Xenobiotica最新文献

This study investigated the impact of single nucleotide polymorphisms (SNPs) in genes involved in doxorubicin (DOX) transport and metabolism on clinical outcomes and toxicity in Egyptian patients with non-Hodgkin lymphoma.

Ninety-two patients received at least six DOX treatment cycles. SNP genotyping was performed using real-time PCR with high-resolution melting analysis. Laboratory tests were conducted at baseline, during, and after treatment.

The AA genotype of ABCC2 (rs8187710) showed the strongest association with elevated DOX plasma levels and a significantly increased risk of acute cardiotoxicity (OR 26.9; 95% CI: 1.47-492; p = 0.026). The GA genotype was linked to a lower complete response rate and increased risks of leukopoenia (OR 2.66; 95% CI: 1.07-6.61; p = 0.034) and lymphocytopenia (OR 10; 95% CI: 3.57-27.9; p < 0.0001), with intermediate peak DOX levels. For CBR3 (rs8133052), the GA genotype was significantly associated with a higher risk of anaemia (OR 3.5; 95% CI: 1.05-11.7; p = 0.042), acute cardiotoxicity (OR 4.4; 95% CI: 1.86-11.5; p = 0.002), cardiac-related symptoms, and higher peak plasma DOX levels, along with reduced complete response.

Polymorphisms in ABCC2 and CBR3 genes may contribute to individual variability in DOX-related toxicity and treatment response.

This study investigated and evaluated the antihypertensive effects and mechanisms of Ophioglossum vulgatum(OV) through a combination of computational simulations and in vivo experiments.Initially, an in silico analysis using network pharmacology was employed to identify target proteins, followed by molecular docking and molecular dynamics simulations. Network pharmacology data indicated that OV may influence several pathways involved in blood pressure regulation. Molecular docking revealed the effective targets of OV, showing that some of its major active compounds could potentially bind directly to the active sites of angiotensin receptors and calcium channel proteins. In vivo experiments demonstrated that administration of 20 mg/kg crude OV extract to spontaneously hypertensive rats (SHR) significantly reduced mean blood pressure by 31.53% within 60 min, alleviating hypertensive symptoms. Based on our in silico and in vivo evidence, the rapid antihypertensive effects of OV may be related to its action on the RAS and calcium channels, leading to vasodilation.These acute antihypertensive effects suggest that OV has the potential to be a candidate for blood pressure medication, particularly for urgent blood pressure reduction, and an effective antihypertensive agent in plant-based medicine.

Duhaldea nervosa (Wallich ex Candolle) A. Anderberg (Asteraceae) (D. nervosa), has been used as a folk medicine for the treatment of diseases including bone fractures and bone wounds. However, the metabolic profiling of D. nervosa and mechanism of action for treating fracture are unknown.In this study, an integrated analysis method based on UHPLC-Q-Exactive Orbitrap MS and network pharmacology was established to research the metabolic characteristic of D. nervosa. Serum in the blank group and drug group were collected after intragastric administration of D. nervosa. The serum samples were analysed using UHPLC-MS. In addition, network pharmacology and cell proliferation assays were used to analysis the mechanism of fracture healing of D. nervosa.A total of 62 constituents, including 24 prototype compounds and 38 metabolites were identified in rat serum. The result of network pharmacology revealed that the fracture healing effect of 23 metabolites was probably acting through 65 genes targets. Serum samples promoted osteoblast proliferation in a concentration-dependent manner in mouse osteoblast cell line (MC3T3-E1 cells).To our best knowledge, it is the first time to report the constituents in vivo of D. nervosa. This work provided a general method for understanding the bioactive compounds of D. nervosa.

1. Valproic acid (VPA) has great individual differences in clinical efficacy, the study aimed to investigate the effects of VPA-related pharmacogenomics on its antiepileptic efficacy, providing evidence for clinical rational drug use.

2. The patients were followed up for one year, and the number of seizures within one year was used as the evaluation index of efficacy. The target SNPS were genotyped by SNP scan method.

