10 results on '"Oggianu L"'
Search Results
2. Oxidized von Willebrand factor is associated with thrombotic micro- and macro-angiopaties in diabetes mellitus: PB 3.44–4
- Author
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De Cristofaro, R, Oggianu, L, Lancellotti, S, Pitocco, D, Zaccardi, F, Rizzo, P, Martini, F, and Ghirlanda, G
- Published
- 2013
3. Oxidation of Met1606 in von Willebrand factor is a risk factor for thrombotic and septic complications in chronic renal failure
- Author
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Lancellotti, S, Maset, F, Spolaore, B, Pozzi, N, Gambaro, G, Oggianu, L, Calo', Lorenzo, and De Cristofaro, R.
- Published
- 2012
4. PK/PD analysis of trazodone and gabapentin in neuropathic pain rodent models: Translational PK-PD modeling from nonclinical to clinical development.
- Author
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Oggianu L, Garrone B, Fiorentini F, Del Bene F, Rosignoli MT, Di Giorgio FP, and Kaminski RM
- Subjects
- Humans, Mice, Animals, Gabapentin, Rodentia, Analgesics pharmacology, Acetic Acid, Models, Biological, Trazodone pharmacology, Neuralgia drug therapy
- Abstract
A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the time course of writhings after intraperitoneal injection of acetic acid in mice. The model was applied to investigate the antinociceptive effect of trazodone and gabapentin alone and in combination. Writhings time course was described by a transit compartment model with the delay due to the transit of the acetic acid being represented by a chain of intermediate compartments. In the drug-treated animals, the number of writhings decreases according to a k
2 factor linking drug concentration and antinociceptive effect. Compounds' potency parameters were 10.9 and 0.0459 L/μmoles/min for trazodone and gabapentin, respectively, indicating a much higher in vivo potency of trazodone in the PD writhing test. The PK/PD parameters were used to simulate the expected writhing counts in mice at combined doses without efficacy alone, assuming pharmacological additivity. Simulation results indicated that, at low dose combinations, experimental data were mostly below the simulated writhings median, suggesting possible synergic effect. Such hypothesis was tested by adding the γ parameter in the PK/PD model to represent the deviation from the assumption of no-interaction, leading to a reduction of the objective function compared to the additive model. On this basis, several simulations were performed to identify possible starting dose combinations of trazodone and gabapentin in humans, by selecting doses yielding systemic exposures close to those being synergic in the mouse. Simulations indicated that doses of 50-100 mg trazodone could enhance gabapentin antinociceptive effect in humans, supporting the development of a low dose combination for optimal analgesia treatment., (© 2023 Angelini Pharma S.p.A. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2023
- Full Text
- View/download PDF
5. Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations.
- Author
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Oggianu L, Di Dato G, Mangano G, Rosignoli MT, McFeely S, Ke AB, Jones HM, and Comandini A
- Subjects
- Antidepressive Agents, Brain, Delayed-Action Preparations, Humans, Depressive Disorder, Major drug therapy, Trazodone
- Abstract
Trazodone is approved for the treatment of major depressive disorders, marketed as immediate release (IR), prolonged release, and once a day (OAD) formulation. The different formulations allow different administration schedules and may be useful to facilitate patients' compliance to the antidepressant treatment. A previously verified physiologically-based pharmacokinetic model based on in vitro and in vivo information on trazodone pharmacokinetics was applied, aiming at predicting brain receptor occupancy (RO) after single and repeated dosing of the IR formulation and repeated dosing of the OAD formulation in healthy subjects. Receptors included in the simulations were selected using static calculations of RO based on the maximum unbound brain concentration (C
max,brain,u ) of trazodone for each formulation and dosing scheme, resulting in 16 receptors being simulated. Seven receptors were simulated for the IR low dose formulation (30 mg), with similar tonset and duration of coverage (range: 0.09-0.25 h and 2.1->24 h, respectively) as well as RO (range: 0.64-0.92) predicted between day 1 and day 7 of dosing. The 16 receptors evaluated for the OAD formulation (300 mg) showed high RO (range: 0.97-0.84 for the receptors also covered by the IR formulation and 0.73-0.48 for the remaining) correlating with affinity and similar duration of time above the target threshold to the IR formulation (range: 2->24 h). The dose-dependent receptor coverage supports the multimodal activity of trazodone, which may further contribute to its fast antidepressant action and effectiveness in controlling different symptoms in depressed patients., (© 2022 Angelini Pharma S.P.A. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2022
- Full Text
- View/download PDF
6. Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and In Vivo Activity in a Mood Disorder Model.
