complexation study
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Metallacarboranes and their derivatives are the recently discovered inhibitors of HIV protease. The main goal of this work was to study the interaction of parent metallacarborane derivatives with cyclodextrins (CD) differing in the inner cavity size. This interaction can improve the drug solubility and its transport to the cells. For ?-, ß- and ?-CD, NMR titrations with sodium cobalt(III) bis(1,2-dicarbollide) were performed at various CD concentrations. It was found that the greatest change in the 1H NMR chemical shift is observed at position 3 of CD on the inner broader rim of the cone-shaped molecule of CD. For ?-CD, the NMR titration curves correspond to the 1:1 stoichiometry and to the stability constant ca. 900. For ß- CD, simultaneous formation of 1:1 and 2:1 complexes and higher stability constants at least by two orders of magnitude follow from the titration curves. For ?-CD, more than two types of complexes are present. It was shown for ß- CD that the increased temperature does not significantly influence the titration curves. The model, consisting of a high number of adjustable parameters, for the determination of stability constants of the complexes must be confirmed by independent analytical methods such as isothermal calorimetry and X-ray structure determination.
Byla stanovena rozpustnost nového antileukotrienického léčiva quinlukast (kyselina 4-{[4-(2-chinolylmethoxy) fenyl]sulfanyl}benzoová) ve vodě a ve vodných roztocích α-cyklodextrinu (α-CD), ß-cyklodextrinu (ß-CD), hydroxypropyl-ß-cyklodextrinu (HP-ß-CD, průměrný stupeň substituce 0,8) a methyl-ß-cyklodextrinu (M-ß-CD, průměrný stupeň substituce 1,8). Stanovená rozpustnost quinlukastu ve vodě byla 0,081±0,008 mmol/l (3,12±0,30 mg/100ml) a v roztocích ß-CD se pozorovalo pouze nevýznamné zvýšení rozpustnosti quinlukastu. Tři dobře rozpustné cyklodextriny však byly solubilizačně účinné, ve vodných roztocích s nevelkou koncentrací cyklodextrinu 5 g/100 ml se pozorovalo 12násobné zvýšení rozpustnosti quinlukastu v případě M-ß-CD a 10násobné zvýšení rozpustnosti v případě HP-ß-CD a α-CD. Byly stanoveny fázové diagramy rozpustnosti quinlukastu ve vodných roztocích těchto cyklodextrinů (do 0,05 mol/l). V případě M-ß-CD a HP-ß-CD byly diagramy rozpustnosti lineární (AL) a odpovídaly tvorbě rozpustného inkluzního komplexu quinlukast–cyklodextrin 1:1, s vyhodnocenými konstantami stability K11 300±35 l/mol (M-ß-CD) resp. 260± 30 l/mol (HP-ß-CD). Fázový diagram rozpustnosti quinlukastu ve vodných roztocích α-CD se vyznačoval výraznou pozitivní odchylkou od linearity (AP), solubilizační účinnost zředěných roztoků α-CD byla poměrně nízká, avšak progresivně vzrůstala s koncentrací α-CD. Při celkovém hodnocení se cyklodextriny α-CD, HP-ß-CD a M-ß-CD ukázaly být vhodnými solubilizéry quinlukastu do vodného roztoku.
Solubility of the new antileukotrienic drug quinlukast (4-{[4-(2-quinolylmethoxy)phenyl]sulfanyl}benzoic acid) was determined in water and in aqueous solutions of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), hydroxypropyl- β-cyclodextrin (HP-β-CD, average degree of substitution 0.8), and methyl-β-cyclodextrin (M-β-CD, average degree of substitution 1.8). The determined solubility of quinlukast in water was 0.081±0.008 mmol/l (3.12± 0.30 mg/100ml) and only an insignificant increase in quinlukast solubility was observed in aqueous solutions of β-CD. However, three well soluble cyclodextrins showed a marked solubilizing effect, in aqueous solutions with a moderate cyclodextrin concentration 5 g/100ml, a 12-fold increase in quinlukast solubility was observed in the case of M-β-CD, and a 10-fold increase in the case of both HP-β-CD and α-CD. Phase solubility diagrams of quinlukast in aqueous solutions of these cyclodextrins (up to 0.05 mol/l) were determined. In the cases of M-β-CD and HP-β-CD, the solubility diagrams were linear (AL) and they corresponded to the formation of a soluble inclusion complex quinlukast – cyclodextrin 1:1 with the evaluated stability constants K11 300±35 l/mol and 260±30 l/mol for M-β-CD and HP-β-CD, respectively. The phase solubility diagram of quinlukast in aqueous solutions of α-CD showed a marked positive deviation (AP) from linearity, the solubilization efficiency of dilute α-CD solutions was relatively low but it increased progressively with the increasing α-CD concentration. In the overall evaluation, the cyclodextrins α-CD, HP-β-CD and M-β-CD appeared to be suitable for the quinlukast solubilization into aqueous solutions.