3. A total of 253 patients with epilepsy treated with valproate monotherapy were enrolled in this study, including 125 patients in the valproate-sensitive group and 128 patients in the valproate-resistant group. χ² Test showed that the frequency of C allele of CACNA1H rs3751664 in valproate-sensitive group was significantly higher than that in valproate-resistant group (93.6% vs. 87.5%, p = 0.023), and the difference was still statistically significant after adjusting for confounding factors by logistic regression analysis (p = 0.037). Haplotype analysis showed no association between gene polymorphisms and efficacy of valproic acid.

4. CACNA1C rs1051375 GG and GA genotype patients have a lower risk of drug resistance than AA genotype patients, CACNA1H rs3751664 T allele is a risk factor for VPA monoresistance, while APEH rs3816877 CT genotype patients have a trend of drug resistance during VPA treatment.

Crack cocaine is a widely consumed illicit substance worldwide, with Brazil identified as its largest consumer. This study evaluated its harmful effects on various organs in rats.Twenty-four male Wistar rats were distributed into four groups: G1-exposed to 25 mg of crack cocaine; G2-50 mg; G3-100 mg; and a control group with no intervention. The experimental groups inhaled crack cocaine smoke once daily for five days.Histopathological changes were observed in the liver of G3 and in the kidneys of all exposed groups. Increased 8-OHdG immunoexpression occurred in the kidneys of G1 and G2. Ki-67 immunoexpression in the liver and kidneys was elevated in G1 and G2. GST-P-positive foci increased in G1 and G2. Micronucleated cells in bone marrow were significantly higher in all exposed groups. In the liver, hepatocytes with micronuclei increased in G1 and G2, while binucleated cells were more frequent in G3. Karyolysis increased in G2 and G3, and karyorrhectic hepatocytes were more frequent in G1 and G2.These findings demonstrate that crack cocaine inhalation induces degenerative and genotoxic effects in the liver, kidneys, and bone marrow of Wistar rats, supporting its potential carcinogenicity and underscoring the need for targeted public health interventions.

Model Informed Formulation Development (MIFD) uses physiologically based pharmacokinetic (PBPK) modelling and other in silico tools to facilitate new product development. These tools help set target profiles, predict in vivo formulation performance, guide iterative development, define dissolution parameters, and convince the regulatory agencies about a drug's safety and efficacy.This study involves development of a sustained release formulation for Hydroxyzine, an anti-histamine with sedation as a significant side effect. The aim was to design a formulation that releases the drug slowly, reducing the peak plasma concentration without losing on the effectiveness. A preliminary absorption model was developed using immediate release formulation data, and various hypothetical dissolution profiles were evaluated in this model. The new drug product, manufactured using Matrixeal^TM technology, underwent preliminary bioequivalence (BE) studies in healthy volunteers. These results were used to refine the model and further modify the formulation, whose performance was predicted via virtual BE studies. Confirmatory BE studies with 70 volunteers under fasting state validated the new formulation. The model also established clinically relevant dissolution specifications and assessed the food effect on the drug product.This work showcases the application of PBPK modelling in developing new modified release drug product of Hydroxyzine.

We aimed to elucidate the molecular processes involved in how nicotine affects PD.Toxicogenomic, molecular mechanisms, physicochemical properties, pharmacokinetic profile, and biological activity were analysed.We found that the therapeutic potential of nicotine in PD may be attributed to its ability to modulate the expression of 38 genes, especially GAPDH, TNF, IL6, and BDNF. The molecular mechanisms underlying the protective effects of nicotine against PD involve several pathways, including the 'Parkinson's disease pathway', 'the selenium micronutrient network', 'the oxidative stress response', 'dopamine binding', 'Parkinsonian disorders', and 'Lewy body disease'. miRNAs like hsa-miRNA-203a-3p and miRNA-26b-5p and transcription factors like HNF4, MAPK3, and EVI1 explained how nicotine protects neurons from PD.An assessment was also carried out on drug candidates (polaprezinc) and miRNA sponges (hsa-miR-181a-5p, hsa-miR-124-3p, hsa-miR-1-3p) that may possess the capability to synergize the effects of nicotine. Nicotine's physicochemical properties, pharmacokinetic profile, and biological activity are conducive to its favourable attributes in the context of PD, including high gastrointestinal absorption, ability to penetrate the blood-brain barrier, non-P-glycoprotein nature, and antiparkinsonian effects.Nicotine plays crucial roles in the pathophysiology of PD. Further work is needed to evaluate the impact of nicotine on non-motor symptoms.

