ADMET and DMPK最新文献

Background and purpose: Metronidazole (MRNZ) is a highly efficacious pharmacological agent for treating protozoal infections, including trichomoniasis, giardiasis, and disorders caused by anaerobic bacteria.

Experimental approach: In the present investigation, a solvothermal approach is employed to synthesize a composite of multiwalled carbon nanotubes (MWCNTs-COOH) with UiO-66-NH₂, resulting in the formation of UiO-66-NH₂@MWCNTs. Given the exceptional electrocatalytic characteristics of the UiO-66-NH₂@MWCNTs nanocomposite, it was selected as the sensing material and subsequently integrated onto the surface of a bare screen-printed carbon electrode.

Key results: Under optimal experimental conditions, the developed electrochemical sensor exhibited outstanding metrics of repeatability, stability, selectivity, and reproducibility for detection across an extensive concentration range, specifically from 0.5 to 350.0 μM, while achieving a limit of detection of 0.1 μM. Furthermore, the practical application of the sensor was rigorously assessed using MRNZ tablet samples and urine specimens, resulting in a commendable recovery rate of MRNZ, ranging from 97.3 to 104.0 %.

Conclusion: This research elucidates a straightforward, expedited, and significant methodology for the application of UiO-66-NH₂@MWCNTs within the domain of electrochemical sensing.

Background and purpose: Dietary interventions are a cornerstone in the management of type 2 diabetes mellitus. The efficiency, however, depends on pharmacokinetic factors, including the interaction of food ingredients with plasma proteins. The concept of this study was to investigate the binding effects of three pronounced antioxidants present in the Mediterranean diet: resveratrol, (dihydro)lipoic acid and oleuropein, with albumin isolated from persons with diabetes (HbA1c 63±7 mmol/mol, or 7.9±0.6%) and healthy persons, carrying its intrinsic ligands.

Experimental approach: Spectrofluorometric analysis, native electrophoresis and immunoblotting were performed with albumin before and after the interaction with antioxidants.

Key results: Fluorescence spectra of the protein from two study groups were similar, whereas a spectrum of methylglyoxal-modified albumin (in vitro oxidised) was different. Calculated binding constants were also similar for the two study groups for all three ligands. Kinetic fluorescence measurements revealed significantly altered activity of albumin-bound (dihydro)lipoic acid in persons with diabetes compared to healthy individuals, and no significant difference in the activity of resveratrol in expressing antioxidant protection of albumin upon its exposure to oxidative stress.

Conclusions: Although the findings should be further validated using other antioxidants and glycated albumin derived from persons stratified according to the severity of a disease, the results have documented that in vitro methylglyoxal-oxidised albumin, routinely employed for diabetes-simulated investigations, was shown not to reflect this pathophysiological condition properly and not to be adequate for the assessment of relevant nutritional/biochemical potential of food antioxidants.

Background and purpose: Theobromine (THB), an alkaloid present in various plants, is widely used in pharmaceutical formulations and food products. Increased consumption leads to health risks in both humans and animals.

Experimental approach: An electrochemically polymerized polyvaline-modified graphite paste sensor (PVMGPS) was developed in this work to investigate the mechanistic and kinetic pathways of the electrooxidation of THB. Electrochemical impedance spectroscopy and scanning electron microscopy were used for characterizing the designed sensors. The fabricated PVMGPS under optimal conditions produced enhanced current responses compared to the bare graphite paste sensor (BGPS). Multiple parameters were investigated using cyclic voltammetry and differential pulse voltammetry.

Key results: The electroactive surface areas of the BGPS and PVMGPS were evaluated as 0.025 and 0.252 cm², respectively. The study of the effect of pH of phosphate buffer solution (PBS) and further analysis revealed that the electro-oxidation involves equivalent numbers of electrons and protons. Scan rate dependence revealed that the oxidation of THB proceeds through diffusion-controlled kinetics. The limit of detection and limit of quantification were evaluated to be 1.22 and 4.08 μM, respectively. Moreover, the voltammetric assay demonstrated a good recovery rate, proving the efficacy of the proposed sensor in detecting THB-containing food samples.

Conclusions: The outcome of the analysis substantiated the efficacy, selectivity and sensitivity of the developed novel sensor for THB detection.

Background and purpose: Breast cancer remains a significant global health burden, especially in low-resource settings where standard therapies are limited. This study aimed to explore Mallotus glomerulatus, a lesser-known Thai medicinal plant, as a potential source of novel anti-breast cancer agents.

Experimental approach: A phytochemical investigation of M. glomerulatus resulted in the isolation and structural characterization of a novel xanthone (Compound 1) and cleistanthin A (Compound 10) using UV, IR, NMR, and HRMS techniques. Cytotoxicity of the compounds was evaluated in vitro against MCF-7 (ER-positive) and MDA-MB-231 (triple-negative) breast cancer cell lines, along with HepG2 liver cells. Molecular docking studies were conducted to assess their interaction with vacuolar H⁺-ATPase (V-ATPase).

