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1. Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis

Author

Bondue, Tjessa, Berlingerio, Sante Princiero, Siegerist, Florian, Sendino-Garví, Elena, Schindler, Maximilian, Baelde, Hans Jacobus, Cairoli, Sara, Goffredo, Bianca Maria, Arcolino, Fanny Oliveira, Dieker, Jürgen, Janssen, Manoe Jacoba, Endlich, Nicole, Brock, Roland, Gijsbers, Rik, van den Heuvel, Lambertus, and Levtchenko, Elena

Published
2023
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4. Pharmacokinetic Evaluation of Oral Viscous Budesonide in Paediatric Patients with Eosinophilic Oesophagitis in Repaired Oesophageal Atresia.

Author

Simeoli, Raffaele, Lava, Sebastiano A. G., Di Deo, Alessandro, Roversi, Marco, Cairoli, Sara, Tambucci, Renato, Rea, Francesca, Malamisura, Monica, Angelino, Giulia, Biondi, Isabella, Simonetti, Alessandra, De Angelis, Paola, Dionisi Vici, Carlo, Rossi, Paolo, Pontrelli, Giuseppe, Della Pasqua, Oscar, and Goffredo, Bianca Maria

Subjects
ESOPHAGEAL atresia, EOSINOPHILIC esophagitis, CHILD patients, PHARMACOKINETICS, HYDROCORTISONE
Abstract

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression. [ABSTRACT FROM AUTHOR]

Published
2024
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5. MFSD12 depletion reduces cystine accumulation without improvement in proximal tubular function in experimental models for cystinosis.

Author

Bondue, Tjessa, Khodaparast, Laleh, Khodaparast, Ladan, Cairoli, Sara, Goffredo, Bianca Maria, Gijsbers, Rik, van den Heuvel, Lambertus, and Levtchenko, Elena

Subjects
CYSTINE, FANCONI syndrome, RENAL tubular transport disorders, KIDNEY diseases, GENE expression, LYSOSOMAL storage diseases, GENOME editing
Abstract

Cystinosis is an autosomal recessive lysosomal storage disorder, caused by mutations in the CTNS gene, resulting in an absent or altered cystinosin (CTNS) protein. Cystinosin exports cystine out of the lysosome, with a malfunction resulting in cystine accumulation and a defect in other cystinosin-mediated pathways. Cystinosis is a systemic disease, but the kidneys are the first and most severely affected organs. In the kidney, the disease initially manifests as a generalized dysfunction in the proximal tubules (also called renal Fanconi syndrome). MFSD12 is a lysosomal cysteine importer that directly affects the cystine levels in melanoma cells, HEK293T cells, and cystinosis patient-derived fibroblasts. In this study, we aimed to evaluate MFSD12 mRNA levels in cystinosis patient-derived proximal tubular epithelial cells (ciPTECs) and to study the effect of MFSD12 knockout on cystine levels. We showed similar MFSD12 mRNA expression in patient-derived ciPTECs in comparison with the control cells. CRISPR MFSD12 knockout in a patient-derived ciPTEC (CTNSΔ57kb) resulted in significantly reduced cystine levels. Furthermore, we evaluated proximal tubular reabsorption after injection of mfsd12a translation-blocking morpholino (TB MO) in a ctns−/− zebrafish model. This resulted in decreased cystine levels but caused a concentration-dependent increase in embryo dysmorphism. Furthermore, the mfsd12a TB MO injection did not improve proximal tubular reabsorption or megalin expression. In conclusion, MFSD12 mRNA depletion reduced cystine levels in both tested models without improvement of the proximal tubular function in the ctns−/− zebrafish embryo. In addition, the apparent toxicity of higher mfsd12a TB MO concentrations on the zebrafish development warrants further evaluation. NEW & NOTEWORTHY: In this study, we show that MFSD12 depletion with either CRISPR/Cas9-mediated gene editing or a translation-blocking morpholino significantly reduced cystine levels in cystinosis ciPTECs and ctns−/− zebrafish embryos, respectively. However, we observed no improvement in the proximal tubular reabsorption of dextran in the ctns−/− zebrafish embryos injected with mfsd12a translation-blocking morpholino. Furthermore, a negative effect of the mfsd12a morpholino on the zebrafish development warrants further investigation. [ABSTRACT FROM AUTHOR]

Published
2024
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6. A New and Rapid LC-MS/MS Method for the Determination of Cysteamine Plasma Levels in Cystinosis Patients.

Author

Simeoli, Raffaele, Cairoli, Sara, Greco, Marcella, Bellomo, Francesco, Mancini, Alessandro, Rossi, Chiara, Dionisi Vici, Carlo, Emma, Francesco, and Goffredo, Bianca Maria

Subjects
*LIQUID chromatography-mass spectrometry, *CYSTEAMINE, *ORAL drug administration
Abstract

