scholarly journals Biodistribution and Anticancer Characteristics of Les-3833, A Novel 4-thiazolidinone-Based Lead Compound

2020 ◽  
Vol 88 (2) ◽  
pp. 18 ◽  
Author(s):  
Lesya Kobylinska ◽  
Andrii Lozynskii ◽  
Roman Lesyk ◽  
Rostyslav Stoika ◽  
Sandor G. Vari
Keyword(s):  
Maximum Concentration ◽  
High Performance ◽  
Maximum Level ◽  
Lead Compound ◽  
Short Period ◽  
Liquid Chromatography Tandem Mass ◽  
Liver And Kidney ◽  
The Brain

Recently, we identified the promising anticancer potential of the synthetic 4-thiazolidinone-based anticancer lead compound Les-3833 which demonstrated tumor-suppressing action in vitro and in vivo. Based on the results of previous studies, the aim of this research was to investigate the cytotoxicity in vitro and the biodistribution in laboratory mice to support the biotherapeutic drug development of Les-3833. Les-3833 (2.5 mg/kg) was intravenously injected into male Balb/c mice. Measurements were performed at 5 min, 15 min, 1 h, 4 h, and 24 h time points in blood plasma, brain, liver, and kidney using high-performance liquid chromatography/tandem mass spectrometry. After the administration of Les-3833, the maximum level of this compound was observed in plasma at 2.08 min. In the brain, the mean maximum concentration of Les-3833 was 7.17 ng/mL at 5 min, while after 15 min, it was not found. In the liver, at 5 min, the maximum concentration was 1190 ng/g. At 15 min, concentration of Les-3833 in the liver decreased by 14.3%; at 6 h by 22.8%; and after 24 h by 64.7%. Its maximum concentration in kidney was 404 ng/g within 5–15 min, at 1 h it decreased by 36.1%, and after 24 h by 49.3%. Thus, Les-3833 was rapidly taken up by different organs from the bloodstream, partially metabolized in the liver, and excreted mainly through the kidneys, while in the brain, a very low concentration could be observed for only a short period of time.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff–Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. Results The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = − 0.985, p = 0.015). Conclusion The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

TMOD-31. AN ORGANOTYPIC TISSUE PLATFORM TO BRIDGE IN VITRO AND IN VIVO ASSAYS FOR BRAIN CANCER TREATMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi222-vi222
Author(s):  
Breanna Mann ◽  
Noah Bell ◽  
Denise Dunn ◽  
Scott Floyd ◽  
Shawn Hingtgen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Brain Cancer ◽  
Brain Slice ◽  
Brain Slices ◽  
In Vitro Assays ◽  
Preclinical Model ◽  
Short Period ◽  
The Brain

Abstract Brain cancers remain one of the greatest medical challenges. The lack of experimentally tractable models that recapitulate brain structure/function represents a major impediment. Platforms that enable functional testing in high-fidelity models are urgently needed to accelerate the identification and translation of therapies to improve outcomes for patients suffering from brain cancer. In vitro assays are often too simple and artificial while in vivo studies can be time-intensive and complicated. Our live, organotypic brain slice platform can be used to seed and grow brain cancer cell lines, allowing us to bridge the existing gap in models. These tumors can rapidly establish within the brain slice microenvironment, and morphologic features of the tumor can be seen within a short period of time. The growth, migration, and treatment dynamics of tumors seen on the slices recapitulate what is observed in vivo yet is missed by in vitro models. Additionally, the brain slice platform allows for the dual seeding of different cell lines to simulate characteristics of heterogeneous tumors. Furthermore, live brain slices with embedded tumor can be generated from tumor-bearing mice. This method allows us to quantify tumor burden more effectively and allows for treatment and retreatment of the slices to understand treatment response and resistance that may occur in vivo. This brain slice platform lays the groundwork for a new clinically relevant preclinical model which provides physiologically relevant answers in a short amount of time leading to an acceleration of therapeutic translation.

