Lipophilic Agents Research Articles

Changes in tissues and organs through PMCTA carrier substances.

To date, lipophilic contrast agents mixed with oil, usually paraffin oil, are the most commonly used contrast agents in post-mortem computed tomography angiography (PMCTA). Iodine-based hydrophilic contrast media in combination with a water-soluble carrier, e.g. polyethylene glycol (PEG), are also common. However, their influence on different tissues and organs is poorly understood. In order to analyse the changes in the cadavers caused by the different carrier substances, we evaluated the effects of PEG 200 and oil on the different tissues and organs. Therefore, during a forensic autopsy, liquid femoral vein blood and samples of different organs and vessels were taken and preserved at room temperature in the two liquids mentioned. The condition of the samples was documented during the autopsy and 24, 48 and 72h after preservation. Microscopic examination took place after 72h. After 24h, the samples placed in PEG 200 already showed a clear solidification of almost all structures. Crumbly blood agglomerates had formed in the previously liquid blood. In contrast, the samples stored in oil showed signs of classic cadaveric decomposition after 24h, which increased with time. The microscopic and immunohistochemical evaluation of the samples stored in PEG showed a good diagnostic quality. The analysis of tissues stored in oil was much more difficult due to putrefaction. PEG and oil show significantly different effects on human tissues, mainly conservation and dehydration are affected. It is crucial to be aware of these differences in order to choose the most appropriate PMCTA method for each forensic case.

Effect of carboxymethyl cellulose incorporation to gelatin‐sunflower oil bigel on the physicochemical and structural properties

AbstractBigels are innovative and appealing heterogeneous matrices composed of two structured‐gel (hydrogel and oleogel) phases, which suitable for the entrapment of both hydrophilic and lipophilic active agents. As structuring the bigel phases using convenient materials can enhance the main characteristics, this study aimed to develop bigel system based on a hybrid hydrogel consisting of gelatin and carboxymethylcellulose (CMC). The impact of incorporating various concentrations of CMC (0, 0.5, 1, 2, and 3% w/w) into gelatin‐based hydrogel at a constant organogel/hydrogel ratio of 60:40 was investigated on bigel properties. The integration of gelatin and CMC significantly affected the solvent holding capacity (SHC), microstructure, rheology, thermal, and textural properties. The results showed that bigel samples containing gelatin‐CMC had lower SHC compared to gelatin‐based samples. The integration of CMC to bigel formulation resulted in a significant decrease in hardness, cohesiveness, and adhesiveness also smooth texture. Differential scanning calorimeter (DSC) analysis of the bigels showed a descending trend in melting point from 99.07 to 98.60°C for bigel samples as the CMC concentration increased from 0% to 2%. This was followed by an increase in melting temperature (100.95°C) in the bigel containing 3% CMC. Particle size distribution data indicated that the droplet sizes of the bigels increased with the incorporation of CMC into the hydrogel phase, without displaying a distinct concentration‐dependent trend. The rheological characteristics of strain sweep, frequency sweep, and loss factor affected by gelatin/CMC concentration. Overall obtained results highlight that CMC incorporation to gelatin plays a crucial role in bigel offering different textural, rheological and thermal properties. So that carefully selection and optimization of gelatin and CMC concentrations in hydrogel phase are essential for tailoring the mechanical strength and stability of bigels for various applications such as drug delivery, cosmetic, and food industries. Regarding the desired properties of CMC, it could be recommend to use by combination with gelatin to create a structure–function aimed bigels.

Enhancing Oral Bioavailability of Domperidone Maleate: Formulation, In vitro Permeability Evaluation In-caco-2 Cell Monolayers and In situ Rat Intestinal Permeability Studies.

The domperidone maleate, a lipophilic agent classified as a Biopharmaceutical Classification System Class II substance with weak water solubility. Self- Emulsifying Drug Delivery System is a novel approach to improve water solubility and, ultimately bioavailability of drugs. This study aimed to develop and characterize new domperidone-loaded self-emulsifying drug delivery systems as an alternative formulation and to evaluate the permeability of domperidone-loaded self-emulsifying drug delivery systems by using Caco-2 cells and via single-pass intestinal perfusion method. Three self-emulsifying drug delivery systems were prepared and characterized in terms of pH, viscosity, droplet size, zeta potential, polydispersity index, conductivity, etc. Each formulation underwent 10, 100, 200, and 500 times dilution in intestinal buffer pH 6.8 and stomach buffer pH 1.2, respectively. Female Sprague Dawley rats were employed for in situ single-pass intestinal perfusion investigations. Results of the study revealed that the ideal self-emulsifying drug delivery systems formulation showed narrow droplet size, ideal zeta potential, and no conductivity. Additionally, as compared to the control groups, the optimum formulation had better apparent permeability (12.74 ± 0.02×10-4) from Caco-2 cell monolayer permeability experiments. The study also revealed greater Peff values (2.122 ± 0.892×10-4 cm/s) for the optimal formulation from in situ intestinal perfusion analyses in comparison to control groups (Domperidone; 0.802 ± 0.418×10-4 cm/s). To conclude, prepared formulations can be a promising way of oral administration of Biopharmaceutical Classification System Class II drugs.

