BMC Pharmacology & Toxicology最新文献

Background: Dermatophytes, the primary causative agents of superficial cutaneous fungal infections in humans, present a significant therapeutic challenge owing to the increasing prevalence of recurrent infections and the emergence of antifungal resistance. To address this critical gap, this study was designed to investigate the antifungal potential of 3-benzylideneindolin-2-one against dermatophytes and assess its in vivo toxicological profile using brine shrimp and zebrafish embryo models.

Methods: The antifungal activity of 3-benzylideneindolin-2-one was evaluated against 30 clinical isolates of dermatophyte species, including Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum gypseum, Microsporum canis, and Epidermophyton floccosum, by determining the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) using the broth microdilution method. The fungicidal activity was evaluated using time-kill assays. Toxicological effects were investigated using the brine shrimp lethality assay to determine Artemia salina nauplii mortality after 48 h of exposure, and the fish embryo acute toxicity test, which assessed lethality and developmental abnormalities in zebrafish (Danio rerio) embryos over a 96 h post-fertilization period.

Results: 3-Benzylideneindolin-2-one exhibited consistent fungicidal activity across all dermatophyte species, with MICs ranging from 0.25 to 8 mg/L and MFCs ranging from 1 to 32 mg/L. Time-kill assays revealed a concentration-dependent fungicidal effect on the microconidia. The compound exhibited moderate toxicity to A. salina nauplii, with LC50 values of 69.94 mg/L and 52.70 mg/L at 24 and 48 h, respectively, while showing no significant lethality within the MIC range. In zebrafish embryos, concentrations below 7.5 mg/L did not significantly affect lethality, hatchability, or induce morphological abnormalities. However, at a concentration of 10 mg/L, the compound induced mild toxicity in embryos, evidenced by a significant increase in mortality and the presence of morphological anomalies such as yolk-sac and pericardial edema compared to the control group.

Conclusions: The consistent antifungal activity of 3-benzylideneindolin-2-one against clinically significant dermatophyte species, combined with its low toxicity within the therapeutic window, underscores its potential as a promising lead compound for the development of effective therapeutics for dermatophytosis.

Movento an insecticide containing spirotetramat, has been shown to cause severe toxicity in humans and rats. Due to the widespread use of the Movento in agriculture, and since the cardiac effects of this toxin have not been investigated in any study so far, in this study, for the first time, the effect of movento on the structure and function of the heart in rats was investigated. 24 adults' male Wistar rats randomly divided to 4 experimental groups: 1- control (CTL), 2- Movento (M) 3- M + Basal media (BM) 4- M + Conditioned medium (CM). Animals were subjected to deep anesthesia to record the ECG and blood pressure. H&E staining was performed to determine the degree of damage. Oxidative stress markers and inflammatory factors were investigated with related kits. In rats that received Movento's insecticide, mean arterial pressure (MAP), amplitude of the P wave and total antioxidant capacity (TAC) decreased compared to the control group and treatment with CM increased them significantly compared to M and M + BM group. Also, Movento increased histological score, MDA, TNF-α and IL-6 compared to the control group and CM significantly decreased them compared to M and M + BM groups. CM derived from mesenchymal stem cells (MSC) can be used as a therapy for heart disorders caused by movento toxin in the heart of rats. Also, it seems that this treatment could be a promising way to improve heart complications in farmers exposed to this toxin in the future.

Background: Diabetic neuropathy (DN) is a heterogeneous condition characterized by complex pathophysiological changes affecting both autonomic and somatic components of the nervous system. Inflammation and oxidative stress are recognized contributors to the pathogenesis of DN. This study aims to evaluate the therapeutic potential of dichloroacetic acid (DCA) in alleviating DN symptoms, focusing on its anti-inflammatory and antioxidant properties.

Methods: Thirty-two adult male Sprague Dawley rats were divided into four groups: Control, Diabetic, and two DCA-treated groups receiving 5 mg/kg and 10 mg/kg of DCA, respectively. Diabetes was induced with streptozotocin (STZ) injections. Assessments included lipid peroxidation levels, plasma fibroblast growth factor-21 (FGF-21) and transforming growth factor-beta (TGF-β) levels, electrophysiological measurements, histological examination of the sciatic nerve, and motor function tests.

