Among different substance classes, New Psychoactive Substances (NPS) comprise chiral amphetamines for stimulant and empathic effects. There is little knowledge in terms of clinical studies about possibly different effects of the two enantiomers of novel amphetamine derivatives. For this reason, there is a big demand for enantioseparation method development of this new substance class. Regarding gas chromatography, cyclodextrins proved to be effective for enantioseparation of NPS. In our attempt, an Astec® ChiraldexTM G-PN column containing 2,6-di-O-pentyl-3-propionyl-γ-cyclodextrin and a LipodexTM D column containing heptakis-(2,6-di-O-pentyl-O-acetyl)-β-cyclodextrin as chiral selector served as stationary phases in a Shimadzu GCMS-QP2010 SE system. Because of the special coating, maximum temperature is limited to 200 °C isothermal or 220 °C in programmed mode. To ensure detection, trifluoroacetic anhydride (TFAA) was used to increase sample volatility.1 As a result, 35 amphetamines were tested as their TFAA-derivatives. A screening method with a temperature gradient from 140 °C to 200 °C at a heating ramp of 1 °C per minute and final time of 5 min, showed baseline separation for seven and partial separations for 16 trifluoro acetylated amphetamines using the ChiraldexTM G-PN column. Six baseline and nine partial separations were observed with the LipodexTM D column, respectively.
The thermo- and pain-sensitive Transient Receptor Potential Melastatin 3 and 8 (TRPM3 and TRPM8) ion channels are functionally associated in the lipid rafts of the plasma membrane. We have already described that cholesterol and sphingomyelin depletion, or inhibition of sphingolipid biosynthesis decreased the TRPM8 but not the TRPM3 channel opening on cultured sensory neurons. We aimed to test the effects of lipid raft disruptors on channel activation on TRPM3- and TRPM8-expressing HEK293T cells in vitro, as well as their potential analgesic actions in TRPM3 and TRPM8 channel activation involving acute pain models in mice. CHO cell viability was examined after lipid raft disruptor treatments and their effects on channel activation on channel expressing HEK293T cells by measurement of cytoplasmic Ca2+ concentration were monitored. The effects of treatments were investigated in Pregnenolone-Sulphate-CIM-0216-evoked and icilin-induced acute nocifensive pain models in mice. Cholesterol depletion decreased CHO cell viability. Sphingomyelinase and methyl-beta-cyclodextrin reduced the duration of icilin-evoked nocifensive behavior, while lipid raft disruptors did not inhibit the activity of recombinant TRPM3 and TRPM8. We conclude that depletion of sphingomyelin or cholesterol from rafts can modulate the function of native TRPM8 receptors. Furthermore, sphingolipid cleavage provided superiority over cholesterol depletion, and this method can open novel possibilities in the management of different pain conditions.
- MeSH
- Analgesics pharmacology therapeutic use MeSH
- beta-Cyclodextrins * pharmacology MeSH
- Pain chemically induced drug therapy metabolism MeSH
- CHO Cells MeSH
- Cholesterol metabolism MeSH
- Cricetulus MeSH
- HEK293 Cells MeSH
- TRPM Cation Channels * metabolism genetics MeSH
- Humans MeSH
- Membrane Microdomains metabolism drug effects MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Pregnenolone pharmacology MeSH
- Pyrimidinones pharmacology MeSH
- Sphingomyelin Phosphodiesterase * metabolism pharmacology MeSH
- Cell Survival drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Non-alcoholic fatty liver disease (NAFLD) is a general term for fatty liver disease not caused by viruses or alcohol. Fibrotic hepatitis, cirrhosis, and hepatocellular carcinoma can develop. The recent increase in NAFLD incidence worldwide has stimulated drug development efforts. However, there is still no approved treatment. This may be due in part to the fact that non-alcoholic steatohepatitis (NASH) pathogenesis is very complex, and its mechanisms are not well understood. Studies with animals are very important for understanding the pathogenesis. Due to the close association between the establishment of human NASH pathology and metabolic syndrome, several animal models have been reported, especially in the context of overnutrition. In this study, we investigated the induction of NASH-like pathology by enhancing cholesterol absorption through treatment with hydroxypropyl-beta-cyclodextrin (CDX). Female Sprague-Dawley rats were fed a normal diet with normal water (control group); a high-fat (60 kcal%), cholesterol (1.25 %), and cholic acid (0.5 %) diet with normal water (HFCC group); or HFCC diet with 2 % CDX water (HFCC+CDX group) for 16 weeks. Compared to the control group, the HFCC and HFCC+CDX groups showed increased blood levels of total cholesterol, aspartate aminotransferase, and alanine aminotransferase. At autopsy, parameters related to hepatic lipid synthesis, oxidative stress, inflammation, and fibrosis were elevated, suggesting the development of NAFLD/NASH. Elevated levels of endoplasmic reticulum stress-related genes were evident in the HFCC+CDX group. In the novel rat model, excessive cholesterol intake and accelerated absorption contributed to NAFLD/NASH pathogenesis.