The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice.

We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABAA receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo. Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [13C12]sucrose as a permeability marker was injected as IV bolus 15min after start of the infusions. Brain uptake clearance, Kin, of sucrose was calculated from the brain concentrations at 30min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point. The Kin value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma. Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.

The role of lipid peroxidation in epithelial–mesenchymal transition of retinal pigment epithelial cells

Epithelial–Mesenchymal Transition (EMT) of retinal pigment epithelial (RPE) cells is recognized as pivotal in various retinal diseases. Previous studies have suggested a reciprocal regulation between reactive oxygen species (ROS) and EMT, though the involvement of peroxidized lipids or the effects of reducing them has remained unclear. The present study disclosed that EMT of ARPE-19 cells induced by TGF-β2 and TNF-α involves increased lipid peroxidation, and Ferrostatin-1 (Fer-1), a lipophilic antioxidative agent, successfully inhibited the increase in lipid peroxidation. Fer-1 suppressed the formation of EMT-associated fibrotic deposits, while EMT induction or Fer-1 treatment did not influence the cell viability or proliferation. Functionally, Fer-1 impeded EMT-driven cell migration and reduction in transepithelial electrical resistance. It demonstrated regulatory prowess by downregulating the mesenchymal marker fibronectin, upregulating the epithelial marker ZO-1, and inhibiting the EMT-associated transcriptional factor ZEB1. Additionally, VEGF, a major pathogenic cytokine in various retinal diseases, is also upregulated during EMT, and Fer-1 significantly mitigated the effect. The present study disclosed the involvement of lipid peroxidation in EMT of RPE cells, and suggests the suppression of lipid peroxidation may be a potential therapeutic target in retinal diseases in which EMT is implicated.

The Reducing Agent Dithiothreitol Modulates the Ventilatory Responses That Occur in Freely Moving Rats during and following a Hypoxic-Hypercapnic Challenge.

The present study examined the hypothesis that changes in the oxidation-reduction state of thiol residues in functional proteins play a major role in the expression of the ventilatory responses in conscious rats that occur during a hypoxic-hypercapnic (HH) gas challenge and upon return to room air. A HH gas challenge in vehicle-treated rats elicited robust and sustained increases in minute volume (via increases in frequency of breathing and tidal volume), peak inspiratory and expiratory flows, and inspiratory and expiratory drives while minimally affecting the non-eupneic breathing index (NEBI). The HH-induced increases in these parameters, except for frequency of breathing, were substantially diminished in rats pre-treated with the potent and lipophilic disulfide-reducing agent, L,D-dithiothreitol (100 µmol/kg, IV). The ventilatory responses that occurred upon return to room air were also substantially different in dithiothreitol-treated rats. In contrast, pre-treatment with a substantially higher dose (500 µmol/kg, IV) of the lipophilic congener of the monosulfide, N-acetyl-L-cysteine methyl ester (L-NACme), only minimally affected the expression of the above-mentioned ventilatory responses that occurred during the HH gas challenge or upon return to room air. The effectiveness of dithiothreitol suggests that the oxidation of thiol residues occurs during exposure to a HH gas challenge and that this process plays an essential role in allowing for the expression of the post-HH excitatory phase in breathing. However, this interpretation is contradicted by the lack of effects of L-NACme. This apparent conundrum may be explained by the disulfide structure affording unique functional properties to dithiothreitol in comparison to monosulfides. More specifically, the disulfide structure may give dithiothreitol the ability to alter the conformational state of functional proteins while transferring electrons. It is also possible that dithiothreitol is simply a more efficient reducing agent following systemic injection, although one interpretation of the data is that the effects of dithiothreitol are not due to its reducing ability.

