191 results on '"Jessica Cusato"'
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2. Pharmacokinetics Profile and Genetics of Double Antiviral Therapy with Remdesivir and Nirmatrelvir/Ritonavir for Prolonged COVID-19 in Patients Treated with Rituximab: A Real-Life Study and Literature Review
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Ilaria De Benedetto, Silvia Corcione, Carlotta Giambra, Matteo Ferrante, Simone Mornese Pinna, Elisa Zanotto, Alice Palermiti, Francesca Sidoti, Luca Scaglione, Cecilia Grosso, Martina Billi, Tommaso Lupia, Sara Soloperto, Jessica Cusato, Cristina Costa, Antonio D’Avolio, and Francesco Giuseppe De Rosa
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pharmacokinetics ,pharmacogenetics ,therapeutic drug monitoring ,COVID-19 ,remdesivir ,nirmatrelvir/ritonavir ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Introduction: Patients with hematologic malignancies are more likely to develop severe and prolonged SARS-CoV-2 infection, often showing viral persistence despite the use of authorized antivirals. Herein, we report the cases of four patients who received rituximab for different conditions and developed persistent COVID-19 treated with an extended course of dual antivirals, Nirmatrelvir/Ritonavir and Remdesivir. Moreover, we describe the pharmacokinetics and pharmacogenetics (PK/PG) characteristics of Nirmatrelvir/Ritonavir and Remdesivir treatment in two of these patients. Methods: Plasma specimens for evaluation of trough concentrations (Ctrough) were collected 10 min before the daily dose administration, in addition to 3 h (Cmax), 4 h (C4h), 6 h (C6h) and 1 h (Cmax) after the administration of Nirmatrelvir/Ritonavir and Remdesivir, respectively. The following gene single-nucleotide polymorphisms (SNPs) were investigated: ABCB1 3435 (rs1045642) C > T, ABCB1 1236 (rs1128503) C > T, PXR 63396 (rs2472667) T > C, CYP2D6 (rs1135840) G > C, and CYP3A4*1B (rs2740574) G > A. Results: Double antiviral treatment was successful in terms of symptoms resolution, whereas three out of four patients achieved microbiological eradication. Based on our results, concentrations of Nirmatrelvir ranging from 50 to 5000 ng/mL were effective, whereas a higher concentration (range 1068–3377 ng/mL), compared to that previously reported in patients with similar weight and BMI, was evidenced for Ritonavir. Considering the genetic variant analysis, ABCB1 3435 CT and 1236 CT genotypes were found in patient 1; and ABCB1 3435 CC and 1236 CC in patient 2. In conclusion, this real-life study supports the usefulness of TDM and genetics in immunocompromised patients with persistent SARS-CoV-2 infection, a challenging setting for clinicians in which personalized medicine may improve outcome.
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- 2024
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3. Cannabinoid levels description in a cohort of patients with chronic and neuropathic pain treated with Cannabis decoction: A possible role of TDM
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Alessandra Manca, Cristina Valz, Francesco Chiara, Jacopo Mula, Alice Palermiti, Martina Billi, Miriam Antonucci, Amedeo De Nicolò, Nicola Luxardo, Daniele Imperiale, Flavio Vischia, David De Cori, Jessica Cusato, and Antonio D’Avolio
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THC ,TDM ,Cannabinoids ,Pain ,Medical Cannabis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity.Medical Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety.Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation.In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively.Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method.Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis, between male and female and cigarette smokers.For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data.
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- 2024
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4. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide fumarate in a cohort of patients with HBV infection: A retrospective study
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Giacomo Stroffolini, Valentina Dodaro, Amedeo De Nicolò, Jessica Cusato, Giovanni Di Perri, Antonio D'Avolio, and Lucio Boglione
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HBV ,Tenofovir disoproxil fumarate ,Tenofovir alafenamide fumarate ,Nephrotoxicity ,Infectious and parasitic diseases ,RC109-216 - Abstract
Background: Tenofovir disoproxil fumarate (TDF) as first-line therapy for chronic HBV infection is related to nephrotoxicity. Tenofovir alafenamide fumarate (TAF) has been approved with a similar virological and serological response, but lower toxicity. TAF is available for older patients, with bone or kidney impairment. Methods: The primary objective was the evaluation of renal function modification in patients who are switching from TDF to TAF; secondary objective was the use of urinary concentration of tenofovir (TFV) as early marker of renal function improvement or worsening.Retrospective study including all HBV patients treated with TDF or TAF. Two groups were selected: patients who are switched from TDF to TAF and who continued with TDF. Follow-up was six months. Results: 42 subjects were included; 17 were in TAF group (40 %) and 25 in TDF group (60 %). In TDF group, no estimated glomerular filtration rate (eGFR) improvement was observed, while in TAF group increased by 9 ml/min (p
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- 2024
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5. Studying the Changes in Physical Functioning and Oxidative Stress-Related Molecules in People Living with HIV after Switching from Triple to Dual Therapy
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Jessica Cusato, Anna Mulasso, Micol Ferrara, Alessandra Manca, Miriam Antonucci, Guido Accardo, Alice Palermiti, Gianluca Bianco, Francesco Chiara, Jacopo Mula, Maria Grazia Maddalone, Maria Cristina Tettoni, Simone Cuomo, Giulia Trevisan, Stefano Bonora, Giovanni Di Perri, Corrado Lupo, Alberto Rainoldi, and Antonio D’Avolio
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antioxidants ,ROS ,HAART ,antiretroviral treatment ,physical functioning ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: Physical activity could increase the production of oxidative stress biomarkers, affecting the metabolism and excretion of antiretroviral drugs and, consequently, the clinical outcome. Nowadays, people living with HIV (PLWH) are mostly switching from triple to dual therapy, but no data are available in terms of physical functioning and oxidative stress. The aim of this study was to evaluate if some antioxidant biomarkers and physical functioning tests could be different according to triple or dual antiretroviral therapy. Methods: PLWH were evaluated at baseline (BL), while treated with three drugs, and six months after the switch to dual therapy. Physical functioning was quantified using validated tools. Mitochondrial and cytosol antioxidant molecules were evaluated through liquid chromatography. Results: Twenty-five patients were analyzed. A statistically significant difference between triple and dual therapy was found for mitochondrial glutathione, but not for physical tests. Evaluating differences between physically active and inactive individuals, the following statistically significant differences were suggested, considering triple therapy (mitochondrial n-formyl-methionine p = 0.022, triglycerides p = 0.023) and double therapy (mitochondrial glycine p = 0.035, cytosol glutamic acid p = 0.007, cytosol s-adenosylmethionine p = 0.021). Conclusions: For the first time, this study suggests possible differences in terms of antioxidant molecules and physical functioning in PLWH switching from triple to dual therapy.
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- 2024
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6. Therapeutic Drug Monitoring as a Tool for the Clinical Outcome Prediction in Vedolizumab-Treated Patients: An Italian Pilot Study
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Jessica Cusato, Davide Giuseppe Ribaldone, Michela Helga Falzone, Alessandra Manca, Miriam Antonucci, Alice Palermiti, Giorgio Maria Saracco, Linda Ceccarelli, Francesco Costa, Andrea Bottari, Ginevra Fornaroli, Gian Paolo Caviglia, Antonio D’Avolio, and Lorenzo Bertani
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IBD ,TDM ,monoclonal antibody ,personalized therapy ,Biology (General) ,QH301-705.5 - Abstract
Over the years, vedolizumab (VDZ) has emerged as a more effective target therapy for inflammatory bowel disease. The aim of this work was to analyze a cohort of inflammatory bowel disease patients, evaluating the association between VDZ serum concentrations at 6 months from starting therapy and their clinical and biochemical indexes within one year of treatment, correlating drug levels with response and clinical remission. Forty patients treated with VDZ were enrolled. Drug concentrations were quantified through ELISA methods. VDZ levels correlated with hemoglobin levels at twelve months of therapy (p = 0.03) and with clinical remission at twelve months of therapy (p = 0.03); patients who reached clinical remission showed higher VDZ concentrations. A VDZ cut-off value of 43.1 μg/mL was suggested, predicting clinical remission at twelve months of therapy. A statistically significant association between VDZ levels at T6 and calprotectin p = 0.04). Furthermore, the optimal threshold value of VDZ levels at T6 associated with calprotectin
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- 2024
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7. Correlation between Polymorphisms of Vitamin D Metabolism Genes and Perianal Disease in Crohn’s Disease
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Jessica Cusato, Carla Cafasso, Miriam Antonucci, Alice Palermiti, Alessandra Manca, Gian Paolo Caviglia, Marta Vernero, Angelo Armandi, Giorgio Maria Saracco, Antonio D’Avolio, and Davide Giuseppe Ribaldone
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polymorphism ,vitamin D ,metabolism ,genes ,perianal ,Crohn’s disease ,Biology (General) ,QH301-705.5 - Abstract
Although the role of vitamin D (VD) in the pathogenesis and progression of Crohn’s disease (CD) is known, the association between single-nucleotide polymorphisms (SNPs) of genes linked to vitamin D pathway and CD risk is still under study. Furthermore, no significant association has been previously found between these SNPs and perianal CD (pCD), a severe phenotypic manifestation of CD that may present as perianal fistula, abscess, and recto-vaginal fistula. Among the mechanisms involved in its pathogenesis, local inflammation and intestinal microbiota alteration are recognized. VD seems to act on these elements. The aim of this study was to evaluate the presence of an association between SNPs of genes coding for enzymes, transporters, and receptors involved in the VD pathway and the occurrence of pCD. Blood samples of 206 patients with CD, including 34 with pCD, were analyzed for VDR, CYP27B1, CYP24A1, and GC genetic variants. VDR Apal Aa genotype and VDR BsmI Bb genotype resulted in an association with pCD (p = 0.01 and p = 0.02, respectively). Our study demonstrates for the first time the impact of the polymorphisms of genes associated with the VD pathway on the onset of pCD. Future multicenter studies are needed to confirm these data.
