Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors,Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A_2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.     

Radiophotolumenescence of Irradiated Polymethylmethacrylate Doped with Some Charge Transfer Complexes

Radiophotolumenescence (RPL) of irradiated and non irradiated thin films of polymethylmethacrylate (PMMA) doped with anthracene (Anth) as a donor, and tetracyanoquinodimethane (TCNQ) as an acceptor, has been investigated. The RPL – glow spectrum was recorded to study the characterizing emission bands from the point of view of glow peak position and intensity and hence the prospective relative sensitivities. RFL – signal fading after one month storage in dark at room temperature post gamma irradiation was also studied. PMMA doped with 6:4 donor to acceptor ratio has been proved to be the most sensitive one with less fading regarding gamma detection. On the other hand 2 Anth: 8 TCNQ was found to be the proper dopant concentration ratio for thermal neutron detection.     

Structural features of human tooth tissues affected by high dose of external ionizing radiation after nuclear catastrophe of Chernobyl plant

The application of micro-Raman spectroscopy is discussed for the analysis of structural features of human tooth tissues affected by high doses of external ionizing radiation (0.5–1.7 Gy) after the nuclear plant catastrophe in Chernobyl in 1986. The results have shown significant changes in the mineral matrix of dental enamel that lead to the decrease of tooth enamel hardness. Destruction of the collagen chain of the organic matrix has been observed for dentin and cementum.     

About some physical mechanisms of statistics of radiation-induced effects formation and non-linear cell response in low dose area

A new cascade-stochastic approach to solve the direct and inverse problems of radiation-induced effect statistics in track biodetectors is presented in this paper. The analysis of the experimental data has made it possible to establish a non-linear nature of the “dose–effect” dependence in low dose area. For the first time, a new determination of the relative biological efficiency and quality coefficient of ionizing radiation in area of low doses are proposed.     

Effect of high gamma dose on the PADC properties

The effect of the properties of PADC nuclear track detectors after exposure to high doses of gamma absorbed doses up to 5×10⁵ Gray (50 Mrad) were studied. The gamma source was a 9.03 PBq (244 KCi), Co-60 source. Results indicate that each of the bulk etch rate (V_b), the tracks etch rate (V_t) and the sensitivity (V) of the detectors increases with the high gamma absorbed dose, but there is a drop in these parameters at the low gamma absorbed dose. Signs of surface roughness were observed by increasing the gamma absorbed doses and changes in color observed for doses larger than 2×10⁵ Gray. The temperature of detectors during irradiation time reached 41°C. The fission fragment tracks (from Cf-252 source) disappeared quickly within the etching time (minutes) for total absorbed doses greater than 3×10⁵ Gray due to their high bulk etch rate.     

Gamma-Radiolyse von Dimethylglyoxim

Die Strahlenresistenz von reinem und an Aktivkohle sorbiertem Dimethylglyoxim (DMG), das für die selektive Abtrennung von Palladium aus Abfallösungen der Kernbrennstoffwiederaufarbeitung geeignet ist, wurde untersucht. Die Bestrahlung erfolgte bei 20–40 °C mit einer ⁶⁰Co-γ-Bestrahlungsanlage mit Dosisleistungen von 0,6 bis 1,7 Gy/s in einem Dosisbereich von 2 kGy bis 5 MGy. Die Radiolyseprodukte wurden mit verschiedenen Methoden analysiert und die G-werte bestimmt. Es wurde gezeigt, daβ DMG bis zu Dosen von etwa 110 kGy relativ strahlenresistent ist. Bei höheren Dosen werden die reaktiven NOH-Gruppen des DMG teilweise zerstört, so daβ sie nicht mit Palladium reagieren können. In Verfahren zur Abtrennung von Palladium aus radioaktiven Abfallösungen werden diese Dosen jedoch nicht erreicht. Auf eine unzureichende Strahlenresistenz von DMG zurückzuführende Komplikationen können deshalb ausgeschlossen werden.     

Darstellung und Weitergabe der Expositionseinheit Röntgen im DAMW Teil II: Die Hohlraum-Ionisationskammern für 60Co- und 137Cs-γ-Strahlung

Nachdem in ersten Teil der Arbeit eine Beschreibung der Normalmeβeinrichtungen (Freiluft-Ionisationskammern) des DAMW zur Darstellung der Einheit der Exposition für den Energiebereich der Röntgenstrahlung erfolgte, werden hier die entsprechenden Einrichtungen für die Gammastrahlung von ⁶⁶Co und ¹³⁷Cs behandelt. Grundlage für die definitionsgemäβe Bestimmung der Einheit bilden dabei verschidene Hohlraum-Inoisationskammern aus Reinstgraphit, deren Aufbau erläwtert wird. Sie sind vom zylindrischen Typ und haben Meβvolumina von ca. 2 cm³, 8 cm³ cm³ und 100 cm³. Als Ladungsmeβeinrichtung wird ebenfalls ein elektromctrischer Fotozellenkompensator verwendet. Die Bestimmung der in kollimierten Strahlenbündeln notwendigen Korrektionsfaktoren wird im einzelnen behandelt. Der maximale Fehler bei der Darstellung der Einheit der Exposition betrāgt 2%.     

Über die Möglichkeit einer strahlenchemischen Reinigung von Abwässern,die Dodezylbenzolsulfonat und Nonylphelylpolyglykoläther enthalten

Es wurde die Möglichkeit des strahlenchemischen Abbaus einiger Detergenzien untersucht, die in Abwässern enthalten sind. Es wurde festgestellt, daß von den oberflächenaktiven Substanzen (OFAS) die den Hauptteil der aktiven Substanz der Detergenzien darstellen, die ionogenen (z. B. Dodezylbenzolsulfonat) bei verhältnismäßig niedrigeren Dosen zersetzt werden als die nichtionogenen (z. B. Nonylphenylpolyglykoläther). Bei gleicher Konzentration beider Stoffe bewirken Dosen in der Größenordnung von 5 bis 6 kGy einen höheren Grad des Abbaus bei Dodezylbenzolsulfonat als Dosen von 10 bis 20 kGy beim Nonylphenylpolyglykoläther. Versuche mit realen Abwässern, die die Präparate ?Biopon”, ?Alkasuper” und ?Kitka” enthalten, bestätigen die erkannte Gesetzmäßigkeit und zeigen die Perspektive eines strahlenchemischen Abbaus für die Reinigung von Abwässern, die ionogenc OFAS enthalten.     

Intercomparison of Gafchromic™ films,TL detectors and TL foils for the measurements of skin dose in interventional radiology

Several passive solid state dosemeters, such as Gafchromic™ films and thermoluminescence (TL) detectors, are used to estimate and monitor patient skin doses in interventional radiology. To determine the suitability of XR-TypeR Gafchromic™ films and of detectors based on TL materials: pellets, chips and foils to measure skin dose, an intercomparison exercise has been organized within European Dosimetry Radiation Group – Working Group 12 “European Medical ALARA Network” (EURADOS WG12). To test response detectors were exposed to X-ray beams of energies and qualities applied clinically. A blind test was also performed to investigate the accuracy of the dose estimate by detectors exposed to unknown doses. We found the response of films to be strongly dependent on beam quality and filtration (increasing by up to 80% with respect to reference beam quality). The response of TL detectors was found to be less dependent on beam quality (less than 25% variation), with TL foils showing less than 10% variation with respect to reference beam quality. To accurately estimate patient skin doses in interventional radiology it is important to choose the quality of the calibration beam to be as close as possible to the quality of beams actually applied in clinical work.