Institute of Clinical Pharmacology

Udine, Italy

Institute of Clinical Pharmacology

Udine, Italy
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Weth D.,Innsbruck Medical University | Benetti C.,Innsbruck Medical University | Rauch C.,Innsbruck Medical University | Gstraunthaler G.,Innsbruck Medical University | And 5 more authors.
Frontiers in Neuroscience | Year: 2015

At the site of injury activated platelets release various mediators, one of which is sphingosine 1-phosphate (S1P). It was the aim of this study to explore whether activated human platelets had a pronociceptive effect in an in vivo mouse model and whether this effect was based on the release of S1P and subsequent activation of neuronal S1P receptors 1 or 3. Human platelets were prepared in different concentrations (105/μl, 106/μl, 107/μl) and assessed in mice with different genetic backgrounds (WT, S1P1fl/fl, SNS-S1P1-/-, S1P3-/-). Intracutaneous injections of activated human platelets induced a significant, dose-dependent hypersensitivity to noxious thermal stimulation. The degree of heat hypersensitivity correlated with the platelet concentration as well as the platelet S1P content and the amount of S1P released upon platelet activation as measured with LC MS/MS. Despite the significant correlations between S1P and platelet count, no difference in paw withdrawal latency (PWL) was observed in mice with a global null mutation of the S1P3 receptor or a conditional deletion of the S1P1 receptor in nociceptive primary afferents. Furthermore, neutralization of S1P with a selective anti-S1P antibody did not abolish platelet induced heat hypersensitivity. Our results suggest that activated platelets release S1P and induce heat hypersensitivity in vivo. However, the platelet induced heat hypersensitivity was caused by mediators other than S1P. © 2015 Weth, Benetti, Rauch, Gstraunthaler, Schmidt, Geisslinger, Sabbadini, Proia and Kress.


Pea F.,Institute of Clinical Pharmacology | Pea F.,University of Udine
Current Opinion in Pharmacology | Year: 2015

The elderly population is increasing worldwide and shows an increasing prevalence of frailty. Frailty is recognized as an important factor for inappropriate drug prescribing in elderly patients. Appropriate drug prescription, either in terms of drug choice or in terms of drug dosage, is of paramount importance among the frail elderly patients, this requiring the need of a difficult balance between efficacy, safety and tolerability. Bacterial infections are quite frequent among the elderly, and use of antimicrobials may be associated with severe adverse events in this population, especially when in presence of co-medications and/or of co-morbidities. The aim of this paper is to argue about the most recent published evidences on how to prevent major adverse events whenever antimicrobials should be co-prescribed in frail elderly patients. © 2015 Elsevier Ltd. All rights reserved.


Cao L.,Second Xiangya Hospital | Xu L.,Institute of Clinical Pharmacology | Huang B.,Central South University | Wu L.,Central South University
Pharmacology | Year: 2012

Background/Aims: Propofol, a widely used sedative-hypnotic agent for induction/maintenance of anesthesia and sedation of critically ill patients, reportedly has therapeutic potential for hypertension. Angiotensin-converting enzyme 2 (ACE2) is a promising therapeutic target for pulmonary arterial hypertension. In the present study, we explored the effect of propofol on ACE2 expression in human pulmonary artery endothelial cells (HPAECs). Methods: HPAECs were treated with propofol in different concentrations (1, 10, 20, 40 or 50 μmol/l) for different lengths of time (6, 12, 18, 24 or 30 h) with or without transcription inhibitor actinomycin D or phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Results: Propofol increased the ACE2 mRNA level in a dose- and time-dependent manner within 24 h. Propofol treatment dose-dependently increased the ACE2 protein level and the cell membrane ACE2 activity. Transcription inhibitor actinomycin D and PI3K inhibitor LY294002 abrogated the augmenting effect of propofol on the mRNA level of ACE2 in HPAECs. Conclusion: Propofol enhances the ACE2 expression in HPAECs by increasing the transcription of ACE2 via a PI3K-dependent mechanism, which leads to increased ACE2 activity on the cell membrane. This study provides new insights into propofol's vascular protective effects as well as its therapeutic potential for pulmonary arterial hypertension. Copyright © 2012 S. Karger AG, Basel.


