Румунський етнографічний aтлас

In Romania, the crisis of the popular culture and the necessity to preserve its characteristic elements by publishing a Romanian Ethnographic Atlas was realized later. The Romanian ethnographers had the possibility to make major methodological innovation for this type of works, such as the replacement of the explicative texts of the maps with the integral publishing of the ethnographic documents, exactly as they were recorded on the field. These two works – thesaurus which shelter the registered for the XX century ethnographic data will have, when finished, 30 toms: 25 with document of oral history and five with maps and images regarding their territorial distribution.În România criza culturii populare şi necesitatea de a păstra elementele ei caracteristice prin publicarea Atlasului Etnografic Român s-a constatat mai târziu. Etnografii români au avut mai apoi posibilitatea de a folosi inovaţii metodologice majore pentru asemenea gen de lucrări, cum ar fi înlocuirea textelor explicative ale hărţilor cu publicarea integrală a documentelor etnografice în felul în care au fost înregistrare pe teren. Aceste două tipuri de lucrări cu caracter de tezaur care acoperă toate datele etnografice înregistrate în secolul al XX-lea vor avea, cînd se vor încheia, 30 de volume: 25 cu documente de istorie orală şi cinci cu hărţi şi imagini referitoare la distribuţia lor teritorială

Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?

Purpose: There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increased risk for paclitaxel-induced neutropenia. Methods: Paclitaxel plasma concentration-time data, pooled from multiple different studies, was combined with available respective neutrophil count data during the first treatment cycle. Paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) d

Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment

Item does not contain fulltextPemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m(2) would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment

Clinical pharmacology in leishmaniasis: treatment optimization of a neglected disease

This thesis presents various novel applications of clinical pharmacokinetics and pharmacodynamics in the treatment of leishmaniasis, by which diverse clinically relevant issues, mainly related to the efficacy and safety of miltefosine, could be elucidated. Throughout this thesis, the added value of population modeling and simulation in clinical pharmacology is exemplified, for instance by making full use of sparse datasets, translational preclinical-to-clinical extrapolation of toxicity and drug exposure, and design and in silico evaluation of optimal dosing regimens specifically aimed at pediatric populations. Additionally, investigations into the issues of poor-quality medicines for the treatment of neglected tropical diseases are presented and global solutions against this looming threat are discussed. This thesis attempts to further improve the treatment for patients suffering from the neglected tropical disease leishmaniasis by optimizing the available treatment options and making them safer to use

Pharmacokinetics and pharmacodynamics of oral oleylphosphocholine in a hamster model of visceral leishmaniasis

INTRODUCTION Oleylphosphocholine (OlPC) is in the same chemical class as miltefosine (MIL) and was shown to be of superior efficacy and safety at equivalent doses (Fortin et al. 2012; 2014). In the current study, the pharmacokinetic (PK) properties of OlPC were evaluated in hamsters following single oral dose administration. The prophylactic activity of the drug was also explored to establish exposure-activity relationships. Finally, based on knowledge gained on PK, the curative efficacy of a 2× 5 days administration of 20 mg/kg was tested in the context of a longer post-treatment evaluation period. METHODS Female golden hamsters (4-8/group) were administered single oral doses of 20, 50 and 100 mg/kg and blood samples were collected after 2, 6, 24, 32, 72 and 168 h for analysis. For prophylactic studies hamsters (6-7/gr) were given a 100 mg/kg single-dose on day -7, -4, -1 or -4 h prior to infection. The animals were infected on day 0 with 2× 107amastigotes of L. infantum and parasitic burdens were measured in the liver, spleen and bone marrow on day 21. In the curative model, the animals (6/gr) were infected on day 0 and treatment started on day 21. OlPC and MIL were orally dosed at 20 mg/kg for 2× 5 days. Amastigote burdens were determined on day 42 (10 days post end of treatment, dpt) or day 72 (40 dpt). RESULTS OlPC had an elimination t1/2 of ∼l50 hrs and doseproportionality was seen between 20, 50 and 100 mg/kg. A onecompartment disposition model with first-order absorption and elimination fitted best the data. The prophylactic activity of OlPC was in agreement with respective drug exposures, showing dose-dependent residual activity. Interestingly, a 100 mg/kg single dose administered on - 4 day still reduced the overall parasitic burden by ∼l 50%. In the curative model, a ≥99% clearance of the infection was observed at 10 dpt in all OlPCtreated animals and remained the same at 40 dpt. For MIL, a good efficacy was measured at 10 dpt (98, >99 and 90% of reduction in liver, spleen and bone marrow), but the parasite loads had increased at 40 dpt (67, 99 and 79%, respectively), reflecting relapse of the infection and inferiority to OlPC. CONCLUSION This study reveals that total OlPC plasma exposure is a good predictor of the prophylactic and curative efficacy in the hamster VL model. Translated to human, these results suggest that the daily dosing of OlPC will be adjustable to avoid side effects while retaining maximum drug efficacy

