Tarquini, P, Puoti, M, Taliani, G, Sarmati, L, Picciotto, A, Vullo, V, Caporaso, N, Paoloni, M, Pasquazzi, C, Rizzardini, G, Parruti, G, Craxì, A, Babudieri, S, Andreoni, M, Angelico, M, Perno, C, Ceccherini-Silberstein, F, Velia C. Di Maio, Valeria Cento, Ilaria Lenci, Marianna Aragri, Piera Rossi, Silvia Barbaliscia, Michela Meli, Gabriella Verucchi, Carlo F. Magni, Elisabetta Teti, Ada Bertoli, Francesco Paolo Antonucci, Maria C. Bellocchi, Valeria Micheli, Chiara Masetti, Simona Landonio, Simona Francioso, Francesco Santopaolo, Adriano M. Pellicelli, Vincenza Calvaruso, Laura Gianserra, Massimo Siciliano, Dante Romagnoli, Raffaele Cozzolongo, Antonio Grieco, Jacopo Vecchiet, Filomena Morisco, Manuela Merli, Giuseppina Brancaccio, Antonio Di Biagio, Elisabetta Loggi, Claudio M. Mastroianni, Valeria Pace Palitti, Pierluigi Tarquini, Massimo Puoti, Gloria Taliani, Loredana Sarmati, Antonino Picciotto, Vincenzo Vullo, Nicola Caporaso, Maurizio Paoloni, Caterina Pasquazzi, Giuliano Rizzardini, Giustino Parruti, Antonio Craxì, Sergio Babudieri, Massimo Andreoni, Mario Angelico, Carlo F. Perno, Francesca Ceccherini-Silberstein, for the HCV Italian Resistance Network Study Group: [.., P. Andreone, E. Loggi, G. Verucchi, ], Di Maio, Velia C., Cento, Valeria, Lenci, Ilaria, Aragri, Marianna, Rossi, Piera, Barbaliscia, Silvia, Melis, Michela, Verucchi, Gabriella, Magni, Carlo F., Teti, Elisabetta, Bertoli, Ada, Antonucci, Francescopaolo, Bellocchi, Maria C., Micheli, Valeria, Masetti, Chiara, Landonio, Simona, Francioso, Simona, Santopaolo, Francesco, Pellicelli, Adriano M., Calvaruso, Vincenza, Gianserra, Laura, Siciliano, Massimo, Romagnoli, Dante, Cozzolongo, Raffaele, Grieco, Antonio, Vecchiet, Jacopo, Morisco, Filomena, Merli, Manuela, Brancaccio, Giuseppina, Di Biagio, Antonio, Loggi, Elisabetta, Mastroianni, Claudio M., Pace Palitti, Valeria, Tarquini, Pierluigi, Puoti, Massimo, Taliani, Gloria, Sarmati, Loredana, Picciotto, Antonino, Vullo, Vincenzo, Caporaso, Nicola, Paoloni, Maurizio, Pasquazzi, Caterina, Rizzardini, Giuliano, Parruti, Giustino, Craxã¬, Antonio, Babudieri, Sergio, Andreoni, Massimo, Angelico, Mario, Perno, Carlo F., Ceccherini-Silberstein, Francesca, Nicolini, L. A., Magni, C. F., Russo, M. L., Gaeta, G. B., Di Marco, V., Di Maio, V. C., Sorbo, M. C., Mura, M. S., Di Maio, Velia C, Magni, Carlo F, Bellocchi, Maria C, Pellicelli, Adriano M, Mastroianni, Claudio M, Craxì, Antonio, Perno, Carlo F, and Ceccherini Silberstein, Francesca

Subjects
Male, 0301 basic medicine, hepatitis C virus, Sustained Virologic Response, Sofosbuvir, Hepacivirus, Drug Resistance, resistance-associated substitutions, Viral Nonstructural Proteins, VARIANTS, NS5A, medicine.disease_cause, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, INFECTION, antiviral therapy, Medicine, hepatitis C viru, Viral, Treatment Failure, Chronic, direct-acting antivirals, resistance test, hepatology, biology, GENOTYPE 1, virus diseases, Middle Aged, Settore MED/07 - Microbiologia e Microbiologia Clinica, Hepatitis C, Italy, Combination, Interferon, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Author Keywords:antiviral therapy, RIBAVIRIN, Sequence Analysis, Human, medicine.drug, medicine.medical_specialty, Daclatasvir, Genotype, Hepatitis C virus, Antiviral Agents, LONG-TERM PERSISTENCE, DACLATASVIR, 03 medical and health sciences, Drug Therapy, Aged, Drug Resistance, Viral, Hepatitis C, Chronic, Humans, Interferons, Mutation, Ribavirin, Sequence Analysis, DNA, Hepatology, TREATMENT-NAIVE, Internal medicine, Antiviral Agent, resistance-associated substitution, direct-acting antiviral, Hepaciviru, resistance test KeyWords Plus:HEPATITIS-C VIRUS, business.industry, Viral Nonstructural Protein, DNA, biology.organism_classification, Clinical trial, 030104 developmental biology, SOFOSBUVIR, chemistry, Sequence Analysi, Immunology, business
Abstract

Background & Aims: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures. Methods: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N= 200) and whenever possible at baseline (N= 70). Results: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P= 2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure. Conclusions: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.

Published
2017

8. Effect of S-adenosyl-L-methionine and dilinoleoylphosphatidylcholine on liver lipid composition and ethanol hepatotoxicity in isolated perfused rat liver

Author

Gigliozzi, A., Romeo, R., Fraioli, F., Cantafora, A., DELLE MONACHE, M., Cardilli, A., Attili, Adolfo Francesco, Scafato, E., Carli, L., and Alvaro, Domenico

Subjects
Male, S-Adenosylmethionine, S-adenosyl-L-methionine, Ethanol, Phosphatidylethanolamines, In Vitro Techniques, isolated perfused rat liver, Glutathione, Lipids, dilinoleoylphosphatidylcholine, Rats, Cholesterol, Oxygen Consumption, Liver, Microsomes, Liver, Phosphatidylcholines, ethanol, bile secretion, S-adenosyl-L-methionine, dilinoleoylphosphatidylcholine, isolated perfused rat liver, Animals, Bile, Rats, Wistar, bile secretion, Phospholipids
Abstract

We investigated whether S-adenosyl-L-methionine (SAMe), dilinoleoylphosphatidylcholine (DLPC), or SAMe + DLPC influence liver lipid composition as well as acute ethanol hepatotoxicity in the isolated perfused rat liver (IPRL). SAMe (25 mg/kg intramuscularly three times a day) was administered for five consecutive days, while DLPC was administered intraperitoneally for five days. The liver was then isolated, perfused with taurocholate to stabilize bile secretion, and exposed to 0.5% ethanol for 70 min. SAMe, without changing total phospholipid (PL) content, induced an increase in the phosphatidylcholine/phosphatidylethanolamine (PC/PE) molar ratio in both liver homogenate and microsomes and a significant enrichment of 16:0-20:4 and 18:0-20:4 PC molecular species. DLPC induced a significant enrichment of PL in liver homogenate and microsomes due to a contemporary increase in PC and PE. The PC enrichment specifically involved 16:0-20:4 and 18:0-20:4 PC molecular species besides the HPLC peak containing the administered 18:2-18:2 PC species. DLPC + SAMe increased the concentration of PC in liver homogenate and microsomes due to a specific enrichment of 16:0-22:6, 16:0-20:4, and 18:0-20:4 PC molecular species, and the HPLC peak containing the administered 18:2-18:2 PC species. Ethanol acute exposure in the control IPRLs for 70 min induced a depletion of cholesterol in both liver homogenate and microsomes without significant changes in the composition of PL classes and PC molecular species. SAMe, DLPC, or SAMe + DLPC counteracted the cholesterol depletion induced by ethanol, indicating that phospholipid changes promoted by these treatments all induce a major resistance of liver membranes to the effect of ethanol. Ethanol administration in control IPRLs induced a fivefold increase of AST and LDH release in the perfusate, depletion of glutathione in homogenates and mitochondria, decreased oxygen liver consumption, and inhibition of bile flow. These effects of ethanol were significantly antagonized by SAMe. In contrast, DLPC alone only minimally attenuated enzyme release in the perfusate and the inhibitory effect of ethanol on bile flow, but it failed to influence the depletion of total and mitochondrial glutathione or the depressed oxygen consumption induced by ethanol. DLPC, administered together with SAMe, added nothing to the protective effect of SAMe against ethanol hepatotoxicity and cholestasis. In conclusion, this study demonstrates that both SAMe and DLPC induced marked modifications in the lipid composition of liver membranes with a similar enrichment of polyunsaturated PC molecular species. Only SAMe, however, significantly protected against the hepatotoxic and cholestatic effect of acute ethanol administration, an effect associated with maintained normal glutathione mitochondrial levels and oxygen liver consumption. This indicates that the protective effect of SAMe against ethanol toxicity is linked to multiple mechanisms, the maintenance of glutathione levels probably being one of the most important.

