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ABSTRACT: Retrospective studies have documented a significant association between linezolid (LNZ) plasma concentrations and drug-related haematological toxicity. However, the safe upper threshold level for LNZ plasma trough concentrations (Cmin values) has not been defined with certainty. A prospective observational study was performed aimed at comparing LNZ Cmin values in patients developing drug-related side effects with those measured in patients not experiencing LNZ toxicity. LNZ Cmin values were measured from the first week after starting therapy and were repeated periodically up to the end of treatment. Fifty patients, for a total of 210 LNZ Cmin evaluations, were considered. All patients (n=9) who developed drug-related haematological toxicity also had significantly higher plasma LNZ Cmin values during the first week of therapy (9.0±6.4mg/L vs. 4.9±3.7mg/L; P<0.01) and thereafter (9.3±5.4mg/L vs. 4.4±3.4mg/L; P<0.01). The significant association between LNZ plasma concentrations and haematological toxicity was also confirmed by multivariate logistic regression analysis including age, serum creatinine and concomitant medications as independent variables. A causal relationship between LNZ concentrations and the risk of developing drug-related haematological toxicity was observed. Accordingly, application of therapeutic drug monitoring may improve the safety outcome of patients receiving LNZ therapy.
International journal of antimicrobial agents 04/2013; · 3.03 Impact Factor
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Dario Cattaneo,
Sara Baldelli,
Matteo Cerea,
Simona Landonio,
Paola Meraviglia,
Emanuela Simioni, Valeria Cozzi,
Serena Fucile,
Andrea Gazzaniga,
Emilio Clementi,
Massimo Galli,
Giuliano Rizzardini,
Cristina Gervasoni
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ABSTRACT: The pharmacokinetics of raltegravir (RAL) in HIV patients is characterised by high inter/intra-patient variability. We investigated the potential contribution of the drug pharmaceutical formulation on RAL pharmacokinetics.We firstly compared in vivo the pharmacokinetics of RAL from 67 patients in which the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients that chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated in vitro the dissolution of RAL tablets under different conditions.In the in vivo study we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterised by significantly higher RAL absorption compared with patients receiving the drug by swallowing. The in vitro studies showed that when the whole tablets were exposed to an acidic medium the release of RAL was very low, whereas when crushed the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL.HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in the tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics.
Antimicrobial Agents and Chemotherapy 09/2012; · 4.84 Impact Factor
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ABSTRACT: Limited studies in healthy volunteers and in HIV-1-infected patients have shown that raltegravir pharmacokinetics are characterized by high inter-patient variability. Only scanty data are, however, available on intra-patient raltegravir variability. The present study was designed to evaluate in parallel the inter- and intra-patient variability of raltegravir pharmacokinetics in HIV-1-infected patients during routine therapeutic drug monitoring (TDM).
Fifteen HIV-infected patients treated with highly active antiretroviral therapy containing 400 mg of raltegravir twice daily were included in the study. Pharmacokinetic evaluations were performed during two consecutive visits. Only patients given raltegravir for at least 1 month and with no changes in antiretroviral and concomitant therapy between the two pharmacokinetic evaluations were considered. Raltegravir plasma concentrations were determined by a validated HPLC method. Blood samples were collected at 0, 1, 2, 3 and 4 h after the morning drug dose. Raltegravir AUC(0-12) was estimated using a recently developed algorithm.
The pharmacokinetic evaluation was repeated after an average of 52 ± 68 days. Raltegravir AUC(0-12) values ranged from 1495 to 49 051 ng · h/mL. The main finding was that intra-patient variability was a large component of the overall variability in raltegravir pharmacokinetics. In some instances the difference between raltegravir AUC(0-4) and AUC(0-12) measured in the same patient during two consecutive evaluations exceeded 110% and 75%, respectively.
The pharmacokinetics of raltegravir in HIV-1-infected subjects are characterized not only by inter-patient variability but also by high intra-patient variability. This condition limits the application of TDM for raltegravir, and might potentially affect patient outcome.
