„Pharmacokinetic study of a new compound derived aminopropane-2-ol using a LC-ESI/MS/MS technique”

β-blocker medications are the primary group of compounds used in the treatment of cardiovascular diseases. The chemical structure of these compounds are based on the fragment of 2-alkylamine ethane, subjected to numerous chemical modifications among them there are derivatives of 1-aryl-2-alkylamine ethanol and derivatives of aryloxypropranolamine. A compound tentatively named ANBL is a derivative of carvedilol, results from the search of a new compound with a β-blocker activity. During preliminary pharmacodynamic studies the compound proved hypotensive and prophylactic antiarrhythmic action. The aim of this study was to carry out a pilot assessment of the pharmacokinetic profile of this compound with regard to potential metabolites created during this process.A validated method using a LC-ESI/MS/MS technique was used to measure the compound concentration. The pilot study of pharmacokinetic profile of ANBL compound in rat proved that the compound is characterized by a relatively short drug half-life, approximately 110 minutes, large distribution volume (1.4 L/kg) indicating possibility to penetrate the substance into distal compartment. Although the study compound is absorbed relatively quickly (tmax = 10 min), its biological availability is quite poor, depending on the compound dose.Leki β-adrenolityczne należą do podstawowej grupy związków stosowanych w terapii schorzeń układu krążenia. Budowa chemiczna tej grupy związków opiera się na fragmencie 2-alkiloaminoetanu, poddanego licznym modyfikacjom chemicznym, wśród których wyróżnia się pochodne 1-arylo-2-alkiloaminoetanolu oraz pochodne aryloksypropranoloaminowe. Efektem poszukiwań nowego związku o aktywności β-adrenolitycznej jest pochodna karwedilolu, związek roboczo nazwany ANBL. Związek ten we wstępnych badaniach farmakodynamicznych wykazywał działanie hipotensyjne oraz profilaktyczne działanie przeciwarytmiczne.Celem pracy była pilotażowa ocena profilu farmakokinetycznego badanego związku w organizmie szczura z uwzględnieniem tworzonych w trakcie tego procesu potencjalnych metabolitów. Do pomiaru stężenia badanego związku zastosowano zwalidowaną metodę z wykorzystaniem techniki LC-ESI/MS/MS.Wstępna ocena właściwości farmakokinetycznych związku ANBL w organizmie szczura wykazała, że badany związek cechuje się stosunkowo krótkim okresem półtrwania, wynoszącym ok. 110 min, dużą objętością dystrybucji (1.4 L/kg) wskazującą na możliwość penetracji substancji do kompartymentu obwodowego. Badany związek wchłania się z przewodu pokarmowego stosunkowo szybko (tmax = 10 min), lecz jego dostępność biologiczna jest niewielka, zależna od dawki substancji

A preliminary metabolites identification of a novel compound with β-adrenolytic activity

BACKGROUND: The identification of main metabolites and assessment of renal excretion of a novel compound with β-adrenolytic activity (2RS)-1-(1H-indol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol, briefly called (RS)-9 or 2F109, were studied in vivo in rat serum, urine, faeces, liver, intestine, lungs and kidneys, and in vitro in rat liver microsomes. METHODS: Structures of the metabolites have been developed by comparing the high-resolution product ion mass spectra of metabolites and the parent compound based on the differences in mass values of main fragments. Quantitative analysis of (RS)-9 was done using a system of liquid chromatography coupled with a triple quadrupole mass spectrometer API 2000. Identification studies of predicted metabolites were made by a high-resolution mass spectrometer LTQ XL Orbitrap Discovery and using a Roxy(™) system, for online electrochemical mimicry of oxidative metabolism by cytochrome P450s connected to QTRAP 5500. RESULTS: For (RS)-9 (m/z 357.2084) phase I metabolites derived from oxidation process: hydroxyl derivatives (m/z 373.2470) and dihydroxyl derivatives (m/z 389.4318), and phase II metabolites: N-methylated compound (m/z 371.1612), O-glucuronide (m/z 533.5118), and sulfate (m/z 437.2350) were identified. CONCLUSION: (RS)-9 was extensively metabolised to several phase I and II metabolites, and renal excretion was a minor route in its elimination. GRAPHIC ABSTRACT: [Image: see text

COVID-19-related social isolation and symptoms of depression and anxiety in young men in Poland: Does insomnia mediate the relationship?

