The archaeological ensemble from Campoverde (Agro Pontino, central Italy): new constraints on the Last Interglacial sea level markers.

We present a combined geomorphological and biochronological study aimed at providing age constraints to the deposits forming a wide paleo-surface in the coastal area of the Tyrrhenian Sea, south of Anzio promontory (central Italy). We review the faunal assemblage recovered in Campoverde, evidencing the occurrence of the modern fallow deer subspecies Dama dama dama, which in peninsular Italy is not present before MIS 5e, providing a post-quem terminus of 125 ka for the deposit hosting the fossil remains. The geomorphological reconstruction shows that Campoverde is located within the highest of three paleosurfaces progressively declining towards the present coast, at average elevations of 36, 26 and 15 m a.s.l. The two lowest paleosurfaces match the elevation of the previously recognized marine terraces in this area; we define a new, upper marine terrace corresponding to the 36 m paleosurface, which we name Campoverde complex. Based on the provided evidence of an age as young as MIS 5e for this terrace, we discuss the possibility that previous identification of a tectonically stable MIS 5e coastline ranging 10-8 m a.s.l. in this area should be revised, with significant implications on assessment of the amplitude of sea-level oscillations during the Last Interglacial in the Mediterranean Sea.

Alexithymic characteristics in pediatric patients with primary headache: a comparison between migraine and tension-type headache.

BACKGROUND: Alexithymia is a personality construct characterized by difficulties in verbal emotional expression and a limited ability to use one's imagination. Evidence of alexithymic characteristics was found in adults suffering from headache, while little is known about children. The aim of this study was to establish the prevalence of alexithymia in two different subgroups of children and adolescents suffering from primary headache. We also looked for correlation between alexithymia in children and in their mothers. METHODS: This study involved 89 participants: 47 (11 males, 36 females, aged 8 to 17 years) suffering from tension-type headache (TTH), and 42 (18 males, 24 females, aged 8 to 17 years) suffering from migraine (M), based on the International Classification of Headache Disorders (ICHD 2013). A control group of 32 headache-free subjects (26 females and 6 males, aged 8 to 17 years) was also considered. Two questionnaires were administered to measure alexithymia: the Alexithymia Questionnaire for Children to young patients and controls, and the Toronto Alexithymia Scale (TAS-20) to the mothers. RESULTS: Higher rates of alexithymia emerged in the TTH group compared to the M group. In particular, TTH sufferers had difficulty identifying their feelings. The mothers of children with headaches didn't score higher in alexithymia compared to other mothers. In the M and in the control group, there was a significant correlation between the rates of alexithymia in young people and in their mothers. CONCLUSIONS: To date no other study has investigated alexithymia in subgroups of primary headaches in developmental age. Our results suggest that patients suffering from TTH are more alexithymic than M patients. This pave the way to etiopathogenetic and clinical considerations, calling for a comprehensive and multidisciplinary approach to tackle the problem of headache.

Approaches for dosage individualisation in critically ill patients.

INTRODUCTION: Pharmacokinetic variability in critically ill patients is the result of the overlapping of multiple pathophysiological and clinical factors. Unpredictable exposure from standard dosage regimens may influence the outcome of treatment. Therefore, strategies for dosage individualisation are recommended in this setting. AREAS COVERED: The authors focus on several approaches for dosage individualisation that have been developed, ranging from the well-established therapeutic drug monitoring (TDM) up to the innovative application of pharmacogenomics criteria. Furthermore, the authors summarise the specific population pharmacokinetic models for different drugs developed for critically ill patients to improve the initial dosage selection and the Bayesian forecasting of serum concentrations. The authors also consider the use of Monte Carlo simulation for the selection of dosage strategies. EXPERT OPINION: Pharmacokinetic/pharmacodynamics (PK/PD) modelling and dosage individualisation methods based on mathematical and statistical criteria will contribute in improving pharmacologic treatment in critically ill patients. Moreover, substantial effort will be necessary to integrate pharmacogenomics criteria into critical care practice. The lack of availability of target biomarkers for dosage adjustment emphasizes the value of TDM which allows a large part of treatment outcome variability to be controlled.

Osmophobia in migraine classification: a multicentre study in juvenile patients.