- MeSH
- Cholesterol MeSH
- Diet, High-Fat adverse effects MeSH
- 2-Hydroxypropyl-beta-cyclodextrin metabolism therapeutic use MeSH
- Hypercholesterolemia * metabolism MeSH
- Hyperlipidemias * MeSH
- Liver metabolism MeSH
- Rats MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Non-alcoholic Fatty Liver Disease * chemically induced MeSH
- Rats, Sprague-Dawley MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Svalová relaxancia jsou nejčastějšími léčivy způsobujícími alergické reakce v perioperačním období. Vzhledem k intravenóznímu podání léčiv během celkové anestezie mohou být tyto reakce potenciálně život ohrožující. V kazuistice popisujeme případ rokuroniem indukovaného anafylaktického šoku u 26leté ženy s podezřením na mimoděložní těhotenství úspěšně léčeného podáním sugammadexu.
Muscle relaxants are the most common cause of allergic reactions during the perioperative period. This reaction could be potentially life-threatening because of the intravenous route of administration of the drugs used for general anesthesia. We describe a case of rocuronium-induced anaphylactic shock in a 26-years-old woman with suspected extrauterine pregnancy successfully treated with sugammadex.
- MeSH
- Anaphylaxis * etiology drug therapy MeSH
- Adult MeSH
- Humans MeSH
- Pregnancy, Ectopic surgery MeSH
- Rocuronium * adverse effects MeSH
- Sugammadex administration & dosage therapeutic use MeSH
- Pregnancy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Svalová relaxancia se používají při téměř dvou třetinách anestezií. V případě jejich použití je důležitá následná důsledná reverze nervosvalové blokády, neboť pooperační reziduální kurarizace zvyšuje pooperační morbiditu. K reverzi svalové blokády lze využít sugammadex, který se vyznačuje velmi dobrou účinností a výhodným bezpečnostním profilem; největší přínos z jeho použití byl dokumentován u nemocných ve věku > 65 let, se skóre ASA ≥ III či s indexem tělesné hmotnosti > 35 a u pacientů podstupujících laparoskopický výkon. Podání sugammadexu brání vzniku pooperačních komplikací, zvyšuje bezpečnost pro pacienta a v současné době lze sugammadex považovat za standard, jehož využití by mělo být zvažováno u výrazně většího spektra pacientů, než tomu bylo dosud.
Muscle relaxants are used in almost two-thirds of anaesthesias. In case they are used, subsequent adequate reversal of neuromuscular blockade is crucial, as post- operative residual curarisation increases postoperative morbidity. For neuromuscular blockade reversal sugammadex can be used which has a very good efficacy and favourable safety profile; the greatest benefit from its use has been shown in patients aged > 65 years, with ASA score ≥ III or body mass index > 35, and in patients undergoing laparoscopic surgery. The administration of sugammadex prevents the development of postoperative complications and increases safety of the patients. Currently, sugammadex can be considered as a standard of care and should be offered to a much wider range of patients than has been the case to date.
Due to the increase in fungal resistance to existing drugs, a need exists to search for new antifungals. This study aimed to evaluate the antifungal activity of α, β, and δ-damascone and inclusion complexes with β-cyclodextrin against different Candida spp. The inclusion complex of β-damascone was prepared by the co-evaporation method using three molar proportions (1:1; 2:1; 3:1 (βDA-βCD)) and analyzed using Fourier transform infrared spectroscopy (FTIR). Standard Candida albicans (CA INCQS 40,006), Candida krusei (CK INCQS 40,095), and Candida tropicalis (CT INCQS 40,042) strains were used to evaluate antifungal activity. The substances were tested individually or in association with fluconazole (FCZ). The IC50 and cell viability curve constructions were performed using the microdilution method. The minimum fungicidal concentration (MFC) was determined by the subculture method in a solid medium. The α, β, and δ-DA isolated or in combination with fluconazole (FCZ) showed significant antifungal activity. β-damascone showed effective complexation in the three molar proportions assayed; however, none of the inclusion complexes was demonstrated clinically significant effects against the fungal tested. Then, all compounds have shown promising antifungal activities; however, in vivo assays are necessary to have therapeutical application in the future.