Population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome

Aim The aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome. Methods Non-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were receiving 2.5mg kg-1 levamisole (or placebo) orally once every other day. One hundred and thirty-six plasma samples were collected from 38 children from India and Europe and included in the analysis. A one compartment model described the data well. Results The apparent clearance rate (CL/F) and distribution volume (V/F) were 44l h-1 70kg-1 and 236l 70kg-1, respectively; estimated interindividual variability was 32-42%. In addition to allometric scaling of CL/F and V/F to body weight, we identified a significant proportional effect of age on CL/F (-10.1% per year). The pharmacokinetics parameters were not affected by gender, tablet strength or study centre. The median (interquartile range) maximum plasma concentration of levamisole was 438.3 (316.5-621.8) ng ml-1, and the median area under the concentration-time curve was 2847 (2267-3761) ng ml-1 h. Median tmax and t1/2; values were 1.65 (1.32-2.0) h and 2.60 (2.06-3.65) h, respectively. Conclusions Here, we present the first pharmacokinetic data regarding levamisole in children with steroid-sensitive nephrotic syndrome. The pharmacokinetic profile of levamisole in children was similar to findings reported in adults, although the elimination rate was slightly higher in children

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens

Pharmacolog

Validation and clinical evaluation of a novel method to measure miltefosine in leishmaniasis patients using dried blood spot sample collection

To facilitate future pharmacokinetic studies of combination treatments against leishmaniasis in remote regions in which the disease is endemic, a simple cheap sampling method is required for miltefosine quantification. The aims of this study were to validate a liquid chromatography-tandem mass spectrometry method to quantify miltefosine in dried blood spot (DBS) samples and to validate its use with Ethiopian patients with visceral leishmaniasis (VL). Since hematocrit (Ht) levels are typically severely decreased in VL patients, returningto normal during treatment, the method was evaluated over a range of clinically relevant Ht values. Miltefosine was extracted from DBS samples using a simple method of pretreatment with methanol, resulting in >97% recovery. The method was validated over a calibration range of 10 to 2,000 ng/ml, and accuracy and precision were within ±11.2% and ≤7.0% (≤19.1% at the lower limit of quantification), respectively. The method was accurate and precise for blood spot volumes between 10 and 30 μl and for Ht levels of 20 to 35%, although a linear effect of Ht levels on miltefosine quantification was observed in the bioanalytical validation. DBS samples were stable for at least 162 days at 37°C. Clinical validation of the method using paired DBS and plasma samples from 16 VL patients showed a median observed DBS/plasma miltefosine concentration ratio of 0.99, with good correlation (Pearson's r = 0.946). Correcting for patient-specific Ht levels did not further improve the concordance between the sampling methods. This successfully validated method to quantify miltefosine in DBS samples was demonstrated to be a valid and practical alternative to venous blood sampling that can be applied in future miltefosine pharmacokinetic studies with leishmaniasis patients, without Ht correction