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2. Fentanyl enhances immune cell response through TLR4/MD-2 complex.

Author

Chemello, Chiara, Facci, Laura, Marcolin, Emma, Ramaschi, Giovanni Eugenio, Barbierato, Massimo, Giusti, Pietro, Bolego, Chiara, and Zusso, Morena

Subjects
OXAZOLINE derivatives, FENTANYL, MICROGLIA, IMMUNE response, CD14 antigen, OPIOID receptors
Abstract

Introduction: Opioids have been shown to induce neuroinflammation and immune cell activation, that might contribute to some of the opioid side effects, such as opioid-induced tolerance and paradoxical hyperalgesia. In this context, TLR4/MD-2 complex has been proposed as an off-target site for opioid action. This study was aimed at investigating the effect of fentanyl on lipopolysaccharide (LPS)-induced TLR4/MD-2 activation in rat primary microglia and human monocyte-derived macrophages (MDM). Materials and Methods: The effect of fentanyl was first explored by measuring the expression and release of different proinflammatory mediators in primary rat microglia and human MDM by real-time PCR and ELISA. Then, the involvement of TLR4/MD-2 signaling was investigated studying NF-κB activation in HEK293 cells stably transfected with human TLR4, MD-2, and CD14 genes (HEK-Blue hTLR4 cells) and in human MDM. Results: Fentanyl increased mRNA levels, as well as the LPS-induced secretion of proinflammatory mediators in primary microglia and MDM. Two inhibitors of TLR4/MD-2 signaling, namely the oxazoline derivative of N-palmitoylethanolamine (PEA-OXA) and CLI-095, blocked the production and release of proinflammatory cytokines by microglia stimulated with LPS and fentanyl, suggesting that TLR4/MD-2 could be the target of the proinflammatory activity of fentanyl. Finally, we showed that fentanyl in combination with LPS activated NF-κB signaling in human MDM and in HEKBlue hTLR4 cells and this effect was blocked by inhibitors of TLR4/MD-2 complex. Discussion: These results provide new insight into the mechanism of the proinflammatory activity of fentanyl, which involves the activation of TLR4/MD-2 signaling. Our findings might facilitate the development of novel inhibitors of TLR4/MD-2 signaling to combine with opioid-based analgesics for effective and safe pain management. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Contributors

Author

Abraham, David, primary, Ahmetov, Ildus I., additional, Al-Khelaifi, Fatima, additional, Antoni, Caimari, additional, Baumert, Philipp, additional, Buriani, Alessandro, additional, Cagnin, Stefano, additional, Calò, Carla Maria, additional, Caudullo, Giada, additional, Chemello, Francesco, additional, Cięszczyk, Pawel, additional, Collins, Malcolm, additional, Cuevas, María J., additional, de Oliveira, Bruno A. Parenti, additional, Diboun, Ilhame, additional, Drozdovska, Svitlana, additional, Elrayess, Mohamed A., additional, El-Sohemy, Ahmed, additional, Eny, Karen, additional, Erskine, Robert M., additional, Estébanez, Brisamar, additional, Fernandez-Gonzalo, Rodrigo, additional, Fie, Sarah Mc, additional, Fortinguerra, Stefano, additional, Fuku, Noriyuki, additional, Garcia-Bailo, Bibiana, additional, Gibbon, Andrea, additional, Giusti, Pietro, additional, González-Gallego, Javier, additional, Guest, Nanci S., additional, Guilherme, João Paulo L.F., additional, Hall, Elliott C., additional, Honma, Hiroki, additional, Joffre, Sara, additional, Jordi, Mayneris-Perxachs, additional, Kalinski, Michael, additional, Kikuchi, Naoki, additional, Kumagai, Hiroshi, additional, Leońska-Duniec, Agata, additional, Lluís, Arola, additional, Lucía, Alejandro, additional, Lucignano, Flavio, additional, Maciejewska-Skrendo, Agnieszka, additional, Miyamoto-Mikami, Eri, additional, Murakami, Haruka, additional, Massidda, Myosotis, additional, Nakazato, Koichi, additional, Miyamoto, Naokazu, additional, Nicoletti, Carolina Ferreira, additional, Noemí, Boqué, additional, Nonino, Carla Barbosa, additional, Núria, Canela, additional, Pinhel, Marcela A. Souza, additional, Pol, Herrero, additional, Puiggròs, Francesc, additional, Rahim, Masouda, additional, Rees, Tim, additional, Rodriguez-Miguelez, Paula, additional, Beckley, Samantha, additional, Sawczuk, Marek, additional, Seaborne, Robert A., additional, Semenova, Ekaterina A., additional, September, Alison V., additional, Sharples, Adam P., additional, Sorrenti, Vincenzo, additional, Valeeva, Elena V., additional, Williams, Alun G., additional, Zempo, Hirofumi, additional, and Zusso, Morena, additional