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- 2024
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8. Vitamin D impact in affecting clozapine plasma exposure: A potential contribution of seasonality
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Alessandra Manca, Jacopo Mula, Alice Palermiti, Flavio Vischia, David De Cori, Sara Venturello, Guido Emanuelli, Domenico Maiese, Miriam Antonucci, Amedeo De Nicolò, Elisa Delia De Vivo, Jessica Cusato, and Antonio D'Avolio
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Clozapine ,Vitamin D ,Pharmacokinetics ,Therapeutic drug monitoring ,Antipsychotics ,Seasonality ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Schizophrenia affects approximately 24 million people worldwide and clozapine is the most effective antipsychotic drug. Nevertheless, its use in therapy is limited due to adverse effects.Therapeutic drug monitoring is a clinical tool useful to reduce the clozapine toxicity. In the literature, papers showed how psychiatric disorders could be associated with low vitamin D levels, but a few studies focusing on its role in affecting clozapine exposure are available. A TDM repository was analyzed: clozapine and vitamin D levels measured with liquid chromatography were considered. 1261 samples obtained from 228 individuals were evaluated: 624 patients (49.5%) showed clozapine plasma levels in therapeutic range (350–600 ng/mL). Clozapine toxic plasma levels (>1000 ng/mL) were more present in winter (p = 0.025), compared to other seasons. Concerning vitamin D, a sub-analysis of 859 samples was performed: 326 (37.81%) were deficient ( ng/mL), 490 (57.12%) had insufficient concentrations (10–30 ng/mL), while 43 (5.02%) had sufficient (>30 ng/mL) levels. A correlation between vitamin D and clozapine plasma levels (p = 0.007, Pearson coefficient=0.093) was observed. The role of seasonal variation in clozapine plasma exposure in psychiatric patients treated with clozapine was suggested. Further studies in larger cohorts are needed in order to clarify these aspects.
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- 2023
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9. Analytical validation of a novel UHPLC-MS/MS method for 19 antibiotics quantification in plasma: Implementation in a LC-MS/MS Kit
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Jacopo Mula, Francesco Chiara, Alessandra Manca, Alice Palermiti, Domenico Maiese, Jessica Cusato, Marco Simiele, Francesco Giuseppe De Rosa, Giovanni Di Perri, Amedeo De Nicolò, and Antonio D’Avolio
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Antibiotic agents ,ATB ,UHPLC-MS/MS ,Kit System ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: Therapeutic drug monitoring (TDM) for antibiotic drugs represents a consolidated practice to optimize the effectiveness and to limit the toxicity of specific drugs by guiding dosage adjustments. The comparison of TDM results with drug-specific pharmacokinetic/pharmacodynamic (PK/PD) parameters, based on killing dynamics and bacterial susceptibility, increases the probability of therapeutic success. Purpose: The aim of this study was the analytical validation of a new UHPLC-MS/MS assay for the quantification of 19 antibiotics divided in two different sets considering their chemical/pharmacological properties. This method has been implemented in an analytical LC-MS/MS Kit System by CoQua Lab s.r.l (Turin). Methods: The analytical validation is developed in accordance with “ICH Harmonized Guideline M10 on bioanalytical method validation and study sample analysis” and “Guidelines for regulatory auditing of quality management system of medical device manufacturers''. Method suitability in the clinical context was tested by analysing clinical samples from patients treated with antibiotic drugs. Results: This method allows for simultaneous TDM of the following molecules: dalbavancin, daptomycin, linezolid, tedizolid, levofloxacin, moxifloxacin, meropenem, ertapenem, vaborbactam, avibactam, sulbactam, tazobactam, ceftazidime, ceftriaxone, ceftolozane, ceftobiprole, cefiderocol, ceftaroline and piperacillin. These drugs were quantified showing analytical performance parameters compliant with guidelines in terms of repeatability, reproducibility, robustness, bias, LOD, LOQ and linearity. The method was capable to successfully monitor drug concentrations in 65 samples from 52 patients undergoing treatment. Conclusion: The UHPLC-MS/MS method described in this work can be useful for TDM of the reported antimicrobial agents. The analytical protocol is rapid and suitable to be used in routine analysis.
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- 2023
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10. Stability Study of Fosfomycin in Elastomeric Pumps at 4 °C and 34 °C: Technical Bases for a Continuous Infusion Use for Outpatient Parenteral Antibiotic Therapy
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Alessandra Manca, Alice Palermiti, Jacopo Mula, Jessica Cusato, Domenico Maiese, Marco Simiele, Amedeo De Nicolò, and Antonio D’Avolio
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Fosfomycin ,UHPLC ,stability ,OPAT ,bridge therapy ,Pharmacy and materia medica ,RS1-441 - Abstract
Background: Fosfomycin acts against aerobic Gram−/+ bacteria by blocking the synthesis of peptidoglycan. Its use has been currently re-evaluated for intravenous administration for the treatment of systemic infections by multidrug-resistant bacteria. Concentration-/time-dependent activity has been suggested, with potential clinical advantages from prolonged or continuous infusion. Nevertheless, little is known about Fosfomycin stability in elastomeric pumps. The aim of the present work was stability investigation before administration at 4 °C and during administration at 34 °C. Methods: InfectoFos® (InfectoPharm s.r.l., Milan, Italy) preparation for intravenous use in elastomeric pumps at 4 °C and 34 °C was analyzed following EMA guidelines for drug stability. Samples were analyzed with an ultra-high performance liquid chromatography coupled with tandem mass spectrometry method on a LX50® UHPLC system equipped with a QSight 220® (Perkin Elmer, Milan, Italy) tandem mass spectrometer. Results: Fosfomycin in elastomeric preparation is stable for at least 5 days at a storage temperature of 4 °C and 34 °C. Conclusions: The results suggest Fosfomycin eligibility for continuous infusion even in the context of outpatient parenteral antibiotic therapy. Therefore, this approach should be tested in clinical and pharmacokinetic studies, in order to evaluate the possible gains in the pharmacokinetic profile and the clinical effectiveness.
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- 2023
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11. Hormone Receptors and Epithelial Ovarian Cancer: Recent Advances in Biology and Treatment Options
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Fulvio Borella, Stefano Fucina, Luca Mangherini, Stefano Cosma, Andrea Roberto Carosso, Jessica Cusato, Paola Cassoni, Luca Bertero, Dionyssios Katsaros, and Chiara Benedetto
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ovarian cancer ,hormone therapy ,endocrine therapy ,hormone receptors ,aromatase inhibitors ,fulvestrant ,Biology (General) ,QH301-705.5 - Abstract
Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women. Despite advances in diagnosis and treatment, EOC remains a challenging disease to manage, and the 5-year survival rate is still poor. The role of hormone receptors (HRs) in EOC carcinogenesis and prognosis has been actively explored; however, the role of hormone therapy (HT) in the treatment of these tumors is not well established. Most available data on HT mainly come from retrospective series and small early clinical trials. Several of these studies suggest that HT may have a role in adjuvant, maintenance therapy, or in the case of recurrent disease, especially for some subtypes of EOC (e.g., low-grade serous EOC). Furthermore, HT has recently been combined with targeted therapies, but most studies evaluating these combinations are still ongoing. The main aim of this review is to provide an overview of the progress made in the last decade to characterize the biological and prognostic role of HRs for EOC and the developments in their therapeutic targeting through HT.
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- 2023
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12. A new UHPLC-MS/MS method for cannabinoids determination in human plasma: A clinical tool for therapeutic drug monitoring
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Alessandra Manca, Francesco Chiara, Jacopo Mula, Alice Palermiti, Domenico Maiese, Sandra Zeaiter, Amedeo De Nicolò, Daniele Imperiale, Giacomo De Filippis, Flavio Vischia, David De Cori, Jessica Cusato, and Antonio D’Avolio
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Cannabinoids ,Δ8-THC ,Δ9-THC ,Liquid chromatography ,Tandem mass spectrometry ,Medical cannabis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Cannabinoid derivates have been largely used for different medical purpose. In the literature, several methods capable of separating THC and its principles metabolites are described, although Δ8- and Δ9-THC separation has not been completely achieved. THC metabolism has not been fully understood and metabolites plasma distribution in healthy and pathological patients remains to further deepen. The aim of this study was the validation of UHPLC-MS/MS method for the quantification of 10 cannabinoids in human plasma, as important tool for improving clinical efficacy of cannabis administration. Obtained results were in accordance with recommendations of ICH Harmonised Guideline for bioanalytical method validation, showing a good linearity, optimal accuracy as well as satisfactory results in terms of intra-day and inter-day precision and matrix effect. Furthermore, blood sampling study was performed to investigate the better collection method. Optimal separation of Δ-9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) was obtained. The present method showed optimal linearity and satisfactory results in terms of specificity and selectivity. Recovery was between 92.0% and 96.5% for all analytes. The matrix-effect showed good performance; no carry over was observed. Cannabinoid metabolites present in higher plasma concentrations were: 11–Hydroxy–Δ9–tetrahydrocannabinol, 11–Nor–9carboxy–Δ9–tetrahydrocannabinol and THC-COOH-glucuronide. Method performance makes it suitable for routine purposes and a potential tool for therapeutic ranges definition. The present work will be used to test several samples in a long-term clinical study, paving the way for further future works.
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- 2022
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13. A Novel UHPLC-MS/MS Method for the Quantification of Seven Opioids in Different Human Tissues
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Alessandra Manca, Amedeo De Nicolò, Elisa Delia De Vivo, Micol Ferrara, Sharon Oh, Sahar Khalili, Niamh Higgins, Robert G. Deiss, Stefano Bonora, Jessica Cusato, Alice Palermiti, Jacopo Mula, Sara Gianella, and Antonio D’Avolio
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LC-MS ,tissue ,morphine ,fentanyl ,opioids ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Background: Opioids are considered the cornerstone of pain management: they show good efficacy as a first-line therapy for moderate to severe cancer pain. Since pharmacokinetic/pharmacodynamic information about the tissue-specific effect and toxicity of opioids is still scarce, their quantification in post-mortem autoptic specimens could give interesting insights. Methods: We describe an ultra-high-performance liquid chromatography coupled with tandem mass spectrometry method for the simultaneous quantification of methadone, morphine, oxycodone, hydrocodone, oxymorphone, hydromorphone and fentanyl in several tissues: liver, brain, kidney, abdominal adipose tissue, lung and blood plasma. The presented method has been applied on 28 autoptic samples from different organs obtained from four deceased PLWH who used opioids for palliative care during terminal disease. Results: Sample preparation was based on tissue weighing, disruption, sonication with drug extraction medium and a protein precipitation protocol. The extracts were then dried, reconstituted and injected onto the LX50 QSight 220 (Perkin Elmer, Milan, Italy) system. Separation was obtained by a 7 min gradient run at 40 °C with a Kinetex Biphenyl 2.6 µm, 2.1 × 100 mm. Concerning the analyzed samples, higher opioids concentrations were observed in tissues than in plasma. Particularly, O-MOR and O-COD showed higher concentrations in kidney and liver than other tissues (>15–20 times greater) and blood plasma (>100 times greater). Conclusions: Results in terms of linearity, accuracy, precision, recovery and matrix effect fitted the recommendations of FDA and EMA guidelines, and the sensitivity was high enough to allow successful application on human autoptic specimens from an ethically approved clinical study, confirming its eligibility for post-mortem pharmacological/toxicological studies.