The need for physical distancing due to COVID-19 mitigation efforts forced prolonged social isolation, which may affect sleep and lead to mental health problems. Previous research has shown that young adults are particularly vulnerable to psychological stress caused by social isolation, the negative psychological impact of the pandemic, and greater frequency and severity of sleep problems. Therefore, the main goal of the present study was to examine whether insomnia could constitute a mediation mechanism that explains the relationship between social isolation experienced during the COVID-19 pandemic and mental health outcomes (depression and anxiety) reported up to 1.5 years later. The study was conducted among young (M±SD; 24.08±3.75) men (N = 1025) in Poland. Data were collected by means of self-report questionnaires, including The Social Isolation Index, The Athens Insomnia Scale, The State-Trait Anxiety Inventory (STAI-S) and Beck's Depression Inventory (BDI-II). The results show that insomnia mediates the relationships between social isolation and both anxiety and depression. The current findings emphasize the role of insomnia in the relationships between social isolation experienced during COVID-19 and negative emotional states. From a clinical perspective, the results suggest that implementing therapeutic components that address social isolation in insomnia treatment programs may prevent the development of depression and anxiety symptoms among young men

Comparison of anti-cancer effects of novel protein disulphide isomerase (PDI) inhibitors in breast cancer cells characterized by high and low PDIA17 expression

Protein disulphide isomerases (PDIs) play an important role in cancer progression. However, the relative contribution of the various isoforms of PDI in tumorigenesis is not clear

Protein disulfide isomerase-A1 regulates intraplatelet reactive oxygen speciesthromboxane A<SUB>2</SUB>-dependent pathway in human platelets

BACKGROUND: Platelet‐derived protein disulfide isomerase 1 (PDIA1) regulates thrombus formation, but its role in the regulation of platelet function is not fully understood. AIMS: The aim of this study was to characterize the role of PDIA1 in human platelets. METHODS: Proteomic analysis of PDI isoforms in platelets was performed using liquid chromatography tandem mass spectometry, and the expression of PDIs on platelets in response to collagen, TRAP‐14, or ADP was measured with flow cytometry. The effects of bepristat, a selective PDIA1 inhibitor, on platelet aggregation, expression of platelet surface activation markers, thromboxane A(2) (TxA(2)), and reactive oxygen species (ROS) generation were evaluated by optical aggregometry, flow cytometry, ELISA, and dihydrodichlorofluorescein diacetate‐based fluorescent assay, respectively. RESULTS: PDIA1 was less abundant compared with PDIA3 in resting platelets and platelets stimulated with TRAP‐14, collagen, or ADP. Collagen, but not ADP, induced a significant increase in PDIA1 expression. Bepristat potently inhibited the aggregation of washed platelets induced by collagen or convulxin, but only weakly inhibited platelet aggregation induced by TRAP‐14 or thrombin, and had the negligible effect on platelet aggregation induced by arachidonic acid. Inhibition of PDIA1 by bepristat resulted in the reduction of TxA(2) and ROS production in collagen‐ or thrombin‐stimulated platelets. Furthermore, bepristat reduced the activation of αIIbβ3 integrin and expression of P‐selectin. CONCLUSIONS: PDIA1 acts as an intraplatelet regulator of the ROS‐TxA(2) pathway in collagen‐GP VI receptor‐mediated platelet activation that is a mechanistically distinct pathway from extracellular regulation of αIIbβ3 integrin by PDIA3

Systemic administration of insulin receptor antagonist results in endothelial and perivascular adipose tissue dysfunction in mice

Hyperglycemia linked to diabetes results in endothelial dysfunction. In the present work, we comprehensively characterized effects of short-term hyperglycemia induced by administration of an insulin receptor antagonist, the S961 peptide, on endothelium and perivascular adipose tissue (PVAT) in mice. Endothelial function of the thoracic and abdominal aorta in 12-week-old male C57Bl/6Jrj mice treated for two weeks with S961 infusion via osmotic pumps was assessed in vivo using magnetic resonance imaging and ex vivo by detection of nitric oxide (NO) production using electron paramagnetic resonance spectroscopy. Additional methods were used to analyze PVAT, aortic segments and endothelial-specific plasma biomarkers. Systemic disruption of insulin signaling resulted in severe impairment of NO-dependent endothelial function and a loss of vasoprotective function of PVAT affecting the thoracic as well as abdominal parts of the aorta, however a fall in adiponectin expression and decreased uncoupling protein 1-positive area were more pronounced in the thoracic aorta. Results suggest that dysfunctional PVAT contributes to vascular pathology induced by altered insulin signaling in diabetes, in the absence of fat overload and obesity

Direct thrombin inhibitor dabigatran compromises pulmonary endothelial integrity in a murine model of breast cancer metastasis to the lungs; the role of platelets and inflammation-associated haemostasis

Activation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastatic spread in a murine model of breast cancer metastasis. Dabigatran etexilate (100 mg kg(−1)) was administered to mice twice daily by oral gavage. Pulmonary metastasis, pulmonary endothelium permeability in vivo, and platelet reactivity were evaluated after intravenous injection of 4T1 breast cancer cells into BALB/c mice. The effect of dabigatran on platelet-dependent protection of pulmonary endothelial barrier in the presence of an inflammatory stimulus was also verified in vitro using human lung microvascular endothelial cell (HLMVEC) cultures. Dabigatran-treated mice harbored more metastases in their lungs and displayed increased pulmonary endothelium permeability after cancer cell injection. It was not associated with altered lung fibrin deposition, changes in INFγ, or complement activation. In the in vitro model of the pulmonary endothelial barrier, dabigatran inhibited platelet-mediated protection of pulmonary endothelium. In a murine model of breast cancer metastasis, dabigatran treatment promoted pulmonary metastasis by the inhibition of platelet-dependent protection of pulmonary endothelial barrier integrity