Immunologia

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Pipeline Immunologia

Ladarixin

INN (International Non-proprietary Name): Ladarixin
phase III

Ladarixin is a non-competitive allosteric inhibitor of CXCL8 receptors, CXCR1 and CXCR2, able to inhibit the intracellular signal transduction events activated by CXCL8 without affecting binding of CXCL8 to CXCR1 and CXCR2. Chemical computational studies and alanine-replacement mutagenesis studies have identified the binding site of Ladarixin on CXCR1/2 in the transmembrane domain of the receptors.

On going Clinical studies
LDX0119

Ladarixin in obese pre-diabetic patients eligible to bariatric surgery

LDX0419

A Study to Assess Efficacy/Safety of Ladarixin in Type 1 Diabetes Patients With Preserved ß-cell Function at Baseline

LDX0319

A Study of Oral Ladarixin in New-onset Type 1 Diabetes and a Low Residual β-cell Function

Completed Clinical studies
MEX0114

A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes

Pubblicazioni su Immunologia

Frontiers in Immunology ottobre 2020

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice

Matheus Silverio Mattos et al.

Immunity maggio 2020

CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps That Interfere With Immune Cytotoxicity

Á. Teijeira et al.

Biomedicine & Pharmacotherapy febbraio 2020

Inhibition of CXCL1-CXCR2 axis ameliorates cisplatin-induced acute kidney injury by mediating inflammatory response

Liu P et al.

Aging gennaio 2020

Autocrine CXCL8-dependent invasiveness triggers modulation of actin cytoskeletal network and cell dynamics

A Antonosante et al.

Diabetes Care gennaio 2020

Targeting CXCR1/2 does not improve insulin secretion after pancreatic islet transplantation: A phase 3, double-blind, randomized, placebo-controlled trial in type 1 diabetes

Paola Maffi et al.

Breast Cancer Research gennaio 2020

A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer

Lori J. Goldstein et al.

Molecular cancer therapeutics dicembre 2019

Fenretinide, Tocilizumab, and Reparixin Provide Multifaceted Disruption of Oral Squamous Cell Carcinoma Stem Cell Properties: Implications for Tertiary

Mallert SR et al.

Frontiers in oncology settembre 2019

Targeting the Interplay Between Cancer Fibroblasts, Mesenchymal Stem Cells, and Cancer Stem Cells in Desmoplastic Cancers

Tze-Sian Chan et al.

Cell agosto 2019

Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7

Jaeger K et al.

Nature agosto 2019

DF2726A, a new IL-8 signalling inhibitor, is able to counteract chemotherapy-induced neuropathic pain

L Brandolini et al.

Cancers luglio 2019

The Role of Breast Cancer Stem Cells as a Prognostic Marker and a Target to Improve the Efficacy of Breast Cancer Therapy

Scioli MG et al.

Journal of immunotherapy of cancer giugno 2019

Tumor-targeted IL-12 combined with tumor resection yields a survival-favorable immune profile

Zhao Q et al.

International journal of molecular sciences giugno 2019

Chemokine Signaling in Chemotherapy-Induced Neuropathic Pain

L Brandolini et al.

Frontiers in oncology febbraio 2019

The CXCL8-CXCR1/2 Axis as a Therapeutic Target in Breast Cancer Stem-Like Cells

PA Ruffini

The American journal of pathology febbraio 2019

Inflammatory Stress Causes N-Glycan Processing Deficiency in Ocular Autoimmune Disease

AM Woodward et al.

ACS Omega novembre 2018

1,3-Dibromo-1,1-difluoro-2-propanone as a Useful Synthon for a Chemoselective Preparation of 4-Bromodifluoromethyl Thiazoles

M Colella et al.

European Respiratory Journal settembre 2018

Cigarette smoke upregulating the expression of mir 21 increases IL-8 in airway epithelial cells

Elisabetta Pace, Serena Di Vincenzo, Eleonora Di Salvo, Maria Ferraro Paola Dino, Federico Saibene, Luigi Lanata, Sebastiano Gangemi

JCI Insight agosto 2018

IL-6 and CXCL8 Mediate Osteosarcoma-Lung Interactions Critical to Metastasis

AC Gross et al.

