Search Results (55)

Background/Objectives: WenTong HuoXue Cream (WTHXC) plays a significant role in the treatment of diabetic peripheral neuropathy (DPN). However, the material basis and quality control methods for this formulation remain largely unexplored. Methods: In this study, UPLC-HRMS/MS combined with standard reference substances was employed to comprehensively identify and confirm the chemical constituents of WTHXC. Furthermore, a rapid and sensitive UPLC-MS/MS method based on multiple reaction monitoring (MRM) mode was developed and validated for the simultaneous quantification of the marker components. Results: Nine compounds were unambiguous characterized, including Di-hydrocapsaicin (DHC), Oxypeucedanin hydrate (OPH), Imperatorin (IMP), Isoimperatorin (IIMP), Xanthotoxin (XAN), Hydroxysafflor yellow A (HSYA), Chlorogenic acid (CGA), Ferulic Acid (FA) and Ligustilide (LIG). The results of method validation denotes that all the analytes showed good linearity between concentration and peak area in the tested ranges, with correlation coefficients (r) not less than 0.9990. The relative standard deviation (RSD) of precision was in the range of 0.57–7.11%. The accuracy of the method, verified by recovery experiments at three concentration levels, ranged from 96.51% to 101.04% for all analytes. Transdermal behavior determination results demonstrate that OPH, HYSA, CGA, FA and LIG exhibited favorable skin permeability and may serve as the key active components of WTHXC. Conclusions: This study elucidates the material basis of WTHXC, providing a scientific foundation for the development of quality control methods and facilitating its broader clinical application. Full article

Musculoskeletal (MSK) pain is a prevalent clinical condition that significantly impairs quality of life, and current treatment options are not effective on all patients or have severe, long-term side effects. Sustained Acoustic Medicine (SAM) delivers therapeutic ultrasound, providing diathermic and mechanical stimulation to local tissue and facilitating healing. Additionally, therapeutic ultrasound has been shown to enhance transdermal drug delivery via sonophoresis. Cannabidiol (CBD) is a small molecule that has been shown to have anti-inflammatory effects drug delivery. However, CBD has never been studied in conjunction with therapeutic ultrasound, and its potential effects on ultrasound efficacy are unknown. Therefore, this study compares standard high viscosity ultrasound (US) gel and commercially available CBD gel both in terms of acoustic properties and in an ex vivo bovine muscle model with SAM treatment. The acoustic properties of CBD & US gels were measured using a hydrophone, an oscilloscope and a function generator. The function generator propagated a pulsed wave through each gel, and the time between the original and reflected waves was used to determine the acoustic coefficients. Then, a SAM transducer was positioned and placed into the coupling bandage and gel depot on the bovine muscle with 3 mL of US gel or CBD gel. Tissue was stimulated by SAM for 240 min with a 60-min cooldown, and internal muscle temperatures at 1 cm, 2 cm, and 5 cm were continuously monitored. US gel and CBD had no significant differences in their acoustic properties. There were no significant differences in the change in temperature for SAM treatment with CBD gel compared to SAM treatment with US gel at 1 cm (Δ12.06 ± 1.04 °C vs. Δ12.52 ± 1.84 °C, p > 0.05), 2 cm (Δ8.13 ± 1.01 °C vs. Δ8.97 ± 1.04 °C, p > 0.05), and 5 cm (Δ4.83 ± 0.91 °C vs. Δ3.83 ± 0.66 °C, p > 0.05). CBD gel does not compromise SAM’s ultrasonic delivery and diathermic efficacy, making this combination a novel option for musculoskeletal rehabilitation. Future studies could explore changes in transdermal CBD delivery with SAM treatment for deep tissue delivery. Full article

