Sugammadex (SGM) is the first cyclodextrin (CD)-based selective relaxant binding agent. We investigated its ability to capture natural aminosteroid phytotoxins, and assessed its potential as an antidote for intoxication. Solasodine (SS), a toxic alkaloid from the Solanaceae family, was chosen as the model compound. Complexation was studied using nuclear magnetic resonance (NMR) spectroscopy, molecular modelling, and isothermal titration calorimetry (ITC). NMR in various D2O/DMSO‑d6 media revealed a particularly stable inclusion-type complex, identifying a slow exchange process between the CD and the aminosteroid along with a less significant fast exchange between DMSO and SGM. Using various NMR techniques, the structure and kinetic/thermodynamic parameters of the inclusion complex were explored. Theoretical calculations showed the secondary amino head of SS near the carboxylate ends of the SGM sidechains, facilitating intermolecular ionic interactions. ITC experiments in an aqueous environment provided Ka stability constants of 7.03 × 106 M-1 and 4.17 × 106 M-1 at 25 °C and 37 °C, respectively, similar to previously reported SGM complexes with aminosteroid neuromuscular blockers. Finally, SGM significantly increased cell survival and reduced SS toxicity in mHippoE-14 mouse hippocampal embryonic cells, supporting the hypothesis that SGM could act as an antidote to SS's toxic effects.

• Klíčová slova
• Antidote, Competitive titration, ITC, NMR spectroscopy, Solasodine, Sugammadex,
• MeSH
• alkaloidy Solanaceí * chemie   farmakologie   MeSH
• buněčné linie MeSH
• hipokampus účinky léků   MeSH
• molekulární modely MeSH
• myši MeSH
• sugammadex * chemie   farmakologie   MeSH
• termodynamika MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy Solanaceí * MeSH
• solasodine MeSH Prohlížeč
• sugammadex * MeSH

The present study describes a rapid and effective capillary electrophoresis (CE) method for the enantioseparation of pindolol using single-isomer octa(6-O-sulfo)-γ-cyclodextrin. The complexation parameters were determined under neutral and high pH conditions to identify optimal separation conditions using a theoretical model. Baseline separation of pindolol enantiomers was achieved within 6 min in a sodium/MOPS buffer, pH 7.2, with a selector concentration of 6 mM. The method was validated according to the ICH guidelines using imidazole as an internal standard. Low limits of detection and quantification were found, specifically 1.2 μg/mL and 4 μg/mL (0.6 μg/mL and 2 μg/mL per enantiomer), respectively. The calibration curves showed good linearity, with a coefficient of determination R2 ≥ 0.999 over a 5 - 55 μg/mL concentration range and over a 50 - 300 μg/mL concentration range of the racemic mixture. The relative standard deviations (%RSD) of intra-day and inter-day precision were lower than 8% at LOQ level, lower than 3% at 50 μg/mL level and lower than 1.5% at 300 μg/mL level. Accuracy ranged from 95 to 103% (106% at LOQ level). The proposed method was successfully tested on a medical formulation of Visken® Sandoz intravenous solution and Visken® Teofarma pills for oral use.

• Klíčová slova
• Capillary electrophoresis, Enantioseparation, Method validation, Pindolol, Single-isomer cyclodextrin, β-blockers,
• MeSH
• časové faktory MeSH
• elektroforéza kapilární metody   MeSH
• gama-cyklodextriny chemie   MeSH
• kalibrace MeSH
• koncentrace vodíkových iontů MeSH
• limita detekce MeSH
• pindolol izolace a purifikace   MeSH
• pufry MeSH
• reprodukovatelnost výsledků MeSH
• software * MeSH
• stereoizomerie MeSH
• Publikační typ
• časopisecké články MeSH
• validační studie MeSH
• Názvy látek
• gama-cyklodextriny MeSH
• gamma-cyclodextrin MeSH Prohlížeč
• pindolol MeSH
• pufry MeSH