AIMS: This study was planned to investigate the diagnostic utility of osmophobia as criterion for migraine without aura (MO) as proposed in the Appendix (A1.1) of the International Classification of Headache Disorders (ICHD-II, 2004). METHODS: We analysed 1020 patients presenting at 10 Italian juvenile headache centres, 622 affected by migraine (M) and 328 by tension-type headache (TTH); 70 were affected by headache not elsewhere classified (NEC) in ICHD-II. By using a semi-structured questionnaire, the prevalence of osmophobia was 26.9%, significantly higher in M than TTH patients (34.6% vs 14.3%). RESULTS: Osmophobia was correlated with: (i) family history of M and osmophobia; and (ii) other accompanying symptoms of M. By applying these 'new' criteria, we found an agreement with the current criteria for the diagnosis of migraine without aura (MO) in 96.2% of cases; 54.3% of previously unclassifiable patients received a 'new' diagnosis. CONCLUSIONS: In conclusion, this study demonstrates that this new approach, proposed in the Appendix (A1.1), appears easy to apply and should improve the diagnostic standard of ICHD-II in young patients too.

Determination of electroactive organic acids by anion-exchange chromatography using a copper modified electrode.

An ion-chromatographic method combined with electrochemical detection at a copper-based chemically modified glassy carbon electrode (Cu-GC) has been shown to provide a simple analytical approach for the determination of some common organic acids in alkaline medium. Under the optimized isocratic chromatographic conditions (i.e. 0.1 M NaOH plus 80 mM CH3COONa), organic acids such as gallic, ascorbic, gluconic, lactobionic, galacturonic and glucuronic acid could be separated in less than 20 min. Under constant potential amperometric detection (i.e. 0.55 V vs. Ag-AgCl) the Cu-GC modified electrode allowed detection limits between 2 and 5 pmol for all investigated organic acids while the linear dynamic range spanned generally over three orders of magnitude. Examples of applications included the separation and quantitation of some common organic acids in vinegar, honey and tea samples, are given.

Electrochemical and XPS characterization of composite modified electrodes obtained by nickel deposition on noble metals

A chemically modified electrode composed of nickel oxyhydroxide film deposited on noble metals (i.e., gold or platinum) was characterized in an alkaline medium by cyclic voltammetry and XPS (X-ray photoelectron spectroscopy) techniques. The nickel was deposited on the gold substrate in an alkaline medium by various strategies: cycling the potential between -0.1 and 0.65 V vs SCE, in potentiostatic conditions at potentials comprised between 0.0 and 0.55 V and by simple immersion of the electrode in non-deaerated 0.2 M NaOH solutions containing 3 mM K2Ni(CN)4. The effects of several experimental parameters such as applied potentials, pH, tetracyanonickelate concentration, electrode substrate, etc., on the nickel film formation and growth were evaluated. The electroactivity of the resulting composite gold-nickel electrode was investigated in an alkaline medium toward the oxidation of carbohydrates using arabinose as a model compound.

Amperometric determination of underivatized amino acids at a nickel-modified gold electrode by anion-exchange chromatography.

A nickel-based composite electrode obtained by anodic electrodeposition of nickel (III) oxyhydroxide film on the gold electrode substrate was characterized as an amperometric sensor and successfully applied to the determination of underivatised amino acids in flow-through systems. The electrodeposition of nickel oxyhydroxide films was obtained by cycling a gold electrode between 0.0 V and +1.0 V vs. a saturated calomel electrode in a 80 microM Ni2+ solution buffered at pH 10 with NaHCO3/Na2CO3. The resulting Au-Ni composite electrode exhibits good stability in alkaline medium and can be used as an amperometric sensor of underivatised amino acids at a fixed applied potential (+0.55 V vs. Ag/AgCl). The detection limits (S/N=3) for all investigated compounds ranged between 5 and 30 pmol injected, while the linear ranges spanned over two or three orders of magnitude. The contents of several free amino acids in two sample cheeses from different brands were evaluated by calibration graphs.

Population pharmacokinetics of amikacin in patients with haematological malignancies.

