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Background: Intravenous lipid emulsion is recognised as a therapy for rescue in cases of local anaesthetic toxicity, but its use in reversing overdose or toxicity related to other drugs remains the subject of debate. This in vitro study sought to expand our understanding of the importance of partitioning in determining the impact of intravenous lipid emulsion on aqueous free drug concentrations. Methods: Twenty-seven drugs and associated metabolites were screened for the ability of intravenous lipid emulsion to reduce the amount of free drug in the aqueous phase, using specialised cassettes designed for this purpose. The relative amount of drug equilibrating across the membrane from plasma to phosphate-buffered saline was measured, using liquid chromatography–mass spectrometry, at a 6 h timepoint in plasma samples treated with intravenous lipid emulsion and paired, untreated controls. Results: The data obtained were plotted against measures of partition (LogP and cLogD7.4) and with log-transformed non-protein bound drug. There were significant inverse correlations between the capacity for intravenous lipid emulsion to reduce drug detected in the phosphate-buffered saline compartment and LogP and cLogD7.4, and a direct association with log [non-protein-bound drug]. However, a number of drugs showed substantial variance between different plasma samples. Conclusions: Modulation of free drug in the aqueous compartment is broadly predictable by the partition coefficient, although ramipril was identified to be an outlier in this regard. Further mechanistic and clinical exploration is merited to establish a standardised protocol for lipid emulsion therapy.

Background: Intravenous lipid emulsion is recognised as a therapy for rescue in cases of local anaesthetic toxicity, but its use in reversing overdose or toxicity related to other drugs remains the subject of debate. This in vitro study sought to expand our understanding of the importance of partitioning in determining the impact of intravenous lipid emulsion on aqueous free drug concentrations., Methods: Twenty-seven drugs and associated metabolites were screened for the ability of intravenous lipid emulsion to reduce the amount of free drug in the aqueous phase, using specialised cassettes designed for this purpose. The relative amount of drug equilibrating across the membrane from plasma to phosphate-buffered saline was measured, using liquid chromatography-mass spectrometry, at a 6 h timepoint in plasma samples treated with intravenous lipid emulsion and paired, untreated controls., Results: The data obtained were plotted against measures of partition (LogP and cLogD 7.4 ) and with log-transformed non-protein bound drug. There were significant inverse correlations between the capacity for intravenous lipid emulsion to reduce drug detected in the phosphate-buffered saline compartment and LogP and cLogD 7.4 , and a direct association with log [non-protein-bound drug]. However, a number of drugs showed substantial variance between different plasma samples., Conclusions: Modulation of free drug in the aqueous compartment is broadly predictable by the partition coefficient, although ramipril was identified to be an outlier in this regard. Further mechanistic and clinical exploration is merited to establish a standardised protocol for lipid emulsion therapy., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Authors.)

The aim of this study was to evaluate the transfer of the most widely used antibiotics in dairy goats from milk to cheese as well as their effect on the cheese-making process and cheese characteristics during ripening. Antibiotic-free milk was spiked individually with 7 veterinary drugs (amoxicillin, benzylpenicillin, cloxacillin, erythromycin, ciprofloxacin, enrofloxacin, and oxytetracycline) at an equivalent concentration of the European Union maximum residue limit. Spiked goat milk was used to make mature Tronchón cheeses, which were analyzed at 0, 30, and 60 d of maturation to determine pH, chemical composition, proteolytic and lipolytic activities, and color and textural properties. A sensory evaluation of 60-d ripened cheeses was carried out. Cheeses from raw antibiotic-free goat milk were made simultaneously to be used as reference. The cheese-making process was unaffected by the presence of most antibiotics evaluated. Only erythromycin and oxytetracycline significantly increased the time required for cheese production (122 ± 29 and 108 ± 25 min, respectively). However, variable amounts of antibiotics, ranging from 7.4 to 68%, were transferred from milk to cheese, with oxytetracycline and quinolones showing the highest retention rates. In general, antibiotic residues present in the cheeses at the beginning of maturation decrease significantly along time. Thus, β-lactams and erythromycin residues were not detectable after 30 d of ripening. However, relatively high concentrations of enrofloxacin (148 ± 12 μg/kg) and ciprofloxacin (253 ± 24 μg/kg) residues were found in the cheeses after 60 d of maturation. The quality characteristics of the Tronchón cheeses were only slightly affected by such substances, with few significant differences in the free fatty acid concentration and color and textural properties of the cheeses. Results herein indicate that the use of goat milk containing antibiotics, such as quinolones, at the European Union maximum residue limit for cheese production could adversely affect the safety of the final products because relatively high concentrations of these substances could be retained in soft and semi-mature cheeses, making it necessary to assess the risk for consumer health. Studies on the partition of the antibiotic substances during cheese-making, using specific technologies, would be convenient to guarantee the safety of cheese and related products. [ABSTRACT FROM AUTHOR]

