BMC Pharmacology & Toxicology最新文献

Background: Rupture of unstable coronary atherosclerotic plaque leads to acute ST-segment elevation myocardial infarction (STEMI). Dual anti-platelet therapy is one of the main treatments, and the combination of Aspirin and Clopidogrel is recognized as the standard oral regimen in most cases. Ticagrelor is a new generation of P2Y12 receptor inhibitors. We aimed to compare the effect of Ticagrelor and Clopidogrel in the treatment of patients post-STEMI.

Methods: This study investigated Pub Med, Scopus, Google Scholar Web of Science, and Embase Cochrane Library clinical trials.gov databases. Heterogeneity between studies was assessed using the I2 index and the Q statistic. The random effects model was used to combine studies and the Funnel plot and Egger's test were used to assess the publication bias.

Results: Eleven studies were included in this meta-analysis. 5274 patients in the Ticagrelor and 5,295 patients in the Clopidogrel groups were examined. The mean age of the patients was 58.84 years (2.70) and 59.92 years (3.19) in the Ticagrelor and Clopidogrel groups, respectively. Based on the results of the meta-analysis, compared to Clopidogrel, Ticagrelor had decreased the outcomes of mortality, recurrent myocardial infarction, stroke, and Major Adverse Cardiovascular Events (MACE). However, the post-myocardial infarction bleeding according to Bleeding Academic Research Consortium (BARC) criteria and reperfusion state regarding thrombolysis in myocardial infarction (TIMI) Flow Grading system showed no differences in both groups. However, these effects were not statistically significant.

Conclusions: Ticagrelor decreased the chance of mortality, re-infarction, stroke, and MACE in post-STEMI patients compared to clopidogrel. But there was no difference in the chance of major bleedings (BARC ≥ 3) and improvement in TIMI grade flow between these two drugs. However, none of these findings were statistically significant, and more studies are needed to reach definitive results.

Background: Local drug presentation made possible by drug-eluting depots provides benefits for a vast array of diseases, including cancer, microbial infection, and wound healing. Drug-eluting depots provide sustained drug release of therapeutics directly at disease sites with tunable kinetics, remove the need for drugs to access disease sites from circulation, and reduce the side effects associated with systemic therapy. Recently, we introduced an entirely novel approach to local drug presentation named Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs enables local drug presentation without any material carriers, capitalizing on innate tissue structures to anchor drugs at the site of administration.

Methods: In this report, we comprehensively evaluate the local and systemic toxicological profile of a paclitaxel version of TRAPs in mice by clinical observations, body weight monitoring, histopathological evaluations of injection sites and major organs, as well as blood and urine analyses.

Results: We find that intradermal administration of TRAP-paclitaxel does not induce substantial toxic effects. Localized inflammatory responses were observed at the injection sites and secondary minimal, non-specific inflammation was observed in the liver. All other organs displayed unremarkable histological findings.

Conclusions: These findings support the potential of TRAP-paclitaxel as a promising candidate for localized cancer treatment, offering high-concentration drug delivery while mitigating scarring and adverse side effects.

Introduction: Use of antibiotic prophylaxis before transurethral resection of the prostate (TURP) is highly recommended. However, there is no agreement on the use of a single antibiotic for this purpose. This study aimed to compare the prophylactic effect of cefazolin injection with oral levofloxacin on postoperative complications in TURP surgery.

Trial design: Body temperature and urine culture results were obtained two and five days after surgery. Drugs' side effects as well as surgery and catheterization time were also recorded.

Methods: In an analytical-comparative trial, the participants were randomly divided into two groups to receive cefazolin or levofloxacin before the surgery.

Results: The duration of surgery (min) and catheterization (days) were 41.5 ± 11.7 and 4.7 ± 1.8 for levofloxacin-treated group and 43.9 ± 11.9 and 4.7 ± 1.8 for cefazolin-treated group, respectively. The number of positive urine cultures, 2 and 5 days post-surgery were 12 and 14 for levofloxacin-treated group and 9 and 12 for cefazolin-treated group, respectively. Furthermore, both groups reported one fever two days after surgery and had no fever after 5 days. In total, no significant difference was observed between the two groups. Additionally, no correlation was observed between the demographic data (i.e. age, BMI and prostate volume) and the postoperative complications (i.e. fever and urinary culture tests), except between age and urinary culture 2 days after the surgery.

