BMC Pharmacology & Toxicology最新文献

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.

Background: UpToDate, no drugs have been approved to treat nonalcoholic steatohepatitis, the advanced stage of the most prevalent liver disease, non-alcoholic fatty liver disease. The present study was conducted to explore the potential influences of L-carnitine on the pathomechanisms of hepatic injury that mediate progression to non-alcoholic steatohepatitis in dexamethasone-toxified rats.

Methods: Male Wistar rats were allocated as follows: dexamethasone group, rats received dexamethasone (8 mg/kg/day, intraperitoneally) for 6 days; DEXA-LCAR300, DEXA-LCAR500, and DEXA-MET groups, rats administered L-carnitine (300 or 500 mg/kg/day, IP) or metformin (500 mg/kg/day, orally) one week prior to dexamethasone injection (8 mg/kg/day, IP) and other six days alongside dexamethasone administration. Two groups of age-matched normal rats received either the drug vehicle (the control group) or the higher dose of L-carnitine (the drug-control group). At the end of the experiment, sets of biochemical, histological, and immunohistochemical examinations were performed.

Results: L-carnitine (mainly at the dose of 500 mg/kg/day) markedly abolished dexamethasone-induced alterations in glucose tolerance, hepatic histological features, and serum parameters of hepatic function and lipid profile. Moreover, it significantly ameliorated dexamethasone-induced elevations of hepatic oxidative stress, SREBP-1 and p-MLKL protein levels, and nuclear FOXO1, LC3, P62, and caspase-3 immunohistochemical expression. Furthermore, it markedly diminished dexamethasone-induced suppression of hepatic Akt phosphorylation and Bcl2 immunohistochemical expression. The effects of L-carnitine (500 mg/kg/day) were comparable to those of metformin in most assessments and better than its corresponding lower dose.

Conclusion: These findings introduce L-carnitine as a potential protective drug that may mitigate the rate of disease progression in non-alcoholic fatty liver disease patients with early stages or those at the highest risks.

Background: Cancer is the deadliest disease, and neurological disorders are also marked as slow progressive diseases, ultimately leading to death. Stopping two mouths with one morsel was the strategy that we used in this study.

Methods: We have synthesized peony-shaped zinc oxide nanoflowers (ZnO-NFs) and characterized them using various photophysical tools like UV-vis spectroscopy, zeta potential analysis, dynamic light scattering (DLS), FTIR, and scanning electron microscopy (SEM), and utilized these nanoflowers to monitor their anticancer and anti-amyloid activity. In vitro biocompatibility was assessed using fibroblasts and undifferentiated rat phaeochromocytoma cells, and in vivo, biocompatibility was estimated using haemolysis assay and zebrafish embryo development.

Results: The results demonstrated high biocompatibility of the as-synthesized ZnO-NFs up to a dose of 200 µg/ml. In vitro anticancer activity was evaluated using adherent (A375) and non-adherent (Dalton's Lymphoma Ascites, DLA) cancer cell lines. The results indicated that the ZnO-NFs significantly killed the cancer cells in a dose-dependent way, showing an extraordinary effect on DLA cells. The anti-amyloid activity in vitro was explored using a spectrum of assays that were hallmarks in anti-amyloid studies like ThT fluorescence assay, DLS, turbidity assay, atomic force microscopy (AFM), and SEM analysis. Excellent anti-amyloid activity was observed in vitro at 50 µg/ml of ZnO-NFs.

Conclusion: We can conclude from the above results that the as-synthesized ZnO-NFs have a dual role as an anticancer as well as an anti-amyloid agent. In the future, animal models can be used to study the efficacy of the ZnO-NFs in cancer inhibition and amyloid degradation.

Background: The belzutifan is a hypoxia inducible factor-2 alpha (HIF-2α) inhibitor for the treatment of advanced or metastatic clear cell renal cell carcinoma (mccRCC) and has exhibited good safety and efficacy in clinical trials. We conducted a meta-analysis of relevant studies to further clarify the efficacy and safety of belzutifan for the treatment of mccRCC.

