Search Results (104)

This conceptual narrative review explores the intricate dynamics of the ‘stimulant paradox’ in adult ADHD, highlighting the timing-dependent trade-offs associated with stimulant medication. The paradox underscores the complexity of balancing therapeutic benefits against potential side effects, contingent on the timing of administration. Chronopharmacotherapy emerges as a promising framework, integrating circadian and homeostatic processes with pharmacokinetic and pharmacodynamic considerations. This approach suggests that aligning medication timing with individual biological rhythms may optimize outcomes, although the conceptual nature of this integration remains non-prescriptive. ADHD coaching is examined as a complementary strategy, focusing on the development of skill-oriented routines that are sensitive to timing. This adjunctive support may facilitate the practical implementation of chronopharmacotherapy principles, enhancing adherence and effectiveness. Figures and heuristics within the review serve as illustrative tools intended to guide understanding rather than dictate clinical practice. The review identifies critical areas for future research, emphasizing the need for empirical investigation into optimal clock-time windows, phase measures, and chronotype stratification. Additionally, assumptions regarding medication formulations warrant further scrutiny to refine timing-sensitive interventions in adult ADHD management. Full article

The lysosome is no longer viewed as a simple degradative “trash can” of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical “microreactor” that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5–5), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective “safe house,” yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome’s broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody–drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine–thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies. Full article

Over the past decade, near-infrared-II (NIR-II, 1000–1700 nm) fluorescence imaging has become a focal point in tumor imaging due to its advantages of low light scattering, weak biological autofluorescence, extraordinary penetration depth, high signal-to-background ratio, and micron-level high resolution. To date, a large number of NIR-II materials have been developed for tumor imaging. Among them, NIR-II organic small-molecule fluorophores have emerged as research hotspots owing to their distinctive advantages, such as superior optical properties, excellent controllability, favorable biocompatibility, and tunable pharmacokinetics. In this review, we summarize the latest progress in lNIR-II fluorescent probes based on organic small-molecule fluorophores for tumor imaging, focusing on their structural features, design principles of NIR-II fluorescent probes, and applications in tumor imaging. Finally, we will discuss the challenges, future prospects, and development directions of organic small-molecule fluorophores for NIR-II fluorescence imaging of tumors. Full article

Background: Tetrabenazine, a VMAT2 inhibitor used for hyperkinetic disorders, shows considerable pharmacokinetic variability due to extensive first-pass metabolism. Standardization of clinical trial conditions, including posture, may reduce variability and improve bioequivalence assessments. Objective: The aim of this study was to determine the impact of postural restriction on the pharmacokinetics of tetrabenazine and its active metabolite, dihydrotetrabenazine (HTBZ), under controlled conditions. Methods: A randomized, open-label, four-period replicate crossover study enrolled 72 healthy fasted adults who received a single 25 mg tetrabenazine dose under two conditions: 4 h semirecumbent posture versus unrestricted movement. Plasma drug concentrations were measured across 36 h using validated LC–MS/MS method. Pharmacokinetic parameters were estimated via non-compartmental analysis and compared with Wilcoxon signed-rank tests. Results: Postural restriction significantly increased tetrabenazine exposure (AUC_0–t: +16.4%, p < 0.0001) and half-life (p = 0.002), with a nonsignificant rise in C_max. For HTBZ, C_max decreased (−16.2%, p = 0.018), whereas AUC was unchanged. Parent-to-metabolite ratios increased by 24–29%. Replicate design analyses showed reduced intra-subject variability for tetrabenazine AUC with posture control (~24% vs. >28%). Simulation suggested that posture restriction could lower sample size requirements by 15–30% in two-period average bioequivalence trials. Conclusions: Maintaining a semirecumbent posture after dosing enhances tetrabenazine’s bioavailability, attenuates early metabolite formation, and reduces pharmacokinetic variability. Incorporating posture control into bioequivalence trial protocols may optimize study design, reduce participant exposure, and align with ICH-GCP ethical principles. Full article