Conversion to renin of exogenously administered recombinant human prorenin in liver and kidney of monkeys

1990 ◽  
Vol 258 (3) ◽  
pp. E451-E458
Author(s):  
S. Kim ◽  
M. Hosoi ◽  
F. Ikemoto ◽  
K. Murakami ◽  
Y. Ishizuka ◽  
...  
Keyword(s):  
Blood Circulation ◽  
High Performance ◽  
Slow Component ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Gel Permeation ◽  
Liver And Kidney ◽  
The Brain ◽  
No Activation

Highly purified recombinant human prorenin, labeled with 125I (125I-prorenin), was intravenously given to monkeys to examine the possible in vivo conversion of this prorenin to renin. 125I-prorenin and 125I-renin were detected using specific anti-prorenin prosegment antibody and anti-renin antibody, respectively. The plasma disappearance of immunoreactive 125I-prorenin in marmosets showed two exponential components with a half-life of 10.4 +/- 0.2 min for the rapid component and 165.7 +/- 12.6 min for the slow component. Fifteen minutes after the injection of 125I-prorenin, 38.7 +/- 2.8 and 3.9 +/- 0.5% of the administered dose accumulated in the liver and kidney, respectively. Less than 1% of the dose injected distributed in the other organs, including the brain, submandibular gland, lung, heart, aorta, adrenal gland, spleen, uterus, ovary, and testis. Thus the labeled prorenin was predominantly taken up by the liver and kidney. Analysis of liver and kidney extracts and plasma, by both gel permeation high-performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, demonstrated that 125I-prorenin (Mr = 46,000) taken up by the liver and kidney was significantly converted to 125I-renin (Mr = 42,000), whereas only a negligible amount of 125I-renin (Mr = 42,000) was present in the plasma. Although there seems to be no activation of prorenin in the blood circulation, prorenin does seem to be activated by the liver and kidney.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity, radiochemical purity, radiochemical concentration, were evaluated by high performance liquid chromatography (HPLC). Metabolic kinetics and brain level of 18F-deoxy-thiamine in mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 minutes after injection as represented by the area under the curve (AUC) and blood thiamine levels were investigated. Results: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61±0.53 in the liver within 1 minute, 18.67±7.04 in the kidney within half a minute. The SUV dropped to 0.72±0.05 and 0.77±0.35 after 60 minutes of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 minutes after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency by thiamine-deprived diet (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 minutes was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = -0.985, p = 0.015).Conclusion: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

scholarly journals Implication of Opioid Receptors in the Antihypertensive Effect of a Novel Chicken Foot-Derived Peptide

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 992
Author(s):  
Anna Mas-Capdevila ◽  
Lisard Iglesias-Carres ◽  
Anna Arola-Arnal ◽  
Gerard Aragonès ◽  
Begoña Muguerza ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Opioid Receptors ◽  
High Performance ◽  
Antihypertensive Effect ◽  
High Resolution Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

The peptide AVFQHNCQE demonstrated to produce nitric oxide-mediated antihypertensive effect. This study investigates the bioavailability and the opioid-like activity of this peptide after its oral administration. For this purpose, in silico and in vitro approaches were used to study the peptide susceptibility to GI digestion. In addition, AVFQHNCQE absorption was studied both in vitro by using Caco-2 cell monolayers and in vivo evaluating peptide presence in plasma from Wistar rats by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and by ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Both in vivo and in vitro experiments demonstrated that peptide AVFQHNCQE was not absorbed. Thus, the potential involvement of opioid receptors in the BP-lowering effect of AVFQHNCQE was studied in the presence of opioid receptors-antagonist Naloxone. No changes in blood pressure were recorded in rats administered Naloxone, demonstrating that AVFQHNCQE antihypertensive effect is mediated through its interaction with opioid receptors. AVFQHNCQE opioid-like activity would clarify the antihypertensive properties of AVFQHNCQE despite its lack of absorption.

