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1. Scaling up health knowledge at European level requires sharing integrated data: an approach for collection of database specification

Author

Menditto E, Bolufer de Gea A, Cahir C, Marengoni A, Riegler S, Fico G, Costa E, Monaco A, Pecorelli S, Pani L, and Prados-Torres A

Subjects
healthcare-databases, adherence, electronic health records, outcome research, Medicine (General), R5-920, Therapeutics. Pharmacology, RM1-950
Abstract

Enrica Menditto,1 Angela Bolufer De Gea,2 Caitriona Cahir,3,4 Alessandra Marengoni,5 Salvatore Riegler,1 Giuseppe Fico,6 Elisio Costa,7 Alessandro Monaco,8 Sergio Pecorelli,5 Luca Pani,8 Alexandra Prados-Torres9 1School of Pharmacy, CIRFF/Center of Pharmacoeconomics, University of Naples Federico II, Naples, Italy; 2Directorate-General for Health and Food Safety, European Commission, Brussels, Belgium; 3Division of Population Health Sciences, Royal College of Surgeons in Ireland, 4Department of Pharmacology and Therapeutics, St James’s Hospital, Dublin, Ireland; 5Department of Clinical and Experimental Science, University of Brescia, Brescia; 6Life Supporting Technologies, Photonics Technology and Bioengineering Department, School of Telecomunications Engineering, Polytechnic University of Madrid, Madrid, Spain; 7Faculty of Pharmacy, University of Porto, Porto, Portugal; 8Italian Medicines Agency – AIFA, Rome, Italy; 9EpiChron Research Group on Chronic Diseases, Aragón Health Sciences Institute (IACS), IIS Aragón REDISSEC ISCIII, Miguel Servet University Hospital, University of Zaragoza, Zaragoza, Spain Abstract: Computerized health care databases have been widely described as an excellent opportunity for research. The availability of “big data” has brought about a wave of innovation in projects when conducting health services research. Most of the available secondary data sources are restricted to the geographical scope of a given country and present heterogeneous structure and content. Under the umbrella of the European Innovation Partnership on Active and Healthy Ageing, collaborative work conducted by the partners of the group on “adherence to prescription and medical plans” identified the use of observational and large-population databases to monitor medication-taking behavior in the elderly. This article describes the methodology used to gather the information from available databases among the Adherence Action Group partners with the aim of improving data sharing on a European level. A total of six databases belonging to three different European countries (Spain, Republic of Ireland, and Italy) were included in the analysis. Preliminary results suggest that there are some similarities. However, these results should be applied in different contexts and European countries, supporting the idea that large European studies should be designed in order to get the most of already available databases. Keywords: health care databases, adherence, electronic health records, outcome research

Published
2016

2. Towards a framework for treatment effectiveness in schizophrenia

Author

Juckel G, de Bartolomeis A, Gorwood P, Mosolov S, Pani L, Rossi A, and Sanjuan J

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Georg Juckel,1 Andrea de Bartolomeis,2 Philip Gorwood,3 Sergey Mosolov,4 Luca Pani,5 Alessandro Rossi,6 Julio Sanjuan7 1Department of Psychiatry, LWL-University Hospital, Ruhr-University Bochum, Bochum, Germany; 2Laboratory of Molecular Psychiatry and Unit of Treatment Resistant Psychosis, University School of Medicine of Naples Federico II, Napoli, Italy; 3Groupe Hospitalier Sainte-Anne (CMME), Paris-Descartes University, Paris, France; 4Moscow Research Institute of Psychiatry, Moscow, Russia; 5Institute of Translational Pharmacology, Italian National Research Council, Rome, Italy; 6Università de L’Aquila, L’Aquila, Italy; 7Clinic Hospital, Spanish Mental Health Network (CIBERSAM), University of Valencia, Valencia, Spain Introduction: Prompt administration of antipsychotic treatment that is adhered to is essential for the optimal treatment of schizophrenia. Many patients have benefited from the advent of second-generation antipsychotics, which can offer good symptomatic control with reduced incidence of extrapyramidal symptoms, although with higher risk of metabolic side effects. It is unsurprising that accounts as to whether first- and second-generation antipsychotics differ in their efficacy vary, since treatment effectiveness is a broad notion and difficult to define. Objectives: Numerous factors may be used to gauge treatment effectiveness and, while it has largely been defined in terms of improvements in four domains (symptoms of disease, treatment burden, disease burden, and health and wellness), the real-world clinical utility of this consensus is unclear. Therefore, this article aims to provide a framework that can aid psychiatrists in making assessments about treatment effectiveness. Methods and results: A panel of 12 psychiatrists and psychopharmacologists convened to develop and propose an accessible and globally-applicable framework for assessing the effectiveness of antipsychotic treatments in patients with schizophrenia. Following presentation of a preliminary proposal to a wider group of psychiatrists from across Europe, it was refined into a framework comprising five domains: symptomatic remission and retention of treatment; affective symptoms; cognitive functioning; treatment satisfaction; and personal and social functioning – each of which is discussed in this article. Conclusions: This article provides a framework that can aid psychiatrists in making assessments about treatment effectiveness. It is anticipated that the framework outlined here may contribute to improving clinical practice through the promotion of a patient-centered approach to the assessment of treatment effectiveness, using five specified domains, in patients with schizophrenia. Keywords: antipsychotic, assessment scales, functioning, mental illness, satisfaction

Published
2014

3. Prevalence and diagnostic distribution of medically unexplained painful somatic symptoms across 571 major depressed outpatients

Author

Fornaro M, Maremmani I, Canonico PL, Carbonatto P, Mencacci C, Muscettola G, Pani L, Torta R, Vampini C, Parazzini F, Dumitriu A, and Perugi G