Cancer Research luglio 2018

IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis

Ryan D. Roberts. Hakan Cam, Laura Brandolini, John M. Hinckley, Amy C. Gross

British Journal of Pharmacology giugno 2018

Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice

A Zarbock, M Allegretti, K Ley

European journal of medicinal chemistry aprile 2018

Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors

La Pietra V et al.

Molecular Cancer Therapeutics aprile 2018

Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib

Kahraman DC et al.

European Journal of immunology marzo 2018

CXCR2 Is Critical for Bacterial Control and Development of Joint Damage and Pain in Staphylococcus Aureus-Induced Septic Arthritis in Mouse

D Boff et al. Eur J Immunol

Frontiers in immunology gennaio 2018

Intravital Microscopic Evaluation of the Effects of a CXCR2 Antagonist in a Model of Liver Ischemia Reperfusion Injury in Mice

THC de Oliveira et al.

Frontiers in immunology dicembre 2017

CXCR1/2 Antagonism Is Protective During Influenza and Post-Influenza Pneumococcal Infection

LP Tavares et al.

Italian Journal of Pediatrics ottobre 2017

Management of acute respiratory diseases in the pediatric population: the role of oral corticosteroids

R. Cutrera, E. Baraldi, L. Indinnimeo, M. Miraglia Del Giudice, G. Piacentini, F. Scaglione, N. Ullmann, L. Moschino, F. Galdo, M. Duse

Clinical Cancer Research settembre 2017

Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer

A. F. Schott, L. J. Goldstein, M. Cristofanilli, P. A. Ruffini, S. McCanna, J. M. Reuben, R. P. Perez, G. Kato, M. Wicha

Oncotarget maggio 2017

Multiple Anti-Tumor Effects of Reparixin on Thyroid Cancer

F Liotti et al.

Oncotarget. aprile 2017

CXCR1/2 pathways in paclitaxel-induced neuropathic pain

Brandolini L, Benedetti E, Ruffini PA, Russo R, Cristiano L, Antonosante A, d'Angelo M, Castelli V, Giordano A, Allegretti M, Cimini A.

Oncotarget febbraio 2017

Ladarixin, a Dual CXCR1/2 Inhibitor, Attenuates Experimental Melanomas Harboring Different Molecular Defects by Affecting Malignant Cells and Tumor Microenvironment

DM Kemp et al.

Central nervous system agents in medicinal chemistry gennaio 2017

Synthesis and Antioxidant Properties of Novel Memantine Derivatives

Fornasari E et al.

Clin Cancer Res. agosto 2016

Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)

Alfaro C., Teijeira A., Oñate C., Pérez G1, Sanmamed M.F., Andueza M.P., Alignani D., Labiano S., Azpilikueta A., Rodriguez-Paulete A., Garasa S., Fusco J.P., Aznar A., Inogés S., De Pizzol M., Allegretti M., Medina-Echeverz J., Berraondo P., Perez-Gracia J.L., Melero I.

Cancer Research luglio 2016

A single arm, preoperative, pilot study to evaluate the safety and biological effects of orally administered reparixin in early breast cancer patients who are candidates for surgery

Lori J. Goldstein, Raymond P. Perez, Denise A. Yardley, Linda K Han, James M. Reuben, Susan McCanna, Beth Butler, Pier Adelchi Ruffini, Jenny C. Chang

Multidiscip Respir Med giugno 2016

Prospective study of the efficacy of antibiotics versus antitussive drugs for the management of URTI-related acute cough in children

A. Zanasi, L. Lanata, F. Saibene, G. Fontana, P. Dicpinigaitis, V. Venier, F. De Blasio

Frontiers in Immunology maggio 2016

Allosteric Modulation of Chemoattractant Receptors

Marcello Allegretti, Maria Candida Cesta and Massimo Locati

Cancer Research febbraio 2016

A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for triple-negative breast cancer (fRida)

JC Chang, AF Schott, MS Wicha, M Cristofanilli, PA Ruffini, S McCanna, LJ Goldstein

Pharmacological research gennaio 2016

DF2755A, a Novel Non-Competitive Allosteric Inhibitor of CXCR1/2, Reduces Inflammatory and Post-Operative Pain

AH Lopes et al.