A capillary electrophoresis method for the simultaneous determination of the enantiomeric purity and of impurities of the chiral calcimimetic drug cinacalcet hydrochloride has been developed following Quality by Design principles. The scouting phase was aimed to select the separation operative mode and to identify a suitable chiral selector. Among the tested cyclodextrins, (2-carboxyethyl)-β-cyclodextrin and (2-hydroxypropyl)-γ-cyclodextrin (HPγCyD) showed good chiral resolving capabilities. The selected separation system was solvent-modified capillary zone electrophoresis with the addition of HPγCyD and methanol. Voltage, buffer pH, methanol concentration and HPγCyD concentration were investigated as critical method parameters by a multivariate strategy. Critical method attributes were represented by enantioresolution and analysis time. A Box-Behnken Design allowed the contour plots to be drawn and quadratic and interaction effects to be highlighted. The Method Operable Design Region (MODR) was identified by applying Monte-Carlo simulations and corresponded to the multidimensional zone where both the critical method attributes fulfilled the requirements with a desired probability π≥90%. The working conditions, with the MODR limits, corresponded to the following: capillary length, 48.5cm; temperature, 18°C; voltage, 26kV (26-27kV); background electrolyte, 150mM phosphate buffer pH 2.70 (2.60-2.80), 3.1mM (3.0-3.5mM) HPγCyD; 2.00% (0.00-8.40%) v/v methanol. Robustness testing was carried out by a Plackett-Burman matrix and finally a method control strategy was defined. The complete separation of the analytes was obtained in about 10min. The method was validated following the International Council for Harmonisation guidelines and was applied for the analysis of a real sample of cinacalcet hydrochloride tablets.

• Klíčová slova
• Capillary electrophoresis, Chiral separation, Cinacalcet, Impurities, Method operable design region, Quality by Design,
• MeSH
• beta-cyklodextriny chemie   MeSH
• cinakalcet chemie   izolace a purifikace   MeSH
• elektroforéza kapilární metody   MeSH
• gama-cyklodextriny chemie   MeSH
• hodnocení rizik MeSH
• koncentrace vodíkových iontů MeSH
• kontaminace léku MeSH
• metoda Monte Carlo MeSH
• pravděpodobnost MeSH
• rozpouštědla MeSH
• stereoizomerie MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• beta-cyklodextriny MeSH
• betadex MeSH Prohlížeč
• cinakalcet MeSH
• gama-cyklodextriny MeSH
• gamma-cyclodextrin MeSH Prohlížeč
• rozpouštědla MeSH

Herein we report on the synthesis, characterization and the novel capillary electrophoretic use of octakis-(2,3-di-O-methyl-6-O-carboxymethyl)-γ-cyclodextrin sodium salt (ODMCM). ODMCM is the first single-isomer carboxymethyl-γ-cyclodextrin that is fully methylated on its secondary side and carries ionizable carboxymethyl functions on its primary side. ODMCM was prepared with high isomeric purity through a four-step synthetic procedure. The purity of each intermediate was characterized by appropriate chromatographic methods, while the isomeric purity of the carboxymethylated product was determined by an HPLC method using a CD-Screen-IEC column and by a capillary electrophoretic method using indirect UV detection, as well. The structural identification of the ODMCM was carried out by 1D, 2D NMR spectroscopy and ESI-MS. The acid-base characterization of the chiral selector was carried out by 1H NMR-pH titration. The chiral separation ability of the synthesized selector was studied by chiral capillary electrophoresis. ODMCM was used as a background electrolyte additive to separate enantiomers of representative pharmacologically significant model molecules such as propranolol, citalopram, ketamine, tapentadol and dapoxetine. The effects of the selector concentration and the pH of the background electrolyte on the enantiorecognition properties were investigated. 1H NMR spectroscopy was further applied to get deeper insight of the host-guest inclusion complex formation. The pH-dependent enantioselectivity of this new single-isomer chiral selector was demonstrated by chiral capillary electrophoresis and 1H NMR spectroscopy.

• Klíčová slova
• (1)H NMR, Chiral capillary electrophoresis, Cyclodextrin synthesis, Enantioseparation, Host-guest interaction, Single-isomer,
• MeSH
• elektroforéza kapilární * MeSH
• gama-cyklodextriny chemie   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací * MeSH
• indikátory a reagencie MeSH
• koncentrace vodíkových iontů MeSH
• magnetická rezonanční spektroskopie MeSH
• spektrofotometrie ultrafialová * MeSH
• stereoizomerie MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• carboxymethyl-gamma-cyclodextrin MeSH Prohlížeč
• gama-cyklodextriny MeSH
• indikátory a reagencie MeSH