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Michele Fornaro1, Icro Maremmani2,3, Pier Luigi Canonico4, Paolo Carbonatto5, Claudio Mencacci6, Giovanni Muscettola7, Luca Pani8, Riccardo Torta9, Claudio Vampini10, Fabio Parazzini11, Arina Dumitriu12, Giulio Perugi2,31Department of Neurosciences, Section of Psychiatry, University of Genova, Genoa, Italy; 2Dipartimento di Psichiatria Università di Pisa, Pisa, Italy; 3Institute of Behavioural Sciences "G. De Lisio", Pisa, Italy; 4Università di Novara, Novara, Italy; 5Societa' Italiana di Medicina Generale (SIMG) Turin, Italy; 6Ospedale Fatebenefratelli, Milan, Italy; 7Università di Napoli, Naples, Italy; 8Istituto di Neurogenetica e Neurofarmacologia, CNR, Cagliari, Italy; 9Ospedale Molinette, Turin, Italy; 10Ospedale Maggiore, Verona, Italy; 11GPA net, Milan, Italy; 12Boehringer Ingelheim S.p.A., Milan, ItalyObjective: To assess the prevalence and distribution of medically unexplained painful somatic symptoms (PSSs) versus nonpainful somatic symptoms (NPSSs) in patients diagnosed with major depressive episode (MDE).Method: A total of 571 outpatients diagnosed with MDE according to DSM-IV-TR criteria were consecutively enrolled into a cross-sectional, multicentric, observational study over a period of 7 months. Subjects were evaluated by means of the ad hoc validated 30-item Somatic Symptoms Checklist (SSCL-30) and Zung's questionnaires for depression and anxiety. The 32-item Hypomania Checklist (HCL-32) was also administered in order to explore any eventual association of PSSs or NPSSs with sub-threshold (DSM-IV-TR [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision] not recognized) bipolar disorder (BD).Results: In our sample, just 183 patients (32%) did not report painful somatic symptoms (NPSSs). Of these, 90 patients (15.76%) had no somatic symptoms at all. The remaining 388 (68%) had at least one PSS being subdivided as follows: 248 (43%) had one or two PSSs, while 140 (25%) experienced two or more. Patients with at least one PSS also reported a greater number of nonpainful somatic symptoms than NPSS. Bipolar patients (associated with higher HCL-32 scores) were less represented across PSS cases than NPSS subjects. Conversely, females were more prone to having a higher number of total somatic symptoms (and bipolar features).Conclusion: PSSs are common in patients with MDE, especially among those patients reporting fewer somatic symptoms in general as opposed to those patients who exhibit more somatic symptoms (both PSSs and NPSSs) with lower relative number of PSSs. A major therapeutic implication is that antidepressant monotherapy could be used with more confidence in unexplained PSS patients than in NPSS patients because of the latter group's lower frequency of (sub)-threshold bipolar features.Keywords: major depressive episode, MDE, bipolar disorder, BD

Published
2011

5. HTA307 Evolving Principles for Defining and Assessing the Economic and Societal Value of Cancer Therapies

Author

Lee, M., primary, Abrams, K., additional, Baird, A.M., additional, Brown, S., additional, Bruns, J., additional, Clark, R., additional, Cortes, J., additional, Curigliano, G., additional, Ferris, A., additional, Garrison, L., additional, Lyman, G., additional, Pani, L., additional, Kanesvaran, R., additional, Pemberton-Whiteley, Z., additional, Salmonson, T., additional, Sawicki, P., additional, Stein, B., additional, Suh, D., additional, Velikova, G., additional, and Grueger, J., additional

Published
2023
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6. The future is now: Model‐based clinical trial design for Alzheimer's disease

Author

Romero, K, Ito, K, Rogers, JA, Polhamus, D, Qiu, R, Stephenson, D, Mohs, R, Lalonde, R, Sinha, V, Wang, Y, Brown, D, Isaac, M, Vamvakas, S, Hemmings, R, Pani, L, Bain, LJ, Corrigan, B, and Diseases**, Alzheimer's Disease Neuroimaging Initiative for the Coalition Against Major

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Dementia, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Clinical Trials and Supportive Activities, Aging, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Neurological, Alzheimer Disease, Clinical Trials as Topic, Computer Simulation, Drug Approval, Europe, Humans, United States, United States Food and Drug Administration, Alzheimer's Disease Neuroimaging Initiative, Coalition Against Major Diseases, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease. CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).

Published
2015

7. Clinical trials and late‐stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014

Author

Schneider, LS, Mangialasche, F, Andreasen, N, Feldman, H, Giacobini, E, Jones, R, Mantua, V, Mecocci, P, Pani, L, Winblad, B, and Kivipelto, M

Subjects
Patient Safety, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Aging, Acquired Cognitive Impairment, Neurosciences, Brain Disorders, Clinical Research, Dementia, Neurodegenerative, Alzheimer's Disease, 5.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Alzheimer Disease, Biomarkers, Cholinesterase Inhibitors, Dopamine Agents, Drug Monitoring, Humans, Medication Therapy Management, Memantine, Memory Disorders, Nootropic Agents, Practice Guidelines as Topic, Randomized Controlled Trials as Topic, Alzheimer, clinical trial, dementia, drug development, treatment, Clinical Sciences, Cardiovascular System & Hematology
Abstract

The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

Published
2014

10. Efficacy of esmethadone in patients with major depressive disorder and antidepressant tolerance (antidepressant tachyphylaxis)

Author

Fava, M., primary, Stahl, S.M., additional, Pani, L., additional, De Martin, S., additional, Guidetti, C., additional, Alimonti, A., additional, Comai, S., additional, Mattarei, A., additional, Folli, F., additional, Bushnell, D., additional, O'Gorman, C., additional, Traversa, S., additional, Inturrisi, C.E., additional, Manfredi, P.L., additional, and Pappagallo, M., additional

Published
2023
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11. A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials

Author

Sforzini, L, Worrell, C, Kose, M, Anderson, IM, Aouizerate, B, Arolt, V, Bauer, M, Baune, BT, Blier, P, Cleare, AJ, Cowen, PJ, Dinan, TG, Fagiolini, A, Ferrier, IN, Hegerl, U, Krystal, AD, Leboyer, M, McAllister-Williams, RH, McIntyre, RS, Meyer-Lindenberg, A, Miller, AH, Nemeroff, CB, Normann, C, Nutt, D, Pallanti, S, Pani, L, Penninx, BWJH, Schatzberg, AF, Shelton, RC, Yatham, LN, Young, AH, Zahn, R, Aislaitner, G, Butlen-Ducuing, F, Fletcher, C, Haberkamp, M, Laughren, T, Mantyla, F-L, Schruers, K, Thomson, A, Arteaga-Henriquez, G, Benedetti, F, Cash-Gibson, L, Chae, WR, De Smedt, H, Gold, SM, Hoogendijk, WJG, Mondragon, VJ, Maron, E, Martynowicz, J, Melloni, E, Otte, C, Perez-Fuentes, G, Poletti, S, Schmidt, ME, van de Ketterij, E, Woo, K, Flossbach, Y, Ramos-Quiroga, JA, Savitz, AJ, Pariante, CM, Sforzini, L, Worrell, C, Kose, M, Anderson, IM, Aouizerate, B, Arolt, V, Bauer, M, Baune, BT, Blier, P, Cleare, AJ, Cowen, PJ, Dinan, TG, Fagiolini, A, Ferrier, IN, Hegerl, U, Krystal, AD, Leboyer, M, McAllister-Williams, RH, McIntyre, RS, Meyer-Lindenberg, A, Miller, AH, Nemeroff, CB, Normann, C, Nutt, D, Pallanti, S, Pani, L, Penninx, BWJH, Schatzberg, AF, Shelton, RC, Yatham, LN, Young, AH, Zahn, R, Aislaitner, G, Butlen-Ducuing, F, Fletcher, C, Haberkamp, M, Laughren, T, Mantyla, F-L, Schruers, K, Thomson, A, Arteaga-Henriquez, G, Benedetti, F, Cash-Gibson, L, Chae, WR, De Smedt, H, Gold, SM, Hoogendijk, WJG, Mondragon, VJ, Maron, E, Martynowicz, J, Melloni, E, Otte, C, Perez-Fuentes, G, Poletti, S, Schmidt, ME, van de Ketterij, E, Woo, K, Flossbach, Y, Ramos-Quiroga, JA, Savitz, AJ, and Pariante, CM

