ADMET and DMPK最新文献

Background and purpose: Traditional diabetic chronic skin wound dressings often lack the bioactivity required to promote regeneration in these complex wounds. The use of human amniotic membrane (hAM) has been identified as a promising natural option for diabetic skin wound regeneration, but hAM is susceptible to rejection and release of growth factors, so cells must be decellularized and supplemented with biomaterials such as spidroin, a hydrogel delivery system. This study aims to analyse and evaluate a composite hydrogel combining hAM and spidroin proteins to enhance the healing of diabetic chronic wounds.

Experimental approach: Hydrogels were synthesized and characterized using scanning electron microscope (SEM), attenuated total reflectance Fourier transform infrared spectroscopy, physical tests, gel fraction and swelling ratio. Wound healing studies were performed using alloxan-induced diabetic mice. Full-thickness wounds were created and treated with the hydrogel formulations. Macroscopic progress of wound healing was monitored, and histological analysis was performed to assess reepithelialization, inflammatory response, and collagen deposition.

Key results: The functional groups of hAMD components were identified at the characteristic absorption peaks of 1650 cm^-1, while spidroin showed a peak at 1530 cm^-1. In particular, the 10 % composite (hAMD + spidroin) showed significantly faster wound closure compared to the control group and other treatment groups. Histological findings confirmed that the 10 % composite was able to facilitate cell proliferation, reduce inflammation, enhance epithelial regeneration, angiogenesis, fibroblast formation and regular collagen matrix and decrease transforming growth factor beta in the remodelling phase.

Conclusion: Composite (hAMD + spidroin) 10 % showed promising wound healing efficacy in diabetic conditions, indicating its potential as a bioactive wound dressing for chronic diabetes.

Background and purpose: Liver fibrosis, a progressive liver disease arising from viral or metabolic causes, poses a major global health challenge due to its potential progression to cirrhosis and hepatocellular carcinoma. Due to the complex aetiology and epidemiology of liver fibrosis, most therapies fail in the clinic, and very few drugs have been approved by the US FDA.

Approach: This review highlights the pathophysiological features of liver fibrosis, with a focus on novel targets in hepatic stellate cells (HSCs), key players in the fibrogenesis process, to develop successful therapeutic approaches using both pharmacological agents and active targeting strategies. The review also examines current therapeutic strategies targeting liver fibrosis, both in preclinical lab setups and clinical trials. Furthermore, various receptors involved in HSC-mediated liver fibrosis and active drug delivery targeting strategies are reviewed to enhance therapeutic outcomes. This article also integrates existing knowledge to identify research gaps and guide future investigations and clinical translation in liver fibrosis treatment. In addition, novel pathways pertaining to liver fibrosis, such as the RSPO3-LGR4/5-β-catenin cascade, the CD47/YAP/TEAD4 signalling axis, and HAb18G/CD147, are briefly elaborated in the context of therapeutic approaches for arresting HSC activation. Single-cell RNA sequencing of HSCs is presented to provide a clearer picture of liver fibrosis.

Conclusion: The review highlights critical research gaps in liver fibrosis therapy and promising active targeting strategies and pharmacological interventions to improve therapeutic outcomes. Overall, this review provides a robust foundation for scientists and clinicians to advance active targeting of the disease pathology and to develop new pharmaceutical formulations that are pharmacologically safer and more efficacious.

Background and purpose: Predicting the food effect on oral drug absorption by physiologically based biopharmaceutical modelling (PBBM) remains challenging. The bile micelle unbound fraction (f _u) is one of the primary determinants of the negative food effect for high solubility drugs. To calculate the pH-f _u profile for PBBM, the bile micelle partition coefficients of ionized and un-ionized drug species (K _bm,z, z: charge) are required. The general rules for the ratio of the partition coefficients of ionized and un-ionized drug species have been reported for the octanol/water (P _oct) and phosphatidylcholine liposome/water partition coefficients. However, the general rule for the bile micelle partition coefficient has not yet been investigated. The purpose of the present study was to clarify the general rule for K _bm,z≠0/K _bm,0.

