Computational study of radicals derived from hydroxyurea and its methylated analogues.

Structural and electronic properties and chemical fate of free radicals generated from hydroxyurea (HU) and its methylated analogues N-methylhydroxyurea (NMHU) and O-methylhydroxyurea (OMHU) are of utmost importance for their biological and pharmacological effects. In this work the cis/trans conformational processes, tautomerizations, and intramolecular hydrogen and methyl migrations in hydroxyurea-derived radicals have been considered. Potential energy profiles for these reactions have been calculated using two DFT functionals (BP86 and B3LYP) and two composite models (G3(MP2)RAD and G3B3). Solvation effects have been included both implicitly (CPCM) and explicitly. It has been shown that calculated energy barriers for free radical rearrangements are significantly reduced when a single water molecule is included in calculations. In the case of HU-derived open-shell species, a number of oxygen-, nitrogen-, and carbon-centered radicals have been located, but only the O-centered radicals (e1 and z1) fit to experimental isomeric hyperfine coupling constants (hfccs) from EPR spectra. The reduction of NMHU and OMHU produces O-centered and N-centered radicals, respectively, with the former being more stable by ca. 60 kJ mol−1. The NMHU-derived radical e4 undergoes rearrangements, which can result in formation of several conceivable products. The calculated hfccs have been successfully used to interpret the experimental EPR spectra of the most probable rearranged product 10. Reduction potentials of hydroxyureas, radical stabilization energy (RSE) and bond disocciation energy (BDE) values have been calculated to compare stabilities and reactivities of different subclasses of free radicals. It has been concluded, in agreement with experiment, that reductions of biologically relevant tyrosyl radicals by HU and NMHU are thermochemically favorable processes, and that the order of reactivity of hydroxyureas follows the experimentally observed trend NMHU > HU > OMHU

Propisivačke medikacijske pogreške za hospitalizirane bolesnike: Prospektivna studija

The aims of this prospective study were to determine the incidence and types of prescribing medication errors and ways to prevent them from reaching patients. Data were collected from 4951 prescriptions over a 25 week period in 2002. Medication errors were classified as: incorrect dose, incorrect dose interval, duplication of therapy and drug interactions. The medical record analysis was used to compare prescribing with Croatian literature drug data and AHFS first Web version 2 (American Society of Health System Pharmacists). The incidence of medication errors in the entire sample, including all potential drug interactions, was 14.7%. However, as only 8 interactions (out of 356 potentially possible interactions) were assessed as clinically significant, then the total number of all types of medication errors equals 379. This resulted in an incidence of 7.7%. Dosage errors were the most frequent errors, followed by incorrect interval, drug duplication and drug interaction. The difference between the incidence of potentially possible and clinically significant drug interactions was quite large (7.2 vs. 0.2%). Thus, a critical attitude is necessary when evaluating data on drug interactions. Our findings point to the need of systematic control of prescribed therapies, which could be ensured by the application of the Unit Dose Drug Distribution System. A medication errors reporting program should be established both at hospital and at national levels in Croatia.Svrha ove prospektivne studije je ispitivanje pojavnosti i vrsta medikacijskih pogrešaka u propisivanju i prevenciji njihovog nastanka. Podaci ispitivanja odnose se na 4951 propisani lijek, u razdoblju od 25 tjedana 2002. godine. Ispitivane medikacijske pogreške definirane su kao: pogrešna doza, pogrešan interval doziranja, dupliciranje terapije, te interakcija lijekova. Pojavnost medikacijskih pogrešaka propisivanja na ispitivanom uzorku, ukljucujuci sve teoretski moguce interakcije lijekova, iznosila je 14.7%. Medutim, kako je samo 8 interakcija (od ukupno 356 teoretski mogucih) ocijenjeno klinicki znacajnim, ukupan broj medikacijskih pogrešaka iznosio je 379 (od 4951 zapisa), što odgovara pojavnosti od 7.7%. Pogreška doziranja lijeka bila je najcešca vrsta uocenih medikacijskih pogrešaka. Utvrdena je velika razlika izmedu incidencije teoretski mogucih i klinicki znacajnih interakcija lijekova (7.2 vs. 0.2%). Nužan je kriticki pristup procjeni dostupnih podataka vezanih za interakcije lijekova. Rezultati našeg istraživanja upucuju na nužnost sustavnog nadzora propisane terapije, koji bi se mogao osigurati primjenom sustava raspodjele jedinicne terapije. U Hrvatskoj bi se trebao uspostaviti program pracenja medikacijskih pogrešaka, kako u bolnicama tako i na nacionalnoj razini

Propisivačke medikacijske pogreške za hospitalizirane bolesnike: Prospektivna studija