Abstract

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Published
2022

21. Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis

Author

Ascione, A, De Luca, M, Melazzini, M, Montilla, S, Trotta, M, Petta, S, Puoti, M, Sangiovanni, V, Messina, V, Bruno, S, Izzi, A, Villa, E, Aghemo, A, Zignego, A, Orlandini, A, Fontanella, L, Gasbarrini, A, Marzioni, M, Giannini, E, Craxi, A, Abbati, G, Alberti, A, Andreone, P, Andreoni, M, Angeli, P, Angelico, M, Angarano, G, Angrisani, D, Antinori, A, Antonini, C, Avancini, I, Barone, M, Bruno, R, Benedetti, A, Bernabucci, V, Blanc, P, Boarini, C, Boffa, N, Boglione, L, Borghi, V, Borgia, G, Brancaccio, G, Brunetto, M, Cacciola, I, Calabrese, P, Calvaruso, V, Campagnolo, D, Canovari, B, Caporaso, N, Capra, F, Carolo, G, Cassola, G, Castelli, F, Cauda, R, Silberstein, F, Cecere, R, Chessa, L, Chiodera, A, Chirianni, A, Ciancio, A, Cima, S, Coco, B, Colombo, M, Coppola, N, Corti, G, Cosco, L, Corradori, S, Cozzolongo, R, Cristaudo, A, Danieli, E, Monforte, A, Monache, M, Del Poggio, P, de Luca, A, Dentone, C, Di Biagio, A, Di Leo, A, Di Perri, G, Di Stefano, M, D'Offizi, G, Donato, F, Durante, E, Erne, E, Fagiuoli, S, Falasca, K, Federico, A, Felder, M, Ferrari, C, Gaeta, G, Ganga, R, Gatti, P, Giacomet, V, Giacometti, A, Gianstefani, A, Giordani, M, Giorgini, A, Grieco, A, Guerra, M, Gulminetti, R, Ieluzzi, D, Imparato, M, Iodice, V, La Monica, S, Lazzarin, A, Lenzi, M, Levrero, M, Lichtner, M, Lionetti, R, Guercio, C, Madonna, S, Magnani, S, Maida, I, Marignani, M, Marrone, A, Marsetti, F, Martini, S, Masarone, M, Maserati, R, Mastroianni, C, Memoli, M, Menzaghi, B, Merli, M, Miele, L, Milella, M, Mondelli, M, Montalbano, M, Monti, M, Morelli, O, Morisco, F, Nardone, G, Novara, S, Onnelli, G, Onofrio, M, Paganin, S, Pani, L, Parisi, M, Parruti, G, Pasquazzi, C, Pasulo, L, Perno, C, Persico, M, Piai, G, Picciotto, A, Pigozzi, G, Piovesan, S, Piras, M, Pirisi, M, Piscaglia, A, Ponti, L, Potenza, D, Pravadelli, C, Quartini, M, Quirino, T, Raimondo, G, Rapaccini, G, Rendina, M, Rizzardini, G, Rizzetto, M, Rizzo, S, Romagnoli, D, Romano, A, Rossi, C, Rumi, M, Russello, M, Russo, F, Russo, M, Sansonno, D, Santantonio, T, Saracco, G, Schimizzi, A, Serviddio, G, Simeone, F, Solinas, A, Soria, A, Tabone, M, Taliani, G, Tarantino, G, Tarquini, P, Tavio, M, Termite, A, Teti, E, Toniutto, P, Torti, C, Tundi, P, Vecchiet, G, Verucchi, G, Gentilucci, U, Vinci, M, Vullo, V, Zolfino, T, Zuin, M, Ascione A., De Luca M., Melazzini M., Montilla S., Trotta M. P., Petta S., Puoti M., Sangiovanni V., Messina V., Bruno S., Izzi A., Villa E., Aghemo A., Zignego A. L., Orlandini A., Fontanella L., Gasbarrini A., Marzioni M., Giannini E. G., Craxi A., Abbati G., Alberti A., Andreone P., Andreoni M., Angeli P., Angelico M., Angarano G., Angrisani D., Antinori A., Antonini C., Avancini I., Barone M., Bruno R., Benedetti A., Bernabucci V., Blanc P., Boarini C., Boffa N., Boglione L., Borghi V., Borgia G., Brancaccio G., Brunetto M., Cacciola I., Calabrese P., Calvaruso V., Campagnolo D., Canovari B., Caporaso N., Capra F., Carolo G., Cassola G., Castelli F., Cauda R., Silberstein F. C., Cecere R., Chessa L., Chiodera A., Chirianni A., Ciancio A., Cima S., Coco B., Colombo M., Coppola N., Corti G., Cosco L., Corradori S., Cozzolongo R., Cristaudo A., Danieli E., Monforte A. D. A., Monache M., Del Poggio P., de Luca A., Dentone C., Di Biagio A., Di Leo A., Di Perri G., Di Stefano M., D'Offizi G., Donato F., Durante E., Erne E., Fagiuoli S., Falasca K., Federico A., Felder M., Ferrari C., Gaeta G. B., Ganga R., Gatti P., Giacomet V., Giacometti A., Gianstefani A., Giordani M., Giorgini A., Grieco A., Guerra M., Gulminetti R., Ieluzzi D., Imparato M., Iodice V., La Monica S., Lazzarin A., Lenzi M., Levrero M., Lichtner M., Lionetti R., Guercio C. L., Madonna S., Magnani S., Maida I., Marignani M., Marrone A., Marsetti F., Martini S., Masarone M., Maserati R., Mastroianni C. M., Memoli M., Menzaghi B., Merli M., Miele L., Milella M., Mondelli M., Montalbano M., Monti M., Morelli O., Morisco F., Nardone G., Novara S., Onnelli G., Onofrio M., Paganin S., Pani L., Parisi M. R., Parruti G., Pasquazzi C., Pasulo L., Perno C. F., Persico M., Piai G., Picciotto A., Pigozzi G. M., Piovesan S., Piras M. C., Pirisi M., Piscaglia A. M., Ponti L., Potenza D., Pravadelli C., Quartini M., Quirino T., Raimondo G., Rapaccini G. L., Rendina M., Rizzardini G., Rizzetto M., Rizzo S., Romagnoli D., Romano A., Rossi C., Rumi M. G., Russello M., Russo F. P., Russo M. L., Sansonno D. E., Santantonio T. A., Saracco G., Schimizzi A. M., Serviddio G., Simeone F., Solinas A., Soria A., Tabone M., Taliani G., Tarantino G., Tarquini P., Tavio M., Termite A., Teti E., Toniutto P., Torti C., Tundi P., Vecchiet