Results: Treatment with DCA significantly reduced malondialdehyde (MDA) levels, indicating decreased lipid peroxidation. Plasma TGF-β levels were also lower in the DCA-treated groups, suggesting diminished inflammation. Conversely, plasma FGF-21 levels were elevated. Electrophysiological assessments revealed enhanced compound muscle action potential (CMAP) amplitudes and reduced distal latencies in DCA-treated rats, indicative of improved nerve conduction. Histopathological examinations showed reduced perineural thickness in the sciatic nerves of DCA-treated rats, pointing to decreased fibrosis. Enhanced performance in motor function tests was observed in these rats, implying improved muscle strength and motor capacity.

Conclusions: The study demonstrates that DCA therapy significantly reduces oxidative stress and inflammation in a rat model of DN, thereby ameliorating neuropathic symptoms. These results support the potential of DCA as a promising therapeutic agent for DN treatment. Further research is warranted to explore its clinical applications and to provide more detailed insights.

Objective: To determine the relative effectiveness of combination therapy of antidepressants with low-dose methylfolate versus antidepressant monotherapy in patients with depressive disorder.

Methods: In an open-label clinical trial, forty-four patients with depressive disorder (6A70, 6A71, and 6A72 according to ICD-11) received an evidence-based antidepressant therapy (either escitalopram 10-20 mg, sertraline 50-100 mg, fluoxetine 20-40 mg, duloxetine 30-60 mg, mirtazapine 15-30 mg, venlafaxine 75-150 mg, trazodone 50-100 mg, amitriptyline 25-75 mg, or clomipramine 25-75 mg orally daily for 4 weeks). The experimental group, Group B was additionally given a dose of methylfolate 800 µg daily for four weeks. The psychometric testing of depression was achieved through administration of Patient Health Questionnaire-9 (PHQ-9) on days 0, 14, and 28, to find the improvement in the depressive score on day 28, the remission rate on day 28, and decrease in the time lag on day 14. Adverse effects were analyzed by self-assessment questionnaire to observe the tolerability. The paired sample t-test and the independent sample t-test were applied for analysis by using SPSS v27.0. The p-value ≤ 0.05 was considered statistically significant.

Results: On day 28, patients on low dose methylfolate and antidepressant combination therapy showed a 40.33% improvement in depression symptoms, compared to 26.43% in patients on antidepressant monotherapy (p-value < 0.05). This treatment strategy had no effect on the time-lag of outcomes on day 14 and the remission rate on day 28 was not found statistically significant. Only one patient reported insomnia, while another mentioned irritability.

Conclusion: Combination therapy of antidepressants with low-dose methylfolate may provide a safe and effective treatment strategy for patients with depressive disorder.

Clinical trial identifier: NCT05931965.

Clinicaltrials: gov. https://classic.

Clinicaltrials: gov/ct2/show/NCT05931965.

Background: Cypermethrin (CYP), a synthetic pyrethroid widely used to control plant pests, has been associated with various diseases in humans exposed to pesticides, either directly or indirectly. This study aimed to examine the effects of CYP on learning and memory functions, as well as anxiety-like behavior.

Methods: Forty male Wistar rats (8 weeks old) were randomly assigned to 4 groups: The first group served as the control, while the other three groups received different doses of CYP (5, 20, and 80 mg/kg) via gavage once daily for one month. Passive avoidance learning (PAL) and memory were assessed using the shuttle box test, cognitive memory was evaluated using the novel object recognition (NOR) test, and spatial memory was measured with the Morris water maze (MWM) test. The elevated plus-maze (EPM) and open field tests were used to assess locomotor activity and anxiety levels.

Results: In the PAL test, significant differences were observed in the time spent in the dark compartment (TDC) and step-through latency in the retention trial (STLr) in rats receiving 80 mg/kg of CYP. MWM results indicated memory impairment in rats treated with 20 and 80 mg/kg of CYP. Additionally, rats treated with the highest dose of CYP (80 mg/kg) showed a reduction in the number of entries into the open arms of the EPM compared to the control group.

Conclusion: This study demonstrates that CYP negatively affects learning and memory retention. Further research is needed to explore the precise mechanisms by which this toxin impacts cognitive functions.

Background: Few Chinese study compared the impacts of idarubicin and daunorubicin based "3+7" intensive chemotherapies on early and long-term outcomes of AML patients through exploring their real-world data.

Patients and methods: Our none promyelocytic AML patients inducted with "3+7" regimens were studied to find out the factors relating with induction response and long term survival.

