Pharmaceutics最新文献

Background/Objectives: Citicoline, also known as CDP-choline, is a nootropic agent currently used in the treatment of glaucoma and is undergoing evaluation as a first-line therapy in a multi-center, international, phase III, randomized clinical trial involving citicoline eyedrops (ClinicalTrials.gov ID: NCT05710198). Numerous clinical and preclinical studies have linked the neuroenhancement and neuroprotective effects of citicoline to its role as a metabolic precursor for structural and functional components of cell membranes (such as phosphatidylcholine and sphingomyelin) and for neurotransmitters (e.g., acetylcholine and dopamine). However, compelling evidence suggests that the molecular mechanisms underlying its cytoprotective activity involve additional as-yet uncharacterized pharmacological actions. Methods: To further elucidate its pharmacology, we investigated the effect of two cytoprotective doses of citicoline (0.1 mM and 1 mM) on the global proteome of neuroblastoma cells using an unbiased shotgun proteomics approach. Results: With over 4000 unique proteins identified and quantified per experimental condition, the proteomics analysis revealed that citicoline, after 6 h of stimulation, induces a profound and robust remodeling of the intracellular proteome compared to untreated cells. Importantly, this effect was observed to significantly diminish by 18 h of stimulation, highlighting its transient nature (data are available via ProteomeXchange with identifier PXD061053). The clustering and rationalization of proteins upregulated by citicoline treatment identified the enrichment of key pathways for mRNA splicing, protein translation, proteostasis balance through the ubiquitin proteasome system (UPS), and mitochondrial metabolism. Conclusions: These proteomics findings introduce previously uncharacterized biological effects of citicoline and foster the working hypothesis that this drug may exert its cytoprotective activity through molecular mechanisms linked to the hormesis principle. These data further support the rationale for its clinical application in neurodegenerative processes and human disorders characterized by proteotoxicity.

Cosmeceuticals are cosmetic formulations that are intended to alleviate skin conditions that affect its appearance and functionality. They are not considered medications but contain molecules that exert biological action on the skin beyond traditional cosmetic actions. Sometimes, the bioactives used have limitations for transdermal passage, and it has been suggested that the use of nanocarriers can increase the effectiveness of cosmeceutical products. The degree of sophistication of nanocosmeceuticals requires that safety and efficacy aspects be verified before going on the market. In this regard, the application of the Quality by Design (QbD) approach during product development ensures that products meet the consumer needs in full. This review analyzes the implementation of QbD in the development of nanocosmeceuticals, considering the main characteristics of the most used bioactive groups and nanocarriers that have proven to be ideal vehicles for topical and transdermal applications.

Tuberculosis (TB) remains a leading infectious killer, increasingly complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease; current regimens, although effective, are prolonged, toxic, and often fail to reach intracellular bacilli in heterogeneous lung lesions. This narrative review synthesizes how next-generation antimycobacterial strategies can be translated "from molecule to patient" by coupling potent therapeutics with delivery platforms tailored to the lesion microenvironment. We survey emerging small-molecule classes, including decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) inhibitors, mycobacterial membrane protein large 3 (MmpL3) inhibitors, and respiratory chain blockers, alongside optimized uses of established agents and host-directed therapies (HDTs). These are mapped to inhalable and nanocarrier systems that improve intralesional exposure, macrophage uptake, and targeted release while reducing systemic toxicity. Particular emphasis is placed on pulmonary dry powder inhalers (DPIs) and aerosols for direct lung targeting, stimuli-responsive carriers that trigger release through pH, redox, or enzymatic cues, and long-acting depots or implants that shift daily dosing to monthly or quarterly schedules to enhance adherence, safety, and access. We also outline translational enablers, including model-informed pharmacokinetic/pharmacodynamic (PK/PD) integration, device formulation co-design, manufacturability, regulatory quality frameworks, and patient-centered implementation. Overall, aligning stronger drugs with smart delivery platforms offers a practical pathway to shorter, safer, and more easily completed TB therapy, improving both individual outcomes and public health impact.

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain and are metabolized in the liver via cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs). Methods: A narrative review of the literature was conducted by searching the PubMed database up to December 2025, with English as the only language restriction. Relevant studies were identified using the keywords "opioids," "pharmacogenetic," "cytochrome mutations," and "interactions." Results: Polymorphisms in CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition by concomitant drugs or compounds (herbal products or food) are sources of variability factors in drug response that may be predictable. Conclusions: This review article summarizes current evidence on the role of pharmacogenetics and opioid-related interactions, offering a framework to better understand interindividual variability in opioid response and to inform future multimodal approaches.

