Search

(±)-Bis-tetralone (BisT) crystallizesas a stable conglomeratethat can be resolved by preferential crystallization. This preferentialcrystallization was performed by autoseeded polythermic programmedpreferential crystallization (AS3PC) and autoseeded preferential crystallizationinduced by solvent evaporation (ASPreCISE) variants in dimethylformamideand dichloromethane. Prior to performance of these resolutions, anextensive purification was necessary because the presence of impuritieshad a strong negative impact on the stereoselective crystal growth.Moreover, the presence of multiepitaxy phenomena required a vigorousstirring during the preferential crystallization in order to avoida poor optical purity of the crops. Several preferential crystallizationattempts demonstrate that ASPreCISE is recommended when there is anunfavorable variation of solubility versus temperature or when chemicaldegradation occurs on heating. [ABSTRACT FROM AUTHOR]

Background & Aims: Oxidative stress is recognized as a major driver of non-alcoholic steatohepatitis (NASH) progression. The transcription factor NRF2 and its negative regulator KEAP1 are master regulators of redox, metabolic and protein homeostasis, as well as detoxification, and thus appear to be attractive targets for the treatment of NASH., Methods: Molecular modeling and X-ray crystallography were used to design S217879 - a small molecule that could disrupt the KEAP1-NRF2 interaction. S217879 was highly characterized using various molecular and cellular assays. It was then evaluated in two different NASH-relevant preclinical models, namely the methionine and choline-deficient diet (MCDD) and diet-induced obesity NASH (DIO NASH) models., Results: Molecular and cell-based assays confirmed that S217879 is a highly potent and selective NRF2 activator with marked anti-inflammatory properties, as shown in primary human peripheral blood mononuclear cells. In MCDD mice, S217879 treatment for 2 weeks led to a dose-dependent reduction in NAFLD activity score while significantly increasing liver Nqo1 mRNA levels, a specific NRF2 target engagement biomarker. In DIO NASH mice, S217879 treatment resulted in a significant improvement of established liver injury, with a clear reduction in both NAS and liver fibrosis. αSMA and Col1A1 staining, as well as quantification of liver hydroxyproline levels, confirmed the reduction in liver fibrosis in response to S217879. RNA-sequencing analyses revealed major alterations in the liver transcriptome in response to S217879, with activation of NRF2-dependent gene transcription and marked inhibition of key signaling pathways that drive disease progression., Conclusions: These results highlight the potential of selective disruption of the NRF2-KEAP1 interaction for the treatment of NASH and liver fibrosis., Impact and Implications: We report the discovery of S217879 - a potent and selective NRF2 activator with good pharmacokinetic properties. By disrupting the KEAP1-NRF2 interaction, S217879 triggers the upregulation of the antioxidant response and the coordinated regulation of a wide spectrum of genes involved in NASH disease progression, leading ultimately to the reduction of both NASH and liver fibrosis progression in mice., Competing Interests: All the authors are/were employees of Servier. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Brivaracetam, or (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide, is an active pharmaceutical ingredient designed for the treatment of epilepsy. During the development of the IV administration mode, a liquid-liquid miscibility gap has been observed with pure water, isotonic and hypertonic solutions (vehicle at 0.9% w/w and 5%w/w NaCl respectively). The study reveals that the NaCl concentration has a direct impact on the extent of the demixing domain; from a sub-micronic demixing in pure water towards a macroscopic miscibility gap in hypertonic aqueous solutions. The thorough exploration of these heterogeneous equilibria led to define experimental parameters for safe IV injections without risk of liquid - liquid miscibility gap at 37°C., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The effects of continuous stray voltage were evaluated on growing-finishing pigs between the ages of 8 and 21 weeks. Seventy-two pigs were assigned to six blocks of 12 animals each. The following treatments were randomly distributed in each block according to a 2 x 3 factorial design: feeding level (restricted or ad libitum) and voltage level (0, 2 or 5 volts (V) as a difference of potential between feeder or drinker and the metallic floor). During daytime, stray voltage at 5 V decreased (p less than 0.05) the eating frequency in both feeding groups and the drinking frequency in restricted-fed pigs. The mean duration of drinking bouts and the total time spent at the drinker were also lower (p less than 0.05) in this last group during the hour following meal distribution. Daily feed intake and average daily gain were lower (p less than 0.05 and less than or equal to 0.08, respectively) in the 5 V group than in the 2 V and the control groups from 17 to 21 weeks of age. Finally, gastric lesions, hematological and biochemical variables were not affected (p greater than 0.05) by stray voltage.