Key results: Compound 1 demonstrated selective cytotoxicity toward MCF-7 cells, whereas cleistanthin A exhibited potent cytotoxicity against both breast cancer lines, with nanomolar IC₅₀ values and a high selectivity index (>100) for MDA-MB-231 compared to HepG2 cells. Docking analysis revealed favourable binding of both compounds at the a-c subunit interface of V-ATPase, suggesting a mechanism involving proton pump inhibition and lysosomal dysfunction.

Conclusion: The findings highlight M. glomerulatus, particularly cleistanthin A, as a promising source of safe and affordable anti-breast cancer compounds with potential therapeutic value. Further studies on the mechanism and in vivo efficacy are warranted.

Background and purpose: Prediction of metabolism and solubility of tablet-form drugs is essential in pharmaceutical development, impacting drug efficacy, safety and formulation strategies. This study aimed to develop predictive models for classifying drugs according to metabolism and solubility within the Biopharmaceutical Drug Disposition Classification System.

Experimental approach: A dataset of 220 tablet-form drugs characterized by eleven molecular descriptors was analysed. The Kruskal-Wallis test identified relevant descriptors for metabolism (extensive vs. poor) and solubility (high vs. low) classifications. Probabilistic Neural Networks were employed for predictive modelling, with model parameters optimized to enhance accuracy.

Key results: Six molecular descriptors (hydrogen bond acidity, logarithm of the partition coefficient, distribution coefficient, hydrogen bond acceptor count, molecular weight and polar surface area) predicted metabolism class with 97 % accuracy. For solubility classification, five descriptors (dipolarity/polarizability, logarithm of the partition coefficient, distribution coefficient, hydrogen bond donor count and molecular weight) achieved 88 % accuracy. Removal of key descriptors significantly reduced model performance, confirming their importance.

Conclusion: The developed models demonstrate robust predictive capability for drug metabolism and solubility classes as defined by the Biopharmaceutical Drug Disposition Classification System, supporting early-stage drug screening based solely on molecular structure. The lower accuracy observed for solubility prediction reflects its complex and multifactorial nature, highlighting the need for further refinement of molecular descriptors. These findings advance the field by providing effective computational tools to predict key biopharmaceutical properties, potentially accelerating the drug development process.

Background and purpose: Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET), play crucial roles in embryogenesis, tissue regeneration, and cancer progression. Dysregulation of EMT/MET pathways in cancer contributes to metastasis and drug resistance.

Approach: This review discusses the signalling pathways that are correlated with EMT in cancer and investigates the therapeutic potential of naturally occurring compounds in modulating these processes. The intricate relationship between stromal cells, drug resistance, and EMT is discussed, highlighting the emerging role of MET in stabilizing distant metastasis. Additionally, the impact of p53 on EMT and its implications in cancer metastasis are discussed. The review also provides an overview of therapeutic molecules, both plant- and animal-derived, that regulate EMT, highlighting their potential in cancer treatment. Specifically, plant-based compounds from Atractylodes lancea, Dendrobium officinale, Panax ginseng and Platycodon grandiflorus, as well as animal-derived substances like bee venom and snake venom, are highlighted. Furthermore, marine-based compounds, including caprolactin C, laminaran sulfate, BFP-3, bryostatin 1, sinulariolide, manzamines, halichondrin B, eribulin and biemamides, exhibit significant anti-metastatic effects by targeting EMT-associated pathways.

Conclusion: The diverse range of therapeutic molecules discussed in this review provides promising therapeutic avenues for developing targeted strategies against EMT in cancer.

Background and purpose: Due to their unique application and action, inhalation products require specific quality tests, such as Uniformity of Delivered Dose and Aerodynamic Assessment of Fine Particles. While there's no current official requirement for dissolution tests, new draft guidelines are introducing them as a supportive or required measure; however, a universally accepted methodology for such testing remains elusive. The aim of the present study was to explore the discriminatory ability and in vivo predictability of the newly developed dissolution assembly.

Experimental approach: The applied experimental approach to biopharmaceutical characterization of inhalation products involved developing a biorelevant method for testing the dissolution rate of the selected active substances. Seven commercially available products, formulated as pressurized metered dose inhalers, containing either salmeterol xinafoate or beclomethasone dipropionate, have been studied. The research strategy combined in vitro testing within silico simulations.

Key results: The developed dissolution method did not detect significant differences in the case of products containing highly soluble salmeterol, but it did reveal differences for products containing poorly soluble beclomethasone dipropionate. Moreover, a correlation was identified between the dissolution test results and absorption constants for beclomethasone dipropionate.

Conclusion: The obtained results indicated that the investigated products would not be considered bioequivalent based on the aerodynamic particle size distribution. It was demonstrated that a discriminative dissolution method can be developed through a well-established paradigm of dissolution testing, while taking into account the specificities of the inhalation route of administration.

Background and purpose: Calcium folinate is frequently co-administered with methotrexate and 5-fluorouracil in chemotherapeutic treatments to enhance therapeutic efficacy and reduce toxicity. Therefore, simple and accurate determination of calcium folinate in the presence of these agents is essential for therapeutic monitoring and pharmaceutical analysis.