Heusser K.,Institute of Clinical Pharmacology | Tank J.,Institute of Clinical Pharmacology | Engeli S.,Institute of Clinical Pharmacology | Diedrich A.,Vanderbilt University | And 6 more authors.
Hypertension | Year: 2010

In animals, electric field stimulation of carotid baroreceptors elicits a depressor response through sympathetic inhibition. We tested the hypothesis that the stimulation acutely reduces sympathetic vasomotor tone and blood pressure in patients with drug treatment-resistant arterial hypertension. Furthermore, we tested whether the stimulation impairs the physiological baroreflex regulation. We studied 7 men and 5 women (ages 43 to 69 years) with treatment-resistant arterial hypertension. A bilateral electric baroreflex stimulator at the level of the carotid sinus (Rheos) was implanted ≥1 month before the study. We measured intra-arterial blood pressure, heart rate, muscle sympathetic nerve activity (microneurography), cardiac baroreflex sensitivity (cross-spectral analysis and sequence method), sympathetic baroreflex sensitivity (threshold technique), plasma renin, and norepinephrine concentrations. Measurements were performed under resting conditions, with and without electric baroreflex stimulation, for ≥6 minutes during the same experiment. Intra-arterial blood pressure was 193±9/94±5 mm Hg on medications. Acute electric baroreflex stimulation decreased systolic blood pressure by 32±10 mm Hg (range: +7 to-108 mm Hg; P=0.01). The depressor response was correlated with a muscle sympathetic nerve activity reduction (r2=0.42; P<0.05). In responders, muscle sympathetic nerve activity decreased sharply when electric stimulation started. Then, muscle sympathetic nerve activity increased but remained below the baseline level throughout the stimulation period. Heart rate decreased 4.5±1.5 bpm with stimulation (P<0.05). Plasma renin concentration decreased 20±8% (P<0.05). Electric field stimulation of carotid sinus baroreflex afferents acutely decreased arterial blood pressure in hypertensive patients, without negative effects on physiological baroreflex regulation. The depressor response was mediated through sympathetic inhibition. Copyright © 2010 American Heart Association. All rights reserved.


Cojutti P.,Institute of Clinical Pharmacology | Cojutti P.,University of Udine | Maximova N.,Institute for Maternal and Child Health | Crichiutti G.,Clinics of Pediatrics | And 3 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2015

Objectives: To report on linezolid exposure in a paediatric population who routinely underwent therapeutic drug monitoring (TDM) for dosage optimization and to assess the factors affecting interpatient variability. Methods: We performed a retrospective study of patients whose plasma Cmin and Cmax levels were measured during linezolid treatment. Adequate exposure was defined as a Cmin of 2-7 mg/L and/or an estimated AUC24 of 160-300 mg·h/L. Patients were divided into two subgroups (Group 1, 2-11 years; Group 2, 12-18 years). Monte Carlo simulation was performed to investigate whether or not the currently recommended dosages might enable a high probability of target attainment (PTA) of two thresholds for linezolid efficacy (AUC24/MIC ≥ 80 or ≥ 100). Data on demographic characteristics, disease, microbiology and haematochemical parameters and outcomes were collected. Results: A total of 23 patients were included. Standard dosages were suboptimal in 50.0% and 44.4% of patients in Group 1 and Group 2, respectively. Among those who underwent multiple instances of TDM, the dosages were increased in 33.3% of cases in both groups, and decreased in 6.6% and 9.5% of cases in Group 1 and Group 2, respectively. Co-treatment with phenobarbital, proton pump inhibitors and amiodarone accounted for most of the variability in Cmin (adjusted R2 of 0.692). Simulations showed a PTA of ≥90% with the current dosing regimens in both groups only for pathogens with an MIC ≤1 mg/L. Conclusions: Higher dosages of linezolid may be needed, especially in Group 1 when in the presence of pathogens with an MIC >1 mg/L. The role of TDM should be encouraged for optimization of linezolid exposure in the paediatric setting in the presence of infections caused by pathogens with borderline susceptibility and/or for patients co-treated with drugs that may alter linezolid exposure. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Blot S.I.,Ghent University | Blot S.I.,University of Queensland | Pea F.,Institute of Clinical Pharmacology | Pea F.,University of Udine | And 2 more authors.
Advanced Drug Delivery Reviews | Year: 2014

Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward. © 2014.