Experimental approach: The pH-f _u profiles of 4 monovalent weak acids, 8 monovalent weak bases, 2 divalent weak bases, and 2 zwitterion drugs were measured by dynamic dialysis in the pH range about pK _a ± 2. Bile micelles consisted of taurocholic acid (TC)/egg lecithin (15 mM/ 3.75 mM). K _bm,z was calculated from the pH-f_u profiles.

Key results: K _bm,-1/K _bm,0 was ≤ 0.03 for all monovalent acids. K _bm,+1/K _bm,0 ranged from 0.24 to 2.6. K _bm,+2/K _bm,0 was about 0.3. For the two zwitterionic drugs, K _bm,-1/K _bm,±0 was 1.1 and 2.3, and K _bm,+1/K _bm,±0 was 3.9 and 20, respectively. K _bm,0 roughly correlated with P _oct (r = 0.68).

Conclusion: The bile micelle binding of anionic drug species (z = -1) is generally negligible, whereas that of cationic drug species (z = +1) can be significant. A general rule for K _bm,+1/K _bm,0 was not found. K _bm,+1/K _bm,0 can be greater than 1 in several cases, suggesting an attractive electrostatic interaction between the positive charge of a drug and the negative charge of TC. These points should be considered in food effect prediction.

Background and purpose: Imbalances in biomarkers such as dopamine and NADH are linked to neurological and metabolic disorders, including Parkinson's disease, depression, and stroke, underscoring the need for rapid and accessible diagnostics. This study presents a smartphone-assisted, 3D origami microfluidic paper-based analytical device (μPAD) modified with photochemically synthesized graphene/platinum (G/Pt) nanocatalysts for multiplex colorimetric detection of dopamine and NADH.

Experimental approach: G/Pt catalysts were prepared using 2.5 to 10 mM Pt precursors under UV irradiation. μPADs were laser-printed on commercial-grade filter paper, patterned, and folded into three layers of 3D Origami.

Key results: The optimized 10 mM G/Pt catalyst significantly improved reaction rates (18× faster), leading to a rapid detection time constant of 6.69 and 4.59 s for dopamine and NADH, respectively. Furthermore, the utilization of 10 mM G/Pt catalyst increased colour intensity (2.48×) on the μPAD platform. An application for smartphones integrated with an image processing algorithm was developed using Kotlin to enable automatic quantification of colorimetric signals from saturation and hue channels for dopamine and NADH, respectively. The detection exhibited the lowest mean absolute percentage errors of 0.52 and 0.07 % as well as a limit of detection of 0.56 and 0.99 mM for dopamine and NADH, respectively.

Conclusion: The 3D origami structure facilitates efficient fluid handling and multiplex detection, while the nanocatalyst modification improves pore infiltration and sensitivity. This work demonstrates, for the first time, a cost-effective, portable, and high-performance biosensor for dual biomarker detection, offering substantial promise for point-of-care diagnostics in neurological and metabolic health monitoring.

Background and purpose: Treatment of chronic myeloid leukaemia includes targeted therapy with tyrosine kinase inhibitors (TKIs): imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib. This review aims to prove that electrochemical sensors provide a reliable alternative to the conventional analytical methods for highly sensitive and cost-effective assay of TKIs in pharmaceutical formulations and biofluids. These platforms have significant advantages in fast detection and portability because they could be designed as miniaturized hand-held devices suitable for real-time point-of-care analysis, providing quick results for enabling personalized therapeutic drug monitoring.

Experimental approach: The paper covers recent developments in substrate materials, various electrode designs, the advantages, and limitations of sensors for TKIs, encompassing both basic and applied research.

Key results: This is a pioneering study that provides a general review on emerging trends, technologies, and practical applications of electrochemical sensors for TKIs analysis. The article provides researchers with a clear introduction and concise guide to the design and application of electrochemical sensors in the clinical analysis of TKIs.