Methods: Multiple databases and abstracts from major scientific meetings were systematically reviewed for eligible articles published before June 1, 2024. The following outcomes were analyzed: objective response rate (ORR), disease control rate (DCR), median duration of response (mDOR), median progression-free survival (mPFS), median overall survival (mOS), and treatment-related adverse events (TRAes). 426 records were reviewed, and data were extracted by at least two individuals.

Results: Seven studies involving 715 patients were included in this meta-analysis. The pooled ORR was 34% (95% confidence interval [CI]: 23-46%), the DCR was 79% (95% CI: 66-90%), the mDOR was 21.8 months (95% CI: 14.82-28.78), and the mPFS time was 8.8 months (95% CI: 6.15-11.44). The pooled incidence of grade 3-5 TRAes was 46%, and the most common TRAe was anemia. Further subgroup analysis revealed that, compared with belzutifan monotherapy, the combination of belzutifan with tyrosine kinase inhibitors (TKIs) as second- or later-line therapy was associated with a statistically significant increase in the ORR. Toxicity was also greater with combined inhibition therapy.

Conclusions: Our meta-analysis revealed moderate antitumor activity and a manageable safety profile of the inhibitor belzutifan in patients with mccRCC.

Background: H1-antihistamines are widely used to treat symptoms depending on histamine release in a variety of conditions. However, neurological adverse events have been reported in post-marketing surveillance studies and there are limited literatures comparing the neurological disorders associated with newer-generation H1-antihistamines from real-world datasets.

Aims: We performed a comparative analysis of nervous system disorders and several newer-generation H1-antihistamines including: cetirizine, loratadine, levocetirizine, desloratadine and fexofenadine.

Methods: Disproportionality analysis was used to identify the suspected drug neurological adverse events associated with H1-antihistamines of interest via the Food and Drug Administration Adverse Event Reporting System. The proportional reporting ratio (PRR), χ² (chi-square) and the reporting odds ratio (ROR) with 95% confidence interval (CI) were used to estimate the association.

Results: AE reports of 43,815 cases from 2017 to 2021 were extracted from FAERS. The H1-antihistamines included in our study were associated with various neurological adverse events that could be classified into 12 aspects, containing 42 preferred terms. The majority of adverse event reports were concentrated at somnolence: cetirizine [N = 1342, ROR (95%CI) = 11.8 (11.2-12.5), PRR = 10.8, χ² = 11755.4], levocetirizine [N = 1276, ROR(95%CI) = 28.5 (26.7-30.3), PRR = 22.7, χ² = 26218.4], loratadine[N = 516, ROR(95%CI) = 4.6 (4.2-5.0), PRR = 4.4, χ² = 1378.1], desloratadine [N = 33, ROR(95%CI) = 6.1 (4.3-8.6), PRR = 5.8, χ² = 131.9], fexofenadine [N = 498, ROR(95%CI) = 5.0 (4.6-5.5), PRR = 4.8, χ² = 1519.0].

Conclusion: Neurological AEs associated with individual newer generation H1-antihistamines of interest varies a lot, whereas somnolence was the most common AE reports. Fexofenadine was highly associated with headaches. Sedative effects associated with levocetirizine and cetirizine should arouse more concern. Seizures significantly associated with levocetirizine and desloratadine were infrequently reported, further research is needed to avoid possible serious outcomes. Patients taking cetirizine probably have higher risk of dystonia and anticholinergic syndrome.

Background: Post-myocardial infarction (MI) remodeling involves various structural and functional changes, such as inflammation and fibrosis. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is linked to the progression of cardiovascular diseases, including myocardial infarction. The inhibitory effects of paroxetine on GRK2 are recognized, yet its protective effect on post-MI remodeling has not been elucidated. Here, we investigated the cardioprotective effect of paroxetine in an animal model of MI, focusing on post-MI cardiac remodeling and comparing its effect to a β-blocker and an angiotensin receptor antagonist.