Nanoparticles (NPs) have significantly changed the field of drug delivery, offering control over pharmacokinetics, biodistribution, and targeted therapy. Among these, ultrasmall nanoparticles (USNPs) with sizes of approximately 5–15 nm have garnered significant interest due to their unique physicochemical properties, including enhanced cellular uptake, deeper tissue penetration, and prolonged systemic circulation. This review explores the fundamental principles governing sub-15 nm nanoparticles, their classification, and their distinctive advantages in pharmaceutical applications. Various types of nanoparticles, including polymeric, lipid-based, metallic, and carbon-based nanosystems, are examined in the context of drug delivery in cancer therapy. We detail how sub-15 nm polymeric nanoparticles (PNPs) are emerging as transformative drug delivery platforms for cancer therapy. The impact of nanoparticle size, surface modifications, and biocompatibility on therapeutic performance is critically analyzed. Furthermore, we discuss emerging applications of these ultrasmall nanoparticles in cancer therapy, neurological disorders, vaccine delivery, and imaging. Despite their promise, key challenges such as stability, aggregation, toxicity, and regulatory concerns remain significant hurdles for clinical translation. This review provides insights into the potential of 5–15 nm nanoparticles to reshape modern drug delivery and highlights future directions for research and development in this rapidly evolving field. Full article

Extracorporeal membrane oxygenation (ECMO) is increasingly used to support critically ill adults with severe cardiac or respiratory failure, but ECMO circuits and the physiological disturbances of critical illness significantly alter drug pharmacokinetics (PK) and pharmacodynamics (PD), complicating dosing and monitoring. This narrative review synthesizes current clinical evidence on ECMO-related PK/PD alterations and provides practical guidance for optimizing pharmacotherapy in adult intensive care. A structured literature search (January–May 2025) was conducted across PubMed/MEDLINE, EMBASE, Scopus, Cochrane Library, Sage Journals, ScienceDirect, Taylor & Francis Online, SpringerLink, and specialized databases, focusing on seven therapeutic classes commonly used in ECMO patients. Eligible studies included clinical trials, observational studies, systematic reviews, and practice guidelines in adults, while pediatric and preclinical data were excluded. Evidence quality varied substantially across drug classes. Hydrophilic, low-protein-bound agents such as β-lactams, aminoglycosides, fluconazole, and caspofungin generally showed minimal ECMO-specific PK alterations, with dose adjustment mainly driven by renal function. Conversely, lipophilic and highly protein-bound drugs including fentanyl, midazolam, propofol, voriconazole, and liposomal amphotericin B exhibited substantial circuit adsorption and variability, often requiring higher loading doses, prolonged infusions, and rigorous therapeutic drug monitoring. No ECMO-specific data were identified for certain neuromuscular blockers, antivirals, and electrolytes. Overall, individualized dosing guided by therapeutic drug monitoring (TDM), organ function, and validated PK principles remains essential to optimize therapy in this complex population. Full article

We present a hybrid partial differential equation-agent-based model (PDE-ABM). In our framework, tumor cells secrete tumor angiogenic factor (TAF), while endothelial cells chemotactically migrate and branch in response. Reaction–diffusion PDEs for TAF, oxygen, and cytotoxic drug are coupled to discrete stochastic dynamics of tumor cells and endothelial tip cells, ensuring multiscale integration. Motivated by observed perfusion heterogeneity in tumors and its pharmacokinetic consequences, we conduct a linear stability analysis for a reduced endothelial–TAF reaction–diffusion subsystem and derive an explicit finite-domain threshold for Turing instability. We demonstrate that bidirectional coupling, where endothelial cells both chemotactically migrate along TAF gradients and secrete TAF, is necessary and sufficient to generate spatially periodic vascular clusters and inter-cluster hypoxic regions. These emergent patterns produce heterogeneous drug penetration and resistant niches. Our results identify TAF clearance, chemotactic sensitivity, and endothelial motility as effective levers to homogenize perfusion. The model is two-dimensional and employs simplified kinetics, and we outline necessary extensions to three dimensions and saturable kinetics required for quantitative calibration. The study links reaction–diffusion mechanisms with clinical principles and suggests actionable strategies to mitigate resistance by targeting endothelial–TAF feedback. Full article