Conclusion: Considering the lack of significant differences between the two groups, the use of oral levofloxacin is suggested as an easy to take and cost-effective alternative to injection of cefazolin before TURP surgery.

Trial registration: Iranian registry of clinical trials, IRCT registration number IRCT20160514027893N4, available through www.irct.ir , Registration date: 2024-03-13 (Retrospectively registered).

Objectives: Melatonin has been demonstrated to exert a preventive effect on delirium. This meta-analysis sought to investigate the preventive effects of melatonin and melatonin receptor agonists (ramelteon) on delirium in hospitalized elderly patients.

Methods: This systematic review and meta-analysis delineates the risk of delirium events in older hospitalized patients with melatonin/ramelteon compared with placebo, incorporating randomized controlled trials published up to 8 July 2024. The databases searched were PubMed, Embase and the Cochrane Library. The primary outcome measures were the incidence of delirium, while the secondary outcome measures were the length of hospital stay and mortality. The results are presented as odds ratios (OR) or mean differences (MD) with a 95% confidence interval. The review of publications was conducted in accordance with the guidelines set forth in the Cochrane Handbook and the Preferred Reporting Project for Systematic Review and Meta-Analysis (PRISMA). This study has been registered with INPLASY (number INPLASY202470044).

Results: A total of 2086 patients were included in 13 randomized controlled trials. The primary outcome of this meta-analysis demonstrated a statistically difference in the incidence of delirium between the melatonin and placebo groups in hospitalized elderly patients (OR = 0.59, 95% CI: 0.40-0.87, P < 0.01, I² = 60%), particularly in those who had undergone surgery (OR = 0.60, 95%CI: 0.40-0.89, P = 0.01, I² = 53%). No statistically differences were observed in terms of length of stay (MD=-0.07, 95%CI:-1.09-0.94, P = 0.89, I² = 72%) and mortality (OR = 0.79, 95%CI:0.58-1.06, P = 0.12, I² = 0%).

Conclusions: Melatonin has been demonstrated to exert a protective effect on delirium in elderly patients who are hospitalized, particularly in the context of perioperative care.

Background: Chemotherapy is often ineffective as a first-line treatment for head and neck squamous cell carcinoma (HNSCC), and a more precise and effective therapeutic option is urgently needed.

Methods: High-throughput screening of a histone demethylase inhibitor library was performed to identify potential drugs for treating HNSCC. The Cancer Genome Atlas (TCGA) and single-cell sequencing were used to evaluate the potential diagnostic value and expression distribution of candidate drug targets. Colony formation, transwell assays, and flow cytometry analyses were used to assess the antitumor function of the potential drugs. The CCK-8 assay was used to compare the antitumor activity of the candidate drug and the traditional chemotherapy drug. Bioinformatic analysis based on TCGA database was used for unveiling the upstream signaling.

Results: Pulrodemstat, a selective KDM1A inhibitor that is ongoing clinical trial, stood out as the most effective candidate anti-HNSCC drug based on the high-throughput screening. IC₅₀ analysis revealed that Pulrodemstat might possess stronger anti-tumor activity than 5-Fu. Additionally, Pulrodemstat dramatically suppressed HNSCC cell proliferation and migration without inducing toxicity in normal cells. TCGA analysis revealed that KDM1A is positively associated with tumor proliferation, DNA repair, and DNA replication in HNSCC. Consistent with these results, Pulrodemstat substantially induced apoptosis in the HNSCC cells. Furthermore, TCGA analysis revealed that KDM1A was aberrantly overexpressed in HNSCC, positively correlated with malignancy, and negatively associated with the clinical outcomes of HNSCC patients. Notably, single-cell analysis indicated that KDM1A was mainly distributed in the malignant cells of HNSCC samples, highlighting that Pulrodemstat may be a more precise therapeutic option for HNSCC. In addition, methylation occupancies in the KDM1A promoter were substantially low in HNCC tumors, and low methylation occupancies in the KDM1A promoter predicted poor clinical outcomes in HNSCC. These data are consistent with the KDM1A expression in HNSCC. Moreover, TET3, a DNA demethylase, was strongly and positively correlated with KDM1A expression.

Conclusions: Pulrodemstat is an effective therapeutic drug for HNSCC. Thus, the TET3/KDM1A axis may account for the malignant phenotype of HNSCC.

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.