G., Verucchi G., Gentilucci U. V., Vinci M., Vullo V., Zolfino T., Zuin M., Ascione, A, De Luca, M, Melazzini, M, Montilla, S, Trotta, M, Petta, S, Puoti, M, Sangiovanni, V, Messina, V, Bruno, S, Izzi, A, Villa, E, Aghemo, A, Zignego, A, Orlandini, A, Fontanella, L, Gasbarrini, A, Marzioni, M, Giannini, E, Craxi, A, Abbati, G, Alberti, A, Andreone, P, Andreoni, M, Angeli, P, Angelico, M, Angarano, G, Angrisani, D, Antinori, A, Antonini, C, Avancini, I, Barone, M, Bruno, R, Benedetti, A, Bernabucci, V, Blanc, P, Boarini, C, Boffa, N, Boglione, L, Borghi, V, Borgia, G, Brancaccio, G, Brunetto, M, Cacciola, I, Calabrese, P, Calvaruso, V, Campagnolo, D, Canovari, B, Caporaso, N, Capra, F, Carolo, G, Cassola, G, Castelli, F, Cauda, R, Silberstein, F, Cecere, R, Chessa, L, Chiodera, A, Chirianni, A, Ciancio, A, Cima, S, Coco, B, Colombo, M, Coppola, N, Corti, G, Cosco, L, Corradori, S, Cozzolongo, R, Cristaudo, A, Danieli, E, Monforte, A, Monache, M, Del Poggio, P, de Luca, A, Dentone, C, Di Biagio, A, Di Leo, A, Di Perri, G, Di Stefano, M, D'Offizi, G, Donato, F, Durante, E, Erne, E, Fagiuoli, S, Falasca, K, Federico, A, Felder, M, Ferrari, C, Gaeta, G, Ganga, R, Gatti, P, Giacomet, V, Giacometti, A, Gianstefani, A, Giordani, M, Giorgini, A, Grieco, A, Guerra, M, Gulminetti, R, Ieluzzi, D, Imparato, M, Iodice, V, La Monica, S, Lazzarin, A, Lenzi, M, Levrero, M, Lichtner, M, Lionetti, R, Guercio, C, Madonna, S, Magnani, S, Maida, I, Marignani, M, Marrone, A, Marsetti, F, Martini, S, Masarone, M, Maserati, R, Mastroianni, C, Memoli, M, Menzaghi, B, Merli, M, Miele, L, Milella, M, Mondelli, M, Montalbano, M, Monti, M, Morelli, O, Morisco, F, Nardone, G, Novara, S, Onnelli, G, Onofrio, M, Paganin, S, Pani, L, Parisi, M, Parruti, G, Pasquazzi, C, Pasulo, L, Perno, C, Persico, M, Piai, G, Picciotto, A, Pigozzi, G, Piovesan, S, Piras, M, Pirisi, M, Piscaglia, A, Ponti, L, Potenza, D, Pravadelli, C, Quartini, M, Quirino, T, Raimondo, G, Rapaccini, G, Rendina, M, Rizzardini, G, Rizzetto, M, Rizzo, S, Romagnoli, D, Romano, A, Rossi, C, Rumi, M, Russello, M, Russo, F, Russo, M, Sansonno, D, Santantonio, T, Saracco, G, Schimizzi, A, Serviddio, G, Simeone, F, Solinas, A, Soria, A, Tabone, M, Taliani, G, Tarantino, G, Tarquini, P, Tavio, M, Termite, A, Teti, E, Toniutto, P, Torti, C, Tundi, P, Vecchiet, G, Verucchi, G, Gentilucci, U, Vinci, M, Vullo, V, Zolfino, T, Zuin, M, Ascione A., De Luca M., Melazzini M., Montilla S., Trotta M. P., Petta S., Puoti M., Sangiovanni V., Messina V., Bruno S., Izzi A., Villa E., Aghemo A., Zignego A. L., Orlandini A., Fontanella L., Gasbarrini A., Marzioni M., Giannini E. G., Craxi A., Abbati G., Alberti A., Andreone P., Andreoni M., Angeli P., Angelico M., Angarano G., Angrisani D., Antinori A., Antonini C., Avancini I., Barone M., Bruno R., Benedetti A., Bernabucci V., Blanc P., Boarini C., Boffa N., Boglione L., Borghi V., Borgia G., Brancaccio G., Brunetto M., Cacciola I., Calabrese P., Calvaruso V., Campagnolo D., Canovari B., Caporaso N., Capra F., Carolo G., Cassola G., Castelli F., Cauda R., Silberstein F. C., Cecere R., Chessa L., Chiodera A., Chirianni A., Ciancio A., Cima S., Coco B., Colombo M., Coppola N., Corti G., Cosco L., Corradori S., Cozzolongo R., Cristaudo A., Danieli E., Monforte A. D. A., Monache M., Del Poggio P., de Luca A., Dentone C., Di Biagio A., Di Leo A., Di Perri G., Di Stefano M., D'Offizi G., Donato F., Durante E., Erne E., Fagiuoli S., Falasca K., Federico A., Felder M., Ferrari C., Gaeta G. B., Ganga R., Gatti P., Giacomet V., Giacometti A., Gianstefani A., Giordani M., Giorgini A., Grieco A., Guerra M., Gulminetti R., Ieluzzi D., Imparato M., Iodice V., La Monica S., Lazzarin A., Lenzi M., Levrero M., Lichtner M., Lionetti R., Guercio C. L., Madonna S., Magnani S., Maida I., Marignani M., Marrone A., Marsetti F., Martini S., Masarone M., Maserati R., Mastroianni C. M., Memoli M., Menzaghi B., Merli M., Miele L., Milella M., Mondelli M., Montalbano M., Monti M., Morelli O., Morisco F., Nardone G., Novara S., Onnelli G., Onofrio M., Paganin S., Pani L., Parisi M. R., Parruti G., Pasquazzi C., Pasulo L., Perno C. F., Persico M., Piai G., Picciotto A., Pigozzi G. M., Piovesan S., Piras M. C., Pirisi M., Piscaglia A. M., Ponti L., Potenza D., Pravadelli C., Quartini M., Quirino T., Raimondo G., Rapaccini G. L., Rendina M., Rizzardini G., Rizzetto M., Rizzo S., Romagnoli D., Romano A., Rossi C., Rumi M. G., Russello M., Russo F. P., Russo M. L., Sansonno D. E., Santantonio T. A., Saracco G., Schimizzi A. M., Serviddio G., Simeone F., Solinas A., Soria A., Tabone M., Taliani G., Tarantino G., Tarquini P., Tavio M., Termite A., Teti E., Toniutto P., Torti C., Tundi P., Vecchiet G., Verucchi G., Gentilucci U. V., Vinci M., Vullo V., Zolfino T., and Zuin M.