Background: Nebulized polymyxin B (PMB) therapy is widely used in intensive care units for treating hospital-acquired and ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria, yet its pulmonary delivery performance during invasive mechanical ventilation remains poorly characterized. Methods: An in vitro adult mechanical ventilation model was used. We evaluated two nebulizers (vibrating mesh nebulizer [VMN] and jet nebulizer [JN]) at three positions (standalone nebulizer, 15 cm from the Y-piece, and the humidifier's dry end) with two artificial airway types (endotracheal and tracheostomy tubes). Lung deposition was predicted using the multiple-path particle dosimetry model, incorporating the Yeh/Schum five-lobe adult lung model. Results: In the standalone setup, the percentage of delivered dose of VMN and JN was approximately 40% and 34%, respectively. Mechanical ventilation significantly reduced the delivered dose (all p ≤ 0.0085), with VMN at the humidifier's dry end delivering only 2.14-2.99% of the nominal dose. In all the tested ventilation scenarios, both the use of the JN and positioning the nebulizer 15 cm from the Y-piece significantly increased aerosol delivery (all p ≤ 0.021). While the ventilator circuit reduced the total drug amount, it filtered larger aerosols. This resulted in a smaller mass median aerodynamic diameter and a higher fine particle fraction (all p < 0.0001), which doubled the predicted alveolar deposition fraction (from 13-14% in standalone to 23-28% in ventilation scenarios) and eliminated extrathoracic deposition. Conclusions: This study provides the first in vitro and in silico assessment of PMB aerosol delivery during invasive mechanical ventilation. Nebulizer type, its placement within the circuit, and the artificial airway are critical factors that significantly alter the pulmonary delivery of PMB aerosol and subsequently impact its lung deposition.

Nano- and submicron particles (NSPs) with folate for targeting are actively used for the treatment and diagnosis of cancer and inflammatory diseases. Albumin-containing systems have enhanced biocompatibility, circulation time, and colloidal stability, which are important for medical applications. The outstanding binding properties of albumin allow the transport of numerous therapeutic and/or imaging agents. This review summarizes multiple aspects of binding a folate residue (or folic acid) to NSPs and the functioning of folate-albumin-NSPs. Special attention in the review is given to the types of bonds between folic acid and albumin, i.e., covalent and non-covalent, and to the confirmation and quantification of binding by different physicochemical methods. The process of binding, the qualitative and quantitative characteristics of binding and forming product, and its functioning are interconnected with the binding conditions; thus, an analysis of reaction conditions is provided. For the proper functioning of folate-albumin-NSPs, the state of albumin within them is important; thus, considerable focus in the review is placed on the features of structure modification of serum albumin in folate-albumin binding, i.e., the amino acid residues involved in this process and the conformational state of the protein. The stability and the functioning of the protein within folate-albumin-NSPs are discussed. Also, the effectiveness of targeting by folate is viewed as dependent on many characteristics of folate-albumin-NSPs, particularly on the peculiarities of binding between the folic acid residue and albumin. Furthermore, the authors discussed and suggested solutions concerning the shortcomings highlighted in the studies devoted to obtaining folate-modified albumin-containing NSPs.

Inflammatory bowel disease is a result of inappropriate continuous non-specific inflammation in the intestinal tract, which in turn is aggravated by defects in the activation of the mucosal immune system and in the barrier function of the intestinal epithelium. The most prominent manifestations of IBD are ulcerative colitis (UC) and Crohn's disease (CD). UC is characterized by a continuous pattern that commonly starts with lesions in rectum mucosa and is contained in the colon. On the other hand, CD affects the ileum and colon in a discontinuous pattern, and the lesions are often transmural. Conventional therapies often face limitations such as systemic side effects, poor drug stability, and low site-specificity. In recent years, nanoparticle (NP) systems have emerged as a promising strategy to overcome these challenges, offering improved targeting, controlled release, and enhanced therapeutic efficacy. Several studies have shown that the preferential accumulation of NPs in the inflamed colon is influenced by the pathophysiological changes associated with IBD, including alterations in transit time, pH value, enzymatic activity, microbial composition, and mucus integrity. These disease-specific characteristics provide unique opportunities to design smart and responsive NPs that enhance drug delivery and therapeutic efficacy while minimizing systemic exposure. This work presents an overview of novel technologies based on nanosystems, with the ability to specifically target the affected areas of the GI tract in inflammatory bowel disease.