Cystinosis is a rare lysosomal storage disorder caused by autosomal recessive mutations in the CTNS gene that encodes for the cystine transporter cystinosin, which is expressed on the lysosomal membrane mediating the efflux of cystine. Cysteamine bitartrate is a cystine-depleting aminothiol agent approved for the treatment of cystinosis in children and adults. In this study, we developed and validated a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the determination of cysteamine levels in plasma samples. This LC-MS/MS method was validated according to the European Medicines Agency (EMA)'s guidelines for bioanalytical method validation. An ultra-performance liquid chromatograph (UPLC) coupled with a 6470 mass spectrometry system was used for cysteamine determination. Our validated method was applied to plasma samples from n = 8 cystinosis patients (median, interquartile range (IQR) = 20.5, 8.5–26.0 years). The samples were collected before cysteamine oral administration (pre-dose) and 1 h after (post-dose). Our bioanalytical method fulfilled the regulatory guidelines for method validation. The cysteamine plasma levels in pre-dose samples were 2.57 and 1.50–3.31 μM (median and IQR, respectively), whereas the post-dose samples reported a cysteamine median concentration of 28.00 μM (IQR: 17.60–36.61). Our method allows the rapid determination of cysteamine plasma levels. This method was successfully used in cystinosis patients and, therefore, could be a useful tool for the evaluation of therapy adherence and for future pharmacokinetic (PK) studies involving a higher number of subjects. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Cenobamate as add-on therapy for drug resistant epilepsies: effectiveness, drug to drug interactions and neuropsychological impact. What have we learned from real word evidence?

Author

Pietrafusa, Nicola, primary, Falcicchio, Giovanni, additional, Russo, Emilio, additional, Lattanzi, Simona, additional, Goffredo, Bianca, additional, Simeoli, Raffaele, additional, Cairoli, Sara, additional, Corsetti, Tiziana, additional, Roberti, Roberta, additional, De Tommaso, Marina, additional, Vigevano, Federico, additional, La Neve, Angela, additional, and Specchio, Nicola, additional

Published
2023
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9. Impact of Continuous Kidney Replacement Therapy and Hemoadsorption with CytoSorb on Antimicrobial Drug Removal in Critically Ill Children with Septic Shock: A Single-Center Prospective Study on a Pediatric Cohort

Author

Bottari, Gabriella, primary, Goffredo, Bianca Maria, additional, Marano, Marco, additional, Maccarrone, Cristina, additional, Simeoli, Raffaele, additional, Bianco, Giuseppe, additional, Vallesi, Leonardo, additional, Beetham, Joseph Charles Charlie, additional, Mazzeo, Anna Teresa, additional, Cappoli, Andrea, additional, Cairoli, Sara, additional, Labbadia, Raffaella, additional, Cecchetti, Corrado, additional, Bernaschi, Paola, additional, Corsetti, Tiziana, additional, Morabito, Santo, additional, Taccone, Fabio Silvio, additional, and Guzzo, Isabella, additional

Published
2023
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10. Continuous Fentanyl Infusion in Newborns with Hypoxic–Ischemic Encephalopathy Treated with Therapeutic Hypothermia: Background, Aims, and Study Protocol for Time-Concentration Profiles

Author

Lugli, Licia, primary, Garetti, Elisabetta, additional, Goffredo, Bianca Maria, additional, Candia, Francesco, additional, Crestani, Sara, additional, Spada, Caterina, additional, Guidotti, Isotta, additional, Bedetti, Luca, additional, Miselli, Francesca, additional, Della Casa, Elisa Muttini, additional, Roversi, Maria Federica, additional, Simeoli, Raffaele, additional, Cairoli, Sara, additional, Merazzi, Daniele, additional, Lago, Paola, additional, Iughetti, Lorenzo, additional, and Berardi, Alberto, additional

Published
2023
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11. Impact of CKRT and Hemoadsorption with CytoSorb on Antimicrobials Drugs Removal in Critically Ill Children with Septic Shock: A Single Center Prospective Study in a Pediatric Cohort

Author

Bottari, Gabriella, primary, Goffredo, Bianca, additional, Marano, Marco, additional, Maccarrone, Crisitna, additional, Simeoli, Raffaele, additional, Bianco, Giuseppe, additional, Vallesi, Leonardo, additional, Beetham, Joseph Charles Charlie, additional, Mazzeo, Anna Teresa, additional, Cappoli, Andrea, additional, Cairoli, Sara, additional, Labbadia, Raffaella, additional, Cecchetti, Corrado, additional, Bernaschi, Paola, additional, Corsetti, Tiziana, additional, Morabito, Santo, additional, Taccone, Fabio Silvio, additional, and Guzzo, Isabella, additional

Published
2023
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15. CTNS mRNA as a potential treatment for nephropathic cystinosis

Author

Bondue, Tjessa, primary, Berlingerio, Sante Princiero, additional, Siegerist, Florian, additional, Sendino-Garví, Elena, additional, Schindler, Maximilian, additional, Cairoli, Sara, additional, Goffredo, Bianca Maria, additional, Arcolino, Fanny Oliveira, additional, Dieker, Jürgen, additional, Janssen, Manoe, additional, Endlich, Nicole, additional, Brock, Roland, additional, Gijsbers, Rik, additional, van den Heuvel, Lambertus, additional, and Levtchenko, Elena, additional

Published
2023
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16. Plasma and Cerebrospinal Fluid Concentrations of Micafungin Administered at High Doses in Critically Ill Infants with Systemic Candidiasis: A Pooled Analysis of Two Studies

