scholarly journals Acute and Chronic Dosing of a High-Affinity Rat/Mouse Chimeric Transferrin Receptor Antibody in Mice

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 852 ◽  
Author(s):  
Demi M. Castellanos ◽  
Jiahong Sun ◽  
Joshua Yang ◽  
Weijun Ou ◽  
Alexander C. Zambon ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Plasma Concentrations ◽  
Fusion Partner ◽  
Constant Region ◽  
Non Invasive ◽  
High Affinity ◽  
Brain Drug Delivery ◽  
Plasma Pharmacokinetics ◽  
And Control ◽  
Receptor Antibodies

Non-invasive brain delivery of neurotherapeutics is challenging due to the blood-brain barrier. The revived interest in transferrin receptor antibodies (TfRMAbs) as brain drug-delivery vectors has revealed the effect of dosing regimen, valency, and affinity on brain uptake, TfR expression, and Fc-effector function side effects. These studies have primarily used monovalent TfRMAbs with a human constant region following acute intravenous dosing in mice. The effects of a high-affinity bivalent TfRMAb with a murine constant region, without a fusion partner, following extravascular dosing in mice are, however, not well characterized. Here we elucidate the plasma pharmacokinetics and safety of a high-affinity bivalent TfRMAb with a murine constant region following acute and chronic subcutaneous dosing in adult C57BL/6J male mice. Mice received a single (acute dosing) 3 mg/kg dose, or were treated for four weeks (chronic dosing). TfRMAb and control IgG1 significantly altered reticulocyte counts following acute and chronic dosing, while other hematologic parameters showed minimal change. Chronic TfRMAb dosing did not alter plasma- and brain-iron measurements, nor brain TfR levels, however, it significantly increased splenic-TfR and -iron. Plasma concentrations of TfRMAb were significantly lower in mice chronically treated with IgG1 or TfRMAb. Overall, no injection related reactions were observed in mice.

scholarly journals Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
David P. Nicolau
Keyword(s):  
Iron Overload ◽  
Plasma Concentrations ◽  
Infection Model ◽  
Iron Dextran ◽  
Iron Availability ◽  
Murine Models ◽  
Plasma Pharmacokinetics ◽  
And Control

ABSTRACT Siderophore-antibiotic conjugates have increased in vitro activity in low-iron environments where bacteria express siderophores and associated transporters. The host immune hypoferremic response reduces iron availability to bacteria; however, patients with iron overload or deficiency may have altered ability to restrict iron, which may affect the efficacy of siderophore-antibiotic conjugates. In vivo models of infection with iron overload and deficiency are needed to perform this assessment. The standard neutropenic murine thigh infection model was supplemented with iron-altering treatments: iron dextran at 100 mg/kg of body weight daily for 14 days to load iron or deferoxamine at 100 mg/kg daily plus a low-iron diet for up to 30 days to deplete iron. Human-simulated regimens of cefiderocol and meropenem were administered in both models to assess any impact of iron alteration on plasma pharmacokinetics. Median iron in overloaded mice was significantly higher than that of controls in plasma (1,657 versus 336 μg/dl; P < 0.001), liver (2,133 versus 11 μg/g; P < 0.001), and spleen (473 versus 144 μg/g; P < 0.001). At 30 days, depleted mice had significantly lower iron than controls in liver (2.4 versus 6.5 μg/g; P < 0.001) and spleen (72 versus 133 μg/g; P = 0.029) but not plasma (351 versus 324 μg/dl; P = 0.95). Cefiderocol and meropenem plasma concentrations were similar in iron overloaded and control mice but varied in iron-depleted mice. The iron-overloaded murine thigh infection model was established, and human-simulated regimens of cefiderocol and meropenem were validated therein. While deferoxamine successfully reduced liver and splenic iron, this depleting treatment altered the pharmacokinetics of both antimicrobials.

scholarly journals Evaluating the Possibility of Translating Technological Advances in Non-Invasive Continuous Lactate Monitoring into Critical Care