The aim of this study was to analyse the pharmacokinetic behaviour of amikacin in patients with haematological malignancies using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 207 haematology patients divided into two groups: one for computing the population model (n = 134) and the other for validation (n = 73). A one-compartment model was used and the following covariates were tested for their influence on clearance and volume of distribution: age, gender, weight, parenteral nutrition, creatinine clearance, stage of antineoplastic treatment (induction, consolidation, intensification), number of weeks postchemotherapy, clinical diagnosis, Eastern Cooperative Oncology Group score, neutropenia, hypoalbuminaemia, concomitant medication (vancomycin and/or amphotericin B), overhydration, and autologous or allogenic bone marrow transplant. The nonlinear mixed-effect model (NONMEM) was used to assess the population pharmacokinetic model of amikacin in these patients. Apart from bodyweight and renal function, acute myeloblastic leukaemia and hypoalbuminaemia proved to be the most important covariates explaining the interindividual variability in amikacin pharmacokinetics in patients with haematological malignancies. The predictive performance of this population model for amikacin serum concentrations seems suitable for clinical purposes.

Influence of clinical diagnosis in the population pharmacokinetics of amikacin in intensive care unit patients.

The aim of the present study was to analyse the pharmacokinetic behaviour of amikacin in intensive care unit (ICU) patients using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 158 medical ICU patients divided into two groups: one for computing the population model (n = 120) and the other for validation (n = 38). A 1-compartment model was used and the following covariates were tested for their influence on clearance (CL) and volume of distribution (Vd): age, gender, weight, parenteral nutrition, creatinine clearance, duration of therapy and clinical diagnosis. The nonlinear mixed-effect model (NONMEM) was used to assess the population pharmacokinetic model of amikacin in this patient population. In this study, the final population model accounting for amikacin pharmacokinetics in ICU patients was: CL = 0.93 CL(CR) (1 + 0.22 Trauma), Vd = 0.39 TBW (1 + 0.24 Sepsis), where CL(CR) and TBW corresponded to the patients' creatinine clearance and total bodyweight, respectively. The 'Trauma' and 'Sepsis' variables referred to the clinical diagnosis of the patients. This model was subsequently used to predict amikacin serum levels obtained in the validation population by a priori and Bayesian methods. The predictive performance was adequate for clinical purposes, pointing to the feasibility of our population model to provide reference values for a priori prediction as well as the Bayesian approach for individualisation of amikacin therapy in ICU patients.

Population pharmacokinetics of caffeine in premature neonates.

OBJECTIVE: To determine population pharmacokinetic parameters of caffeine in premature neonates. METHODS: This population analysis was done using 145 serum concentration measurements gathered from 75 hospitalized patients during their routine clinical care. The data were analysed by use of NONMEM (mixed effects modeling) according to a one-compartment open model with either zero or first-order absorption and first-order elimination. The effect of a variety of developmental, demographic and clinical factors (gender, birth weight, current weight, gestational age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. RESULTS: The final pharmacostatistical model with influential covariates were as follows: clearance (m1.h-1) = 5.81-current weight (kg) + 1.22.postnatal age (weeks), multiplied by 0.757 if gestational age < or = 28 weeks and 0.836 if the current primary source of patients' nutrition is parenteral nutrition, and volume of distribution (ml) = 911.current weight (kg). The inter-individual variability in clearance and the residual variability, expressed as coefficients of variation, were 14.8%, and 18.44%, respectively. Due to the lack of information on the data set we were unable to characterize the interindividual variability for volume of distribution. CONCLUSION: In this study, which involved on average only two serum concentrations of caffeine per patient, the use of NONMEM gave us significant and consistent information about the pharmacokinetic profile of caffeine when compared with available bibliographic information. Additionally, parenteral nutrition and low gestational age (< or = 28 weeks) may even come to be considered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caffeine concentrations in premature infants.

Pharmacokinetics of amikacin in intensive care unit patients.

OBJECTIVE: To characterize the population pharmacokinetics of amikacin in intensive care unit (ICU) patients and to analyse whether these patients show different kinetic behaviour on the basis of their clinical diagnoses. METHOD: The patient population comprised 104 medical ICU patients on amikacin treatment for several presumed or documented Gram-negative infections. Four study groups were defined according to patients' clinical diagnosis: sepsis group (n = 39), trauma group (n = 20), pneumonia group (n = 21) and 'other diagnosis' group (n = 24). The pharmacokinetic parameters for amikacin in these patients were then compared. RESULTS: The ICU patients were found to have increased values for the amikacin volume of distribution (0.52 +/- 0.21 litres/kg), whereas total amikacin clearance expressed as a linear function of creatinine clearance was Cl (ml/min/kg) = 0.13 +/- 0.86 ClCR, which is not significantly different from other estimations reported in the literature. However, this relationship revealed statistically significant differences among the four groups of ICU patients. Moreover, the septic and trauma patients showed higher (but not statistically significant) values for the amikacin volume of distribution. CONCLUSION: The amikacin pharmacokinetic parameters obtained should allow Bayesian individualization of amikacin doses in patients admitted to medical ICUs, on the basis of their clinical diagnoses.