Abstract

Purpose: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years. Methods: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12). Results: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0–4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3–9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17–20.71, p = 0.029) as the only variable independently associated with SVR12. Conclusion: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

Published
2018

22. The Italian compassionate use of sofosbuvir in HCV patients waitlisted for liver transplantation: A national real-life experience

Author

Martini, S, Donato, M, Mazzarelli, C, Rendina, M, Visco-Comandini, U, Fili, D, Gianstefani, A, Fagiuoli, S, Melazzini, M, Montilla, S, Pani, L, Petraglia, S, Russo, P, Trotta, M, Carrai, P, Caraceni, P, Angeli, P, Ballardini, G, Bernabucci, V, Bhoori, S, Burra, P, Civolani, A, D'Offizi, G, Felder, M, Gaeta, G, Ganga, R, Ginanni Corradini, S, Iemmolo, R, Lenci, I, Lionetti, R, Montalbano, M, Morelli, M, Picciotto, A, Sapere, C, Serviddio, G, Tame, M, Verucchi, G, Zignego, A, Martini S., Donato M. F., Mazzarelli C., Rendina M., Visco-Comandini U., Fili D., Gianstefani A., Fagiuoli S., Melazzini M., Montilla S., Pani L., Petraglia S., Russo P., Trotta M. P., Carrai P., Caraceni P., Angeli P., Ballardini G., Bernabucci V., Bhoori S., Burra P., Civolani A., D'Offizi G., Felder M., Gaeta G. B., Ganga R., Ginanni Corradini S., Iemmolo R. M., Lenci I., Lionetti R., Montalbano M., Morelli M. C., Picciotto A., Sapere C., Serviddio G., Tame M., Verucchi G., Zignego A. L., Martini, S, Donato, M, Mazzarelli, C, Rendina, M, Visco-Comandini, U, Fili, D, Gianstefani, A, Fagiuoli, S, Melazzini, M, Montilla, S, Pani, L, Petraglia, S, Russo, P, Trotta, M, Carrai, P, Caraceni, P, Angeli, P, Ballardini, G, Bernabucci, V, Bhoori, S, Burra, P, Civolani, A, D'Offizi, G, Felder, M, Gaeta, G, Ganga, R, Ginanni Corradini, S, Iemmolo, R, Lenci, I, Lionetti, R, Montalbano, M, Morelli, M, Picciotto, A, Sapere, C, Serviddio, G, Tame, M, Verucchi, G, Zignego, A, Martini S., Donato M. F., Mazzarelli C., Rendina M., Visco-Comandini U., Fili D., Gianstefani A., Fagiuoli S., Melazzini M., Montilla S., Pani L., Petraglia S., Russo P., Trotta M. P., Carrai P., Caraceni P., Angeli P., Ballardini G., Bernabucci V., Bhoori S., Burra P., Civolani A., D'Offizi G., Felder M., Gaeta G. B., Ganga R., Ginanni Corradini S., Iemmolo R. M., Lenci I., Lionetti R., Montalbano M., Morelli M. C., Picciotto A., Sapere C., Serviddio G., Tame M., Verucchi G., and Zignego A. L.

Abstract

Background & Aims: This study aimed to assess the real-life clinical and virological outcomes of HCV waitlisted patients for liver transplantation (LT) who received sofosbuvir/ribavirin (SOF/R) within the Italian compassionate use program. Methods: Clinical and virological data were collected in 224 patients with decompensated cirrhosis and/or hepatocellular carcinoma (HCC) receiving daily SOF/R until LT or up a maximum of 48 weeks. Results: Of 100 transplanted patients, 51 were HCV-RNA negative for >4 weeks before LT (SVR12: 88%) and 49 negative for <4 weeks or still viraemic at transplant: 34 patients continued treatment after LT (bridging therapy) (SVR12: 88%), while 15 stopped treatment (SVR12: 53%). 98 patients completed SOF/R without LT (SVR12: 73%). In patients with advanced decompensated cirrhosis (basal MELD ≥15 and/or C-P ≥B8), a marked improvement of the scores occurred in about 50% of cases and almost 20% of decompensated patients without HCC reached a condition suitable for inactivation and delisting. Conclusions: These real-life data indicate that in waitlisted patients: (i) bridging antiviral therapy can be an option for patients still viraemic or negative <4 weeks at LT; and (ii) clinical improvement to a condition suitable for delisting can occur even in patients with advanced decompensated cirrhosis.

Published
2018

32. Nutraceuticals: opening the debate for a regulatory framework

Author

Santini A., Cammarata S. M., Capone G., Ianaro A., Tenore G. C., Pani L., Novellino E., Santini, A., Cammarata, S. M., Capone, G., Ianaro, A., Tenore, G. C., Pani, L., and Novellino, E.

Subjects
claim, Functional Food, label, health, regulation, nutraceutical, regulatory, Legislation, Food, Dietary Supplement, Human, Diet
Abstract

Currently, nutraceuticals do not have a specific definition distinct from those of other food-derived categories, such as food supplements, herbal products, pre- and probiotics, functional foods, and fortified foods. Many studies have led to an understanding of the potential mechanisms of action of pharmaceutically active components contained in food that may improve health and reduce the risk of pathological conditions while enhancing overall well-being. Nevertheless, there is a lack of clear information and, often, the claimed health benefits may not be properly substantiated by safety and efficacy information or in vitro and in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed. An officially shared and accepted definition of nutraceuticals is still missing, as nutraceuticals are mostly referred to as pharma-foods, a powerful toolbox to be used beyond the diet but before the drugs to prevent and treat pathological conditions, such as in subjects who may not yet be eligible for conventional pharmaceutical therapy. Hence, it is of utmost importance to have a proper and unequivocal definition of nutraceuticals and shared regulations. It also seems wise to assess the safety, mechanism of action and efficacy of nutraceuticals with clinical data. A growing demand exists for nutraceuticals, which seem to reside in the grey area between pharmaceuticals and food. Nonetheless, given specific legislation from different countries, nutraceuticals are experiencing challenges with safety and health claim substantiation.