Author

De Rose, Domenico Umberto, primary, Bersani, Iliana, additional, Ronchetti, Maria Paola, additional, Piersigilli, Fiammetta, additional, Cairoli, Sara, additional, Dotta, Andrea, additional, Desai, Amit, additional, Kovanda, Laura Lynn, additional, Goffredo, Bianca Maria, additional, and Auriti, Cinzia, additional

Published
2023
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17. Neurologic outcome following liver transplantation for methylmalonic aciduria

Author

Martinelli, Diego, primary, Catesini, Giulio, additional, Greco, Benedetta, additional, Guarnera, Alessia, additional, Parrillo, Chiara, additional, Maines, Evelina, additional, Longo, Daniela, additional, Napolitano, Antonio, additional, De Nictolis, Francesca, additional, Cairoli, Sara, additional, Liccardo, Daniela, additional, Caviglia, Stefania, additional, Sidorina, Anna, additional, Olivieri, Giorgia, additional, Siri, Barbara, additional, Bianchi, Roberto, additional, Spagnoletti, Gionata, additional, Dello Strologo, Luca, additional, Spada, Marco, additional, and Dionisi‐Vici, Carlo, additional

Published
2023
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18. CTNSmRNA as a potential treatment for nephropathic cystinosis

Author

Afd Pharmacology, Pharmacology, Bondue, Tjessa, Berlingerio, Sante P., Siegerist, Florian, Sendino-Garví, Elena, Schindler, Maximilian, Cairoli, Sara, Goffredo, Bianca M., Arcolino, Fanny O., Dieker, Jürgen, Janssen, Manoe, Endlich, Nicole, Brock, Roland, Gijsbers, Rik, Heuvel, Lambertus van den, Levtchenko, Elena, Afd Pharmacology, Pharmacology, Bondue, Tjessa, Berlingerio, Sante P., Siegerist, Florian, Sendino-Garví, Elena, Schindler, Maximilian, Cairoli, Sara, Goffredo, Bianca M., Arcolino, Fanny O., Dieker, Jürgen, Janssen, Manoe, Endlich, Nicole, Brock, Roland, Gijsbers, Rik, Heuvel, Lambertus van den, and Levtchenko, Elena

Published
2023

19. Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis

Author

Afd Pharmacology, Pharmacology, Bondue, Tjessa, Berlingerio, Sante Princiero, Siegerist, Florian, Sendino-Garví, Elena, Schindler, Maximilian, Baelde, Hans Jacobus, Cairoli, Sara, Goffredo, Bianca Maria, Arcolino, Fanny Oliveira, Dieker, Jürgen, Janssen, Manoe Jacoba, Endlich, Nicole, Brock, Roland, Gijsbers, Rik, van den Heuvel, Lambertus, Levtchenko, Elena, Afd Pharmacology, Pharmacology, Bondue, Tjessa, Berlingerio, Sante Princiero, Siegerist, Florian, Sendino-Garví, Elena, Schindler, Maximilian, Baelde, Hans Jacobus, Cairoli, Sara, Goffredo, Bianca Maria, Arcolino, Fanny Oliveira, Dieker, Jürgen, Janssen, Manoe Jacoba, Endlich, Nicole, Brock, Roland, Gijsbers, Rik, van den Heuvel, Lambertus, and Levtchenko, Elena

Published
2023

20. Impact of Continuous Kidney Replacement Therapy and Hemoadsorption with CytoSorb on Antimicrobial Drug Removal in Critically Ill Children with Septic Shock: A Single-Center Prospective Study on a Pediatric Cohort

Author

Bottari, Gabriella, Goffredo, Bianca Maria, Marano, Marco, Maccarrone, Cristina, Simeoli, Raffaele, Bianco, Giuseppe, Vallesi, Leonardo, Beetham, Joseph Charles Charlie, Mazzeo, Anna Teresa, Cappoli, Andrea, Cairoli, Sara, Labbadia, Raffaella, Cecchetti, Corrado, Bernaschi, Paola, Corsetti, Tiziana, Morabito, Santo, Taccone, Fabio, Guzzo, Isabella, Bottari, Gabriella, Goffredo, Bianca Maria, Marano, Marco, Maccarrone, Cristina, Simeoli, Raffaele, Bianco, Giuseppe, Vallesi, Leonardo, Beetham, Joseph Charles Charlie, Mazzeo, Anna Teresa, Cappoli, Andrea, Cairoli, Sara, Labbadia, Raffaella, Cecchetti, Corrado, Bernaschi, Paola, Corsetti, Tiziana, Morabito, Santo, Taccone, Fabio, and Guzzo, Isabella

Abstract

Background: Extracorporeal therapies (ET) are increasingly used in pediatric settings as adjuvant therapeutic strategies for overwhelming inflammatory conditions. Although these treatments seem to be effective for removing inflammatory mediators, their influence on antimicrobials pharmacokinetic should not be neglected. Methods: A prospective observational study of children admitted to the pediatric intensive care unit (PICU) with a diagnosis of sepsis/septic shock. All critically ill children received hemoadsorption treatment with CytoSorb (CS) in combination with CKRT. Therapeutic drug monitoring has been performed on 10 critically ill children, testing four antimicrobial molecules: meropenem, ceftazidime, amikacin and levofloxacin. In order to evaluate the total and isolated CKRT and CS contributions to antibiotic removal, blood samples at each circuit point (post-hemofilter, post-CS and in the effluent line) were performed. Therefore, the clearance and mass Removal (MR) of the hemofilter and CS were calculated. Results: Our preliminary report describes a different impact of CS on these target drugs removal: CS clearance was low for amikacine (6–12%), moderate for ceftazidime (43%) and moderate to high for levofloxacine (52–72%). Higher MR and clearance were observed with CKRT compared to CS. To the best of our knowledge, this is the first report regarding pharmacokinetic dynamics in critically ill children treated with CKRT and CS for septic shock., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2023

22. Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine

Author

De Leo, Ester, primary, Taranta, Anna, additional, Raso, Roberto, additional, Polishchuk, Elena, additional, D’Oria, Valentina, additional, Pezzullo, Marco, additional, Goffredo, Bianca Maria, additional, Cairoli, Sara, additional, Bellomo, Francesco, additional, Battafarano, Giulia, additional, Camassei, Francesca Diomedi, additional, Del Fattore, Andrea, additional, Polishchuk, Roman, additional, Emma, Francesco, additional, and Rega, Laura Rita, additional

Published
2022
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24. Use of Antibiotics in Preterm Newborns

Author

Simeoli, Raffaele, primary, Cairoli, Sara, additional, Decembrino, Nunzia, additional, Campi, Francesca, additional, Dionisi Vici, Carlo, additional, Corona, Alberto, additional, and Goffredo, Bianca Maria, additional

Published
2022
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26. Therapeutic Drug Monitoring of Amphotericin-B in Plasma and Peritoneal Fluid of Pediatric Patients after Liver Transplantation: A Case Series

Author

Tortora, Francesca, primary, Dei Giudici, Luigi, additional, Simeoli, Raffaele, additional, Chiusolo, Fabrizio, additional, Cairoli, Sara, additional, Bernaschi, Paola, additional, Bianchi, Roberto, additional, Picardo, Sergio Giuseppe, additional, Dionisi Vici, Carlo, additional, and Goffredo, Bianca Maria, additional

Published
2022
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27. Use of Meropenem and Other Antimicrobial Lock Therapy in the Treatment of Catheter-Related Blood Stream Infections in Neonates: A Retrospective Study.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, Piersigilli, Fiammetta, Auriti, Cinzia, Dotta, Andrea, Goffredo, Bianca Maria, Cairoli, Sara, Savarese, Immacolata, Campi, Francesca, Corsetti, Tiziana, Bersani, Iliana, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, Piersigilli, Fiammetta, Auriti, Cinzia, Dotta, Andrea, Goffredo, Bianca Maria, Cairoli, Sara, Savarese, Immacolata, Campi, Francesca, Corsetti, Tiziana, and Bersani, Iliana

Abstract

BACKGROUND: Newborns admitted to Neonatal Intensive Care Units (NICUs) often require the placement of central vascular catheters (CVC), which are a major risk factor for hospital infection. Numerous strategies exist to prevent central line-associated blood stream infections (CLABSIs) and catheter-related bloodstream infections (CRBSIs), with only a few offering options to save the catheter when it is impossible to replace. CRBSIs continue to be a major problem for neonates in NICUs. Most CRBSIs are resistant to systemic antibiotics due to the presence of intraluminal bacterial biofilm. Therefore, catheter removal is frequently necessary when a CRBSI occurs. The so-called Antibiotic Lock Therapy (ALT) is an antimicrobial therapeutic strategy which seems to be promising in neonates when catheter removal is difficult due to critical conditions. To date, evidence about the use of ALT in the neonatal period is still fragmentary, since only poor and heterogeneous data exist. METHODS: We report our successful experience with ALT in seriously ill neonates with CRBSI for whom the replacement of the catheter could have been life threatening. RESULTS: ALT repetitively performed for at least 12 h was effective in 11 out of 13 infants (84.6%). It was not effective in two infants in whom ALT was performed for only 6 h. Moreover, we present new data about the stability testing of meropenem for its use during ALT in neonates. CONCLUSIONS: When CRBSI occurs-bearing in mind that the optimal management is catheter removal if antibiotic therapy is not effective within 48 h-ALT seems to be a valid alternative therapy when removal is impractical due to critical conditions.

Published
2022

29. Justification of empiric methodology to determine dexmedetomidine dose for the TREX study.

Author

Disma, Nicola, Goffredo, Bianca M., Cairoli, Sara, Cirillo, Ginevra, Morse, James, Anderson, Brian J., Bonfiglio, Rachele, Cordani, Ramona, Garrone, Marco, Patrone, Elisa, Iengo, Annalisa, Bocca, Paola, Izzo, Francesca, Diotto, Veronica, Lenares, Elena, Robino, Chiara, Neri, Simona, Colantonio, Laura, Calderini, Edoardo, and Picardo, Sergio

Subjects
DEXMEDETOMIDINE, CARDIAC intensive care, CHILD care, CARDIAC surgery
Abstract