Sensors ◽  
2021 ◽  
Vol 21 (3) ◽  
pp. 879
Author(s):  
Robert D. Crapnell ◽  
Ascanio Tridente ◽  
Craig E. Banks ◽  
Nina C. Dempsey-Hibbert
Keyword(s):  
Critical Care ◽  
Continuous Monitoring ◽  
Performance Monitoring ◽  
Plasma Concentrations ◽  
Lactate Production ◽  
Anaerobic Exercise ◽  
Response To Treatment ◽  
Diverse Range ◽  
Non Invasive ◽  
Technological Advances

Lactate is widely measured in critically ill patients as a robust indicator of patient deterioration and response to treatment. Plasma concentrations represent a balance between lactate production and clearance. Analysis has typically been performed with the aim of detecting tissue hypoxia. However, there is a diverse range of processes unrelated to increased anaerobic metabolism that result in the accumulation of lactate, complicating clinical interpretation. Further, lactate levels can change rapidly over short spaces of time, and even subtle changes can reflect a profound change in the patient’s condition. Hence, there is a significant need for frequent lactate monitoring in critical care. Lactate monitoring is commonplace in sports performance monitoring, given the elevation of lactate during anaerobic exercise. The desire to continuously monitor lactate in athletes has led to the development of various technological approaches for non-invasive, continuous lactate measurements. This review aims firstly to reflect on the potential benefits of non-invasive continuous monitoring technology within the critical care setting. Secondly, we review the current devices used to measure lactate non-invasively outside of this setting and consider the challenges that must be overcome to allow for the translation of this technology into intensive care medicine. This review will be of interest to those developing continuous monitoring sensors, opening up a new field of research.

scholarly journals Variability of serum IgG sialylation and galactosylation degree in women with advanced endometriosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katarzyna Sołkiewicz ◽  
Hubert Krotkiewski ◽  
Marcin Jędryka ◽  
Ewa M. Kratz
Keyword(s):  
Cluster Analysis ◽  
Sialic Acid ◽  
Control Group ◽  
Clinical Tool ◽  
Non Invasive ◽  
Healthy Women ◽  
Serum Igg ◽  
And Cluster Analysis ◽  
Invasive Diagnostics ◽  
And Control

AbstractEndometriosis is an inflammatory disease which diagnostics is difficult and often invasive, therefore non-invasive diagnostics methods and parameters are needed for endometriosis detection. The aim of our study was to analyse the glycosylation of native serum IgG and IgG isolated from sera of women classified as: with endometriosis, without endometriosis but with some benign ginecological disease, and control group of healthy women, in context of its utility for differentiation of advanced endometriosis from the group of healthy women. IgG sialylation and galactosylation/agalactosylation degree was determined using specific lectins: MAA and SNA detecting sialic acid α2,3- and α2,6-linked, respectively, RCA-I and GSL-II specific to terminal Gal and terminal GlcNAc, respectively. The results of ROC and cluster analysis showed that the serum IgG MAA-reactivity, sialylation and agalactosylation factor may be used as supplementary parameters for endometriosis diagnostics and could be taken into account as a useful clinical tool to elucidate women with high risk of endometriosis development. Additionally, we have shown that the analysis of native serum IgG glycosylation, without the prior time-consuming and expensive isolation of the protein, is sufficient to differentiation endometriosis from a group of healthy women.

scholarly journals Impact on Antibiotic Resistance, Therapeutic Success, and Control of Side Effects in Therapeutic Drug Monitoring (TDM) of Daptomycin: A Scoping Review

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 263
Author(s):  
Carolina Osorio ◽  
Laura Garzón ◽  
Diego Jaimes ◽  
Edwin Silva ◽  
Rosa-Helena Bustos
Keyword(s):  
Side Effects ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Bacterial Resistance ◽  
Plasma Concentrations ◽  
Resistant Bacteria ◽  
Therapeutic Drug ◽  
Therapeutic Success ◽  
Favorable Clinical Outcome ◽  
And Control