Oncotarget. dicembre 2015

Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling

Brandolini L, Cristiano L, Fidoamore A, De Pizzol M, Di Giacomo E, Florio TM, Confalone G, Galante A, Cinque B, Benedetti E, Ruffini PA, Cifone MG, Giordano A, Alecci M, Allegretti M, Cimini A.

Annual of the rheumatic diseases dicembre 2015

A Homeostatic Function of CXCR2 Signalling in Articular Cartilage

J Sherwood et al.

Pharmacological research agosto 2015

Novel Immunological Strategies for Islet Transplantation

S Tezza et al.

American Diabetes Association aprile 2015

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

Antonio Citro, Andrea Valle, Elisa Cantarelli, Alessia Mercalli, Silvia Pellegrini, Daniela Liberati, Luisa Daffonchio, Olga Kastsiuchenka, Pier Adelchi Ruffini, Manuela Battaglia, Marcello Allegretti and Lorenzo Piemonti

Curr Med Chem. marzo 2015

P2X receptors and diabetes

Carmen Fotino, Andrea Vergani, Paolo Fiorina and Antonello Pileggi

Transplantation dicembre 2014

Islet allotransplantation in type 1 diabetes: Phase 2 pilot study with CXCL8 inhibitor (reparixin)

Maffi P, Daffonchio L, Ruffini PA, Allegretti M, Citro A, Magistretti P, Melzi R, Mercalli A, Nano R, Sordi V, Secchi A, Piemonti L

Nanoscale novembre 2014

Targeting FR-expressing cells in ovarian cancer with Fab-functionalized nanoparticles: a full study to provide the proof of principle from in vitro to in vivo

Alessandra Quarta, Davide Bernareggi, Fabio Benigni, Elena Luison, Giuseppe Nano, Simone Nitti, Maria Candida Cesta, Luciano Di Ciccio, Silvana Canevari, Teresa Pellegrino and Mariangela Figini

Cancer Immunology, Immunotherapy ottobre 2014

Armed antibodies for cancer treatment: A promising tool in a changing era

Riccardo Danielli, Roberto Patuzzo, Pier Adelchi Ruffini, Andrea Maurichi, Leonardo Giovannoni, Giuliano Elia, Dario Neri, Mario Santinami

Biodrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy giugno 2014

Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial

MP Ferrari et al.

Toxicol In Vitro marzo 2014

Oxidative stress and innate immunity responses in cigarette smoke stimulated nasal epithelial cells

E. Pace, M. Ferraro, S. Di Vincenzo, S. Gerbino, A. Bruno, L. Lanata, M. Gjomarkaj.

Annals of the Rheumatic Diseases gennaio 2014

A phase IB clinical trial in rheumatoid arthritis of dekavil (F8-IL10), a novel anti-inflammatory immunocytokine

M. Galeazzi, L. Bazzichi, G. Sebastiani, D. Neri, L. Giovannoni, F. Bacchion, J. Wilton, E. Garcia Gonzalez, P. Ruffini, M. Bardelli, C. Baldi, E. Selvi, G. Minisola, R. Caporali, E. Prisco, S. Bombardieri

The Journal of Clinical Investigation ottobre 2012

CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

Antonio Citro, Elisa Cantarelli,Paola Maffi,Rita Nano,Raffaella Melzi,Alessia Mercalli,Erica Dugnani,Valeria Sordi, Paola Magistretti,Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio and Lorenzo Piemonti

Transplantation International settembre 2012

CXCR2 inhibition improves islet transplantation

Antonio Citro, Elisa Cantarelli, Paola Maffi, Rita Nano, Raffaella Melzi, Alessia Mercalli, Erica Dugnani, Valeria Sordi, Paola Magistretti, Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio, Lorenzo Piemonti

Immunology letters luglio 2012

Current Status of Chemokine Receptor Inhibitors in Development

M Allegretti et al.