• MeSH
• androstanoly * MeSH
• celková anestezie * MeSH
• císařský řez MeSH
• dospělí MeSH
• gama-cyklodextriny * MeSH
• lidé MeSH
• myotonia congenita chirurgie   MeSH
• nervosvalové látky nedepolarizující * MeSH
• probouzení z anestezie MeSH
• rokuronium MeSH
• sugammadex MeSH
• těhotenství MeSH
• vzácné nemoci * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH
• Názvy látek
• androstanoly * MeSH
• gama-cyklodextriny * MeSH
• nervosvalové látky nedepolarizující * MeSH
• rokuronium MeSH
• sugammadex MeSH

BACKGROUND: Rocuronium for cesarean delivery under general anesthesia is an alternative to succinylcholine for rapid-sequence induction of anesthesia because of the availability of sugammadex for reversal of neuromuscular blockade. However, there are no large well-controlled studies in women undergoing general anesthesia for cesarean delivery. The aim of this noninferiority trial was to determine whether rocuronium and sugammadex confer benefit in time to tracheal intubation (primary outcome) and other neuromuscular blockade outcomes compared with succinylcholine, rocuronium, and neostigmine in women undergoing general anesthesia for cesarean delivery. METHODS: We aimed to enroll all women undergoing general anesthesia for cesarean delivery in the 2 participating university hospitals (Brno, Olomouc, Czech Republic) in this single-blinded, randomized, controlled study. Women were randomly assigned to the ROC group (muscle relaxation induced with rocuronium 1 mg/kg and reversed with sugammadex 2-4 mg/kg) or the SUX group (succinylcholine 1 mg/kg for induction, rocuronium 0.3 mg/kg for maintenance, and neostigmine 0.03 mg/kg for reversal of the neuromuscular blockade). The interval from the end of propofol administration to tracheal intubation was the primary end point with a noninferiority margin of 20 seconds. We recorded intubating conditions (modified Viby-Mogensen score), neonatal outcome (Apgar score <7; umbilical artery pH), anesthesia complications, and subjective patient complaints 24 hours after surgery. RESULTS: We enrolled 240 parturients. The mean time to tracheal intubation was 2.9 seconds longer in the ROC group (95% confidence interval, -5.3 to 11.2 seconds), noninferior compared with the SUX group. Absence of laryngoscopy resistance was greater in the ROC than in the SUX groups (ROC, 87.5%; SUX, 74.2%; P = 0.019), but there were no differences in vocal cord position (P = 0.45) or intubation response (P = 0.31) between groups. No statistically significant differences in incidence of anesthesia complications or in neonatal outcome were found (10-minute Apgar score <7, P = 0.07; umbilical artery pH, P = 0.43). The incidence of postpartum myalgia was greater in the SUX group (ROC 0%; SUX 6.7%; P = 0.007). The incidence of subjective complaints was lower in the ROC group (ROC, 21.4%; SUX, 37.5%; P = 0.007). CONCLUSIONS: We conclude that rocuronium for rapid-sequence induction is noninferior for time to tracheal intubation and is accompanied by more frequent absence of laryngoscopy resistance and lower incidence of myalgia in comparison with succinylcholine for cesarean delivery under general anesthesia.

• MeSH
• androstanoly aplikace a dávkování   škodlivé účinky   MeSH
• antidota aplikace a dávkování   škodlivé účinky   MeSH
• časové faktory MeSH
• celková anestezie * škodlivé účinky   MeSH
• cholinesterasové inhibitory aplikace a dávkování   škodlivé účinky   MeSH
• císařský řez * škodlivé účinky   MeSH
• dospělí MeSH
• gama-cyklodextriny aplikace a dávkování   škodlivé účinky   MeSH
• intratracheální intubace MeSH
• jednoduchá slepá metoda MeSH
• laryngoskopie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myalgie etiologie   prevence a kontrola   MeSH
• neostigmin aplikace a dávkování   škodlivé účinky   MeSH
• nervosvalová blokáda škodlivé účinky   metody   MeSH
• nervosvalové látky nedepolarizující aplikace a dávkování   škodlivé účinky   MeSH
• pooperační bolest etiologie   prevence a kontrola   MeSH
• porodnická anestezie škodlivé účinky   metody   MeSH
• rokuronium MeSH
• sugammadex MeSH
• sukcinylcholin aplikace a dávkování   MeSH
• těhotenství MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• androstanoly MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• gama-cyklodextriny MeSH
• neostigmin MeSH
• nervosvalové látky nedepolarizující MeSH
• rokuronium MeSH
• sugammadex MeSH
• sukcinylcholin MeSH