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- 2023
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14. COVID-19: Focusing on the Link between Inflammation, Vitamin D, MAPK Pathway and Oxidative Stress Genetics
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Jessica Cusato, Alessandra Manca, Alice Palermiti, Jacopo Mula, Martina Costanzo, Miriam Antonucci, Francesco Chiara, Elisa Delia De Vivo, Domenico Maiese, Micol Ferrara, Stefano Bonora, Giovanni Di Perri, Antonio D’Avolio, and Andrea Calcagno
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SARS-CoV-2 ,MAPK ,vitamin D ,Therapeutics. Pharmacology ,RM1-950 - Abstract
An uncontrolled inflammatory response during SARS-CoV-2 infection has been highlighted in several studies. This seems to be due to pro-inflammatory cytokines whose production could be regulated by vitamin D, ROS production or mitogen-activated protein kinase (MAPK). Several genetic studies are present in the literature concerning genetic influences on COVID-19 characteristics, but there are few data on oxidative stress, vitamin D, MAPK and inflammation-related factors, considering gender and age. Therefore, the aim of this study was to evaluate the role of single nucleotide polymorphisms in these pathways, clarifying their impact in affecting COVID-19-related clinical features. Genetic polymorphisms were evaluated through real-time PCR. We prospectively enrolled 160 individuals: 139 patients were positive for SARS-CoV-2 detection. We detected different genetic variants able to affect the symptoms and oxygenation. Furthermore, two sub-analyses were performed considering gender and age, showing a different impact of polymorphisms according to these characteristics. This is the first study highlighting a possible contribution of genetic variants of these pathways in affecting COVID-19 clinical features. This may be relevant in order to clarify the COVID-19 etiopathogenesis and to understand the possible genetic contribution for further SARS infections.
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- 2023
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15. COVID-19: A Possible Contribution of the MAPK Pathway
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Jessica Cusato, Alessandra Manca, Alice Palermiti, Jacopo Mula, Martina Costanzo, Miriam Antonucci, Mattia Trunfio, Silvia Corcione, Francesco Chiara, Elisa Delia De Vivo, Alice Ianniello, Micol Ferrara, Giovanni Di Perri, Francesco Giuseppe De Rosa, Antonio D’Avolio, and Andrea Calcagno
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SARS-CoV-2 ,molecular pathway ,PBMCs ,inflammation mechanism ,oxygenation ,Biology (General) ,QH301-705.5 - Abstract
Background: COVID-19 is characterized by an uncontrolled inflammatory response with high pro-inflammatory cytokine production through the activation of intracellular pathways, such as mitogen-activated protein kinase (MAPK). Viruses are able to exploit the MAPK pathway to their advantage; this pathway relevance to severe COVID-19 is poorly described. The aim of this study was to quantify biomarkers involved in the MAPK pathway and to clarify its possible role in affecting some COVID-19-related clinical features. Methods: H-RAS, C-RAF, MAPK1, MAPK2, and ERK were quantified through ELISA, and genetic polymorphisms were evaluated through real-time PCR. Results: We prospectively recruited 201 individuals (158 positive and 43 negative for SARS-CoV-2): 35 were male, and their median age was 65 years. MAPK-related biomarker levels were increased in SARS-CoV-2-positive participants (n = 89) compared to negative ones (n = 29). Dyspnea was reported by 48%; this symptom was associated with PBMC C-RAF levels in positive participants (p = 0.022) and type of ventilation (p = 0.031). The highest degree of ventilation was used by 8% for invasive ventilation and 41% for continuous positive airway pressure (CPAP). Conclusions: This is the first study that showed a possible contribution of MAPK-related biomarkers in affecting COVID-19 clinical features, and this may be relevant for identifying COVID-19 positive participants at risk of serious complications.
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- 2023
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16. Editorial: Bench Research Behind Lung Cancer Surgery
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Luca Bertolaccini, Lorenzo Spaggiari, and Jessica Cusato
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lung cancer ,thoracic surgery ,bench and pilot test ,methodology ,basic research ,Surgery ,RD1-811 - Published
- 2022
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17. Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants
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Jessica Cusato, Valeria Avataneo, Miriam Antonucci, Mattia Trunfio, Letizia Marinaro, Alice Palermiti, Alessandra Manca, Giovanni Di Perri, Jacopo Mula, Stefano Bonora, Antonio D’Avolio, and Andrea Calcagno
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pharmacogenetics ,ART ,CSF ,pharmacokinetics ,neopterin ,Medicine (General) ,R5-920 - Abstract
Neurocognitive impairments are common in people living with HIV. Some conditions, such as chronic inflammation, astrocyte infection and an impaired blood–brain barrier (BBBi), along with host genetic variants in transporter genes, may affect antiretroviral (ARV) exposure in the cerebrospinal fluid (CSF). The aim of this study was to evaluate ARV CSF penetration according to compartmental inflammation, BBB permeability and single-nucleotide polymorphisms (SNPs) in drug transporter encoding genes. CSF neopterin (ELISA), plasma and CSF ARV concentrations (HPLC) and host genetic variants in ABCC2, HNF4α, SLCO1A2 and SLC22A6 (real-time PCR) were measured. Bi- and multivariate analyses were performed for single ARV and classes. We included 259 participants providing 405 paired plasma and CSF samples. CSF/plasma ratios (CPR) showed an increase for NRTIs and nevirapine with low penetrations for the majority of ARVs. At bi-variate analysis, several associations, including the effect of BBBi (emtricitabine, raltegravir), age (zidovudine and darunavir), and high CSF neopterin (NRTIs and border-line for PIs) were suggested. An association was found between genetic variants and integrase strand transfer (ABCC2 and HNF4α), non-nucleoside reverse transcriptase inhibitors (SLCO1A2), and protease inhibitors (SLC22A6). At multivariate analysis age, gender, BMI, and altered BBB were independent predictors of nucleoside reverse transcriptase CSF concentrations; age (for protease inhibitors) and body mass index and altered BBB (integrase strand transfer inhibitors) were also associated with ARV CSF exposure. We describe factors associated with CSF concentrations, showing that demographic, BBB integrity and, partially, genetic factors may be predictors of drug passage in the central nervous system.
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- 2023
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18. A Non-Invasive Method for Detection of Antihypertensive Drugs in Biological Fluids: The Salivary Therapeutic Drug Monitoring
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Valeria Avataneo, Elvira Fanelli, Amedeo De Nicolò, Franco Rabbia, Alice Palermiti, Marco Pappaccogli, Jessica Cusato, Francesco Giuseppe De Rosa, Antonio D'Avolio, and Franco Veglio
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antihypertensive drugs ,hypertension ,liquid chromatography ,tandem mass spectrometry ,therapeutic drug monitoring ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Objectives: Arterial hypertension is still the most frequent cause of cardiovascular and cerebrovascular morbidity and mortality. Antihypertensive treatment has proved effective in reduction of cardiovascular risk. Nevertheless, lifestyle interventions and pharmacological therapy in some cases are ineffective in reaching blood pressure target values, despite full dose and poly-pharmacological treatment. Poor adherence to medications is an important cause of treatment failure. Different methods to assess therapeutic adherence are currently available: Therapeutic drug monitoring in biological fluids has previously demonstrated its efficacy and reliability. Plasma and urine have been already used for this purpose, but they may be affected by some practical limitations. Saliva may represent a feasible alternative.Methods: Fourteen antihypertensive drugs and two metabolites were simultaneously tested in plasma, urine, and saliva. Tested molecules included: atenolol, nebivolol, clonidine, ramipril, olmesartan, telmisartan, valsartan, amlodipine, nifedipine, doxazosin, chlorthalidone, hydrochlorothiazide, indapamide, sacubitril, ramiprilat, and sacubitrilat. Therapeutic drug monitoring was performed using ultra-high performance liquid chromatography, coupled to tandem mass spectrometry (UHPLC-MS/MS). The method has been preliminarily evaluated in a cohort of hypertensive patients.Results: The method has been validated according to US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The application on a cohort of 32 hypertensive patients has demonstrated sensibility and specificity of 98% and 98.1%, respectively, with a good feasibility in real-life clinical practice.Conclusion: Saliva may represent a feasible biological sample for therapeutic drug monitoring by non-invasive collection, prompt availability, and potential accessibility also in out-of-clinic settings.
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- 2022
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19. Dolutegravir Discontinuation for Neuropsychiatric Symptoms in People Living with HIV and Their Outcomes after Treatment Change: A Pharmacogenetic Study
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Jessica Cusato, Alberto Borghetti, Elisabetta Teti, Maurizio Milesi, Maria Cristina Tettoni, Stefano Bonora, Mattia Trunfio, Antonio D’Avolio, Mirko Compagno, Simona Di Giambenedetto, Giovanni Di Perri, and Andrea Calcagno
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psychiatric symptoms ,depression ,dolutegravir ,pharmacogenetics ,discontinuation ,Microbiology ,QR1-502 - Abstract
Neuropsychiatric symptoms have been reported in patients receiving dolutegravir, a known inhibitor of the renal and neuronal-expressed organic anion transporter 2 (encoded by SLC22A2 gene). The effect of the genetic variant SLC22A2 808C>A on dolutegravir discontinuation was assessed and analyzed by real-time PCR. We enrolled 627 participants: CA/AA carriers showed a higher prevalence of pre-existing psychiatric comorbidities and use of antidepressants. After 27.9 months, 108 participants discontinued dolutegravir, 64 for neuropsychiatric symptoms. Patients with pre-existing psychiatric comorbidities were at higher risk of dolutegravir discontinuation, while patients carrying the SLC22A2 CA/AA genotype were not. Combining the two variables, an opposite effect of SLC22A2 variants according to pre-existing psychiatric disorders was observed. Using multivariate Cox models, the combined variable pre-existing psychiatric comorbidities/SLC22A2 variants and the use of non-tenofovir alafenamide containing antiretroviral regimens were predictors of dolutegravir discontinuation for neuropsychiatric symptoms. Within 30 days, the majority of participants had a complete resolution of symptoms (61.8%), while 32.7% and 5.5% had partial or no change after dolutegravir discontinuation, respectively. Discontinuation of dolutegravir for neuropsychiatric symptoms was not uncommon and more frequent in participants with pre-existing psychiatric disorders. We described an interaction between SLC22A2 genetic variant and psychiatric comorbidities. In 38.2% of patients, a complete neuropsychiatric symptoms resolution was not observed after dolutegravir discontinuation suggesting the involvement of additional factors.