Pai M.P.,Albany College of Pharmacy and Health Sciences | Cojutti P.,Institute of Clinical Pharmacology | Cojutti P.,University of Udine | Pea F.,Institute of Clinical Pharmacology | Pea F.,University of Udine
Clinical Pharmacokinetics | Year: 2014

Background: Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses. Objective: The current investigation was performed to characterize the pharmacokinetics (PK) and evaluate the influence of alternate body size descriptors and renal function as predictors of levofloxacin clearance (CL) and the area under the curve over 24 h (AUC 24). Methods: A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients ≥18 years of age with a body mass index ≥40 kg/m2. A maximum a posteriori probability Bayesian approach using a two-compartment linear PK model was used to estimate individual PK parameters and AUC24. Results: A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250 kg were evaluated. The median (5th, 95th percentile) daily dose and AUC24 was 1,000 (250, 1,500) mg and 90.7 (44.4, 228) mg·h/L, respectively. Levofloxacin CL was significantly (p < 0.05) related to height but not weight. As a result, levofloxacin CL was best related (R 2 = 0.57) to creatinine CL (CLcr) estimated by the Cockcroft-Gault (CG) equation and ideal body weight (IBW) because IBW is a height transformation. An empiric four-category daily-dose regimen (500, 750, 1,000, 1,250 mg) stratified by CLcr (CG-IBW) is expected to have >90 % probability of achieving an AUC 24 of 50-150 mg·h/L in morbidly obese patients. Subsequent application of TDM and integration with pathogen-specific information could then be applied to tailor the levofloxacin regimen. Conclusions: The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese. © 2014 Springer International Publishing Switzerland.


Pea F.,Institute of Clinical Pharmacology | Pea F.,University of Udine
Current Opinion in Infectious Diseases | Year: 2016

Purpose of review: This article gives an overview of the practical concept of pharmacokinetic/pharmacodynamic principles useful for clinicians in the management of skin and soft tissue infections (SSTIs). Recent findings: Recent studies suggest that distinguishing between bacteriostatic or bactericidal activity when choosing an antimicrobial for the treatment of severe infections could probably be clinically irrelevant. Conversely, what could help clinicians in maximizing the therapeutic efficacy of the various drugs in routine practice is taking care of some pharmacokinetic/pharmacodynamic principles. Concentration-dependent agents may exhibit more rapid bacterial killing than observed with time-dependent agents. Serum concentrations may not always adequately predict tissue exposure in patients with SSTIs, and measuring concentrations at the infection site is preferable. Hydrophilic antimicrobials showed generally lower penetration rates than the lipophilic ones and might require alternative dosing approaches in the presence of severe sepsis or septic shock. Conversely, tissue penetration of lipophilic antimicrobials is often unaffected by the pathophysiological status. Real-time therapeutic drug monitoring may be a very helpful tool for optimizing therapy of severe infections. Summary: Taking care of pharmacokinetic/pharmacodynamic principles deriving from the most recent findings may help clinicians in maximizing treatment of SSTIs with antimicrobials in every situation. © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Pea F.,Institute of Clinical Pharmacology | Pea F.,University of Udine | Crapis M.,Clinic of Infectious Diseases | Cojutti P.,Institute of Clinical Pharmacology | And 2 more authors.
Infection | Year: 2014

We describe the case of an intravenous drug user affected by life-threatening Staphylococcus aureus-complicated skin and soft tissue infection with associated bacteraemia who, while on replacement therapy with methadone, required 11 mg/kg/day daptomycin to achieve trough (Cmin) and peak (Cmax) plasma levels similar to those observed with the standard dosage of 6 mg/kg in healthy volunteers (mean ± standard deviation: Cmin 12.35 ± 0.80 mg/L, C max 63.90 ± 8.71 mg/L). Clinical pharmacological advice based on real time therapeutic drug monitoring may be helpful for optimizing daptomycin exposure in these patients. Physicians should take into account that dosages much higher than the standard ones may be needed, probably as a consequence of augmented drug clearance. © Springer-Verlag 2013.


Kotarsky K.,Lund University | Sitnik K.M.,Lund University | Stenstad H.,Lund University | Kotarsky H.,Lund University | And 4 more authors.
Mucosal Immunology | Year: 2010

Intestinal-derived chemokines have a central role in orchestrating immune cell influx into the normal and inflamed intestine. Here, we identify the chemokine CCL6 as one of the most abundant chemokines constitutively expressed by both murine small intestinal and colonic epithelial cells. CCL6 protein localized to crypt epithelial cells, was detected in the gut lumen and reached high concentrations at the mucosal surface. Its expression was further enhanced in the small intestine following in vivo administration of LPS or after stimulation of the small intestinal epithelial cell line, mIC c12, with IFNγ, IL-4 or TNFα. Recombinant-and intestinal-derived CCL6 bound to a subset of the intestinal microflora and displayed antibacterial activity. Finally, the human homologs to CCL6, CCL14 and CCL15 were also constitutively expressed at high levels in human intestinal epithelium, were further enhanced in inflammatory bowel disease and displayed similar antibacterial activity. These findings identify a novel role for constitutively expressed, epithelial-derived chemokines as antimicrobial peptides in the intestinal mucosa. © 2010 Society for Mucosal Immunology.

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