Introduction: Dexmedetomidine is the sedative agent administered in combination with remifentanil and low dose of sevoflurane in the interventional arm of the ongoing TREX trial (Trial Remifentanil DExmedetomidine). The TREX pilot study (published in Paediatr Anaesth 2019;29:59–67) established infusion rates higher than those initially proposed. This could be attributed to an inappropriate target concentration for sedation or incorrect initial pharmacokinetic parameter estimates. Methods: The TREX study is a Phase III, randomized, active controlled, parallel group, blinded evaluator, multicenter, superiority trial comparing neurological outcome after standard sevoflurane anesthesia with dexmedetomidine/remifentanil, and low dose sevoflurane anesthesia in children aged less than 2 years undergoing anesthesia of 2 h or longer. In this report, dexmedetomidine pharmacokinetics were analyzed in the interventional arm of the Italian population. Results: There were 162 blood samples from 32 infants (22 male and 10 female). The median (IQR) age was 12 (5.2–15.5) months, weight 9.9 (7.3–10.8) kg. Duration of anesthesia ranged from 2 to 6 h. None of the children were born premature (median postnatal age 39 weeks, IQR 38–40 weeks). A 3‐compartment PK model that incorporated allometric scaling and a maturation function demonstrated plasma concentration observations from the current Italian arm of the TREX study were consistent with those predicted by a "universal" model using pooled data obtained from neonates to adults. Conclusions: This current PK analysis from the Italian arm of the TREX study confirms that plasma concentration of dexmedetomidine is predictable using known covariates such as age and size. The initial target concentration (0.6 μg.L−1) used to sedate children cared for in the intensive care after cardiac surgery was inadequate for infants in the current TREX study. A target concentration 1 mcg.L−1, corresponding to a loading dose of 1 mcg.kg−1 followed by an infusion of 1 mcg.kg−1.h−1, provided adequate sedation. [ABSTRACT FROM AUTHOR]

Published
2023
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31. The diagnostic challenge of mild citrulline elevation at newborn screening

Author

Siri, Barbara, primary, Olivieri, Giorgia, additional, Angeloni, Antonio, additional, Cairoli, Sara, additional, Carducci, Claudia, additional, Cotugno, Giovanna, additional, Di Michele, Silvia, additional, Giovanniello, Teresa, additional, La Marca, Giancarlo, additional, Lepri, Francesca Romana, additional, Novelli, Antonio, additional, Rossi, Claudia, additional, Semeraro, Michela, additional, and Dionisi-Vici, Carlo, additional

Published
2022
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32. Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Author

Taranta, Anna, elmonem, mohamed a, Bellomo, Francesco, Leo, Ester De, Boenzi, Sara, Janssen, Manoe J., Jamalpoor, Amer, Cairoli, Sara, Pastore, Anna, Stefanis, Cristiano De, Colucci, Manuela, Rega, Laura R., giovannoni, isabella, Francalanci, Paola, Heuvel, Lambertus P. van den, Dionisi-Vici, Carlo, Goffredo, Bianca M., Masereeuw, Rosalinde, Levtchenko, Elena, Emma, Francesco, Afd Pharmacology, Pharmacology, Afd Pharmacology, and Pharmacology

Subjects
Embryo, Nonmammalian, mice, QH301-705.5, Cystinosis, Cystine, disulfiram, Apoptosis, Pharmacology, Article, Mice, chemistry.chemical_compound, All institutes and research themes of the Radboud University Medical Center, cystinosis, zebrafish, Nephropathic Cystinosis, Toxicity Tests, Disulfiram, medicine, Animals, Humans, Disulfides, Biology (General), Zebrafish, Mice, Knockout, Medicine(all), business.industry, General Medicine, medicine.disease, Acetylcysteine, Disease Models, Animal, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Cystinosin, chemistry, Larva, Symporter, Toxicity, Kidney Diseases, Cysteamine, business, medicine.drug
Abstract

Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Current therapy with cysteamine only partially reverts some of these changes, highlighting the need to develop additional treatments. Among compounds that were identified in a previous drug-repositioning study, disulfiram (DSF) was selected for in vivo studies. The cystine depleting and anti-apoptotic properties of DSF were confirmed by secondary in vitro assays and after treating Ctns-/- mice with 200 mg/kg/day of DSF for 3 months. However, at this dosage, growth impairment was observed. Long-term treatment with a lower dose (100 mg/kg/day) did not inhibit growth, but failed to reduce cystine accumulation, caused premature death, and did not prevent the development of renal lesions. In addition, DSF also caused adverse effects in cystinotic zebrafish larvae. DSF toxicity was significantly more pronounced in Ctns-/- mice and zebrafish compared to wild-type animals, suggesting higher cell toxicity of DSF in cystinotic cells. ispartof: CELLS vol:10 issue:12 ispartof: location:Switzerland status: published

Published
2021

33. Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

Author

Dionisi, Marco, primary, Cairoli, Sara, additional, Simeoli, Raffaele, additional, De Gennaro, Francesca, additional, Paganelli, Valeria, additional, Carta, Roberto, additional, Rossi, Francesca, additional, Dionisi-Vici, Carlo, additional, Palumbo, Giuseppe, additional, and Goffredo, Bianca Maria, additional

Published
2021
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34. Renal and Extra Renal Manifestations in Adult Zebrafish Model of Cystinosis

Author

Berlingerio, Sante Princiero, primary, He, Junling, additional, De Groef, Lies, additional, Taeter, Harold, additional, Norton, Tomas, additional, Baatsen, Pieter, additional, Cairoli, Sara, additional, Goffredo, Bianca, additional, de Witte, Peter, additional, van den Heuvel, Lambertus, additional, Baelde, Hans J., additional, and Levtchenko, Elena, additional