Development of a technique for postmortem CT angiography of fetuses with a lipophilic contrast agent

Background and objectivesPostmortem examinations of fetuses play a crucial role in confirming abnormalities, especially vascular and cardiac malformations leading to fetal demise. This study aims at developing and assessing a method for acquiring Post-Mortem CT-Angiography (PMCTA) with the injection of a lipophilic contrast agent (CA) to better visualize the great vessels of the trunk and head. Materials and methods25 human fetuses (gestational age at death between 106 days and 28 weeks) were included. Examinations were performed using a dual-energy Multidetector Computed Tomography (MDCT) scanner. Three imaging sequences were acquired, before CA injection, after injection of 7mL of CA through umbilical artery (arterial phase), and after an injection of 15mL of CA through umbilical vein (venous phase). CA-induced vascular opacification was scored per-vessel in both phases as follows: 0 = none, 1 = partial, 2 = complete. Total opacification was defined as the sum of the per-vessel opacification scores. ResultsIn 23/25 subjects, CA injection into the umbilical vessels was feasible manually using flexible catheters. After the first injection, at least a partial opacification of the arterial network was achieved in 15/23 (65%) subjects. After the second injection, a complete opacification of the venous network was achieved in 18/23 (78%) subjects. Failures occurred in 10/25 (40%) subjects and were mostly due to the preservation status. ConclusionPMCTA performed with a two-phase intra-umbilical injection of a lipophilic CA enabled to visualize the vascular network, even after a significant a postmortem interval. This protocol may help in detecting vascular malformations, improving clinical diagnoses and prenatal counselling.

The Role of Radionuclide Imaging in Brain Death Diagnosis.

Brain death is defined as the complete and irreversible cessation of the entire brain function, including the brainstem. For the most part, the diagnosis is clinical, and ancillary testing is only needed when clinical criteria are not satisfied. Differences exist in brain death diagnosis policy in the confirmation of brain death with ancillary testing and the particular test used. Demonstration of the absence of cerebral circulation is a reliable indicator of brain death. Currently, there are no agreed-on universal criteria for ancillary imaging investigation. However, several guidelines and meta-analyses have referred to radionuclide imaging as the most reliable, accurate, and validated ancillary imaging procedure in the confirmation of brain death. Whenever available, lipophilic agents should be preferred using tomographic imaging in all or as needed. False results may occur because of slight temporal delays in flow-function interaction, and such findings may carry prognostic information. Detectable cerebral circulation in the clinical presence of brain death most probably indicates that the process of dying is not yet complete. The results of radionuclide studies may also suggest that the loss of viability in a significant proportion of brain tissue is not compatible with life.

Lipophilic Group-Modified Manganese(II)-Based Contrast Agents for Vascular and Hepatobiliary Magnetic Resonance Imaging.

Effective vascular and hepatic enhancement and better safety are the key drivers for exploring gadolinium-free hepatobiliary contrast agents. Herein, a facile strategy proposes that the high lipophilicity may be favorable to enhancing sequentially vascular and hepatobiliary signal intensity based on the structure-activity relationship that both hepatic uptake and interaction with serum albumins partly depend on lipophilicity. Therefore, 11 newly synthesized derivatives of manganese o-phenylenediamine-N,N,N',N'-tetraacetic acid (MnLs) were evaluated as vascular and hepatobiliary agents. The maximum signal intensities of the heart, liver, and kidneys were strongly correlated with log P, a key indicator of lipophilicity. The most lipophilic agent, MnL6, showed favorable relaxivity when binding with serum albumin, good vascular enhancement, rapid excretion, and reliable hepatobiliary phases comparable to a classic hepatobiliary agent, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) for in vivo liver tumor imaging. Inhibition experiments confirmed the hepatic targeting of MnL6 is mediated by organic anion-transporting polypeptides.

Novel Chitosan-Coated Liposomes Coloaded with Exemestane and Genistein for an Effective Breast Cancer Therapy.

