BACKGROUND:Diabetes mellitus is a major global health concern. DPP-4 (dipeptidyl peptidase-4) inhibitors containing a 2-cyanopyrrolidine scaffold are in clinical use; however, systematic evaluation of amides derived from amino acids adjacent to the N-2 position of GLP-1 (glucagon-like peptide-1) has not been reported. METHODS:A total of eight 2-cyanopyrrolidine derivatives, grouped into three series, were synthesized from N-Boc-protected amino acids via condensation with 2-cyanopyrrolidine followed by deprotection. The compounds were characterized by nuclear magnetic resonance (NMR), elemental analysis, and mass spectrometry (MS). DPP-4 inhibitory activity was evaluated in vitro using a DPP-IV Glo™ assay, with sitagliptin as a control. IC50 (Half Maximal Inhibitory Concentration) values were determined from three independent replicates (n = 3) and calculated by nonlinear regression. RESULTS:Compounds 4d, 4g, and 4h exhibited excellent DPP-4 inhibition, with IC50 values of 1.36 ± 0.09, 5.24 ± 0.31, and 4.83 ± 0.22 nM, respectively. Compound 4d (histidine) was more potent than sitagliptin (6.13 ± 0.42 nM). The bis-cyanopyrrolidine derivatives 4g and 4h also showed strong activity. The remaining compounds (4a-4c, 4e, 4f) displayed moderate inhibition (IC50 112-181 nM). CONCLUSIONS:Aminoacyl-2-cyanopyrrolidine derivatives bearing an imidazole or bis-cyanopyrrolidine structure are potent DPP-4 inhibitors. These findings highlight the importance of neighboring GLP-1 amino acid residues (positions 1 and 3) in inhibitor design. Further cellular and in vivo studies are warranted to evaluate the therapeutic potential of these compounds.
BACKGROUND:Orally disintegrating films (ODFs) disintegrate and dissolve in the mouth, which creates challenges such as bitter taste and particle roughness. One of the most useful methods for suppressing bitterness in solid dosage forms is coating drug particles with a polymer to physically prevent contact between the drug and the taste buds. Because ODFs are extremely thin, the volume available for particle incorporation is limited; therefore, it is necessary to prepare fine coated drug particles with a size smaller than 200 µm, which also helps mitigate particle roughness in the oral cavity. In this study, we designed and prepared ODFs incorporating taste-masked drug particles for easy administration and improved adherence to drug therapy. METHODS:We used quinine hydrochloride (QH) as a model bitter active pharmaceutical ingredient (API), polyvinylacetal diethylaminoacetate (AEA), a pH-dependent polymer, as a coating agent, and hydroxypropyl methylcellulose (HPMC) as the film-forming agent. The ODFs containing taste-masked QH granules and the corresponding granules themselves were evaluated using a taste-sensing system. The disintegration, drug dissolution profiles, and physical properties of the ODFs were also evaluated. RESULTS:We prepared QH granules with the targeted median diameter (d50) and geometric standard deviation (σg), and the initial release of QH from these granules was less than 5% within 2 min. We also demonstrated, using the same system, that ODFs containing these granules delayed and suppressed the emergence of QH-induced bitterness. The disintegration time of the ODFs was less than 30 s, and their tensile strength remained above the 2 MPa threshold required for handling. CONCLUSION:We successfully prepared ODFs that suppressed the bitterness of QH while maintaining a short disintegration time and practical mechanical strength.
