scholarly journals Therapeutic Doses of Eltrombopag do not Inhibit Hepatic BCRP in Healthy Volunteers: Intravenous Ceftriaxone as a Model

2018 ◽  
Vol 21 ◽  
pp. 236-246 ◽  
Author(s):  
Daniel Valente Neves ◽  
Carolina Pinto Vieira ◽  
Adriana Rocha ◽  
Vera Lucia Lanchote
Keyword(s):  
Human Subjects ◽  
Total Concentration ◽  
Cancer Resistance ◽  
Clinical Pharmacokinetics ◽  
Pharmacokinetic Drug Interaction ◽  
Coefficients Of Variation ◽  
Assay Precision ◽  
Therapeutic Doses ◽  
Oral Doses

PURPOSE: Ceftriaxone elimination occurs through breast cancer resistance transporter (BCRP) and multidrug resistance-associated protein 2 (MRP-2) which are expressed on the canalicular membrane of hepatocytes. Eltrombopag, a thrombopoetin receptor agonist used in the treatment of immune thrombocytopenic purpura, is reported in in vitro studies as an inhibitor of intestinal BCRP but not an inhibitor of hepatic BCRP. Thus, the present study evaluates the effect of therapeutic doses of eltrombopag on the clinical pharmacokinetics of intravenous ceftriaxone. METHODS: Healthy adult (n=12) were treated with oral doses of eltrombopag (0, 25 or 50 mg) 28 and 4 h prior to intravenous ceftriaxone administration (1g). Serial blood samples were collected up to 48 h after ceftriaxone administration and plasma samples were analysed by LC-MS/MS using 50 μL aliquots (total concentration) and 100 μL (unbound concentration). RESULTS: A method to analyze total and unbound ceftriaxone in plasma using LC-MS/MS was developed and validated with linearity from 1 to 200 μg/mL. Both methods are sensitive, precise and accurate with coefficients of variation less than 15% in the study of inter- and intra-assay precision and accuracy. Ceftriaxone pharmacokinetics in healthy adults were described using a bicompartmental model, with a mean clearance of 0.96 L/h (CI95% 0.71-1.20) and AUC0-∞of 1106 mg.h/mL (CI95% 811-1400) for volunteers that received only ceftriaxone; clearance of 0.95 L/h (CI95% 0.77-1.13) and AUC0-∞ of 1083 mg.h/mL (CI95% 876-1290) for volunteers that received ceftriaxone plus 25 mg of eltrombopag and clearance of 0.96 L/h (CI95% 0.74-1.19) and AUC0-∞ of 1072 mg.h/mL (CI95% 872-1273) for volunteers that received ceftriaxone plus 50 mg of eltrombopag. CONCLUSIONS: The results do not support the existence of a clinical pharmacokinetic drug interaction involving hepatic BCRP in human subjects receiving intravenous ceftriaxone and oral eltrombopag. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Effect of L-Asparaginase on Mouse Bone Marrow, Assayed by In Vitro Culture

Blood ◽  
1970 ◽  
Vol 36 (3) ◽  
pp. 385-389 ◽  
Author(s):  
CLARENCE H. BROWN ◽  
GEORGE P. CANELLOS ◽  
PAUL P. CARBONE
Keyword(s):  
Bone Marrow ◽  
In Vitro Culture ◽  
Rat Liver ◽  
Culture System ◽  
Human Subjects ◽  
Culture Technique ◽  
Mouse Bone Marrow ◽  
Therapeutic Doses ◽  
Marrow Cellularity

Abstract L-asparaginase administered in therapeutic doses to mice was found to reduce the total number of nucleated marrow cells and colony-forming cells when assayed 4 hours after administration by a methylcellulose bone marrow culture technique. Both marrow cellularity and the fraction of surviving IVCFC/femur were normal by 24 hours after injection, except with very large doses, at a time when there were sufficient quantities of L-asparaginase free or cellularly bound within the marrow to be toxic to the culture system. The enzyme could be removed from the marrow specimens with repeated washings. It is postulated that the bone marrow of the mouse is similar to the regenerating rat liver in that both have the ability to compensate for Lasparagine depletion, even in the presence of active L-asparaginase. The rarity of clinically observed myelosuppression in human subjects could be the result of a similar mechanism.

scholarly journals Fluorometric quantification of protoporphyrin IX in biological skin samples from in vitro penetration/permeation studies