Results: Idarubicin induction was related with less chemotherapy refractory rate comparing with daunorubicin induction (10% vs 25%, P = 0.02). But cytogenetic molecular risk classification was the only independent factor relating with achieving CR after initial induction or chemotherapy refractory (P = 0.000 and 0.036). Both to overall survival (OS) and progress free survival (PFS), having transplantation and chemotherapy refractory were independent factors related, MLL rearrangement and DNA methylating related genes' mutations as well. CR at time of transplantation and MLL rearrangement were independent factors relating both with OS after transplantation and relapse free survival after transplantation.

Conclusion: Traditional "3+7" chemotherapy regimen with idarubicin plays better in CR induction than that with daunorubicin. But the patient's long-term survival related with clinical practice aspects, like having stem cell transplantation, as well as genetic alterations equally, like MLL rearrangement and DNA methylating related genes' mutations.

Background: Interleukin-23 (IL-23) inhibitors and the IL-12/23 inhibitor ustekinumab constitute a pivotal class of therapeutic agents employed in the clinical management of Psoriasis, a chronic immune-mediated skin disorder. Notwithstanding their therapeutic efficacy, concerns have arisen due to the emergence of multiple adverse events (AEs) associated with their usage. This study aims to provide a comprehensive examination of the distribution and characteristics of these AEs concerning IL-23 and IL-12/23 inhibitors, with a specific focus on guselkumab, tildrakizumab, risankizumab, and ustekinumab.

Methods: In this research endeavor, we conducted an extensive analysis of data extracted from the FDA Adverse Event Reporting System (FAERS), spanning the timeframe from January 1, 2014, to September 30, 2022. To identify potential signals of AEs, we rigorously applied disproportionality analysis, utilizing both reporting odds ratio (ROR) and information component (IC) metrics. A signal was considered present when the lower limit of the 95% confidence interval (CI) for ROR (ROR025) exceeded one or when IC (IC025) surpassed zero, with a minimum requirement of three or more reported cases.

Results: Our investigation encompassed a substantial dataset, comprising a total of 41,408,408 reports detailing drug-AE associations and involving 13,271,168 individuals. Among these, 704, 13,164, and 11,399 patients were identified as users of the IL-23 inhibitors tildrakizumab, guselkumab, and risankizumab, respectively, while 62,853 patients were identified as users of the IL-12/23 inhibitor ustekinumab. The analysis revealed the presence of 8, 20, 107, and 115 signals for these respective drugs. Significantly, the System Organ Class (SOC) exhibiting the highest incidence was "infections and infestations," with documented occurrences in tildrakizumab (6/8), guselkumab (5/20), ustekinumab (50/107), and risankizumab (25/115).

Conclusion: Our pharmacovigilance analysis has brought to light a substantial frequency of AEs linked to IL-23 and IL-12/23 inhibitors. These findings underscore the pivotal role of IL-23 and IL-12/23 inhibitors in modulating immune function and raise concerns regarding their potential to heighten susceptibility to infections and malignancies. However, limitations inherent to the FAERS database, including underreporting, lack of denominator data, potential duplicate records, and inability to confirm causality, should be acknowledged of particular significance is risankizumab, which, despite having fewer reported cases and a later market introduction compared to ustekinumab, exhibited a higher incidence of AEs. These results emphasize the necessity for ongoing vigilance, further investigation, and a reevaluation of the safety profile of IL-23 and IL-12/23 inhibitors in the clinical management of Psoriasis.

The study evaluated the anti-hyperlipidemic effects of myrcenol and curzerene on a high fat diet induced hyperlipidemia rat model. Thirty male albino rats were fed on a high-fat diet for four months. The HFD-induced hyperperlipidemia rats were treated with rosuvastatin (10 mg/kg), curzerene (130 mg/kg) and myrcenol (100 mg/kg) for four weeks. Blood samples were collected for further analysis. Aorta and heart were harvested for histopathological evaluation. Hepatic lipase and HMG-CoA reductase were determined by ELISA. FST and Y-maze tests were performed to assess the stress level in hyperlipidemia rats. The phytochemical compounds (Curzerene and Myrcenol) and the standard drug (Rosuvastatin) resulted in decreased body weight as well as reduced levels of LDL, TG, TC, AST and ALT as compared to the diseased group. Additionally, the treated groups displayed improved HDL levels and less depressed behavior. The ELISA results revealed that the Curzerene and myrcenol had significantly increased the protein concentration of hepatic lipase than the diseased group whereas both compounds significantly lowered the HMG-CoA reductase concentrations compared to the diseased group. The findings suggested that myrcenol and curzerene had the potential to be therapeutic agents for managing hyperlipidemia and reducing the risk of heart-related conditions associated with high lipid levels.