Kinetoplastids are protozoa that possess a unique organelle called a kinetoplast. These include the parasites Trypanosoma cruzi, T. brucei and related African trypanosomes, and Leishmania spp. These parasites cause a variety of neglected tropical diseases in humans and livestock, with devastating consequences. In the absence of any vaccine, pharmaceutical interventions are the mainstay of control, but these have historically been underfunded, fragmented, and inadequately aligned with the complex zoonotic and ecological realities of the parasites’ transmission dynamics. In this review, the landscape of current and emerging drugs for treating leishmaniasis, Chagas disease, and African trypanosomiasis is critically evaluated across both veterinary and human contexts. It examines the challenges of legacy compounds, the pharmacological shortcomings in multi-host, multi-tropic and multi-stage disease systems, and the gaps in veterinary therapeutics, specifically for African animal trypanosomiasis and canine leishmaniasis but also the animal reservoir of T. cruzi. Emphasis is placed on pharmacokinetic divergence between species, the accompanying risks with the use of off-label human drugs in animals, and the ecological effects of environmental drug exposure. We propose a far-reaching One Health framework for pharmaceutical research and development, promoting dual-indication co-development, ecological pharmacology, regulatory harmonisation, and integrated delivery systems. In this context, we argue that the drug development pipeline must be rationalised as a transdisciplinary and ecologically embedded process, able to interrupt parasite transmission to human, animal, and vector interfaces. Our findings reveal that we can bridge age-old therapeutic gaps, advance towards sustainable control, and eventually eliminate the neglected diseases caused by kinetoplastid protozoan parasites by aligning pharmaceutical innovation with One Health principles. This article aims to promote future research and development of innovative drugs that are sustainable under the One Health framework. Full article

Background: Infections following cardiac surgery are a significant cause of morbidity and mortality, particularly in intensive care units (ICUs). The role of antibiotic prophylaxis (AP) in preventing surgical site infections (SSIs) and other nosocomial infections is crucial; however, the optimal approach to agent selection, dosing, and duration remains controversial. Objective: This narrative review aims to summarise the current evidence and expert recommendations regarding the use of perioperative antibiotic prophylaxis (AP) in adults undergoing cardiac surgery, with a particular focus on intensive care settings, transplant recipients, and adult patients on extracorporeal membrane oxygenation (ECMO). Methods: A comprehensive review of recent literature was conducted, focusing on pharmacokinetic/pharmacodynamic (PK/PD) principles, microbial epidemiology, antimicrobial resistance (AMR), and practical strategies for tailored prophylaxis in high-risk populations. Results: Cefazolin remains the first-line agent for most procedures, with vancomycin or clindamycin reserved for patients who are allergic to β-lactams or who are colonised with MRSA. Redosing is recommended in cases of prolonged surgery or cardiopulmonary bypass. Evidence supports limiting prophylaxis to ≤24 h, with a potential extension to 48 h in select high-risk cases; however, continuation beyond this is discouraged due to the risk of resistance. In heart transplantation, multimodal prophylaxis against bacteria, fungi, and viruses is essential but must be tailored to the individual patient. In the ECMO setting, the current evidence does not support the routine administration of prophylaxis (AP), and therapy should be tailored based on pharmacokinetics (PK)/pharmacodynamics (PD) changes and the clinical context. A multidisciplinary, evidence-based approach to AP in cardiac surgery is essential. Prophylaxis should be patient-specific, microbiologically guided, and limited in duration to reduce the emergence of multidrug-resistant organisms. Integrating antimicrobial stewardship, non-pharmacological measures, and rigorous surveillance is crucial for optimising the prevention of infections in this vulnerable population. Full article