Published
1998

10. Hormonal regulation of bicarbonate secretion in the biliary epithelium

Author

Domenico Alvaro, Gigliozzi A, Fraioli F, Romeo R, Papa E, Delle Monache M, and Capocaccia L

Subjects
Ion Transport, Cystic Fibrosis Transmembrane Conductance Regulator, digestive system, digestive system diseases, Antiporters, Epithelium, Hormones, Bicarbonates, Electrolytes, Animals, Bile, Humans, Calcium, Chloride-Bicarbonate Antiporters, Biliary Tract, hormones, hormone substitutes, and hormone antagonists, Adenylyl Cyclases, Research Article
Abstract

Bicarbonate excretion in bile is a major function of the biliary epithelium. It is driven by the apically located Cl-/HCO3- exchanger which is functionally coupled with a cAMP-dependent Cl- channel (CFTR). A number of hormones and/or neuropeptides with different mechanisms and at different intracellular levels regulate, in concert, the processes underlying bicarbonate excretion in the biliary epithelium. Secretin induces a bicarbonate rich choleresis by stimulating the activity of the Cl-/HCO3- exchanger by cAMP and protein kinase A mediated phosphorylation of CFTR regulatory domain. Protein phosphatase 1/2A are involved in the run-down of secretory stimulus after secretin removal. Acetylcholine potentiates secretin-choleresis by inducing a Ca(++)-calcineurin mediated "sensitization" of adenyl cyclase to secretin. Bombesin and vasoactive intestinal peptide also enhance the Cl-/HCO3- exchanger activity, but the intracellular signal transduction pathway has not yet been defined. Somatostatin and gastrin inhibit basal and/or secretin-stimulated bicarbonate excretion by down-regulating the secretin receptor and decreasing cAMP intracellular levels induced by secretin.

Published
1997

13. [527] THE EXTENT OF RIBAVIRIN-INDUCED HAEMOLYSIS DURING TREATMENT FOR HEPATITIS C IS UNRELATED TO ADMINISTERED DOSE, RATHER DEPENDS ON BASELINE HAEMOGLOBIN LEVEL AND DRUG ERYTHROCYTE CONCENTRATION

Author

Baiocchi, L., primary, Longhi, C., additional, Delle Monache, M., additional, Nosotti, L., additional, Morrone, A., additional, Conti, L.R., additional, Telesca, C., additional, Carbone, M., additional, De Leonardis, F., additional, and Angelico, M., additional

Published
2007
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18. Effect of pharmacological modulation of liver P-glycoproteins on cyclosporin A biliary excretion and cholestasis: a study in isolated perfused rat liver.

Author

Delle Monache, M D, Gigliozzi, A, Benedetti, A, Marucci, L, Bini, A, Francia, C, Papa, E, Di Cosimo, E, Fraioli, F, Jezequel, A M, and Alvaro, D

Subjects
ANIMAL experimentation, ANIMALS, BILE, CARCINOGENS, CHOLESTASIS, CYCLOSPORINE, GLYCOPROTEINS, IMMUNOSUPPRESSIVE agents, LIVER, PERFUSION, RATS, TIME, VERAPAMIL, PHARMACODYNAMICS
Abstract

In different cell types P-glycoproteins (P-gp) are involved in the transport of cyclosporin A (CyA). The aim of this study was to evaluate the effect of the pharmacological modulation of the hepatic P-gp on biliary secretion of CyA and on cholestasis induced by acute administration of CyA in the isolated perfused rat liver (IPRL). Verapamil was used as a P-gp specific inhibitor and acetylaminofluorene (AAF) as a P-gp inducer. CyA biliary excretion was determined by administering in the IPRL a tracer dose of [3H]CyA with or without verapamil or AAF. The effect on bile flow was evaluated by administering increasing doses of CyA (2.8, 8, and 20 mg/kg body wt) in the IPRL. Morphological evidence of damage was evaluated by optical and electron microscopy in the liver as well as in primary culture of rat hepatocytes exposed to CyA +/- verapamil. Verapamil significantly inhibited the biliary excretion of a tracer dose of [3H]CyA (0.15+/-0.04 vs 0.33+/-0.07%; P < 0.05). In contrast, pretreatment with AAF significantly increased the biliary excretion of [3H]CyA, (0.61+/-0.10 vs 0.33+/-0.07%; P < 0.05). CyA induced a dose-dependent inhibition of bile flow with a maximal effect at 20 mg/kg CyA (-49.3+/-4.5% decrease of basal bile flow). CyA cholestasis was significantly worsened by the P-gp inhibitor, verapamil (-75.5+/-7.5%; P < 0.05), but it was unaffected by induction of P-gp via AAF pretreatment (-44.9+/-1.7%). During CyA cholestasis, the cumulative biliary excretion of [3H]CyA was lower than in the absence of cholestasis (0.22+/-0.05 vs 0.33+/-0.07%; P < 0.05), was inhibited by verapamil (0.08+/-0.01%; P < 0.05), but was unaffected by AAF (0.23+/-0.05%). No morphological evidence of damage was observed in the liver, and no evidence of cytoskeleton derangement was seen in primary cultures of rat hepatocytes exposed to CyA +/- verapamil. We demonstrated that pharmacological modulation of P-gp may influence the biliary excretion of CyA. The acute cholestatic effect of CyA is worsened by P-gp inhibitors, while it is unaffected by P-gp inducers. This indicates CyA should not be given with other P-gp substrates or inhibitors. [ABSTRACT FROM AUTHOR]

Published
1999

19. Effect of pharmacological modulation of liver P-glycoproteins on cyclosporin A biliary excretion and cholestasis: A study in isolated perfused rat liver

Author

Delle Monache, M., Gigliozzi, A., Antonio Benedetti, Marucci, L., Bini, A., Francia, C., Papa, E., Di Cosimo, E., Fraioli, F., Jezequel, A. M., and Alvaro, D.

Subjects
Male, ATP Binding Cassette Transporter, Subfamily B, Cholestasis, Time Factors, 2-Acetylaminofluorene, Rats, Perfusion, Liver, Verapamil, Cyclosporine, Animals, Bile, Rats, Wistar, Immunosuppressive Agents
Abstract

In different cell types P-glycoproteins (P-gp) are involved in the transport of cyclosporin A (CyA). The aim of this study was to evaluate the effect of the pharmacological modulation of the hepatic P-gp on biliary secretion of CyA and on cholestasis induced by acute administration of CyA in the isolated perfused rat liver (IPRL). Verapamil was used as a P-gp specific inhibitor and acetylaminofluorene (AAF) as a P-gp inducer. CyA biliary excretion was determined by administering in the IPRL a tracer dose of [3H]CyA with or without verapamil or AAF. The effect on bile flow was evaluated by administering increasing doses of CyA (2.8, 8, and 20 mg/kg body wt) in the IPRL. Morphological evidence of damage was evaluated by optical and electron microscopy in the liver as well as in primary culture of rat hepatocytes exposed to CyA +/- verapamil. Verapamil significantly inhibited the biliary excretion of a tracer dose of [3H]CyA (0.15+/-0.04 vs 0.33+/-0.07%; P0.05). In contrast, pretreatment with AAF significantly increased the biliary excretion of [3H]CyA, (0.61+/-0.10 vs 0.33+/-0.07%; P0.05). CyA induced a dose-dependent inhibition of bile flow with a maximal effect at 20 mg/kg CyA (-49.3+/-4.5% decrease of basal bile flow). CyA cholestasis was significantly worsened by the P-gp inhibitor, verapamil (-75.5+/-7.5%; P0.05), but it was unaffected by induction of P-gp via AAF pretreatment (-44.9+/-1.7%). During CyA cholestasis, the cumulative biliary excretion of [3H]CyA was lower than in the absence of cholestasis (0.22+/-0.05 vs 0.33+/-0.07%; P0.05), was inhibited by verapamil (0.08+/-0.01%; P0.05), but was unaffected by AAF (0.23+/-0.05%). No morphological evidence of damage was observed in the liver, and no evidence of cytoskeleton derangement was seen in primary cultures of rat hepatocytes exposed to CyA +/- verapamil. We demonstrated that pharmacological modulation of P-gp may influence the biliary excretion of CyA. The acute cholestatic effect of CyA is worsened by P-gp inhibitors, while it is unaffected by P-gp inducers. This indicates CyA should not be given with other P-gp substrates or inhibitors.

21. Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study

Author

Petta, Salvatore, Marzioni, Marco, Russo, Pierluigi, Aghemo, Alessio, Alberti, Alfredo, ASCIONE, ANTONIO, Antinori, Andrea, Bruno, Raffaele, Bruno, Savino, Chirianni, Antonio, Gaeta, Giovanni Battista, Giannini, Edoardo G, Merli, Manuela, Messina, Vincenzo, Montilla, Simona, Perno, Carlo Federico, Puoti, Massimo, Raimondo, Giovanni, Rendina, Maria, Silberstein, Francesca Ceccherini, Villa, Erica, Zignego, Anna Linda, Pani, Luca, Craxì, Antonio, Tabone, Marco, Andreoni, Massimo, Teti, Elisabetta, Angelico, Mario, Persico, Marcello, Masarone, Mario, Chiodera, Aledssandro, Solinas, Attilio, delle Monache, Marco, Cecere, Roberto, Maria Schimizzi, Anna, Piovesan, Sara, Campagnolo, Davide, Chiara Piras, Maria, Zolfino, Teresa, Paolo Russo, Francesca, Morelli, Olivia, Sangiovanni, Vincenzo, Onofrio, Mirella, Iodice, Valentina, Izzi, Antonio, Pirisi, Massimo, Danieli, Elena, Vinci, Maria, Rizzardini, Giuliano, Fagiuoli, Stefano, Pasulo, Luisa, D'Arminio Monforte, Antonella, Zuin, Massimo, Giorgini, Alessia, Simeone, Filomena, Piali, Guido, Lo Guercio, Carmela, Federico, Alessandro, Brancaccio, Giuseppina, Marrone, Aldo, Abbati, Giuseppe, Boarini, Chiara, Borghi, Vanni, Bernabucci, Veronica, Corti, Giampaolo, Monti, Monica, Rizzetto, Mario, Martini, Silvia, Andreone, Pietro, Gianstefani, Alice, Lenzi, Marco, Verucchi, Gabriella, Toniutto, Pierluigi, Borgia, Guglielmo, Caporaso, Nicola, Morisco, Filomena, Nardone, Gaetano, Angrisani, Debora, Giacometti, Andrea, Benedetti, Antonio, Tarantino, Giuseppe, Marsetti, Fabio, Tavio, Marcello, Novara, Sergio, Antonia Santantonio, Teresa, Serviddio, Gaetano, Brunetto, Maurizia, Coco, Barbara, Angarano, Gioacchino, Milella, Michele, BARONE, MICHELE, Di Leo, Alfredo, Ettore Sansonno, Domenico, Cacciola, Irene, Boffa, Nicola, Saracco, Giorgio, Di Biagio, Antonio, Picciotto, Antonino, de Luca, Andrea, Calvaruso, Vincenza, Corradori, Silvia, Ferrari, Carlo, Orlandini, Alessandra, Maida, Ivana, Torti, Carlo, Chessa, Luchino, Felder, Martina, Vespasiani Gentilucci, Umberto, Angeli, Paolo, Romano, Antonietta, Ludovico Rapaccini, Gian, Miele, Luca, Cima, Serena, Luisa Russo, Maria, Cozzolongo, Raffaele, Onnelli, Giovanna, D'Offizi, Giampiero, Lionetti, Raffaella, Montalbano, Marzia, Guerra, Michele, Di Perri, Giovanni, Boglione, Lucio, Capra, Franco, Carolo, Giada, Ieluzzi, Donatella, Antonini, Cinzia, Termite, Antonio, Madonia, Salvatore, Tarquini, Pierluigi, Parruti, Giustino, Vecchiet, Giacomo, Falasca, Katia, Menzaghi, Barbara, Quirino, Tiziana, Dentone, Chiara, Maria Piscaglia, Anna, Rossi, Cristina, Giordani, Maria, Fontanella, Luca, Cassola, Giovanni, Russello, Maurizio, Cristaudo, Antonio, Giacomet, Vania, Colombo, Massimo, Donato, Francesca, Durante, Emanuele, Cosco, Lucio, Marignani, Massimo, Quartini, Mariano, Memoli, Massimo, Ganga, Roberto, Ponti, Laura, Soria, Alessandro, Grazia Rumi, Maria, Gulminetti, Roberto, Maserati, Renato, Mondelli, Mario, Lazzarin, Adriano, Rita Parisi, Maria, Canovari, Benedetta, Avancini, Ivo, Pravadelli, Cecilia, Blanc, Pier, Pasquazzi, Caterina, Maria Mastroianni, Claudio, Lichtner, Myriam, Distefano, Marco, Magnani, Silvia, Paganin, Simona, Erne, Elke, Gatti, Pietro, Tundi, Paolo, Calabrese, Paolo, Gasbarrini, Antonio, Grieco, Antonio, Coppola, Nicola, Del Poggio, Paolo, Levrero, Massimo, Talliani, Gloria, Vullo, Vincenzo, Cauda, Roberto, La Monica, Silvia, Potenza, Domenico, Rizzo, Salvatore, Castelli, Francesco, Marie Pigozzi, Grazielle, Ciancio, Alessia, Romagnoli, Dante, Barchetti, Federica, Ivanovic, Jelena, Longo, Olimpia, Petraglia, Sandra, Paola Trotta, Maria, NARDONE, GERARDO ANTONIO PIO, Petta, Salvatore, Marzioni, Marco, Russo, Pierluigi, Aghemo, Alessio, Alberti, Alfredo, Ascione, Antonio, Antinori, Andrea, Bruno, Raffaele, Bruno, Savino, Chirianni, Antonio, Gaeta, Giovanni Battista, Giannini, Edoardo G, Merli, Manuela, Messina, Vincenzo, Montilla, Simona, Perno, Carlo Federico, Puoti, Massimo, Raimondo, Giovanni, Rendina, Maria, Silberstein, Francesca Ceccherini, Villa, Erica, Zignego, Anna Linda, Pani, Luca, Craxì, Antonio, Tabone, Marco, Andreoni, Massimo, Teti, Elisabetta, Angelico, Mario, Persico, Marcello, Masarone, Mario, Chiodera, Aledssandro, Solinas, Attilio, delle Monache, Marco, Cecere, Roberto, Maria Schimizzi, Anna, Piovesan, Sara, Campagnolo, Davide, Chiara Piras, Maria, Zolfino, Teresa, Paolo Russo, Francesca, Morelli, Olivia, Sangiovanni, Vincenzo, Onofrio, Mirella, Iodice, Valentina, Izzi, Antonio, Pirisi, Massimo, Danieli, Elena, Vinci, Maria, Rizzardini, Giuliano, Fagiuoli, Stefano, Pasulo, Luisa, D'Arminio Monforte, Antonella, Zuin, Massimo, Giorgini, Alessia, Simeone, Filomena, Piali, Guido, Lo Guercio, Carmela, Federico, Alessandro, Brancaccio, Giuseppina, Marrone, Aldo, Abbati, Giuseppe, Boarini, Chiara, Borghi, Vanni, Bernabucci, Veronica, Corti, Giampaolo, Monti, Monica, Rizzetto, Mario, Martini, Silvia, Andreone, Pietro, Gianstefani, Alice, Lenzi, Marco, Verucchi, Gabriella, Toniutto, Pierluigi, Borgia, Guglielmo, Caporaso, Nicola, Morisco, Filomena, Nardone, Gaetano, Angrisani, Debora, Giacometti, Andrea, Benedetti, Antonio, Tarantino, Giuseppe, Marsetti, Fabio, Tavio, Marcello, Novara, Sergio, Antonia Santantonio, Teresa, Serviddio, Gaetano, Brunetto, Maurizia, Coco, Barbara, Angarano, Gioacchino, Milella, Michele, Barone, Michele, Di Leo, Alfredo, Ettore Sansonno, Domenico, Cacciola, Irene, Boffa, Nicola, Saracco, Giorgio, Di Biagio, Antonio, Picciotto, Antonino, de Luca, Andrea, Calvaruso, Vincenza, Corradori, Silvia, Ferrari, Carlo, Orlandini, Alessandra, Maida, Ivana, Torti, Carlo, Chessa, Luchino, Felder, Martina, Vespasiani Gentilucci, Umberto, Angeli, Paolo, Romano, Antonietta, Ludovico Rapaccini, Gian, Miele, Luca, Cima, Serena, Luisa Russo, Maria, Cozzolongo, Raffaele, Onnelli, Giovanna, D'Offizi, Giampiero, Lionetti, Raffaella, Montalbano, Marzia, Guerra, Michele, Di Perri, Giovanni, Boglione, Lucio, Capra, Franco, Carolo, Giada, Ieluzzi, Donatella, Antonini, Cinzia, Termite, Antonio, Madonia, Salvatore, Tarquini, Pierluigi, Parruti, Giustino, Vecchiet, Giacomo, Falasca, Katia, Menzaghi, Barbara, Quirino, Tiziana, Dentone, Chiara, Maria Piscaglia, Anna, Rossi, Cristina, Giordani, Maria, Fontanella, Luca, Cassola, Giovanni, Russello, Maurizio, Cristaudo, Antonio, Giacomet, Vania, Colombo, Massimo, Donato, Francesca, Durante, Emanuele, Cosco, Lucio, Marignani, Massimo, Quartini, Mariano, Memoli, Massimo, Ganga, Roberto, Ponti, Laura, Soria, Alessandro, Grazia Rumi, Maria, Gulminetti, Roberto, Maserati, Renato, Mondelli, Mario, Lazzarin, Adriano, Rita Parisi, Maria, Canovari, Benedetta, Avancini, Ivo, Pravadelli, Cecilia, Blanc, Pier, Pasquazzi, Caterina, Maria Mastroianni, Claudio, Lichtner, Myriam, Distefano, Marco, Magnani, Silvia, Paganin, Simona, Erne, Elke, Gatti, Pietro, Tundi, Paolo, Calabrese, Paolo, Gasbarrini, Antonio, Grieco, Antonio, Coppola, Nicola, Del Poggio, Paolo, Levrero, Massimo, Talliani, Gloria, Vullo, Vincenzo, Cauda, Roberto, La Monica, Silvia, Potenza, Domenico, Rizzo, Salvatore, Castelli, Francesco, Marie Pigozzi, Grazielle, Ciancio, Alessia, Romagnoli, Dante, Barchetti, Federica, Ivanovic, Jelena, Longo, Olimpia, Petraglia, Sandra, Paola Trotta, Maria, Petta, S., Marzioni, M., Russo, P., Aghemo, A., Alberti, A., Ascione, A., Antinori, A., Bruno, R., Bruno, S., Chirianni, A., Gaeta, G., Giannini, E., Merli, M., Messina, V., Montilla, S., Perno, C., Puoti, M., Raimondo, G., Rendina, M., Silberstein, F., Villa, E., Zignego, A., Pani, L., Craxi, A., Tabone, M., Andreoni, M., Teti, E., Angelico, M., Persico, M., Masarone, M., Chiodera, A., Solinas, A., delle Monache, M., Cecere, R., Maria Schimizzi, A., Piovesan, S., Campagnolo, D., Chiara Piras, M., Zolfino, T., Paolo Russo, F., Morelli, O., Sangiovanni, V., Onofrio, M., Iodice, V., Izzi, A., Pirisi, M., Danieli, E., Vinci, M., Rizzardini, G., Fagiuoli, S., Pasulo, L., D'Arminio Monforte, A., Zuin, M., Giorgini, A., Simeone, F., Piali, G., Lo Guercio, C., Federico, A., Brancaccio, G., Marrone, A., Abbati, G., Boarini, C., Borghi, V., Bernabucci, V., Corti, G., Monti, M., Rizzetto, M., Martini, S., Andreone, P., Gianstefani, A., Lenzi, M., Verucchi, G., Toniutto, P., Borgia, G., Caporaso, N., Morisco, F., Nardone, G., Angrisani, D., Giacometti, A., Benedetti, A., Tarantino, G., Marsetti, F., Tavio, M., Novara, S., Antonia Santantonio, T., Serviddio, G., Brunetto, M., Coco, B., Angarano, G., Milella, M., Barone, M., Di Leo, A., Ettore Sansonno, D., Cacciola, I., Boffa, N., Saracco, G., Di Biagio, A., Picciotto, A., de Luca, A., Calvaruso, V., Corradori, S., Ferrari, C., Orlandini, A., Maida, I., Torti, C., Chessa, L., Felder, M., Vespasiani Gentilucci, U., Angeli, P., Romano, A., Ludovico Rapaccini, G., Miele, L., Cima, S., Luisa Russo, M., Cozzolongo, R., Onnelli, G., D'Offizi, G., Lionetti, R., Montalbano, M., Guerra, M., Di Perri, G., Boglione, L., Capra, F., Carolo, G., Ieluzzi, D., Antonini, C., Termite, A., Madonia, S., Tarquini, P., Parruti, G., Vecchiet, G., Falasca, K., Menzaghi, B., Quirino, T., Dentone, C., Maria Piscaglia, A., Rossi, C., Giordani, M., Fontanella, L., Cassola, G., Russello, M., Cristaudo, A., Giacomet, V., Colombo, M., Donato, F., Durante, E., Cosco, L., Marignani, M., Quartini, M., Memoli, M., Ganga, R., Ponti, L., Soria, A., Grazia Rumi, M., Gulminetti, R., Maserati, R., Mondelli, M., Lazzarin, A., Rita Parisi, M., Canovari, B., Avancini, I., Pravadelli, C., Blanc, P., Pasquazzi, C., Maria Mastroianni, C., Lichtner, M., Distefano, M., Magnani, S., Paganin, S., Erne, E., Gatti, P., Tundi, P., Calabrese, P., Gasbarrini, A., Grieco, A., Coppola, N., Del Poggio, P., Levrero, M., Talliani, G., Vullo, V., Cauda, R., La Monica, S., Potenza, D., Rizzo, S., Castelli, F., Marie Pigozzi, G., Ciancio, A., Romagnoli, D., Barchetti, F., Ivanovic, J., Longo, O., Petraglia, S., Paola Trotta, M., Savino, Bruno, Nardone, GERARDO ANTONIO PIO, Petta, S, Marzioni, M, Russo, P, Aghemo, A, Alberti, A, Ascione, A, Antinori, A, Bruno, R, Bruno, S, Chirianni, A, Gaeta, G, Giannini, E, Merli, M, Messina, V, Montilla, S, Perno, C, Puoti, M, Raimondo, G, Rendina, M, Silberstein, F, Villa, E, Zignego, A, Pani, L, Craxì, A, and Fagiuoli, S

