Search Results (6,035)

Intranasal administration is a promising drug delivery route enabling precise and rapid central nervous system targeting. In our previous work, twelve hybrid colloidal dispersions were developed, consisting of synthetic poly(ethylene-oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) block copolymers with an increasing proportion of the hydrophobic PCL segment, Tween 80 (Tw80) and β-cyclodextrin derivatives (βCD), either methyl-β-CD (MβCD) or hydroxy-propyl-β-CD (HPβCD) for IN delivery of ropinirole hydrochloride (RH). Colloidal dispersions were prepared at different weight ratios (system/RH equal to 10:1 and 10:5), characterized and evaluated in vitro. The aim of this study is to evaluate the ex vivo permeation through rabbit nasal mucosa and determine the pharmacokinetic parameters of RH, when administered intranasally as a colloidal dispersion, compared with oral and intranasal RH solutions in C57BL/6J mice. Ex vivo permeation studies showed that all formulations significantly enhanced RH permeation compared to the pure RH solution (0.5 mg/mL, pH 5.6). Among them, F4 [(PEO-b-PCL₁/Tw80/HPβCD)/RH 10:5] was selected for further investigation. Pharmacokinetic analysis showed that F4 significantly enhanced both systemic and brain exposure of RH, achieving higher serum AUC and C_max values, despite a 3-fold lower administered dose compared to the oral dose. It showed high systemic (F_rel(Serum) = 1815%) and brain (F_rel(Brain) = 363%) relative bioavailability compared with oral administration, underscoring its potential as an intranasal delivery system for efficient CNS targeting. Full article

Background: Kinkeliba (Combretum micranthum G. Don), commonly used in West African traditional pharmacopeia for its anti-inflammatory and gastrointestinal properties, remains poorly studied regarding its potential role in the prevention or treatment of ulcerative colitis. Objective: This study evaluated the therapeutic potential of the ethanolic extract of Combretum micranthum (EECM) in a murine model of chronic DSS-induced colitis. Methods: Male C57BL/6 mice were subjected to three cycles of 1.5% DSS administration over nine weeks to induce chronic colitis. EECM was administered orally at 50, 100, or 200 mg/kg during the final week. Disease severity was evaluated using the Disease Activity Index (DAI), colon length, biochemical and hematological markers, along with histopathological and immunohistochemical assessment of colonic tissue. Results: EECM treatment significantly improved clinical parameters and prevented colon shortening in chronic DSS-induced colitis. These improvements were associated with the restoration of serum biochemical and hematological profiles, along with reduced histopathological damage and preservation of colonic tissue architecture. Immunohistochemical analysis further demonstrated decreased CD3-positive T-lymphocyte infiltration in colonic tissue, suggesting modulation of local immune cell responses. Conclusions: These findings highlight the therapeutic potential EECM in ulcerative colitis and support further investigations to elucidate its mechanisms of action and evaluate its efficacy in future translational studies. Full article

Annona cherimola is a plant species widely used in Mexican traditional medicine, particularly in the management of diabetes. This study aimed to investigate the antihyperglycemic properties of the petroleum ether extract of A. cherimola leaves (PEEAcL), as well as to evaluate their effects on glycated hemoglobin and toxicity. In addition, the work was directed to determine its potential as an SGLT-1 and α-glucosidase inhibitor. The effect as a potential SGLT-1 and α-glucosidase inhibitor of PEEAcL was evaluated utilizing intestinal glucose absorption (IGA), oral glucose tolerance (OGT), oral sucrose tolerance (OST) and intestinal sucrose hydrolysis (ISH) tests. PEEAcL administered at doses of 200 mg/kg showed significant antihyperglycemic activity after 1 h of treatment, and the maximum effect was seen at 4 h in male and female diabetic mice. In the OST, OLT, and OGT tests, PEEAcL generated a reduction in the postprandial glucose peak at 2 h after the administration of a carbohydrate load, showing an effect comparable to that of acarbose and canagliflozin. In the IGA trial, PEEAcL significantly reduced glucose uptake in the small intestine. Similarly, in the ISH, PEEAcL recorded a significant reduction in glucose concentration in the external aqueous medium. Taken together, these results suggest that the antihyperglycemic effect of PEEAcL could be mediated, at least in part, by inhibition of SGLT-1 and the enzyme α-glucosidase. Full article