Personalized transdermal drug delivery systems (TDDS) represent a transformative approach in precision medicine by enabling patient-specific, non-invasive, and controlled therapeutic administration. Conventional transdermal patches are limited by fixed dosing, passive diffusion, and interindividual variability in skin permeability and metabolism, often leading to suboptimal therapeutic outcomes. Recent advances in materials science, nanotechnology, microneedle engineering, and digital health have enabled the development of next-generation personalized TDDS capable of programmable, adaptive, and feedback-controlled drug release. Smart wearable patches integrating biosensors, microfluidics, microneedles, and wireless connectivity allow real-time monitoring of physiological and biochemical parameters, enabling closed-loop drug delivery tailored to individual metabolic profiles. Nanocarriers such as lipid nanoparticles, polymeric nanoparticles, and stimuli-responsive hydrogels further enhance drug stability, penetration, and controlled release, while 3D-printing technologies facilitate patient-specific customization of patch geometry, drug loading, and release kinetics. Artificial intelligence (AI) and machine learning tools are increasingly being employed to predict drug permeation behavior, optimize enhancer combinations, and personalize dosing regimens based on pharmacogenomic and pharmacokinetic data. Despite these advances, regulatory complexity, manufacturing standardization, long-term biocompatibility, and cybersecurity considerations remain critical challenges for clinical translation. This review highlights recent innovations in personalized TDDS, discusses their clinical potential, and examines regulatory and technological barriers. Collectively, these emerging smart transdermal platforms offer a promising pathway toward adaptive, patient-centered therapeutics that can significantly improve treatment efficacy, safety, and compliance. Future research should focus on integrating multimodal biosensing, advanced biomaterials, scalable manufacturing strategies, and robust regulatory frameworks to enable clinically validated, fully autonomous transdermal systems that can dynamically adapt to real-time patient needs in diverse therapeutic settings. Full article

Background and Objectives: Menopausal hormone therapy (MHT) is the most efficacious treatment for vasomotor symptoms and genitourinary conditions associated with menopause. Modern menopause care increasingly encompasses women with multimorbidity, renal or hepatic impairment, previous malignancies or thromboembolic disorders, advanced age, and polypharmacy—groups frequently underrepresented in randomized clinical trials. This evidence gap prompts significant inquiries about the relevance of trial-based recommendations to actual clinical practice. Materials and Methods: This narrative review offers a concentrated assessment of prominent worldwide clinical guidelines regarding menopausal hormone therapy through thematic synthesis. We examined position statements from the North American Menopause Society (NAMS), the European Menopause and Andropause Society (EMAS), NICE clinical guidelines, the ACOG Practice Bulletin on menopausal symptom management, the Endocrine Society clinical practice guideline, and pertinent UK guidance from RCOG, BMS, and BGCS. Data from systematic reviews, meta-analyses, and extensive observational studies were analyzed to contextualize guideline recommendations for populations often underrepresented in clinical trials, including women aged ≥65 years and individuals with multimorbidity or polypharmacy. Results: Only the NICE and EMAS recommendations expressly acknowledge clinical vulnerability or complexity (multimorbidity, frailty, and cancer survivorship) as foundational principles. NAMS and ACOG delineate risk categories but fail to offer a cohesive taxonomy of vulnerability. Polypharmacy and drug–drug interactions are inconsistently addressed across guidelines, and there is a deficiency of standardized prescribing algorithms. While routine safety monitoring is universally advocated, the intervals for follow-up and methods for risk categorization differ. Observational evidence consistently indicates route-dependent variations in cardiovascular and thromboembolic risk, with transdermal estrogen linked to a more advantageous safety profile in higher-risk individuals. Conclusions: Present menopausal therapy guidelines are methodologically sound; however, they insufficiently address the complexities of multimorbidity, polypharmacy, and organ dysfunction. A systematic conceptual framework that incorporates areas of clinical vulnerability may facilitate personalized benefit–risk evaluation in practical applications. Future guideline revisions should enhance clarity by incorporating polypharmacy concerns, monitoring strategies, and systematic risk stratification methods for clinically complicated patients. Full article

Background/Objectives: Migraine is a leading cause of disability in women and is intricately linked to hormonal fluctuations and systemic health. This review aims to unravel the complex relationship between migraine, cardiovascular disease, and metabolic syndrome throughout the female reproductive lifespan. Methods: A comprehensive narrative review was conducted using the PubMed database for studies published between January 1988 and December 2025. Keywords included “migraine”, “cardiovascular risk”, “metabolic syndrome”, “pregnancy”, and “hormonal therapy”. Articles were selected to synthesize the latest pathophysiological evidence and clinical guidelines. Results: Migraine prevalence in women is two to threefold higher than in men, peaking during fertile age. Hormonal milestones, particularly estrogen withdrawal, trigger menstrual migraine. Metabolic syndrome is significantly more common in migraineurs than the general population. Obesity and insulin resistance have been associated with higher migraine attack frequency and severity. Experimental evidence suggests that hyperinsulinemia may sensitize TRPV1 receptors on trigeminal neurons and enhance CGRP release, potentially lowering the activation threshold for migraine attacks; however, direct confirmation of this pathway in humans remains limited. Furthermore, migraine with aura is linked to a doubled risk of ischemic stroke and increased risk of cardiovascular events. In pregnancy, migraine is an independent risk factor for stroke, myocardial infarction, and spontaneous coronary artery dissection. Conclusions: Migraine is a critical marker for cardiovascular and metabolic risk, necessitating routine screening and multidisciplinary management. Clinicians must prioritize cardiovascular counselling, metabolic evaluations, and careful monitoring in these patients, especially during pregnancy. Hormonal therapy choices should be individualized, preferring progestin-only contraceptives for those with aura and transdermal routes for hormone replacement therapy to minimize cardiometabolic impact. Full article