For achieving high effectiveness in the management of breast cancer, coadministration of drugs has attracted a lot of interest as a mode of therapy when compared to a single chemotherapeutic agent that often results in reduced therapeutic end results. Owing to their proven effectiveness, good patient compliance, and lower costs, oral anticancer drugs have received much attention. In the present work, we formulated the chitosan-coated nanoliposomes loaded with two lipophilic agents, namely, exemestane (EXE) and genistein (GEN). The formulation was prepared using the ethanol injection method, which is considered a simple method for getting the nanoliposomes. The formulation was optimized using Box-Behnken design (BBD) and was extensively characterized for particle size, ζ-potential, Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) analysis. The sizes of conventional and coated liposomes were found to be 104.6 ± 3.8 and 120.3 ± 6.4 nm with a low polydispersity index of 0.399 and 0.381, respectively. The ζ-potential of the liposomes was observed to be -16.56 mV, which changed to a positive value of +22.4 mV, clearly indicating the complete coating of the nanoliposomes by the chitosan. The average encapsulation efficiency was found to be between 70 and 80% for all prepared formulations. The compatibility of the drug with excipients and complete dispersion of the drug inside the system were verified by FTIR, XRD, and DSC studies. Furthermore, the in vitro release studies concluded the sustained release pattern following the Korsmeyer-Peppas model as the best-fitting model with Fickian diffusion. Ex vivo studies showed better permeation of the chitosan-coated liposomes, which was further confirmed by confocal studies. The prepared chitosan-coated liposomes showed superior antioxidant activity (94.56%) and enhanced % cytotoxicity (IC50 7.253 ± 0.34 μM) compared to the uncoated liposomes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay displayed better cytotoxicity of the chitosan-coated nanoliposomes compared to the plain drug, showing the better penetration and enhanced bioavailability of drugs inside the cells. The formulation was found to be safe for administration, which was confirmed using the toxicity studies performed on an animal model. The above data suggested that poorly soluble lipophilic drugs could be successfully delivered via chitosan-coated liposomes for their effective delivery in breast cancer.

REVOLUTIONIZING PHARMACEUTICALS: A DEEP DIVE INTO SELF NANO EMULSIFYING DRUG DELIVERY SYSTEMS

From nearly a decade’s time, there has been an increased inclination with respect to nanoemulsions owing to their augmented and ameliorated characteristics in comparison to conventional methods of drug delivery. Self-nano-emulsifying drug delivery systems (SNEDDS) have substantiated their effectiveness in enhancing the solubility and bioavailability of poorly soluble substances. These systems, often isotropic mixtures, consist of oils, surfactants, and cosurfactants/cosolvents. They possess the capability to create nanoemulsions or fine oil-in-water (o/w) emulsions with mild stirring and dilution by the water phase along the gastrointestinal tract. This system has proven its worth in enhancing the absorption of lipophilic agents constrained by dissolution rate. SNEDDS are extremely efficacious in improving the oral bioavailability of lipophilic products and is quite promising for managing drugs unapt for oral delivery. Additionally, it's noteworthy that SNEDDS can be formulated into various solid dosage forms suitable for both oral and parenteral administration. This overview incorporates the advancements of SNEDDS' the mechanism involved in its spontaneous formation, its subcategories, composition, approaches employed for formulation, characterization, merits and limitations, and future potential. The review also lays stress on the progress in solid self-emulsifying delivery mechanisms and dosage forms.

Synthesis of (10-hydroxycamptothecin intercalated layered zinc hydroxide nitrate)@liposome nanocomposites for improving drug-release performance

A hierarchical nanocomposite of 10-hydroxycamptothecin (HCPT), a nonionic and lipophilic anticancer agent, intercalated layered zinc hydroxide nitrate (LZH) encapsulated in liposomes was fabricated. HCPT molecules were incorporated into sodium cholate (Ch) micelles, and the resulting negatively charged HCPT-loaded Ch micelles were then introduced into the LZH galleries to form an HCPT/Ch intercalated LZH (designated HCPT-Ch-LZH) host-guest nanohybrid. The nanohybrid particles were then coated with liposomes (LSs), resulting in the formation of a core-shell nanocomposite denoted as (HCPT-Ch-LZH)@LS. Using XRD, FT-IR, SEM, TEM, DLS, and elemental analyses, the obtained samples were characterized. Particular attention was paid to the effect of liposome-coating on the HCPT-Ch-LZH's water solubility and drug release. The results demonstrate that the nanocomposite has superior water dispersity and enhanced drug sustained-release performance compared to HCPT-Ch-LZH, indicating that the liposome-coating of drug-LZH nanohybrids is an effective strategy for improving their water dispersity and sustained-release performances. This study presents an efficient strategy for constructing LZH-based drug delivery systems for nonionic and lipophilic medicines.

