Institute of Clinical Pharmacology

Udine, Italy

Institute of Clinical Pharmacology

Udine, Italy

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Jakupi M.H.,Institute of Clinical Pharmacology | Ustalar-Ozgen S.Z.,Acibadem University
Middle East Journal of Anesthesiology | Year: 2011

Background: Preemptive analgesia is an antinociceptive treatment that prevents central sensitization. Antinociceptive effects of diclofenac are well-known. The aim of this study was to investigate preemptive analgesic effects of intraperitoneally administrated diclofenac, before and after acute and inflammatory induced pain in rat model. Methods: Forty eight male Sprague Dawley rats were included in the study. The rats are divided in five groups (n = 8 per each group); Group A, diclofenac at 10 mg/kg given ip, 30 min before the nociceptive stimulus realized with hot plate test; Group B, diclofenac at 10 mg/kg given ip, 5 min after the nociceptive stimulus, realized with hot plate test; Group C, diclofenac at 10 mg/kg given ip, 30 min before the nociceptive stimulus realized with formalin test, and; Group D, diclofenac at 10 mg/kg given ip, 5 min after the nociceptive stimulus, realized with formalin test. Saline was used as a control. Paw movements in response to induced pain with hot plate test and formalin test were measured during 60 minutes. Results: Preemptive analgesic effect was significant in both groups when diclofenac was administrated before the pain stimuli (P<0.01 and P<0.001). The significant decrease in paw movements started in 15 min after pain stimuli in group A and in 25 min, in group C. Conclusion: Intraperitoneally administered diclofenac had preemptive analgesic effects on acute thermal, and inflammatory induced pain in rats. Our results contain the preemptive analgesic effect of systematically administrated diclofenac.


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.


Franceschi L.,Institute of Clinical Pharmacology | Franceschi L.,University of Udine | Cojutti P.,Institute of Clinical Pharmacology | Cojutti P.,University of Udine | And 4 more authors.
Therapeutic Drug Monitoring | Year: 2014

Administration by continuous infusion may represent an effective tool for the treatment of multidrug-resistant gram-negative related infections with meropenem. Currently, no data on chemical stability of generic bioequivalent versions of meropenem over time are available. Triplicate samples of 5 mg/mL solutions of a generic meropenem formulation, Hospira, were evaluated for chemical stability at increasing temperatures (25°C, 30°C, 35°C, and 40°C) by means of a high-performance liquid chromatography technique over 4 separate days. Degradation of generic meropenem was both time and temperature dependent, and the aqueous solutions were stable for up to 8 hours in the temperature range between 25°C and 35°C, and for up to 5 hours at 40°C. Continuous infusion of generic meropenem Hospira may be applied in clinical settings with ambient temperature below 35°C, provided that the 5 mg/mL aqueous solution is reconstituted at most after 6-8 hours. Copyright © 2014 by Lippincott Williams & Wilkins.


PubMed | University of Udine and Institute of Clinical Pharmacology
Type: Journal Article | Journal: Journal of public health research | Year: 2017

Polypharmacy is a main issue of patient safety in all healthcare settings (i.e. increase adverse drug reactions and incidence of drug-drug interactions, etc.). The main object of the study was to evaluate the prevalence of polypharmacy and the appropriateness of drugs prescriptions in the regional health system (RHS) of Friuli Venezia-Giulia Region, Italy.We carried out a point prevalence study in May 2014; 1582 patients 65 years were included from: 14 acute hospitals, 46 Long Term Care Facilities (LTCFs) and 42 general practitioners (GPs) clinics. Data analysis included the evaluation of Patients in therapy with 10 drugs or more were 13.5%: 15.2% in hospitals, 9.7% in GPs clinics and 15.6% in LTCFs. According to Beers criteria we identified 1152 PIPs that involved globally almost half of patients (46.0%): 41.9% in hospitals, 59.6% in LTCFs and 37.0% in GPs clinics. The 53.9% of patients received at least one mainly kidney excreted drug; for these patients the evaluation of serum creatinine was overall present in the 87.7% (747/852): 96.4% in hospital ones, 87.5% in GPs clinics and 77.8% in LTCFs. LTCFs residents were significantly (P<0.05) more exposed to PIPs and less monitored for the renal function.A reliable estimation of the phenomenon in all the main healthcare settings is a necessary prerequisite to set tailored policies for facing polypharmacy within a RHS; the results showed the necessity to put a special attention on LTCFs.


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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