Subjects
Cyclopropanes, Compassionate Use Trials, Liver Cirrhosis, Male, chemistry.chemical_compound, 0302 clinical medicine, 2-Naphthylamine, HCV, direct-acting antiviral, mixed cryoglobulinemia, RBV, Anilides, 030212 general & internal medicine, Longitudinal Studies, Prospective Studies, Chronic, Adult, Aged, Antiviral Agents, Carbamates, Drug Therapy, Combination, Female, Genotype, Hepatitis C, Chronic, Humans, Macrocyclic Compounds, Middle Aged, Ribavirin, Ritonavir, Sulfonamides, Treatment Outcome, Uracil, Settore MED/12 - Gastroenterologia, Dasabuvir, HCV DAA, Gastroenterology, virus diseases, Valine, Settore MED/07 - Microbiologia e Microbiologia Clinica, Hepatitis C, Hepatology, Combination, 030211 gastroenterology & hepatology, medicine.drug, medicine.medical_specialty, Proline, Lactams, Macrocyclic, Hepatitis C virus genotype 1, Hepatitis C virus genotype 4, decompensated liver cirrhosis, antiviral therapy, dasabuvir, ombitasvir, paritaprevir, 03 medical and health sciences, Drug Therapy, Internal medicine, medicine, Decompensation, Adverse effect, business.industry, Virology, Ombitasvir, Clinical trial, chemistry, Paritaprevir, business
Abstract

Summary Background We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy. Methods In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study. Findings 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83–12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients. Interpretation Our findings suggest that the safety and effectiveness of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin in patients with HCV genotype 1 or 4 infection and cirrhosis at high risk of decompensation in a real-life setting are similar to those reported in clinical trials. The concordance with clinical trials provides reassurance that the reported efficacy of this treatment in clinical trials will translate to its use in routine clinical practice. Funding Dipartimento Biomedico di Medicina Interna e Specialistica dell'Universita di Palermo.

Published
2017

22. HCV NS3 sequencing as a reliable and clinically useful tool for the assessment of genotype and resistance mutations for clinical samples with different HCV-RNA levels