Published
2021
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35. Synergistic Meropenem/Vaborbactam Plus Fosfomycin Treatment of KPC Producing K. pneumoniae Septic Thrombosis Unresponsive to Ceftazidime/Avibactam: From the Bench to the Bedside

Author

Oliva, Alessandra, primary, Curtolo, Ambrogio, additional, Volpicelli, Lorenzo, additional, Cogliati Dezza, Francesco, additional, De Angelis, Massimiliano, additional, Cairoli, Sara, additional, Dell’Utri, Donatella, additional, Goffredo, Bianca Maria, additional, Raponi, Giammarco, additional, and Venditti, Mario, additional

Published
2021
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36. Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Author

Afd Pharmacology, Pharmacology, Taranta, Anna, elmonem, mohamed a, Bellomo, Francesco, Leo, Ester De, Boenzi, Sara, Janssen, Manoe J., Jamalpoor, Amer, Cairoli, Sara, Pastore, Anna, Stefanis, Cristiano De, Colucci, Manuela, Rega, Laura R., giovannoni, isabella, Francalanci, Paola, Heuvel, Lambertus P. van den, Dionisi-Vici, Carlo, Goffredo, Bianca M., Masereeuw, Rosalinde, Levtchenko, Elena, Emma, Francesco, Afd Pharmacology, Pharmacology, Taranta, Anna, elmonem, mohamed a, Bellomo, Francesco, Leo, Ester De, Boenzi, Sara, Janssen, Manoe J., Jamalpoor, Amer, Cairoli, Sara, Pastore, Anna, Stefanis, Cristiano De, Colucci, Manuela, Rega, Laura R., giovannoni, isabella, Francalanci, Paola, Heuvel, Lambertus P. van den, Dionisi-Vici, Carlo, Goffredo, Bianca M., Masereeuw, Rosalinde, Levtchenko, Elena, and Emma, Francesco

Published
2021

37. High-Dose Micafungin in Neonates and Young Infants with Invasive Candidiasis: Results of a Phase 2 Study.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, Auriti, Cinzia, Goffredo, Bianca M, Ronchetti, Maria P, Piersigilli, Fiammetta, Cairoli, Sara, Bersani, Iliana, Dotta, Andrea, Bagolan, Pietro, Pai, Manjunath P, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, Auriti, Cinzia, Goffredo, Bianca M, Ronchetti, Maria P, Piersigilli, Fiammetta, Cairoli, Sara, Bersani, Iliana, Dotta, Andrea, Bagolan, Pietro, and Pai, Manjunath P

Abstract

Limited data are available on the most appropriate dosing, efficacy, and safety of micafungin in neonates and young infants with invasive candidiasis (IC). This study evaluated plasma levels, efficacy, and safety of micafungin at a dose of 8 mg/kg daily for a mean of 13.3 days (±5.2 days) in 35 neonates and young infants with IC. Micafungin plasma concentrations were 5.70 mg/liter preadministration and 17.23, 15.59, and 10.27 mg/liter after 1, 2, and 8 h, respectively. The resolution of the infection was achieved in 86.7% of patients treated for ≥14 days. In 20.0% of patients, we observed a transient hypertransaminasemia. Micafungin at a dose of 8 mg/kg daily is effective and well tolerated in neonates and young infants with IC. (This study has been registered at ClinicalTrials.gov under identifier NCT03421002 and in the EU Clinical Trials Register under number 2014-003087-20.).

Published
2021

39. Cell-Based Phenotypic Drug Screening Identifies Luteolin as Candidate Therapeutic for Nephropathic Cystinosis

Author

De Leo, Ester, Elmonem, Mohamed A., Berlingerio, Sante Princiero, Berquez, Marine, Festa, Beatrice Paola, Raso, Roberto, Bellomo, Francesco, Starborg, Tobias, Janssen, Manoe Jacoba, Abbaszadeh, Zeinab, Cairoli, Sara, Goffredo, Bianca Maria, Masereeuw, Rosalinde, Devuyst, Olivier, Lowe, Martin, Levtchenko, Elena, Luciani, Alessandro, Emma, Francesco, Rega, Laura Rita, Afd Pharmacology, Pharmacology, University of Zurich, Emma, Francesco, Rega, Laura Rita, Afd Pharmacology, and Pharmacology

Subjects
0301 basic medicine, Cystinosis, Drug Evaluation, Preclinical, Antioxidants, 10052 Institute of Physiology, Kidney Tubules, Proximal, chemistry.chemical_compound, Mice, 0302 clinical medicine, Sequestosome-1 Protein, Taverne, Lysosomal storage disease, Luteolin, Cells, Cultured, Zebrafish, 2727 Nephrology, apoptosis, General Medicine, 3. Good health, Low Density Lipoprotein Receptor-Related Protein-2, Phenotype, Cystinosin, lysosomal storage disease, Nephrology, autophagy, Cystine, 610 Medicine & health, 03 medical and health sciences, Nephropathic Cystinosis, medicine, Animals, Humans, endocytosis, RNA, Messenger, business.industry, Fanconi syndrome, medicine.disease, Disease Models, Animal, Oxidative Stress, 030104 developmental biology, Basic Research, Amino Acid Transport Systems, Neutral, chemistry, Cancer research, 570 Life sciences, biology, Cysteamine, reactive, business, Lysosomes, 030217 neurology & neurosurgery
Abstract

