Current drug metabolism最新文献

A majority of the global population suffers from eye diseases, but few effective treatment options are available with ophthalmic drug therapies. The reasons that have been identified are (1) lack of awareness about the options for treatments, drugs, polymeric science, or physiological barriers, (2) limitations in bringing drug therapies to the posterior segment of the eye due to physiological or anatomical limitations, and (3) regulatory and production difficulties of ocular drug products. Innovative ocular medication delivery and therapies are covered in this study, including hydrogels, nano micelles, implants, nanoparticles, microparticles, liposomes, in situ gels, and microneedles. Moreover, due to their potential to capture both hydrophilic and lipophilic medications, increase ocular permeability, prolong the period of residence, enhance drug stability, and increase bioavailability, this review includes nanotechnology-based carriers. The research encompassed various eye disorders, obstacles to ocular delivery, multiple ocular administration routes, a range of nanostructured platforms, characterization approaches, methods to improve ocular delivery, and emerging technologies. This review aims to provide information on the anatomy of the eye, various ocular conditions, and obstacles to ocular delivery. The benefits and drawbacks of various ocular dose forms or delivery techniques are also evaluated. Finally, it describes methods for increasing ocular bioavailability.

Traditional treatment methods for the management of diabetes, such as oral hypoglycemic medications and insulin injections, include drawbacks like systemic adverse effects, inconsistent medication levels, and low compliance. To avoid difficulties, glycemic levels in diabetic patients, a long-term metabolic condition, must be precisely and consistently controlled. Smart therapeutic systems allow for precise, on-demand medication release in response to local physiological or environmental cues, such as glucose levels, pH, temperature, or enzyme activity. They provide a possible substitute for conventional diabetic therapies. As these systems only administer medications when and where needed, they reduce side effects while simultaneously increasing therapeutic efficacy and patient compliance. These systems are designed to respond to signals from external sources (such as light, ultrasound, or magnetic fields) or stimuli like temperature, pH, glucose levels, and enzymes. As they use glucose-sensitive substances like phenylboronic acid, glucose oxidase, or polymers to precisely release insulin in hyperglycemic circumstances, glucose-responsive delivery methods are essential for diabetes. This review discusses a stimuli-responsive drug delivery system designed for diabetes treatment, with a focus on the developments in biomaterials, nanotechnology, and engineering that improve its effectiveness and biocompatibility. Along with the possibility of combining a stimuli-responsive drug delivery system with wearable technology for continuous glucose monitoring and intelligent insulin delivery, issues, such as manufacturing complexity, stability, and patient safety, are also addressed. The stimuli-responsive drug delivery system has the potential to revolutionize diabetes management by bridging the gap between physiological needs and therapeutic delivery, providing better glucose control, fewer side effects, and an enhanced standard of living for patients.

Cirrhosis is a very serious, gradual liver disease characterized by the overproduction of collagen and scarring, which together may result in liver failure or hepatocellular cancer. It typically develops based on fibrosis, which may be reversible when diagnosed in its initial stages. Viral hepatitis, alcohol, non-alcoholic fatty liver disease, and drug-induced hepatotoxicity are some of the etiologies of the disease. It is worth noting that about half of the cases of hepatic damage in patients are known to be caused by drug-induced liver injury. The existence of the pathophysiological complexity and therapeutic reactions of cirrhosis requires experimental models that are reliable. This review gives insight into the different in vivo, ex vivo, and operative animal models employed to cause hepatic injury by application of chemicals, drugs, dietary, and bile duct ligation particulars. The focus is on the mechanistic understanding of the actions of hepatotoxic substances, their involvement in oxidative stress, mitochondrial pathology, and the inflammatory process. Each model is critically discussed in terms of its advantages, limitations, and translational relevance.Additionally, this work highlights emerging alternatives, such as organ-on-a-chip systems, 3D co-cultures, and hepatic bioengineered tissues, as solutions that aim to reduce animal use and increase physiological relevance. The review also discusses biomarkers, histopathological endpoints, and important molecular players in hepatic fibrosis and cirrhosis. The review also examines data from preclinical studies of hepatoprotective substances and modulators of fibrosis, as it facilitates the integration of data from various experimental platforms. The next steps involve personalized pathology based on decellularized liver scaffolding and patient cells, aiming to better determine clinical outcomes and treatment responses.