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon characterized by dysregulated mucosal immunity and progressive epithelial injury. Upadacitinib (UPA), a selective Janus kinase 1 (JAK1) inhibitor, has demonstrated clinical efficacy in UC, but its therapeutic application is often constrained by adverse effects arising from systemic drug exposure. This underscores the need for advanced, site-specific delivery systems that enhance local efficacy while minimizing systemic toxicity. Here, we developed a colon-targeted natural lipid nanoparticle formulation of UPA (UPA-nLNP) to improve therapeutic performance and safety. UPA-nLNP was prepared by thin-film hydration using digalactosyldiacylglycerol (DGDG), monogalactosyldiacylglycerol (MGDG), and phosphatidic acid (PA), mimicking the lipid composition of ginger-derived exosomal particles, and was characterized for particle size, surface charge, and encapsulation efficiency. The formulation exhibited excellent mucus-penetrating capability and was evaluated in a dextran sulfate sodium (DSS)-induced acute colitis model in C57BL/6 mice following oral administration (5 mg/kg). Pharmacokinetic analysis demonstrated increased colonic accumulation with reduced systemic exposure compared to free UPA. Treatment with UPA-nLNP improved body weight recovery, reduced disease biomarkers, and suppressed key proinflammatory cytokines in the colon, with no evidence of systemic toxicity. This innovative strategy holds strong potential to enhance the clinical utility of JAK1 inhibitors by providing a safer and more effective therapeutic approach for ulcerative colitis. Full article

Background/Objectives: Following prior in vitro and in vivo investigations on the bone health benefits of green onions and oats, we aimed to assess the effects of WCO31, Allium fistulosum L. (green onion) root and Avena sativa L. (oat) mixtures, on height growth and safety. Methods: This multi-center, randomized, double-blind, placebo-controlled study included 150 children aged 6–8 years (75 males and 75 females) who fell between the 3rd and 50th percentiles of the Korean National Growth Charts but had not yet developed secondary sexual characteristics. They were randomly assigned to receive daily oral administration of WCO31 (1.2 g/day) or a placebo for 24 weeks. For efficacy analysis, height, growth rate, growth rate standard deviation score (SDS), height SDS, and growth-related parameters were measured. To evaluate the safety of the intervention, several safety parameters (including the incidence of adverse events, laboratory tests, and vital signs) were monitored. Results: The WCO31 group demonstrated significantly superior outcomes, including height, growth rate, growth rate SDS, height SDS, and height-for-age Z-score, than the placebo group (all p < 0.001). Moreover, no safety-related concerns were identified. Conclusions: WCO31 positively influences height growth and demonstrates a favorable safety profile, with no observable adverse effects. This study provides the first clinical evidence supporting growth enhancement using natural extracts, suggesting that WCO31 could serve as a cost-effective, safe, and accessible complementary strategy for promoting child growth. Full article

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a major chronic liver disorder that progresses through inflammation and fibrosis to cirrhosis, yet no effective pharmacological therapy is available. Extracellular vesicles (EVs), which are key mediators of intercellular communication, have recently been reported to exert preventative and therapeutic effects in disease models. This study evaluated the oral efficacy of EVs derived from the microalga Chlorella vulgaris (CEVs) in an MASLD mouse model. Male C57BL/6J mice were assigned to a control group (normal diet), an MASLD group (choline- and methionine-deficient high-fat diet; CDHF), or CEV group (CDHF + CEVs). Twelve-week CEV administration did not alter the CDHF-induced reduction in circulating lipid levels or produce an increase in hepatic lipid content. However, CEV treatment significantly suppressed CDHF-induced fibrosis with collagen accumulation and reduced the mRNA expression of fibrosis-related genes, including Col1a1, Acta2, Mmp2, and Timp1. CEVs also significantly downregulated the expression of macrophage-derived inflammatory mediators—Ccl2, Ccr2, Il6 and Il1b—and reduced lobular inflammatory foci. These findings suggest that CEVs attenuate hepatic fibrosis by modulating early inflammation associated with steatosis and inhibiting hepatic stellate cell activation. This study supports the potential of CEVs as a novel oral intervention for slowing MASLD progression. Full article

Wound healing research has advanced through nanotechnology-based delivery systems that enhance the stability and therapeutic potential of bioactive compounds. Resveratrol, a natural polyphenol with antioxidant and anti-inflammatory properties, shows promise for wound healing but is limited by poor bioavailability. This study investigates the efficacy of nano-liposome-encapsulated resveratrol in enhancing skin wound repair in adult zebrafish (Danio rerio). Using a laser-based ablation method, precise full-thickness skin wounds were induced and monitored over 50 days. Resveratrol-loaded liposomes were prepared and orally administered via gavage to facilitate systemic exposure. Compared to the control and blank liposome groups, resveratrol liposome treatment significantly accelerated wound closure, achieving earlier healing milestones (25%, 50%, and 75%). The zebrafish model provided a regenerative platform for real-time evaluation of nanomedicine-based therapies. This study demonstrates the wound healing effects of resveratrol and liposomal encapsulation, offering a targeted, systemically administered strategy for advanced systemic healing and highlighting zebrafish as a valuable model for preclinical regenerative medicine research. Full article