Published
2019
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9. Real-practice thromboprophylaxis in atrial fibrillation

Author

Deambrosis Paola, Bettiol Alessandra, Bolcato Jenny, Pirolo Roberta, Franchin Giulia, Themistoclakis Sakis, Pellizzari Michele, Chinellato Alessandro, and Giusti Pietro

Subjects
atrial fibrillation, thromboprophylaxis, realpractice, vitamin k antagonists, stroke risk, Pharmaceutical industry, HD9665-9675
Abstract

This retrospective observational study was based on databases of the Local Health Authority of Treviso, Italy. It evaluated the prevalence and the effectiveness of oral anticoagulation treatment (OAT) for the management of nonvalvular atrial fibrillation (NVAF) in everyday clinical practice. Out of 6,138 NVAF patients, only 3,024 received vitamin K antagonist (VKA). Potential barriers decreasing the probability of being treated with VKA were female sex, older age, antiplatelet treatment and history of bleeding. In addition, VKA-treatment was not in line with current ESC and AIAC guidelines, since the patients at high or low risk of stroke were under- or over-treated, resp. Among VKAtreated patients, 73 % of subjects were not at target with anticoagulation. OAT resulted to be effective in reducing stroke risk. However, stroke events were significantly influenced also by previous stroke or transient ischemic attack (hazard ratio, HR = 2.99, p < 0.001) and by previous bleeding events (HR = 1.60, p < 0.001).

Published
2017
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44. Twenty Years of Hepatitis C in the Treviso District (Local Health Unit 2): Treatments, Clinical Management and Cost Analysis

Author

Bellin, Annachiara, Franchin, Giulia, Bolcato, Jenny, Bettiol, Alessandra, Pirolo, Roberta, Schiavon, Alberto, Giusti, Pietro, Tessarin, Michele, Chinellato, Alessandro, Bellin, Annachiara, Franchin, Giulia, Bolcato, Jenny, Bettiol, Alessandra, Pirolo, Roberta, Schiavon, Alberto, Giusti, Pietro, Tessarin, Michele, and Chinellato, Alessandro

Abstract

Chronic hepatitis C virus (HCV) infection is a global health problem, and about 10-30% of patients develop cirrhosis or hepatocellular carcinoma several years after being infected. In past decades, treatment of HCV infection was based on peginterferon and ribavirin, which lead to a sustained virologic response (SVR) in only 50-60% of patients. Since 2014, direct acting antiviral (DAA) agents have been available. Patients administered DAA agents usually reach SVR in 12 weeks. The aim of this study was to estimate the cost analysis of these innovative drugs while also taking into account the total health expenditure for managing HCV infection. The pharmaceutical and hospitalisation databases of the Local Health Unit (ULSS2) of Treviso were retrospectively analysed between 1997 and 2016 for each HCV patient. During this twenty-year period, people affected by HCV totalled 2,949; 277 of these patients were treated with DAA and, of these, only 2% did not reach SVR. The HCV genotype 1b was the most common, accounting for 58% of the total patients. The treatment for HCV genotype 3 was associated with higher costs. The expenses for the new treatments were found to be significantly higher compared to those for the old ones (i.e., peginterferon and ribavirin). The average costs for a cycle of therapy were €8,000 and €24,000 for interferon and DAA therapy, respectively. Total health care costs associated with HCV (excluding DAA treatments) for an individual HCV infection patient were estimated to be €32,000. Our results confirm the high efficacy of DAA therapy. Furthermore, these agents improve the clinical conditions and reduce both the treatment cost and health care in patients with HCV infection.

Published
2019

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