- Author
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Prati F, Buonfiglio R, Furlotti G, Cavarischia C, Mangano G, Picollo R, Oggianu L, di Matteo A, Olivieri S, Bovi G, Porceddu PF, Reggiani A, Garrone B, Di Giorgio FP, and Ombrato R
- Abstract
Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3β (GSK-3β) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3β inhibitors with good in vivo efficacy and safety profile associated with high brain exposure is required. Accordingly, we have previously reported the selective indazole-based GSK-3 inhibitor 1 , which showed excellent efficacy in a mouse model of mania. Despite the favorable preclinical profile, analog 1 suffered from activity at the hERG ion channel, which prevented its further progression. Herein, we describe our strategy to improve this off-target liability through modulation of physicochemical properties, such as lipophilicity and basicity. These efforts led to the potent inhibitor 14 , which possessed reduced hERG affinity, promising in vitro ADME properties, and was very effective in a mood stabilizer in vivo model., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)
- Published
- 2020
- Full Text
- View/download PDF
7. Estimation of an Appropriate Dose of Trazodone for Pediatric Insomnia and the Potential for a Trazodone-Atomoxetine Interaction.
- Author
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Oggianu L, Ke AB, Chetty M, Picollo R, Petrucci V, Calisti F, Garofolo F, and Tongiani S
- Subjects
- Adolescent, Antidepressive Agents, Second-Generation administration & dosage, Antidepressive Agents, Second-Generation pharmacokinetics, Child, Child, Preschool, Dose-Response Relationship, Drug, Drug Interactions, Humans, Trazodone pharmacokinetics, Atomoxetine Hydrochloride pharmacology, Models, Biological, Sleep Initiation and Maintenance Disorders drug therapy, Trazodone administration & dosage
- Abstract
There is a paucity of clinical trials for the treatment of pediatric insomnia. This study was designed to predict the doses of trazodone to guide dosing in a clinical trial for pediatric insomnia using physiologically-based pharmacokinetic (PBPK) modeling. Data on the pharmacokinetics of trazodone in children are currently lacking. The interaction potential between trazodone and atomoxetine was also predicted. Doses predicted in the following age groups, with exposures corresponding to adult dosages of 30, 75, and 150 mg once a day (q.d.), respectively, were: (i) 2- to 6-year-old group, doses of 0.35, 0.8, and 1.6 mg/kg q.d.; (ii) >6- to 12-year-old group, doses of 0.4, 1.0, and 1.9 mg/kg q.d.; (iii) >12- to 17-year-old group, doses of 0.4, 1.1, and 2.1 mg/kg q.d. An interaction between trazodone and atomoxetine was predicted to be unlikely. Clinical trials based on the aforementioned predicted dosing are currently in progress, and pharmacokinetic data obtained will enable further refinement of the PBPK models., (© 2019 ANGELINI S.p.A. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
- Full Text
- View/download PDF
8. Juvenile rat and pediatric trazodone studies: how to gain extra sensitivity to overcome bioanalytical challenges.
- Author
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Olivieri S, Bovi G, Petrucci V, Alfieri A, Oggianu L, Picollo R, Devastato C, Dragone P, Garofolo F, and Tongiani S
- Subjects
- Animals, Anti-Anxiety Agents administration & dosage, Blood Specimen Collection instrumentation, Calibration, Capillaries, Chromatography, Liquid, Dose-Response Relationship, Drug, Female, Male, Rats, Reference Standards, Reproducibility of Results, Sensitivity and Specificity, Tandem Mass Spectrometry, Toxicokinetics, Trazodone administration & dosage, Anti-Anxiety Agents blood, Blood Specimen Collection methods, Trazodone blood
- Abstract
Aim: Trazodone (TZD) is used for the treatment of depression in adults and, off-label, as a sleep medication in adult and pediatric populations. The off-label use is well documented, however further clinical studies are needed to confirm its efficacy and safety for the treatment of sleep disorders. In this scenario, we developed a bioanalytical method to quantify low TZD concentrations in samples collected by capillary microsampling (CMS) to support dose finding, Good Laboratory Practice juvenile rat toxicokinetic and upcoming pediatric studies., Methodology: A method using only 8 μl of plasma was developed and successfully used for analyzing CMS samples from juvenile rats throughout toxicokinetic study., Conclusion: By harmoniously maximizing each analytical step, we achieved a sensitive method to quantify TZD in CMS samples.