Published
2018

33. The Italian compassionate use of sofosbuvir observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes

Author

Carrai, P, Morelli, C, Cordone, G, Romano, A, Tame, M, Lionetti, R, Pietrosi, G, Lenci, I, Piai, G, Russo, F, Coppola, C, Melazzini, M, Montilla, S, Pani, L, Petraglia, S, Russo, P, Trotta, M, Martini, S, Toniutto, P, Bandiera, F, Bhoori, S, Brillanti, S, Burra, P, Corsale, S, De Luca, A, Fagiuoli, S, Fattovich, G, Fava, G, Felder, M, Forte, P, Galeota-Lanza, A, Gitto, S, Grieco, A, Grossi, P, Ialungo, A, Iemmolo, R, Loiacono, L, Mangia, A, Merli, M, Piacentini, A, Pellicelli, A, Rigamonti, C, Gabriella, V, Zignego, A, Carrai P., Morelli C., Cordone G., Romano A., Tame M., Lionetti R., Pietrosi G., Lenci I., Piai G., Russo F. P., Coppola C., Melazzini M., Montilla S., Pani L., Petraglia S., Russo P., Trotta M. P., Martini S., Toniutto P., Bandiera F., Bhoori S., Brillanti S., Burra P., Corsale S., De Luca A., Fagiuoli S., Fattovich G., Fava G., Felder M., Forte P., Galeota-Lanza A., Gitto S., Grieco A., Grossi P., Ialungo A. M., Iemmolo R. M., Loiacono L., Mangia A., Merli M., Piacentini A., Pellicelli A., Rigamonti C., Gabriella V., Zignego A. L., Carrai, P, Morelli, C, Cordone, G, Romano, A, Tame, M, Lionetti, R, Pietrosi, G, Lenci, I, Piai, G, Russo, F, Coppola, C, Melazzini, M, Montilla, S, Pani, L, Petraglia, S, Russo, P, Trotta, M, Martini, S, Toniutto, P, Bandiera, F, Bhoori, S, Brillanti, S, Burra, P, Corsale, S, De Luca, A, Fagiuoli, S, Fattovich, G, Fava, G, Felder, M, Forte, P, Galeota-Lanza, A, Gitto, S, Grieco, A, Grossi, P, Ialungo, A, Iemmolo, R, Loiacono, L, Mangia, A, Merli, M, Piacentini, A, Pellicelli, A, Rigamonti, C, Gabriella, V, Zignego, A, Carrai P., Morelli C., Cordone G., Romano A., Tame M., Lionetti R., Pietrosi G., Lenci I., Piai G., Russo F. P., Coppola C., Melazzini M., Montilla S., Pani L., Petraglia S., Russo P., Trotta M. P., Martini S., Toniutto P., Bandiera F., Bhoori S., Brillanti S., Burra P., Corsale S., De Luca A., Fagiuoli S., Fattovich G., Fava G., Felder M., Forte P., Galeota-Lanza A., Gitto S., Grieco A., Grossi P., Ialungo A. M., Iemmolo R. M., Loiacono L., Mangia A., Merli M., Piacentini A., Pellicelli A., Rigamonti C., Gabriella V., and Zignego A. L.

Abstract

Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3–F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child–Pugh class and model of end stage liver disease (MELD) scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (P < 0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (P = 0.049). A significant association was found between patients who worsened from Child–Pugh class A and who experienced viral relapse (4/26 vs. 8/189, P = 0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs. 6/10, P = 0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function.

Published
2017

40. La valutazione Economica dei Farmaci

Author

Bonaretti, P, Cerreta, F, Curto, A, Scroccaro, G, Scaccabarozzi, M, Spandonaro, F, Xaxi, E, and Pani, L

Subjects
Settore SECS-P/06 - Economia Applicata
Published
2017

41. Reflections on Decisions Made on the Well-Established Use of Medicinal Products by EU Regulators and the ECJ

Author

Borg, J. J., Laslop, A., Pani, L., Maciulaitis, R., and Melchiorri, D.

Subjects
Autorizzazione mine in commercio, uso consolidato, salute pubblica, European Commission, Abridged applications, Medical audit, Medicine -- Europe, Well-established use, Administrative agencies -- Europe, Public health -- Europe, Risk communication, Regulatory affairs, Generics, Generic drugs, Medicinal products, Drug utilization – Europe, Research Article
Abstract

Background: In the European Union (EU), a medicinal product needs a marketing authorization (MA) to be placed on the market. The EU’s medicinal products’ legislative framework allows for a reduced application for medicines outside their data exclusivity. One such type of application is the well-established use (WEU) medicinal product application (i.e. bibliographic applications). Recently, these MA applications have been subject to arbitration procedures at the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) because of disagreements between member states during the authorisation process. This paper reflects on these cases and highlights their potential impact on future WEU applications. Methods: Decisions adopted by the European Commission on WEU applications between 2009 and 2012 were identified from the EU Community Register on medicinal products for human use. Subsequently, decisions were reviewed to understand the potential serious risk to public health (PSRPH) that EU regulators raised during MA application procedures. Results: Four decisions were adopted by the EU commission between 2009 and 2012. Three followed disagreements between member states on PSRPH grounds. One decision was the outcome of a centralised marketing authorisation application. Six key messages were identified from the four cases reviewed and presented. Conclusion: A guideline on WEU to implement the technical specifications to fulfil Annex I of Directive 2001/83/EC for MA applications is not available. Thus, reflections on recent decisions on WEU applications provide scientific direction to the industry as well as the medicinal product regulators on the documentation required to successfully file and obtain a WEU MA., peer-reviewed

Published
2014

42. Impact of reimbursement limits on patient access to direct-acting antivirals in Italy: analysis of data from national registries.

Author

RUSSO, P., PANI, L., STANISCIA, T., ROMANO, F., and MARZIONI, M.