BACKGROUND:Rheumatoid arthritis (RA) is a chronic autoimmune disease and one of the most prevalent complex inflammatory disorders. Capparis spinosa L. (C. spinosa) is recognized for its diverse medicinal properties. Traditionally, the plant has been employed to alleviateconditions such as paralysis, gastrointestinal infections, rheumatism, diabetes, anemia, pain, and eye infections. This study aimed to investigate the potential interactions and predicted pharmacological relevance of major compounds identified in the essential oil of C. spinosa leaves using computational approaches. METHODS:Drug-likeness potential was determined using Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling and molecular docking. Gas chromatography-tandem mass spectrometry (GC-MS) was used to characterize the chemical composition of the essential oil. Drug-likeness studies were performed with SwissADME, while molecular docking was conducted using PyRx and BIOVIA Discovery Studio. RESULTS:Fourteen major compounds were computationally screened against RA-associated molecular targets to evaluate their potential ligand-target interactions and drug-likeness characteristics. Absorption, Distribution, Metabolism, and Excretion (ADME) and drug-likeness were evaluated according to Lipinski's "rule of five" to determine whether the compounds exhibited suitable pharmacokinetic properties, consistent with criteria for pharmaceutical development. Six major phytoconstituents, i.e., tau-cadinol (M1), diisobutyl phthalate (M5), (Z)-3-hexenyl benzoate (M7), farnesyl acetone (M8), dibutyl phthalate (M10), and 1-(4-tert-butylphenyl)propan-2-one (M12), identified via GC-MS were docked with tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), nitric oxide synthase (NOS), and cyclooxygenase-2 (COX-2). This is the first report describing an in silico screening of GC-MS-identified compounds from C. spinosa for their predicted pharmacological potential. Docking ligand scores for all ligands against the target proteins ranged from -4.7 to -8.0 kcal mol-1. Diisobutyl phthalate (M5) showed the most favorable binding energies against IL-1β and NOS, relative to the other compounds and co-crystallized ligands; meanwhile, tau-cadinol (M1) exhibited the highest binding energy for TNF-α. Six prevalent phytochemicals demonstrated highly favorable predicted docking affinities toward IL-6 and COX-2, with M10 showing the lowest docking energy values among the tested compounds under the applied computational conditions. CONCLUSIONS:These findings suggest that the examined phytochemicals may exhibit potential affinity toward RA-related molecular targets. As this is a preliminary computational investigation, the results should be interpreted with caution and warrant further computational and experimental studies to confirm their biological and therapeutic relevance.
BACKGROUND:Disrupted bile acid homeostasis represents a central feature of cholestatic liver injury, for which effective therapeutic options remain limited. Saxifraga umbellulata Hook. f. et Thoms. (SU) has traditionally been used in Tibetan medicine to treat hepatobiliary disorders, yet the pharmacological basis of SU remains unclear. Therefore, this study aimed to evaluate the effects of SU on cholestatic liver injury and explore the regulatory mechanisms underlying these effects. METHODS:A mouse model of cholestatic liver injury was established by administering α-naphthyl isothiocyanate (ANIT). The effects of SU were evaluated using serum biochemical measurements, liver histopathology, and targeted profiling of hepatic bile acids. Protein expression associated with farnesoid X receptor (FXR) signaling was assessed by Western blotting in liver and ileal tissues. Representative triterpenoids in the SU extract were further examined using molecular docking and HepG2 cell experiments. RESULTS:SU administration reduced serum markers of hepatocellular injury and cholestasis and lessened hepatic necrosis and inflammatory cell infiltration in ANIT-treated mice. SU also shifted the altered hepatic bile acid profile toward a more balanced state, including partial correction of the disturbed proportions of primary and secondary bile acids. These metabolic changes were accompanied by reduced hepatic CYP7A1 expression and increased expression of BSEP and MRP2. In addition, SU increased ileal FXR and FGF15 expression and hepatic FGFR4 expression, a pattern consistent with coordinated regulation of the intestinal FXR-FGF15/hepatic FGFR4 axis. Meanwhile, molecular docking and HepG2 cell experiments suggested that cucurbitacin IIb and saxifragic acid may contribute to the observed FXR-related responses. CONCLUSIONS:SU mitigated ANIT-induced cholestatic liver injury and promoted partial recovery of hepatic bile acid homeostasis. The protective effects of SU were associated with coordinated changes in hepatic and intestinal FXR-related signaling and with reduced inflammatory injury. These results provide experimental evidence supporting the traditional use of SU for hepatobiliary disorders and highlight cucurbitacin IIb and saxifragic acid as potential bioactive triterpenoids.