ACS Medicinal Chemistry Letters agosto 2011

Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors

A Moriconi et al.

British Journal of Pharmacology giugno 2011

Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor

R. Bertini, L.S. Barcelos, A.R. Beccari, B. Cavalieri, A. Moriconi, C. Bizzarri, P. Di Benedetto, C. Di Giacinto, I. Gloaguen, E. Galliera, M.M. Corsi, R.C. Russo, S.P. Andrade, M.C. Cesta, G. Nano, A. Aramini, J.C. Cutrin, M. Locati, M. Allegretti and M.M. Teixeira

The Journal of Clinical Investigation febbraio 2010

CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

Christophe Ginestier, Suling Liu, Mark E. Diebel, Hasan Korkaya, Ming Luo, Marty Brown, Julien Wicinski, Olivier Cabaud, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Jun-Lin Guan, Gabriela Dontu, and Max S. Wicha

Bioorganic & medicinal chemistry letters agosto 2009

Structure-Activity Relationship of Novel Phenylacetic CXCR1 Inhibitors

MR Sablone et al.

Journal of chromatography B luglio 2009

Development and Validation of an LC-MS/MS Method for Determination of Methanesulfonamide in Human Urine

R Anacardio et al.

Arthritis and Rheumatism agosto 2008

The chemokine receptors CXCR1/CXCR2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature

Fernanda M Coelho, Vanessa Pinho, Flávio A Amaral, Daniela Sachs, Vívian V Costa, David H Rodrigues, Angélica T Vieira, Tarcília A Silva, Daniele G Souza, Riccardo Bertini, Antônio L Teixeira, Mauro M Teixeira

American Journal of Respiratory Cell and Molecular Biology luglio 2008

Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis

Remo C. Russo, Rodrigo Guabiraba, Cristiana C. Garcia,  Lucíola S. Barcelos,  Ester Roffê,  Adriano L. S. Souza, Flávio A. Amaral,  Daniel Cisalpino, Geovanni D. Cassali, Andrea Doni, Riccardo Bertini, Mauro M. Teixeira 

Neuroimmunomodulation aprile 2008

Chemokine MIP-2/CXCL2, acting on CXCR2, induces motor neuron death in primary cultures

Massimiliano De Paola, Pasquale Buanne, Leda Biordi, Riccardo Bertini, Pietro Ghezzi, Tiziana Mennini

Journal of leukocyte biology novembre 2007

Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice

P Buanne et al.

British Journal of Pharmacology settembre 2007

Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats

M M Barsante, T M Cunha, M Allegretti, F Cattani, F Policani, C Bizzarri, W L Tafuri, S Poole, F Q Cunha, R Bertini, M M Teixeira

Journal of Pharmacology and experimental Therapeutics giugno 2007

Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes recovery of function after traumatic lesion to the spinal cord

Alfredo Gorio, Laura Madaschi, Giorgia Zadra, Giovanni Marfia, Barbara Cavalieri, Riccardo Bertini, Anna Maria Di Giulio

Transplantation Proceedings maggio 2007

Protective effect of an inhibitor of interleukin-8 (Meraxin) from ischemia and reperfusion injury in a rat model of kidney transplantation

F Neri, L Puviani, M Tsivian, D Prezzi, V Pacilé, G Cavallari, R Bertelli, E Bianchi, G L Piras, M Pariali, B Cavalieri, R Bertini, A Faenza, B Nardo

Molecular Medicine aprile 2007

The interleukin-8 (IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-term inflammation in permanent and transient cerebral ischemia in rats

Pia Villa, Sara Triulzi, Barbara Cavalieri, Rosa Di Bitondo, Riccardo Bertini, Sara Barbera, Paolo Bigini, Tiziana Mennini, Paolo Gelosa, Elena Tremoli, Luigi Sironi, Pietro Ghezzi

Journal of Medical Chemistry gennaio 2007

Design of Noncompetitive Interleukin-8 Inhibitors Acting on CXCR1 and CXCR2

Alessio Moriconi, Maria Candida Cesta, Maria Neve Cervellera, Andrea Aramini, Silvia Coniglio, Sandro Colagioia, Andrea Rosario Beccari, Cinzia Bizzarri, Michela Rita Cavicchia, Massimo Locati, Emanuela Galliera, Paola Di Benedetto, Paolo Vigilante, Riccardo Bertini and Marcello Allegretti