Journal of Antimicrobial Chemotherapy 11/2011; 67(2):460-4. · 5.07 Impact Factor
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ABSTRACT: Stepwise multiple regression analyses were applied to 44 atazanavir pharmacokinetic profiles from 44 HIV-1 infected patients concomitantly treated with raltegravir with the goal of identifying limited sampling strategies for the prediction of drug AUC(0-12) . Atazanavir trough-based equations failed to reliably predict daily drug exposure in patients with low drug bioavailability. Conversely, different algorithms based on few samples and associated with good correlation, acceptable bias and imprecision with the measured atazanavir AUC(0-12) were identified. These models could be used to predict atazanavir exposure for clinic or research purposes.
Fundamental and Clinical Pharmacology 11/2011; · 1.80 Impact Factor
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ABSTRACT: The potential drug-to-drug interaction between darunavir and raltegravir in the setting of HIV infection is a highly debated issue still unresolved. In the present study we have evaluated the pharmacokinetics of darunavir and ritonavir in 53 HIV-1 infected patients with or without concomitant raltegravir administration. The assessment of trough plasma drug concentrations was carried out in all subjects and the potential influence of raltegravir on darunavir and ritonavir disposition, assessed by specific pharmacokinetic evaluations in a subgroup of 25 patients. No significant differences on darunavir and ritonavir plasma trough levels were observed between patients receiving or not raltegravir. Co-administration of raltegravir was, however, associated with a 40% reduction in darunavir C(max) and estimated AUC(0-24), as well a 60% increase in the estimated darunavir clearance compared with values measured in patients not given raltegravir. Notably, this interaction was independent of the dosage of darunavir and not due to effects of raltegravir on the pharmacokinetics of ritonavir. These results should be taken into account when darunavir-based regimens are implemented in the setting of HIV, especially considering that this drug is usually administered at fixed daily dose and no therapeutic drug monitoring is performed in most centres.
Pharmacological Research 09/2011; 65(2):198-203. · 4.44 Impact Factor
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ABSTRACT: Stepwise multiple regression analyses were applied to 50 raltegravir pharmacokinetic profiles from 50 HIV patients with the goal to identify limited sampling strategies for the prediction of drug area under the time-concentration curve (AUC(0-12)). Raltegravir single sampling point-based equations failed to reliably predict daily drug exposure. Conversely, different algorithms based on few samples and associated with good correlation, acceptable bias, and imprecision with the measured raltegravir AUC(0-12) were identified. These models could used to predict raltegravir exposure for clinic or research purposes.
The Journal of Clinical Pharmacology 03/2011; 52(3):440-5. · 2.91 Impact Factor
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ABSTRACT: An HIV-infected patient with very low atazanavir (ATV) plasma trough concentrations despite clinical signs of poor drug tolerability was described. By therapeutic drug monitoring (TDM), the authors found that the patient had an atypical ATV pharmacokinetics characterized by rapid drug absorption followed by very fast drug clearance probably attributable to his genetic background. This case underlines the importance of traditional and pharmacogenetic-based TDM for the individualization of ATV therapy in HIV-1 patients.
Fundamental and Clinical Pharmacology 01/2011; 26(2):204-6. · 1.80 Impact Factor
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European Journal of Clinical Pharmacology 11/2010; 67(4):429-31. · 2.85 Impact Factor
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ABSTRACT: Raltegravir (RAL) is primarily metabolized by uridine diphosphate-glucorunosyl transferase 1A1 (UGT1A1). Atazanavir (ATV), a strong inhibitor of UGT1A1, has been shown to increase plasma concentrations of RAL by approximately 50% in healthy volunteers. However, the extent of this interaction has not been studied in HIV-infected patients. A pharmacokinetic study was performed in 22 HIV-infected adults treated with 400 mg RAL plus 300 mg ATV 300 twice a day. Both drugs showed high pharmacokinetic variability (RAL AUC 0-12 7649 ± 4862 ng*h/mL; ATV AUC 0-12 = 19237 ± 13136 ng*h/mL). Notably, RAL trough concentrations were significantly higher compared with those measured in HIV subjects (n = 24) on RAL plus nucleoside reverse transcriptase inhibitors (506 ± 411 versus 177 ± 262 ng/mL, P < 0.01). A significant correlation was found between RAL and ATV area under the curve (AUC) (r = 0.611, P = 0.005). Notably, patients with ATV AUC 0-12 above the mean or with concentrations exceeding the half maximal inhibitory concentration for UGT1A1 had twofold higher RAL AUCs compared with patients with lower ATV exposure. Coadministration of ATV significantly increased plasma concentrations of RAL, especially in HIV-1-infected patients exposed to high concentrations of the protease inhibitor. This pharmacokinetic drug interaction could be handled by routine measurements of ATV trough concentrations and by the assessment of plasma RAL concentrations 2 to 3 hours after the morning drug intake.