Background Mutations in the gene that encodes the lysosomal cystine transporter cystinosin cause the lysosomal storage disease cystinosis. Defective cystine transport leads to intralysosomal accumulation and crystallization of cystine. The most severe phenotype, nephropathic cystinosis, manifests during the first months of life, as renal Fanconi syndrome. The cystine-depleting agent cysteamine significantly delays symptoms, but it cannot prevent progression to ESKD and does not treat Fanconi syndrome. This suggests the involvement of pathways in nephropathic cystinosis that are unrelated to lysosomal cystine accumulation. Recent data indicate that one such potential pathway, lysosome-mediated degradation of autophagy cargoes, is compromised in cystinosis.Methods To identify drugs that reduce levels of the autophagy-related protein p62/SQSTM1 in cystinotic proximal tubular epithelial cells, we performed a high-throughput screening on the basis of an in-cell ELISA assay. We then tested a promising candidate in cells derived from patients with, and mouse models of, cystinosis, and in preclinical studies in cystinotic zebrafish.Results Of 46 compounds identified as reducing p62/SQSTM1 levels in cystinotic cells, we selected luteolin on the basis of its efficacy, safety profile, and similarity to genistein, which we previously showed to ameliorate other lysosomal abnormalities of cystinotic cells. Our data show that luteolin improves the autophagy–lysosome degradative pathway, is a powerful antioxidant, and has antiapoptotic properties. Moreover, luteolin stimulates endocytosis and improves the expression of the endocytic receptor megalin.Conclusions Our data show that luteolin improves defective pathways of cystinosis and has a good safety profile, and thus has potential as a treatment for nephropathic cystinosis and other renal lysosomal storage diseases.

Published
2020

40. Cell-Based Phenotypic Drug Screening Identifies Luteolin as Candidate Therapeutic for Nephropathic Cystinosis

Author

Afd Pharmacology, Pharmacology, De Leo, Ester, Elmonem, Mohamed A., Berlingerio, Sante Princiero, Berquez, Marine, Festa, Beatrice Paola, Raso, Roberto, Bellomo, Francesco, Starborg, Tobias, Janssen, Manoe Jacoba, Abbaszadeh, Zeinab, Cairoli, Sara, Goffredo, Bianca Maria, Masereeuw, Rosalinde, Devuyst, Olivier, Lowe, Martin, Levtchenko, Elena, Luciani, Alessandro, Emma, Francesco, Rega, Laura Rita, Afd Pharmacology, Pharmacology, De Leo, Ester, Elmonem, Mohamed A., Berlingerio, Sante Princiero, Berquez, Marine, Festa, Beatrice Paola, Raso, Roberto, Bellomo, Francesco, Starborg, Tobias, Janssen, Manoe Jacoba, Abbaszadeh, Zeinab, Cairoli, Sara, Goffredo, Bianca Maria, Masereeuw, Rosalinde, Devuyst, Olivier, Lowe, Martin, Levtchenko, Elena, Luciani, Alessandro, Emma, Francesco, and Rega, Laura Rita

Published
2020

41. Cell-Based Phenotypic Drug Screening Identifies Luteolin as Candidate Therapeutic for Nephropathic Cystinosis

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, De Leo, Ester, Elmonem, Mohamed A., Berlingerio, Sante Princiero, Berquez, Marine, Festa, Beatrice Paola, Raso, Roberto, Bellomo, Francesco, Starborg, Tobias, Janssen, Manoe Jacoba, Abbaszadeh, Zeinab, Cairoli, Sara, Goffredo, Bianca Maria, Masereeuw, Rosalinde, Devuyst, Olivier, Lowe, Martin, Levtchenko, Elena, Luciani, Alessandro, Emma, Francesco, Rega, Laura Rita, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, De Leo, Ester, Elmonem, Mohamed A., Berlingerio, Sante Princiero, Berquez, Marine, Festa, Beatrice Paola, Raso, Roberto, Bellomo, Francesco, Starborg, Tobias, Janssen, Manoe Jacoba, Abbaszadeh, Zeinab, Cairoli, Sara, Goffredo, Bianca Maria, Masereeuw, Rosalinde, Devuyst, Olivier, Lowe, Martin, Levtchenko, Elena, Luciani, Alessandro, Emma, Francesco, and Rega, Laura Rita

