Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new αAR agonists chemotypes that lack the sedation conferred by known αAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G and G signaling. Experimental structures of αAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC) of 52 nanomolar] and two analogs, '7075 and PS75 (EC 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.
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http://dx.doi.org/10.1126/science.abn7065 | DOI Listing |
Daru
December 2024
Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, POB 11795, Egypt.
Background: Bile salts enriched nanovesicles (bilosomes) have been attention worthy in the past few years due to their distinctive effect on the enhancement of drug delivery through various physiological administration routes. Oral delivery of multifunctioning phytochemical curcumin has faced a lot of difficulties due to its scarce solubility and poor oral bioavailability.
Objective: The current investigation aimed to develop curcumin loaded bilosomes for improvement of oral curcumin bioavailability with maximum efficiency and safety.
J Mol Histol
December 2024
Department of Clinical Laboratory, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan City, 250000, Shandong Province, China.
The purpose of this study was to explore the inhibitory effect of andrographolide on the expression of key regulatory genes involved in the biofilm formation of Staphylococcus epidermidis (SE). Taking the film-producing strain Staphylococcus epidermidis SE1457 as the research object, the effect of andrographolide on the formation of Staphylococcus epidermidis biofilms was analyzed via crystal violet staining, and biofilm models of SE adhesion, aggregation and maturity were established in vitro. RT‒PCR was used to detect the effects of the expression of icaA-, atlE-, aap- and luxS-related genes of andrographolide on biofilm formation in SE.
View Article and Find Full Text PDFAnn Surg Open
December 2024
Department of Anesthesiology, University of Michigan, Ann Arbor, MI.
Objective: To evaluate opioid consumption for 21 procedures over 4 years from the Michigan Surgical Quality Collaborative (MSQC) registry and update post-discharge prescribing guidelines.
Background: Opioids remain a common treatment for postoperative pain of moderate-to-severe intensity not adequately addressed by nonopioid analgesics, but excessive prescribing correlates with increased usage. This analysis provides updates and compares patient-reported consumption in response to new guidelines.
Best Pract Res Clin Gastroenterol
December 2024
Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Acute liver failure (ALF) is defined as the loss of hepatic function in conjunction with hepatic encephalopathy and coagulopathy. There is histological evidence of profound hepatocyte damage. If it is not aggressively managed, ALF can be fatal within a few days.
View Article and Find Full Text PDFBest Pract Res Clin Gastroenterol
December 2024
Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India. Electronic address:
Acute liver failure (ALF) is a rare but preventable cause of acute hepatic dysfunction which is associated with significant mortality, unless treated appropriately. There are significant regional variations in the etiologies of ALF globally and this determines the outcomes of the disease as well as the long-term survival in patients receiving liver transplantation for management. Improvements in understanding of disease pathophysiology and critical care medicine have led to better outcomes over the last few decades.
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