Insulin therapy remains essential for the management of diabetes mellitus; however, conventional subcutaneous injection continues to impose significant physical, psychological, and behavioral barriers that negatively affect treatment adherence and metabolic outcomes. Injection-related pain, fear of needles, local tissue complications, and psychological insulin resistance contribute to delayed insulin initiation, inadequate dose titration, and suboptimal glycemic control worldwide. In response, alternative insulin delivery routes (including oral, pulmonary, nasal, and transdermal strategies) have been explored to reduce invasiveness and improve patient experience. Among these, transdermal insulin delivery has emerged as a particularly promising approach due to its potential to bypass gastrointestinal degradation, provide controlled absorption, and enhance patient acceptance. Recent advances in microneedle-based systems and needle-free jet injectors have enabled effective transdermal insulin administration by overcoming the skin barrier while minimizing pain and discomfort. This narrative review synthesizes current evidence on insulin delivery technologies with a specific focus on transdermal and needle-free systems. We discuss the biological and physicochemical challenges of insulin transport, the mechanisms underlying emerging delivery platforms, and clinical evidence regarding metabolic efficacy, glycemic variability, and patient-reported outcomes. The integration of these technologies with continuous glucose monitoring is also explored. Finally, we address translational challenges and future perspectives, highlighting the role of needle-free insulin delivery as a patient-centered strategy to improve adherence and metabolic control in diabetes care. Full article

Background: Among hormone therapy options for menopause, subcutaneous estradiol pellets offer sustained hormone release, avoid first-pass hepatic metabolism, and maintain a near-physiological estradiol-to-estrone ratio. Despite clinical use since the 1940s, standardized protocols remain lacking. Methods: We performed a critical narrative review following SANRA criteria. PubMed, Scopus, Embase, and LILACS were searched from 1949 to 2024 for randomized trials, cohort studies, and case series on estradiol pellets and outcomes in symptom control, bone health, pharmacokinetics, and safety. Animal studies, editorials, and reports without primary clinical data were excluded. Results: Following an initial peak within the first week, pellets maintain stable serum estradiol levels within the early-to-mid follicular range (50–113 pg/mL depending on dose) for four to six months, with a near-physiological E2:E1 ratio of approximately 1.5:1. The 25 mg dose achieves mean levels of 50–70 pg/mL, effectively controls vasomotor symptoms, and increases bone mineral density. Compared with oral estradiol, pellets bypass hepatic first-pass metabolism, resulting in neutral or favorable metabolic and thrombotic profiles. Compared with transdermal therapy, pellets provide more predictable pharmacokinetics, especially in women with low skin absorption. Safety concerns, including bleeding, tachyphylaxis, and supraphysiological levels, are mainly associated with excessive dosing, premature reimplantation, or lack of endometrial protection in women with a uterus. Conclusions: Estradiol pellets are an effective option for women with poor transdermal absorption, low adherence to daily regimens, or surgical menopause. Safety depends on clinical management with individualized dosing, adequate endometrial protection, and laboratory monitoring. Long-term comparative studies are needed to standardize protocols and support broader evidence-based use. Full article

MDM hydantoin (MDMH), a formaldehyde-releasing preservative widely used in cosmetics, poses potential health risks due to its conversion to formaldehyde and systemically absorbed metabolites. Current safety assessments lack quantitative exposure data due to rapid degradation of MDMH in biological matrices. In the present study, we developed a validated LC-MS/MS assay for simultaneous determination of MDMH and its stable metabolite DMH in rat plasma, and characterized their toxicokinetics using population modeling following intravenous and transdermal administration. MDMH exhibited extremely rapid elimination (t_1/2 = 0.4 ± 0.1 min) with near-complete conversion to DMH (97.6 ± 9.6%), while DMH demonstrated prolonged retention (t_1/2 = 174.2 ± 12.2 min) and complete bioavailability (100.9 ± 18.0%) after transdermal application. Population modeling estimated that 84% (relative standard error: 42.8%) of applied MDMH undergoes cutaneous absorption and metabolism to DMH and formaldehyde within skin tissues. This study demonstrates that stable metabolite monitoring combined with population modeling enables toxicokinetic characterization of rapidly degrading compounds following dermal exposure. Full article