Decreased aminotransferase activity of serum and various tissues in the rat after cefazolin treatment.

1979 ◽  
Vol 25 (7) ◽  
pp. 1263-1266 ◽  
Author(s):  
M S Dhami ◽  
R Drangova ◽  
R Farkas ◽  
T Balazs ◽  
G Feuer
Keyword(s):  
Enzyme Activity ◽  
Pyruvate Carboxylase ◽  
Aminotransferase Activity ◽  
Liver And Kidney ◽  
Mixed Function Oxidase System ◽  
The Brain ◽  
Microsomal Mixed Function Oxidase ◽  
Alanine Aminotransferase Activity

Abstract Treatment of rats with cefazolin in vivo significantly suppressed activity of alanine and aspartate aminotransferases in serum and in the liver, brain, kidney, and heart. Simultaneous administration of pyridoxal further reduced enzyme activity except in the liver, where there was no change. Pyridoxal 5'-phosphate partly reversed the decreased enzyme activity in the serum, liver, and kidney, but did not return it to the amount observed in the control animals; enzyme activity remained suppressed in the brain and heart. The effect of cefazolin was dose related, but there was no sex-related difference. In contrast to its action on am-notransferase activity, cefazolin elicited no effect on alkaline phosphatase (pyridoxal-5'-phosphate hydrolase) in serum or on pyruvate carboxylase in the liver, heart, and kidney. Cefazolin exposed to the hepatic microsomal mixed-function oxidase system in vitro was partly converted into metabolites that inhibited serum alanine aminotransferase activity in vitro. The latter inhibition was reversed by the addition of pyridoxal 5'-phosphate.

scholarly journals Multifunctional Superparamagnetic Stiff Nanoreservoirs for Blood Brain Barrier Applications

Nanomaterials ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 449 ◽  
Author(s):  
Zulema Vargas-Osorio ◽  
Andrés Da Silva-Candal ◽  
Yolanda Piñeiro ◽  
Ramón Iglesias-Rey ◽  
Tomas Sobrino ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Neurological Diseases ◽  
Developed Countries ◽  
Large Set ◽  
In Vivo Experiments ◽  
Liver And Kidney ◽  
The Brain

Neurological diseases (Alzheimer’s disease, Parkinson’s disease, and stroke) are becoming a major concern for health systems in developed countries due to the increment of ageing in the population, and many resources are devoted to the development of new therapies and contrast agents for selective imaging. However, the strong isolation of the brain by the brain blood barrier (BBB) prevents not only the crossing of pathogens, but also a large set of beneficial drugs. Therefore, an alternative strategy is arising based on the anchoring to vascular endothelial cells of nanoplatforms working as delivery reservoirs. In this work, novel injectable mesoporous nanorods, wrapped by a fluorescent magnetic nanoparticles envelope, are proposed as biocompatible reservoirs with an extremely high loading capacity, surface versatility, and optimal morphology for enhanced grafting to vessels during their diffusive flow. Wet chemistry techniques allow for the development of mesoporous silica nanostructures with tailored properties, such as a fluorescent response suitable for optical studies, superparamagnetic behavior for magnetic resonance imaging MRI contrast, and large range ordered porosity for controlled delivery. In this work, fluorescent magnetic mesoporous nanorods were physicochemical characterized and tested in preliminary biological in vitro and in vivo experiments, showing a transversal relaxivitiy of 324.68 mM−1 s−1, intense fluorescence, large specific surface area (300 m2 g−1), and biocompatibility for endothelial cells’ uptake up to 100 µg (in a 80% confluent 1.9 cm2 culture well), with no liver and kidney disability. These magnetic fluorescent nanostructures allow for multimodal MRI/optical imaging, the allocation of therapeutic moieties, and targeting of tissues with specific damage.

scholarly journals PHARMACOKINETIC PROFILE OF 75 MG CLOPIDOGREL IN PLASMA OF INDONESIAN HEALTHY SUBJECTS BY ULTRA HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