Bayesian forecasting in paediatric populations.

Bayesian forecasting offers several important advantages for dosage individualisation in children, although, unlike for adults, its use in this population is much lower. Indeed, currently Bayesian methods are underused in this patient population. The paucity of paediatric population pharmacokinetic parameters, and the unavailability of specific clinical pharmacokinetic software for the whole paediatric population, are the main limitations to the application of Bayesian methods in these patients. When these problems have been overcome, this approach will allow clinicians to achieve therapeutic concentrations more readily, faster and more precisely, thus making the methodology highly attractive in the paediatric setting.

Cost-effectiveness analysis of serum vancomycin concentration monitoring in patients with hematologic malignancies.

OBJECTIVE: This study evaluates the cost-effectiveness of vancomycin serum concentration monitoring in patients with hematologic malignancies. METHODS: The study was designed as a prospective randomized study. Seventy immunocompromised febrile patients with hematologic malignancies were randomly assigned to either a vancomycin therapeutic drug monitoring group (TDM group; n = 37) or to a control group (n = 33). Intervention in the TDM group involved patient follow-up by a clinical pharmacist to obtain and pharmacokinetically interpret serum vancomycin concentrations for dosage individualization. RESULTS: Evaluation of all patients included global clinical response and nephrotoxicity, as well as the economic costs and effectiveness derived from the vancomycin monitoring program. There were no significant differences between the TDM and control groups in the outcome measures, except for the incidence of nephrotoxicity: the rates of minor nephrotoxicity were 33.3% and 13.5% in the control and TDM groups, respectively. The corresponding figures for moderate nephrotoxicity were 9.1% and 0%. Logistic regression analysis confirmed that TDM independently reduced the incidence of nephrotoxicity in this patient population. On the basis of this reduced nephrotoxicity, a incremental cost of $435 per case of nephrotoxicity prevented was found for vancomycin serum concentration monitoring. CONCLUSIONS: A decreased incidence of nephrotoxicity provides evidence of a real clinical benefit to patient management in patients with hematologic malignancies. The TDM for vancomycin therapy in this high-risk population has been shown to be a cost-effective procedure.

Influence of pharmacokinetic model on vancomycin peak concentration targets.

The aim of this study was to adapt the vancomycin therapeutic range to the kinetic models usually employed in clinical settings (one- and two-compartment models). Estimates of vancomycin pharmacokinetic parameters were obtained for both models in 22 hematologically malignant patients on vancomycin treatment using two serum concentrations and a bayesian algorithm. From these individually estimated pharmacokinetic parameters, an estimation of the maximum (Cssmax), 2 h postinfusion (Css2), and minimum (Cssmin) steady-state vancomycin serum concentrations for the one- and two-compartment models was made for a fixed 30 mg/kg/day dose. The linear regression equations between the predicted Css2 and Cssmin for the one- and two-compartment models do not differ significantly from the identity line, whereas the corresponding equation for Cssmax points to a 61% underestimation of Cssmax when the one-compartment model is used. From this latter regression equation, it is possible to define 20 mg/L (range of 18-21 mg/L) as a target Cssmax vancomycin serum concentration when a one-compartment model is used to monitor vancomycin therapy. Another practical approach would be to define the target concentration by a desired range at 2 h, which corresponds to a Cssmax value of 30-40 mg/L.

Individualizing vancomycin dosing regimens: an evaluation of two pharmacokinetic dosing programs in critically ill patients.