Fentanyl, a potent synthetic opioid used in pain management, has seen a marked rise in outpatient use in Portugal between 2015 and 2022. During this period, consumption nearly doubled, with transdermal patches and sublingual tablets dominating the market. Rapid-onset formulations lacking abuse-deterrent features pose have heightened the risks of misuse and diversion. Despite these concerns, no abuse-deterrent fentanyl products are currently available in Portugal. These findings expose critical regulatory and pharmaceutical gaps. To mitigate public health and environmental risks, a coordinated strategy—encompassing prescription monitoring, education, safer formulations, and a One Health approach—is urgently needed to ensure responsible opioid use and stewardship. Full article

Objective: This study evaluated the systemic bioavailability of L-thyroxine (L-T4) in healthy women following repeated cutaneous application of a new gel formulation containing L-T4 and escin. Plasma concentrations of free triiodothyronine (FT3), reverse triiodothyronine (rT3), and thyroid-stimulating hormone (TSH) were also assessed, along with local and systemic tolerability. Methods: Thirty healthy women participated in a single-group, open-label trial. L-thyroxine gel was applied at 20 g/day for the first 2 days and 10 g/day for the following 26 days (equivalent to 20 mg/day and 10 mg/day of L-T4, respectively). Blood samples were collected at Baseline, 5 and 24 h after the first application, and on Days 14, 28 (End of Treatment, EOT), and 42 (End of Study, EOS). Tolerability and safety were monitored throughout. Results: Plasma FT4 concentrations remained stable throughout the study, with no clinically significant changes from Baseline (1.13 ± 0.15 ng/dL) to EOT (1.11 ± 0.13 ng/dL). FT3 and TSH levels also remained within physiological ranges, with only a transient, non-clinically relevant decrease observed 5 h after the first application. No changes in rT3 concentrations were detected at any time point. No serious adverse events were reported. Conclusions: This study confirms that repeated application of L-thyroxine/escin gel over 28 days (total exposure of 300 g) does not affect systemic thyroid hormone levels and is well tolerated in healthy women. These findings support the hypothesis that intact skin acts as an effective barrier to transdermal L-T4 absorption. Full article

As the proportion of the elderly population increases, there is an urgent need for anti-aging technologies. Since the skin is the most visibly aging organ in the human body, it is crucial to develop active ingredients to slow down skin aging. Currently, identified anti-aging active substances include antioxidants, retinoids, peptides, growth factors, and compounds derived from biofermentation. However, they have limitations such as poor stability, low transdermal permeability, skin irritation, high effective concentrations, slow onset of efficacy, single-action mechanisms, and high production costs. These limitations highlight the necessity of developing new anti-aging technologies that are multifunctional and cause low irritation. This study aimed to investigate the anti-aging effects and mechanisms of fructosazine (FZ) and deoxyfructosazine (DOF) on the skin as well as their potential applications in skincare. The methods included ELISA tests to assess the viability of human dermal fibroblast (NHDF) cells and related factors, and monitoring in Sprague-Dawley (SD) rats. The results showed that FZ promoted cell viability. Both FZ and DOF enhanced the secretion of type I collagen (Col I) and hyaluronic acid (HA), inhibited matrix metalloproteinase-1 (MMP-1), boosted catalase (CAT), and reduced malondialdehyde (MDA), reactive oxygen species (ROS), and β-galactosidase. They also nourished the epidermis and increased fiber content. In conclusion, FZ and DOF can stimulate the production of anti-aging substances, exhibit antioxidant activity, and have potential in skincare. Full article

Background/Objectives: Reverse iontophoresis (R-IP) is a technology that transdermally delivers components from inside the body to outside the body using electroosmotic flow (EOF) generated by applying a low electric current through the skin. It has attracted attention as a non-invasive sampling method for therapeutic drug monitoring (TDM). The purpose of this study was to determine whether urea and Tween 80 effectively enhance drug extraction from beneath the skin using R-IP. Methods: An in vitro drug extraction test using hairless mouse skin and R-IP was performed with a 3-chamber Franz cell and Ag|AgCl electrodes by applying a constant current (0.25 mA/cm²) for 6 h. Acetaminophen was chosen as the model drug, and its solution (30, 100, or 300 μg/mL) was placed in the subdermal compartment. The pH of both the electrode and subdermal compartment solutions was maintained at 7.4. Results: Acetaminophen was gradually extracted into the electrode compartment in a concentration-dependent manner and was more abundant in the cathode compartment than in the anode compartment. In addition, urea significantly promoted drug extraction, particularly on the cathode side, and a linear relationship was observed between the subdermal concentration and extracted amount. This effect is likely due to skin hydration caused by urea, which enhances EOF generation in the skin. Conversely, Tween 80 had no effect on drug extraction. Conclusions: R-IP combined with urea is expected to not only shorten the treatment time but also enable its application to drugs with low concentrations in blood. Full article