Methods: Albino Wistar rats were divided into five groups (control; untreated MI; and MI pre-treated with either paroxetine, metoprolol, or irbesartan). MI was induced using isoproterenol (100 mg.kg^-1) on days 16 and 17. Cardioprotective effects were determined by assessing markers of cardiac injury, histopathology, inflammation, oxidative stress, and fibrosis. Statistical analysis performed using a one-way analysis of variance, followed by an appropriate post hoc test, the differences between the groups were considered significant when the (P < 0.05).

Results: Paroxetine significantly attenuated cardiac injury biomarkers including serum Tn-I and CK-MB levels. In terms of cardiac remodeling, paroxetine significantly reduced the relative HW/BW index and the plasms FGF23 level. Furthermore, it modulated markers of fibrosis, inflammation, and oxidative stress.

Conclusion: The current findings suggest that pre-treatment with paroxetine may exert a beneficial effect that protects against post-MI remodeling, including modulating fibrotic, inflammatory, and angiogenesis-related factors. Therefore, the current findings show the promising role of paroxetine as a cardioprotective that attenuates post-MI remodeling processes.

Background: Cronkhite-Canada syndrome (CCS) is a rare non-hereditary chronic inflammatory disease characteristic of gastrointestinal polyps and ectodermal abnormalities. Corticosteroid therapy is the mainstay medication for CCS. Few studies indicated immunosuppressants might be the choices for patients with steroid refractory, steroid dependent or intolerant.

Aim: To examine the efficacy and safety of azathioprine (AZA) in CCS patients.

Method: We retrospectively reviewed the records of 12 CCS patients treated with azathioprine between July 2014 and October 2023 and the clinical data including demographic characteristics, treatment regimen and adverse events were subsequently collected and analyzed. The genetic variants of TPMT and NUDT15 genes were also retrospectively assessed using sanger sequencing in 11 patients.

Outcome: All patients were in active stage at baseline and 9 patients (75%) were in combination with corticosteroid. On account of the indication, 6 patients were steroid dependent or intolerant and another 6 patients needed augmentation therapy. The target dose of AZA was 1.0 to 1.5 mg/kg per day. Ten (83.3%) patients achieved clinical response, of whom 3 cases had endoscopic remission and 5 cases had endoscopic improvement respectively. Three (25%) patients suffered from pneumocystis carinii pneumonia, liver dysfunction and leukopenia, respectively, resulting in cessation of AZA in the initial 3 months. Four heterozygous missense variants of TPMT and NUDT15 were identified in four patients. One patient who had TPMT*6 and took AZA with the dose of 2.04 mg/kg per day suffered from severe leukopenia.

Conclusion: Azathioprine might be a good alternative medication in CCS patients who are steroid dependent or intolerant, or need augmentation therapy. The adverse events should be closely monitored especially myelosuppression and the tests of TPMT and NUDT15 genotypes before therapy may be helpful for medication guidance.

Background: In the past few years, an increasing number of research studies have documented the utilization of durvalumab in the field of immunotherapy for cancerous tumors. However, there remains insufficient documentation regarding its associated adverse event (AEs). In order to enhance our comprehension of its toxicological profile, this investigation retrospectively examined the AEs linked to durvalumab using data from the US Food and Drug Administration adverse event reporting system (FAERS).

Methods: Using data from FAERS for the period 2004 to 2024, the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and mu-item gamma Poisson shrinker (MGPS) four algorithms were used to quantify durvalumab related AEs. SAS 9.4 was used for statistical analysis.

Results: We collected nonduplicated reported 17,629,340 patients from the FAERS database and 19,709 AEs cases in the target population with durvalumab as the primary drug of suspicion. There were 6 significantly disproportionate preferred terms (PTs) that fit all four algorithms simultaneously. The AEs commonly reported include death, radiation pneumonitis, pneumonitis, and lung disorders. Furthermore, durvalumab has been associated with additional AEs, such as metastases to the central nervous system and drug-induced liver injury.

