Introduction: Molecular hydrogen (H2) has gained attention as a therapeutic agent due to its antioxidant and anti-inflammatory properties. However, human Pharmacokinetic (PK) data remain limited, particularly for Hydrogen-Rich Water (HRW). This study aimed to characterize blood hydrogen kinetics following oral HRW intake in healthy adults. Methods: Twelve healthy participants (mean age 28.8 ± 3.8 years; BMI 23.4 ± 3.2 kg/m²; 50% female) were enrolled in the study. After an overnight fast, participants consumed a single dose of HRW. Blood samples were collected at baseline and at multiple time points up to 120 minutes postingestion. Hydrogen concentrations were measured using a Clark-type microsensor. PK parameters were calculated using non-compartmental analysis, and time-dependent changes were assessed using linear mixed-effects modeling. Results: Baseline hydrogen concentration was 0.25 ± 0.05 μg/L. Peak concentration (Cmax) reached 0.83 ± 0.18 μg/L at 42.9 ± 8.4 minutes (Tmax). The elimination half-life was 144.8 ± 41.7 minutes, and total systemic exposure (AUC₀–∞) was 128.6 ± 27.1 μg/L·min. Hydrogen levels were significantly elevated at 15, 60, and 90 minutes compared to baseline. Notable inter-individual variability was observed, and no sex-related differences were detected. Discussion: Oral HRW intake resulted in measurable systemic hydrogen exposure, with a biphasic concentration pattern, suggesting rapid absorption possibly followed by redistribution. Observed concentrations approached proposed minimal effective levels but were not sustained, raising questions about optimal dosing strategies. Conclusion: HRW ingestion produces detectable and biologically relevant increases in blood hydrogen levels. These findings support HRW as a viable route of H2 administration and provide a foundation for future studies investigating dosing, kinetics, and therapeutic applications.
Introduction: Over the last decade, the regulation of cannabinoids and cannabis-based medicinal products has undergone significant transformation, determined by growing evidence of their therapeutic value and increasing concerns about safety, misuse, and product diversion. The objective of this review was to examine current regulatory frameworks across major jurisdictions from a public health policy perspective, highlighting how different approaches seek to balance patient access with health protection. Methods: This review followed a targeted literature search in scientific databased (PubMed and Google Scholar) to identify publications in English language addressing the evolution of medical cannabis and cannabinoid policies, with particular emphasis on the regulatory frameworks in various countries. The identified literature was qualitatively analyzed to evaluate the relationship between international policy developments and the evolution of national medical cannabis regulations and research activities. Results: This review identified three primary regulatory models: traditional pharmaceutical approval pathways that require robust clinical evidence; alternative access mechanisms, e.g., compassionate- use and special access programs; and regulatory systems which have varying levels of regulatory oversight, quality control, and patient protections, especially the vulnerable population. Discussion: While there has been an increasing global acceptance of cannabinoid-based therapies, considerable differences in regulatory requirements remain across countries. Such a fragmentation creates barriers to clinical research on cannabinoids and cannabis products, obscures patient access, and limits effective public health surveillance. Additionally, challenges related to product quality, standardization, labeling accuracy, and pharmacovigilance are particularly obvious for botanical cannabis products, where regulatory expectations often differ from those applied to conventional medicines. At the same time, innovative regulatory developments are emerging. Conclusion: The review highlights that a greater international regulatory harmonization, stronger quality assurance frameworks, and evidence-based monitoring systems are required for cannabinoids and cannabis products. These aspects are crucial for protecting public health, supporting scientific research, and enabling the responsible integration of cannabinoid-based therapies into modern healthcare systems.
Abstract: Varying degrees of visual impairment up to complete blindness are widespread and represent a public health problem with a highly demarсated escalation. Currently, the leading causes of blindness are Diabetic Retinopathy (DR), Age-Related Macular Degeneration (AMD), and glaucoma, with an obvious exponential enlargement of vulnerable population groups as a result of urbanization followed by lifestyle changes and growth of the aging population. Management of these diseases is still challenging. The development of intraocular therapy with antiangiogenics or Vascular Endothelial Growth Factor inhibitors (anti-VEGF) opens a new avenue in eye disease treatment; however, despite these advances, new concerns are raised. DR, AMD, and glaucoma represent diseases with bilateral involvement, which underscores a need for oral systemic preventive therapy targeting both eyes simultaneously, as a cost-effectively optimized approach. At the same time, there is a need for a multi-target drug with preventive and therapeutic potential not only for eye diseases, but also for systemic diseases in patients with multimorbidity. Continued research has the potential to enhance druggability of the leading causes of blindness. A growing body of evidence suggests that metformin, as a drug with multimodal activity, has good preventive and therapeutic potential, opening a new avenue in ocular pharmacotherapy.
