Cyclodextrin-Based Polymeric Materials Bound to Corona Protein for Theranostic Applications.

Cyclodextrins (CDs) are cyclic oligosaccharide structures that could be used for theranostic applications in personalized medicine. These compounds have been widely utilized not only for enhancing drug solubility, stability, and bioavailability but also for controlled and targeted delivery of small molecules. These compounds can be complexed with various biomolecules, such as peptides or proteins, via host-guest interactions. CDs are amphiphilic compounds with water-hating holes and water-absorbing surfaces. Architectures of CDs allow the drawing and preparation of CD-based polymers (CDbPs) with optimal pharmacokinetic and pharmacodynamic properties. These polymers can be cloaked with protein corona consisting of adsorbed plasma or extracellular proteins to improve nanoparticle biodistribution and half-life. Besides, CDs have become famous in applications ranging from biomedicine to environmental sciences. In this review, we emphasize ongoing research in biomedical fields using CD-based centered, pendant, and terminated polymers and their interactions with protein corona for theranostic applications. Overall, a perusal of information concerning this novel approach in biomedicine will help to implement this methodology based on host-guest interaction to improve therapeutic and diagnostic strategies.

Comparison of volatile anesthetic-induced preconditioning in cardiac and cerebral system: molecular mechanisms and clinical aspects.

Volatile anesthetic-induced preconditioning (APC) has shown to have cardiac and cerebral protective properties in both pre-clinical models and clinical trials. Interestingly, accumulating evidences demonstrate that, except from some specific characters, the underlying molecular mechanisms of APC-induced protective effects in myocytes and neurons are very similar; they share several major intracellular signaling pathways, including mediating mitochondrial function, release of inflammatory cytokines and cell apoptosis. Among all the experimental results, cortical spreading depolarization is a relative newly discovered cellular mechanism of APC, which, however, just exists in central nervous system. Applying volatile anesthetic preconditioning to clinical practice seems to be a promising cardio-and neuroprotective strategy. In this review, we also summarized and discussed the results of recent clinical research of APC. Despite all the positive experimental evidences, large-scale, long-term, more precisely controlled clinical trials focusing on the perioperative use of volatile anesthetics for organ protection are still needed.

In silico investigation of propofol binding sites in human serum albumin using explicit and implicit solvation models.

All-atom molecular dynamics (MD) simulations are presented on general anesthetic propofol bound to human serum albumin (HSA) due to the drug pharmacokinetics and pharmacodynamics in the circulatory system. We implemented the explicit and implicit solvation models to compare the binding affinity of propofol at the different binding sites (PR1 and PR2) in the HSA protein. Only the implicit solvation models provided the evidence in accordance with the experimental data indicating that the HSA-ligand interactions are dominanted by hydrophobic forces due to the higher drug affinity at the PR1 position with a ΔGMM-PB/SA value of -23.44kcalmol-1. Overall, this study provides important information on the accuracy of explicit and implicit solvation models to characterize the propofol interaction with different HSA binding sites.

In Silico Modeling of Indigo and Tyrian Purple Single-Electron Nano-Transistors Using Density Functional Theory Approach.

The purpose of this study was to develop and implement an in silico model of indigoid-based single-electron transistor (SET) nanodevices, which consist of indigoid molecules from natural dye weakly coupled to gold electrodes that function in a Coulomb blockade regime. The electronic properties of the indigoid molecules were investigated using the optimized density-functional theory (DFT) with a continuum model. Higher electron transport characteristics were determined for Tyrian purple, consistent with experimentally derived data. Overall, these results can be used to correctly predict and emphasize the electron transport functions of organic SETs, demonstrating their potential for sustainable nanoelectronics comprising the biodegradable and biocompatible materials. In silico model and gate coupling of indigoid single-electron nano-transistors.

A Novel Approach for the Control of Inflammatory Pain: Prostaglandin E2 Complexation by Randomly Methylated ß-Cyclodextrins.