BACKGROUND: Trauma-induced coagulopathy (TIC) substantially contributes to mortality in bleeding trauma patients. OBJECTIVE: The aim of the study was to administer fibrinogen concentrate in the prehospital setting to improve blood clot stability in trauma patients bleeding or presumed to bleed. DESIGN: A prospective, randomised, placebo-controlled, double-blinded, international clinical trial. SETTING: This emergency care trial was conducted in 12 Helicopter Emergency Medical Services (HEMS) and Emergency Doctors' vehicles (NEF or NAW) and four trauma centres in Austria, Germany and Czech Republic between 2011 and 2015. PATIENTS: A total of 53 evaluable trauma patients aged at least 18 years with major bleeding and in need of volume therapy were included, of whom 28 received fibrinogen concentrate and 25 received placebo. INTERVENTIONS: Patients were allocated to receive either fibrinogen concentrate or placebo prehospital at the scene or during transportation to the study centre. MAIN OUTCOME MEASURES: Primary outcome was the assessment of clot stability as reflected by maximum clot firmness in the FIBTEM assay (FIBTEM MCF) before and after administration of the study drug. RESULTS: Median FIBTEM MCF decreased in the placebo group between baseline (before administration of study treatment) and admission to the Emergency Department, from a median of 12.5 [IQR 10.5 to 14] mm to 11 [9.5 to 13] mm (P = 0.0226), but increased in the FC Group from 13 [11 to 15] mm to 15 [13.5 to 17] mm (P = 0.0062). The median between-group difference in the change in FIBTEM MCF was 5 [3 to 7] mm (P < 0.0001). Median fibrinogen plasma concentrations in the fibrinogen concentrate Group were kept above the recommended critical threshold of 2.0 g l-1 throughout the observation period. CONCLUSION: Early fibrinogen concentrate administration is feasible in the complex and time-sensitive environment of prehospital trauma care. It protects against early fibrinogen depletion, and promotes rapid blood clot initiation and clot stability. TRIAL REGISTRY NUMBERS: EudraCT: 2010-022923-31 and ClinicalTrials.gov: NCT01475344.
- MeSH
- dospělí MeSH
- fibrinogen * MeSH
- lidé MeSH
- mladiství MeSH
- pilotní projekty MeSH
- prospektivní studie MeSH
- urgentní zdravotnické služby * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Česká republika MeSH
- Německo MeSH
- Rakousko MeSH
The interactions of valinomycin, macrocyclic depsipeptide antibiotic ionophore, with ammonium cation NH4+ have been investigated. Using quantum mechanical density functional theory (DFT) calculations, the most probable structure of the valinomycin-NH4+ complex species was predicted. In this complex, the ammonium cation is bound partly by three strong hydrogen bonds to three ester carbonyl oxygen atoms of valinomycin and partly by somewhat weaker hydrogen bonds to the remaining three ester carbonyl groups of the valinomycin ligand. The strength of the valinomycin-NH4+ complex was evaluated experimentally by capillary affinity electrophoresis. From the dependence of valinomycin effective electrophoretic mobility on the ammonium ion concentration in the background electrolyte, the apparent binding (association, stability) constant (Kb) of the valinomycin-NH4+ complex in methanol was evaluated as log Kb = 1.52 +/- 0.22.
INTRODUCTION: Pre-eclampsia affects ~5%-7% of pregnancies. Although improved obstetric care has significantly diminished its associated maternal mortality, it remains a leading cause of maternal morbidity and mortality in the world. Term pre-eclampsia accounts for 70% of all cases and a large proportion of maternal-fetal morbidity related to this condition. Unlike in preterm pre-eclampsia, the prediction and prevention of term pre-eclampsia remain unsolved. Previously proposed approaches are based on combined third-trimester screening and/or prophylactic drugs, but these policies are unlikely to be widely implementable in many world settings. Recent evidence shows that the soluble fms-like tyrosine kinase-1 (s-Flt-1) to placental growth factor (PlGF) ratio measured at 35-37 weeks' gestation predicts term pre-eclampsia with an 80% detection rate. Likewise, recent studies demonstrate that induction of labour beyond 37 weeks is safe and well accepted by women. We hypothesise that a single-step universal screening for term pre-eclampsia based on sFlt1/PlGF ratio at 35-37 weeks followed by planned delivery beyond 37 weeks reduces the prevalence of term pre-eclampsia without increasing the caesarean section rates or worsening the neonatal outcomes. METHODS AND ANALYSIS: We propose an open-label randomised clinical trial to evaluate the impact of a screening of term pre-eclampsia with the sFlt-1/PlGF ratio followed by planned delivery in asymptomatic nulliparous women at 35-37 weeks. Women will be assigned 1:1 to revealed (sFlt-1/PlGF known to clinicians) versus concealed (unknown) arms. A cut-off of >90th centile is used to define the high risk of subsequent pre-eclampsia and offer planned delivery from 37 weeks. The efficacy variables will be analysed and compared between groups primarily following an intention-to-treat approach, by ORs and their 95% CI. This value will be computed using a Generalised Linear Mixed Model for binary response (study group as fixed effect and the centre as intercept random effect). ETHICS AND DISSEMINATION: The study is conducted under the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 20 November 2020. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT04766866.