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- 2022
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20. Possible Impact of Vitamin D Status and Supplementation on SARS-CoV-2 Infection Risk and COVID-19 Symptoms in a Cohort of Patients with Inflammatory Bowel Disease
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Amedeo De Nicolò, Jessica Cusato, Cristina Bezzio, Simone Saibeni, Marta Vernero, Michela Disabato, Gian Paolo Caviglia, Alice Ianniello, Alessandra Manca, Antonio D’Avolio, and Davide Giuseppe Ribaldone
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vitamin D ,cholecalciferol ,IBD ,Crohn’s disease ,ulcerative colitis ,monoclonal antibodies ,Nutrition. Foods and food supply ,TX341-641 - Abstract
The coronavirus disease (COVID-19) pandemic represents a global health challenge, particularly considering concomitant diseases. Patients with inflammatory bowel diseases (IBD) can be considered a population at risk. On the other hand, the risk of developing IBD and COVID-19 have both been described as modulated by vitamin D (VD) levels. In this work, a cohort of 106 adult patients affected by IBD was prospectively enrolled, during the second wave of the pandemic in Italy. In these patients, VD plasma levels, demographic, and clinical characteristics were tested for a correlation/an association with the risk of infection with SARS-CoV-2 in the study period (anti-spike IgG positivity) and the severity of COVID-19 symptoms. By multivariate logistic regression analysis, VD supplementation (Odds Ratio; OR 0.116, p = 0.002), therapy with monoclonal antibodies (OR 0.227, p = 0.007), and the use of mesalazine (OR 2.968, p = 0.046) were found to be independent predictors of SARS-CoV-2 positivity. Moreover, hypertension was associated with severe disease (p = 0.019), while a VD level higher than 30 ng/mL (p = 0.031, OR 0.078) was associated with asymptomatic infection. No interplay between IBD activity and COVID-19 risk of infection or symptoms was observed. These results confirm the importance of VD levels in defining the risk of COVID-19 and give encouraging data about the safety of maintaining immunomodulatory treatments for IBD during the COVID-19 pandemic.
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- 2022
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21. Clinical Effectiveness and Pharmacokinetics of Dalbavancin in Treatment-Experienced Patients with Skin, Osteoarticular, or Vascular Infections
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Giacomo Stroffolini, Amedeo De Nicolò, Alberto Gaviraghi, Jacopo Mula, Giuseppe Cariti, Silvia Scabini, Alessandra Manca, Jessica Cusato, Silvia Corcione, Stefano Bonora, Giovanni Di Perri, Francesco Giuseppe De Rosa, and Antonio D’Avolio
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dalbavancin ,long-acting ,Gram-positive ,PK/PD ,osteoarticular infections ,Pharmacy and materia medica ,RS1-441 - Abstract
Dalbavancin (DBV) is a lipoglycopeptide approved for the treatment of Gram-positive infections of the skin and skin-associated structures (ABSSSIs). Currently, its off-label use at different dosages for other infections deserves attention. This work aimed to study the clinical effectiveness and tolerability of DBV in outpatients with ABSSSIs, osteoarticular (OA), or other infections, treated with either one or two 1500 mg doses of dalbavancin, for different scheduled periods. A liquid chromatography–tandem mass spectrometry method was used to measure total DBV concentrations. PK/PD parameters and the clinical and microbiological features of this cohort were evaluated in order to investigate the best predictors of treatment success in real-life settings. Of the 76 screened patients, 41 completed the PK study. Long-term PK was comparable to previous studies and showed significant differences between genders and dosing schedules. Few adverse events were observed, and treatment success was achieved in the vast majority of patients. Failure was associated with lower PK parameters, particularly Cmax. Concluding, we were able to describe DBV PK and predictors of treatment success in selected infections in this cohort, finding DBV Cmax as a possible candidate for therapeutic drug-monitoring purposes, as well as highlighting the dual-dose one-week-apart treatment as the optimal choice for OA infections.
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- 2022
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22. Pregnancy and COVID-19: The Possible Contribution of Vitamin D
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Alessandra Manca, Stefano Cosma, Alice Palermiti, Martina Costanzo, Miriam Antonucci, Elisa Delia De Vivo, Alice Ianniello, Fulvio Borella, Andrea Roberto Carosso, Silvia Corcione, Francesco Giuseppe De Rosa, Chiara Benedetto, Antonio D’Avolio, and Jessica Cusato
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SARS-CoV-2 ,vitamin D ,genetic polymorphisms ,VDR ,biomarkers ,newborn ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Background: Vitamin D deficiency has been associated with the severity of COVID-19. The role of vitamin D in pregnant women with COVID-19 has been poorly investigated to date. The aim of this study was to evaluate the influence of vitamin D in affecting some clinical features in pregnancy between SARS-CoV-2 positive and negative patients. Methods: Vitamin D pathway related polymorphisms and 25-hydroxyvitamin D levels were quantified in pregnant women followed from the first to the third trimester of pregnancy. Vitamin D deficiency was considered with values ≤ 30 ng/mL. Results: In total, 160 women were enrolled: 23 resulted positive for at least one SARS-CoV-2 related test (molecular swab or antibody tests). Vitamin D-associated polymorphisms were able to affect vitamin D levels in SARS-CoV-2 negative and positive subjects: remarkably, all the VDR TaqICC genotype patients were negative for SARS-CoV-2. In a sub-population (118 patients), vitamin D levels correlated with pregnancy-related factors, such as alpha-fetoprotein levels. Third-trimester vitamin D levels were lower in preterm births compared to full-term pregnancy: this trend was highlighted for SARS-CoV-2 positive patients. Conclusions: This is the first study demonstrating a role of vitamin D in affecting the clinical characteristics of pregnant women during the COVID-19 era. Further studies in larger and different cohorts of patients are required to confirm these findings.
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- 2022
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23. Antifungal Drug Plasma Exposures: A Possible Contribution of Vitamin D-Related Gene Variants
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Jessica Cusato, Alice Palermiti, Alessandra Manca, Jacopo Mula, Miriam Antonucci, Amedeo De Nicolò, Sarah Allegra, Silvia De Francia, Francesco Chiara, Giovanni Di Perri, Francesco Giuseppe De Rosa, Andrea Calcagno, and Antonio D’Avolio
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genetics ,azoles ,pharmacokinetics ,VDR ,CYP27B1 ,CYP24A1 ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Vitamin D (VD) seems to influence drug clearance and outcome. Antifungal drugs (AFU) are the most used azoles in clinical practice. In the literature, no data are available concerning VD’s impact on AFU therapy. The aim of this study was to analyze if VD pathway-related polymorphisms may influence voriconazole (VRC), itraconazole (ITC), and posaconazole (PSC) drug concentrations in order to identify patients with the highest probability of response and toxicity. Allelic discrimination was performed through real-time PCR, whereas drug concentrations were through liquid chromatography. A total of 636 samples of AFU-treated patients were included in the analysis. Concerning VRC, concentrations higher than the 1000 ng/mL efficacy cut-off value were predicted by Caucasian ethnicity, CYP24A1 3999, and CYP27B1 + 2838 polymorphisms, whereas levels higher than the 5000 ng/mL toxicity value by Caucasian, female sex, e.v. administration, and GC 1296. Considering PSC, concentrations higher than the 700 ng/mL efficacy cut-off value were predicted by VDR Cdx2, CYP27B1 − 1260, and GC 1296. Finally, for ITC, VDR BsmI was the only predictor of drug exposure higher than the 500 ng/mL efficacy cut-off value, whereas female sex, CYP27B1 − 1260, and VDR TaqI remained in the final regression model related to concentrations higher than the 1000 ng/mL toxicity-associated cut-off value. This is the first study reporting the influence of VD pathway-related gene SNPs on AFU exposures, efficacy, and toxicity.
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- 2022
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24. Preterm birth is not associated with asymptomatic/mild SARS-CoV-2 infection per se: Pre-pregnancy state is what matters
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Stefano Cosma, Andrea Roberto Carosso, Jessica Cusato, Fulvio Borella, Marco Carosso, Fiammetta Gervasoni, Ilaria Stura, Mario Preti, Valeria Ghisetti, Giovanni Di Perri, and Chiara Benedetto
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Medicine ,Science - Abstract
Evidence for the real impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on preterm birth is unclear, as available series report composite pregnancy outcomes and/or do not stratify patients according to disease severity. The purpose of the research was to determine the real impact of asymptomatic/mild SARS-CoV-2 infection on preterm birth not due to maternal respiratory failure. This case-control study involved women admitted to Sant Anna Hospital, Turin, for delivery between 20 September 2020 and 9 January 2021. The cumulative incidence of Coronavirus disease-19 was compared between preterm birth (case group, n = 102) and full-term delivery (control group, n = 127). Only women with spontaneous or medically-indicated preterm birth because of placental vascular malperfusion (pregnancy-related hypertension and its complications) were included. Current or past SARS-CoV-2 infection was determined by nasopharyngeal swab testing and detection of IgM/IgG antibodies in blood samples. A significant difference in the cumulative incidence of Coronavirus disease-19 between the case (21/102, 20.5%) and the control group (32/127, 25.1%) (P= 0.50) was not observed, although the case group was burdened by a higher prevalence of three known risk factors (body mass index > 24.9, asthma, chronic hypertension) for severe Coronavirus disease-19. Logistic regression analysis showed that asymptomatic/mild SARS-CoV-2 infection was not an independent predictor of spontaneous and medically-indicated preterm birth due to pregnancy-related hypertension and its complications (0.77; 95% confidence interval, 0.41-1.43). Pregnant patients without comorbidities need to be reassured that asymptomatic/mild SARS-CoV-2 infection does not increase the risk of preterm delivery. Preterm birth and severe Coronavirus disease-19 share common risk factors (i.e., body mass index > 24.9, asthma, chronic hypertension), which may explain the high rate of indicated preterm birth due to maternal conditions reported in the literature.
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- 2021
25. Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy
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Jessica Cusato, Lucio Boglione, Amedeo De Nicolò, Gian Paolo Caviglia, Simone Mornese Pinna, Alessia Ciancio, Giulia Troshina, Antonina Smedile, Miriam Antonucci, Valeria Avataneo, Alice Palermiti, Jacopo Mula, Alessandra Manca, Giuseppe Cariti, Marco Cantù, Giorgio Maria Saracco, Giovanni Di Perri, and Antonio D’Avolio
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DAAs ,single nucleotide polymorphism ,pharmacokinetics ,ABCB1 ,ABCG2 ,HNF4α ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF–RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future.