In this study, a sensitive platform was designed for the electrocatalytical oxidation and recognition of ascorbic acid (AA) based on poly(β-cyclodextrin) modified glassy carbon electrode (p(β-CD-GCE). Electropolymerization of β-CD on the surface of GCE was performed on the potential range of -1 to 1.5 V. So, a novel biopolymer was prepared on the surface of GCE towards sensitive recognition of AA in human plasma samples. The developed platform has good sensitivity and accuracy for electrooxidation and detection of AA with lower limit of quantification (LLOQ) of 1 nM and linear range of 1 nM to 100 mM. Moreover, the designed electrochemical sensor was employed for the analysis of AA on human plasma samples with high sensitivity. Based on advantages of p(β-CD) prepared by electropolymerization procedure (green, fast, homogeny, and efficient eletrocatalytical behaviour), this conductive biopolymer showed excellent analytical behaviour towards electrooxidation of AA. It is expected that the prepared polymeric interface is able to use in the analysis of biological species in clinical samples.
- MeSH
- beta-Cyclodextrins MeSH
- Biocompatible Materials MeSH
- Biopolymers MeSH
- Electrochemical Techniques * methods MeSH
- Ascorbic Acid * MeSH
- Humans MeSH
- Propylene Glycols MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.
- MeSH
- Adamantane chemistry MeSH
- beta-Cyclodextrins chemistry MeSH
- K562 Cells MeSH
- Cyclin-Dependent Kinase 2 antagonists & inhibitors MeSH
- Protein Kinase Inhibitors pharmacology MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Purines chemistry MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Boron cluster compounds are extensively studied due to their possible use in medicinal chemistry, mainly in the boron neutron capture anticancer therapy and as new innovative pharmacophores. Concerning this research, the chiral separations of exceptionally stable anionic 7,8-dicarba-nido-undecaborate(1-) and metal bis(dicarbollide(1-) derivatives with asymmetric substitutions remain the unsolved challenge of the chiral chromatography nowadays. Although the successful enantioseparation of some anionic 7,8-dicarba-nido-undecaborate(1-) ion derivatives were achieved in CZE with native β-cyclodextrins, it has not been observed with HPLC, yet. This study aimed to systematically investigate the enantioseparation of selected compounds in HPLC using native β-cyclodextrin and brominated β-cyclodextrin. The findings revealed positively charged strong adsorption sites on a stationary phase, identified as the cationic metal impurities in the silica-gel backbone. All the anionic species under the study were at least partially enantioseparated when a chelating agent blocked these cationic sites. Consequently, the first-ever HPLC enantioseparations of the 7,8-dicarba-nido-undecaborates(1-) were achieved. The brominated β-cyclodextrin seemed to be a better chiral selector for separation of these species, whereas the native β-cyclodextrin separated the anionic cobalt bis(dicarbollide(1-). The results of this study bring new information concerning the chiral separation of anionic boron clusters and might be used in the chiral method development process on other chiral selectors. Furthermore, the possibility of chiral separation of these species could influence the ongoing research areas of anionic boron clusters.
- MeSH
- Anions MeSH
- Cyclodextrins * MeSH
- Cations MeSH
- Boron Compounds * MeSH
- Stereoisomerism MeSH
- Chromatography, High Pressure Liquid MeSH
- Publication type
- Journal Article MeSH
The biological electron transfer reactions play an important role in the bioactivity of drugs; thus, the knowledge of their electrochemical behavior is crucial. The formation of radicals during oxidation or reduction, the presence of short-living intermediates, the determination of reaction mechanisms involving electron and proton transfers, all contribute to the comprehension of drug activities and the determination of their mode of action and their metabolites. In addition, if a drug is encapsulated in the cyclodextrin cavity, its electrochemical properties can change compared to a free drug molecule. Here we describe the combination of cyclic voltammetry, UV-Vis spectroelectrochemistry, GC-MS, HPLC-DAD, and HPLC-MS/MS as techniques for evaluating the oxidation mechanism of a drug encapsulated in the cavity of a cyclodextrin. The cavity of cyclodextrin plays a significant role in increasing the stability of the encapsulated products; therefore the identification of oxidation intermediates as semiquinone and benzofuranone derivatives of quercetin is possible in these conditions. The differences in oxidation potentials of the bioactive flavonol quercetin and its cyclodextrin complex relating to its antioxidant activity and the oxidation mechanism are herein discussed.