Pharmacokinetic and pharmacodynamic properties of a chiral drug can significantly differ between application of the racemate and single enantiomers. During drug development, the characteristics of candidate compounds have to be assessed prior to clinical testing. Since biotransformation significantly influences drug actions in an organism, metabolism studies represent a crucial part of such tests. Hence, an optimized and economical capillary electrophoretic method for on-line studies of the enantioselective drug metabolism mediated by cytochrome P450 enzymes was developed. It comprises a diffusion-based procedure, which enables mixing of the enzyme with virtually any compound inside the nanoliter-scale capillary reactor and without the need of additional optimization of mixing conditions. For CYP3A4, ketamine as probe substrate and highly sulfated γ-cyclodextrin as chiral selector, improved separation conditions for ketamine and norketamine enantiomers compared to a previously published electrophoretically mediated microanalysis method were elucidated. The new approach was thoroughly validated for the CYP3A4-mediated N-demethylation pathway of ketamine and applied to the determination of its kinetic parameters and the inhibition characteristics in presence of ketoconazole and dexmedetomidine. The determined parameters were found to be comparable to literature data obtained with different techniques. The presented method constitutes a miniaturized and cost-effective tool, which should be suitable for the assessment of the stereoselective aspects of kinetic and inhibition studies of cytochrome P450-mediated metabolic steps within early stages of the development of a new drug.

• Klíčová slova
• Capillary electrophoresis, Cytochrome P450 3A4, Dexmedetomidine, Enantioselective drug metabolism, Ketamine, Ketoconazole,
• MeSH
• dexmedetomidin metabolismus   farmakokinetika   MeSH
• elektroforéza kapilární metody   MeSH
• gama-cyklodextriny metabolismus   farmakokinetika   MeSH
• inhibitory cytochromu P450 farmakologie   MeSH
• ketamin metabolismus   farmakokinetika   MeSH
• ketokonazol metabolismus   farmakokinetika   MeSH
• stereoizomerie MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dexmedetomidin MeSH
• gama-cyklodextriny MeSH
• gamma-cyclodextrin MeSH Prohlížeč
• inhibitory cytochromu P450 MeSH
• ketamin MeSH
• ketokonazol MeSH
• systém (enzymů) cytochromů P-450 MeSH

Per(2,3,6-tri-O-benzyl)-γ-cyclodextrin was debenzylated by DIBAL-H to produce a mixture of C6(I),C6(IV) and C6(I),C6(V) isomeric diols, which were separated and isolated. The C2-symmetrical C6(I),C6(V) diol was transformed into dithiol and dimerized to produce a γ-cyclodextrin duplex structure. A crystal structure revealed tubular cavity whose peripheries are slightly elliptically distorted. The solvent accessible volume of the cavity of the γ-CD duplex is about 740 Å(3). Due to this large inner space the duplex forms very stable inclusion complexes with steroids; bile acids examined in this study show binding affinities to the γ-cyclodextrin duplex in the range of 5.3 × 10(7) M(-1)-1.9 × 10(8) M(-1).

• MeSH
• chemie farmaceutická metody   MeSH
• dimerizace MeSH
• disulfidy chemie   MeSH
• gama-cyklodextriny chemická syntéza   chemie   MeSH
• imatinib mesylát chemie   MeSH
• kalorimetrie MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• krystalografie rentgenová MeSH
• kyselina lithocholová chemie   MeSH
• kyslík chemie   MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární konformace MeSH
• rozpouštědla chemie   MeSH
• steroidy chemie   MeSH
• sulfhydrylové sloučeniny chemie   MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• disulfidy MeSH
• gama-cyklodextriny MeSH
• gamma-cyclodextrin MeSH Prohlížeč
• imatinib mesylát MeSH
• kyselina lithocholová MeSH
• kyslík MeSH
• rozpouštědla MeSH
• steroidy MeSH
• sulfhydrylové sloučeniny MeSH

Regioselective alkylation of γ-cyclodextrin with allyl or propargyl bromide, using optimized reaction conditions, followed by peracetylation of the remaining hydroxyl groups and separation of isomers resulted in the set of peracetylated 2(I)-O-, 3(I)-O- and 6(I)-O-alkylated cyclodextrins in up to 19% yields. Ozonolysis or oxidative cleavage of peracetylated allyl derivatives resulted in a complete set of peracetylated 2(I)-O-, 3(I)-O-, and 6(I)-O-formylmethyl or -carboxymethyl derivatives. All of these derivatives are useful precursors for further preparation of regioselectively monosubstituted derivatives of γ-cyclodextrin.