Antimicrobial resistance (AR) is a problem that threatens the search for adequate safe and effective antibiotic therapy against multi-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE) and Clostridium difficile, among others. Daptomycin is the treatment of choice for some infections caused by Gram-positive bacteria, indicated most of the time in patients with special clinical conditions where its high pharmacokinetic variability (PK) does not allow adequate plasma concentrations to be reached. The objective of this review is to describe the data available about the type of therapeutic drug monitoring (TDM) method used and described so far in hospitalized patients with daptomycin and to describe its impact on therapeutic success, suppression of bacterial resistance, and control of side effects. The need to create worldwide strategies for the appropriate use of antibiotics is clear, and one of these is the performance of therapeutic drug monitoring (TDM). TDM helps to achieve a dose adjustment and obtain a favorable clinical outcome for patients by measuring plasma concentrations of an administered drug, making a rational interpretation guided by a predefined concentration range, and, thus, adjusting dosages individually.

scholarly journals Transcranial Magnetic Stimulation as a Tool to Investigate Motor Cortex Excitability in Sport

2021 ◽  
Vol 11 (4) ◽  
pp. 432
Author(s):  
Fiorenzo Moscatelli ◽  
Antonietta Messina ◽  
Anna Valenzano ◽  
Vincenzo Monda ◽  
Monica Salerno ◽  
...  
Keyword(s):  
Transcranial Magnetic Stimulation ◽  
Motor Cortex ◽  
Magnetic Stimulation ◽  
Motor Coordination ◽  
Cortical Excitability ◽  
Non Invasive ◽  
Motor Cortex Excitability ◽  
Invasive Method ◽  
And Control ◽  
The Impact

Transcranial magnetic stimulation, since its introduction in 1985, has brought important innovations to the study of cortical excitability as it is a non-invasive method and, therefore, can be used both in healthy and sick subjects. Since the introduction of this cortical stimulation technique, it has been possible to deepen the neurophysiological aspects of motor activation and control. In this narrative review, we want to provide a brief overview regarding TMS as a tool to investigate changes in cortex excitability in athletes and highlight how this tool can be used to investigate the acute and chronic responses of the motor cortex in sport science. The parameters that could be used for the evaluation of cortical excitability and the relative relationship with motor coordination and muscle fatigue, will be also analyzed. Repetitive physical training is generally considered as a principal strategy for acquiring a motor skill, and this process can elicit cortical motor representational changes referred to as use-dependent plasticity. In training settings, physical practice combined with the observation of target movements can enhance cortical excitability and facilitate the process of learning. The data to date suggest that TMS is a valid technique to investigate the changes in motor cortex excitability in trained and untrained subjects. Recently, interest in the possible ergogenic effect of non-invasive brain stimulation in sport is growing and therefore in the future it could be useful to conduct new experiments to evaluate the impact on learning and motor performance of these techniques.

scholarly journals Enhanced Arsenic Accumulation in Engineered Bacterial Cells Expressing ArsR

2004 ◽  
Vol 70 (8) ◽  
pp. 4582-4587 ◽  
Author(s):  
Jan Kostal ◽  
Rosanna Yang ◽  
Cindy H. Wu ◽  
Ashok Mulchandani ◽  
Wilfred Chen
Keyword(s):  
Cell Growth ◽  
Environmental Protection Agency ◽  
Arsenic Removal ◽  
Fusion Partner ◽  
Resting Cells ◽  
Bacterial Cells ◽  
High Affinity ◽  
Affinity Ligand ◽  
Arsenic Accumulation ◽  
Severe Reduction

ABSTRACT The metalloregulatory protein ArsR, which offers high affinity and selectivity toward arsenite, was overexpressed in Escherichia coli in an attempt to increase the bioaccumulation of arsenic. Overproduction of ArsR resulted in elevated levels of arsenite bioaccumulation but also a severe reduction in cell growth. Incorporation of an elastin-like polypeptide as the fusion partner to ArsR (ELP153AR) improved cell growth by twofold without compromising the ability to accumulate arsenite. Resting cells overexpressing ELP153AR accumulated 5- and 60-fold-higher levels of arsenate and arsenite than control cells without ArsR overexpression. Conversely, no significant improvement in Cd2+ or Zn2+ accumulation was observed, validating the specificity of ArsR. The high affinity of ArsR allowed 100% removal of 50 ppb of arsenite from contaminated water with these engineered cells, providing a technology useful to comply with the newly approved U.S. Environmental Protection Agency limit of 10 ppb. These results open up the possibility of using cells overexpressing ArsR as an inexpensive, high-affinity ligand for arsenic removal from contaminated drinking and ground water.