Skin hyperpigmentation is a common dermatological condition characterized by excessive melanin accumulation in the epidermis, dermis, or both, resulting from disorders such as melasma, post-inflammatory hyperpigmentation, drug-induced hyperpigmentation, and solar lentigo. Conventional treatments are mainly based on tyrosinase inhibition; however, many depigmenting agents have limitations, including low stability, poor skin permeation, prolonged treatment durations, and adverse effects such as irritation and dermatitis. In this context, nanotechnology-based delivery systems have emerged as promising alternatives for the topical administration of depigmenting compounds. Therefore, this review discusses recent advances in nanotechnology-based strategies for treating skin hyperpigmentation, with a primary focus on lipid-based nanosystems, including liposomes, nanoemulsions, solid lipid nanoparticles, and nanostructured lipid carriers. A total of 33 studies published between 2000 and 2025 were analyzed. The reviewed studies demonstrated that nanoencapsulation may improve the physicochemical stability, enable controlled release, enhance skin permeation/retention, and increase the therapeutic performance of depigmenting agents while reducing toxicity and adverse effects. In vitro studies also reported enhanced tyrosinase inhibition, high cell viability, and increased accumulation of active compounds in different skin layers. Overall, nanotechnology-based delivery systems represent a promising and versatile approach for improving the efficacy and safety of topical treatments for skin hyperpigmentation.
BACKGROUND:Aberrant platelet activation is a major contributor to thrombotic disorders, prompting interest in naturally derived candidates that can safely regulate platelet function. Sappanchalcone, a chalcone-type flavonoid derived from Caesalpinia sappan L., has diverse biological activities; however, its effects on platelet activation and clot retraction remain unclear. This study evaluated the antiplatelet potential of sappanchalcone and its underlying mechanisms in human platelets. METHODS:Washed human platelets and platelet-rich plasma were used to assess platelet activation and clot retraction, respectively. Samples were pretreated with sappanchalcone (16-128 μM, depending on the assay) and stimulated with collagen or thrombin. Platelet aggregation and cytotoxicity were assessed by light transmission aggregometry and lactate dehydrogenase (LDH) leakage assay. cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and thromboxane B2 (TXB2) levels were quantified using enzyme-linked immunosorbent assay (ELISA) kits, and intracellular Ca2+ mobilization was measured by Fura-2/AM-based fluorescence analysis. Protein phosphorylation was examined by Western blotting, whereas integrin αIIbβ3-fibrinogen binding was analyzed by flow cytometry. Dense granule secretion was evaluated using adenosine triphosphate (ATP) luminescence and serotonin ELISA assays. Thrombin-induced clot retraction was quantified by ImageJ (v1.54k, U.S. National Institutes of Health, Bethesda, MD, USA)-based residual clot area analysis. Data are presented as mean ± standard deviation (SD) and analyzed by one-way analysis of variance (ANOVA) with Tukey-Kramer post hoc test (n = 4; p < 0.05). RESULTS:Sappanchalcone concentration-dependently inhibited collagen-induced platelet aggregation, reducing aggregation from 83.0% to 10.7% at 128 μM, with a half-maximal inhibitory concentration (IC50) of 57.16 μM, without cytotoxicity. At 128 μM, sappanchalcone increased cAMP from 7.02 ± 0.85 to 11.96 ± 0.57 pmol/108 platelets and reduced Ca2+ mobilization from 711.97 ± 47.29 to 66.11 ± 6.83 nM. Vasodilator-stimulated phosphoprotein (VASP) Ser157 and Ser239 phosphorylation increased by 2.97- and 2.07-fold, respectively, whereas fibrinogen binding decreased from 74.43 ± 5.67% to 21.90 ± 1.25%. Phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 phosphorylation was reduced to 0.69-, 0.21-, 1.81-, 0.27-, and 0.49-fold, respectively. ATP secretion, serotonin release, TXB2 levels reflecting thromboxane A2 (TXA2) generation, cytosolic phospholipase A2 (cPLA2) phosphorylation, and thrombin-induced clot retraction were also suppressed. CONCLUSIONS:Sappanchalcone limits platelet activation, aggregation, and clot retraction by enhancing cyclic nucleotide-mediated inhibitory signaling and suppressing PI3K/Akt and mitogen-activated protein kinase (MAPK) phosphorylation. These findings provide mechanistic evidence supporting sappanchalcone as a potential naturally derived antiplatelet candidate.