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- 2022
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26. Monthly Increase in Vitamin D Levels upon Supplementation with 2000 IU/Day in Healthy Volunteers: Result from 'Integriamoci', a Pilot Pharmacokinetic Study
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Valeria Avataneo, Alice Palermiti, Amedeo De Nicolò, Jessica Cusato, Gloria Giussani, Andrea Calcagno, and Antonio D’Avolio
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vitamin D ,LC-MS/MS ,oral integration ,supplements ,micronutrients ,Organic chemistry ,QD241-441 - Abstract
Vitamin D (VD) is a calcium- and phosphate-controlling hormone used to treat bone disorders; yet, several other effects are progressively emerging. VD deficiency is highly prevalent worldwide, with suboptimal exposure to sunlight listed among the leading causes: oral supplementation with either cholecalciferol or calcitriol is used. However, there is a scarcity of clinical studies investigating how quickly VD concentrations can increase after supplementation. In this pilot study, the commercial supplement ImmuD3 (by Erboristeria Magentina®) was chosen as the source of VD and 2000 IU/day was administered for one month to 21 healthy volunteers that had not taken any other VD supplements in the previous 30 days. Plasma VD levels were measured through liquid chromatography coupled to tandem mass spectrometry after 7, 14, and 28 days of supplementation. We found that 95% of the participants had insufficient VD levels at baseline (
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- 2022
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27. Vitamin D-Related Genetics as Predictive Biomarker of Clinical Remission in Adalimumab-Treated Patients Affected by Crohn’s Disease: A Pilot Study
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Jessica Cusato, Lorenzo Bertani, Miriam Antonucci, Cristina Tomasello, Gian Paolo Caviglia, Simone Dibitetto, Alessandro Massano, Michela Mangia, Jacopo Mula, Linda Ceccarelli, Francesco Costa, Federico Zanzi, Marco Astegiano, Davide Giuseppe Ribaldone, and Antonio D’Avolio
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VDR ,CYP27B1 ,GC ,SNPs ,personalized medicine ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Adalimumab (ADA) is a human anti-tumor necrosis factor (TNF-α) monoclonal antibody used in inflammatory bowel diseases, such as Crohn’s disease (CD). Vitamin-D (VD) is important for biological functions, such as the modulation of expression of genes encoding enzymes and transporters involved in drug metabolism and transport. ADA trough levels were associated with VD concentrations in patients with IBD, but no data are present in the literature concerning VD pathway-related gene single-nucleotide polymorphisms (SNPs) in affecting clinical outcomes. For this reason, the aim of this study was to evaluate the ability of VD-related genetics to predict clinical remission at 3 and 12 months in patients affected by CD treated with ADA. Patients affected by CD were included in this study. SNPs in CYP27B1, CYP24A1, GC, and VDR genes were analyzed through real-time PCR. A total of 63 patients were enrolled. Calprotectin, hemoglobin, and C-reactive protein levels were influenced by SNPs in VDR, CYP27B1, and GC genes. After 3 months of therapy, clinical remission was predicted by smoke, systemic steroids, and VDR BsmI, whereas at 12 months by GC 1296AA/AC and VD supplementation. This study reports the association between VD pathway-related genetics and ADA treatment. Further studies are needed to confirm these promising data.
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- 2021
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28. Vitamin D as Modulator of Drug Concentrations: A Study on Two Italian Cohorts of People Living with HIV Administered with Efavirenz
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Jessica Cusato, Massimo Tempestilli, Andrea Calcagno, Alessandra Vergori, Pierluca Piselli, Miriam Antonucci, Valeria Avataneo, Alice Palermiti, Stefania Notari, Andrea Antinori, Giovanni Di Perri, Chiara Agrati, and Antonio D’Avolio
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plasma concentrations ,vitamin D ,seasonality ,drug metabolism ,Nutrition. Foods and food supply ,TX341-641 - Abstract
To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC–PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.
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- 2021
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29. Validation and Clinical Application of a New Liquid Chromatography Coupled to Mass Spectrometry (HPLC-MS) Method for Dalbavancin Quantification in Human Plasma
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Valeria Avataneo, Miriam Antonucci, Elisa Delia De Vivo, Antonio Briozzo, Jessica Cusato, Francesca Bermond, Corrado Vitale, Francesco Vitale, Alessandra Manca, Alice Palermiti, Giovanni Di Perri, Francesco Giuseppe De Rosa, Amedeo De Nicolò, and Antonio D’Avolio
- Subjects
dalbavancin ,therapeutic drug monitoring ,long-acting therapy ,glycopeptides ,MRSA ,skin infections ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Dalbavancin (DBV) is an intravenous long-acting second-generation glycolipopeptide antibiotic with high efficacy and excellent tolerability, approved for use in the treatment of Gram-positive skin and skin structure infections (ABSSSI). Nevertheless, little is known about its pharmacokinetic/pharmacodynamic (PK/PD) properties in real life, which is also due to technical challenges in its quantification in human plasma, preventing an effective application of therapeutic drug monitoring (TDM). In fact, DBV has a high affinity to plasma proteins, possibly resulting in poor recovery after extraction procedure. The aim of this study was to validate a simple, cheap and reliable HPLC-MS method for use in TDM, in accordance with FDA and EMA guidelines. The optimized protein precipitation protocol required 50 μL of plasma, while chromatographic analysis could be performed in 12 min/sample. This method fulfilled the guidelines requirements and then, it was applied for routine DBV TDM in patients receiving off-label high doses (two 1500 + 1500 mg weekly infusions instead of 1000 + 500 mg), with normal renal function or undergoing hemodialysis: continuous hemodiafiltration caused a relevant reduction in DBV exposure, while intermittent dialysis showed comparable DBV concentrations with those of patients with normal renal function. This confirmed the eligibility of the presented method for use in TDM and its usefulness in clinical practice.
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- 2021
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30. Seasonal Variation of Antiretroviral Drug Exposure during the Year: The Experience of 10 Years of Therapeutic Drug Monitoring
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Jessica Cusato, Jacopo Mula, Alice Palermiti, Alessandra Manca, Miriam Antonucci, Valeria Avataneo, Elisa Delia De Vivo, Alice Ianniello, Andrea Calcagno, Giovanni Di Perri, Amedeo De Nicolò, and Antonio D’Avolio
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cytochromes ,plasma exposure ,pharmacokinetics ,seasonality ,gene expression ,Biology (General) ,QH301-705.5 - Abstract
Although studies show an annual trend for immunosuppressive drugs, particularly during different seasons, no data are available for antiretroviral drugs exposures in different periods of the year. For this reason, the aim of this study was to investigate an association between seasonality and antiretroviral drugs plasma concentrations. Antiretroviral drugs exposures were measured with liquid chromatography validated methods. A total of 4148 human samples were analysed. Lopinavir, etravirine and maraviroc levels showed seasonal fluctuation. In detail, maraviroc and etravirine concentrations decreased further in summer than in winter. In contrast, lopinavir concentrations had an opposite trend, increasing more in summer than in winter. The etravirine efficacy cut-off value of 300 ng/mL seems to be affected by seasonality: 77.1% and 22.9% of samples achieved this therapeutic target, respectively, in winter and summer, whereas 30% in winter and 70% in summer did not reach this value. Finally, age over 50 years and summer remained in the final multivariate regression model as predictors of the etravirine efficacy cut-off. This study highlights the seasonal variation in antiretroviral drugs plasma concentrations during the year, leading to a better understanding of inter-individual variability in drug exposures. Studies are required in order to confirm these data, clarifying which aspects may be involved.
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- 2021
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31. Long-Term Pharmacokinetics of Dalbavancin in ABSSSI and Osteoarticular Settings: A Real-Life Outpatient Context
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Amedeo De Nicolò, Giacomo Stroffolini, Miriam Antonucci, Jacopo Mula, Elisa Delia De Vivo, Jessica Cusato, Alice Palermiti, Giuseppe Cariti, Giovanni Di Perri, Silvia Corcione, Francesco Giuseppe De Rosa, and Antonio D’Avolio
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pharmacokinetics ,antibiotics ,anti-infective ,quantitative pharmacology ,pharmacokinetics-pharmacodynamics ,Biology (General) ,QH301-705.5 - Abstract
Dalbavancin is a lipoglycopeptide approved for treatment of Gram-positive infections of skin and skin-associated structures (ABSSSI). Currently, off-label use at high dosages for osteoarticular infections deserves attention. This work aimed to study the long-term plasma pharmacokinetics of dalbavancin in outpatients with ABSSSI or osteoarticular infections, treated either with one or two 1500 mg doses of dalbavancin. A liquid chromatography-tandem mass spectrometry method was used to measure total dalbavancin concentrations in plasma samples. The results were analyzed through a non-compartmental analysis (NCA). Breakpoint minimum inhibitory concentration (MIC) was used to calculate AUC/MIC and T > MIC parameters, adjusted by 93% protein binding. A total of 14 patients were enrolled, 11 with osteoarticular infection and 3 with ABSSSI. Long-term pharmacokinetics showed median T > MIC (0.125 mg/L) of 11.9 and 13.7 weeks for single and dual dose, respectively. Similarly, median AUC0-2w/MIC ratios of 20,590 and 31,366 were observed for single and dual dose regimens, respectively. No adverse events were observed, and treatment success was achieved in 12/14 patients. Failure was associated with the worst clinical conditions, bone infections, and single dose. The results of this study show that dalbavancin exposure exceeds previously suggested pharmacodynamic targets. Optimization of these targets is needed for the osteoarticular setting.
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- 2021
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32. Development and Validation of an Up-to-Date Highly Sensitive UHPLC-MS/MS Method for the Simultaneous Quantification of Current Anti-HIV Nucleoside Analogues in Human Plasma
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Amedeo De Nicolò, Alessandra Manca, Alice Ianniello, Alice Palermiti, Andrea Calcagno, Micol Ferrara, Miriam Antonucci, Jessica Cusato, Valeria Avataneo, Elisa De Vivo, Stefano Bonora, Francesco Giuseppe De Rosa, Giovanni Di Perri, and Antonio D’Avolio
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liquid chromatography ,tandem mass spectrometry ,tenofovir alafenamide ,nucleoside analogues ,NRTIs ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Therapeutic options to treat HIV infection have widened in the past years, improving both effectiveness and tolerability, but nucleoside reverse transcriptase inhibitors (NRTIs) are still considered the standard backbone of the combination regimens. Therapeutic drug monitoring (TDM) can be useful for these drugs, due to concentration–effect relationship, with risk of ineffectiveness, toxicity or adherence concerns: in this scenario, robust and multiplexed methods are needed for an effective TDM activity. In this work, the first validated ultra-high spectrometry liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method is described for the high-sensitive simultaneous quantification of all the currently used NRTIs in human plasma, including tenofovir alafenamide (TAF), following FDA and EMA guidelines. The automated sample preparation consisted in the addition of an internal standard (IS) working solution, containing stable-isotope-linked drugs, protein precipitation and drying. Dry extracts were reconstituted with water, then, these underwent reversed phase chromatographic separation: compounds were detected through electrospray ionization and multiple reaction monitoring. Accuracy, precision, recovery and IS-normalized matrix effect fulfilled guidelines’ requirements. The application of this method on samples from people living with HIV (PLWH) showed satisfactory performance, being capable of quantifying the very low concentrations of tenofovir (TFV) in patients treated with TAF.