Conclusion: The review is intended to serve as a valuable resource for researchers in navigating the latest developments in TKIs' electrochemical sensing platforms. The fast response, high sensitivities and satisfactory recoveries obtained in blood serum and urine samples show the potential for application of the proposed electroanalytical systems in clinical analysis and optimization of chemotherapeutic treatments.

Introduction and background: The world has witnessed several outbreaks, emergence and re-emergence of infectious diseases throughout the 21^st century as a result of climate change, urbanization and migration. Several infectious diseases caused by pathogens such as SARS-CoV-2, Ebola, Zika, Dengue, Marburg viruses, Mycobacterium tuberculosis, etc. have caused a devastating impact on lives and livelihoods around the world. To counter these diseases, medical experts rely on conventional techniques, which include microscopy and serological testing. However, these conventional methods are hindered by several trade-offs, including high cost, longer processing times, low sensitivity, and a likelihood of false positive results. Biomedical sensors have gained momentum in clinical diagnostics due to their low cost, portability, and sensitivity, among other advantages. To improve their performance, scientists have incorporated nanomaterials. Other techniques used to enhance the performance of nanobiosensors include multiplex testing, point-of-care testing (POCT), and smart sensing.

Methodology: Thus, in this review, we present a comprehensive overview of the state-of-the-art nanobiosensors for detecting infectious diseases. The review covers key topics that are centred around the application of nanotechnology in biosensing, multiplex testing, POCT and smart nano-enhanced biosensors.

Findings: The findings of this review highlighted the advantages of biosensors over conventional approaches, with a limit of detection ranging from nanomolar to attomolar concentrations and a time response ranging from 1 to 3 hours.

Conclusion: Despite the prospect of nanobiosensors, several limitations exist, including complexity, extensive processing time, and others. Moreover, the integration of smart technologies in nanobiosensors can offer several benefits, including high accuracy and faster detection and prediction.

Background: Microfluidic nanoprecipitation followed by freeze-drying would yield uniformly sized, stable nanoparticles by preserving their physicochemical property without compromising therapeutic performance. The isoniazid (INH)-loaded poly-ε-caprolactone (PCL) nanoparticles could be developed using a microfluidic technique for the management of tuberculosis.

Experimental approach: The INH-loaded nanoparticles were fabricated via a microreactor-assisted nanoprecipitation method and optimization using a design of experiments factorial design approach. The resulting INH-PCL nanoformulation was characterized for particle size, polydispersity index (PDI), zeta potential (surface charge), Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction analysis and field emission scanning electron microscope.

Key results: The optimized nanoparticles exhibited an average particle size (248.4 ± 5.372 nm) and high encapsulation efficiency (82.26 ± 4.36 %). Thermal and spectroscopic analyses confirmed the absence of drug-polymer interactions, ensuring formulation integrity; stability studies under accelerated conditions demonstrated negligible changes in particle size, PDI, and zeta potential over the period of 6 months, indicating robust colloidal stability. A scanning electron microscopy study revealed rod-shaped nanoparticles with smooth surfaces. Lyophilization (freeze-drying) enhanced long-term stability, yielding a readily re-dispersible powder (reconstitution index ~1.066). Following diffusion-controlled kinetics, in vitro drug release studies in phosphate buffer saline (pH 7.4) showed sustained drug release (92.45 % cumulative release over 48 h).

Conclusion: Our results confirm that the INH-loaded PCL nanoformulation combines excellent stability, high drug-loading capacity, and sustained release, key attributes of effective tuberculosis therapy.

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 (CAR) between lipophilic and size-exclusion membranes in the presence of hydroxypropyl-beta-cyclodextrin (HP-β-CD) using in vitro side-by-side diffusion cell assays.

Experimental approach: Solubility and permeability assays confirmed that HP-β-CD significantly enhanced the solubility of CAR, while simultaneously decreasing its permeability, indicating an interplay between the two parameters.

Key results: A mathematical model based on Fick's first law of diffusion was developed to describe drug transport across the UWL, and generally through the UWL-membrane system, with a particular focus on the role of solubilizing agents.