Effects of chronic triclosan exposure on nephrotoxicity and gut microbiota dysbiosis in adult mice

Triclosan (TCS), a broad-spectrum, lipophilic, and antibacterial agent, has been commonly used in cosmetics, medical devices, and household products. The toxicity of TCS has recently become a research hotspot. Emerging evidence has shown that TCS can easily migrate to humans and animals and cause adverse effects on various target organs. However, the effects of TCS exposure on nephrotoxicity and underlying mechanisms remain unknown. The aim of the present study was to explore TCS-induced nephrotoxicity. Therefore, we establish a mouse model based on adult male mice to explore the effects of 10-week TCS exposure (50 mg/kg) on kidney. After mice were sacrificed, their blood, feces, and renal tissues were harvested for further analysis. We found that TCS treatment dramatically caused kidney structural damage, and increased blood urea nitrogen (BUN) and creatinine (Cr) expression levels, which indicated renal dysfunction. In addition, TCS exposure increased the malondialdehyde (MDA) and decreased superoxide dismutase (SOD) and total cholesterol (TCHO) expression levels, which indicated oxidative stress and lipid metabolism changes. The RNA sequencing (RNA-seq) of kidney tissue identified 221 differentially expressed genes (DEGs) enriched in 50 pathways, including drug metabolism-other enzymes, oxidative phosphorylation, glutathione metabolism, and inflammatory mediator regulation of TRP channels signaling pathways. The full-length 16S rRNA gene sequencing results showed that TCS exposure altered the community of gut microbiota, which was closely related to renal function damage. The above findings provide new insights into the mechanism of TCS-induced nephrotoxicity.

A dual action coumarin-camptothecin polymer for light responsive drug release and photodynamic therapy.

A light-responsive polymer allowing the controlled release of camptothecin and the generation of reactive oxygen species (ROS) is reported. The polymer was prepared by controlled copolymerisation of water-soluble N,N-dimethyl acrylamide with a bromocoumarin methacrylate monomer. The lipophilic chemotherapy agent camptothecin was caged onto the coumarin unit via a photo-cleavable carbonate ester enabling light-triggered cargo release. The polymer showed good biocompatibility in the dark, and high cancer cell killing activity mediated both by the photo-release of camptothecin and ROS generation.

Effect of beta glucan coating on controlled release, bioaccessibility, and absorption of β-carotene from loaded liposomes.

Recently, the use of biopolymers as coating material to stabilise phospholipid-based nanocarriers has increased. One such class of biopolymers is the dietary fibre beta-glucan (βG). In this study, we developed and characterized beta-carotene (βC) loaded βG coated nanoliposomes (GNLs) to investigate the effect of βG coating on the stability, controlled release, bioaccessibility, diffusion and subsequent absorption of the lipophilic active agent. The size, charge (Z-potential), and FTIR spectra were measured to determine the physicochemical stability of GNLs. βG coating reduced the bioaccessibility, provided prolonged release and improved the antioxidant activity of the nanoliposomes. Multiple particle tracking (MPT) data suggested that βC-GNLs were less diffusive in porcine intestinal mucus (PIM). Additionally, the microviscosity of the PIM treated with GNLs was observed to be higher (0.04744 ± 0.00865 Pa s) than the PIM incubated with uncoated NLs (0.015 ± 0.0004 Pa s). An Ex vivo experiment was performed on mouse jejunum to measure the absorption of beta-carotene from coated (βC-GNLs) and uncoated nanoliposomes (βC-NLs). Data showed that after 2 hours, 27.7 ± 1.3 ng mL-1 of βC encapsulated in GNLs and 61.54 ± 3 ng mL-1 of the βC encapsulated in uncoated NLs was absorbed by mouse intestinal mucosa. These results highlight that coating with βG stabilise NLs during gastrointestinal digestion and provides more sustained release of βC from nanoliposomes.

Does Haematological Toxicity Increase with the Use of Lipophilic Chemotherapeutic Agents in Obese Breast Cancer Patients?

Does Haematological Toxicity Increase with the Use of Lipophilic Chemotherapeutic Agents in Obese Breast Cancer Patients?

Changes in the lipid composition of <i>Peltigera canina</i> at an elevated temperature