Author

Di Maio, V C, Cento, V, Di Paolo, D, Aragri, M, De Leonardis, F, Tontodonati, M, Micheli, V, Bellocchi, M C, Antonucci, F P, Bertoli, A, Lenci, I, Milana, M, Gianserra, L, Melis, M, Di Biagio, A, Sarrecchia, C, Sarmati, L, Landonio, S, Francioso, S, Lambiase, L, Nicolini, L A, Marenco, S, Nosotti, L, Giannelli, V, Siciliano, M, Romagnoli, D, Pellicelli, A, Vecchiet, J, Magni, C F, Babudieri, S, Mura, M S, Taliani, G, Mastroianni, C, Vespasiani-Gentilucci, U, Romano, M, Morisco, F, Gasbarrini, A, Vullo, V, Bruno, S, Baiguera, C, Pasquazzi, C, Tisone, G, Picciotto, A, Andreoni, M, Parruti, G, Rizzardini, G, Angelico, M, Perno, C F, Ceccherini-Silberstein, F, Collaborators (129) Mariani R, HCV Italian Resistance Network Study Group., Paoloni, M, Iapadre, N, Grimaldi, A, Menzaghi, B, Quirino, T, Bruzzone, B, De Maria, A, Nicolini, La, Viscoli, C, Casinelli, K, Monache, Md, Lichtner, M, Aghemo, A, Cerrone, M, Colombo, M, Monforte, Ad, Danieli, E, Donato, F, Gubertini, G, Magni, Cf, Mancon, A, Monico, S, Niero, F, Puoti, M, Russo, Ml, Alfieri, R, Gnocchi, M, Orro, A, Milanesi, L, Baldelli, E, Bertolotti, M, Borghi, V, Mussini, C, Brancaccio, G, Caporaso, N, Gaeta, Gb, Lembo, V, Calvaruso, V, Craxì, A, Di Marco, V, Mazzola, A, Petta, S, D'Amico, E, Cacciatore, P, Consorte, A, Palitti, Vp, Pieri, A, Polilli, E, Antenucci, F, Antonucci, Fp, Armenia, D, Baiocchi, L, Bellocchi, M, Biliotti, E, Biolato, M, Carioti, L, Cerasari, G, Cerva, C, Ciotti, M, D'Ambrosio, C, D'Ettorre, G, De Sanctis, A, Di Maio VC, Furlan, C, Gallo, P, Grieco, A, Grieco, S, Lattanzi, B, Malagnino, V, Manuelli, M, Merli, M, Miglioresi, L, Palazzo, D, Perno, Cf, Santopaolo, F, Santoro, Mm, Sforza, D, Sorbo, Mc, Spaziante, M, Svicher, V, Teti, E, Mangia, A, Maida, I, Mura, Ms, Falconi, L, Di Giammartino, D, Tarquini, P., Di Maio, V C, Cento, V, Di Paolo, D, Aragri, M, De Leonardis, F, Tontodonati, M, Micheli, V, Bellocchi, M C, Antonucci, F P, Bertoli, A, Lenci, I, Milana, M, Gianserra, L, Melis, M, Di Biagio, A, Sarrecchia, C, Sarmati, L, Landonio, S, Francioso, S, Lambiase, L, Nicolini, L A, Marenco, S, Nosotti, L, Giannelli, V, Siciliano, M, Romagnoli, D, Pellicelli, A, Vecchiet, J, Magni, C F, Babudieri, S, Mura, M S, Taliani, G, Mastroianni, C, Vespasiani-Gentilucci, U, Romano, M, Morisco, F, Gasbarrini, A, Vullo, V, Bruno, S, Baiguera, C, Pasquazzi, C, Tisone, G, Picciotto, A, Andreoni, M, Parruti, G, Rizzardini, G, Angelico, M, Perno, C F, Ceccherini-Silberstein, F, HCV Italian Resistance Network Study Group., Collaborators (129) Mariani R, Paoloni, M, Iapadre, N, Grimaldi, A, Menzaghi, B, Quirino, T, Bruzzone, B, De Maria, A, Nicolini, La, Viscoli, C, Casinelli, K, Monache, Md, Lichtner, M, Aghemo, A, Cerrone, M, Colombo, M, Monforte, Ad, Danieli, E, Donato, F, Gubertini, G, Magni, Cf, Mancon, A, Monico, S, Niero, F, Puoti, M, Russo, Ml, Alfieri, R, Gnocchi, M, Orro, A, Milanesi, L, Baldelli, E, Bertolotti, M, Borghi, V, Mussini, C, Brancaccio, G, Caporaso, N, Gaeta, Gb, Lembo, V, Calvaruso, V, Craxì, A, Di Marco, V, Mazzola, A, Petta, S, D'Amico, E, Cacciatore, P, Consorte, A, Palitti, Vp, Pieri, A, Polilli, E, Antenucci, F, Antonucci, Fp, Armenia, D, Baiocchi, L, Bellocchi, M, Biliotti, E, Biolato, M, Carioti, L, Cerasari, G, Cerva, C, Ciotti, M, D'Ambrosio, C, D'Ettorre, G, De Sanctis, A, Di Maio, Vc, Furlan, C, Gallo, P, Grieco, A, Grieco, S, Lattanzi, B, Malagnino, V, Manuelli, M, Merli, M, Miglioresi, L, Palazzo, D, Perno, Cf, Santopaolo, F, Santoro, Mm, Sforza, D, Sorbo, Mc, Spaziante, M, Svicher, V, Teti, E, Mangia, A, Maida, I, Mura, M, Falconi, L, Di Giammartino, D, Tarquini, P., Di Maio, V. C, Bellocchi, M. C, Antonucci, F. P, Nicolini, L. A, Magni, C. F, Mura, M. S, Vespasiani Gentilucci, U, Morisco, Filomena, Perno, C. F, Ceccherini Silberstein, F., Caporaso, Nicola, Di Maio, V., Cento, V., Di Paolo, D., Aragri, M., De Leonardis, F., Tontodonati, M., Micheli, V., Bellocchi, M., Antonucci, F., Bertoli, A., Lenci, I., Milana, M., Gianserra, L., Melis, M., Di Biagio, A., Sarrecchia, C., Sarmati, L., Landonio, S., Francioso, S., Lambiase, L., Nicolini, L., Marenco, S., Nosotti, L., Giannelli, V., Siciliano, M., Romagnoli, D., Pellicelli, A., Vecchiet, J., Magni, C., Babudieri, S., Mura, M., Taliani, G., Mastroianni, C., Vespasiani-Gentilucci, U., Romano, M., Morisco, F., Gasbarrini, A., Vullo, V., Bruno, S., Baiguera, C., Pasquazzi, C., Tisone, G., Picciotto, A., Andreoni, M., Parruti, G., Rizzardini, G., Angelico, M., Perno, C., Ceccherini-Silberstein, F., Mariani, R., Paoloni, M., Iapadre, N., Grimaldi, A., Menzaghi, B., Quirino, T., Bruzzone, B., De Maria, A., Viscoli, C., Casinelli, K., Delle Monache, M., Lichtner, M., Aghemo, A., Cerrone, M., Colombo, M., D'Arminio Monforte, A., Danieli, E., Donato, F., Gubertini, G., Mancon, A., Monico, S., Niero, F., Puoti, M., Russo, M., Alfieri, R., Gnocchi, M., Orro, A., Milanesi, L., Baldelli, E., Bertolotti, M., Borghi, V., Mussini, C., Brancaccio, G., Caporaso, N., Gaeta, G., Lembo, V., Calvaruso, V., Craxã­, A., DI MARCO, V., Mazzola, A., Petta, S., D'Amico, E., Cacciatore, P., Consorte, A., Pace Palitti, V., Pieri, A., Polilli, E., Antenucci, F., Armenia, D., Baiocchi, L., Biliotti, E., Biolato, M., Carioti, L., Cerasari, G., Cerva, C., Ciotti, M., D'Ambrosio, C., D'Ettorre, G., De Sanctis, A., Furlan, C., Gallo, P., Grieco, A., Grieco, S., Lattanzi, B., Malagnino, V., Manuelli, M., Merli, M., Miglioresi, L., Palazzo, D., Santopaolo, F., Santoro, M., Sforza, D., Sorbo, M., Spaziante, M., Svicher, V., Teti, E., Mangia, A., Maida, I., Falconi, L., and Di Giammartino, D.

Subjects
0301 basic medicine, ns3, Genotyping Techniques, viruses, Drug Resistance, Hepacivirus, Viral Nonstructural Proteins, medicine.disease_cause, Gastroenterology, Telaprevir, chemistry.chemical_compound, genotype, genotyping techniques, hepacivirus, hepatitis C, humans, RNA viral, retrospective studies, sequence analysis, DNA, viral nonstructural proteins, drug resistance, viral, mutation, pharmacology, infectious diseases, 0302 clinical medicine, Retrospective Studie, Genotype, Pharmacology (medical), Viral, Hepatitis C, Humans, RNA, Viral, Retrospective Studies, Sequence Analysis, DNA, Drug Resistance, Viral, Mutation, Proteolytic enzymes, virus diseases, Settore MED/07 - Microbiologia e Microbiologia Clinica, hcv-rna levels, Infectious Diseases, HCV-RNA, 030211 gastroenterology & hepatology, Sequence Analysis, medicine.drug, Human, Microbiology (medical), medicine.medical_specialty, Hepatitis C virus, Concordance, Settore MED/12 - GASTROENTEROLOGIA, Pharmacology, Biology, 03 medical and health sciences, Boceprevir, Internal medicine, medicine, hcv, Genotyping, Hepaciviru, Viral Nonstructural Protein, Settore MED/09 - MEDICINA INTERNA, Virology, digestive system diseases, 030104 developmental biology, chemistry, Sequence Analysi, RNA, Genotyping Technique
Abstract

OBJECTIVES: This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen. METHODS: NS3 protease sequencing was performed by in-house-developed HCV-1 subtype-specific protocols. Phylogenetic analysis was used to test sequencing reliability and concordance with previous genotype/subtype assignment by commercial genotyping assays. RESULTS: Five hundred and sixty-seven HCV plasma samples with quantifiable HCV-RNA from 326 HCV-infected patients were collected between 2011 and 2014. Overall, the success rate of NS3 sequencing was 88.9%. The success rate between the two subtype protocols (HCV-1a/HCV-1b) was similarly high for samples with HCV-RNA >3 log IU/mL (>92% success rate), while it was slightly lower for HCV-1a samples with HCV-RNA ≤3 log IU/mL compared with HCV-1b samples. Phylogenetic analysis confirmed the genotype/subtype given by commercial genotyping assays in 92.9% (303/326) of cases analysed. In the remaining 23 cases (7.1%), 1 was HCV-1g (previously defined as subtype 1a), 1 was HCV-4d (previously defined as genotype 1b) and 1 was HCV-1b (previously defined as genotype 2a/2c). In the other cases, NS3 sequencing precisely resolved the either previous undetermined/discordant subtype 1 or double genotype/subtype assignment by commercial genotyping assays. Resistance-associated variants (RAVs) to PI were detected in 31.0% of samples. This prevalence changed according to PI experience (17.1% in PI-naive patients versus 79.2% in boceprevir/telaprevir/simeprevir-failing patients). Among 96 patients with available virological outcome following boceprevir/telaprevir treatment, a trend of association between baseline NS3 RAVs and virological failure was observed (particularly for HCV-1a-infected patients: 3/21 failing patients versus 0/22 achieving sustained virological response; P = 0.11). CONCLUSIONS: HCV-NS3 sequencing provides reliable results and at the same time gives two clinically relevant pieces of information: a correct subtype/genotype assignment and the detection of variants that may interfere with the efficacy of PI.