The aims of this prospective study were to determine the incidence and types of prescribing medication errors and ways to prevent them from reaching patients. Data were collected from 4951 prescriptions over a 25 week period in 2002. Medication errors were classified as: incorrect dose, incorrect dose interval, duplication of therapy and drug interactions. The medical record analysis was used to compare prescribing with Croatian literature drug data and AHFS first Web version 2 (American Society of Health System Pharmacists). The incidence of medication errors in the entire sample, including all potential drug interactions, was 14.7%. However, as only 8 interactions (out of 356 potentially possible interactions) were assessed as clinically significant, then the total number of all types of medication errors equals 379. This resulted in an incidence of 7.7%. Dosage errors were the most frequent errors, followed by incorrect interval, drug duplication and drug interaction. The difference between the incidence of potentially possible and clinically significant drug interactions was quite large (7.2 vs. 0.2%). Thus, a critical attitude is necessary when evaluating data on drug interactions. Our findings point to the need of systematic control of prescribed therapies, which could be ensured by the application of the Unit Dose Drug Distribution System. A medication errors reporting program should be established both at hospital and at national levels in Croatia.Svrha ove prospektivne studije je ispitivanje pojavnosti i vrsta medikacijskih pogrešaka u propisivanju i prevenciji njihovog nastanka. Podaci ispitivanja odnose se na 4951 propisani lijek, u razdoblju od 25 tjedana 2002. godine. Ispitivane medikacijske pogreške definirane su kao: pogrešna doza, pogrešan interval doziranja, dupliciranje terapije, te interakcija lijekova. Pojavnost medikacijskih pogrešaka propisivanja na ispitivanom uzorku, ukljucujuci sve teoretski moguce interakcije lijekova, iznosila je 14.7%. Medutim, kako je samo 8 interakcija (od ukupno 356 teoretski mogucih) ocijenjeno klinicki znacajnim, ukupan broj medikacijskih pogrešaka iznosio je 379 (od 4951 zapisa), što odgovara pojavnosti od 7.7%. Pogreška doziranja lijeka bila je najcešca vrsta uocenih medikacijskih pogrešaka. Utvrdena je velika razlika izmedu incidencije teoretski mogucih i klinicki znacajnih interakcija lijekova (7.2 vs. 0.2%). Nužan je kriticki pristup procjeni dostupnih podataka vezanih za interakcije lijekova. Rezultati našeg istraživanja upucuju na nužnost sustavnog nadzora propisane terapije, koji bi se mogao osigurati primjenom sustava raspodjele jedinicne terapije. U Hrvatskoj bi se trebao uspostaviti program pracenja medikacijskih pogrešaka, kako u bolnicama tako i na nacionalnoj razini

Mécanismes de chélation, d'oxydo-réduction et de transport de métaux par des ligands analogues de sidérophores bactériens et d'antibiotiques