International Journal of Immunopathology and Pharmacology gennaio 2007

Reparixin, a specific interleukin-8 inhibitor, has no effects on inflammation during endotoxemia

J M Leitner, F B Mayr, C Firbas, A O Spiel, B Steinlechner, R Novellini, B Jilma

Pharmacology & therapeutics ottobre 2006

ELR+ CXC Chemokines and Their Receptors (CXC Chemokine Receptor 1 and CXC Chemokine Receptor 2) as New Therapeutic Targets

C Bizzarri et al.

Xenobiotica maggio 2006

Species differences in the pharmacokinetics an metabolism of reparixin in rat and dog

I Midgley, K Fitzpatrick, S J Wright, B A John, A J Peard, R M Major, J D Holding, A McBurney, R Anacardio, R Novellini, M P Ferrari

European cytokine network marzo 2006

The role of CXCR2 activity in the contact hypersensitivity response in mice

F Cattani et al.

European Cytokine Network marzo 2006

Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its efficacy in a model of transient cerebral ischemia in the rat

Angela Garau, Riccardo Bertini, Marco Mosca, Cinzia Bizzarri, Roberto Anacardio, Sara Triulzi, Marcello Allegretti, Pietro Ghezzi, Pia Villa

Antioxid Redox Signal ottobre 2005

Requirements for the Different Cysteines in the Chemotactic and Desensitizing Activity of Human Thioredoxin

C Bizzarri et al.

Journal of chemical chemistry giugno 2005

2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors

M Allegretti et al.

Cytokine maggio 2005

Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia

Angela Garau, Riccardo Bertini, Francesco Colotta, Federica Casilli, Paolo Bigini, Alfredo Cagnotto, Tiziana Mennini, Pietro Ghezzi, Pia Villa

Journal of Medicinal Chemistry aprile 2005

Predicting human serum albumin affinity of interleukin-8 (CXCL8) inhibitors by 3D-QSPR approach

Loretta Aureli, Gabriele Cruciani, Maria Candida Cesta, Roberto Anacardio, Lucio De Simone, Alessio Moriconi

Biochemical pharmacology febbraio 2005

Inhibition of interleukin-8 (CXCL8/IL-8) Responses by Repertaxin, a New Inhibitor of the Chemokine Receptors CXCR1 and CXCR2

F Casilli et al.

PNAS, Proceedings of the National Academy of Sciences agosto 2004

Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury

Riccardo Bertini, Marcello Allegretti, Cinzia Bizzarri, Alessio Moriconi, Massimo Locati, Giuseppe Zampella, Maria N. Cervellera, Vito Di Cioccio, Maria C. Cesta, Emanuela Galliera, Fernando O. Martinez, Rosa Di Bitondo, Giulia Troiani, Vilma Sabbatini, Gaetano D’Anniballe, Roberto Anacardio, Juan C. Cutrin, Barbara Cavalieri, Fabrizio Mainiero, Raffaele Strippoli, Pia Villa, Maria Di Girolamo, Franck Martin, Marco Gentile, Angela Santoni, Daniela Corda, Giuseppe Poli, Alberto Mantovani, Pietro Ghezzi and Francesco Colotta

Immunology aprile 2004

Key Role of Proline-Rich Tyrosine Kinase 2 in interleukin-8 (CXCL8/IL-8)-mediated Human Neutrophil Chemotaxis

V Di Cioccio et al.

European citokine network aprile 2003

Glycosylation Enhances Functional Stability of the Chemotactic Cytokine CCL2

P Ruggiero et al.

European cytokine network giugno 2002

Thioredoxin specifically cross-desensitizes monocytes to MCP-1

S Pagliei et al.

Biochemical pharmacology ottobre 2001

Role of tumor necrosis factor-alpha in endotoxin-induced lung parenchymal hyporesponsiveness in mice

L Brandolini et al.