Published
2016

23. Noninvasive Evaluation of Liver Fibrosis in a Sample of Putative Inactive HBV Carriers in Rome, Italy.

Author

Delle Monache M, Petrelli A, Rossi A, Cecere R, Mirisola C, Costanzo G, Francia C, Cerini F, Cavani A, and Nosotti L

Abstract

Background: Noninvasive methods are useful for investigating patients with chronic HBV infection. The severity of liver disease in inactive HBsAg carriers can be noninvasively assessed by transient elastography (TE) alone or in association with biochemical markers of fibrosis., Objectives: The study evaluates the effectiveness of the TE compared to common fibrosis scores (FSs), APRI, Forns Index, and FIB4, for identifying significant fibrosis in Italian and foreigner HBsAg carriers. To investigate the risk of progression of the liver disease, liver stiffness (LS) and HBV-DNA were monitored over time., Methods: Viral load, biochemical parameters, and LS have been retrospectively evaluated in 125 putative inactive HBV carriers, who visited two outpatient departments (Colleferro Hospital and INMP) from 01/03/2014 to 31/12/2019. Differences in clinical, biochemical, and demographic variables between Italians and foreigners were analyzed. 66 of 125 patients were followed up for 24 months by monitoring liver stiffness and HBV-DNA., Results: Mean overall LS was 5.55 ± 1.92 kPa; 18 (14.4%) patients had a LS ≥7.5 kPa. Mean of APRI, Forns, and FIB4 was 0.29 ± 0.11, 4.15 ± 1.63, and 1.16 ± 0.59, respectively. FS did not differ between the patients with LS <7.5 kPa and those with LS ≥7.5 kPa. Italians displayed a significant lower ALT (0.53 ± 0.18 vs. 0.67 ± 0.33, p < 0.05) and AST (0.59 ± 0.16 vs. 0.70 ± 0.21, p < 0.01) value than foreigners. No differences in LS and HBV-DNA levels were observed. In 66 patients followed up for 24 months, HBV-DNA increased by ≥2000 UI/ml after 12 months in 15 individuals and remained ≥2000 UI/ml after 24 months in 10/15 individuals. 7/10 patients showed LS ≥ 7.5 kPa after 24 months, and 4 of them underwent antiviral therapy for HBV. Patients with HBV-DNA <2000 IU/ml had a significantly lower LS than those with HBV-DNA ≥2000 IU/ml (5.30 ± 1.43 vs. 7.69 ± 1.07, p < 0.0001)., Conclusions: Analysis shows lower effectiveness of FS vs. TE in the assessment of putative inactive HBV carriers. Furthermore, using FibroScan® and HBV-DNA can identify "false" inactive carriers., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2021 Marco Delle Monache et al.)

Published
2021
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24. Combining Genetic Variants to Improve Risk Prediction for NAFLD and Its Progression to Cirrhosis: A Proof of Concept Study.

Author

Vespasiani-Gentilucci U, Dell'Unto C, De Vincentis A, Baiocchini A, Delle Monache M, Cecere R, Pellicelli AM, Giannelli V, Carotti S, Galati G, Gallo P, Valentini F, Del Nonno F, Rosati D, Morini S, Antonelli-Incalzi R, and Picardi A

Subjects
Adult, Aged, Case-Control Studies, Disease Progression, Gene Frequency, Genetic Loci, Genotype, Humans, Liver Cirrhosis etiology, Liver Cirrhosis pathology, Middle Aged, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease diagnostic imaging, Polymorphism, Single Nucleotide, Proof of Concept Study, Risk Factors, Kruppel-Like Factor 6 genetics, Lipase genetics, Liver Cirrhosis genetics, Membrane Proteins genetics, Non-alcoholic Fatty Liver Disease genetics, Phosphatidate Phosphatase genetics, Superoxide Dismutase genetics
Abstract

Background & Aims: Identifying NAFLD patients at risk of progression is crucial to orient medical care and resources. We aimed to verify if the effects determined by different single nucleotide polymorphisms (SNPs) could add up to multiply the risk of NAFLD and NASH-cirrhosis., Methods: Three study populations, that is, patients diagnosed with NASH-cirrhosis or with noncirrhotic NAFLD and healthy controls, were enrolled. PNPLA3 rs738409, TM6SF2 rs58542926, KLF6 rs3750861, SOD2 rs4880, and LPIN1 rs13412852 were genotyped., Results: One hundred and seven NASH-cirrhotics, 93 noncirrhotic NAFLD, and 90 controls were enrolled. At least one difference in allele frequency between groups was significant, or nearly significant, for the PNPLA3, TM6SF2, and KLF6 variants ( p < 0.001, p < 0.05, and p = 0.06, resp.), and a risk score based on these SNPs was generated. No differences were observed for SOD2 and LPIN1 SNPs. When compared to a score of 0, a score of 1-2 quadrupled, and a score of 3-4 increased 20-fold the risk of noncirrhotic NAFLD; a score of 3-4 quadrupled the risk of NASH-cirrhosis., Conclusions: The effects determined by disease-associated variants at different loci can add up to multiply the risk of NAFLD and NASH-cirrhosis. Combining different disease-associated variants may represent the way for genetics to keep strength in NAFLD diagnostics.

Published
2018
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25. Plasma/erythrocyte ribavirin x100 ratio as an indicator of sustained virological response in HCV genotype 1 patients with early virological response.

Author

Baiocchi L, De Leonardis F, Delle Monache M, Nosotti L, Conti RL, Lenci I, Carbone M, Di Paolo D, Cucchiarelli S, and Angelico M

Subjects
Adult, Aged, Antiviral Agents therapeutic use, Drug Therapy, Combination, Female, Genotype, Hepacivirus classification, Hepacivirus genetics, Hepatitis C, Chronic virology, Humans, Interferon alpha-2, Interferon-alpha therapeutic use, Male, Middle Aged, Polyethylene Glycols therapeutic use, Predictive Value of Tests, RNA, Viral blood, Recombinant Proteins, Ribavirin therapeutic use, Sensitivity and Specificity, Treatment Outcome, Young Adult, Antiviral Agents blood, Erythrocytes chemistry, Hepacivirus drug effects, Hepatitis C, Chronic drug therapy, Plasma chemistry, Ribavirin blood
Abstract

Background: On-treatment predictors during antiviral therapy of HCV are useful because they allow discontinuation of an unnecessary treatment in non-responders. Our aim was to evaluate the usefulness of plasma and erythrocyte ribavirin levels in predicting sustained virological response (SVR) in HCV genotype 1 patients undergoing antiviral treatment., Methods: A total of 40 HCV genotype 1 patients treated with pegylated interferon-alpha2a 180 microg weekly plus ribavirin 1,000 or 1,200 mg daily (according to body weight) were included in the study. Plasma and erythrocyte ribavirin levels were evaluated in all patients at week 12 by HPLC. At week 24, ribavirin levels were reassessed in those achieving early virological response (EVR)., Results: A total of 27 patients achieved EVR, whereas 17 achieved SVR. There was no difference among EVR and non-EVR patients in terms of plasma and erythrocyte ribavirin concentrations at week 12. At week 24, EVR patients obtaining SVR exhibited higher mean +/-sd levels of ribavirin in plasma and lower levels in erythrocytes compared with non-SVR patients (in plasma 12.8 +/-10 versus 5.8 +/-4 microM [P<0.02] and in erythrocytes 1,053 +/-504 versus 1,613 +/-589 microM [P<0.03]). When the plasma ribavirin/erythrocyte ribavirin x100 ratio was compared, the difference was enhanced (1.5 +/-1.3 versus 0.4 +/-0.3 microM; P<0.01). Receiver operating characteristic curve analysis identified a cutoff for plasma ribavirin/erythrocyte ribavirin x100 ratio in predicting SVR of 0.71 with a negative predictive value of 0.8 and a positive predictive value of 0.9, whereas those related to EVR were 1 and 0.6, respectively., Conclusions: Plasma ribavirin/erythrocyte ribavirin x100 ratio at week 24 seems to be a good indicator of SVR in HCV genotype 1 patients achieving EVR.

Published
2010
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26. What kind of hepatitis?

Author

Santolamazza M, Marinelli RM, Bacosi M, D'Innocenzo S, Miglioresi L, Patrizi F, Delle Monache M, and Ricci GL

Subjects
Adult, Female, Hepatitis, Viral, Human virology, Humans, Male, Middle Aged, RNA, Viral isolation & purification, Hepatitis, Viral, Human classification, Hepatitis, Viral, Human diagnosis
Abstract

Finding one major hepatotropic virus may not be enough to identify the aetiology of liver disease when risk factors are present, particularly in patients with past or present infection with other viral agents, or chronic liver disease. The pathogenic process in these cases is often complex. In the five cases we report, acute hepatitis (initiated by halothane, cytomegalovirus or Epstein-Barr virus) preceded the reactivation of hepatitis B infection, and these events occurred in patients with chronic hepatitis C infection. Each case demonstrates how several viruses can be implicated in the development of hepatitis, either as single agents or via cross-activation of T cells. The nosography of hepatitis, therefore, and the optimum therapeutic choices, can puzzle the clinical team.