Experimental approach: The current work is focused on designing and developing a simple and sensitive modified screen-printed carbon electrode (SPCE)-based electrochemical sensor for the determination of calcium folinate in the presence of methotrexate and 5-fluorouracil. For this purpose, a nanostructure of UiO-66/CdS composite was prepared. Then, we used the prepared UiO-66/CdS composite to modify SPCE towards the development of an electrochemical sensing platform (UiO-66/ /CdS/SPCE).

Key results: The cyclic voltammetry studies revealed that the UiO-66/CdS/SPCE could significantly improve the detection of calcium folinate with a higher response peak current at a lower overpotential compared to other SPCEs. Also, the UiO-66/CdS/SPCE sensor demonstrated a good ability in the quantitative determination of calcium folinate by the differential pulse voltammetry (DPV) method. Based on DPV measurements, a linearity plot was achieved for the concentration range of 0.1 to 300.0 μM calcium folinate with a limit of detection (LOD) of 0.04 μM and a high sensitivity of 0.0503 μA μM^-1. Furthermore, the UiO-66/ /CdS/SPCE sensor showed three well-separated oxidation peaks for the simultaneous determination of calcium folinate, methotrexate, and 5-fluorouracil without interfering with each other. Finally, the UiO-66/CdS/SPCE sensor was used to detect calcium folinate, methotrexate, and 5-fluorouracil in real samples, and the values of recovery and relative standard deviation (RSD) were satisfactory.

Conclusion: The results from this study show that the designed sensor can be used as an efficient and promising platform for the determination of these species.

Background and purpose: The effective transport of an active pharmaceutical ingredient across various membrane systems is critical for enhancing its bioavailability, especially in formulations involving solubilizing agents. This study aims to investigate the permeability differences of carvedilol between lipophilic (organic solvent) and size-exclusion membranes in the presence of 2-hydroxypropyl-beta-cyclodextrin in just the acceptor compartment or both sides of the membrane using in vitro side-by-side diffusion cell assays.

Experimental approach: Cyclodextrins (CDs) on the acceptor side significantly improved flux and permeability for the lipophilic membrane. In contrast, with size-exclusion membranes that allow the permeation of CDs and their complexes, the benefits of sink conditions were completely diminished. When the same amount of CD was introduced on both sides, the negative effect of CD on the donor side surpassed the positive sink effects on the acceptor side, resulting in reduced flux and permeability across all membrane types.

Key results: A novel aspect of this work is the assessment of the applicability of a previously described general mathematical equation for sink conditions. Findings indicated that the supersaturation ratio between donor and acceptor compartments serves as the primary driving force of the membrane transport. For the lipophilic membrane, CDs on the acceptor side not only influenced the driving force of the transport by enhancing the solubility of carvedilol in the acceptor compartment but also altered the proportionality coefficient, hence modifying the apparent thickness of the unstirred water layer. The impact was not observed with size-exclusion membranes. The applicability of the mathematical model was additionally evaluated for CD placed on both sides of the membrane.

Conclusion: The model effectively describes the impact of CD placed on the donor side when the solid membrane permits only the drug's permeation, as in the case of a lipophilic membrane, where the solubilizing additive cannot pass through. It is also applicable when the solubilizing additive permeates slowly and has minimal influence on transport, such as with a size-exclusion membrane with a 1 kDa molecular weight cut-off. The model remains suitable if the additive is small enough in hydrodynamic size to permeate the membrane, but no concentration gradient exists to drive its transport, for example, with a 6 kDa size-exclusion membrane containing the same CD concentration on both sides of the membrane.

Background and purpose: Multifunctional nanoparticles (NPs) are gaining significant interest in biomedical research because of their versatility and potential across various applications, especially in cancer imaging and therapy. These composite systems consist of assorted materials, such as metallic elements, metal oxides, polymers, and carbon-based nanostructures, that are combined to form a single platform featuring improved and synergistic properties.

Experimental approach: This study aims to design and synthesize a novel class of silver-coated carbon dot-capped manganese ferrite NPs that were functionalized with lipids (L-Ag@MnFe@C) to improve their cytocompatibility and enable cancer therapy with multimodal imaging functionalities. Carbon-capped manganese ferrite NPs (MnFe@C) were synthesized by a one-pot hydrothermal method, followed by the fabrication of nano-silver coated over the surface (Ag@MnFe@C) using a modified Tollens method, and lipid functionalization was done by the rotary evaporation method for the development of low-cost and biodegradable theranostic agents.

Key results: The physicochemical characterization reveals that the engineered L-Ag@MnFe@C exhibits a higher stability, with a zeta potential of -50.6 mV, a hydrodynamic diameter of 279.4 nm and a quantum yield of 69.4 %. The engineered NPs exhibit contrast capabilities in longitudinal magnetic resonance imaging, transverse magnetic resonance imaging, fluorescence imaging, and computed tomography imaging. Furthermore, L-Ag@MnFe@C demonstrated excellent anticancer activity on the lung cancer cell line (A549).

Conclusion: Based on these studies, it can be concluded that the engineered L-Ag@MnFe@C exhibits multimodal imaging abilities and demonstrates anticancer properties, thereby confirming it as a potential theranostic agent.