Journal of immunology marzo 2001

Lymphocytes From Autoimmune MRL Lpr/Lpr Mice Are Hyperresponsive to IL-18 and Overexpress the IL-18 Receptor Accessory Chain

D Neumann et al.

European cytokine network marzo 2001

Balance between autocrine interleukin-1beta and caspases defines life versus death of polymorphonuclear cells

P Bossù et al.

Journal of immunology settembre 2000

The membrane form of the type II IL-1 receptor accounts for inhibitory function

D Neumann et al.

European cytokine network settembre 2000

IL-18 and IL-18 receptors in the development of autoimmunity

P Bossù et al.

European cytokine network giugno 2000

R- And S-isomers of Nonsteroidal Anti-Inflammatory Drugs Differentially Regulate Cytokine Production

P Mascagni et al.

Pulmonary pharmacology & therapeutics gennaio 2000

Lipopolysaccharide-induced Lung Injury in Mice. II. Evaluation of Functional Damage in Isolated Parenchyma Strips

L Brandolini et al.

Methods settembre 1999

Interleukin-1 and interleukin-1 Fragments as Vaccine Adjuvants

D Boraschi et al.

The journal of experimental medicine giugno 1999

Thioredoxin, a Redox Enzyme Released in Infection and Inflammation, Is a Unique Chemoattractant for Neutrophils, Monocytes, and T Cells

R Bertini et al.

European cytokine network dicembre 1997

Interaction Between interleukin-1 and Ciliary Neurotrophic Factor in the Regulation of Neuroblastoma Cell Functions

P Bossù et al.

European cytokine network giugno 1997

Interleukin-1 Beta Primes interleukin-8-stimulated Chemotaxis and Elastase Release in Human Neutrophils via Its Type I Receptor

L Brandolini et al.

European cytokine network giugno 1997

Functional Epitope Mapping of Human interleukin-1 Beta by Surface Plasmon Resonance

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Frontiers in bioscience: a journal and virtual library ottobre 1996

Structure-function Relationship in the IL-1 Family

D Boraschi et al.

Journal of leukocyte biology marzo 1996

IL-1 beta primes IL-8-activated human neutrophils for elastase release, phospholipase D activity, and calcium flux

L Brandolini et al.

The American journal of pathology dicembre 1995

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Vaccine gennaio 1993

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Storie su Immunologia

LDX0119

Ladarixin in obese pre-diabetic patients eligible to bariatric surgery

Brief summary

Effect of oral ladarixin 400 mg twice a day on insulin sensitivity. A phase 2, randomized, double-blind, placebo-controlled explorative study in obese patients with pre-diabetes eligible to bariatric surgery.

detailed description

Effect of the experimental drug ladarixin administered orally at a dose of 400 mg twice a day on insulin sensitivity. A phase 2, randomized, double-blind, placebo-controlled explorative study in obese patients with pre-diabetes eligible to bariatric surgery.

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LDX0419

A Study to Assess Efficacy/Safety of Ladarixin in Type 1 Diabetes Patients With Preserved ß-cell Function at Baseline

Brief summary

The objectives of this clinical trial are:

detailed description

The study is a phase 2, multicenter, double-blind, placebo-controlled study. It will randomize approximately 75 adult patients with new-onset type 1 diabetes (T1D) and preserved beta-cell function (fasting C-peptide >0.205 nmol/l) at baseline. Patients will be assigned (2:1) to receive either oral ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or placebo (control group).

Recruitment will be competitive among the study sites, until the planned number of patients is randomized.

Ladarixin and placebo will be both administered for 1 year. All patients will be followed-up for 18 months from the 1st administration of the study medication. The study database will be locked and data analyzed when the last patient randomized has completed month 12 follow-up visit. After this time point, the follow-up will continue under open-label conditions up to month 18.