We evaluated the predictive performance of two commercial computer programs (Abbott and Simkin) for pharmacokinetic dosing of vancomycin in 50 critically ill patients, 40 with hematologic malignancies and 10 in intensive care. Predictive performance was assessed for both pharmacokinetics and forecasting vancomycin serum levels by using a set of peak and trough drug levels per patient. The effect of renal function and serum sampling (steady state, nonsteady state) on predictive performance of both programs was also analyzed. No statistically significant differences were found between the programs for predicting either pharmacokinetics or serum levels, regardless of a patient's renal function or serum sampling. The Abbott and Simkin programs were similar for individualizing vancomycin dosage regimens.

Dosage optimization methods applied to imipramine and desipramine in enuresis treatment.

Three methods for estimating maintenance dosage requirements of imipramine were compared retrospectively in 146 enuretic patients. The dosing methods evaluated included individual (serum levels data) and/or population (average pharmacokinetic parameter) information. The use of imipramine and desipramine serum concentrations, as opposed to average population parameters only, improved forecast precision and accuracy for dosage individualization. The clinical acceptability of this was achieved through knowledge of a single serum concentration. No significant differences were seen between non-linear regression and the Bayesian method, this is in agreement with the high contribution of the patient's data to the Bayesian fitting (FF = 0.8). When one or two serum level data were available, a better performance was obtained by estimating pharmacokinetic parameters than level:dose ratios.

Population pharmacokinetics of imipramine in children.

The population pharmacokinetics of imipramine (IMI) and its active metabolite desipramine (DMI) have been evaluated using 177 IMI and DMI serum levels from 49 enuretic children (6-13 y) on IMI treatment. Standard two stage (STS) and maximum likelihood (ML) methods were used to estimate fixed and random effect parameters of IMI. Simultaneous estimation of the drug and metabolite parameters was carried out by the STS method. The mean value of the elimination constant of the drug and metabolite were 0.0425 h-1 and 0.0359, h-1 respectively. Significantly higher variability was found in the pharmacokinetic parameters of the metabolite. According to these estimated pharmacokinetic parameters, the recommended dose for enuretic children should be 1.7 mg.kg-1.day-1. The population pharmacokinetic parameters obtained in the study permit dosage individualisation using a bayesian algorithm.

PIP: Researchers used population pharmacokinetic parameters and data on the concentration effect relationship from 49 6-13 year old children suffering from enuresis who attended an outpatient psychiatric clinic at University Clinical Hospital in Salamanca, Spain to design rational dosing guidelines of the antidepressant imipramine (IMI) for individual patients. They evaluated 177 IMI serum levels and IMI's active metabolite desipramine (DMI) serum levels. The researchers used standard 2-stage (STS) and maximum likelihood methods to conduct the population pharmacokinetic analysis of IMI. They used STS to simultaneously estimate IMI and DMI parameters. The average value of IMI's elimination constant stood at 0.0425 h-1 and that of DMI's elimination constant stood at 0.0359 h-1. The researchers observed more variability in pharmacokinetic parameters of DMI than those of IMI. Based on estimated pharmacokinetic parameters, a dose of 1.7 mg kg-1 day-1 IMI is needed in children to reach the total serum level of 80 ng/ml which was higher than the dose generally administered in clinical practice (1 mg kg-1 day-1). The researchers demonstrated that applying the population pharmacokinetic parameters to Bayesian fitting methods allows clinicians to individualize IMI dose in children.

The influence of clinical and pharmacological factors on enuresis treatment with imipramine.

1. The aim of this study has been to evaluate the response to imipramine treatment in enuretic children through the use of a series of clinical and pharmacological variables and by applying a multivariate (principal components) analysis technique. 2. The study was carried out on 146 children whose ages ranged from 5 to 14 years, and who received variable doses of imipramine (12.5 to 100 mg day-1). 3. The quantitative variables analyzed were: drug dosage, serum levels of imipramine and its metabolite desipramine, the relationship between them both, the duration of treatment, age and weight. 4. The qualitative variables were: compliance, presence of side-effects, enuretic and/or psychiatric antecedents, intelligence quotient (I.Q.), the existence (or absence) of related pathologies, sex, and the type of enuresis. 5. The response to treatment was quantified by means of the percentage of decrease in frequency of enuresis as compared with the initial frequency. 6. The results obtained show that the variables which are most associated with the reduction of enuresis are, in decreasing order: the dosage of imipramine administered, the duration of treatment, compliance and the level/dose ratio for the sum of the drug and metabolite levels.