Pharmacological Reports最新文献

Acute severe ulcerative colitis (ASUC) and acute severe Crohn's disease (CD) flare are potentially life-threatening conditions, for which treatment remains a clinical challenge. Currently available therapeutic options present limited efficacy, with a high rate of colectomy as the final-line treatment method. Therefore, new alternatives of rescue therapy in inflammatory bowel diseases (IBD) are constantly sought. Upadacitinib (UPA), a selective Janus kinase-1 (JAK1) inhibitor, has been approved for the treatment of moderate-to-severe ulcerative colitis (UC) and CD. Interestingly, the most recent data show an increasing off-label use of this medication in the management of acute severe colitis. We present a comprehensive review focusing on rescue therapy with UPA in IBD, both UC and CD. The article examines the outcomes of recent studies evaluating the effectiveness, safety, and tolerability of UPA treatment in adult patients with ASUC and severe CD flare, a new treatment strategy.

Heart regeneration, or the replacement or restoration of damaged myocardium, remains one of the most challenging areas in regenerative medicine, primarily due to the limited regenerative capacity of the adult human heart. Unlike the embryonic heart, which exhibits robust cardiomyocyte proliferation, postnatal cardiac muscle cells permanently exit the cell cycle, resulting in minimal regenerative potential following injury such as myocardial infarction. This limitation contributes significantly to the progression of heart failure, a leading cause of morbidity and mortality worldwide. Recent breakthroughs in understanding the molecular and cellular mechanisms that govern cardiomyocyte proliferation have revealed that targeting signaling pathways (e.g., Hippo-YAP), cell cycle regulators, epigenetic modulators, and extracellular components may be a promising strategy for stimulating heart repair. Despite these advances, cardiac regeneration still faces significant obstacles in replacing damaged tissue and ensuring the regenerated muscle functions effectively within the complex heart system. This review aims to provide a comprehensive analysis of emerging regulatory mechanisms involved in cardiomyocyte proliferation and myocardial regeneration. It critically evaluates current strategies for promoting heart regeneration, with particular emphasis on the most promising molecular pathways and therapeutic approaches with translational potential. Ongoing research, as summarized in this review, continues to expand the potential of regenerative medicine to repair heart damage, offering hope for more effective treatments for heart disease.

Background: Neuromuscular blocking agents (NMBAs) may trigger severe perioperative hypersensitivity reactions. A recently proposed mechanism involves off-target activity of NMBAs. They are thought to directly activate the Mas-related G protein-coupled receptor X2 (MRGPRX2), leading to mast cell degranulation and drug-induced hypersensitivity reactions. This study investigated which NMBAs exert this effect, whether in silico findings are consistent with cell-based experiments, and how the affinity of NMBAs for MRGPRX2 compares with that of fluoroquinolones, known MRGPRX2 agonists. We also sought to predict MRGPRX2 binding-site mutations that might enhance interactions with these drugs.

Methods: Molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area binding free-energy calculations were combined with a β-hexosaminidase release assay in MRGPRX2-expressing RBL-2H3 stable cell line. Computational alanine scanning was performed to predict the impact of receptor mutations.

Results: We demonstrated that atracurium-induced mast cell degranulation can be attributed to its immediate metabolite, laudanosine, which binds strongly to MRGPRX2. Pipecuronium, but not rocuronium, suxamethonium, or vecuronium, exhibited high affinity for MRGPRX2 in MD simulations. Complexes of ciprofloxacin, levofloxacin, and moxifloxacin with MRGPRX2 demonstrated excellent stability in MD simulations. RBL-MX2 responses to NMBAs and fluoroquinolones were highly consistent with our MD findings. Alanine substitutions reduced the affinity of ligands for MRGPRX2.

Conclusions: In contrast to fluoroquinolones, NMBAs displayed different affinity for MRGPRX2. Cellular responses in bench experiments closely reflected the MD predictions. Alanine scanning revealed that the MRGPRX2 binding pocket exhibits low susceptibility to single-site mutations that enhance receptor responsiveness.

Background: Fentanyl, a synthetic opioid with potent analgesic and sedative properties, is widely administered in intensive care. Many critically ill patients present with, or develop, hypothermia driven by multifactorial disturbances such as sepsis, trauma, circulatory shock, or environmental exposure. Because reduced core temperature affects perfusion, metabolism, and clearance, hypothermia may meaningfully alter fentanyl disposition, although these effects remain insufficiently defined. Given these uncertainties, this study investigates how moderate hypothermia (MH) and severe hypothermia (SH) alter the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, compared with normothermic controls.

Methods: Male Wistar rats were divided into three groups and subjected to different environmental temperatures: normothermic controls (37 °C), MH (30 °C), and SH (27 °C). Fentanyl (10 µg/kg) was administered via a short intravenous infusion, and serial blood samples were collected over 60 min. Serum fentanyl and norfentanyl concentrations were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

Results: Maximum fentanyl concentration increased in both MH and SH groups, reaching statistical significance only under severe hypothermia (p < 0.001). The area under the concentration-time curve (AUC) increased markedly (p = 0.009) in SH group, indicating increased overall drug exposure. Clearance decreased by 44% (p = 0.010), and volume of distribution in steady state (V_ss) was reduced in both groups (SH: p < 0.001, MH: p = 0.029), reflecting impaired drug elimination under severe hypothermic conditions. For norfentanyl, exposure increased significantly in the SH group across all parameters, whereas in the MH group increases were limited to C_max and AUC_0-t.

Conclusions: Hypothermia significantly alters fentanyl and norfentanyl pharmacokinetics in a temperature-dependent manner.