- Published
- 2019
- Full Text
- View/download PDF
9. The oxidative modification of von Willebrand factor is associated with thrombotic angiopathies in diabetes mellitus.
- Author
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Oggianu L, Lancellotti S, Pitocco D, Zaccardi F, Rizzo P, Martini F, Ghirlanda G, and De Cristofaro R
- Subjects
- ADAM Proteins metabolism, ADAMTS13 Protein, Adult, Cholesterol, HDL blood, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 2 metabolism, Diabetic Angiopathies etiology, Electrophoresis, Polyacrylamide Gel, Humans, Immunoassay, Italy, Middle Aged, Oxidation-Reduction, Protein Carbonylation physiology, Statistics, Nonparametric, Thrombotic Microangiopathies etiology, Triglycerides blood, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 2 complications, Diabetic Angiopathies metabolism, Thrombotic Microangiopathies metabolism, von Willebrand Factor metabolism
- Abstract
The thrombogenic activity of Von Willebrand factor (VWF) is proportional to its molecular size and inversely related to its proteolysis by ADAMTS-13. Oxidation of VWF severely impairs its proteolysis by the metalloprotease. This study was aimed at assessing in patients with type 1 and type 2 diabetes whether protein carbonyls, marker of oxidative stress, are associated with both the level and oxidation status of VWF as well as with micro- and macroangiopathic complications. Eighty-three diabetic patients (41 type 1 and 42 type 2 diabetic subjects) and their respective eighty-three healthy controls were studied after verifying the availability, through institutional databases, of clinical biochemistry records spanning at least 3 years. VWF and protein carbonyls were measured by immunoassays, whereas VWF multimers were studied by SDS-agarose gel electrophoresis. Type 2 diabetic subjects had higher levels of VWF antigen (VWF:ag), VWF activity (VWF:act) and plasma proteins' carbonyls compared to both their controls and type 1 diabetic subjects. Moreover, high molecular weight VWF multimers and specific VWF-bound carbonyls were significantly increased in subjects with micro- and macro-angiopathic complications. In both type 1 and type 2 diabetic subjects, ADAMTS-13 activity was in the normal range. In a multivariable analysis, only VWF-bound carbonyls were significantly associated with any form of thrombotic angiopathy in the entire group of T1- and T2 diabetic patients. These data provide first evidence that not only high VWF levels but also its oxidation status and the presence of high molecular weight VWF multimers that are not observed in SDS-agarose gel electrophoresis of normal subjects are associated with thrombotic angiopathies in diabetes mellitus. These findings may help identify diabetic patients particularly at risk for these complications and elucidate a new pathophysiological mechanism of thrombotic angiopathies in this clinical setting.
- Published
- 2013
- Full Text
- View/download PDF
10. Oxidation of Met1606 in von Willebrand factor is a risk factor for thrombotic and septic complications in chronic renal failure.
- Author
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De Filippis V, Lancellotti S, Maset F, Spolaore B, Pozzi N, Gambaro G, Oggianu L, Calò LA, and De Cristofaro R
- Subjects
- ADAM Proteins blood, ADAMTS13 Protein, Adhesins, Bacterial blood, Adult, Amino Acid Sequence, Case-Control Studies, Female, Humans, Kidney Failure, Chronic therapy, Male, Methionine chemistry, Middle Aged, Molecular Sequence Data, Molecular Weight, Oxidation-Reduction, Peptide Fragments blood, Peptide Fragments chemistry, Peptide Fragments genetics, Platelet Activation, Protein Multimerization, Renal Dialysis, Risk Factors, Sepsis etiology, Kidney Failure, Chronic blood, Kidney Failure, Chronic complications, Sepsis blood, Thrombosis blood, Thrombosis etiology, von Willebrand Factor chemistry, von Willebrand Factor metabolism
- Abstract
CKD (chronic kidney disease) is a life-threatening pathology, often requiring HD (haemodialysis) and characterized by high OS (oxidative stress), inflammation and perturbation of vascular endothelium. HD patients have increased levels of vWF (von Willebrand factor), a large protein (~240 kDa) released as UL-vWF (ultra large-vWF polymers, molecular mass ~20000-50000 kDa) from vascular endothelial cells and megakaryocytes, and responsible for the initiation of primary haemostasis. The pro-haemostatic potential of vWF increases with its length, which is proteolytically regulated by ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin motifs 13), a zinc-protease cleaving vWF at the single Tyr1605-Met1606 bond, and by LSPs (leucocyte serine proteases), released by activated PMNs (polymorphonuclear cells) during bacterial infections. Previous studies have shown that in vitro oxidation of Met1606 hinders vWF cleavage by ADAMTS-13, resulting in the accumulation of UL-vWF that are not only more pro-thrombotic than shorter vWF oligomers, but also more efficient in binding to bacterial adhesins during sepsis. Notably, HD patients have increased risk of developing dramatic cardiovascular and septic complications, whose underlying mechanisms are largely unknown. In the present study, we first purified vWF from HD patients and then chemically characterized its oxidative state. Interestingly, HD-vWF contains high carbonyl levels and increased proportion of UL-vWF polymers that are also more resistant to ADAMTS-13. Using TMS (targeted MS) techniques, we estimated that HD-vWF contains >10% of Met1606 in the sulfoxide form. We conclude that oxidation of Met1606, impairing ADAMTS-13 cleavage, results in the accumulation of UL-vWF polymers, which recruit and activate platelets more efficiently and bind more tightly to bacterial adhesins, thus contributing to the development of thrombotic and septic complications in CKD.
- Published
- 2012
- Full Text
- View/download PDF
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