Microneedles (MNs) are miniature medical devices, presented as an array of micro-scale needles, each under 1 mm in height with sharp tips. MN technology is becoming a diagnostic platform associated with several qualities: no pain and no risk of infection, offering accuracy, comfort, and usability. Monitoring biomarkers in interstitial fluid (ISF) in real time is crucial for tracking changes in metabolism and assisting in the early diagnosis of chronic illnesses. Some examples of MN sensors are summarized here: the real-time sensing of two metabolites (lactate and glucose or alcohol and glucose), the transdermal tracing of pH, Na⁺, K⁺, Ca²⁺, Li⁺, and Cl⁻, transdermal methotrexate (MTX) monitoring, the transdermal sensing of tyrosinase enzyme as a melanoma biomarker, the integration of CRISPR technology for nucleic acid analysis, and monitoring plant sap pH in the leaves of several plants. The challenges to be addressed to realize the transition to widespread One Health solutions are analyzed. Full article

Nanocellulose-based biomaterials are at the forefront of biomedicine, presenting innovative solutions to longstanding challenges in tissue engineering and wound repair. These advanced materials demonstrate enhanced mechanical properties and improved biocompatibility while allowing for precise tuning of drug release profiles. Recent progress in the design, fabrication, and characterization of these biomaterials underscores their transformative potential in biomedicine. Researchers are employing strategic methodologies to investigate and characterize the structure and functionality of nanocellulose in tissue engineering and wound repair. In tissue engineering, nanocellulose-based scaffolds offer transformative opportunities to replicate the complexities of native tissues, facilitating the study of drug effects on the metabolism, vascularization, and cellular behavior in engineered liver, adipose, and tumor models. Concurrently, nanocellulose has gained recognition as an advanced wound dressing material, leveraging its ability to deliver therapeutic agents via precise topical, transdermal, and systemic pathways while simultaneously promoting cellular proliferation and tissue regeneration. The inherent transparency of nanocellulose provides a unique advantage, enabling real-time monitoring of wound healing progress. Despite these advancements, significant challenges remain in the large-scale production, reproducibility, and commercial viability of nanocellulose-based biomaterials. This review not only underscores these hurdles but also outlines strategic directions for future research, including the need for bioengineering of nanocellulose-based wound dressings with scalable production and the incorporation of novel functionalities for clinical translation. By addressing these key challenges, nanocellulose has the potential to redefine biomedical material design and offer transformative solutions for unmet clinical needs in tissue engineering and beyond. Full article

Electrical stimulation can be used in several applications such as fatigue reduction, muscle rehabilitation, neurorehabilitation, neuro-prosthesis and pain relief. Moreover, electrical stimulation can be used for drug delivery applications or body fluids extraction (e.g., sweat and interstitial fluid) to successively monitor several parameters, such as glucose, lactate, etc. All these applications are performed using electrical stimulator devices capable of applying constant voltage pulses or constant current pulses via electrodes to human tissues. Usually, constant current stimulators are most widely used because of their safety, stability, and repeatability. Thus, the aim of this work was to design, realize and test a mixed-signal electronic interface capable of producing current pulses with custom amplitude, duration, frequency, polarity and symmetry with extended voltage compliance. To achieve this result, we developed a high-voltage current stimulator suitable for iontophoresis applications. Current stimuli can be applied setting the intensity, frequency and duty cycle of the stimulation patterns through a µC. A custom electronic interface was designed to allow the control of the injected current in real time and to prevent electrical injuries to the patient by avoiding potential unwanted short circuits. Moreover, the system was tested in a simulated environment demonstrating its effectiveness and applicability for transdermal monitoring applications. The obtained results show that the device is able to apply monophasic and biphasic pulses, ranging from 0.1 to 10 mA, with a maximum error of about 10% at the minimum intensity; in addition, current stimuli can be applied up to a maximum frequency of 100 kHz with a voltage compliance of 120 V. Full article