Background: The rapid surge in bacterial resistance to classical antibiotics and antimicrobial agents has driven researchers to identify new classes of antimicrobial agents. At the nanoscale, nanotechnological progress has strongly underscored the application of silver and copper since they present high antimicrobial activities toward gram-positive and gram-negative bacteria. Nanostructures containing these two elements-all the more so for hybrid nanocomposites-have been scantily the subject of investigated. The present work aims to develop and study a silver/copper oxide/clay hybrid nanocomposite.

Methods: Nanocomposites of silver, copper oxide, and their hybrid with clay were synthesized via chemical precipitation under controlled pH (9-11) and temperature (60-90°C) conditions. The antibacterial activity was assessed using standard 0.5 McFarland-adjusted bacterial inocula. Characterization was performed using FTIR, XRD, FESEM, and TEM techniques. MIC and MBC were determined through serial dilution, and data were analyzed using one-way ANOVA and Tukey's test (SPSS v26).

Results: The results indicated that the fabricated nanocomposite was impure, with nanosilver particles measuring 30-40 nm and copper oxide particles measuring 200-250 nm. The morphological properties of synthesized Ag/Cu₂O/clay nanocomposites were evaluated using X-ray diffractometer analysis. The minimum inhibitory concentration (MIC) of the hybrid nanocomposite against Staphylococcus aureus and Bacillus subtilis was 1024 μg/ml, and for Escherichia coli and Pseudomonas aeruginosa 2048 μg/ml. The minimum bactericidal concentration (MBC) against Staphylococcus aureus and Bacillus subtilis was 4096 μg/ml, and for Escherichia coli 4096 μg/ml, and Pseudomonas aeruginosa 8192 μg/ml.

Discussion: Silver/copper oxide/clay hybrid nanocomposite exhibited more intensive antibacterial activities towards gram-positive bacteria in the absence of single-component nanocomposites, validating the synergistic effect of silver and copper in aid of clay. Its small efficacy on gram-negative strains also points at the necessity for additional optimization as well as extension. Such outcomes indicate the potential of the hybrid nanocomposite as an aspiring candidate for eventual antimicrobial applications.

Conclusion: These results showed that the antimicrobial property of silver/copper/clay hybrid nanocomposite was better than copper/silver and clay nanocomposite against gram-positive bacteria, while showing a similar effect against gram-negative bacteria.

Moonlighting proteins, defined by their ability to perform distinct, independent functions beyond their primary roles, have garnered attention in metabolic regulation and drug discovery. This review highlights the emerging significance of these proteins in diverse physiological and pathological processes. With examples like glycolytic enzymes and Krebs cycle components, we explore their involvement in transcriptional regulation, immune responses, and stress modulation. Their unique ability to mediate host-pathogen interactions and disease progression underscores their potential as therapeutic targets. Advanced technologies, such as proteomics and bioinformatics, have revolutionized the identification and characterization of these proteins, unraveling their structural and functional complexities. This synthesis aims to bridge gaps in understanding protein multifunctionality and advocates its implications in drug development. By targeting specific functions of moonlighting proteins while preserving their essential roles, new strategies in pharmacology and personalized medicine are envisioned. The review also proposes a roadmap for leveraging these proteins' multifunctionality to address current challenges in therapeutic interventions.

Background: Carboplatin (CP) is a widely used chemotherapeutic agent with poor oral bioavailability and potential systemic toxicity when administered intravenously. There is a growing interest in developing sustained-release oral formulations to improve therapeutic efficacy and patient compliance.

Objective: The present study aimed to develop and evaluate an oral, enteric-coated, PEGylated multi-walled carbon nanotube (MWCNT) formulation (F2) of carboplatin and assess its pharmacokinetic and histopathological profile in comparison with the marketed intravenous product, Kemocarb®.