Objectives: We conducted a meta-analysis to investigate the effect of dexmedetomidine on postoperative delirium in elderly orthopedic surgery patients.

Methods: A meta-analysis was conducted to identify randomized controlled trials of dexmedetomidine in elderly patients undergoing orthopedic surgery. The data was published on October 25, 2024. PubMed, Embase, and Cochrane Library databases were searched. Outcome measures included incidence of delirium, length of hospital stay, visual analogue scale, and postoperative complications. Estimates are expressed as relative risk (RR) or mean difference (MD) with a 95% confidence interval (CI). The publications were reviewed according to the guidelines of the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Results: This study was registered with INPLASY (number INPLASY2024110004). A total of 3159 patients were included in 9 randomized controlled trials. The results showed that dexmedetomidine exhibited a preventive effect on delirium compared with the control group in elderly patients after orthopedic surgery (RR: 0.55, 95% CI: 0.45-0.66, P < 0.01, I² = 0%). Subgroup analysis suggested that dexmedetomidine was significantly different from saline(RR: 0.56; 95% CI: 0.44-0.73, P<0.01, I²=31%) and propofol(RR: 0.52; 95% CI: 0.39-0.70, P<0.01, I²=0%) in reducing postoperative delirium in elderly fracture patients. No statistically significant differences were observed in length of hospital stay, visual analogue scale, and postoperative complications (P > 0.05). Certainty of evidence for postoperative delirium was moderate.

Conclusions: Dexmedetomidine has been shown to have a protective effect on postoperative delirium in elderly patients following orthopedic surgery.

Background: Piperine, a secondary metabolite, affects the antihyperlipidemic effect of Ezetimibe (EZ). Hyperlipidemia is one of the independent risk factors for cardiovascular disorders such as atherosclerosis. Antihyperlipidemic drugs are essential for reducing cardiovascular events and patient mortality. Our study aimed to improve the solubility of EZ, a lipid-lowering drug that belongs to BCS II and has low solubility. Piperine, a bioenhancer, can increase the bioavailability of other pharmaceuticals without modifying their fundamental characteristics or enhancing their efficacy. The objective of this study was to increase the bioavailability of EZ while also improving its potency and reducing its toxicity by using piperine as a bioenhancer. Therefore, rats were given piperine combined with EZ, and their antihyperlipidemic activity was assessed while fed a high-fat diet.

Method: The in vivo antihyperlipidemic effect of EZ with piperine was assessed at doses of 10 and 5-20 mg/kg b.w. The evaluation was conducted using propylthiouracil-induced and triton X-100-induced hyperlipidemia in rats. Give 400 mg/kg body weight of propylthiouracil along with piperine. Serum levels of total cholesterol (TC) (p < 0.01), triglycerides (TG) (p < 0.01), low-density lipoprotein (LDL) (p < 0.01), and very low-density lipoprotein (VLDL) (p < 0.01) all went up significantly. Additionally, it led to the induction of high-density lipoprotein (HDL) (p < 0.01). Administration of Triton X-100 via intraperitoneal injection at a single dose resulted in an elevation of lipid levels.

Results: Lower levels of high-density lipoprotein (LDL), total cholesterol (TC), triglycerides (TG), and very low-density lipoprotein (VLDL) were significantly reduced by EZ at 10 mg/kg b.w. and piperine at 20 mg/kg b.w., respectively (p < 0.01 and p < 0.05). Liver histology studies provided further evidence supporting the present findings. Areas of concentrated periportal lymphocytes and hepatocytes formed a cord pattern in rats with hyperlipidaemia. It seemed like the hepatocytes, periportal area, and centrilobular part of the liver were all normal in the group who had the treatment. An analysis of the EZ plasma drug concentration with time was carried out in a research. The medication's most effective concentration (Cmax) was determined to be within 4 h after delivery, and The quantified concentration of the active medication was detectable in the bloodstream for 24 h.

Conclusion: In combination with piperine, EZ has demonstrated significant antioxidant and antihyperlipidemic effects. This indicates that EZ could be further utilised for treating hyperlipidemia and atherosclerosis due to its potential to boost the bioavailability and oral absorption of the drug.