OBJECTIVE:This study aimed to identify the active fraction of Polyporus umbellatus extract (PUE) for the treatment of hyperuricemia (HUA) and elucidate the associated mechanism of action. METHODS:HUA was induced in mice using hypoxanthine and potassium oxonate. Serum uric acid (UA), urinary UA, creatinine (CRE), blood urea nitrogen (BUN), xanthine oxidase (XOD) activity, inflammatory cytokines (Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α)), and renal urate transporters (Uric acid transporter 1 (URAT1), Organic anion transporter 1 (OAT1)) were subsequently measured. The active fraction was identified by bioactivity-guided fractionation using D101 macroporous resin chromatography. Two major compounds were isolated and evaluated for anti-inflammatory (nitric oxide (NO) production, cytokine mRNA expression) and antioxidant (Malondialdehyde (MDA), Superoxide dismutase (SOD)) activities in monosodium urate (MSU)-induced RAW264.7 macrophages. RESULTS:PUE significantly ameliorated hyperuricemia in HUA mice, reducing serum UA, CRE, BUN, and renal URAT1 expression; increasing urinary UA excretion and OAT1 expression; inhibiting XOD activity; attenuating renal inflammation and histopathological damage. The 95% ethanol eluate was identified as the most active fraction and yielded ergosterol (A) and 5α,8α-epidioxy-(22E,24R)-ergosta-6,22-dien-3β-ol (B). Both compounds suppressed MSU-induced NO release, proinflammatory cytokine expression, and oxidative stress. CONCLUSION:The 95% ethanol eluate of P. umbellatus exerts anti-hyperuricemic effects through multiple mechanisms, possibly related to XOD inhibition, anti-inflammatory activity, antioxidant protection, and regulation of renal uric acid transport proteins. Ergosterol derivatives are proposed as the potential active components in this extract.
OBJECTIVE:Histone deacetylase 1 (HDAC1) exacerbates ventricular remodeling and heart failure by promoting myocardial peroxidative damage. Thus, this study aimed to investigate whether the HDAC1 inhibitor mocetinostat alleviates pathological cardiac hypertrophy via suppressing ferroptosis and to elucidate the potential mechanisms involving the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. METHODS:Primary cardiomyocytes were stimulated with phenylephrine (PE) to induce hypertrophy and ferroptosis in vitro, with or without mocetinostat treatment. The Nrf2 inhibitor ML385 was used to verify pathway specificity. In vivo, a mouse model of pressure-overload-induced cardiac hypertrophy was established using a transverse aortic constriction (TAC)-induced approach. Mocetinostat was administered to evaluate its therapeutic effects. Ferroptosis markers including lipid peroxidation, iron accumulation, and levels of ferroptosis-related proteins, were assessed. The acetylation and nuclear translocation of Nrf2, as well as the expression of the associated downstream targets (Solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferroportin, ferritin heavy chain 1 (FTH1), heme oxygenase-1 (HO-1)), were analyzed. RESULTS:Mocetinostat treatment significantly ameliorated PE-induced cardiomyocyte hypertrophy and ferroptosis in vitro and attenuated TAC-induced cardiac hypertrophy and fibrosis in vivo. Mechanistically, mocetinostat facilitated Nrf2 acetylation and promoted Nrf2 nuclear translocation, leading to the transcriptional activation of downstream antioxidant targets and subsequent inhibition of lipid peroxidation. The protective effects of mocetinostat were abrogated by the Nrf2 inhibitor ML385. CONCLUSION:This study demonstrates that mocetinostat attenuates pathological cardiac hypertrophy by inhibiting ferroptosis through activation of the Nrf2 pathway . These findings indicate the potential of mocetinostat as a therapeutic strategy for delaying heart failure progression.
Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. Intracellular iron promotes the generation of reactive oxygen species via the Fenton reaction, leading to lipid peroxide accumulation, membrane damage, and subsequent cell death. Increasing evidence indicates that ferroptosis plays a critical role in cancer progression and therapeutic response. Recent studies have identified a diverse range of ferroptosis-inducing compounds, including natural products, semi-synthetic derivatives, and synthetic small molecules, which exert antitumor effects by targeting key regulatory nodes such as iron metabolism, system Xc-, and glutathione peroxidase 4. However, the clinical translation of ferroptosis-based strategies remains limited by insufficient tumor selectivity, systemic toxicity, the lack of reliable biomarkers, and adaptive resistance mechanisms. In this review, we summarize the molecular regulatory networks governing ferroptosis, critically evaluate representative ferroptosis-inducing compounds and the associated mechanisms of action, and discuss current translational challenges and unresolved controversies. Furthermore, an integrative framework is proposed to define ferroptosis as a context-dependent metabolic vulnerability in tumors, thereby providing a conceptual basis for the rational development of ferroptosis-based anticancer therapies.
Diabetic retinopathy (DR) remains a leading cause of blindness among individuals with diabetes mellitus (DM), with a continuously rising global prevalence. While anti-vascular endothelial growth factor (anti-VEGF) therapy, corticosteroids, laser photocoagulation, and vitreoretinal surgery have improved outcomes, none can permanently prevent disease progression. The complex pathophysiology of DR, which includes inflammation, oxidative stress, and neurodegeneration, highlights the need for additional systemic strategies. This narrative review was informed by a structured search of PubMed, Scopus, and Web of Science covering the period from January 2000 to September 10, 2025. Original studies, systematic reviews, and meta-analyses were included, whereas case reports and editorials were excluded. Findings were synthesized qualitatively. Preclinical models suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert neuroprotective, anti-inflammatory, and antioxidant effects on the retina, preserve the blood-retinal barrier, and reduce vascular endothelial growth factor (VEGF) expression. However, whether these retinal effects are only partially independent of glycemic control remains speculative, as clinical studies have not adequately controlled for changes in glycated hemoglobin (HbA1c) or for differences in concomitant glucose-lowering therapies. Observational clinical studies have associated SGLT2 inhibitor use with a lower risk of DR progression, a reduced incidence of proliferative DR, and fewer vision-threatening interventions compared with some other antihyperglycemic agents. Owing to the established indications in heart failure and chronic kidney disease associated with SGLT2 inhibitors, these agents appear promising for DR prevention and risk modification. However, current clinical evidence is based mainly on observational and retrospective studies and remains vulnerable to confounding and selection bias. Prospective randomized studies with ophthalmic endpoints are needed before firm conclusions can be drawn.
BACKGROUND:Switching from branded to generic extended-release (ER) metoprolol formulations is common practice due to cost considerations. Although generics are approved as bioequivalent, subtle differences in formulation, such as coating composition, may influence drug release under real-life conditions across patients. OBJECTIVE:This study aimed to evaluate potential differences in drug release between the originator product Beloc-Zok 95 mg and randomly selected generic ER metoprolol succinate formulations available on the German market. METHODS:Formulations were assessed under variable, interindividual, physiologically relevant in vitro conditions simulating gastrointestinal transit. RESULTS:All formulations demonstrated controlled drug release; however, the release profiles were not fully overlapping. One generic formulation consistently exhibited slightly slower release across all test scenarios. These findings indicate that minor differences in release behavior can occur even among bioequivalent ER formulations. While such variations are generally clinically negligible, they may contribute to pharmacokinetic and pharmacodynamic differences in sensitive individuals, potentially explaining reported adverse effects such as bradycardia, hypotension, chest pain, or increased blood pressure when switching to generic products. CONCLUSIONS:The results underscore the importance of considering patient-specific variability when switching from branded to generic formulations. Incorporating physiologically relevant in vitro studies combined with physiologically based pharmacokinetic and pharmacodynamic modeling in future research may improve predictions of in vivo performance and support safer therapeutic decisions.