Methods: A sensitive and robust HPLC method was developed for the quantification of CP in rabbit plasma. Stability studies were performed at 4 °C for 4 hours and -80°C for 4 weeks. Histopathological evaluation was conducted on major organs of mice to assess toxicity. CP and caffeine were extracted with minimal matrix interference. Pharmacokinetic studies were performed following oral administration of the F2 formulation and compared with Kemocarb®.

Results: The developed HPLC method demonstrated good sensitivity, accuracy, and robustness. CP was stable under both short-term and long-term storage conditions. Histological analysis revealed no significant pathological damage in mice organs. The F2 formulation exhibited sustained drug release for up to 24 hours. The Tmax, Cmax, and MRT of CP for F2 were different compared to Kemocarb®, with a relative bioavailability of 1.182 ± 0.24. The Cmax and MRT of F2 were 12.327 ± 0.03* and 3.5805 ± 0.26 h, respectively.

Conclusion: The developed F2 formulation of carboplatin demonstrates sustained release and improved relative bioavailability following oral administration. It may offer a promising alternative to commercial intravenous CP injections (Kemocarb®), potentially supporting metronomic chemotherapy strategies with improved patient compliance and reduced systemic toxicity.

Background: Numerous chronic illnesses, including diabetes, cancer, cardiovascular disease, and neurological disorders, are mostly caused by oxidative stress, which is defined as an imbalance between the body's antioxidant defenses and the generation of reactive oxygen species (ROS). The success of traditional treatments for oxidative stress has been limited because antioxidant medications are not well-absorbed, are quickly broken down, and do not target specific areas of the body.

Methods: Drug delivery methods based on nanotechnology offer a viable solution to these issues by providing therapeutic molecules with improved release characteristics, enhanced bioavailability, and targeted capabilities. Recent developments in nanotechnology have enabled the creation of multipurpose carriers that can simultaneously transmit genes for endogenous antioxidant enzymes and antioxidants.

Results: This integration promotes a long-term healing response and addresses the immediate oxidative stress. Likewise, functionalizing nanocarriers with particular ligands improves localization to oxidative stress locations, including inflammatory tissues or tumor microenvironments, boosting therapeutic efficacy. The potential of nanotherapeutics in reducing oxidative stress-driven diseases is examined in this article.

Discussion: Nanotechnology-based drug delivery approaches offer a novel avenue for the treatment of several oxidative stress-induced diseases. These delivery systems are highly target-specific and have a longer duration of action. Still, more research is needed to address issues, such as safety margins, largescale production, and approval of medicine use.

Conclusion: We address several nanocarrier platforms, such as liposomes, polymeric nanoparticles, dendrimers, and metallic nanoparticles that have proven more effective in delivering therapeutic drugs and antioxidants to specific sites of oxidative damage. Furthermore, nanotherapeutics may enhance their therapeutic potential by protecting these bioactive substances from premature degradation and clearance.

Background: Vincosamide, an indole alkaloid extracted from Nauclea officinalis, exhibits a range of pharmacological activities, such as anti-tumor, antibacterial, and anti-inflammatory properties. However, despite its promising therapeutic applications, there is a notable gap in research focused on the metabolic pathways of vincosamide.

Objectives: This study aims to investigate the metabolism of vincosamide both in vitro and in vivo in rats, and to elucidate its metabolic pathways.

Methods: Samples of liver microsomal incubation, plasma, bile, urine, and feces following vincosamide administration were analyzed by ultra-high performance liquid chromatography-quadrupole-Exactive Orbitraphigh resolution mass spectrometry (UHPLC-Q-Exactive Orbitrap HRMS). The collected data were analyzed using Compound Discovery 3.2 software and the molecular network method. The metabolites identified through these methodologies were subsequently validated using Xcalibur 4.1 software, which provided information on retention times, parent ions, and characteristic fragment ions.

Results: A total of 37 metabolites were identified, including 8 in vitro and 32 in vivo (3 in plasma, 7 in bile, 22 in urine, and 17 in feces). While the metabolism of vincosamide differs in vitro and in vivo in rats, the type of metabolic reaction that occurs is well-defined. The predominant metabolic pathways are oxidation, reduction, deglycosylation, hydration, glucuronidation, methylation, sulfation, glycine conjugation, cysteine conjugation, taurine conjugation, and complex reactions.

