BMC Pharmacology & Toxicology最新文献

Febuxostat is commonly used in clinic for the treatment of hyperuricemia. Multiple-peak phenomenon has been observed in human plasma concentration-time profiles of febuxostat, but has not been paid enough attention in previous research. This study takes a pivotal step forward by conducting a comprehensive population pharmacokinetic (PopPK) analysis of febuxostat in a healthy Chinese cohort, with a central focus on delineating its absorption profile under contrasting fasting and fed conditions, while concurrently assessing the influence of food alongside other potential covariates on febuxostat's PK profile. The plasma concentration data used for modeling was obtained from two bioequivalence (BE) studies. Subjects were administered febuxostat 20 mg or 80 mg under fasting or fed condition. Goodness-of-fit plots, visual predict check (VPC), and normalized prediction distribution error (NPDE) were used for model evaluation. Based on the established model, PK profiles in healthy Caucasian subjects were simulated with parameter adjustment for race difference on clearance and bioavailability. Data from 128 subjects were used in the PopPK analysis. Febuxostat concentration-time curves were described by a two-compartment model with two deposit absorption compartments and lag times (Tlag). Prandial states (Food) showed significant impact on absorption rate ka1 and ka2, as well as Tlag1, and body weight was identified as a significant covariate on the apparent distribution volume. The PopPK analysis of febuxostat in healthy Chinese volunteers, under both fasted and fed conditions, successfully characterized its PK profile and underscored the significant influence of food on absorption. The potential difference of absorption between Chinese population and Caucasian population indicated from the simulations needs further investigation.

Background: Direct oral anticoagulants (DOACs) have high potency against their therapeutic target and are widely used in the treatment of atrial fibrillation (AF). Most DOACs are often claimed to have adverse effects due to off-target inhibition of essential proteins. Human serum paraoxonase 1 (PON1), one of the essential proteins, known for its anti-inflammatory and antioxidant properties, could be affected by DOACs. Thus, a comparative evaluation of DOACs and their effect on PON1 protein will aid in recommending the most effective DOACs for AF treatment. This study aimed to assess the impact of DOACs on PON1 through a combination of computational and experimental analyses.

Methods: We focus on apixaban, dabigatran, and rivaroxaban, the most recommended DOACs in AF treatment, for their impact on PON1 through molecular docking and molecular dynamics (MD) simulation to elucidate the binding affinity and drug-protein structural stability. This investigation revealed the most influential DOACs on the PON1 protein. Then experimental validation was performed in DOAC-treated AF participants (n = 42; 19 treated with dabigatran and 23 treated with rivaroxaban) compared to a healthy control group (n = 22) through gene expression analysis in peripheral blood mononuclear cells (PBMC) and serum enzyme concentration.

Results: Our computational investigation showed rivaroxaban (-4.24 kcal/mol) exhibited a lower affinity against the PON1 protein compared to apixaban (-5.97 kcal/mol) and dabigatran (-9.03 kcal/mol) through molecular docking. Dabigatran holds complex interactions with PON1 at GLU53, TYR197, SER193, and ASP269 by forming hydrogen bonds. Additionally, MD simulation revealed that dabigatran disrupts PON1 stability, which may contribute functional changes. Further experimental validation revealed a significant down-regulation (p < 0.05) of PON1 gene expression in PBMC and decreased serum PON1 enzyme concentration on DOAC treatment. Rivaroxaban as about 48% has inhibitory percentage and dabigatran as about 75% of inhibitory percentage compared to healthy control.

Conclusion: Overall, our computational and experimental results clearly show the higher inhibitory effect of dabigatran than rivaroxaban. Hence, rivaroxaban will be a better drug candidate for improving the outcome of AF.

Background: Metamizole is banned in some countries because of its toxicity, although it is widely used in some European countries. In addition, there is limited information on its safety profile, and it is still debated whether it is toxic to the heart, lungs, liver, kidneys, and stomach.

Aims: Our study investigated the effects of metamizole on the heart, lung, liver, kidney, and stomach tissues of rats.

Methods: Eighteen rats were divided into three groups, wassix healthy (HG), 500 mg/kg metamizole (MT-500), and 1000 mg/kg metamizole (MT-1000). Metamizole was administered orally twice daily for 14 days. Meanwhile, the HG group received pure water orally. Biochemical, histopathologic, and macroscopic examinations were performed on blood samples and tissues.

Results: Malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) in the lung and gastric tissues of MT-500 and MT-1000 groups were almost the same as those of the HG (p > 0.05). However, MDA levels in the heart and liver tissues of MT-500 and MT-1000 groups were higher (p < 0.05) compared to the HG, while tGSH levels and SOD, and CAT activities were lower (p < 0.05). MDA levels of MT-500 and MT-1000 groups in the kidney tissue increased the most (p < 0.001), and tGSH levels and SOD and CAT activities decreased the most (p < 0.001) compared to HG. Metamizole did not cause oxidative damage in the lung and gastric tissue. While metamizole did not change troponin levels, it significantly increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine levels compared to HG. Histopathologically, mild damage was detected in heart tissue, moderate damage in liver tissue, and severe damage in renal tissue. However, no histopathologic damage was found in any groups' lung and gastric tissues.

