scholarly journals Unexpected scaffold rearrangement product of pirenzepine found in commercial samples

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marius Ozenil ◽  
Lukas Skos ◽  
Alexander Roller ◽  
Natalie Gajic ◽  
Wolfgang Holzer ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Safety Issue ◽  
Muscarinic Acetylcholine Receptor ◽  
Research Community ◽  
Rearrangement Product ◽  
Oral Application ◽  
Molecular Events ◽  
Acidic Conditions ◽  
Pharmacological Target

AbstractPharmacovigilance aims at a better understanding of the molecular events triggered by medications to prevent adverse effects, which despite significant advances in our analytical repertoire plague the use of drugs until today. In this study, we find that clinically prescribed and commercially available pirenzepine may not be the correct compound. Pirenzepine can undergo an unexpected scaffold rearrangement from the pharmaceutical active ingredient (API) to a previously uncharacterized benzimidazole. The rearrangement occurs under highly acidic conditions, which were believed to favour the dihydrochloride formation of pirenzepine. The rearranged products of pirenzepine and the structurally related telenzepine have significantly decreased affinity for the muscarinic acetylcholine receptor, the pharmacological target of these compounds. Fortunately, in situ rearrangement after oral application is no safety issue, as we show that reaction kinetics in gastric acid prevent rearrangement. The research community should consider appropriate measures to perform reliable receiving inspections in the commercial supply of well described and frequently used chemicals, in particular if experiments yield unexpected results.

scholarly journals Break–apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements

2015 ◽  
Vol 172 (5) ◽  
pp. 571-582 ◽  
Author(s):  
Chiara Colato ◽  
Caterina Vicentini ◽  
Silvia Cantara ◽  
Serena Pedron ◽  
Paolo Brazzarola ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Chromosomal Rearrangements ◽  
Study Cohort ◽  
Fish Analysis ◽  
Papillary Thyroid ◽  
Qrt Pcr ◽  
Molecular Events ◽  
On The Road

ObjectiveChromosomal rearrangements of theRETproto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort ofBRAFWT PTCs by fluorescencein situhybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes.DesignFortyBRAFWT PTCs were analyzed by FISH for RET rearrangements. As controls, sixBRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed.MethodsWe performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break–apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR.ResultsSplit RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off.ConclusionsFISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy.

Development of a Multi-DOF Tuned Dynamic Absorber for Reducing Hand Vibrations on an Off-Highway Vehicle

2020 ◽  
Author(s):  
Hongan Xu ◽  
David Clark ◽  
Marlin Zeis ◽  
Mike Hill ◽  
Tony Zambito
Keyword(s):  
Vibration Control ◽  
Safety Issue ◽  
Control Measures ◽  
Steering Wheel ◽  
Bench Test ◽  
Vibration Modes ◽  
Quality And Safety ◽  
Important Quality ◽  
Dynamic Absorber

Abstract A variety of off-highway vehicles are subject to significant steering wheel vibrations during operation. Typical examples of such machines are vibratory asphalt and soil compactors. Large compacting forces, while essential for the proper compacting operation, will inevitably cause undesired effects such as severe vibrations of steering wheels. Traditional vibration control measures are often found either impractical or less effective in reducing the level of hand vibrations which is considered an important quality and safety issue in compacter design and sales. In this paper, an advanced concept of reducing hand vibrations is presented in the context of Multi-degree-of-freedom Tuned Dynamic Absorbers (MTDA). The MTDA essentially represents an assembly of simple dynamic absorbers individually tuned to different targeted vibration modes in different degree of freedoms. While the design concept and associated parameters are numerically determined by FEA, the prototype is fine tuned to the desired vibration modes through a bench test. The effectiveness of the MTDA is experimentally verified in-situ through a sequence of tests which are carefully designed to adequately reflect its performance under field conditions.

Highly Selective One-Pot Synthesis of Polysubstituted Isoflavanes using Styryl Ethers and Electron-Withdrawing ortho-Quinone Methides Generated In Situ

Synlett ◽  
2018 ◽  
Vol 30 (02) ◽  
pp. 189-192 ◽  
Author(s):  
Yujiro Hoshino ◽  
Kiyoshi Honda ◽  
Kenta Tanaka ◽  
Mami Kishimoto ◽  
Naoya Ohtsuka ◽  
...  
Keyword(s):  
Biologically Active ◽  
Quinone Methides ◽  
One Pot ◽  
One Pot Synthesis ◽  
Reaction Proceeds ◽  
Acidic Conditions ◽  
High Yields

A highly selective one-pot synthesis of polysubstituted isoflavanes has been developed. The reaction proceeds through the cycloaddition of methyl styryl ethers, derived from phenylacetaldehyde dimethyl acetals under acidic conditions, with electron-withdrawing ortho-quinone methides generated in situ. When phenylacetaldehyde dimethyl acetals were reacted with salicylaldehydes, the reaction proceeded smoothly to afford the corresponding isoflavanes stereoselectively in high yields and with excellent regioselectivities. The present reaction provides versatile access to functionalized isoflavanes, and constitutes a useful tool for the synthesis of biologically active molecules.

