BMC Pharmacology & Toxicology最新文献

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.

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.

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.

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.

Hepatic encephalopathy (HE) is a syndrome that arises from acute or chronic liver failure. This study was devised to assess the impact of a combination of boswellic acid (BA) and low doses of gamma radiation (LDR) on thioacetamide (TAA)-induced HE in an animal model. The effect of daily BA treatment (175 mg/kg body weight, for four weeks) and/or fractionated low-dose γ-radiation (LDR; 0.25 Gy, twice the total dose of 0.5 Gy) was evaluated against TAA (200 mg/kg, intraperitoneal) twice-weekly for four weeks to induce liver damage and HE in rats. TAA-exposed rats exhibited a significant elevation in serum activities of liver enzymes (GGT, ALP) and plasma ammonia levels at P < 0.05 (Duncan's test) compared to the control group. Moreover, there was an increase in the levels of proinflammatory cytokines (IL6, IL12, IL18) in the TAA-exposed animals accompanied by a depletion in the activities of paraoxonase-1 and neurotransmitter contents compared with normal control rats (P < 0.05). However, the administration of BA alone or in combination with LDR led to improvements in liver and brain parameter indices. Furthermore, the histopathological assessments of liver and brain tissues supported the findings of the biochemical investigations. From the statistical analysis, it can be concluded that the combined administration of BA and exposure to LDR may possess potential hepatoprotective effects against hepatic encephalopathy-associated hyperammonemia and the consequent damage to the liver and brain. This study proposes that a combination of therapeutic approaches, LDR and BA could be a new therapeutic candidate for the management of hepatic encephalopathy.

Objective: The occurrence of hypofibrinogenemia after tocilizumab treatment has attracted increasing attention, which may cause bleeding and even life-threatening. This study aims to explore the risk factors for tocilizumab-induced hypofibrinogenemia (T-HFIB) and construct a risk prediction model.

Methods: A total of 221 inpatients that received tocilizumab from 2015 to 2023 were retrospectively collected and divided into T-HFIB group or control group. The risk factors for T-HFIB were obtained by logistic regression equation and used to establish the nomogram.

Results: T-HFIB was observed in 121 of 221 patients (54.75%). Multifactorial logistic regression analysis revealed that infection (OR = 2.002, 95%CI:1.018 ~ 3.935), COVID-19 (OR = 3.752, 95%CI:1.264 ~ 11.139), CAR-T therapy (OR = 4.409, 95%CI:2.017 ~ 0.894), and concomitant glucocorticoids (OR = 5.303, 95%CI:0.227 ~ 0.894) were identified as independent risk factors for T-HFIB, while high baseline fibrinogen level (OR = 0.813, 95%CI:0.670 ~ 0.988) and concomitant antirheumatic drugs (OR = 0.451, 95%CI:0.227 ~ 0.894) were identified as protective factors. A nomogram was established, and area under the curve (AUC) of prediction model was 0.772 (95%CI:0.709 ~ 0.836). Calibration curve showed a good prediction accuracy for the occurrence of T-HFIB.

Conclusion: The infection, COVID-19, CAR-T therapy, and concomitant glucocorticoids were independent risk factors for T-HFIB, while high baseline fibrinogen and concomitant antirheumatic drugs were protective factors. This nomogram can help early identify the patients at potential high risk of developing T-HFIB.

Background: In patients with sepsis, platelets are activated and adhere to neutrophils, forming platelet-leukocyte aggregates (PLAs) that lead to the development of MODS. ARDS is one of the main manifestations of septic MODS. We designed this study to explore the effects of different anti-plate therapy drugs on platelet activation and platelet-leukocyte aggregate (PLA) formation in the early stage of septic ARDS.

Methods: Sixty adult male SD rats were randomly divided into: Control group; ARDS group, ARDS + aspirin group, ARDS + clopidogrel group and ARDS + tirofiban group. ARDS was performed via instill lipopolysaccharide (LPS) intratracheally at a dose of 5 mg/kg. Aspirin or clopidogrel were given by gavage immediately after modeling. Tirofiban were given by intraperitoneal injection immediately after modeling. Rats in every group were euthanized by rapid decapitation 6 h after modeling. Platelet activation and PLA were assessed using flow cytometry and immunofluorescence staining. Histology of lung was performed by hematoxylin and eosin staining.

Results: Aspirin, clopidogrel and tirofiban decreased CRP, IL-1 and TNF-α significantly in septic ARDS (P < 0.05). Aspirin, clopidogrel and tirofiban decreased platelet function and ratio of wet/dry significantly in septic ARDS (P < 0.05). Aspirin, clopidogrel and tirofiban increased PaO₂ significantly in septic ARDS (P < 0.05). Platelet activation and PLA in the ARDS + aspirin group, ARDS + clopidogrel group and ARDS + tirofiban group decreased significantly compared to the ARDS group (P < 0.05). At 6 h after ARDS operation, obvious histological damage was observed in the lungs. All of these histological changes were quantitatively evaluated using injury scores. Aspirin, clopidogrel and tirofiban reduced the histological damages in ARDS group (P < 0.05).

Conclusions: Aspirin, clopidogrel and tirofiban alleviated the inflammatory response and pulmonary edema, reduced platelet function, and alleviated hypoxemia in early septic ARDS. Aspirin, clopidogrel and tirofiban reduced platelet activation and PLA formation in early septic ARDS. Aspirin, clopidogrel and tirofiban ultimately alleviated lung injury in early septic ARDS.