scholarly journals Effects of Dietary Supplementation with Different Polyunsaturated Fatty Acids on Expression of Genes Related to Somatotropic Axis Function in the Liver, Selected Blood Indicators, Milk Yield and Milk Fatty Acids Profile in Dairy Cows

2016 ◽  
Vol 16 (4) ◽  
pp. 1045-1058 ◽  
Author(s):  
Essa Dirandeh ◽  
Armin Towhidi ◽  
Zarbakht Ansari ◽  
Saeeid Zeinoaldini ◽  
Mehdi Ganjkhanlou
Keyword(s):  
Fatty Acids ◽  
Plasma Concentrations ◽  
Dietary Supplementation ◽  
Omega 3 ◽  
Milk Fatty Acids ◽  
Somatotropic Axis ◽  
Fatty Acids Profile ◽  
Expression Of Genes ◽  
Omega 6 ◽  
And Control

Abstract The objective of this study was to investigate whether dietary supplementation with different polyunsaturated fatty acids (PUFA s) affects expression of genes related to somatotropic axis and the plasma concentrations of insulin, glucose, non-esterified fatty acids (NEFA), beta hydroxyl butyrate acids (BHBA) and insulin-like growth factor 1 (IGF1) and milk fatty acids profile. Right after calving, Holstein cows (n=45) were randomly assigned to one of three diets supplemented with roasted whole soybean as a source of omega-6 PUFA (omega-6, n=15), linseed as a source of omega-3 PUFA (omega-3, n=15) or palm oil (control, n=15). Each cow was in the study over a period of 70 days. Blood samples were collected every two weeks from day 1 to 70 of lactation and plasma concentrations of insulin, glucose, NEFA, BHBA and IGF1 were determined. Liver samples were taken from a subset of 18 cows (6 per diet) at day 70 postpartum and hepatic mRNA level of total growth hormone-receptor 1A (GHR1A), insulin receptor (INSR), IGF1 and insulinlike growth factor binding protein (IGFBP2) was assessed. Experimental diets did not affect milk yield. Plasma glucose and insulin concentrations were greater for omega-3 treatment compared to omega-6 and control treatments. Cows fed diets enriched in omega-3 exhibited greater INSR and GHR1A mRNA expression, and a tendency for greater IGF1 mRNA expression in the liver compared to omega-6 and control cows. Plasma IGF1 concentration was significantly higher in omega-3 treatment compared with omega-6 and control treatments. Results of this study suggest that feeding omega-3 PUFA s during early postpartum couples with the somatotropic axis, leading to an increase in plasma IGF1 concentration in dairy cows.

scholarly journals Buprenorphine Metabolites, Buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, Are Biologically Active

2011 ◽  
Vol 115 (6) ◽  
pp. 1251-1260 ◽  
Author(s):  
Sarah M. Brown ◽  
Michael Holtzman ◽  
Thomas Kim ◽  
Evan D. Kharasch
Keyword(s):  
Radioligand Binding ◽  
Competitive Inhibition ◽  
Antinociceptive Effect ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Biologically Active ◽  
Whole Body ◽  
Tail Flick ◽  
High Affinity

Background The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine. Methods Competitive inhibition of radioligand binding to human μ, κ, and δ opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing. Results Buprenorphine-3-glucuronide had high affinity for human μ (Ki [inhibition constant] = 4.9 ± 2.7 pM), δ (Ki = 270 ± 0.4 nM), and nociceptin (Ki = 36 ± 0.3 μM) but not κ receptors. Norbuprenorphine-3-glucuronide had affinity for human κ (Ki = 300 ± 0.5 nM) and nociceptin (Ki = 18 ± 0.2 μM) but not μ or δ receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation. Conclusions Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.

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