BACKGROUND: Inhibitors of cyclooxygenase, which block the formation of prostaglandin (PG) E2, are the standard treatment of inflammatory pain. These drugs, however, have serious gastrointestinal, renal, and cardiovascular side effects that limit their clinical use. Cyclodextrins are neutral glucose oligomers that form a hydrophilic outer and a hydrophobic interior cavity used to carry hydrophilic substances. Methyl-ß-cyclodextrins are used currently in several drugs as enhancers and also to deliver PGs. We therefore hypothesized that randomly methylated ß-cyclodextrins (RAMEB) could be used for pain treatment. METHODS: An in silico screening for important inflammatory mediators (eg, PGE2, substance P, bradykinin, and calcitonin gene-related peptide) was performed to predict the probability of these molecules binding to RAMEB. Thereafter, a comprehensive in vitro study investigated the complexation affinity of the best target toward RAMEB or its RAMEB-fraction L (FL) using capillary electrophoresis.Wistar rats were injected intraplantarly with complete Freund's adjuvant (CFA) for 96 hours to induce inflammatory hyperalgesia. Subsequently, rats were treated intraplantarly or intravenously either with RAMEB or RAMEB FL and compared with the respective controls. Parecoxib was used as positive control. Mechanical (paw pressure threshold, PPT) and thermal (paw withdrawal latency) nociceptive thresholds were determined before injection and at the indicated time points thereafter. Paw tissue was collected after treatments, and PGE2 and PGD2 contents were measured. Analysis of variance was used for data analysis followed by appropriate post hoc comparisons. RESULTS: In silico screening indicated that PGE2, with the highest affinity, was the best candidate for RAMEB binding. Likewise, in capillary electrophoresis experiments, RAMEB had a high affinity to form inclusion complexes with the PGE2 (stability constant [K], 360 1/M; 95% confidence interval [C]: 347.58-372.42 M). Local treatment with RAMEB alleviated CFA-induced mechanical (PPT: 76.25 g; 95% CI: 56.24-96.25 g) and thermal hyperalgesia (PPT: 8.50 seconds; 95% CI: 6.76-10.23 seconds). Moreover, a systemic administration of RAMEB decreased CFA-induced mechanical (PPT: 126.66 g; 95% CI: 114.54-138.77 g) and thermal hyperalgesia (paw withdrawal latency: 11.47 seconds; 95% CI: 9.26-13.68 seconds). RAMEB FL resulted in greater in vitro PGE2-binding capacity and decreased PG content as well as hyperalgesia in vivo to a similar extent. Motor activity of the rats was not altered by RAMEB or RAMEB FL. CONCLUSIONS: Capture of PGs by cyclodextrins could be a novel and innovative tool for the treatment of inflammatory pain and bypassing some unwanted side effects of cyclooxygenase inhibitors.

Characterization, in Vivo Evaluation, and Molecular Modeling of Different Propofol-Cyclodextrin Complexes To Assess Their Drug Delivery Potential at the Blood-Brain Barrier Level.

In this study, we investigated the ability of the general anesthetic propofol (PR) to form inclusion complexes with modified ß-cyclodextrins, including sulfobutylether-ß-cyclodextrin (SBEßCD) and hydroxypropyl-ß-cyclodextrin (HPßCD). The PR/SBEßCD and PR/HPßCD complexes were prepared and characterized, and the blood-brain barrier (BBB) permeation potential of the formulated PR was examined in vivo for the purpose of controlled drug delivery. The PR/SBEßCD complex was found to be more stable in solution with a minimal degradation constant of 0.25 h-1, a t1/2 of 2.82 h, and a Kc of 5.19 × 103 M-1 and revealed higher BBB permeability rates compared with the reference substance (PR-LIPURO) considering the calculated brain-to-blood concentration ratio (logBB) values. Additionally, the diminished PR binding affinity to SBEßCD was confirmed in molecular dynamics simulations by a maximal Gibbs free energy of binding (ΔGbind = -18.44 kcal·mol-1), indicating the more rapid PR/SBEßCD dissociation. Overall, the results demonstrated that SBEßCD has the potential to be used as a prospective candidate for drug delivery vector development to improve the pharmacokinetic and pharmacodynamic properties of general anesthetic agents at the BBB level.

Sevoflurane-Sulfobutylether-ß-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies.

The objective of the present investigation was to study the ability of sulfobutylether-ß-cyclodextrin (SBEßCD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEßCD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (Papp). In addition, SEV binding affinity to SBEßCD was confirmed by a minimal Gibbs free energy of binding (ΔGbind) value of -1.727 ± 0.042 kcal·mol-1 and an average binding constant (Kb) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.

Ionization states, cellular toxicity and molecular modeling studies of midazolam complexed with trimethyl-ß-cyclodextrin.

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-ß-cyclodextrin (trimethyl-ß-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔG(CR)(solv = -9.98 kcal·mol ⁻¹), which has a minimal ΔG(OR)(solv) of -67.01 kcal·mol⁻¹. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding (ΔG(bind)) value of -5.57 ± 0.02 kcal·mol⁻¹, an equilibrium binding constant (K(b)) of 79.89 ± 2.706 µM, and a ligand efficiency index (LE(lig)) of -0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-ß-cyclodextrin to increase drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations.

[DGAI-certified course series anaesthesia focused sonography: module 1: basics of sonography]. / DGAI-zertifizierte Seminarreihe Anästhesie Fokussierte Sonografie - Modul 1: Grundlagen der Sonografie.