Conclusion: Results from both the UWL and membrane limited transport conditions demonstrated that the supersaturation ratio (SSR, defined as the ratio of the drug concentration present in solution to its thermodynamic solubility measured in exactly the same media) between donor and acceptor compartments is the real driving force of the transport, when the complexing agent and the drug- HP-β-CD complex does not penetrate the membrane or the permeation of the solubilizing additive through the membrane is relatively slow, so it does not affect the transport of the API substantially.

In the present work, SnO₂ nanostructures were synthesized and a sensitive voltammetric sensor on a glassy carbon electrode (GCE) was constructed to estimate morphine (MP) in the presence of diclofenac (DLF).

Background and purpose: Because diclofenac (DLF) is an NSAID, its administration can reduce postoperative morphine (MP) requirements in adults; for example, standard DLF dosing has been shown to decrease MP use after abdominal surgery. Hence, devising a simple, cost-effective, and swift assay for these compounds in biological and pharmaceutical specimens is indispensable.

Experimental approach: SnO₂ nanostructures were synthesized, and a sensitive voltammetric sensor on a glassy carbon electrode (GCE) was constructed to estimate MP in the presence of DLF. Cyclic voltammetry was employed to evaluate the electrochemical response of the SnO2 nanostructures/GCE towards MP.

Key results: The SnO₂ nanostructures exhibited a significant effect on the electrochemical reaction of the electrode toward the MP oxidation. The SnO₂ nanostructures/GCE further exhibited a more sensitive detection platform for MP determination with a limit of detection of 0.006 μM using differential pulse voltammetry in a linear range of 0.01 to 340.0 μM.

Conclusion: The SnO₂ nanostructures/GCE exhibited extremely high electrochemical activities towards the simultaneous oxidation of MP and DLF. Moreover, the SnO₂ nanostructures/GCE provided reproducible and stable responses for MP quantitation. The platform prepared showed successful performance for MP and DLF determination in real samples. SnO₂ nanostructures exhibited a significant effect on the electrochemical reaction of the electrode toward the MP oxidation. The SnO₂ nanostructures/GCE further exhibited a more sensitive detection platform for MP determination with a limit of detection of 0.006 μM using differential pulse voltammetry in a linear range of 0.01 to 340.0 μM. Additionally, the SnO₂ nanostructures/GCE exhibited extremely high electrochemical activities towards the simultaneous oxidation of MP and DLF. Moreover, the SnO₂ nanostructures/GCE provided reproducible and stable responses for MP quantitation. The platform prepared showed successful performance for MP and DLF determination in real samples.

Background and purpose: It is generally known that the majority of disorders exhibit symptoms to some degree when the quantities of two crucial substances, epinephrine and folic acid, are low or high. These two chemicals' composition variations may be tracked and utilized to identify conditions such as myocardial infarction, Parkinson's disease, and mental disorders.

Experimental approach: Using a solvothermal technique, we propose the synthesis of a novel MIL-101 (Fe)-NH₂ metal-organic framework/graphene oxide nanocomposite (MOF/GO nanocomposite). The produced nanocomposite's morphology was examined using field-emission scanning electron microscopy. A straightforward, quick, and sensitive electrochemical sensing platform for epinephrine detection was then created by drop-casting the produced MOF/GO nanocomposite onto the screen-printed electrode (SPE).

Key results: Compared to unmodified SPE, cyclic voltammetry revealed that the MOF/GO/SPE considerably enhanced the epinephrine oxidation process, exhibiting a greater detection current at a lower over-potential. The synergistic combination of MOF and GO sheets may cause this discovery. With a low detection limit of 0.07 μM, the MOF/GO/SPE sensor's linear response for voltammetric measurements of epinephrine was found to be between 0.2 and 500.0 μM. A modified electrode was also utilized to measure folic acid and epinephrine simultaneously.

Conclusion: Lastly, the modified SPE effectively demonstrates its high accuracy in identifying folic acid and epinephrine in biological and pharmaceutical samples.