Abstract

OBJECTIVE: Hepatitis C virus (HCV) infection is a global epidemic, still highly prevalent in Europe. Given efficacy and safety of HCV therapy by Direct Antiviral Agents (DAA), World Health Organization called for actions to eliminate HCV infection. A limit is represented by access to care, mostly due to the high costs of medicines. In Italy, in 2015, the access to DAA therapy was reimbursed for patients with advanced disease, whereas in 2017 universal access was granted. The aim of this study was to analyse changes in patient recruitment trends treated with DAA with or without limitations to access to therapy. PATIENTS AND METHODS: 165,105 patients treated with DAA in Italy from 2015 to December 2018 were analysed. Daily patient treatment rate was obtained by segmented regression of interrupted time series analysis. RESULTS: 74,199 patients with advanced disease (62% with cirrhosis) had access to the therapy during the time period from 2015 to 2017. Following the extension of reimbursement criteria, 90,906 additional patients were treated (43.2% with F0-F1 and 22.9% with F2), with an absolute reduction of 59.9% of patients with advanced disease (cirrhosis decreased to 18.5%). Segmented regression of interrupted time series analysis of daily patient treatment rate showed a progressive reduction of patients with advanced disease, offset by those with initial disease. Notably, elimination of restrictions to therapy did not change the overall treatment rate. CONCLUSIONS: This study showed that a no-limit reimbursement policy for DAAs prescriptions to HCV infected individuals in Italy widened the types of treated patients, but the process towards elimination of HCV infection was not significantly changed. [ABSTRACT FROM AUTHOR]

Published
2020

43. Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: Data from the Italian AIFA Anti-diabetics Monitoring Registry

Author

Montilla, S, Marchesini, G, Sammarco, A, Trotta, M, Siviero, P, Tomino, C, Melchiorri, D, Pani, L, Sbraccia, P, Nicolucci, A, Brignoli, O, Coscelli, C, Dell'Aera, M, Mazzaglia, G, Giustini, S, De Rosa, M, Covezzoli, A, Rigazio, A, Roncadori, A, Montilla S, Marchesini G, Sammarco A, Trotta MP, Siviero PD, Tomino C, Melchiorri D, Pani L, Melchiorri D., Sbraccia P, Nicolucci A, Brignoli O, Coscelli C, Dell'Aera M, Mazzaglia G, Giustini SE, De Rosa M, Covezzoli A, Rigazio A, Roncadori A, Montilla, S, Marchesini, G, Sammarco, A, Trotta, M, Siviero, P, Tomino, C, Melchiorri, D, Pani, L, Sbraccia, P, Nicolucci, A, Brignoli, O, Coscelli, C, Dell'Aera, M, Mazzaglia, G, Giustini, S, De Rosa, M, Covezzoli, A, Rigazio, A, Roncadori, A, Montilla S, Marchesini G, Sammarco A, Trotta MP, Siviero PD, Tomino C, Melchiorri D, Pani L, Melchiorri D., Sbraccia P, Nicolucci A, Brignoli O, Coscelli C, Dell'Aera M, Mazzaglia G, Giustini SE, De Rosa M, Covezzoli A, Rigazio A, and Roncadori A

Abstract

Background and aims: In Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry. Methods and results: From February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n=6125 cases), body mass index (BMI) (≥35kg/m2, n=22,015), and metabolic control (HbA1c≥11% ((96mmol/mol), n=3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21-26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27-40% of all discontinuations, after excluding lost to follow-up. HbA1c decreased on average by 0.9-1.0% (9mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0-1.5% with DPP-4 inhibitors. Conclusions: In the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials

Published
2014

44. Identification and characterization of the kynurenine pathway in the pond snail Lymnaea stagnalis

Author

Benatti Cristina, Rivi Veronica, Alboni Silvia, Grilli Andrea, Castellano Sara, Pani Luca, Brunello Nicoletta, Blom Johanna M.C., Bicciato Silvio, and Tascedda Fabio

Subjects
Medicine, Science
Abstract

Abstract Dysregulation of the kynurenine pathway (KP) is implicated in many human diseases and disorders, from immunological, metabolic, neurodegenerative, and neuropsychiatric conditions to cancer, and represents an appealing target for new therapeutic approaches. In this intricate scenario, invertebrates, like Lymnaea stagnalis (LS), provide a flexible tool to unravel the complexity of the KP. Starting from the available LS genome and transcriptome, we identified putative transcripts of all KP enzymes containing an ORF; each predicted protein possessed a high degree of sequence conservation to known orthologues of other invertebrate and vertebrate model organisms. Sequences were confirmed by qualitative PCR and sequencing. At the same time, the qRT-PCR analysis revealed that Lym IDO-like, Lym TDO-like, Lym AFMID-like, Lym KMO-like, Lym AADAT-like, Lym KYAT I/III-like, Lym KYNU-like, Lym HAAO-like, and Lym ACMSD-like showed widespread tissue expression. Then, tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxy-kynurenine, xanthurenic acid, picolinic acid, and quinolinic acid were identified in the hemolymph of LS by UHPLC-Q exactive mass spectrometer. Our study provides the most thorough characterization to date of the KP in an invertebrate model, supporting the value of LS for future functional studies of this pathway at the cellular, synaptic, and behavioral levels.

Published
2022
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45. 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, 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, Fagiuoli, S, Gaeta, GB, Giannini, EG, Perno, CF, Silberstein, FC, Zignego, AL, FAGIUOLI, STEFANO, 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, Fagiuoli, S, Gaeta, GB, Giannini, EG, Perno, CF, Silberstein, FC, Zignego, AL, and FAGIUOLI, STEFANO

Abstract

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%) p

Published
2017

46. Pricing and reimbursement experiences and insights in the EU and US: Lessons learned to approach adaptive payer pathways

Author

Faulkner, S, Lee, M, Qin, D, Morrell, L, Xoxi, E, Sammarco, A, Cammarata, S, Russo, P, Pani, L, and Barker, R

Subjects
health care economics and organizations
Abstract

Earlier patient access to beneficial therapeutics that address unmet need is one of the main requirements of innovation in global healthcare systems– already burdened by unsustainable budgets. ‘Adaptive pathways’ (1), encompass earlier cross-stakeholder engagement, regulatory tools, and iterative evidence generation through the life cycle of the medicinal product. A key enabler of earlier patient access is through more flexible and adaptive payer approaches to pricing and reimbursement that reflect the emerging evidence generated.