2010 ◽  
Vol 46 (4) ◽  
pp. 753-760 ◽  
Author(s):  
Fábia Cristina Rossetti ◽  
Lívia Vieira Depieri ◽  
Antônio Cláudio Tedesco ◽  
Maria Vitória Lopes Badra Bentley
Keyword(s):  
Biological Membrane ◽  
Protoporphyrin Ix ◽  
Extraction Solvent ◽  
Coefficients Of Variation ◽  
Permeation Studies ◽  
Assay Precision ◽  
Phase Solution ◽  
Receptor Phase ◽  
Skin Samples

A fluorometric analytical method was developed for quantification of protoporphyrin IX (PpIX) in skin samples and receptor phase solution after in vitro cutaneous penetration/permeation studies. Analytical conditions used were: excitation and emission wavelengths: 400 nm and 632 nm; bandwidth: 0.5 nm; excitation and emission slits: 10/10. PpIX was recovered from two different layers of skin, the stratum corneum (SC) and the epidermis plus dermis ([E+D]), by vortex homogenization, probe and bath sonication, using DMSO as an extraction solvent. The detection and quantification limits were 0.002 and 0.005 μg/mL, respectively. The assay was linear from 0.005 - 0.5 μg/mL. The within-day and between-day assay precision and accuracy in DMSO and receptor phase solution were each studied at the two concentration levels 0.04 and 0.2 μg/mL, and 0.01 and 0.08 μg/mL, respectively. The coefficients of variation and deviation from the theoretical values were lower than 5%. The skin recovery of PpIX from SC and [E+D] layers using two different concentrations (0.5 and 1.0 μg/mL) were all above 90.0%. The method described has potential application to in vitro penetration/permeation studies of PpIX using porcine skin as a biological membrane model.

Total weak acid concentration and effective dissociation constant of nonvolatile buffers in human plasma

2001 ◽  
Vol 91 (3) ◽  
pp. 1364-1371 ◽  
Author(s):  
Peter D. Constable
Keyword(s):  
Dissociation Constant ◽  
Human Plasma ◽  
Total Concentration ◽  
Weak Acid ◽  
Strong Ion Difference ◽  
Acid Base ◽  
Horse Plasma ◽  
Using Data ◽  
Species Specific

The strong ion approach provides a quantitative physicochemical method for describing the mechanism for an acid-base disturbance. The approach requires species-specific values for the total concentration of plasma nonvolatile buffers (Atot) and the effective dissociation constant for plasma nonvolatile buffers ( K a), but these values have not been determined for human plasma. Accordingly, the purpose of this study was to calculate accurate Atot and K a values using data obtained from in vitro strong ion titration and CO2tonometry. The calculated values for Atot (24.1 mmol/l) and K a (1.05 × 10−7) were significantly ( P < 0.05) different from the experimentally determined values for horse plasma and differed from the empirically assumed values for human plasma (Atot = 19.0 meq/l and K a = 3.0 × 10−7). The derivatives of pH with respect to the three independent variables [strong ion difference (SID), Pco 2, and Atot] of the strong ion approach were calculated as follows: [Formula: see text] [Formula: see text], [Formula: see text]where S is solubility of CO2 in plasma. The derivatives provide a useful method for calculating the effect of independent changes in SID+, Pco 2, and Atot on plasma pH. The calculated values for Atot and K a should facilitate application of the strong ion approach to acid-base disturbances in humans.

scholarly journals Sex-dependent dysregulation of human neutrophil responses by bisphenol A

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Wioletta Ratajczak-Wrona ◽  
Marzena Garley ◽  
Malgorzata Rusak ◽  
Karolina Nowak ◽  
Jan Czerniecki ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Bisphenol A ◽  
Total Concentration ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Human Neutrophils ◽  
Boyden Chamber ◽  
No Production ◽  
Pathogen Elimination ◽  
Latex Beads