Melanocortin-4 receptor (MC4R) is a key receptor in the hypothalamus regulating appetite and energy metabolism. Research has indicated that MC4R agonists have demonstrated potential for weight loss; its antagonists may stimulate appetite and weight gain, showing potential therapeutic applications in patients with anorexia or cachexia or those requiring weight restoration. However, the signaling mechanism, clinical applications, and safety profile of MC4R antagonists still require in-depth investigation. The purpose of this review is to comprehensively summarize the research progress of MC4R antagonists, analyze their mechanism of action and clinical applications, evaluate their safety profile, and explore future research directions. Future studies should focus on developing safer and more effective MC4R antagonists and exploring the therapeutic potential of MC4R in other diseases.
Reactive oxygen species (ROS) have been identified as one of the critical factors in cancer development. ROS have been linked to cancer at all stages, and their applications in cancer treatment have gained attention due to their concentration-dependent implications: (1) low to moderate levels as fundamental signaling molecules, and (2) higher levels in cancer cells as a unique characteristic of cancer and cytotoxic agents. However, resistance and off-target effects are the main barriers that can hinder and limit the therapeutic efficacy of chemotherapies. The main reason for that is the complex tumor microenvironment such as hypoxia. Developing drug nanocarriers that can target ROS represents a potential delivery platform to overcome these barriers. For instance, doxorubicin-encapsulated ROS (nitric oxide) micelles accumulated 6.7-fold more drug in PC3-Luc cancer cells than when using this drug alone. Regrettably, the past studies have merely discussed the micelle alone as a nanocarrier for the delivery of ROS-based therapy in cancer without exploring dendrimers. Instead, this review examines the structural design of dendrimers tailored for oxygen transport, their conjugation with ROS-generating therapies, and therapeutic applications in photodynamic therapy, radiotherapy, and chemotherapy. Besides, it also discusses the translational challenges and future perspectives for ROS-based dendrimers. For the first time, this work also critically compares various dendrimer types and generations, oxygen-delivery strategies, drug loading properties, in vitro/in vivo outcomes, and toxicity data. A dedicated section discussing biodistribution, clearance, biocompatibility, and regulatory considerations of dendrimers was also explored in this study. Finally, this review concludes that the dendrimers can be engineered to carry and deliver active oxygen by using the following delivery strategies: (1) addition of oxygen carriers, (2) enzyme functionalization, (3) the incorporation of photosensitizers and metal ions, and (4) surface alterations.
BACKGROUND:β-lactam allergy labels (BALs) are commonly found in patient records but are often inaccurate. This can lead to suboptimal antibiotic selection, increased healthcare costs, and antimicrobial resistance. Most existing risk assessment tools were developed in Western settings and are not applicable in Chinese clinical contexts. This study developed and pilot-tested a pharmacist-led BAL risk assessment tool tailored to the Chinese healthcare environment. METHODS:The study was conducted in three phases: (1) A systematic review of 90 studies to identify key β-lactam allergy risk factors; (2) Grounded theory and text co-occurrence analysis to extract high-risk features and construct the assessment framework; and (3) A pilot implementation in a tertiary hospital to evaluate the tool's feasibility, clinical impact, and patient outcomes using a quasi-experimental design. RESULTS:The final tool comprised eight dimensions, 35 subdimensions, and over 1328 distinct coded nodes. Of the 289 patients involved in the pilot, 18.7% were classified as high risk. Compared with patients with BALs but without high-risk features, those at lower risk had significantly shorter hospital stays (8.5 ± 4.3 vs. 10.6 ± 5.5 days; p < 0.001), reduced hospitalization costs (17,800 ± 6200 vs. 21,000 ± 7500; p = 0.0011), and lower allergy event rates (0% vs. 6.5%; p = 0.002). β-lactam use increased (75.3% vs. 40.3%; p < 0.001), whereas second-line antibiotic use decreased (24.7% vs. 59.7%; p < 0.001). The tool also demonstrated high feasibility, achieving a 100% completion rate and strong adherence among pharmacists. CONCLUSION:This pharmacist-led risk assessment tool has strong potential for accurately identifying high-risk β-lactam allergy patients and optimising antimicrobial stewardship in Chinese hospitals. Further large-scale validation is warranted.