Abstract

BACKGROUND: Mutations in the gene that encodes the lysosomal cystine transporter cystinosin cause the lysosomal storage disease cystinosis. Defective cystine transport leads to intralysosomal accumulation and crystallization of cystine. The most severe phenotype, nephropathic cystinosis, manifests during the first months of life, as renal Fanconi syndrome. The cystine-depleting agent cysteamine significantly delays symptoms, but it cannot prevent progression to ESKD and does not treat Fanconi syndrome. This suggests the involvement of pathways in nephropathic cystinosis that are unrelated to lysosomal cystine accumulation. Recent data indicate that one such potential pathway, lysosome-mediated degradation of autophagy cargoes, is compromised in cystinosis. METHODS: To identify drugs that reduce levels of the autophagy-related protein p62/SQSTM1 in cystinotic proximal tubular epithelial cells, we performed a high-throughput screening on the basis of an in-cell ELISA assay. We then tested a promising candidate in cells derived from patients with, and mouse models of, cystinosis, and in preclinical studies in cystinotic zebrafish. RESULTS: Of 46 compounds identified as reducing p62/SQSTM1 levels in cystinotic cells, we selected luteolin on the basis of its efficacy, safety profile, and similarity to genistein, which we previously showed to ameliorate other lysosomal abnormalities of cystinotic cells. Our data show that luteolin improves the autophagy-lysosome degradative pathway, is a powerful antioxidant, and has antiapoptotic properties. Moreover, luteolin stimulates endocytosis and improves the expression of the endocytic receptor megalin. CONCLUSIONS: Our data show that luteolin improves defective pathways of cystinosis and has a good safety profile, and thus has potential as a treatment for nephropathic cystinosis and other renal lysosomal storage diseases.

Published
2020

42. Staphylococcal meningitis therapy with linezolid in a young infant: efficacy, CSF levels and side effects.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, Auriti, Cinzia, Piersigilli, Fiammetta, Bersani, Iliana, Cairoli, Sara, Amante, Paolina Giuseppina, Longo, Daniela, Goffredo, Bianca Maria, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, Auriti, Cinzia, Piersigilli, Fiammetta, Bersani, Iliana, Cairoli, Sara, Amante, Paolina Giuseppina, Longo, Daniela, and Goffredo, Bianca Maria

Abstract

BACKGROUND: Linezolid is a synthetic antibiotic which is active against most Gram-positive bacteria, especially on Staphylococcus aureus. Its administration can be required when the infection is due to staphylococcus strains, which are resistant to vancomycin. Although mostly well tolerated, some mild to moderate side effects have been reported. CASE PRESENTATION: This case report describes an infant with multiloculated hydrocephalus, staphylococcal meningitis and prolonged linezolid therapy, in which we observed the association between linezolid administration and a lengthened QTc interval at the electrocardiogram (ECG). To rule out toxic levels during the therapy, plasma and cerebro-spinal fluid concentrations of linezolid were measured and reported. CONCLUSIONS: Although generally well tolerated in neonates and infants, linezolid prolonged administration seems be able to cause QTc interval prolongation. Therefore, its administration in such patients should be limited to cases of bacterial resistance to other antibiotics. In addition to well-known close monitoring of the platelet level, we suggest serial ECG controls before and during linezolid administration. In the case we report, linezolid plasma concentrations resulted within the therapeutic range during therapy, while cerebrospinal fluid (CSF) concentrations appeared lower than those considered effective.

Published
2020

43. Therapeutic Drug Monitoring Is a Feasible Tool to Personalize Drug Administration in Neonates Using New Techniques: An Overview on the Pharmacokinetics and Pharmacodynamics in Neonatal Age

Author

De Rose, Domenico Umberto, primary, Cairoli, Sara, additional, Dionisi, Marco, additional, Santisi, Alessandra, additional, Massenzi, Luca, additional, Goffredo, Bianca Maria, additional, Dionisi-Vici, Carlo, additional, Dotta, Andrea, additional, and Auriti, Cinzia, additional

Published
2020
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45. Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module

Author

Di Magno, Laura, primary, Manni, Simona, additional, Di Pastena, Fiorella, additional, Coni, Sonia, additional, Macone, Alberto, additional, Cairoli, Sara, additional, Sambucci, Manolo, additional, Infante, Paola, additional, Moretti, Marta, additional, Petroni, Marialaura, additional, Nicoletti, Carmine, additional, Capalbo, Carlo, additional, De Smaele, Enrico, additional, Di Marcotullio, Lucia, additional, Giannini, Giuseppe, additional, Battistini, Luca, additional, Goffredo, Bianca Maria, additional, Iorio, Egidio, additional, Agostinelli, Enzo, additional, Maroder, Marella, additional, and Canettieri, Gianluca, additional

Published
2020
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46. Antifungal Drugs for Invasive Candida Infections (ICI) in Neonates: Future Perspectives.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, Bersani, Iliana, Piersigilli, Fiammetta, Goffredo, Bianca Maria, Santisi, Alessandra, Cairoli, Sara, Ronchetti, Maria Paola, Auriti, Cinzia, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, Bersani, Iliana, Piersigilli, Fiammetta, Goffredo, Bianca Maria, Santisi, Alessandra, Cairoli, Sara, Ronchetti, Maria Paola, and Auriti, Cinzia

Abstract

Fungal infections may complicate the neonatal clinical course, and the spectrum of therapies for their treatment in the perinatal period is limited. Polyenes, Azoles and Echinocandins represent the three classes of antifungal drugs commonly used in the neonatal period. The present review provides an overview about the most recent therapeutic strategies for the treatment of fungal infections in neonates.

Published
2019

48. A Modified Holder Pasteurization Method for Donor Human Milk: Preliminary Data

Author

Capriati, Teresa, primary, Goffredo, Bianca Maria, additional, Argentieri, Marta, additional, De Vivo, Liliana, additional, Bernaschi, Paola, additional, Cairoli, Sara, additional, Laureti, Francesca, additional, Reposi, Maria Paola, additional, Marino, Daniela, additional, Benedetti, Sabina, additional, and Diamanti, Antonella, additional

Published
2019
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