Introduction/Objective: Sleep disruption is common among patients with malignancy and may worsen quality of life, treatment tolerance, and symptom burden. Melatonin is a circadianregulating hormone with a favorable safety profile and potential sleep-promoting effects. This metaanalysis and systematic review evaluated the safety and efficacy of melatonin for sleep-related outcomes in patients with cancer. Methods: Scopus, PubMed, Web of Science, ScienceDirect, Cochrane Library, ClinicalTrials.gov, and EMBASE were systematically searched from inception to 1 June 2026 without language or country restrictions. Randomized clinical trials comparing melatonin with placebo or an active control in patients with cancer and reporting sleep-related outcomes were eligible. Data extraction, study selection, and riskof- bias assessment using the Joanna Briggs Institute checklist were performed by two reviewers independently. Random-effects meta-analyses with Hartung-Knapp adjustment were conducted in Stata 17.0. Results: Data from seven studies were pooled in the meta-analysis, and thirteen articles were included in the systematic review. The overall effect of melatonin was insignificant (SMD = -0.85 with a 95% CI of -2.46 to 0.76) with high heterogeneity among studies (I2 = 94.5%). Subgroup analysis revealed a significant decrease in the Pittsburgh Sleep Quality Index (PSQI) in US studies (SMD = -0.57, 95% CI: [-0.99, -0.14], I2 = 31.5%). Meta-analysis of the seven PSQI components showed no significant item-level improvement with melatonin treatment. Studies using non-PSQI sleep outcomes showed mixed findings, with short-term improvement in insomnia severity in one trial but modest or non-significant effects in others. Discussion: While the overall impact of melatonin on sleep quality was not statistically significant, subgroup analyses and qualitative evidence indicate clinically relevant benefits. Conclusion: Melatonin shows promising but uncertain benefits for sleep disruptions in patients with malignancies. However, the evidence should be interpreted cautiously because of substantial clinical and statistical heterogeneity, limited sample sizes, short intervention durations, and predominantly subjective sleep measures. Larger, well-standardized randomized trials using both subjective and objective sleep assessments are needed.
Intrasubject variability (ISV) in bioequivalence (BE) studies remains a critical challenge in generic drug development; however, the mechanistic determinants of this variability are not yet fully characterized. This narrative review synthesizes evidence across physicochemical, pharmacokinetic, physiological, and study design domains using a unified mechanistic framework. Our analysis identified a mechanistic hierarchy. Low solubility (BCS Class II/IV) demonstrated a 4.1-fold higher incidence of highly variable drug (HVD) compared with high-solubility classes. First-pass metabolism was observed in 83% of HVDs but only 21% of non-HVDs, making it the strongest pharmacokinetic predictor of HVD status. Subject recruitment stratified by genotyping of CYP2D6 and CYP3A5 polymorphisms reduced ISV by up to 54% in drugs primarily metabolized by these enzymes. Replicate study designs, enhanced measurement precision, and fed conditions reduced intrasubject variability (ISV) in pharmacokinetic parameters; specifically, fed conditions showed a reduction in ISV in 79.4% of comparisons, whereas multiple-dose studies did not consistently reduce ISV. A cross-population comparison revealed that ISV in drugs metabolized via CYP enzymes was consistently higher in the Mexican population than in the South Korean population. ISV in Cmax exceeded that of AUC0-t in over 80% of products, indicating that variability in absorption rate is the primary contributing factor. A four-stage mechanistic framework, termed the Intrasubject Variability (ISV) Cascade Model, was developed to describe ISV: absorption variability generation (Stage 1), amplification through first-pass metabolism (Stage 2), modulation by study design (Stage 3), and translation into bioequivalence study design requirements (Stage 4). A proposed decision tree provides structured guidance for ISV risk assessment and optimization of BE study design.