• MeSH
• alkylace MeSH
• gama-cyklodextriny chemická syntéza   chemie   MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární struktura MeSH
• oxidace-redukce MeSH
• pargylin analogy a deriváty   chemie   MeSH
• stereoizomerie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• gama-cyklodextriny MeSH
• pargylin MeSH
• propargyl bromide MeSH Prohlížeč

PURPOSE OF THE STUDY: The aim of this clinical observation study was to determine the extent to which muscle relaxation induced by anesthesia must be intra-operatively reversed for a reliable identification, by intra-operative monitoring, of the lumbosacral (LS) nerve roots during extreme lateral interbody fusion (XLIF). MATERAL AND METHODS: General anesthesia (midazolam, propofol, sufentanil, oxygen/air/sevofluran - rocuronium) was administrated to all pa - tients. Train-of-four (TOF) stimulation of the ulnar nerve at 10-second intervals and an electromyographic response of the adductor pollicis muscle were used, and the duration of neuromuscular block was measured by the value of the TOF-ratio. When the level of recovery from neuromuscular block was TOF-count = 2, reversion to normal function was still accelerated by sugammadex administration at a dose of 2 mg.kg-1. Subsequently, it was determined at which level of muscle relaxation subsidence the first responses to LS nerve root stimulation were evident. Intra-operative neurophysiologial monitoring (IOM) with use of the NIM - Neuro® 3.0 device allowed for assessment of a triggered electromyographic reaction (tEMG) of LS roots to stimulation during surgery. The neuromuscular reactions were evaluated in 11 patients, five men and six women. The results were analysed by descriptive statistics and presented as median and interquartile-range values. RESULTS: In all patients a reliable monitoring of the depth of muscle relaxation was established. The value of supramaximal impulse was 46 mA (38 to 64 mA). The period from rocuronium administration to a spontaneous recovery of the TOF-count = 2 took 33 min (29 to 35 min). Duration from sugammadex administration to a TOF ratio of . 0.70 was 90 seconds (50 to 140) and to a TOF ratio of . 0.90 was 190 seconds (100 to 220 s). A reliable tEMG response of LS nerve roots to electric stimulation at 10 mA intensity was recorded at a TOF ratio of 0.68 (0.56 to 0.77) and at a 5 mA intensity it was reliable at a TOF ratio of 0.86 (0.75 to 0.90).. None of the patients reported radicular symptoms after surgery. DISCUSSION: From the anatomy of the greater psoas muscle and varied patterns of its LS plexus it is obvious that none of the zones is absolutely safe. In XLIF procedures it is therefore recommended to disect the psoas muscle under both visual and IOM control. Intra-operative checking of the depth of muscle relaxation then will provide information that conditions not affected by rocuronium administration and necessary for the detection of LS roots have been provided. CONCLUSIONS: 1. For a reliable intra-operative identification of LS nerve roots by electric stimulation at a 10 mA intensity it is recommended to achieve the value of TOF ratio equal to at least 0.70. When stimulation at a lower intensity (5 mA) is used, a TOF ratio of . 0.90 is necessary. 2. Administration of sugammadex to reverse an action of the muscle relaxant rocuronium is an effective and quick method to achieve the values required.

• MeSH
• androstanoly aplikace a dávkování   MeSH
• elektrická stimulace MeSH
• fúze páteře * metody   MeSH
• gama-cyklodextriny aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nervosvalová blokáda * MeSH
• nervosvalové látky nedepolarizující aplikace a dávkování   MeSH
• peroperační monitorování * MeSH
• plexus lumbosacralis anatomie a histologie   fyziologie   MeSH
• relaxace svalu MeSH
• rokuronium MeSH
• sugammadex MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• androstanoly MeSH
• gama-cyklodextriny MeSH
• nervosvalové látky nedepolarizující MeSH
• rokuronium MeSH
• sugammadex MeSH