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- 2021
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33. Analysis of Cannabinoids Concentration in Cannabis Oil Galenic Preparations: Harmonization between Three Laboratories in Northern Italy
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Alice Palermiti, Alessia Cafaro, Sebastiano Barco, Paolo Bucchioni, Paolo Franceschini, Jessica Cusato, Amedeo De Nicolò, Alessandra Manca, Elisa Delia De Vivo, Eleonora Russo, Francesco Cecchi, Federica Pigliasco, Flavia Lillo, Gino Tripodi, Antonio D’Avolio, and Giuliana Cangemi
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cannabinoids stability ,cannabis oil ,medical cannabis ,UHPLC/MS-MS ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Medical cannabis is increasingly being used in the treatment and support of several diseases and syndromes. The quantitative determination of active ingredients (delta-9 tetrahydrocannabinol, THC, and cannabidiol, CBD) in galenic oily preparations is prescribed by law for each produced batch. The aim of this work is to describe the organization of the titration activity centralized at three regional reference laboratories in Northern Italy. Pre-analytical, analytical, and post-analytical phases have been defined in order to guarantee high quality standards. A cross-validation between laboratories allowed for the definition of the procedures that guarantee the interchangeability between reference laboratories. The risk management protocol adopted can be useful for others who need to undertake this activity.
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- 2021
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34. Analytical Validation and Clinical Application of Rapid Serological Tests for SARS-CoV-2 Suitable for Large-Scale Screening
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Amedeo De Nicolò, Valeria Avataneo, Jessica Cusato, Alice Palermiti, Jacopo Mula, Elisa De Vivo, Miriam Antonucci, Stefano Bonora, Andrea Calcagno, Giovanni Di Perri, Francesco Giuseppe De Rosa, and Antonio D’Avolio
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COVID-19 ,serological test ,IgG ,IgM ,antibodies ,immune response ,Medicine (General) ,R5-920 - Abstract
Recently, large-scale screening for COVID-19 has presented a major challenge, limiting timely countermeasures. Therefore, the application of suitable rapid serological tests could provide useful information, however, little evidence regarding their robustness is currently available. In this work, we evaluated and compared the analytical performance of a rapid lateral-flow test (LFA) and a fast semiquantitative fluorescent immunoassay (FIA) for anti-nucleocapsid (anti-NC) antibodies, with the reverse transcriptase real-time PCR assay as the reference. In 222 patients, LFA showed poor sensitivity (55.9%) within two weeks from PCR, while later testing was more reliable (sensitivity of 85.7% and specificity of 93.1%). Moreover, in a subset of 100 patients, FIA showed high sensitivity (89.1%) and specificity (94.1%) after two weeks from PCR. The coupled application for the screening of 183 patients showed satisfactory concordance (K = 0.858). In conclusion, rapid serological tests were largely not useful for early diagnosis, but they showed good performance in later stages of infection. These could be useful for back-tracing and/or to identify potentially immune subjects.
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- 2021
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35. Blood–Brain Barrier Impairment in Patients Living with HIV: Predictors and Associated Biomarkers
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Giulia Caligaris, Mattia Trunfio, Valeria Ghisetti, Jessica Cusato, Marco Nigra, Cristiana Atzori, Daniele Imperiale, Stefano Bonora, Giovanni Di Perri, and Andrea Calcagno
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blood–brain barrier ,biomarkers ,HIV ,Medicine (General) ,R5-920 - Abstract
Despite the substantial changes resulting from the introduction of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders (HAND) remains substantial. Blood–brain barrier impairment (BBBi) is a frequent feature in people living with HIV (PLWH) and it may persist despite effective antiretroviral treatment. A cross-sectional study was performed in PLWH who underwent lumbar puncture for clinical reasons or research protocols and several cerebrospinal fluid biomarkers were studied. BBBi was defined as cerebrospinal fluid-to-serum albumin ratio (CSAR) >6.5 (8 (>40 years). We included 464 participants: 147 cART-naïve and 317 on cART. Male sex was prevalent in both groups (72.1% and 72.2% respectively); median age was 44 (38–52) years in naïve and 49 (43–57) years in treated subjects. BBBi was observed in 35.4% naïve and in 22.7% treated participants; the use of integrase inhibitors was associated with a lower prevalence (18.3 vs. 30.9%, p = 0.050). At multivariate binary logistic regression (including age and sex) nadir CD4 cell count (p = 0.034), presence of central nervous system (CNS) opportunistic infections (p = 0.024) and cerebrospinal fluid (CSF) HIV RNA (p = 0.002) in naïve participants and male sex (p = 0.021), a history of CNS opportunistic infections (p = 0.001) and CSF HIV RNA (p = 0.034) in treated patients were independently associated with BBBi. CSF cells and neopterin were significantly higher in participants with BBBi. BBBi was prevalent in naïve and treated PLWH and it was associated with CSF HIV RNA and neopterin. Systemic control of viral replication seems to be essential for BBB integrity while sex and treatment influence need further studies.
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- 2021
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36. Prenatal Biochemical and Ultrasound Markers in COVID-19 Pregnant Patients: A Prospective Case-Control Study
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Stefano Cosma, Andrea Roberto Carosso, Fulvio Borella, Jessica Cusato, Marialuisa Bovetti, Federica Bevilacqua, Marco Carosso, Fiammetta Gervasoni, Andrea Sciarrone, Luca Marozio, Alberto Revelli, Alessandro Rolfo, Claudia Filippini, Valeria Ghisetti, Giovanni Di Perri, and Chiara Benedetto
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COVID-19 ,fetal congenital anomalies ,fetus ,first trimester ,nuchal translucency ,prenatal screening test ,Medicine (General) ,R5-920 - Abstract
This prospective observational study aimed to evaluate whether women with SARS-CoV-2 infection during the first trimester of pregnancy are at higher risk of noninvasive prenatal screening test alterations and/or of congenital fetal anomalies at the second-trimester fetal anatomy scan. Maternal symptoms were secondly investigated. The study was carried out on 12-week pregnant women admitted for noninvasive prenatal testing (16 April and 22 June 2020). The cohort had seromolecular tests for SARS-CoV-2, after which they were divided into a positive case group and a negative control group. Both groups had 20-week ultrasound screening. Seventeen out of the 164 women tested positive for SARS-CoV-2 (10.3%). There were no significant differences in mean nuchal translucency thickness or biochemical markers (pregnancy-associated plasma protein A, alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol) between cases and controls (p = 0.77, 0.63, 0.30, 0.40, 0.28) or in the fetal incidence of structural anomalies at the second-trimester fetal anatomy scan (p = 0.21). No pneumonia or hospital admission due to COVID-19-related symptoms were observed. Asymptomatic or mildly symptomatic SARS-CoV-2 infection during the first trimester of pregnancy did not predispose affected women to more fetal anomalies than unaffected women. COVID-19 had a favorable maternal course at the beginning of pregnancy in our healthy cohort.
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- 2021
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37. Validation of a UHPLC-MS/MS Method to Quantify Twelve Antiretroviral Drugs within Peripheral Blood Mononuclear Cells from People Living with HIV
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Amedeo De Nicolò, Alice Ianniello, Micol Ferrara, Valeria Avataneo, Jessica Cusato, Miriam Antonucci, Elisa De Vivo, Catriona Waitt, Andrea Calcagno, Alice Trentalange, Giampiero Muccioli, Stefano Bonora, Giovanni Di Perri, and Antonio D'Avolio
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liquid chromatography ,tandem mass spectrometry ,peripheral blood mononuclear cells ,dolutegravir ,intracellular ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Recently, anti-HIV treatment has achieved high efficacy and tolerability. Nevertheless, few data are available about the intracellular penetration of antiretrovirals, partly due to the technical challenges related to intracellular quantification. This work aimed to validate an ultra-high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method for the simultaneous quantification of maraviroc, nevirapine, rilpivirine, dolutegravir, raltegravir, cobicistat, darunavir, ritonavir, atazanavir, efavirenz, elvitegravir, and etravirine within peripheral blood mononuclear cells (PBMCs) and apply it to samples from patients. PBMCs were isolated by density gradient on cell preparation tubes (CPT). Samples were prepared by addition of internal standards (IS), sonication, centrifugation, and drying. Reconstituted extracts underwent chromatographic separation by reversed phase UHPLC and detection was performed by electrospray ionization and multiple reaction monitoring. Method validation followed FDA and EMA guidelines, showing acceptable accuracy, precision, recovery and IS-normalized matrix effect. The application to 56 samples from patients undergoing antiretroviral treatment provided description of intracellular penetration, showing method eligibility for future studies.
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- 2020
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38. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2
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Antonio D’Avolio, Valeria Avataneo, Alessandra Manca, Jessica Cusato, Amedeo De Nicolò, Renzo Lucchini, Franco Keller, and Marco Cantù
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vitamin D ,SARS-CoV-2 ,concentrations ,COVID-19 ,coronavirus ,deficiency ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), with a clinical outcome ranging from mild to severe, including death. To date, it is unclear why some patients develop severe symptoms. Many authors have suggested the involvement of vitamin D in reducing the risk of infections; thus, we retrospectively investigated the 25-hydroxyvitamin D (25(OH)D) concentrations in plasma obtained from a cohort of patients from Switzerland. In this cohort, significantly lower 25(OH)D levels (p = 0.004) were found in PCR-positive for SARS-CoV-2 (median value 11.1 ng/mL) patients compared with negative patients (24.6 ng/mL); this was also confirmed by stratifying patients according to age >70 years. On the basis of this preliminary observation, vitamin D supplementation might be a useful measure to reduce the risk of infection. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations and to confirm our preliminary observation.
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- 2020
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39. Influence of Vitamin D in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab
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Jessica Cusato, Carlo Genova, Cristina Tomasello, Paolo Carrega, Selene Ottonello, Gabriella Pietra, Maria Cristina Mingari, Irene Cossu, Erika Rijavec, Anna Leggieri, Giovanni Di Perri, Maria Giovanna Dal Bello, Simona Coco, Simona Boccardo, Guido Ferlazzo, Francesco Grossi, and Antonio D’Avolio
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monoclonal antibody ,NSCLC ,immunotherapy ,ELISA ,pharmacokinetics ,pharmacogenetics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug metabolism and elimination. Immune system regulation and immunodeficiency is frequent in non-small cell lung cancer patients. To date, no data have been reported about the relationship between nivolumab and VD. The aim of this study was to quantify plasma 25-hydroxyVD (25-VD) and 1,25-VD, nivolumab, and its anti-antibody before starting treatment (baseline) and at 15, 45 and 60 days of therapy. VD-pathway-associated gene single nucleotide polymorphisms (SNPs) were also evaluated. Molecules were quantified through enzyme-linked immunosorbent assay, and SNPs through real-time PCR. Forty-five patients were enrolled. Median nivolumab concentrations were 12.5 μg/mL, 22.3 μg/mL and 27.1 μg/mL at 15, 45 and 60 days respectively. No anti-nivolumab antibodies were found. Correlations were observed between nivolumab concentrations and 25-VD levels. Nivolumab concentrations were affected by VD-pathway-related gene SNPs. VDBP AC/CC genotype and baseline 25-VD < 10 ng/mL predicted a nivolumab concentration cut-off value of
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- 2019
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40. Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection
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Sarah Allegra, Giovanna Fatiguso, Silvia De Francia, Fabio Favata, Elisa Pirro, Chiara Carcieri, Amedeo De Nicolò, Jessica Cusato, Giovanni Di Perri, and Antonio D’Avolio
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therapeutic drug monitoring (TDM) ,triazoles ,HPLC ,antifungal ,invasive fungal infections (IFIs) ,Biology (General) ,QH301-705.5 - Abstract
Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. Hence, posaconazole therapeutic drug monitoring, which is easily available in clinical practice, may improve treatment success and safety. The aim of the study was to describe posaconazole pharmacokinetics, and to evaluate the utility of therapeutic drug monitoring for therapy and prophylaxis in a cohort of adult patients. A fully validated chromatographic method was used to quantify posaconazole concentration in plasma collected from adult patients at the end of the dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney test was used to probe the influence of categorical variables on continuous ones. A high inter-individual variability was shown. Of the 172 enrolled patients, among those receiving the drug by the oral route (N = 170), gender significantly influenced drug exposure: males showed greater posaconazole concentration than females (p = 0.028). This study highlights the importance of therapeutic drug monitoring in those with invasive fungal infections and its significant clinical implications; moreover we propose, for the first time, the possible influence of gender on posaconazole exposure.