Electrospun nanofibers have the potential to achieve high drug loading and the ability to sustain drug release. Mechanical properties of the drug-incorporated fibers suggest the importance of drug–polymer interactions. In this study, we investigated the mechanical properties of electrospun polycaprolactone (PCL) and poly (D,L-lactic- co -glycolic) acid (PLGA) fibers at various blend ratios in the presence and absence of a small molecule hydrophilic drug, tenofovir (TFV). Young׳s modulus of the blend fibers showed dependence on PLGA content and the addition of the drug. At a PCL/PLGA (20/80) composition, Young׳s modulus and tensile strength were independent of drug loading up to 40 wt% due to offsetting effects from drug–polymer interactions. In vitro drug release studies suggested that release of TFV significantly decreased fiber mechanical properties. In addition, mechanically stretched fibers displayed a faster release rate as compared to the non-stretched fibers. Finally, drug partition in the blend fibers was estimated using a mechanical model and then experimentally confirmed with a composite of individually stacked fiber meshes. This work provides scientific understanding on the dependence of drug release and drug loading on the mechanical properties of drug-eluting fibers. [ABSTRACT FROM AUTHOR]

AbstractCentral nervous system (CNS) function is dependent on the stringent regulation of metabolites, drugs, cells, and pathogens exposed to the CNS space. Cellular blood-brain barrier (BBB) structures are highly specific checkpoints governing entry and exit of all small molecules to and from the brain interstitial space, but the precise mechanisms that regulate the BBB are not well understood. In addition, the BBB has long been a challenging obstacle to the pharmacologic treatment of CNS diseases; thus model systems that can parse the functions of the BBB are highly desirable. In this study, we sought to define the transcriptome of the adult Drosophila melanogaster BBB by isolating the BBB surface glia with FACS and profiling their gene expression with microarrays. By comparing the transcriptome of these surface glia to that of all brain glia, brain neurons, and whole brains, we present a catalog of transcripts that are selectively enriched at the Drosophila BBB. We found that the fly surface glia show high expression of many ABC and SLC transporters, cell adhesion molecules, metabolic enzymes, signaling molecules, and components of xenobiotic metabolism pathways. Using gene sequence-based alignments, we compare the Drosophila and Murine BBB transcriptomes and discover many shared chemoprotective and small molecule control pathways, thus affirming the relevance of invertebrate models for studying evolutionary conserved BBB properties. The Drosophila BBB transcriptome is valuable to vertebrate and insect biologists alike as a resource for studying proteins underlying diffusion barrier development and maintenance, glial biology, and regulation of drug transport at tissue barriers.

Abstract: Hemolysis is a common phenomenon in clinical studies. Despite the growing interest in hemolysis matrix effect, how hemolysis impacts the representability of hemolyzed plasma samples was rarely evaluated. The purpose of this research is to perform such an evaluation by theoretical consideration and experiment. A formula for estimating the impact is proposed, which includes the degree of hemolysis and the drug''s red blood cell (RBC): plasma concentration ratio. The impact of hemolysis on the representability of hemolyzed plasma samples is compound-dependant. Given the same degree of hemolysis, the stronger a drug binds to RBCs, the more significant the impact of hemolysis. For a drug with high affinity to RBCs, the results of hemolyzed plasma samples may not be useful even though they are accurate. There is an overall agreement between theoretical predication and experimental results. Among the ten different drug compounds tested, only methazolamide, which binds strongly to RBCs, showed significant change in plasma concentration due to hemolysis. [Copyright &y& Elsevier]

The presence of fat in the gastric environment can affect the pharmacokinetic behaviour of drugs with mechanisms which have not been yet fully understood. The objective of the current study was to assess the drug partition to the lipid part of the fed gastric content under different emulsification conditions, using in vitro discriminating setups. The model drugs used in the study were selected on the basis of different physicochemical properties (lipophilicity, ionization, molecular weight and aqueous solubility) and different food effect observed in in vivo human studies. Fed State Simulated Gastric Fluid prepared with skimmed milk (FeSSGF sk) and anhydrous milk fat were used as surrogates for the aqueous and fat portions of the fed gastric environment respectively. An optimized biphasic model was developed so as to predict the differences in partition rate constants to fat, for model drugs of a wide range of the properties mentioned above. The experimental data and the use of statistical analysis revealed that molecular weight, molecular weight and log D pH 5 interaction and negative food effect act as negative factors to the rate constants of fat partition, while absence of food effect and logD pH 5 interaction with aqueous solubility affect the rate constants of partition to fat favourably. Image, graphical abstract [ABSTRACT FROM AUTHOR]