Avocado (Persea americana), originally from Mesoamerica, has emerged as a focus of intense scientific and industrial interest due to its unique combination of nutritional richness, bioactive potential, and technological versatility. Its pulp, widely consumed across the globe, is notably abundant in monounsaturated fatty acids, especially oleic acid, which can comprise over two-thirds of its lipid content. In addition, it provides significant levels of dietary fiber, fat-soluble vitamins such as A, D, E and K, carotenoids, tocopherols, and phytosterols like β-sitosterol. These constituents are consistently associated with antioxidant, anti-inflammatory, glycemic regulatory, and cardioprotective effects, supported by a growing body of experimental and clinical evidence. This review offers a comprehensive and critical synthesis of the chemical composition and functional properties of avocado, with particular emphasis on its lipid profile, phenolic compounds, and phytosterols. It also explores recent advances in environmentally sustainable extraction techniques, including ultrasound-assisted and microwave-assisted processes, as well as the application of natural deep eutectic solvents. These technologies have demonstrated improved efficiency in recovering bioactives while aligning with the principles of green chemistry. The use of avocado-derived ingredients in nanostructured delivery systems and their incorporation into functional foods, cosmetics, and health-promoting formulations is discussed in detail. Additionally, the potential of native cultivars and the application of precision nutrition strategies are identified as promising avenues for future innovation. Taken together, the findings underscore the avocado’s relevance as a high-value matrix for sustainable development. Future research should focus on optimizing extraction protocols, clarifying pharmacokinetic behavior, and ensuring long-term safety in diverse applications. Full article

Regional anesthesia techniques such as the ultrasound-guided PECS II (pectoral nerve block) block are increasingly employed to optimize perioperative analgesia while minimizing systemic anesthetic exposure. Ropivacaine is commonly used for its favorable pharmacological profile; however, clinical data on its pharmacokinetics and systemic metabolite behavior following interpectoral administration remain limited. This study aimed to characterize the plasma concentration–time profile of ropivacaine and its main active metabolite, 3-OH-ropivacaine, in patients undergoing interpectoral nerve block, using a validated LC-MS/MS (liquid chromatography coupled with mass spectrometry) method. Venous blood samples were collected from 18 patients at predefined time points (0, 1, 3, 6, and 24 h) following a PECS II block performed with a ropivacaine-lidocaine mixture. Plasma concentrations were quantified via a validated LC-MS/MS protocol in accordance with FDA (Food and Drug Administration) and EMA (European Medicines Agency) guidelines. Pharmacokinetic parameters were derived using non-compartmental analysis. Ropivacaine reached a mean peak plasma concentration (Cmax—maximum concentration) of 167.5 ± 28.3 ng/mL at 1.3 ± 0.2 h (Tmax—maximum time). The metabolite 3-OH-ropivacaine peaked at 124.1 ± 21.4 ng/mL at 2.3 ± 0.3 h. The terminal elimination half-life was 19.4 ± 2.8 h for ropivacaine and 29.2 ± 3.1 h for its metabolite. Plasma levels demonstrated prolonged systemic exposure with predictable pharmacokinetics. The PECS II block using ropivacaine results in sustained systemic levels of both the parent drug and its primary metabolite, supporting its role in prolonged perioperative analgesia. These data provide a pharmacokinetic foundation for personalized regional anesthesia protocols. This strategy facilitates the adaptation of anesthetic protocols to the individual characteristics of each patient, aligning with the principles of personalized medicine, particularly in patients with altered metabolic capacity. Full article

Most solutions of fractional differential equations (FDEs) that model real-world phenomena in various fields of science, industry, and engineering are complex and cannot be solved analytically. This paper mainly aims to present some useful results for studying the qualitative properties of solutions of FDEs involving the new generalized Hattaf mixed (GHM) fractional derivative, which encompasses many types of fractional operators with both singular and non-singular kernels. In addition, this study also aims to unify and generalize existing results under a broader operator. Furthermore, the obtained results are applied to some linear systems arising from medicine. Full article

