BMC Pharmacology & Toxicology最新文献

Background: Heat stroke (HS) can lead to the development of pulmonary ferroptosis. The inhibition of pulmonary ferroptosis during HS improves patient prognosis. The aim of this study was to investigate the effects of resveratrol (RES) on heat stress at an ambient temperature of 42 °C.

Methods: Heat stress was induced in Beas-2B cells and lung injury was induced in HS rats at an ambient temperature of 42 °C. The anti-oxidative stress and anti-ferroptotic effects of RES were confirmed through tail vein injection of nuclear factor-2 associated factor (Nrf2) shRNA recombinant adeno-associated virus 6 (AAV6-shNrf2).

Results: RES treatment attenuated the upregulation of reactive oxygen species (ROS) and malondialdehyde (MDA) levels and alleviated glutathione inhibition in HS. In addition, RES treatment reduced the accumulation of Fe²⁺ in heat-stressed Beas-2B cells and increased the ferroptosis resistance-related proteins FTH1, GPX4, and SLC7A11 as well as the anti-oxidative stress pathway proteins Nrf2, NQO1, and HO-1. The antioxidant and anti-ferroptotic effects of RES in heat-stressed Beas-2B cells were effectively reversed upon treatment with Nrf2-IN-1, an Nrf2 pathway inhibitor. In the HS rat model, the antioxidant and anti-ferroptotic effects of RES were reversed by an ambient temperature of 42 °C and relative humidity of 60 ± 5%.

Conclusions: RES effectively protected HS rats from lung injury, inhibited the accumulation of Fe²⁺, ROS, and MDA in the lung, and upregulated FTH1, GPX4, SLC7A11, Nrf2, NQO1, and HO-1.

Excessive fluoride exposure beyond the tolerable limit may adversely impacts brain functionality. Betaine (BET), a trimethyl glycine, possesses antioxidant, anti-inflammatory and anti-apoptotic functions, although the underlying mechanisms of the role of BET on fluoride-induced neurotoxicity remain unelucidated. To assess the mechanism involved in the neuro-restorative role of BET on behavioural, neurochemical, and histological changes, we employed a rat model of sodium fluoride (NaF) exposure. Animals were treated with NaF (9 mg/kg) body weight (bw) only or co-treated with BET (50 and 100 mg/kg bw) orally uninterrupted for 28 days. We obtained behavioural phenotypes in an open field, performed negative geotaxis, and a forelimb grip test, followed by oxido-inflammatory, apoptotic, and histological assessment. Behavioural endpoints indicated lessened locomotive and motor and heightened anxiety-like performance and upregulated oxidative, inflammatory, and apoptotic biomarkers in NaF-exposed rats. Co-treatment with BET significantly enhanced locomotive, motor, and anxiolytic performance, increased the antioxidant signalling mechanisms and demurred oxidative, inflammatory, and apoptotic biomarkers and histoarchitectural damage in the cerebrum and cerebellum cortices mediated by NaF. The in-silico analysis suggests that multiple hydrogen bonds and hydrophobic interactions of BET with critical amino acid residues, including arginine (ARG380 and ARG415) in the Keap1 Kelch domain, which may disrupt Keap1-Nrf2 complex and activate Nrf2. This may account for the observed increased in the Nrf2 levels, elevated antioxidant response and enhanced anti-inflammatory response. The BET-Keap1 complex was also observed to exhibit structural stability and conformational flexibility in solvated biomolecular systems, as indicated by the thermodynamic parameters computed from the trajectories obtained from a 100 ns full atomistic molecular dynamics simulation. Therefore, BET mediates neuroprotection against NaF-induced cerebro-cerebellar damage through rats' antioxidant, anti-inflammatory, and anti-apoptotic activity, which molecular interactions with Keap1-Nrf2 may drive.

Purpose: Cinnamaldehyde, has various therapeutic potentials including glucose-lowering effect, and insulinotropic effect; however, its glycation inhibitory mechanism is not known yet. In this study, we explored the effects of cinnamaldehyde for its AGEs inhibitory mechanism in a streptozotocin-complete Freund's adjuvant (STZ-CFA) induced diabetic nephropathy (DN) rat model.

Methods: Pre-clinical DN model was developed by the administration of multiple low doses of STZ-CFA in rats, mainly characterized by abnormal blood parameters and nephrotic damages. Diabetes-related systemic profile and histopathological hallmarks were evaluated using biochemical assays, microscopic imaging, immunoblot, and real-time PCR analyses, supported by cinnamaldehyde-albumin interaction assessed using STD-NMR and in silico site-directed interactions in the presence of glucose.