- MeSH
- biologické markery MeSH
- císařský řez MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- novorozenec MeSH
- placentární růstový faktor MeSH
- prediktivní hodnota testů MeSH
- preeklampsie * diagnóza prevence a kontrola epidemiologie MeSH
- randomizované kontrolované studie jako téma MeSH
- receptor 1 pro vaskulární endoteliální růstový faktor MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- protokol klinické studie MeSH
The interaction between 2-amino-6-fluorobenzothiazole (AFBT) and ß-cyclodextrin (ß-CDx) has been investigated in aqueous solution and in the solid state. The stoichiometry and binding constant of the complex between AFBT and ß-CDx in solution were determined by steady-state and time-resolved fluorescence spectroscopy. The FT-IR spectral data and SEM images of the solid complex confirmed the formation of inclusion complex. The proton transfer behaviour of AFBT has been investigated in aqueous and ß-CDx solutions.
INTRODUCTION: Patients who have sustained extensive burns frequently exhibit substantial damage to skeletal muscle and associated complications. The rehabilitation of these patients can be challenging due to the nature of the injury and the subsequent complications. Nevertheless, there is a possibility that functional proprioceptive stimulation (illusory movements) may facilitate effective rehabilitation in patients with limited physiotherapy options. Nevertheless, this approach has yet to be tested in patients with burn injuries. MATERIAL AND METHODOLOGY: A prospective, randomised, crossover trial was conducted at a burn centre in a tertiary teaching hospital. The objective was to assess the effects of illusory movements on energy metabolism, insulin sensitivity, and skeletal muscle biology in adult critically ill patients with deep burns covering 30 % or more of the total body surface area. Two 30-minute daily sessions of functional proprioceptive stimulation were administered in addition to the standard physical therapy or physical activity regimen. Subsequently, the patients proceeded to the next stage of the trial, which involved a two-week crossover period. MEASUREMENTS AND MAIN RESULTS: Daily indirect calorimetry and calculation of nitrogen balance. Skeletal muscle biopsies from vastus lateralis for high resolution respirometry and euglycemic clamps to assess whole body glucose disposal were performed three times: at baseline and then fortnightly after each intervention period. The intervention was feasible and well tolerated in both early and late stages of burn disease. It did not change energy expenditure (mean change -33 [95 % CI: -292;+227] kcal .24 h-1, p = 0.79), nitrogen balance (+2.0 [95 % CI: -3.1;+7.1] g N .1.73 m-2 BSA .24 h-1), or insulin sensitivity (mean change of insulin-mediated glucose disposal -0.33 [95 % CI: -1.18;+0.53] mmol.h-1). At the cellular level, the intervention increased the capacity of mitochondria to synthesize ATP by aerobic phosphorylation and tended to increase mitochondrial coupling. Functional capacities of fatty acid oxidation and electron transfer chain complexes I, II, and IV were unaffected. CONCLUSIONS: Compared to physical therapy alone, two daily sessions of functional proprioceptive stimulation in addition to usual physical therapy in patients with extensive burns did not change energy expenditure, insulin sensitivity, nitrogen balance, or energy substrate oxidation. At cellular level, the intervention improved the capacity of aerobic phosphorylation in skeletal muscle mitochondria. Clinical effects remain to be demonstrated in adequately powered trials.
- MeSH
- dospělí MeSH
- energetický metabolismus * fyziologie MeSH
- inzulinová rezistence fyziologie MeSH
- klinické křížové studie * MeSH
- kosterní svaly * metabolismus patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nepřímá kalorimetrie MeSH
- popálení * metabolismus terapie rehabilitace patofyziologie komplikace MeSH
- povrch těla MeSH
- propriocepce fyziologie MeSH
- prospektivní studie MeSH
- techniky fyzikální terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
The model of electromigration of a multivalent weak acidic/basic/amphoteric analyte that undergoes complexation with a mixture of selectors is introduced. The model provides an extension of the series of models starting with the single-selector model without dissociation by Wren and Rowe in 1992, continuing with the monovalent weak analyte/single-selector model by Rawjee, Williams and Vigh in 1993 and that by Lelièvre in 1994, and ending with the multi-selector overall model without dissociation developed by our group in 2008. The new multivalent analyte multi-selector model shows that the effective mobility of the analyte obeys the original Wren and Row's formula. The overall complexation constant, mobility of the free analyte and mobility of complex can be measured and used in a standard way. The mathematical expressions for the overall parameters are provided. We further demonstrate mathematically that the pH dependent parameters for weak analytes can be simply used as an input into the multi-selector overall model and, in reverse, the multi-selector overall parameters can serve as an input into the pH-dependent models for the weak analytes. These findings can greatly simplify the rationale method development in analytical electrophoresis, specifically enantioseparations.