Background/Objectives: Cancer is a major health concern involving abnormal cell growth. Combining anticancer agents can enhance efficacy and overcome resistance by targeting multiple pathways and creating synergistic effects. Methods: This study used in silico approaches to evaluate the physicochemical and pharmacokinetic profiles of the innovative organoselenium nucleoside analog Di3a, followed by the design of two nanocarriers. Di3a-loaded PLGA nanocapsules and nanostructured lipid carriers based on compritol were prepared and evaluated alone and combined with doxorubicin (DOX) and docetaxel (DTX) for a synergistic effect. Results: Di3a subtly violated some of Lipinski's rules, but still showed suitable pharmacokinetic properties. Both nanoparticles presented nanometric size, negative zeta potential and polydispersity index values < 0.20. Hemolysis assay suggested a pH-dependent pattern conferred by the surfactant 77KL, and evidenced the biocompatibility of the formulations, aligning with the results observed in the nontumor L929 cell line. The lack of drug release studies under varying pH conditions constitutes a limitation and warrants further investigation to validate the pH-responsive properties of the nanocarriers. MTT assay revealed that both formulations exhibited significant cytotoxic effects in the A549 cell line. However, neither formulation exhibited marked toxicity toward NCI/ADR-RES, a resistant tumor cell line. Conversely, when combined with DOX or DTX, the treatments were able to sensitize these resistant cells, achieving expressive synergistic antitumor activity. Conclusions: Despite the limitations in the in silico studies, the study highlights the potential of combining the proposed nanocarriers with conventional antitumor drugs to sensitize multidrug-resistant cancer cells and emphasizes the safety of the developed nanoformulations.

Background/Objectives: Three-dimensional (3D) cell cultures are increasingly used because 3D cell aggregates better mimic tissue-level biological mechanisms and support studies of tissue physiology and drug screening. However, existing laboratory methods and commercial microwell platforms often yield inconsistent results and can be error-prone, time-consuming, or costly. The objective of this work was to develop a reproducible, high-yield, and cost-effective approach for generating homogeneous cell aggregates using custom 3D-printed microwell stamps. Methods: Custom conical and semi-spherical microwell stamps were fabricated using 3D printing. Stamp resolution was characterized by scanning electron microscopy (SEM). Negative imprints were cast in polydimethylsiloxane (PDMS), a biocompatible and hydrophobic polymer conducive to cell aggregation. These PDMS microwells were then used to generate pluripotent stem cell aggregates (embryoid bodies, EBs) and tumor spheroids from adherent cancer cell lines. Results: The 3D-printed stamps produced high-resolution conical and semi-spherical microwells in PDMS. Semi-spherical microwells enabled rapid, simple, and cost-effective formation of pluripotent stem cell aggregates that were homogeneous in size and shape. These aggregates outperformed those produced using commercial microwell plates and ultra-low attachment plates. The fabricated microwells also generated uniform tumor spheroids from adherent cancer cells, demonstrating their versatility. Conclusions: The in-house 3D-printed microwell stamps offer a reproducible, efficient, and economical platform for producing homogeneous cell aggregates. This system improves upon commercial alternatives and supports a broad range of applications, including pluripotent stem cell embryoid body formation and tumor spheroid generation.

Background/Objectives: Phytochemicals are known to be active contributors to a healthy life, providing valuable wound healing benefits. Methods: This research took an innovative approach that successfully overcame the bioavailability limits of herbal extracts, by entrapping CentellaA with HypericumP in nanostructured lipid carriers (NLCs) and hybrid hyaluronic acid (HA-NLCs) as valuable formulations with enhanced bioactivity. Results: NLCs and HA-NLCs showed excellent entrapping efficiency values for CentellaA and HypericumP ranging from 89.5 to 95.3%. Co-entrapping of CentellaA:HypericumP in a weight ratio of 4:1 and 2:1 led to diameters of 221.4 ± 2.08 nm for NLC-CentellaA-HypericumP and 220.3 ± 1.74 nm for hybrid HA-NLC-CentellaA-HypericumP. The bimodal calorimetric profile of NLCs contributed to a lower degree of lipid core structural organization. HA-NLC-CentellaA showed the safest biocompatibility behavior with BJ skin cells. Conclusions: The cells treated with NLC-CentellaA exhibited a favorable scratch wound closure and promoted the fastest BJ cell migration. NLC- and HA-NLC herbal extracts remodeled the cytoskeleton of BJ fibroblast cells. The morphological fluorescence changes revealed that the fibroblast cells retained intact their cytoskeleton, characteristic of a viable cell with no obvious stress. An active motility of cells treated with NLCs in the wound area was detected, indicating strong pro-migratory properties; e.g., for NLC-CentellaA, the wound was almost closed after 30 h. Designing NLCs with HA adaptability to reinforce the skin wound healing action represents a desired step for the development of herbal products that meets the challenge of combining the benefits of phytochemicals and nanotechnology to create value-added herbal products.