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LDX0319

A Study of Oral Ladarixin in New-onset Type 1 Diabetes and a Low Residual β-cell Function

Brief summary

The objective of this clinical trial is to assess whether ladarixin treatment is effective in preserving beta-cell function and delaying the progression of type 1 diabetes (T1D) in adolescent and adult patients. The safety of ladarixin in the specific clinical setting will be also evaluated.

detailed description

This is a phase 3, multicenter, double-blind, placebo-controlled study. It has been designed to further evaluate whether ladarixin is effective in preserving beta-cell function and slowing-down the progression of T1D) in patients with a more severe disease presentation.

The study is planned to be performed at about 40 study centers in EU, US and in other countries, if appropriated. At each study center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is conducted according to the signed Investigator agreement, the protocol, GCP guidelines, and local regulations.

The study is planned to involve -327 patients with new-onset T1D, to include about 200 adolescents (14-17 years). Patients will be randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or matched placebo (control group). The two groups will be balanced within centers.

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MEX0114

A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes

Brief summary

The objective of this clinical trial is to investigate whether ladarixin has sufficient activity (preservation of β-cell function and slow-down of the progression of T1D) to warrant its further development (proof of concept trial). The safety of ladarixin in the specific clinical setting will be also evaluated.

The study is a phase 2, multicentre, double-blind study. 72 patients with new-onset type 1 diabetes (T1D) were planned to be involved, randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off - treatment group) or placebo (control group).

Recruitment was competitive among the study sites, until the planned number of patients was enrolled. A total of 76 patients were actually recruited.

detailed description

T1D is an organ-specific autoimmune disease in which the immune system attacks the insulin-producing β-cells. The onset of the disease typically occurs before adulthood and seriously affects a person's quality of life.

T1D is treated with life-long daily exogenous insulin injections and monitoring of blood glucose levels. However, even optimization of glucose control through the most recent technologies cannot adequately substitute for the finely tuned normal balance of the glucose levels. Therefore, despite marked improvements in diabetes care in recent years, insulin-dependent diabetes results in secondary long-term complications and is one of the leading causes of end-stage renal disease, blindness and amputation. Additionally, hypoglycaemia unawareness is a serious consequence of recurrent hypoglycaemia often requiring emergency care.

Maintenance of residual β-cell function (as measured by C-peptide response) was demonstrated to be associated with reduced rate of microvascular complications and hypoglycaemia, improved quality of life, and overall reduction in morbidity and associated management costs. Therefore, pharmacological approaches aimed at controlling the autoimmune response and restoring self-tolerance to pancreatic β-cells had attracted the clinical/scientific interest.

Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed to phase III clinical trials. Other agents, including cytokines modulators such as anti-TNF or anti-IL1, are under clinical evaluation. Unfortunately, even if safe preservation of β-cell function and improvement of glycaemic control have been evidenced for some of the pharmacological approaches evaluated so far, none has been definitely approved for the "treatment" of diabetes onset. New strategies are being evaluated which combine agents targeting sequential arms of the immune and inflammatory response involved in β-cell disruption. In this regard, IL-8 appears to be an important mediator in the progression of type 1 diabetes. Production and secretion of pro-inflammatory IL-8 has been demonstrated from human pancreatic islets upon enterovirus infections, and LPS-induced production of IL-8 by neutrophils is increased in type 1 pre-diabetic and diabetic patients. In parallel, circulating levels of IL-8 were elevated in children with T1D compared to non-diabetic controls. Specifically, levels of IL-8 correlate with glycaemic control, higher level being associated to poorer or unfavorable glucose control.

As a result of these findings, the modulation or inhibition of IL8 activity is considered a valid target for the development of innovative treatments aimed to control the progression of T1D.

Results obtained with ladarixin in mouse models of T1D, and particularly reversal of "diabetes" in the NOD mice, clearly showed the ability of this CXCR1/2 inhibitor to protect β-cells and either prevent or delay the progression of hyperglycaemia. The positive effects of ladarixin, coupled with the safety shown in phase 1 studies, provided a sound rationale for a clinical study aimed at evaluating the effect of ladarixin in patients with new onset diabetes and supported the conduct of the present study.

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Dompé farmaceutici S.p.A. Socio Unico / Capitale sociale € 50.000.000,00
REA MI 289519 - Registro Imprese di Milano / Codice Fiscale e Partita IVA (VAT) IT00791570153