Conclusion: This study elucidates the metabolism of vincosamide in vitro and in vivo in rats, thereby expanding the metabolite profile of vincosamide. These findings provide a foundation for the potential development of new drugs based on vincosamide.

Introduction: Lornoxicam is a non-steroidal anti-inflammatory drug belonging to the oxicam class. This study aimed to develop a niosomal gel containing orange oil for improving the anti-inflammatory effect of lornoxicam.

Methods: Lornoxicam-loaded niosomes (LOR-OR-NIO) were prepared using film hydration followed by the sonication method. Particle size, entrapment efficiency, and ex vivo permeation were all considered during the optimization of the niosomal gels by employing the Box-Behnken design. Dermatokinetics and in vivo anti-inflammatory studies were performed using male Wistar rats.

Results: The particle size, entrapment efficiency, and skin permeation ability of the optimized LOR-ORNIO formulation were found to be 354.3 nm, 83.56 %, and 105.63 μg/cm2, respectively. The ex vivo studies indicated that the optimized LOR-OR-NIO gel demonstrated superior drug penetration properties (105.43 μg/cm²) compared to both the LOR-NIO gel (69.23 μg/cm²) and the LOR gel (35.34 μg/cm²). The activation energy values of LOR gel, LOR-NIO gel, and LOR-OR-NIO gel were 2.74 Kcal mol^-1, 1.93 Kcal mol^-1, and 0.94 Kcal mol^-1, respectively.

Discussion: The lower activation energy of the LOR-OR-NIO gel contributed to more skin penetration of the drug. Dermatokinetics investigation demonstrated that the LOR-OR-NIO gel had superior penetration in the epidermal and dermal areas compared to the LOR gel. In vivo anti-inflammatory studies indicated that the LOR-OR-NIO gel exhibited greater edema inhibition compared to both the LOR-NIO gel and LOR gel. These results demonstrated the enhanced anti-inflammatory activity of the LOR-ORNIO gel.

Conclusion: The study concluded that orange oil enhanced skin permeability and influenced the dermatokinetics of the LOR-OR-NIO gel, leading to an improvement in in vivo anti-inflammatory properties.

Introduction: Type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and hepatic ectopic lipid deposition (ELD), poses a complex metabolic challenge. This study aimed to elucidate the mechanisms of Yiqi Huazhuo Decoction (YD) through an integrated approach combining network pharmacology and metabolomics. T2DM is marked by impaired insulin signaling and disrupted hepatic lipid metabolism, resulting in a vicious cycle that accelerates disease progression. While Traditional Chinese Medicine (TCM), such as YD, demonstrates potential in modulating these dysfunctions, its underlying molecular mechanisms remain to be fully clarified.

Materials and methods: A diabetic fat rat model was used to evaluate the efficacy of YD. UPLC-MS characterized the main metabolites found in YD. After an 8-week intervention, physiological indices and hepatic pathology were assessed. Network pharmacology identified bioactive metabolites and targets, which were validated by molecular docking. Untargeted metabolomics was employed to analyze hepatic metabolic changes.

Results: YD improved glucose/lipid metabolism, insulin sensitivity, and hepatic function. Network pharmacology revealed that YD acts via the EGFR and PI3K-Akt/IL-17 pathways. Molecular docking confirmed luteolin-EGFR binding. Metabolomics identified 20 altered metabolites in the biosynthesis of unsaturated fatty acids. Multi-omics analysis revealed that YD regulated EGFR and hepatic metabolic networks.

Discussion: The multi-metabolite, multi-target mechanism of YD distinguishes it apart from single-target drugs, such as metformin. The binding of luteolin to EGFR may potentially reactivate the PI3K-Akt signaling pathway, thereby enhancing insulin sensitivity. Regulation of metabolic pathways, including the biosynthesis of unsaturated fatty acids, contributes to the reduction of hepatic lipid deposition. These findings underscore the capacity of YD to disrupt the IR-ELD cycle in T2DM.

Conclusion: YD ameliorates T2DM-IR and hepatic ELD by modulating EGFR signaling and metabolic pathways, providing multi-omics evidence for its clinical application.