BACKGROUND:Prophylactic opioid rescue therapy is often used to manage cancer-related pain. However, the effect of prophylactic rescue therapy in suppressing increases in breakthrough pain due to body movements has not yet been investigated. Therefore, this study aimed to compare the efficacy and safety of prophylactic rescue therapy before and after administration. METHODS:This multicenter, retrospective survey was conducted in Japan. Participants were patients with cancer who received prophylactic strong opioid rescue therapy for the first time. The primary endpoint was the suppression of an increase in pain, assessed using a Numerical Rating Scale (NRS), before and after administration of prophylactic rescue due to body movement. RESULTS:The overall analysis (193 cases) showed that prophylactic rescue suppressed the increase in the median NRS value by 3.00 (interquartile range: 1.00-4.00, p < 0.001). In addition, subgroup analysis by purpose (meals/bathing/rehabilitation/radiation therapy/others) also showed a significant reduction in the increase in NRS, with all categories exhibiting a decrease of 2.00 or more. CONCLUSIONS:Prophylactic opioid rescue with appropriate patient selection can effectively suppress breakthrough pain caused by body movement.
BACKGROUND:The placenta plays important roles in pregnancy maintenance and fetal development, and chemical-induced functional or structural abnormalities can lead to adverse pregnancy outcomes. However, information on the placental effects of chemicals remains limited. To help address this gap, this study aimed to investigate the effects of two model chemicals, phenytoin and phenobarbital, on syncytialization (the fusion of cytotrophoblasts into multinucleated syncytiotrophoblasts), a critical process in placental development, using the human choriocarcinoma cell line BeWo. METHODS:Phenytoin and phenobarbital, anticonvulsant drugs known to cause major congenital malformations, were each co-treated with forskolin, which promotes syncytialization in BeWo cells, for 48 h. RESULTS:Evaluation of cell fusion showed that phenytoin significantly suppressed forskolin-induced luciferase activity, whereas phenobarbital did not. Enzyme-linked immunosorbent assay showed that the concentration of human chorionic gonadotropin beta (hCGβ) in the cell culture supernatant was decreased in phenytoin-treated syncytialized BeWo cells but increased in phenobarbital-treated cells. Western blotting also showed a similar pattern in the hCG protein expression level. CONCLUSION:Collectively, these results indicate that phenytoin suppresses the process of syncytialization, whereas phenobarbital does not affect cell fusion and instead enhances hCG production.
BACKGROUND:Dexamethasone is typically included in the anti-emetic regimens during the administration of anticancer drugs. However, the incidence and severity of nausea and vomiting in patients receiving anticancer therapy, for whom dexamethasone must be avoided to prevent the recurrence of diabetes mellitus or hepatitis, remain unknown. METHODS:This retrospective, observational study evaluated nausea and vomiting in patients with breast cancer who underwent highly emetogenic chemotherapy, including anthracycline and cyclophosphamide, for breast cancer. In all patients, dexamethasone was completely omitted from the standard antiemetic regimen for reasons such as hepatitis, and only palonosetron and aprepitant were administered. RESULTS:For the 82 evaluated cases, the incidence of nausea was 84.1%, vomiting was 14.6%, and the complete response (CR) rate was 8.5%. In addition, the incidence rate of grade 2 or higher nausea (CTCAE ver. 4) was 47.6%, and the proportion of cases in which anticancer drug doses were reduced in the subsequent course due to nausea and vomiting was 2.4%. Factor analysis showed that treatment regimens, age, drinking history, history of prior chemotherapy, and reasons for omitting dexamethasone had no significant effects on the incidence of chemotherapy-induced nausea and vomiting. CONCLUSIONS:This study confirmed that the antiemetic effect of only administering palonosetron and aprepitant is insufficient for patients receiving highly emetogenic chemotherapy in whom dexamethasone cannot be administered. Prophylactic administration of other antiemetic drugs is necessary to effectively manage nausea and vomiting in patients receiving anticancer therapy who cannot receive dexamethasone.