2018 ◽  
Vol 10 (1) ◽  
pp. 331
Author(s):  
Yahdiana Harahap ◽  
Ganesya Rita Putri ◽  
Herman Suryadi
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Maximum Concentration ◽  
Healthy Subjects ◽  
High Performance ◽  
Pharmacokinetic Profile ◽  
Tandem Mass ◽  
Linear Calibration ◽  
Liquid Chromatography Tandem Mass

Objective: This study aimed to determine clopidogrel in plasma to obtain its pharmacokinetic profile using ultra-high-performance liquidchromatography-tandem mass spectrometry (UPLC-MS/MS).Methods: Clopidogrel analysis was performed in vivo by UPLC-MS/MS using validated methods. Subjects received 75 mg clopidogrel, and plasmasamples were collected at 14 time points after 0 baseline (pre-dose): 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 8, 12, 18, and 24 h.Results: A linear calibration curve was produced in the range of 20–5.000 pg/mL. This method fulfills the criteria for validation according to theEuropean Medicines Agency guidelines. The obtained pharmacokinetic profile of clopidogrel was as follows: Maximum concentration=1.146 ng/mL,time at maximum concentration (tmax)=1 h, half-life (t½)=7.01 h, area under curve (AUC)0−t=7.420 ng h/mL, and AUC0−t=8.111 ng h/mL.Conclusion: Clopidogrel analysis using a UPLC/MS-MS system with liquid-liquid extraction method was successfully conducted using plasma samplesfrom three healthy subjects who administered 75 mg of clopidogrel tablet.

scholarly journals Identification and Quantification of MIDD0301 metabolites

2021 ◽  
Vol 22 ◽  
Author(s):  
M.S. Rashid Roni ◽  
Nicolas M. Zahn ◽  
Brandon N. Mikulsky ◽  
Daniel A. Webb ◽  
Md Yeunus Mian ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Oral Administration ◽  
Imaging Mass Spectrometry ◽  
Lung Parenchyma ◽  
Drug Candidate ◽  
Liquid Chromatography Tandem Mass ◽  
Liver And Kidney ◽  
Kidney Microsomes

Background: MIDD0301 is an oral asthma drug candidate that binds GABAA receptors on airway smooth muscle and immune cells. Objective: The objective of this study is to identify and quantify MIDD0301 metabolites in vitro and in vivo and determine the pharmacokinetics of oral, IP, and IV administrated MIDD0301. Methods: In vitro conversion of MIDD0301 was performed using liver and kidney microsomes/S9 fractions followed by quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A LC-MS/MS method was developed using synthesized standards to quantify MIDD0301 and its metabolites in urine and feces. Blood, lung, and brain were harvested from animals that received MIDD0301 by oral, IP, and IV administration, followed by LCMS/MS quantification. Imaging mass spectrometry was used to demonstrate the presence of MIDD0301 in the lung after oral administration. Results: MIDD0301 is stable in the presence of liver and kidney microsomes and S9 fractions for at least two hours. MIDD0301 undergoes conversion to the corresponding glucuronide and glucoside in the presence of conjugating cofactors. For IP and IV administration, unconjugated MIDD0301 together with significant amounts of MIDD0301 glucoside and MIDD0301 taurine were found in urine and feces. Less conjugation was observed following oral administration, with MIDD0301 glucuronide being the main metabolite. Pharmacokinetic quantification of MIDD0301 in blood, lung, and brain showed very low levels of MIDD0301 in the brain after oral, IV, or IP administration. The drug half-life in these tissues ranged between 4-6 hours for IP and oral and 1-2 hours for IV administration. Imaging mass spectrometry demonstrated that orally administered MIDD0301 distributes uniformly in the lung parenchyma. Conclusion: MIDD0301 undergoes no phase I and moderate phase II metabolism.

Sign in / Sign up

Export Citation Format

Share Document