Published
2016

47. Metformin-associated lactic acidosis requiring hospitalization. A national 10 year survey and a systematic literature review

Author

Renda F, Mura P, Finco G, Ferrazin F, Pani L, Giovanni LANDONI, Renda, F, Mura, P, Finco, G, Ferrazin, F, Pani, L, and Landoni, Giovanni

Subjects
Male, Time Factors, Middle Aged, Prognosis, Health Surveys, Metformin, Hospitalization, Italy, Risk Factors, Adverse Drug Reaction Reporting Systems, Humans, Hypoglycemic Agents, Acidosis, Lactic, Female, Aged
Abstract

BACKGROUND: Metformin is known to be rarely associated with lactic acidosis, a serious condition with a poor prognosis. AIM: To review the National Pharmacovigilance Network of the Italian Medicines Agency reporting cases of metformin-associated lactic acidosis. MATERIALS AND METHODS: The National Pharmacovigilance Network of the Italian Medicines Agency, was searched for cases of lactic acidosis that occurred in a 10 years period (from November 2001 to October 2011). Data were analyzed, to identify associated clinical features. A systematic literature research was performed to identify other large case series on metformin associated lactic acidosis. RESULTS: Metformin was the antidiabetic drug most frequently associated with lactic acidosis in the assessed period. Metformin-associated lactic acidosis was the most frequent serious adverse reaction related to metformin reported to the national authority (18.2% of all 650 adverse drug reactions reported). There were 59 cases of metformin-associated lactic acidosis (mortality rate of 25.4%). In most patients (89.8%) there was at least one risk factor for the occurrence of lactic acidosis. The predictors of death were low arterial blood pH and absence of acute renal failure. The systematic research of the literature identified only six case-series with more than 30 patients. CONCLUSIONS: This is the second largest case series ever reported on metformin-associated lactic acidosis. We confirmed that this rare complication of metformin is frequently fatal. Death can be predicted when the patient arrive in the hospital with low pH and, not intuitively, if the patient has no acute kidney injury. Risk minimisation measures taken at national level to prevent this serious complication are described.

Published
2013

48. Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: A retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database

Author

Fadini, G. P., Avogaro, A., Degli Esposti, L., Russo, P., Saragoni, S., Buda, S., Rosano, G., Pecorelli, S., Pani, L., Martinetti, S., Mero, P., Raeli, L., Migliazza, S., Dellagiovanna, M., Cerra, C., Gambera, M., Piccinelli, R., Zambetti, M., Atzeni, F., Valsecchi, V., Deluca, P., Scopinaro, E., Moltoni, D., Pini, E., Leoni, O., Oria, C., Papagni, M., Nosetti, G., Caldiroli, E., Moser, V., Roni, R., Polverino, A., Bovo, C., Mezzalira, L., Andretta, M., Trentin, L., Palcic, S., Pettinelli, A., Arbo, A., Bertola, A., Capparoni, G., Cattaruzzi, C., Marcuzzo, L., Rosa, F. V., Basso, B., Saglietto, M., Delucis, S., Prioli, M., Filippi, R., Coccini, A., Ghia, M., Sanfelici, F., Radici, S., Scanavacca, P., Campi, A., Bianchi, S., Verzola, A., Morini, M., Borsari, M., Danielli, A., Dal Maso, M., Marsiglia, B., Vujovic, B., Pisani, M., Bonini, P., Lena, F., Aletti, P., Marcobelli, A., Sagratella, S., Fratini, S., Bartolini, F., Riccioni, G., Meneghini, A., Di Turi, R., Fano, V., Blasi, A., Pagnozzi, E., Quintavalle, G., D'Avenia, P., De Matthaeis, M. C., Ferrante, F., Crescenzi, S., Marziale, L., Venditti, P., Bianchi, C., Senesi, I., Baci, R., De Carlo, I., Lavalle, A., Trofa, G., Marcello, G., Pagliaro, C., Troncone, C., Farina, G., Tari, M. G., Motola, G., De Luca, F., Saltarelli, M. L., Granieri, C., Vulnera, M., Palumbo, L., La Viola, F., Florio, L., De Francesco, A. E., Costantino, D., Rapisarda, F., Lazzaro, P. L., Pastorello, M., Parlli, M., Visconti, M., Uomo, I., Sanna, P., and Lombardo, F.

Subjects
Adult, Male, medicine.medical_specialty, Epidemiology, Population, Administration, Oral, Medications, Heart failure, Type 2 diabetes, Lower risk, Diabetes, Incretin, Cardiology and Cardiovascular Medicine, Internal medicine, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, education, Aged, Retrospective Studies, education.field_of_study, Analysis of Variance, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Hazard ratio, Absolute risk reduction, Retrospective cohort study, Middle Aged, medicine.disease, Hospitalization, Endocrinology, Sulfonylurea Compounds, Diabetes Mellitus, Type 2, Italy, Propensity score matching, Female, business, Diabetic Angiopathies
Abstract

Aims Oral glucose-lowering medications are associated with excess risk of heart failure (HF). Given the absence of comparative data among drug classes, we performed a retrospective study in 32 Health Services of 16 Italian regions accounting for a population of 18 million individuals, to assess the association between HF risk and use of sulphonylureas, DPP-4i, and glitazones. Methods and results We extracted data on patients with type 2 diabetes who initiated treatment with DPP-4i, thiazolidinediones, or sulphonylureas alone or in combination with metformin during an accrual time of 2 years. The endpoint was hospitalization for HF (HHF) occurring after the first 6 months of therapy, and the observation was extended for up to 4 years. A total of 127 555 patients were included, of whom 14.3% were on DPP-4i, 72.5% on sulphonylurea, 13.2% on thiazolidinediones, with average 70.7% being on metformin as combination therapy. Patients in the three groups differed significantly for baseline characteristics: age, sex, Charlson index, concurrent medications, and previous cardiovascular events. During an average 2.6-year follow-up, after adjusting for measured confounders, use of DPP-4i was associated with a reduced risk of HHF compared with sulphonylureas [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.62–0.97; P = 0.026]. After propensity matching, the analysis was restricted to 39 465 patients, and the use of DPP-4i was still associated with a lower risk of HHF (HR 0.70; 95% CI 0.52–0.94; P = 0.018). Conclusion In a very large observational study, the use of DPP-4i was associated with a reduced risk of HHF when compared with sulphonylureas.

Published
2015

49. Luongo L, Palazzo E, Tambaro S, Giordano C, Gatta L, Scafuro MA, Rossi FS, Lazzari P, Pani L, de Novellis V, Malcangio M, Maione S. 1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyraz ole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice

Author

LUONGO, Livio, TAMBARO S, GIORDANO C, GATTA L, SCAFURO MA, ROSSI FS, LAZZARI P, PANI L, DE NOVELLIS, Vito, MALCANGIO M, MAIONE S., PALAZZO, Enza, Luongo, Livio, Palazzo, Enza, Tambaro, S, Giordano, C, Gatta, L, Scafuro, Ma, Rossi, F, Lazzari, P, Pani, L, DE NOVELLIS, Vito, Malcangio, M, and Maione, S.

Published
2010

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