Pharmacological Reports最新文献

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.

Background: The present study investigated the combined effects of zofenoprilat (ZOFE) and nebivolol (NEBI) on endothelial function, focusing on their anti-inflammatory and antioxidant properties. The purpose was to evaluate whether these drugs, commonly used in clinical practice, offer a synergistic therapeutic strategy for managing hypertension and protecting vascular health. ZOFE, an ACE inhibitor, demonstrated significant anti-inflammatory activities by reducing inflammatory cytokines, thereby mitigating vascular inflammation, a key factor in hypertension and atherosclerosis. NEBI, a third-generation beta-blocker, exhibited strong antioxidant effects by enhancing nitric oxide (NO) levels, crucial for maintaining endothelial function and reducing oxidative stress.

Methods: The potential effect of ZOFE and NEBI treatment was evaluated using human umbilical vein endothelial cells (HUVEC) as a model. Specifically, cells were challenged with tumor necrosis factor-α (TNF-α) to induce endothelial dysfunction. Subsequently, cell viability, NO production, protein levels of superoxide dismutase (SOD) and catalase (CAT), enzymatic activity of SOD and CAT, intracellular levels of glutathione (GSH), inflammatory status, and levels of interleukin-6 (IL-6) monocyte chemoattractant protein-1 (MCP-1), macrophage inhibitory cytokine-1 (MIC-1), and the active form of nuclear factor kappa B (p-NFκB), were analyzed.

Results: Our results showed that NEBI significantly counteracted oxidative stress, increasing the main antioxidant defenses (SOD, CAT, and GSH). The combination of ZOFE and NEBI resulted in a potentiated effect, enhancing both anti-inflammatory and antioxidant activities. This dual mechanism of action provides a comprehensive approach to protecting endothelial cells and improving vascular function. The combined therapy not only lowered blood pressure more effectively but also offered greater protection against endothelial damage compared to monotherapy with either drug alone. These findings suggest that the combination of ZOFE and NEBI could be particularly beneficial for patients with hypertension, especially those with coexisting inflammatory and oxidative stress-related conditions.

Conclusions: This combination therapy, by addressing multiple pathogenic pathways simultaneously, could potentially be beneficial in patients with cardiovascular risk conditions. In conclusion, the combination of ZOFE and NEBI offers a potentially promising therapeutic approach for managing hypertension and protecting vascular health, aiming at improving clinical outcomes for patients with cardiovascular diseases.

Clinical trial number: Not applicable.