The aim of this study was to investigate how patient background influences the prolonged effect of midazolam, focusing on factors previously reported and albumin levels. A total of 196 patients aged 18 years and older were admitted to the University Hospital and Matsuyama Shimin Hospital intensive care units between January 2015 and May 2022 and received continuous midazolam infusion for at least 24 h were initially considered. Ultimately, 68 patients meeting the inclusion criteria were analyzed. We collected patient data, including background information, laboratory test values, and usage status of sedatives such as midazolam, from medical records. The primary outcome was the time required to see improvement in the Richmond Agitation-Sedation Scale score after midazolam administration. Factors influencing the duration of midazolam's effects were assessed using the Mann-Whitney U test and logistic regression analysis. The improvement in Richmond Agitation-Sedation Scale scores post-midazolam discontinuation occurred within 48 h for 52 patients (76.4%) and exceeded 48 h for 16 patients (23.5%). Risk factors identified in prior studies, and albumin levels were linked to the prolonged effect of midazolam. Multivariate logistic regression analysis indicated that albumin levels significantly affected the duration of midazolam's effects (odds ratio, 0.61; 95% confidence interval, 0.44-0.85; P < .05). In this study, the serum albumin level was identified as a new factor that enhances and prolongs the action of midazolam. Therefore, sedation in patients with low albumin levels should be performed carefully to avoid the prolongation and potentiation of midazolam action.
Chronopharmaceutic drug delivery systems are designed to align the release of active substances with the body's biological rhythms, offering significant advantages in diseases with time-dependent symptom patterns. Delayed-release tablets are widely used in this field to achieve controlled drug release after a defined lag time, typically by modulating the composition of excipients. However, the reliance on excipient-based control may limit the flexibility and predictability of release profiles. This study is the first in the literature to focus on the mechanistic design of chronopharmaceutical tablets by exploring how physical tablet properties-specifically tablet geometry and compression physics-can independently control delayed drug release, without relying on excipient effects. By systematically varying tablet shape, size, and compression force, we aimed to establish a new formulation approach centered on the physical characteristics of the dosage form. Prednisone was selected as a model drug due to its common use in chronotherapy, where precisely timed drug release is essential to improve therapeutic outcomes. In vitro dissolution studies demonstrated that manipulation of tablet geometry and compression parameters effectively modulated lag time and drug release kinetics, independent of excipient composition. These findings suggest that optimizing the mechanistic properties of tablets provides a valuable strategy for the design of advanced chronopharmaceutical systems, potentially enhancing drug efficacy, patient comfort, and treatment adherence.
Equisetum arvense L., commonly known as horsetail, is the most prominent Equisetum species and a widely used medicinal plant in traditional and herbal medicine. This study presents a comprehensive phytochemical characterisation of various pharmaceutical extracts prepared from field horsetail according to a national pharmacopoeia, including aqueous fermented extracts, oil-based extracts and hydroalcoholic extracts. Polar constituents were analysed using HPLC-DAD-ESI-MS n. GC-MS analyses following silylation were performed to elucidate low-molecular-weight compounds. The results revealed different phytochemical compositions of the E. arvense L. extracts, with distinct profiles of compounds including hydroxycinnamic acids and flavonoids. The results of the GC-MS investigations indicated the presence of an even broader variety of compounds, comprising benzoic acids, fatty acids, sugars, and phytosterols. Additionally, chlorophyll and carotenoid contents were quantified in the oil-based extracts by UV-VIS spectroscopy. This study underlines the significant impact of the respective extraction parameters on the phytochemical profile of the corresponding pharmaceutical extracts and highlights the rich history and continuing importance of this medicinal plant in traditional and complementary medicine.