Les travaux de recherche entrepris dans le cadre d'une thèse en cotutelle Franco-Croate, concernent les propriétés chélatrices ou oxydo-réductrices de composés fondés sur des groupes bidentés hydroxyquinoléïnes ou hydroxymates. Le choix de ces deux unités a été guidé par leur présence fréquente dans la structure de chélateurs biologiques.Les deux premiers chapitres concernent les propriétés de reconnaissance ionique de métaux divalents (Cu, Zn, Co, Ni) et trivalents (Eu, Tb) par deux composés pyridinyl-oxine (2-(pyridin-2-yl)quinoléïne-8-ol L1; 6'-(8-hydroxyquinoléïne-2-yl)picolinic acid L2). Grâce à la présence de deux sites de coordination bidentés et adjacents N,N et N,O au sein du même ligand L1 et aux variations conformationelles du motif bipyridinique, les bischélates formés avec les métaux divalents agissent comme des interrupteurs moléculaires sensibles aux protons. En présence d'ions lanthanides, L1 se comporte comme un ligand tridenté qui conduit à la formation successive de mono, bis et trischélates. L'introduction d'une fonction carboxylate confère à L2 les propriétés d'un chélateur tétradenté qui forme exclusivement des complexes monochélates avec les métaux. L2 est, en outre, un chélateur modéré de métaux divalents, comme Cu(II) et Zn(II) aux potentialités intéressantes pour le traitement de maladies neurodégénératives. Dans la troisième partie, nous avons reconsidéré les propriétés de reconnaissance ionique de métaux divalents (Cu, Zn, Ni, Co, Mn) par le clioquinol, un dérivé oxinate aux multiples utilisations thérapeutiques et, aujourd'hui, testé pour le traitement de la maladie d'Alzheimer.Dans une dernière partie de la thèse, nous avons examiné les processus rédox par Fe(CN)63-de l'hydroxyurée, un acide hydroxamique utilisé chez les patients atteints d'anémie à hématies falciformes. L'hydroxyurée réduit Fe(CN)63- en Fe(CN)64- via la formation d'un radical libre instable. Le mécanisme a été élucidé grâce à des études spectroscopiques et cinétiques.The main objective of this PhD dissertation is focused on the coordination properties of new 8-hydroxyquinoline derivatives and on the oxidation mechanism of hydroxyurea, a hydroxamate based compound.The two first chapters deal with the ionic recognition properties of two pyridine-oxine ligands (2-(pyridin-2-yl)quinolin-8-ol L1 and 6'-(8-hydroxyquinolin-2-yl)picolinic acid L2) towards a series of divalent (Cu, Zn, Co, Ni) and trivalent lanthanide cations (Eu, Tb). The presence of N,O- and N,N-bis-compartmental binding sites, as well as the conformational changes of the bipyridyl moiety, allowed the observation by spectrophotometry of the translocation of metals driven by protons in L1 bischelate metallic complexes. With lanthanide ions, L1 acts as a strict tridentate binding unit and affords mono-, bis- and trischelates. The introduction of an additional carboxylate unit in L2 drastically modifies its binding properties, and thus confers to L2 the binding properties of a tetradentate chelator. L2 is a low molecular weight and a moderate chelator of divalent cations, which could find applications in neurodegenerative therapy (Alzheimer's disease; AD).In the third part, we have revisited the coordination properties of clioquinol, an oxine-type active neurological drug in Alzheimer's disease, toward biologically relevant divalent metal ions (Cu, Zn, Ni, Co and Mn). The determination of the stability constants showed an especially strong complexation of the cupric cations. Our data are discussed in the framework of AD.The last part of this thesis is focused on the oxidation reaction by Fe(CN)63- of hydroxyurea, a hydroxamic acid used in the treatment of sickle cell anemia. Hydroxyurea reduces Fe(CN)63- into Fe(CN)64- via the formation and subsequent fading out of a free radical. Spectroscopic and kinetic techniques were used to elucidate the mechanism and allowed us to raise the question of production of NO.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Prescribing medication errors in hospitalised patients: A prospective study

Svrha ove prospektivne studije je ispitivanje pojavnosti i vrsta medikacijskih pogrešaka u propisivanju i prevenciji njihovog nastanka. Podaci ispitivanja odnose se na 4951 propisani lijek, u razdoblju od 25 tjedana 2002. godine. Ispitivane medikacijske pogreške definirane su kao: pogrešna doza, pogrešan interval doziranja, dupliciranje terapije, te interakcija lijekova. Pojavnost medikacijskih pogrešaka propisivanja na ispitivanom uzorku, ukljucujuci sve teoretski moguce interakcije lijekova, iznosila je 14.7%. Medutim, kako je samo 8 interakcija (od ukupno 356 teoretski mogucih) ocijenjeno klinicki znacajnim, ukupan broj medikacijskih pogrešaka iznosio je 379 (od 4951 zapisa), što odgovara pojavnosti od 7.7%. Pogreška doziranja lijeka bila je najcešca vrsta uocenih medikacijskih pogrešaka. Utvrdena je velika razlika izmedu incidencije teoretski mogucih i klinicki znacajnih interakcija lijekova (7.2 vs. 0.2%). Nužan je kriticki pristup procjeni dostupnih podataka vezanih za interakcije lijekova. Rezultati našeg istraživanja upucuju na nužnost sustavnog nadzora propisane terapije, koji bi se mogao osigurati primjenom sustava raspodjele jedinicne terapije. U Hrvatskoj bi se trebao uspostaviti program pracenja medikacijskih pogrešaka, kako u bolnicama tako i na nacionalnoj razini.The aims of this prospective study were to determine the incidence and types of prescribing medication errors and ways to prevent them from reaching patients. Data were collected from 4951 prescriptions over a 25 week period in 2002. Medication errors were classified as: incorrect dose, incorrect dose interval, duplication of therapy and drug interactions. The medical record analysis was used to compare prescribing with Croatian literature drug data and AHFS first Web version 2 (American Society of Health System Pharmacists). The incidence of medication errors in the entire sample, including all potential drug interactions, was 14.7%. However, as only 8 interactions (out of 356 potentially possible interactions) were assessed as clinically significant, then the total number of all types of medication errors equals 379. This resulted in an incidence of 7.7%. Dosage errors were the most frequent errors, followed by incorrect interval, drug duplication and drug interaction. The difference between the incidence of potentially possible and clinically significant drug interactions was quite large (7.2 vs. 0.2%). Thus, a critical attitude is necessary when evaluating data on drug interactions. Our findings point to the need of systematic control of prescribed therapies, which could be ensured by the application of the Unit Dose Drug Distribution System. A medication errors reporting program should be established both at hospital and at national levels in Croatia