Background: Naringenin, a flavonoid compound found in citrus fruits, possesses valuable anticancer properties. However, its potential application in cancer treatment is limited by poor bioavailability and pharmacokinetics at tumor sites. To address this, Naringenin nanoparticles (NARNPs) were prepared using the emulsion diffusion technique and their anticancer effects were investigated in HepG2 cells.

Methods: The particle size of NARNPs was determined by transmission electron microscopy and scanning electron microscopy analysis. NARNP is characterized by Fourier transform infrared spectroscopy and X-ray diffraction. Study the cytotoxic effects of various doses of naringenin, NARNPs and DOX on HepG2 and WI38 cell lines after 24 h and 48 h using the MTT assay. Flow cytometric analysis was used to study the apoptotic cells. The study also examined the expression of apoptotic proteins (p53) and autophagy-related genes ATG5, LC3 after treatment with naringenin, NARNPs, doxorubicin, and their combinations in HepG2 cells.

Results: The particle size of NARNPs was determined by transmission electron microscopy and scanning electron microscopy analysis, showing mean diameters of 54.96 ± 18.6 nm and 31.79 ± 6.8 nm, respectively. Fourier transform infrared spectroscopy confirmed successful conjugation between naringenin and NARNPs. NARNPs were in an amorphous state that was determined by X-ray diffraction. The IC50 values were determined as 22.32 µg/ml for naringenin, 1.6 µg/ml for NARNPs and 0.46 µg/ml for doxorubicin. Flow cytometric analysis showed that NARNPs induced late apoptosis in 56.1% of HepG2 cells and had no cytotoxic effect on WI38 cells with 97% viable cells after 48 h of incubation. NARNPs induced cell cycle arrest in the Go/G1 and G2/M phases in HepG2 cells. The results showed increased expression of ATG5, LC3, and p53 in HepG2 cells treated with IC50 concentrations after 48 h of incubation. NARNPs enhanced the cytotoxic effect of doxorubicin in HepG2 cells but decreased the cytotoxic effect of doxorubicin in WI38 cells.

Conclusions: The study demonstrated that NARNPs effectively inhibit cell proliferation and induce apoptosis in human hepatocellular carcinoma cells. Importantly, NARNPs showed no cytotoxic effects on normal cells, indicating their potential as a promising therapy for hepatocarcinogenesis. Combining NARNPs with chemotherapy drugs could present a novel approach for treating human cancers.

The main objective of this study was to investigate the optimal post-left atrial appendage closure (LAAC) anticoagulation strategy, focusing on minimizing device-related thrombosis (DRT) and thromboembolism (TE) events without increasing bleeding risk. After successful LAAC, consecutive participants were treated with 45-day anticoagulants (rivaroxaban 15 mg daily, dabigatran 110 mg twice a day, and warfarin). The efficacy endpoints included DRT, TE, and hospital readmissions due to cardiac caused, while safety endpoints encompassed bleeding events, monitored over a 12-month follow-up period. The incidence of DRT was relatively lower in the rivaroxaban group compared to both the dabigatran and warfarin groups (rivaroxaban vs. dabigatran: HR = 0.504, 95% CI 0.208-1.223, log-rank P = 0.101; rivaroxaban vs. warfarin: HR = 0.468, 95% CI 0.167-1.316, log-rank P = 0.093). The median [interquartile range] length and width of DRT in the rivaroxaban group were 1.92 [1.68-2.15] mm and 1.49 [1.28-1.76] mm, both significantly lower than those in the dabigatran (length = 2.15 [1.99-2.25] mm, P = 0.036; width = 1.60 [1.54-1.85] mm, P = 0.035) and warfarin groups (length = 2.26 [2.11-2.44] mm, P = 0.006; width = 1.74 [1.54-1.85] mm, P = 0.006). Kaplan-Meier survival analysis indicated that procedural bleeding was more common in the warfarin group. The 12-month incidence of TE was significantly lower in the rivaroxaban group compared to the dabigatran (HR = 0.466, 95% CI 0.221-0.984, log-rank P = 0.029) and warfarin groups (HR = 0.456, 95% CI 0.188-0.966, log-rank P = 0.042). Long-term antithrombotic therapy with reduced dose of rivaroxaban significantly reduced the risk of DRT and composite endpoints without increasing bleeding events, compared to warfarin and dabigatran, for patients following LAAC.

Background: Cerebrovascular accidents are known as a great cause of morbidity and mortality worldwide. Although there are known risk factors for ischemic stroke, the cases that cannot be justified with these risk factors are increasing. Toxic metals as a potential risk factor for other diseases in humans are assessed in this study in the CVA group and compared to controls.

Method: 70 participants (35 each group) have been selected for this study. The group with recent medical history of documented CVA and a control non-CVA group. The serum level of several metals has been assessed using Inductively coupled plasma mass spectrometry (ICP-MS) method. principal components and cluster analyses were employed to compare toxic metal toxicity between the groups.

Results: Cu (p < 0.001) and Pb (p = 0.002) levels were significantly higher in the CVA group whereas Ni (0.003) were significantly lower. There was no significant difference between the smoking (p = 0.56) and opium (p = 0.46) use between these groups. Most of the essential metals were positively correlated with each other in both groups (Ni with Fe, Zn; Fe with Zn with r over 0.6). there was also PCA and CA are crucial in and cluster analysis in which Ni, Fe, and Zn were most similarly correlated in both groups.

Conclusion: we found a complex interaction between toxic metals in the healthy and CVA human body. Due to the lack of data on in vivo interaction of these metals even in healthy individuals, further investigation is needed to evaluate the exact mechanism of such relations.