Understanding the principles of wave physics paves the way for appropriate utilization and interpretation of sonography. In module 1 of the course series "Anesthesia Focused Sonography", the course participants will learn by lectures and practical training, how ultrasonic waves emerge, how they travel in human tissue, and how a picture is generated from their echo signals. Furthermore, the technology of an ultrasound system and the development of artifacts will be demonstrated; moreover, the Doppler effect and its implementation into current sonographic procedures will be presented as a central theme.

The relationship between carotid blood-flow velocity and the left ventricular area during acute regional ischemia.

OBJECTIVE: Myocardial contractility can be described by the relationship between blood-flow velocity in the carotid artery and the left ventricular cross-sectional area. The authors investigated whether critical myocardial ischemia influences the derived contractility index, E'(es). DESIGN: A prospective animal study. SETTING: A university research laboratory. PARTICIPANTS: Eleven Göttinger minipigs. INTERVENTIONS: Within the closed-chest model, the authors placed a U-shaped 8-MHz miniature Doppler probe around the left internal carotid artery and inserted a combined pressure-conductance catheter into the left ventricular cavity via the right internal carotid artery. A balloon occlusion catheter was placed into the inferior caval vein from a femoral vein and acquired transthoracic-view echocardiographic images. An active coronary perfusion catheter was positioned in the proximal left circumflex coronary (LCx) artery. The LCx bed was perfused with blood from the contralateral femoral artery by using a high-precision-output roller pump. MEASUREMENTS AND MAIN RESULTS: Stage analysis during normal perfusion revealed evidence for the following function: E'(es) = 0.066 + 0.121 E(es) (R = 0.96, R(2) = 0.92, and p < 0.0001), which agrees with previously determined equations. Under ischemic conditions, the relationship changed to E'(es) = 0.048 + 0.196.E(es) (R = 0.83, R(2) = 0.69, and p < 0.0001). The limits of precision to detect changes in contractility by E'(es) increased from 16% to 45%; the bias did not notably deviate from zero. The indexes of mechanical dyssynchrony (mechanical dyssynchrony and internal flow fraction) derived from conductance catheter measurements increased significantly. CONCLUSION: The ability of E'(es) to indicate contractility during acute reduced coronary blood flow is limited.

Time-varying elastance concept applied to the relation of carotid arterial flow velocity and ventricular area.

OBJECTIVE: In this study, the relationship V(f)AR, which was obtained from carotid blood-flow velocity (V(f)) and the cross-sectional area (A) of the left ventricle, was used to assess changes in left ventricular (LV) systolic performance as indicated by the LV pressure-volume relationship (PVR) and end-systolic LV elastance (E(es)). BACKGROUND: The relationship of maximum systolic V(f) as a surrogate for LV pressure and end-systolic LV area as a surrogate for end-systolic LV volume may allow for the estimation of LV elastance and ejection properties. METHODS: In 25 pigs, internal carotid V(f) was recorded by using continuous-wave Doppler mode. Echocardiographic measurements of A were continuously performed with an automated border detection system and combined with data for V(f) to display V(f)AR as a series of loop diagrams. These were shifted during acute preload reduction, and an index E'(es) was calculated by applying the time varying elastance concept to end-systolic V(f)AR. Simultaneously, E(es) was acquired by conductance catheter and micromanometer techniques. Comparisons of E'(es) and E(es) were made at various contractility levels obtained by the administration of dobutamine, 5 microg/kg/min, and esmolol, 40 to 60 mg, and at various cardiac load levels, obtained by a fluid bolus infusion or administration of a vasoconstrictor. RESULTS: Highly linear elastance curves (r >or= 0.85, p < 0.0001) were derived from both end-systolic V(f)AR and PVR. Correlation of E'(es) and E(es) revealed an almost linear function: E'(es) = 0.052 + 0.11 E(es) (r = 0.98, p < 0.0001). Administration of dobutamine increased E(es) from 5.8 +/- 3.04 mmHg/mL to 10.1 +/- 4.19 mmHg/mL (p < 0.05), and E('es) from 0.68 +/- 0.288 cm(2)/min/mL to 1.24 +/- 0.458 cm(2)/min/mL (p < 0.05). After administration of esmolol, E(es) and E'(es) both dropped significantly by 3.7 +/- 2.4 mmHg/mL and 0.44 +/- 0.15 cm(2)/min/mL, respectively. No load dependency of E'(es) was seen. Bland-Altman analysis revealed that the change in E'(es), which is required to predict a significant change in E(es), should exceed +16.9% or -13.1% of the preceding value. CONCLUSION: Application of the time-varying elastance concept on the relation of V(f) and LV area allows for the determination of an index E'(es) that may be used to estimate E(es).