Therapeutic drug monitoring 10/2010; 32(6):782-6. · 2.43 Impact Factor
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ABSTRACT: A high-performance liquid chromatographic method for the determination of linezolid in human plasma was developed and validated. After precipitation of plasma proteins with perchloric acid, the protein-free supernatant was separated by isocratic reverse-phase chromatography on a X Bridge C18 column. The mobile phase consisted of a mixture of phosphoric acid 0.05%: acetonitrile (75:25, v/v) with a flow rate of 1 mL/min. The column elute was monitored at 254 nm. The method was linear from 0.2 to 48 mg/L (mean r2 = 0.9996, n = 10). The observed intra- and inter-day assay imprecision ranged from 2.83% to 8.16% (18.80% at the lower limit of quantification); inaccuracy varied between -0.33% and 8.18%. Mean drug recovery was 99.8% for linezolid and 90.0% for the internal standard (para-toluic acid). The method was found to be precise and accurate and suitable for therapeutic drug monitoring of linezolid in routine clinical practice.
Therapeutic drug monitoring 03/2010; 32(4):520-4. · 2.43 Impact Factor
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ABSTRACT: Mitochondria are sources of energy production through their role in producing adenosine triphosphate for cell metabolism. Defective mitochondrial biogenesis and function play relevant roles in the pathophysiology of relevant diseases, including obesity, diabetes mellitus, myopathies, and neurodegenerative diseases. Their function is the product of synthesis of macromolecules within the mitochondria and import of proteins and lipids synthesized outside the organelles. Both are required for mitochondrial proliferation and may also facilitate the growth of preexisting mitochondria. Recent evidence indicates that these events are regulated in a complex way by several agonists and environmental conditions, through activation of specific signaling pathways and transcription factors. Nitric oxide (NO) appears to be a novel modulator of mitochondrial biogenesis. High levels of NO acutely inhibit cell respiration by binding to cytochrome c oxidase. Conversely, chronic, low-grade increases of NO stimulate mitochondrial biogenesis in diverse cell types. Here, we suggest that some types of nutrients, including specific mixtures of amino acids, may improve mitochondrial biogenesis and energy production in energy-defective conditions by increasing endothelial NO synthase expression.
The American Journal of Cardiology 07/2008; 101(11A):22E-25E. · 3.37 Impact Factor
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Alessandra Valerio,
Annalisa Cardile, Valeria Cozzi,
Renata Bracale,
Laura Tedesco,
Addolorata Pisconti,
Letizia Palomba,
Orazio Cantoni,
Emilio Clementi,
Salvador Moncada,
Michele O Carruba,
Enzo Nisoli
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ABSTRACT: Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-alpha. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-alpha downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-alpha. Our findings demonstrate that TNF-alpha impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.
Journal of Clinical Investigation 11/2006; 116(10):2791-8. · 15.39 Impact Factor
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Enzo Nisoli,
Cristina Tonello,
Annalisa Cardile, Valeria Cozzi,
Renata Bracale,
Laura Tedesco,
Sestina Falcone,
Alessandra Valerio,
Orazio Cantoni,
Emilio Clementi,
Salvador Moncada,
Michele O Carruba
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ABSTRACT: Calorie restriction extends life span in organisms ranging from yeast to mammals. Here, we report that calorie restriction for either 3 or 12 months induced endothelial nitric oxide synthase (eNOS) expression and 3',5'-cyclic guanosine monophosphate formation in various tissues of male mice. This was accompanied by mitochondrial biogenesis, with increased oxygen consumption and adenosine triphosphate production, and an enhanced expression of sirtuin 1. These effects were strongly attenuated in eNOS null-mutant mice. Thus, nitric oxide plays a fundamental role in the processes induced by calorie restriction and may be involved in the extension of life span in mammals.