Conclusion: Metamizole should be used under strict control in patients with cardiac and liver diseases and it would be more appropriate not to use it in patients with renal disease.

Background: Econazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in peripheral sensory neurons and serve as sensors for various irritants.

Methods: We investigated the effect of econazole on TRP channel activation by measuring intracellular calcium concentration ([Ca²⁺]_i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from wild-type, TRPA1^(-/-) and TRPV1^(-/-) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection model was employed to assess econazole-induced itch and pain in vivo.

Results: Econazole evoked an increase in [Ca²⁺]_i, which was abolished by the removal of extracellular Ca²⁺ in mouse DRG neurons. The [Ca²⁺]_i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker. Attenuation of the econazole-induced [Ca²⁺]_i responses was observed in the TRPA1^(-/-) mouse DRG neurons but was not significant in the TRPV1^(-/-) neurons. Econazole increased the [Ca²⁺]_i in HEK293 cells expressing TRPA1 (TRPA1-HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca²⁺ mobilization from intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also increased the [Ca²⁺]_i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole. Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole induced itch and pain in wild-type mice, with reduced responses in TRPA1^(-/-) mice.

Conclusions: These findings suggested that the imidazole derivatives econazole and miconazole may induce skin irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the adverse effects of econazole.

Background: Non-small cell lung cancer (NSCLC) is associated with intracellular copper accumulation. Antioxidant 1 (ATOX1) is a copper chaperone. This study aimed to analyze the anti-cancer effects of curcumin on the ATOX1-mediated copper pathway in NSCLC.

Methods: A binding activity between curcumin and ATOX1 was measured using molecular docking. NSCLC cells, A549 and H1299, were treated with different doses of curcumin (10, 20, 40 µM) or DC-AC50 (5, 10, 20 µM) for 24 h. The cell viability and levels of ATOX1, ATP7A and COX17 proteins were observed in cells. Overexpressing ATOX1 in cells was established by pcDNA3.1-ATOX1 transfection for 24 h. The ATOX1 overexpressing cells were treated with 40 µM curcumin or 20 µM DC-AC50 for 24 h to analyze the mechanism of curcumin in NSCLC treatment. Cell viability was measured by CCK-8, and levels of proteins were measured by western blotting. The copper level in cells was labeled by copper sensor-1. Moreover, nude mice models were induced by injection of A549 cells and treated with 20 mg/kg/d DC-AC50 or 40 mg/kg/d curcumin. Tumor growth was observed by measuring tumor volume and tumor weight. The levels of ATOX1, ATP7A and COX17 in tumors were measured by immunohistochemistry and western blotting.

Results: Curcumin bound to ATOX1 (score = -6.1 kcal/mol) and decreased the levels of ATOX1, ATP7A and COX17 proteins in NSCLC cells. The curcumin or DC-AC50 treatment suppressed cell viability by inhibiting the ATOX1-mediated copper signaling in NSCLC cells. The ATOX1 overexpression in cells significantly weakened the effects of curcumin on suppressing copper accumulation and the ATOX1-mediated copper pathway (p < 0.05). In mice models, curcumin or DC-AC50 treatment also suppressed tumor growth by suppressing the ATOX1-mediated copper pathway in tumors.

Conclusion: This study demonstrated that curcumin bound ATOX1 to suppress copper accumulation in NSCLC cells, providing a new mechanism of curcumin for NSCLC treatment.

Background: An increasing body of research implicates inflammatory processes, including alterations in the neutrophil-lymphocyte ratio (NLR), in the pathophysiology of psychiatric illness. The deer mouse (Peromyscus maniculatus bairdii) is commonly studied for its naturalistic expression of compulsive-like behaviour. Towards future efforts to gain an understanding of how innate and adaptive immune processes might be involved in this model, we aimed to study the effects of pegfilgrastim, a pegylated recombinant human granulocyte colony-stimulating factor (g-CSF) analogue, on the NLR of both male and female deer mice.

Methods: Briefly, 54 deer mice (equally distributed between sexes) were exposed to a single injection with either control or pegfilgrastim (0.1 or 1 mg/kg) (n = 18 per group). Six mice of each group (three per sex) were euthanized on days two, four and seven post-administration, their blood collected and the NLR calculated. Data were analysed by means of ordinary three-way ANOVA, followed by Bonferroni post-hoc testing.

Results: Irrespective of dose, pegfilgrastim resulted in higher NLR values in mice of both sexes at days four and seven of testing. However, female mice exposed to the higher dose, presented with significantly higher NLR values irrespective of time, compared to male mice exposed to the same.