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- 2017
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41. Intracellular and Plasma Trough Concentration and Pharmacogenetics of Telaprevir
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Jessica Cusato, Sarah Allegra, Amedeo De Nicolò, Lucio Boglione, Giovanna Fatiguso, Adnan Mohamed Abdi, Giuseppe Cariti, Giovanni Di Perri, and Antonio D’Avolio
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Therapeutics. Pharmacology ,RM1-950 ,Pharmacy and materia medica ,RS1-441 - Abstract
PURPOSE: Triple therapy for HCV-1 infection consists in boceprevir or telaprevir, ribavirin and PEG-interferon. Telaprevir is a P-glycoprotein substrate and it is metabolized by CYP3A4/5. No data have been published on intracellular penetration of telaprevir. We determined peripheral blood mononuclear cells (PBMCs) and trough plasma S and R telaprevir isomers concentrations; moreover, we evaluated the influence of some single nucleotide polymorphisms (SNPs) on these pharmacokinetic data after 1 month of triple therapy in humans. METHODS: Plasma and intracellular telaprevir concentrations were determined at the end of dosing interval (Ctrough) using ULPC-MS/MS validated methods; allelic discrimination was performed through real-time PCR. RESULTS: Median telaprevir Ctrough plasma concentrations were 2579 ng/mL and 2233 ng/mL for the pharmacologically more active S, and R, enantiomers, respectively, with median S/R plasma ratio of 1.11. In PBMC, the medians were 6863 ng/mL and 1096 ng/mL for S and R, respectively, with median S/R being 5.73. The PBMC:plasma ratio for S was 2.59 for R. Plasma ribavirin concentrations were directly correlated with plasma S-telaprevir concentrations. In linear regression analysis, only CYP24A1_rs2585428 SNP (p=0.003) and body mass index (p=0.038) were able to predict S-telaprevir PBMC concentrations. CONCLUSIONS: Our preliminary data could increase the understanding of mechanisms underlying telaprevir intracellular and plasma exposure, suggesting the implementation of pharmacogenetics in these drug kinetic studies. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
- Published
- 2015
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42. Inflammation and intracellular exposure of dolutegravir, darunavir, tenofovir and emtricitabine in people living with HIV
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Micol Ferrara, Jessica Cusato, Elena Salvador, Alice Trentalange, Chiara Alcantarini, Mattia Trunfio, Elvira Stefania Cannizzo, Valeria Bono, Silvia Nozza, Amedeo De Nicolò, Alice Ianniello, Elisa De Vivo, Antonio D'Avolio, Giovanni Di Perri, Stefano Bonora, Giulia Marchetti, and Andrea Calcagno
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immunology ,Pharmacology ,pharmacotherapy ,inflammation ,drug transporters ,Pharmacology (medical) ,infectious diseases ,antiretrovirals ,pharmacokinetics - Abstract
Antiretroviral (ARV) therapy reduces inflammation and immune activation in people with HIV, but not down to the levels observed in people without HIV. Limited drug penetration within tissues has been argued as a potential mechanism of persistent inflammation. Data on the inflammation role on ARV plasma/intracellular (IC) pharmacokinetics (PK) through to expression of cytochrome P450 3A/membrane transporters are limited. The aim of this study was to investigate the correlation between inflammation markers (IM) and plasma/IC PK of ARV regimen in HIV-positive patients.We included ART-experienced patients switching to three different ARV regimens. Plasma and IC ARV drug concentration means at the end of dosing interval (TPlasma and IC drug concentrations were measured in 60 samples. No significative differences between CRP, sCD14, IL-6 and LPS values in the three arms were observed. A significant inverse correlation between tenofovir plasma concentration and sCD14 (rho = -0.79, P .001), and between DRV IC/plasma ratio and LogOur preliminary data support the hypothesis of lower DRV and DTG IC concentrations and lower TFV plasma exposure in patients with higher plasma IM suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.
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- 2022
43. A Novel UHPLC-MS/MS Method for the Quantification of Seven Opioids in Different Human Tissues
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D’Avolio, Alessandra Manca, Amedeo De Nicolò, Elisa Delia De Vivo, Micol Ferrara, Sharon Oh, Sahar Khalili, Niamh Higgins, Robert G. Deiss, Stefano Bonora, Jessica Cusato, Alice Palermiti, Jacopo Mula, Sara Gianella, and Antonio
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LC-MS ,tissue ,morphine ,fentanyl ,opioids - Abstract
Background: Opioids are considered the cornerstone of pain management: they show good efficacy as a first-line therapy for moderate to severe cancer pain. Since pharmacokinetic/pharmacodynamic information about the tissue-specific effect and toxicity of opioids is still scarce, their quantification in post-mortem autoptic specimens could give interesting insights. Methods: We describe an ultra-high-performance liquid chromatography coupled with tandem mass spectrometry method for the simultaneous quantification of methadone, morphine, oxycodone, hydrocodone, oxymorphone, hydromorphone and fentanyl in several tissues: liver, brain, kidney, abdominal adipose tissue, lung and blood plasma. The presented method has been applied on 28 autoptic samples from different organs obtained from four deceased PLWH who used opioids for palliative care during terminal disease. Results: Sample preparation was based on tissue weighing, disruption, sonication with drug extraction medium and a protein precipitation protocol. The extracts were then dried, reconstituted and injected onto the LX50 QSight 220 (Perkin Elmer, Milan, Italy) system. Separation was obtained by a 7 min gradient run at 40 °C with a Kinetex Biphenyl 2.6 µm, 2.1 × 100 mm. Concerning the analyzed samples, higher opioids concentrations were observed in tissues than in plasma. Particularly, O-MOR and O-COD showed higher concentrations in kidney and liver than other tissues (>15–20 times greater) and blood plasma (>100 times greater). Conclusions: Results in terms of linearity, accuracy, precision, recovery and matrix effect fitted the recommendations of FDA and EMA guidelines, and the sensitivity was high enough to allow successful application on human autoptic specimens from an ethically approved clinical study, confirming its eligibility for post-mortem pharmacological/toxicological studies.
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- 2023
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44. A combined role for low vitamin D and low albumin circulating levels as strong predictors of worse outcome in COVID-19 patients
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Gianfranco Sanson, Amedeo De Nicolò, Verena Zerbato, Ludovica Segat, Raffaella Koncan, Stefano Di Bella, Jessica Cusato, Alessandra di Masi, Andrea Palermo, Pietro Caironi, Pierlanfranco D’Agaro, Roberto Luzzati, Antonio D’Avolio, Sanson, Gianfranco, De Nicolò, Amedeo, Zerbato, Verena, Segat, Ludovica, Koncan, Raffaella, Di Bella, Stefano, Cusato, Jessica, di Masi, Alessandra, Palermo, Andrea, Caironi, Pietro, D'Agaro, Pierlanfranco, Luzzati, Roberto, D'Avolio, Antonio, D’Agaro, Pierlanfranco, and D’Avolio, Antonio
- Subjects
COVID-19 ,Human serum albumin ,SARS-CoV-2 ,Vitamin D ,General Medicine - Abstract
Purpose We aimed to assess the combined role of vitamin D and albumin serum levels as predictors of COVID-19 disease progression. Methods We conducted a prospective observational study on adult patients hospitalized for SARS-CoV-2 pneumonia (March–September 2020). Vitamin D and albumin serum levels were measured on admission. These variables were categorized in albumin 2/FiO2 ratio, and 60-day mortality was defined. Results Sixty-nine patients were enrolled, of whom 50% received non-invasive (NIV) or invasive mechanical ventilation (IMV), 10% died, whereas 89% and 66% presented low albumin and low vitamin D serum levels, respectively. No correlation between vitamin D and albumin levels was found. In multivariable logistic regression analyses adjusted for sex and age-corrected comorbidities, patients having albumin OR 3.815; 95% CI 1.122–12.966; p = 0.032), NIV/IMV or death (OR 3.173; 95% CI 1.002–10.043; p = 0.049) and PaO2/FIO2 ≤ 100 (OR 3.410; 95% CI 1.138–10.219; p = 0.029). Conclusion The measurement of both vitamin D and serum albumin levels on COVID-19 patients’ admission, and their combined evaluation, provides a simple prognostic tool that could be employed to guide prompt clinical decisions.