Extremophile organisms can survive under extreme conditions through tolerance mechanisms. Such organisms include lichens, which are symbiotic associations of fungi and algae and/or cyanobacteria. Among other factors, the high stress tolerance of lichens can be attributed to their ability to synthesize a wide range of metabolites, including chemically diverse lipid compounds. Despite their obvious relevance, the biochemical mechanisms of stress tolerance in lichens that are mediated by changes in the lipid profile remain understudied. Peltigerous lichens constitute a separate division of lichens characterized by high growth rates and metabolic activity indices. Taking into account the temperate climate in which these lichens grow, it can be assumed that they may be highly sensitive to temperature fluctuations. These factors led to the choice of Peltigera canina, epigeic lichen, as the subject matter of this study. The present work examined stress-induced changes in the redox status of P. canina, as well as changes in its lipid composition at an elevated temperature (40 °С). The exposure of hydrated lichen thalli to an unfavorable temperature led to an increase in the level of hydrogen peroxide, phenoloxidase activity, and lipid peroxidation, which constitutes an important part of stress response in lichen. The stress-induced changes in the redox status of lichen thalli stimulated an increase in lipophilic antioxidant agents: a dramatic increase in the level of α-tocopherol and an increase in carotenoids, specifically β-carotene. Thus, the accumulation of lipophilic antioxidants constitutes an important part of the lipid-mediated stress response of P. canina to temperature elevation.

A REVIEW ARTICLE ON NOVEL DRUG DELIVERY BIGEL

Gel are semisolid systems made up of a gelling agent and a polar liquid solvent. Gels are used in the food, pharmaceutical, and cosmetics industries. They are classified based on their structural and rheological properties. Scientists are looking for new ways to create gels with better properties. Many bigel formulations have been created and altered recently to satisfy the demands of various applications. Bigels ability to deliver both hydrophilic and lipophilic active agents, their water washability after application to the skin, their easy preparation, good stability, and the enrichment of stratum corneums hydration, which results in a cooling and moisturizing effect, are some of their key characteristics that make them useful for controlled drug delivery. Since bigel formulations are a new class of materials, further research into these systems is necessary before they can be used in real-world applications. When synthesizing bigels by combining organogel and hydrogel, several factors are crucial, such as bigel storage. KEY WORDS: Gels, Bigels, Hydrophilic, Lipophilic, Controlled Drug Delivery

Comparison of Different Ultrafiltration Devices for the Study of Plasma Protein Binding of Carvedilol

Abstract The aim of the present study was to assess the suitability of different Amicon Ultra and Centrifree ultrafiltration devices for the study of the plasma protein binding process in the case of carvedilol, a highly protein-bound and lipophilic beta-blocking agent. Samples at different levels of concentration were prepared in both proteic and non-proteic matrices (human plasma, 5% human serum albumin solution and saline solution) and subjected to the classical ultrafiltration method using the different devices considered. Furthermore, an attempt to apply a previously described modified ultrafiltration method was also made. The analysis and quantification was achieved using a validated LC-MS/MS method. For the Centrifree devices, the determined unbound fractions of carvedilol and the corresponding binding degree were in accordance to literature data, while for the Amicon Ultra devices a great degree of carvedilol adsorbtion to the sample reservoir was observed, the analyte not being detected in the ultrafiltrate samples. Thus, it was further demonstrated that the type of ultrafiltration device used has a significant influence on the outcome of a plasma protein binding study. In the case of carvedilol, the evaluation of the protein binding interaction could be achieved using the Centrifree ultrafiltration devices, but not the Amicon Ultra devices.

Is assessment of skeletal muscle mass useful to predict time-to-awake in awake craniotomies?

Awake craniotomy is the gold standard for the resection of brain lesions near eloquent areas. For the commonly used asleep-awake-asleep technique, the patient must be awake and fully cooperative as soon as possible after discontinuation of anesthetics. A shorter emergence time is essential to decrease the likelihood of adverse events. Previous research found no relationship between body mass index (BMI) and time-to-awake for intravenous anesthesia with propofol, which is a lipophilic agent. As BMI cannot differentiate between fat and muscle tissue, we hypothesize that skeletal muscle mass, particularly when combined with BMI, may better predict time-to-awake from propofol sedation. We aimed to evaluate the relationship between skeletal muscle mass and the time-to-awake in patients undergoing awake craniotomy, as well as the interaction between skeletal muscle mass and BMI. In 260 patients undergoing an awake craniotomy, we used preoperative magnetic resonance imaging to assess temporalis muscle and cross-sectional skeletal muscle area of the masseter muscles and at level of the third cervical vertebra. Time-to-awake was dichotomized as ≤20 and >20 minutes. No association between various measures of skeletal muscle mass and time-to-awake was observed, and no interaction between skeletal muscle mass and BMI was found (all P > .05). Likewise, patients with a high BMI and low skeletal muscle mass (indicating an increased proportion of fat tissue) did not have a prolonged time-to-awake. Skeletal muscle mass did not predict time-to-awake in patients undergoing awake craniotomy, neither in isolation nor in combination with a high BMI.