Conclusion: The data generated from this work highlight important dose- and sex-specific aspects of pegfilgrastim with female mice showing heighted elevation of the NLR in response to high-dose pegfilgrastim administration only. Since the innate immune components of male and female deer mice is differentially sensitive to g-CSF stimulation, our results provide a useful basis for further study of sex-specific immunological processes in deer mice.

Background: Fluoxetine is present in breast milk, yet it is unclear to what extent it, or its active metabolite, norfluoxetine, reaches the brain of the infant and what the effects of such exposure on neurobiological processes are. We therefore aimed to quantify the concentration of passively administered fluoxetine and norfluoxetine in the whole brains of exposed Flinders sensitive line (FSL) offspring and establish their influence on serotonergic function and redox status.

Methods: Adult FSL dams received fluoxetine (10 mg/kg/day), or placebo for fourteen days, beginning on postpartum day 04. Offspring were passively exposed to fluoxetine until postnatal day 18 and euthanized on postnatal day 22. Whole brain fluoxetine, norfluoxetine, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and reduced (GSH) and oxidized glutathione (GSSG) concentrations were measured via liquid chromatography-mass spectrometry (LC-MS) analysis.

Results: Whole-brain serotonin and 5-hydroxyindoleacetic acid concentrations, and serotonin turnover (5-HIAA/5-HT) were comparable between strains. Treatment-naïve FSL rats had lower GSH and higher GSSG whole-brain concentrations, relative to FRL controls, and an overall decreased GSH/GSSG ratio. Passively administered fluoxetine resulted in undetectable whole-brain concentrations, while norfluoxetine averaged 41.28 ± 6.47 ng/g. Serotonin turnover of FSL rats was unaffected by passively administered fluoxetine, while redox status (GSH/GSSG) was decreased.

Conclusion: Our findings confirm that passively administered fluoxetine reaches the infant brain in the form of norfluoxetine and may manipulate processes of oxidative stress regulation. Further studies into the long-term bio-behavioural effects are however needed to effectively inform breast feeding mothers on the safety of antidepressant-use.

This study reports a novel, eco-friendly; fast and cost-effective microwave method for synthesizing carboxymethylated graphene oxide (CMGO) from sugarcane residues. Fourier-transform infrared spectroscopy (FTIR) confirmed successful CMGO synthesis through the presence of characteristic peaks at 1567.93 and 1639.29 cm^-1 (COONa vibrations) and increased CH₂ intensity compared to unmodified graphene oxide (GO). Furthermore, CMGO derived from sugarcane residues demonstrated potential in mitigating the side effects of toxic materials like carbon tetrachloride (CCl₄). Treatment with CMGO partially reduced elevated levels of liver enzymes (ALT and AST) and nitrogenous waste products (urea and uric acid) in CCl₄-induced liver damage models, suggesting an improvement in liver function despite ongoing cellular damage.This work paves the way for a sustainable and economical approach to produce functionalized graphene oxide with promising biomedical applications in alleviating toxin-induced liver injury.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors-palbociclib, abemaciclib, and ribociclib-have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database.

Methods: The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015-2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs.

Results: This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease.

Conclusion: Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.

Background: Addressing critical veterinary drugs, especially drugs with solubility problems like albendazole, and their implications for therapeutic efficacy, in-vitro dissolution studies can indeed provide valuable insights into how different brands of albendazole boluses perform under standardized conditions, helping to assess their dissolution profiles and potential bioavailability.

Methods: Six brands of albendazole 300 mg boluses were collected from December 2020 to May 2021 G.C. The laboratory work was conducted from December 2020 to May 2021 in the National Animal Products and Veterinary Drugs and Feed Quality Assessment Centre (APVD-FQAC) laboratories. The collected brands from government veterinary clinics and private veterinary shops were subjected to model independent and dependent parameters. The dissolution test was conducted according to the USP monograph.

Results: The study found that none of the six brands met the requirements of the dissolution test, as their API release was less than 80% within the specified 60-minute timeframe according to USP standards. Model independence indicated that only one brand (Alb002 = 3.72) achieved a difference factor of ≤ 15%. The remaining four brands (4/6) did not meet this criterion. However, the similarity factor (f2) revealed that all five brands (5/6) were comparable to the comparator products, with f2 values of [Formula: see text]50%. The mean dissolution time results confirmed that three brands (3/6) had the highest dissolution rate and the fastest onset of action. The model-dependent kinetics indicated that the Weibull and Korsemeyer-Peppas models were the best fit for the release of drug substances.

Conclusion: The study highlights issues with albendazole boluses' quality, highlighting the need for national in-vitro dissolution studies. These recommendations could improve quality control, streamline regulatory frameworks, and offer practical, cost-effective methods for evaluating drug efficacy and safety, ensuring veterinary pharmaceuticals meet safety and efficacy standards.