Conclusions: The study revealed that durvalumab immunotherapy is associated with AEs including death, radiation pneumonitis, pneumonitis, metastases to the central nervous system, lung disorder and drug-induced liver injury. In clinical practice, it is crucial to be vigilant and prevent the occurrence of these AEs.

This study explores an eco-friendly approach to mitigate risks associated with organophosphorus insecticides, particularly Chlorpyrifos, by synthesizing silver nanoparticles (AgNPs) using Psidium guajava leaf extract and preparing a nanocomposite (AgNPs/S18) with Chlorpyrifos pesticide. The green-synthesized AgNPs and AgNPs/S18 nanocomposite were characterized using various analytical techniques, confirming the successful synthesis of AgNPs with an average size of 37 nm and forming a stable nanocomposite. Antibacterial assays demonstrated significant activity against Staphylococcus aureus, with AgNPs showing an 87.8% reduction and the nanocomposite achieving a 72% reduction in bacterial population. Cytotoxicity evaluations on normal liver and liver cancer cell lines revealed enhanced cytotoxicity of the nanocomposite compared to AgNPs alone, suggesting potential applications in targeted therapies. In vivo studies on rats revealed the protective effects of AgNPs and the nanocomposite against Chlorpyrifos-induced toxicity in liver and kidney tissues. Histopathological and ultrastructural analyses showed both treatments, particularly the nanocomposite, significantly mitigated cellular damage caused by Chlorpyrifos exposure. These findings suggest that green-synthesized AgNPs and their nanocomposite with Chlorpyrifos offer a promising approach to reducing pesticide hazards while maintaining efficacy. This research contributes to developing safer alternatives in pest management, addressing the need for more environmentally friendly agricultural practices while protecting human health and ecosystems.

Background: The risk of hepatic steatosis (HS) is elevated in patients with type 2 diabetes mellitus (T2D). Antidiabetic medications may contribute to the prevention or treatment of HS. This study aimed to compare the effects of vildagliptin and metformin on hepatic steatosis in newly diagnosed T2D patients, using the Hepatic Steatosis Index (HSI) and ultrasound grading.

Methods: The study included 246 newly diagnosed T2D patients who were randomly assigned to two groups. The first group (117 patients) received 50 mg of vildagliptin orally twice daily. The second group (129 patients) received 500 mg of metformin orally twice daily with meals, and the dosage could be gradually increased by 500 mg per week, up to a maximum daily dose of 2000 mg. Baseline and 6-month follow-up assessments included fasting blood glucose (FBG), HbA1c, weight, body mass index (BMI), waist circumference (WC), hip circumference (HC), the Hepatic Steatosis Index (HSI), and hepatic steatosis grading via ultrasound.

Results: Both groups showed significant improvements in FBG, HbA1c, weight, BMI, WC, HC, HSI, and ultrasound grading of hepatic steatosis from baseline to the 6-month follow-up (p < 0.001). The metformin group demonstrated significantly greater reductions in weight and BMI compared to the vildagliptin group (p = 0.001 and p = 0.009, respectively). However, there was no significant difference between the two groups in terms of hepatic steatosis improvement on ultrasound. Correlation analysis revealed that HSI was significantly associated with HbA1c, BMI, WC, and HC (p < 0.001 for all), as well as FBG (p = 0.008), but not with age. The lipid profile, particularly total cholesterol and LDL, was identified as a stronger predictor of hepatic steatosis, based on high AUC, sensitivity, and specificity values.

Conclusion: Both vildagliptin and metformin are effective in improving glycemic control in newly diagnosed T2D patients, as evidenced by reductions in FBG and HbA1c levels. Additionally, both drugs significantly reduced the HSI, body weight, and BMI, with metformin showing a more pronounced effect on weight and BMI. Both vildagliptin and metformin effectively decreased hepatic steatosis in T2D patients. Total cholesterol and LDL are important predictors of hepatic steatosis.

Trial registration: Trial Registration ID: UMIN000055121, registered on 30/07/2024 (retrospectively registered).