Results: Cinnamaldehyde-treatment significantly reversed DN hallmarks, fasting blood glucose (FBG), serum insulin, glycated hemoglobin (HbA1c), urinary microalbumin, and creatinine contrasted to non-treated DN rats and aminoguanidine, a positive reference advanced glycation end products (AGEs) inhibitor. The pathological depositions of AGEs, receptor for advanced glycation end products (RAGE), and carboxymethyl lysine (CML), and transcriptional levels of AGE-RAGE targeted immunomodulatory factors (IL1β, TNF-α, NF-κB, TGF-β) were significantly improved in cinnamaldehyde treated rats as compared to aminoguanidine. Cinnamaldehyde post-treatment improved pancreatic pathology and systemic glycemic index (0.539 ± 0.01 vs. 0.040 ± 0.001, P < 0.001) in DN rats. Subsequently, in silico profiling of cinnamaldehyde defined the competitive binding inhibition with glucose in AGE and RAGE receptors that was further confirmed by in vitro STD-NMR analysis.

Conclusion: These findings suggest potential role of cinnamaldehyde in reversing STZ-induced diabetic nephropathic impairments; therefore, appears promising candidate for further pharmacological explorations towards diabetes-associated complications.

Background: Beta-blockers are widely used, with continuously updated clinical recommendations. However, their application faces challenges in personalized treatment and safety. The study aimed to investigate the frequency and patterns of prescribing beta-blockers in China and to explore potential adverse event risk signals associated with beta-blockers, providing reference for rational medication use in clinical settings.

Methods: Prescription data for beta-blockers from January 2018 to June 2023 were extracted through the Hospital Prescription Analysis Collaborative Project in China to analyze clinical usage trends. While adverse drug reaction reports for beta-blockers were obtained from the FDA Adverse Event Reporting System (FAERS) database. The classification and standardization of adverse drug event (ADE) reports were based on the preferred terms (PT) and corresponding system organ classes (SOC) from the Medical Dictionary for Regulatory Activities (MedDRA). Signal detection utilized a proportion imbalance method.

Results: In clinical practice, metoprolol dominated beta-blocker prescriptions in China, accounting for 62.2%. Beta-blockers were primarily prescribed to the elderly (65.7%) and male patients (57.0%). However, off-label use of beta-blockers was relatively widespread. For instance, sotalol was prescribed for hypertension at 18.25%, while esmolol was used for angina and heart failure at rates of 12.94% and 14.98%, respectively. In addition, we identified newly discovered adverse reactions associated with beta-blockers, such as BRASH syndrome (metoprolol: n = 186, ROR = 391.285; carvedilol: n = 72, ROR = 256.459), acute kidney injury (bisoprolol: n = 247, ROR = 5.641), premature baby (labetalol: n = 110, ROR = 91.385), and sleep disorder (propranolol: n = 254, ROR = 10.98).

Conclusions: Metoprolol led the beta-blocker market in China. Attention was warranted regarding the newly discovered adverse reactions, such as the risk of acute kidney injury with bisoprolol and the potential for BRASH syndrome with metoprolol and carvedilol.

Effervescent formulation helps in faster and better absorption of drugs, especially those that are rapidly soluble in water. However, these tablets require special packaging in order to prevent them from absorbing moisture, hence increasing cost. We compared an effervescent tablet prepared using an in-house developed method (multi-layer tablet with acid and base part separated by an inert layer) to a European effervescent tablet (Efferalgan®) in a single-center, randomized cross-over study among twelve healthy volunteers. Blood samples were collected for 8 h and analyzed for paracetamol concentration using HPLC. Our results showed that both the products have similar pharmacokinetic profiles with no significant difference observed for C_last, T_half, K_elim, and MRT (p-value > 0.05). Moreover, to assess bioequivalence we did not find any significant difference (p-value > 0.05) in AUC (27.12 ± 6.02 vs. 27.29 ± 2.64 µg.h/ml), C_max (7.42 ± 1.06 vs. 7.83 ± 1.19 µg/ml) and t_max (0.85 ± 0.22 vs. 0.83 ± 0.25 h). The TR ratios for AUC, C_max, and t_max were 0.99, 0.95, and 1.02 respectively, and were all within the specified FDA limits i.e., 0.8-1.25. We found our test tablet to be bioequivalent to that of Efferalgan®.

Background: Renal ischemia-reperfusion injury (IRI) is a significant contributor to renal dysfunction, acute kidney injury (AKI), and associated morbidity and mortality. Resveratrol, a polyphenol and phytoalexin, is known for its anti-inflammatory, antioxidant, and anti-cancer properties. This study investigates the nephroprotective potential of resveratrol in a rat model of renal IRI.

Materials and methods: Twenty-eight male Sprague-Dawley rats were divided into four groups: Sham, IRI, DMSO, and Resveratrol. The Sham group underwent identical procedures without renal pedicle clamping, while the IRI group experienced 30 min of ischemia followed by 2 h of reperfusion. The DMSO group received dimethyl sulfoxide (DMSO) intraperitoneally 30 min before ischemia, and the Resveratrol group received 30 mg/kg resveratrol intraperitoneally 30 min before ischemia. Biochemical parameters (Urea, creatinine, IL-1β, NF-κβ, SOD, GSH, Bcl-2, and caspase-3) and histopathological changes were assessed.