Abstract Background In the present study, we aimed to investigate selected functions of human neutrophils exposed to bisphenol A (BPA) under in vitro conditions. As BPA is classified among xenoestrogens, we compared its action and effects with those of 17β-estradiol (E2). Methods Chemotaxis of neutrophils was examined using the Boyden chamber. Their phagocytosis and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase activity were assessed via Park’s method with latex beads and Park’s test with nitroblue tetrazolium. To assess the total concentration of nitric oxide (NO), the Griess reaction was utilized. Flow cytometry was used to assess the expression of cluster of differentiation (CD) antigens. The formation of neutrophil extracellular traps (NETs) was analyzed using a microscope (IN Cell Analyzer 2200 system). Expression of the investigated proteins was determined using Western blot. Results The analysis of results obtained for both sexes demonstrated that after exposure to BPA, the chemotactic capacity of neutrophils was reduced. In the presence of BPA, the phagocytic activity was found to be elevated in the cells obtained from women and reduced in the cells from men. Following exposure to BPA, the percentage of neutrophils with CD14 and CD284 (TLR4) expression, as well as the percentage of cells forming NETs, was increased in the cells from both sexes. The stimulatory role of BPA and E2 in the activation of NADPH oxidase was observed only in female cells. On the other hand, no influence of E2 on the expression of CD14 and CD284, chemotaxis, phagocytosis, and the amount of NET-positive neutrophils was found for both sexes. The study further showed that BPA intensified NO production and iNOS expression in the cells of both sexes. In addition, intensified expression of all tested PI3K-Akt pathway proteins was observed in male neutrophils. Conclusions The study demonstrated the influence of BPA on neutrophil functions associated with locomotion and pathogen elimination, which in turn may disturb the immune response of these cells in both women and men. Analysis of the obtained data showed that the effect of this xenoestrogen on the human neutrophils was more pronounced than E2.

scholarly journals IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 79
Author(s):  
Stephan Wueest ◽  
Eleonora Seelig ◽  
Katharina Timper ◽  
Mark P. Lyngbaek ◽  
Kristian Karstoft ◽  
...  
Keyword(s):  
Exercise Training ◽  
Human Subjects ◽  
Receptor Blockade ◽  
Model Assessment ◽  
Serum Samples ◽  
Double Blind ◽  
Double Blind Clinical Trial ◽  
Homeostatic Model Assessment ◽  
Obese Human

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (−2.7 ± 8.2% in the placebo vs. −20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity.

Para‐aminosalicylic acid significantly reduced tenofovir exposure in human subjects; mismatched findings from in vitro to in vivo translational research

2021 ◽  
Author(s):  
Md Masud Parvez ◽  
Said Kalkisim ◽  
Phuong Thi Thu Nguyen ◽  
Jin Ah. Jung ◽  
Jeong‐Kon Park ◽  
...  
Keyword(s):  
Translational Research ◽  
Human Subjects ◽  
Aminosalicylic Acid

Analogy Models for Prediction of Human Toxicity

1990 ◽  
Vol 18 (1_part_1) ◽  
pp. 103-116
Author(s):  
Sven Hellberg ◽  
Lennart Eriksson ◽  
Jörgen Jonsson ◽  
Fredrik Lindgren ◽  
Michael Sjöström ◽  
...  
Keyword(s):  
Human Subjects ◽  
Toxicity Testing ◽  
In Vitro Cytotoxicity ◽  
Alternative Methods ◽  
Laboratory Animals ◽  
In Vitro Tests ◽  
Human Toxicity ◽  
Efficient Data ◽  
Basal Cytotoxicity

Estimating the toxicity to humans of chemicals by testing on human subjects is not considered to be ethically acceptable, and toxicity testing on laboratory animals is also questionable. Therefore, there is a need for alternative methods that will give estimates of various aspects of human toxicity. Batteries of in vitro tests, together with physicochemical and toxicokinetic data, analysed by efficient data analytical methods, may enable analogy models to be constructed that can predict human toxicity. It may be possible to model non-specific toxicity relating to lipophilicity, or basal cytotoxicity, for a series of diverse compounds with large variation in chemical structure and physicochemical properties. However, local models for a series of similar compounds are generally expected to be more accurate, as well as being capable of modelling more-specific interactions. Analogy models for the prediction of human toxicity are discussed and exemplified with physicochemical and cytotoxicity data from the first ten chemicals in the multicenter evaluation of in vitro cytotoxicity (MEIC) project.

Morphometric Registration of Cytotoxic Changes of Epithelial Cells In Vitro: A Methodological Study

1990 ◽  
Vol 17 (3) ◽  
pp. 174-176
Author(s):  
Lis Andersen ◽  
Dorthe Arenholt-Bindslev
Keyword(s):  
Culture System ◽  
Optimal Allocation ◽  
Volume Density ◽  
Cell Culture System ◽  
Allocation Of Resources ◽  
Methodological Study ◽  
Epithelial Cell Culture ◽  
Coefficients Of Variation ◽  
And Control

Quantification of toxicity-induced cytomorphological effects in an epithelial cell culture system is described. Estimates of volume density and star volume of mitochondria and lysosomes are given. Mean volumes (n = 5) and coefficients of variation of these parameters were equal in experimental (TPA-treatment) and control cultures. An optimal allocation of resources for estimating cytomorphometric parameters would be to increase the number of culture flasks.

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