Published
2001
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27. The function of alkaline phosphatase in the liver: regulation of intrahepatic biliary epithelium secretory activities in the rat.

Author

Alvaro D, Benedetti A, Marucci L, Delle Monache M, Monterubbianesi R, Di Cosimo E, Perego L, Macarri G, Glaser S, Le Sage G, and Alpini G

Subjects
Alkaline Phosphatase genetics, Alkaline Phosphatase physiology, Animals, Antiporters analysis, Bile Ducts enzymology, Bile Ducts metabolism, Chloride-Bicarbonate Antiporters, Epithelium metabolism, In Vitro Techniques, Levamisole pharmacology, Liver enzymology, Liver pathology, Male, RNA, Messenger analysis, Rats, Rats, Inbred F344, Alkaline Phosphatase pharmacology, Bile metabolism, Bile Ducts drug effects, Liver drug effects
Abstract

We studied the effects of alkaline phosphatase (AP) on the secretory processes of the rat intrahepatic biliary epithelium as well as the role of the intrahepatic biliary epithelium in the uptake and biliary secretion of exogenous AP. The effects of acute and chronic administration of AP on bile secretory parameters were investigated in vivo in normal and bile duct ligated (BDL) rats and in vitro in isolated rat bile duct units (IBDU). In vivo, acute AP administration decreased bile flow and biliary bicarbonate excretion and abolished secretin choleresis in BDL rats but not in normal rats. On the contrary, the AP inhibitor, levamisole, increased in BDL rat bile flow and biliary bicarbonate excretion. In vitro, basal and secretin-stimulated Cl(-)/HCO(3)(-) exchanger activity in IBDU was immediately inhibited by AP intraluminal microinjection (apical exposure) but only after a prolonged exposure to the basolateral pole. Levamisole increased the Cl(-)/HCO(3)(-) exchanger activity of IBDU. A significant basolateral uptake of AP occurs in IBDU with a progressive transport to the apical domain. AP chronic treatment increased AP and gamma-glutamyltranspeptidase (gamma-GT) activities in the intrahepatic bile ducts and hepatocyte canalicular pole, promoted enlargement of bile canaliculi, and decreased bile flow and biliary bicarbonate excretion. In conclusion, the intrahepatic biliary epithelium plays a role in the uptake and biliary secretion of serum AP. AP inhibits the secretory processes of the intrahepatic biliary epithelium and induces features of intrahepatic cholestasis after chronic administration. These findings indicate that AP plays an active role in down-regulating the secretory activities of the intrahepatic biliary epithelium.

Published
2000
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28. Elevated alanine aminotransferase in blood donors: role of different factors and multiple viral infections.

Author

Delle Monache M, Miceli M, Santolamazza M, Mannella E, Mercurio G, Di Lorenzo A, Bacosi M, Gerardi R, Berardo C, Bruno G, Russo F, Miglioresi L, and Ricci GL

Subjects
Antibodies, Viral blood, Humans, Retrospective Studies, Virus Diseases blood, Alanine Transaminase blood, Blood Donors
Abstract

Many different aetiological agents stimulate alanine aminotransferase (ALT) production. Viral markers and other aetiologies were investigated in 2166 individuals, randomly selected from 10,000 consecutive blood donors. Elevation of ALT was found in 10.8% of subjects. Grouping donors according to ALT level and correlating with, respectively, hepatitis B core antibody (HBcAb), cytomegalovirus antibody alone, or associated with HBcAb, showed similar findings (high ALT 11.1%, normal 11.6%; high 85.4%, normal 81.4%; high 10.2%, normal 11.0%, respectively). Hepatitis C virus (HCV) antibody was found to be significantly associated with elevated ALT levels (high 1.7%, normal 0.26%). Other causes of ALT elevation were alcohol abuse (17%), obesity (25%) and dyslipidaemia (38%), but in 11% there was no obvious aetiology. Although HCV is a rare cause of elevated ALT in blood donors, it seems to be the only virus, among those tested, to account for liver damage. This may be due to the non-protective role of HCV antibody, the low specificity of ALT, or the pathogenic role of uninvestigated viruses.

Published
1999
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29. Hormonal regulation of bicarbonate secretion in the biliary epithelium.

Author

Alvaro D, Gigliozzi A, Fraioli F, Romeo R, Papa E, Delle Monache M, and Capocaccia L

Subjects
Adenylyl Cyclases metabolism, Animals, Antiporters metabolism, Bile metabolism, Calcium metabolism, Chloride-Bicarbonate Antiporters, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Electrolytes metabolism, Epithelium metabolism, Humans, Ion Transport, Bicarbonates metabolism, Biliary Tract metabolism, Hormones physiology
Abstract

Bicarbonate excretion in bile is a major function of the biliary epithelium. It is driven by the apically located Cl-/HCO3- exchanger which is functionally coupled with a cAMP-dependent Cl- channel (CFTR). A number of hormones and/or neuropeptides with different mechanisms and at different intracellular levels regulate, in concert, the processes underlying bicarbonate excretion in the biliary epithelium. Secretin induces a bicarbonate rich choleresis by stimulating the activity of the Cl-/HCO3- exchanger by cAMP and protein kinase A mediated phosphorylation of CFTR regulatory domain. Protein phosphatase 1/2A are involved in the run-down of secretory stimulus after secretin removal. Acetylcholine potentiates secretin-choleresis by inducing a Ca(++)-calcineurin mediated "sensitization" of adenyl cyclase to secretin. Bombesin and vasoactive intestinal peptide also enhance the Cl-/HCO3- exchanger activity, but the intracellular signal transduction pathway has not yet been defined. Somatostatin and gastrin inhibit basal and/or secretin-stimulated bicarbonate excretion by down-regulating the secretin receptor and decreasing cAMP intracellular levels induced by secretin.

Published
1997

30. Antibodies anti-parvovirus B19 in chronic hepatitis C virus infection.

Author

Lavorino C, Mannella E, Salvatori L, Delle Monache M, Santolamazza M, Gerardi R, Berardo C, Bacosi M, and Ricci GL

Subjects
Chronic Disease, Erythema Infectiosum complications, Female, Hepatitis C complications, Humans, Male, Antibodies, Viral analysis, Carrier State immunology, Erythema Infectiosum immunology, Hepatitis C immunology, Parvovirus B19, Human immunology
Published
1995

31. Antibody pattern's lack of predictivity in determining the response of viral hepatitis C to interferon therapy.

Author

Berardo C, Gerardi R, Delle Monache M, Del Vecchio S, and Ricci GL

Subjects
Antigens, Viral blood, Biomarkers blood, Chronic Disease, Dose-Response Relationship, Immunologic, Female, Follow-Up Studies, Hepacivirus physiology, Hepatitis C immunology, Hepatitis C Antibodies, Hepatitis C Antigens, Humans, Male, Middle Aged, Prognosis, Recurrence, Time Factors, Transaminases blood, Treatment Outcome, Virus Replication, Hepatitis Antibodies blood, Hepatitis C blood, Hepatitis C therapy, Interferon-alpha therapeutic use
Abstract

The aim of the study was to investigate whether the immunoblot pattern for HCV is a predictor of the response to interferon treatment. In a group of 60 patients with persistent rise of aminotransferase, all were treated with 3-6MU of Alfa-IFN from normal leucocytes every other day for 6 months, followed by one weekly dose of 1-3 MU for 3 months. HCV serum markers were detected before treatment and every three months thereafter. In 22 out of 60 (36.6%) patients aminotransferase normalized and remained so for 3 months after therapy; 12 patients (54.5%) relapsed during a follow-up of 9-12 months. The most frequent pattern in responders and non responders was the positivity to four antibodies (55%). The pattern did not change during or after IFN therapy, nor was it related to the variation of aminotransferases. Three patients lost antibodies linked to viral replication (c100-3, 5-1-1) and 3 others became positive to the same antigens. No changes were observed during the follow-up of patients who had an initial normalization of ALT/AST levels and who then relapsed (either during the maintenance dose or during the whole follow-up:n = 19 pts). Therefore neither the antibody clearance of viral replication (c100-3 and 5-1-1) nor the antibody pattern is a valid predictor as to the efficacy of interferon therapy.

Published
1994

32. Liver pathology in cytomegalovirus infection associated with hepatitis B virus.

Author

Marinelli RM, Delle Monache M, Gerardi R, Berardo C, Santolamazza M, Bruno G, and Ricci GL

Subjects
Alanine Transaminase metabolism, Cytomegalovirus Infections pathology, Hepatitis B pathology, Hepatitis, Chronic complications, Hepatitis, Chronic pathology, Humans, Liver Cirrhosis etiology, Liver Cirrhosis pathology, Retrospective Studies, Risk Factors, Serologic Tests, Cytomegalovirus Infections complications, Hepatitis B complications, Liver pathology
Abstract

A retrospective study was carried out in 56 patients to establish the association of cytomegalovirus (CMV) with active or inactive hepatitis B virus (HBV) infection as a possible risk factor in the development of severe liver disease. Patients with positive CMV serology and active or inactive HBV infection had elevated alanine aminotransferase activity and had a relatively high incidence of more severe lesions (chronic hepatitis and active cirrhosis). In the absence of CMV, only one case of cirrhosis was identified compared with seven cases of hepatic fibrosis. By analogy with hepatitis C virus, CMV may bring about activation of the host inflammatory response against hepatocytes following HBV infection, resulting in the development of severe hepatitic disease.