Results: IRI caused a substantial increase in serum creatinine, Urea, IL-1β, NF-κβ, and caspase-3 levels, while simultaneously decreasing SOD, GSH, and Bcl-2 levels. Resveratrol treatment mitigated these effects by lowering inflammatory and apoptotic markers, enhancing antioxidant defenses, and improving histological outcomes.

Conclusion: Resveratrol demonstrates significant nephroprotective effects in renal IRI, primarily through its antioxidant, anti-inflammatory, and anti-apoptotic properties.

Background: The utilization patterns of opioid analgesics and the proportion of long-term opioid use after surgery in Norway is largely unknown.

Methods: This study aimed to estimate the proportion of one-year long-term prescription opioid use among all Norwegian postoperative opioid users. Complete data from central health registries (NPR, NorPD, Statistics Norway, CoDR) were linked via the personal identification number unique to all citizens. The study period was January 1st 2010 until December 31st 2019. Long-term opioid use was defined as at least two opioid dispensings within two subsequent 90-day periods, with a minimum average use of 10 MME/day for the first 90 days.

Results: The study population consisted of 693 495 post-operative opioid users (53.6% women), whereof 73.2% had not used opioids the year before surgery (new users). Among the postoperative opioid users, 3.8% were one-year long-term opioid users. The corresponding figures for new and previous opioid users were 0.4% and 13.1%, respectively. The highest proportions of long-term opioid use were found after transluminal endoscopy, eye surgery and assessments related to surgical procedures. In previous opioid users, the proportion of one-year long-term use was higher among women than men in all age groups, a difference that increased with age.

Conclusions: The proportion of postoperative long-term opioid use in Norway is generally low. We detected higher proportions of long-term opioid use after certain types of surgery, but our crude surgery definition warrants further examination. Previous opioid users pose a particular challenge in the management of postoperative pain.

Trial registration: The study used national health registry data from the period 2010-2019. A pre-registered analysis plan is available at Open Science Framework.

This study aims to determine the bioequivalence of the reference preparation and the test preparation containing eltrombopag when both were given during the COVID-19 pandemic while fasting. Participants in the research were healthy male Caucasian subjects. One film-coated tablet of the test preparation or one film tablet of the reference preparation, equivalent to 75 mg of eltrombopag, was given to the participants in a randomized order throughout each treatment session. At pre determined blood sampling points, blood samples were taken to determine the pharmacokinetics of eltrombopag. Eltrombopag concentrations in the samples were determined using an LC-MS/MS technique verified using ESI(-). The study results were used to calculate the rate (the maximum plasma concentration, or C_max) and extent (area under the concentration-time curve of plasma, or AUC_(0-72) and AUC_(0-t) of eltrombopag absorption from the test preparation and reference preparation. The 90% confidence intervals (CI) of the ln-transformed AUC_(0-72), AUC_(0-t), and C_max of eltrombopag met the bioequivalence requirements of 80.00-125.00%. Both trial preparations had a similar and very satisfactory safety profile.

Introduction: Oritavancin is a semi-synthetic lipoglycopeptide antibiotic primarily used to treat serious infections caused by Gram-positive bacteria. The aim of this study was to elucidate possible molecular targets of oritavancin in human and microbes in relevance to its mechanism of action and model its pharmacokinetics for optimal dose selection in clinical practice.

Methods: Computational methods were used in this study which include target prediction, molecular docking, molecular dynamics simulation, pharmacokinetics prediction, and physiological-based pharmacokinetics (PBPK) modeling.

Results: Oritavancin was moderately soluble in water and did not permeate the blood-brain barrier. Seven molecular targets were identified in humans. Molecular docking results showed highest binding affinity of oritavancin with PI3-kinase p110-gamma subunit (-10.34 kcal/mol), followed by Acyl-CoA desaturase (-10.07 kcal/mol) and Cytochrome P450 2C19 (-8.384 kcal/mol). Oritavancin PBPK modelling in adult human showed that infusion has lower peak concentrations (Cmax) compared to bolus administration, with 1200 mg dose yielded Cmax of 16.559 mg/L, 800 mg dose yielded Cmax of 11.258 mg/L, and 200 mg over 3 days dose yielded Cmax of 7.526 mg/L. Notably, infusion gave extended half-life (t_1/2) for all doses and slightly higher clearance rates compared to bolus, particularly for the 1200 mg and 800 mg doses. The results corroborated existing clinical pharmacokinetic data, and confirmed the model's accuracy and predictive capability.

Conclusion: This comprehensive computational study has provided invaluable insights into the pharmacological profile of Oritavancin, aiding its further development and optimization for clinical use.