In this study, the adenosine 5'-monophosphate-activated protein kinase (AMPK)-dependent mechanisms underlying the effect of β-aminoisobutyric acid (BAIBA), an exercise-induced myokine, in mitigating doxorubicin (DOX)-induced cardiotoxicity were investigated.In vitro/vivo DOX-induced injury models were constructed, and their cardiac functions were detected by echocardiography/histology. Moreover, serum biomarkers including lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), and brain natriuretic peptide (BNP) were measured. The mitochondrial ultrastructure was examined by transmission electron microscopy (TEM), and the generation of reactive oxygen species (ROS) was checked by MitoSOX^™ Red staining. The analysis results showed that BAIBA significantly preserved the cardiac systolic function, reduced myocardial damage, and attenuated mitochondrial dysfunction, as evidenced by maintained cristae integrity and suppressed ROS overproduction. The mechanism was that BAIBA enhanced cardiac AMPK phosphorylation, while dorsomorphin abrogated the antioxidant effects of AMPK through inhibiting its activation.The findings demonstrate that BAIBA counteracts DOX cardiotoxicity via AMPK-mediated mitochondrial bioenergetic preservation. It provides a novel cardioprotective therapy as an exercise-mimetic adjuvant.

1. Apigenin (APN), a natural flavonoid, showed strong therapeutic potential against skin cancer, but its clinical use is restricted due to its complex physicochemical characteristics.

2. Hence, this study aimed to fabricate APN-loaded solid lipid nanoparticles (APN-SLNs) for improved topical treatment of skin cancer. The developed APN-SLNs were evaluated for particle characterization, compatibility and crystallinity by employing FT-IR, DSC, and XRD. The selected APN-SLNs-loaded hydrogels further evaluated for gel evaluation, permeation and cytotoxicity assessment. The findings also supported with molecular docking study.

3. The developed APN-SLNs demonstrated nanometric size, low polydispersity index, negative surface charge, high encapsulation efficiency and a biphasic release profile. The developed APN-SLNs-loaded hydrogels represented comparatively higher viscosity, firmness, consistency, and cohesiveness compared with the pure APN-loaded hydrogels. The APN-SLNs-loaded hydrogels represented >2 times higher in vitro permeation than pure APN-loaded hydrogels. Further, MTT assay using B16-F10 melanoma cells revealed the superior cytotoxic potential of the developed nanocarrier than the native counterpart. The docking study also supports the findings of the cell viability assay with a high docking score.

4. Therefore, this study suggests that topical delivery of APN encapsulated in SLNs is a promising approach for skin cancer management.

We aimed to establish an approach to quantitatively predict drug-drug interactions arising from cytochrome P450 (CYP) 3A4 induction using chimeric mice with humanised liver.After repeated administration of rifampicin or efavirenz as CYP inducers to chimeric mice, the relative expression of human CYP3A4 in their livers was measured and plotted against the area under the concentration-time curve (AUC) of rifampicin and efavirenz, respectively, in plasma on the final day of administration. Induction curves were obtained by fitting the plots.Assuming a similar relationship of relative CYP3A4 expression to AUC in chimeric mice as in humans, the relative CYP3A4 expression by clinical doses of rifampicin and efavirenz were calculated from the estimated clinical exposure.The calculated relative CYP3A4 expression was reflected in the intrinsic clearance of midazolam or alfentanil coadministered with a CYP inducer. The intrinsic clearance was incorporated into a constructed physiologically based pharmacokinetic model, which successfully predicted the pk change of midazolam or alfentanil coadministered with a CYP inducer or not. The results confirmed that our approach is useful to improve the prediction accuracy of CYP3A4 induction in the preclinical phase.