Published
1993
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33. Primary sclerosing cholangitis: an analysis of 37 retrospective cases.

Author

Delle Monache M, Salvio A, Fiocca F, Basoli A, and Ricci GL

Subjects
Adult, Female, Humans, Inflammatory Bowel Diseases complications, Italy epidemiology, Male, Middle Aged, Retrospective Studies, Cholangitis, Sclerosing blood, Cholangitis, Sclerosing diagnosis, Cholangitis, Sclerosing epidemiology
Abstract

The clinical and laboratory findings of 37 patients with primary sclerosing cholangitis (PSC) were reviewed. Mean age was 43.8 years, sex ratio between males and females was 3:1; IBD was present in 91% of patients with 51% having ulcerative colitis, 23% unclassified colitis and 17% Crohn's disease. Twenty-seven patients (73%) were symptomatic presenting most commonly with fatigue, pruritus and hepato-splenomegaly. Cholangiography revealed abnormalities affecting both extrahepatic and intrahepatic biliary ductal systems in 51.8% of cases, and only the intrahepatic or extrahepatic biliary tree, respectively in 11.1% and in 37% of cases. The last prevalence was very high compared with that previously known. Clinical and biochemical data, when compared between asymptomatics and symptomatics, demonstrated a significant difference only for alkaline phosphatase which increased in the symptomatic group and for prothrombin activity which decreased among symptomatic patients. Nevertheless, predictive value of sALP for the presence of PSC was high when pts were pooled together with a randomly selected group of 36 non-affected persons that underwent ERCP for suspected primary sclerosing cholangitis: sensitivity was 94% and specificity 78%.

Published
1992

34. Prevalence and significance of HCV infection in a consecutive series of patients with HBV antibodies and raised aminotransferases.

Author

Delle Monache M, Santolamazza M, Marinelli RM, and Ricci GL

Subjects
Cross-Sectional Studies, Hepatitis B diagnosis, Hepatitis B immunology, Hepatitis C diagnosis, Hepatitis C immunology, Humans, Incidence, Italy epidemiology, Liver Cirrhosis diagnosis, Liver Cirrhosis epidemiology, Liver Cirrhosis immunology, Aspartate Aminotransferases blood, Hepacivirus immunology, Hepatitis Antibodies analysis, Hepatitis B epidemiology, Hepatitis B Surface Antigens analysis, Hepatitis C epidemiology, Liver Function Tests
Abstract

Fifty-one patients with signs of past HBV infection were investigated for the HCV virus antibody. All patients were at least HBsAb, HBcAb positive. Two groups were selected: patients with increased serum AST activity (32/51) and patients with normal serum AST activity (19/51). Prevalence of HCV infection was higher (81.2%) in the group with high serum aminotransferases as compared to that found in the second group (31.6%) (p less than 0.002). Furthermore, histological findings showed higher prevalence of HCV infection in patients with cirrhosis as compared to patients with hepatic fibrosis. Results show that lack of clinical remission in patients with past HBV infection could be due to the presence of HCV, thus representing an unrecognized cause of "cryptogenetic" liver diseases.

Published
1991

35. Faecal elimination of steroids in rats after oral administration of mepartricin.

Author

Del Vecchio S, Ulissi A, Delle Monache M, Tavanti A, Rapocci M, Ruozi P, De Bernardi M, and Ricci GL

Subjects
Administration, Oral, Animals, Cholesterol metabolism, Female, Intubation, Gastrointestinal, Male, Mepartricin administration & dosage, Rats, Rats, Inbred Strains, Estrogens metabolism, Feces chemistry, Mepartricin pharmacokinetics, Testosterone metabolism
Abstract

Treatment of both male and female rats with 5 IU/day mepartricin for 7-10 days administered by gastric tubing resulted in an increased faecal excretion of some steroids. Mean rate of elimination of total oestrogens was enhanced by 45% in male rats and by 14% in female rats, and the average excretion of conjugated oestrogen was also increased in the female animals. Faecal elimination of cholesterol was 37% and 42% higher in male and female rats, respectively, after mepartricin treatment, and in male rats plasma concentrations of cholesterol were reduced following treatment. It is suggested mepartricin acts either by changing the intestinal flora or by acting directly on the steroid moieties, and it is speculated that a similar mechanism may occur in man.

Published
1990
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36. Changes in the plasma clearance of antipyrine after treatment of healthy male volunteers with epomediol.

Author

Del Vecchio S, Ulissi A, Tavanti A, Delle Monache M, Munoz ME, Ventura P, Schiavi A, and Ricci GL

Subjects
Adult, Antipyrine pharmacokinetics, Bridged Bicyclo Compounds, Heterocyclic, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Humans, Male, Time Factors, Antipyrine blood, Cholagogues and Choleretics pharmacology, Terpenes pharmacology
Published
1990
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37. Changes in the plasma pattern of sex steroids in patients with liver cirrhosis treated with mepartricin.

Author

Tavanti A, Delle Monache M, Ulissi A, Del Vecchio S, Rapocci MA, Ruozi P, De Bernardi M, and Ricci GL

Subjects
Aldosterone blood, Clinical Trials as Topic, Follicle Stimulating Hormone blood, Gynecomastia blood, Gynecomastia etiology, Humans, Liver Cirrhosis blood, Liver Cirrhosis complications, Luteinizing Hormone blood, Male, Prolactin blood, Androgens blood, Estrogens blood, Liver Cirrhosis drug therapy, Mepartricin therapeutic use, Polyenes therapeutic use
Abstract

Mepartricin was given to cirrhotic patients in order to evaluate its effect on the imbalance of sex steroids which is typical of this disorder. Patients were divided into two group: one group received placebo (n = 19) and the other received 150,000 IU/day mepartricin for 30 days (n = 19). The patients were evaluated by separate medical staff who were unaware of the treatment. Mepartricin significantly decreased the plasma concentration of testosterone, oestradiol and prolactin as compared with the values at the start of the trial, while no significant changes were seen in the occurrence of gynaecomastia. No relevant changes were seen in patients receiving the control, except for a slight increase in the peripheral concentration of androstenedione, aldosterone and follicle stimulating hormone.

Published
1989
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38. Lymphocyte function tests in cirrhotic patients under treatment with spironolactone and potassium canrenoate.

Author

Cuppone R, Del Vecchio S, Zanninelli G, Delle Monache M, Ulissi A, Tavanti A, Angeloni A, and Ricci GL

Subjects
B-Lymphocytes classification, B-Lymphocytes drug effects, Complement System Proteins analysis, Female, Follow-Up Studies, Humans, Immunoglobulins analysis, Liver Cirrhosis drug therapy, Male, T-Lymphocytes classification, T-Lymphocytes drug effects, B-Lymphocytes immunology, Canrenoic Acid therapeutic use, Liver Cirrhosis immunology, Lymphocyte Activation drug effects, Pregnadienes therapeutic use, Spironolactone therapeutic use, T-Lymphocytes immunology
Abstract

This controlled study in cirrhotic patients investigated whether two antialdosteronic steroids, spironolactone (100-200 mg/day; n = 12 patient pairs) and potassium canrenoate (50-100 mg/day, n = 32 patient pairs) which are reported to bind to intracellular membranes and modify cytochrome P-450, could also produce nuclear changes. The model used was the response of peripheral lymphocytes to blastogenic agents by studying lymphocyte sub-populations. No changes occurred in the B- and T-lymphocyte sub-populations or in the helper and suppressor sub-types. The response to the blastogenic agents, phytohaemagglutinin and purified protein derived from mycobacteria, did not change significantly from before entry into the study to the follow-up (18.1 +/- 2.9 months). All control patients (n = 44 patient pairs) had slightly greater mitogenic activity compared with patients treated with spironolactone; no difference was found when control patients were compared with patients given potassium canrenoate. The difference between spironolactone and potassium canrenoate might be due to toxicity caused by the thio group of spironolactone. Overall, however, both drugs may be regarded as safe, in terms of effects on lymphatic tissue, occurring during the course of cirrhosis.

Published
1988
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39. [Plasmatic clearance of antipyrine after treatment with epomediol].

Author

Del Vecchio S, Delle Monache M, Basoli A, Munoz ME, Alessandrini A, Ventura P, Schiavi M, and Ricci GL

Subjects
Antipyrine blood, Biotransformation drug effects, Bridged Bicyclo Compounds, Heterocyclic, Dose-Response Relationship, Drug, Humans, Male, Random Allocation, Antipyrine pharmacokinetics, Cholagogues and Choleretics pharmacology, Terpenes pharmacology
Published
1988

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