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- 2023
45. Obstetric and neonatal outcomes after <scp>SARS‐CoV</scp> ‐2 infection in the first trimester of pregnancy: A prospective comparative study
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Federica Bevilacqua, Luca Bertero, Giovanni Di Perri, Marialuisa Bovetti, Chiara Benedetto, Jessica Cusato, Fulvio Borella, Giulio Mengozzi, Andrea Carosso, Raffaela Mazzone, Valeria Ghisetti, and Stefano Cosma
- Subjects
medicine.medical_specialty ,Neonatal intensive care unit ,Infectious Disease Transmission ,COVID-19 ,SARS-CoV-2 ,outcome ,pregnancy ,vertical transmission ,Female ,Humans ,Infant, Newborn ,Infectious Disease Transmission, Vertical ,Pregnancy ,Pregnancy Outcome ,Pregnancy Trimester, First ,Prospective Studies ,Pregnancy Complications, Infectious ,Premature Birth ,Intrauterine growth restriction ,Preeclampsia ,medicine ,Vertical ,Rupture of membranes ,Adverse effect ,First ,Obstetrics ,business.industry ,Infectious ,Infant ,Obstetrics and Gynecology ,Newborn ,medicine.disease ,Pregnancy Complications ,Apgar score ,Pregnancy Trimester ,business ,Cohort study - Abstract
Objective(s) This prospective observational cohort study aimed to evaluate whether women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first trimester of pregnancy are at higher risk of adverse obstetric and neonatal outcomes compared to negative patients. Study design Seromolecular testing for SARS-CoV-2 was performed at 12, 16, 21 weeks, and at delivery; the cohort was then subdivided into a first-trimester SARS-CoV-2-positive (case) group and a SARS-CoV-2-negative (control) group. The primary outcome was a composite adverse obstetric outcome, defined as the presence of either abortion, preterm delivery, preterm prelabor rupture of membranes, preeclampsia, intrauterine growth restriction, stillbirth; and a composite measure of adverse neonatal events, including either 1- and 5-min Apgar score ≤ 7, neonatal intensive care unit admission and congenital birth defects. Maternal symptoms and antibody titer were secondarily assessed. Results A total of 17 of 164 women tested positive for SARS-CoV-2 (10.3%) in the first trimester. One SARS-CoV-2-positive patient who gave birth at another hospital was excluded. Composite adverse obstetric outcome was observed in 6.2% (1/16) SARS-CoV-2-positive and 10.5% (11/105) SARS-CoV-2-negative women; composite adverse neonatal outcome in 12.5% (2/16) and 7.6% (8/105), respectively. In the newborns of women who had developed IgG antibodies, the same antibodies were detected in arterial cord blood and the nasopharyngeal swab tested negative for SARS-CoV-2. No maternal pneumonia or hospital admission due to coronavirus disease-19 were recorded. Conclusion Asymptomatic or mildly symptomatic women during the first trimester of pregnancy did not experience significantly more adverse events than SARS-CoV-2-negative women.
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- 2021
46. Therapeutic drug monitoring of TNFα inhibitors: a spotlight on novel techniques and assays
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Dario Cattaneo and Jessica Cusato
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Pharmacology ,tnfα inhibitors ,Tumor Necrosis Factor-alpha ,immunoassay ,therapeutic drug monitoring ,Humans ,General Medicine ,Drug Monitoring ,Toxicology - Published
- 2022
47. Real‐life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID‐19 pneumonia
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Silvia Scabini, Antonio D'Avolio, Rosario Urbino, Jessica Cusato, Francesca Canta, Luca Brazzi, Simone Mornese Pinna, Giorgia Montrucchio, Chiara Bonetto, Silvia Corcione, Giovanni Di Perri, Valeria Avataneo, Amedeo De Nicolò, and Francesco Giuseppe De Rosa
- Subjects
medicine.medical_specialty ,Icu patients ,Metabolite ,2019n-cov ,ICU ,covid-19 ,pharmacokinetics ,pneumonia ,remdesivir ,sars-cov-2 ,Short Report ,Cmax ,Antiviral Agents ,Gastroenterology ,chemistry.chemical_compound ,Cmin ,sars‐cov‐2 ,Short Reports ,Pharmacokinetics ,Tandem Mass Spectrometry ,Internal medicine ,medicine ,Humans ,2019n‐cov ,Pharmacology (medical) ,covid‐19 ,Pharmacology ,Alanine ,Nucleoside analogue ,SARS-CoV-2 ,business.industry ,medicine.disease ,Adenosine Monophosphate ,COVID-19 Drug Treatment ,Intensive Care Units ,Pneumonia ,chemistry ,Life study ,business ,medicine.drug - Abstract
Remdesivir is one of the most encouraging treatments against SARS‐CoV‐2 infection. After intravenous infusion, RDV is rapidly metabolized (T1/2 1h) within the cells to its active adenosine triphosphate analogue form (GS‐443902) and, then, it can be found in plasma in its nucleoside analogue form (GS‐441524). In this real life study we describe the Remdesivir and GS‐441524 concentrations at 3 time points in nine ICU patients, through a validated UHPLC‐MS/MS method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half‐life of GS‐441524. The mean C min, C max, AUC0–24, were < 0.24 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively for RDV and GS‐441524. Three out of nine patients achieved a C max> 2610 ng/mL and 140 ng/mL and AUC0–24 > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS‐441524, respectively. The mean T1/2 value for GS‐441524 was 26.3 h. Although the low number of patients, these data can represent an interesting preliminary report of the variability of RDV and GS‐441524 concentrations in real‐life ICU setting.
- Published
- 2021
48. DOP20 Genetic of vitamin D as predictor of response to adalimumab in Crohn’s Disease
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C. Tomasello, Lorenzo Bertani, Jessica Cusato, Gian Paolo Caviglia, Davide Giuseppe Ribaldone, Antonio D'Avolio, M. Mangia, S Dibetto, Marco Astegiano, and Miriam Antonucci
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medicine.medical_specialty ,Crohn's disease ,Vitamin D-binding protein ,business.industry ,Gastroenterology ,Vitamin D3 24-Hydroxylase ,Single-nucleotide polymorphism ,General Medicine ,medicine.disease ,Inflammatory bowel disease ,Immune system ,Internal medicine ,Vitamin D and neurology ,medicine ,Adalimumab ,business ,medicine.drug - Abstract
Background Personalised medicine is the direction towards are converging many efforts of experts in inflammatory bowel diseases (IBDs). The advent of biological drugs, with anti-TNF as first category, have revolutionized the managements of these patients. Unfortunately, several unmet needs are present, like an efficacy in about two third of the patients, onset of side effects like infections, paradoxical IMIDs. Being able to treat with these drugs only patients who will respond would avoid losing time without disease improvement and possible side effects. Vitamin D is important for several biological functions, such as regulation of the immune response and modulation of expression of genes encoding enzymes and transporters involved in drug metabolism and transport. Vitamin D is activated by cytochrome (CYP) 27B1, inactivated by CYP24A1, transported in kidney by Vitamin D binding protein (VDBP, encoded by GC gene) and carries out its activities through its receptor (VDR). No data are available concerning vitamin D genetics and response to anti-TNF drug adalimumab. The aim of this study was to describe the relationship between vitamin D pathway-related gene single nucleotide polymorphisms (SNPs) and adalimumab clinical outcome in a cohort of patients affected by Crohn’s disease. Methods We performed a multi-centre prospective study including patients affected by Crohn’s disease who started adalimumab therapy. SNPs in CYP27B1, CYP24A1, GC and VDR genes were analysed. Clinical outcome was considered as clinical response and remission at 3 months of therapy. Results We enrolled 69 patients. Median age was 40 (IQR 31–56) years, males were 40 (58%). Median basal calprotectin was 396 (IQR 188–851) mg/Kg, and 36 (53.7%) had a positive PCR value. We documented the following associations: CYP27B1 + 2838 CT/TT with perianal disease (p= 0.002), basal calprotectin (p= 0.018) and T3 calprotectin (p= 0.035), figure 1; CYP27B1-1260 GT/TT with perianal disease (p= 0.006), basal calprotectin (p= 0.036) and T3 calprotectin (p= 0.024); VDR ApaI CA/AA with basal calprotectin (p= 0.014) and T3 calprotectin (p= 0.036); VDR BsmI GA/AA with perianal disease (p= 0.036), and GC 1296 TG/GG with basal calprotectin (p= 0.014), figure 2. GC 1296 TG/GG genotype polymorphism (p= 0.044, figure 3) predicted clinical remission at multivariate analysis. Finally, median concentrations adalimumab trough levels at 3 months were 7.4 (IQR 5.5; 11.7) ug/mL. CYP24A1 3999 (p=0.025) and VDR TaqI (p=0.016) SNPs affected these levels. Conclusion This is the first study reporting the association between vitamin D pathway-related genetics and adalimumab treatment in a cohort of patients affected by IBD. Further studies in different and larger cohorts are needed to clarify these aspects.
- Published
- 2021
49. Alterations of Neuromuscular Environment Are Associated with Chronic Tissue Hypoxia in β-Thalassemia Patients
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Andrea Piolatto, Gennaro Boccia, Alessandra Manca, Carmen Gaglioti, Teresa Ceglie, Caterina Cosentino, Luca Beratto, Jessica Cusato, Patrizia Falco, Silvia De Carlo, Filomena Longo, Antonella Roetto, Antonio Piga, Antonio D'Avolio, Alberto Rainoldi, and Giovanni Battista Ferrero
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
50. A description of Cannabinoid levels in Cannabis oil by high-performance liquid chromatography-mass spectrometry in a reference laboratory of North-Italy
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Alessandra Manca, Alice Palermiti, Jacopo Mula, Elisa Delia De Vivo, Sandra Zeaiter, Marco Simiele, Amedeo De Nicolò, Marco Cantù, Jessica Cusato, and Antonio D'Avolio
- Subjects
Pharmacology ,Analgesics ,THC ,Cannabinoids ,Pharmaceutical Science ,Bedrocan ,Medical cannabis ,Complementary and alternative medicine ,Tandem Mass Spectrometry ,Drug Discovery ,Humans ,Molecular Medicine ,CBD ,Dronabinol ,Bediol ,Chromatography, High Pressure Liquid ,Cannabis - Abstract
Cannabis oils from FM2®, Bedica®, Bediol®, Bedrocan®, Bedrolite® and Pedanios 22/1® are largely used for medical purposes such as spasticity, chronic pain and appetite stimulating. Several studies showed cannabinoids action on CB1 and CB2 receptors reduces the hyperalgesic phase in inflammatory pain, leading to an improvement of conditions. The active compounds of these galenic preparations show a high variability making titration mandatory. For this reason, the exact oil composition knowledge is fundamental for personalizing therapy. This amis at adapting the correct dose to the patient, improving safety and efficacy of the galenic formulation, choosing the best preparation for each patient.The aim of this study was to investigate oil preparations variability among different galenic laboratories in order to highlight the importance of titration activity.Cannabis pharmacological active compounds titration has been performed in a large cohort of galenic laboratories in Italy. CBD, CBN, THC, THCA and CBDA quantification was carried out by a previous validated method in UHPLC-MS/MS.A number of 4318 samples of Cannabis oil from 83 pharmacies between January 2021 and February 2022 were evaluated. All galenic preparation specialities showed statistically significant differences among galenic laboratories (p-value0.001). THCA and CBDA concentrations were investigated as percentage of the extration yelds for total THC and CBD: these compounds had different values in the same specialities among distinct galenic laboratories. Moreover, seasonal variability in analytes concentrations was observed.This study described a wide range of oily samples from a large number of galenic laboratories, compared to published papers. In conclusion, knowledge of the exact oil composition is fundamental in the perspective of personalized therapy. Further studies aiming at the correlation between galenic composition and cannabinoids pharmacokinetics, clinical outcomes and toxic effects could be useful to improve our knowledge.
- Published
- 2022
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