Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect : comprehensive overview of clinical trials

BACKGROUND: Proarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and disturb electrophysiological activity of cardiac myocytes, but also by many other factors modifying individual risk of QT prolongation and subsequent proarrhythmia propensity. One of those is drug-drug interactions. Since polypharmacy is a common practice in clinical settings, it can be anticipated that there is a relatively high risk that the patient will receive at least two drugs mutually modifying their proarrhythmic potential and resulting either in triggering the occurrence or mitigating the clinical symptoms. The mechanism can be observed either directly at the pharmacodynamic level by competing for the molecular targets, or indirectly by modifying the physiological parameters, or at the pharmacokinetic level by alteration of the active concentration of the victim drug. METHODS: This publication provides an overview of published clinical studies on pharmacokinetic and/or pharmacodynamic drug-drug interactions in humans and their electrophysiological consequences (QT interval modification). Databases of PubMed and Scopus were searched and combinations of the following keywords were used for Title, Abstract and Keywords fields: interaction, coadministration, combination, DDI and electrocardiographic, QTc interval, ECG. Only human studies were included. Over 4500 publications were retrieved and underwent preliminary assessment to identify papers accordant with the topic of this review. 76 papers reporting results for 96 drug combinations were found and analyzed. RESULTS: The results show the tremendous variability of drug-drug interaction effects, which makes one aware of complexity of the problem, and suggests the need for assessment of an additional risk factors and careful ECG monitoring before administration of drugs with anticipated QT prolongation. CONCLUSIONS: DDIs can play significant roles in drugs’ cardiac safety, as evidenced by the provided examples. Assessment of the pharmacodynamic effects of the drug interactions is more challenging as compared to the pharmacokinetic due to the significant diversity in the endpoints which should be analyzed specifically for various clinical effects. Nevertheless, PD components of DDIs should be accounted for as PK changes alone do not allow to fully explain the electrophysiological effects in clinic situations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40360-016-0053-1) contains supplementary material, which is available to authorized users

Krugowcy o Matošu

Antun Gustav Matoš, central figure of Croatian Modernism became an icon and a legend yet in life, which, after the artistʼs death, only strengthened and his influence on the further shape of Croatian literature is difficult to deny. On the other hand, he is not the very often mentioned author the literary journal „Krugovi”, and also he is not considered in the first row of the most influential literary patterns for this generation of writers. However, Antun Gustav Matoš’s image that emerges from the pages of „Krugovi”, although incomplete and fragmentary, is extremely interesting. Young writers attempted to comprehensively educate their literary model reader, so they drew attention to artists who were the most valuable for the native literary tradition. Understanding and acknowledging the importance of his achievements and well-deserved place in the history of Croatian literature, young artists were able, however, to an analytical and critical approach, in the majority of cases presenting a solid argument, not limited to duplication of hackneyed slogans.Antun Gustav Matoš, central figure of Croatian Modernism became an icon and a legend yet in life, which, after the artistʼs death, only strengthened and his influence on the further shape of Croatian literature is difficult to deny. On the other hand, he is not the very often mentioned author the literary journal „Krugovi”, and also he is not considered in the first row of the most influential literary patterns for this generation of writers. However, Antun Gustav Matoš’s image that emerges from the pages of „Krugovi”, although incomplete and fragmentary, is extremely interesting. Young writers attempted to comprehensively educate their literary model reader, so they drew attention to artists who were the most valuable for the native literary tradition. Understanding and acknowledging the importance of his achievements and well-deserved place in the history of Croatian literature, young artists were able, however, to an analytical and critical approach, in the majority of cases presenting a solid argument, not limited to duplication of hackneyed slogans

Controlled self-assembly of stomatosomes by use of single-component fluorinated dendritic amphiphiles

A series of novel non-ionic amphiphiles with dendritic oligoglycerol head groups of different generations ([G1]–[G3]) and lipophilic/fluorophilic tail segments, comprising single or double tail alkyl chains, C8F17-perfluoro rod segments as well as flexible spacer groups of different lengths were designed and synthesized. We expected that the differences in the size of the dendritic head groups in combination with perfluorinated segments would have an impact on the supramolecular structures formed in aqueous solution if compared with the hydrogenated analogues. Investigating the self-assembly behavior mainly by cryogenic transmission electron microscopy (cryo-TEM) and cryo-electron tomography (cryo-ET) we found as a new result the formation of perforated bilayer vesicles (stomatosomes) and bicontinuous network structures. Surprisingly, we have observed stomatosome formation by self-assembly of single component fluorinated dendritic amphiphiles. These assembly structures turned out to be extremely robust against harsh conditions, although there are strong indications that they represent non-equilibrium structures, which eventually transform into a bicontinuous cubic network structure of double diamond symmetry. In general, the molecular asymmetry of amphiphiles tuned by chemical design induced the expected trend from spherical micelles through worm-like micelles to perforated bilayers and three-dimensional network structures

Benzylation of hydroxy groups with tertiary amine as a base

The benzylation of hydroxy groups in the presence of tertiary amines is described. A mixture of an alcohol and a benzyl halide afforded the corresponding benzyl ether in good to excellent yields in the presence of diisopropylethylamine. The importance of solventless conditions was observed. The reaction showed high tolerance to many functional groups including benzoate, even at a reaction temperature of 150 °C. Sodium iodide was found to be an efficient catalyst to accelerate the reaction