Novel peptides based on common amino acid building blocks may serve as possible drug candidates; however, their flexible structures may require stabilization via the incorporation of conformational constraints. The insertion of unusual amino acids is a feasible option that may provide improved pharmacokinetic and pharmacodynamic properties of such peptide-type drugs. The stereochemical purity of these kinds of building blocks must be verified by an efficient separation technique, such as high-performance liquid chromatography. Here, we present and discuss the results of the stereoselective separation mechanism of ß-methylated phenylalanine (ß-MePhe), tyrosine (ß-MeTyr), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (ß-MeTic), and cyclohexylalanine (ß-MeCha) together with non-methylated Phe, Tyr, Tic, and Cha applying Cinchona alkaloid-based chiral stationary phases (CSPs). The studied zwitterionic CSPs acting as ion exchangers provided optimal performance in the polar ionic mode when methanol or a mixture of methanol and acetonitrile was utilized as the mobile phase together with organic acid and base additives. It was found that the basicity of small amines applied as mobile phase additives did not directly influence the chromatographic ion exchange concept. However, the size of the amines and their concentration led to a reduced retention time following the principles of ion exchange chromatography. On the basis of a systematic study of the effects of the eluent composition on the chromatographic behavior, important structure–retention and enantioselectivity relationships could be revealed. Through a temperature study, it has become evident that the composition of the eluent and the structure of analytes markedly affect the thermodynamic properties. Full article

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, remains the third leading cause of maternal mortality globally. Pregnancy-associated physiological adaptations predispose pregnant individuals to infection, impair maternal response to infection, affect antibiotic pharmacokinetics and metabolism, and complicate diagnosing infections and sepsis. Therefore, it is tantamount that clinicians readily recognize maternal sepsis and understand antibiotic regimens and treatment principles to avoid adverse maternal outcomes. In this article, we present an overview of the diagnosis and management of maternal sepsis and the physiological changes in pregnancy that alter antibiotic pharmacokinetics. Common microorganisms implicated in maternal sepsis are discussed with an emphasis on E. coli and Group A Streptococcus due to their prevalence and morbidity in the pregnant population. Lastly, we provide an overview of commonly used antibiotics and dosage recommendations in the treatment of maternal infection and sepsis. Full article

Electroanalysis has emerged as a critical tool in the pharmaceutical industry, offering versatile and sensitive methods for drug analysis. This review explores the principles, techniques, and applications of electroanalysis in pharmaceuticals, emphasizing its role in drug development, quality assurance, pharmacokinetics, and environmental monitoring. Key electroanalytical methods, including voltammetry, potentiometry, and amperometry, are detailed along with their practical applications, such as detecting active pharmaceutical ingredients, monitoring drug metabolites, and ensuring product stability. Innovations in electrode materials and biosensors have enhanced their sensitivity and specificity, paving the way for advanced drug screening and therapeutic monitoring. Challenges like electrode fouling, selectivity issues, and regulatory constraints are discussed, along with strategies to overcome them. Future trends highlight the integration of nanotechnology, AI, and portable sensors to facilitate real-time analysis and personalized medicine. These advancements position electroanalysis as an indispensable component of modern pharmaceutical research and healthcare. Future perspectives emphasize the integration of nanotechnology and artificial intelligence (AI) to optimize experimental processes and data interpretation. This study also predicts the increased adoption of lab-on-a-chip systems and bioelectrochemical sensors to meet the growing demand for precision medicine and sustainable pharmaceutical practices. These advancements position electroanalysis as a cornerstone of pharmaceutical research, paving the way for more efficient drug development, improved patient outcomes and better environmental management. This comprehensive review underscores the transformative potential of electroanalysis in addressing the evolving challenges of the pharmaceutical industry and provides a foundation for future innovations. This review does not explicitly define the timeframe for the considered advancements. However, it discusses recent technological developments, including innovations in nanostructured electrodes, microfluidic integration, and AI-driven data analysis, indicating a focus on advancements primarily from the last few years, i.e., from 2020 to 2025. Full article