Pre-magnetization for enhancing the iron-catalyzed activation of peroxymonosulfate via accelerating the corrosion of Fe0

2019 ◽  
Vol 79 (7) ◽  
pp. 1287-1296 ◽  
Author(s):  
Yunxin Liu ◽  
Peng Zhou ◽  
Xiaowei Huo ◽  
Yang Liu ◽  
Xin Cheng ◽  
...  
Keyword(s):  
Field Gradient ◽  
Oxidation Process ◽  
Zero Valent Iron ◽  
Gradient Force ◽  
Acid Orange 7 ◽  
Lower Field ◽  
Acidic Conditions ◽  
Reactive Radicals ◽  
Better Than

Abstract Our findings proved that micron-scale zero-valent iron (mZVI) particles with pre-magnetization combined with peroxymonosulfate (PMS) can markedly enhance the removal of acid orange 7 (AO7). Investigation into the mechanism showed that PMS accelerated the corrosion of ZVI to release Fe2+ under acidic conditions, and the in-situ generated Fe2+ further activated PMS to produce SO4•− and •OH, resulting in AO7 removal. Further, the Lorentz force strengthened the convection in the solution and the field gradient force tended to move Fe2+ from a higher to a lower field gradient at the pre-magnetized ZVI (Pre-ZVI) particle surfaces, thus indicating that pre-magnetization promoted the corrosion of ZVI to release Fe2+, which resulted in the enhancement of PMS activation. Nano-scale ZVI (nZVI) was more effective than mZVI in activating PMS to degrade AO7, but the pre-magnetization effect on mZVI was better than on nZVI. AO7 removal increased with higher ZVI and PMS dosage, lower AO7 concentration, and acidic conditions (pH = 2, 3). This study helps to understand the reactive radicals-based oxidation process with application of pre-magnetized ZVI in activating PMS.

Opening of the blood-brain barrier with an unfocused ultrasound device in rabbits

2013 ◽  
Vol 119 (4) ◽  
pp. 887-898 ◽  
Author(s):  
Kevin Beccaria ◽  
Michael Canney ◽  
Lauriane Goldwirt ◽  
Christine Fernandez ◽  
Clovis Adam ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Blood Brain Barrier ◽  
Ultrasonic Transducer ◽  
Brain Barrier ◽  
Single Element ◽  
Blood Brain ◽  
The Us ◽  
The Brain ◽  
Bbb Opening

Object The blood-brain barrier (BBB) is a major impediment to the intracerebral diffusion of drugs used in the treatment of gliomas. Previous studies have demonstrated that pulsed focused ultrasound (US) in conjunction with a microbubble contrast agent can be used to open the BBB. To apply the US-induced opening of the BBB in clinical practice, the authors designed an innovative unfocused US device that can be implanted in the skull and used to transiently and repeatedly open the BBB during a standard chemotherapy protocol. The goal of this preliminary work was to study the opening of the BBB induced by the authors' small unfocused US transducer and to evaluate the effects of the sonications on brain parenchyma. Methods Craniectomy was performed in 16 healthy New Zealand White rabbits; epidural application of a single-element planar ultrasonic transducer operating at 1 MHz was then used with a pulse-repetition frequency of 1 Hz, pulse lengths of 10–35 msec, in situ acoustic pressure levels of 0.3–0.8 MPa, and sonication for 60–120 seconds. SonoVue was intravenously injected during the US applications, and opening of the BBB was determined by detecting extravasation of Evans blue dye (EBD) in brain tissues, quantitative measurement of EBD with UV-visible spectrophotometry, and contrast enhancement after Gd injection in 4.7-T MRI. A histological study was performed to determine adverse effects. Results An opening of the BBB was observed over a large extent of the US beam in the brain corresponding to in situ pressures of greater than 0.2 MPa. The BBB opening observed was highly significant for both EBD (p < 0.01) and MRI Gd enhancement (p < 0.0001). The BBB opening was associated with minor adverse effects that included perivascular red blood cell extravasations that were less than 150 μm in size and not visible on MR images. Moderate edema was visible on FLAIR sequences and limited to the extent of the sonication field. Conclusions The results demonstrate that the BBB can be opened in large areas of the brain in rabbits with lowpower, pulsed, and unfocused US with limited damage to healthy tissue.

In-Situ SAXS Studies on the Formation of Silicate/Surfactant Mesophases with Solubilized Benzene under Acidic Conditions

Langmuir ◽  
2002 ◽  
Vol 18 (26) ◽  
pp. 10053-10057 ◽  
Author(s):  
Michael Tiemann ◽  
Valérie Goletto ◽  
Raphaël Blum ◽  
Florence Babonneau ◽  
Heinz Amenitsch ◽  
...  
Keyword(s):  
Acidic Conditions

In situ-generated Co@nitrogen-doped carbon nanotubes derived from MOFs for efficient hydrogen evolution under both alkaline and acidic conditions

2017 ◽  
Vol 41 (19) ◽  
pp. 10966-10971 ◽  
Author(s):  
Ji-Sen Li ◽  
Bing Du ◽  
Zhi-Hua Lu ◽  
Qing-Ting Meng ◽  
Jing-Quan Sha
Keyword(s):  
Carbon Nanotubes ◽  
Hydrogen Evolution ◽  
Metal Organic Frameworks ◽  
Nitrogen Doped ◽  
Metal Organic ◽  
Acidic Conditions ◽  
Nitrogen Doped Carbon

In situ-generated Co@nitrogen-doped carbon nanotubes derived from metal–organic frameworks were fabricated by a facile method and corresponding HER performances were investigated in detail.

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