Science 11/2005; 310(5746):314-7. · 31.20 Impact Factor
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Enzo Nisoli,
Sestina Falcone,
Cristina Tonello, Valeria Cozzi,
Letizia Palomba,
Mara Fiorani,
Addolorata Pisconti,
Silvia Brunelli,
Annalisa Cardile,
Maura Francolini,
Orazio Cantoni,
Michele O Carruba,
Salvador Moncada,
Emilio Clementi
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ABSTRACT: We recently found that long-term exposure to nitric oxide (NO) triggers mitochondrial biogenesis in mammalian cells and tissues by activation of guanylate cyclase and generation of cGMP. Here, we report that the NO/cGMP-dependent mitochondrial biogenesis is associated with enhanced coupled respiration and content of ATP in U937, L6, and PC12 cells. The observed increase in ATP content depended entirely on oxidative phosphorylation, because ATP formation by glycolysis was unchanged. Brain, kidney, liver, heart, and gastrocnemius muscle from endothelial NO synthase null mutant mice displayed markedly reduced mitochondrial content associated with significantly lower oxygen consumption and ATP content. In these tissues, ultrastructural analyses revealed significantly smaller mitochondria. Furthermore, a significant reduction in the number of mitochondria was observed in the subsarcolemmal region of the gastrocnemius muscle. We conclude that NO/cGMP stimulates mitochondrial biogenesis, both in vitro and in vivo, and that this stimulation is associated with increased mitochondrial function, resulting in enhanced formation of ATP.
Proceedings of the National Academy of Sciences 12/2004; 101(47):16507-12. · 9.68 Impact Factor
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Enzo Nisoli,
Emilio Clementi,
Clara Paolucci, Valeria Cozzi,
Cristina Tonello,
Clara Sciorati,
Renata Bracale,
Alessandra Valerio,
Maura Francolini,
Salvador Moncada,
Michele O Carruba
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ABSTRACT: Nitric oxide was found to trigger mitochondrial biogenesis in cells as diverse as brown adipocytes and 3T3-L1, U937, and HeLa cells. This effect of nitric oxide was dependent on guanosine 3',5'-monophosphate (cGMP) and was mediated by the induction of peroxisome proliferator-activated receptor gamma coactivator 1alpha, a master regulator of mitochondrial biogenesis. Moreover, the mitochondrial biogenesis induced by exposure to cold was markedly reduced in brown adipose tissue of endothelial nitric oxide synthase null-mutant (eNOS-/-) mice, which had a reduced metabolic rate and accelerated weight gain as compared to wild-type mice. Thus, a nitric oxide-cGMP-dependent pathway controls mitochondrial biogenesis and body energy balance.
Science 03/2003; 299(5608):896-9. · 31.20 Impact Factor
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ABSTRACT: The intracellular localization and activity of the nitric oxide synthase (NOS) isoforms were investigated in rat brown adipocytes. Immunohistochemistry showed cytoplasmic and nuclear staining for the endothelial NOS (eNOS) and inducible NOS (iNOS) isoforms; accordingly, anti-L-citrulline antibody, a marker of NOS activity, immunostained both the cytoplasm and the nucleus. The presence of metabolically active NOS in the nucleus was further confirmed by immunoblotting analyses of subcellular fractions of homogenates from cultured brown adipocytes and by measurements of NOS activity in the cytosol and nucleus. Sympathetic stimulation in vivo (i.e. cold exposure or beta(3)-adrenergic agonist treatment) and in vitro (i.e. noradrenaline treatment of cultured cells) significantly increased both cytosolic and nuclear eNOS and iNOS expression and activities. By contrast, the number of iNOS-positive, but not eNOS-positive, nuclei was significantly lower in the functionally impaired brown fat of genetically obese Zucker fa/fa rats. These data suggest the existence of a noradrenaline-modulated functional NOS system in the nucleus of brown adipocytes.
FEBS Letters 04/2002; 514(2-3):135-40. · 3.54 Impact Factor