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutation subtype in non-small cell lung cancer (NSCLC), accounting for approximately 4–12% of all EGFR-mutated cases. Unlike classical EGFR mutations, ex20ins mutations confer inherent resistance to first-, second- and third-generation EGFR tyrosine kinase inhibitors (TKIs) due to unique structural alterations that lock the αC-helix in an active orientation, creating steric hindrance within the drug-binding pocket. Until recently, platinum-based chemotherapy remained the standard first-line treatment, with objective response rates (ORR) of 19–47% and a median progression-free survival (PFS) of 6–7 months. Over the past five years, the therapeutic landscape has shifted, driven by the development of selective inhibitors and bispecific antibodies. Amivantamab, a bispecific EGFR–mesenchymal–epithelial transition factor (MET) antibody combined with chemotherapy, demonstrated superior efficacy in the PAPILLON trial, with an ORR of 73% and a median PFS of 11.4 months in the first-line setting. Sunvozertinib, an oral, selective EGFR inhibitor, received U.S. Food and Drug Administration (FDA) accelerated approval in 2025, with an ORR of 46% and a median duration of response (DOR) of 11.1 months in platinum-pretreated patients. Emerging therapies, including zipalertinib and furmonertinib, have shown promising results in early-phase trials, with zipalertinib demonstrating activity in patients pretreated with amivantamab (ORR 31.5%) and furmonertinib achieving remarkable responses in treatment-naive patients (ORR 78.6% at 240 mg). This comprehensive review analyzes the molecular biology, structural mechanisms, current therapeutic options, and novel investigational agents for EGFR ex20ins-mutated NSCLC. Full article

This study compared the regulatory effects of dietary supplementation with natural clinoptilolite (CLN) versus a dietary cation-anion difference (DCAD) regimen on calcium homeostasis in dairy cows during the last 21 days prepartum. Results showed that cows in the DCAD group exhibited significantly higher blood ionized calcium (iCa) and parathyroid hormone (PTH) concentrations than those in the CLN group (p < 0.05). Serum PTH concentrations displayed a declining trend in both groups prepartum, which deviates from the classical theory of compensatory PTH secretion, suggesting that alternative compensatory pathways may be involved in the regulation of calcium homeostasis during the periparturient period in dairy cows. Monitoring of calcium homeostasis and related metabolic parameters following postpartum oral calcium bolus administration revealed that the incidence of subclinical hypocalcemia in the DCAD group was 26%, lower than the 62% observed in the CLN group. However, blood iCa concentrations returned to normal levels more rapidly in the CLN group. Additionally, CLN supplementation was associated with more stable blood pH and lower prepartum serum potassium concentrations (p < 0.05) that remained within the physiological range, which may contribute to improved tissue sensitivity to PTH. Full article

Probiotics are commonly applied to maintain the balance of gut microbiota and regulate the intestinal metabolic function of companion animals. In the present study, complex probiotics (Bacillus coagulans SNZ-1969, Bacillus subtilis, and Bacillus licheniformis) were added into the basal diet of domestic cats to investigate their influence on the intestinal microbiome and metabolic characteristics. Results revealed that the alpha diversity of the gut microbiota in the probiotic group was enhanced when compared to the control group. The beta diversity of the gut microbiota was also altered by the oral consumption of the complex probiotics. Compared to the control group, the relative abundance of beneficial microbes (such as Clostridium, Bacteroides, Phocaeicola, and Ruminococcus) in the probiotic group was enhanced, while the relative abundance of opportunistic pathogens (such as Escherichia, Gallibacter, Corynebacterium) was decreased. Additionally, the intestinal metabolic characteristics of domestic cats were also changed. The metabolomic analysis identified 408 differential metabolites between the two groups, and the KEGG function pathway analysis proved that the dominant pathway related to the differential metabolites were the amino acid metabolism, lipid metabolism, carbohydrate metabolism, energy metabolism, endocrine system, digestive system, immune system, and other metabolic pathways. Spearman’s correlation analysis revealed that the beneficial microbes had positive correlations with the differential metabolites. In conclusion, the current study demonstrated that oral administration of complex probiotics could regulate overall health and well-being in domestic cats through modulating the gut microbiome and metabolic characteristics. Full article

Background and Objectives: Tamoxifen, a cornerstone selective estrogen receptor modulator in breast cancer therapy, is increasingly recognized to be associated with retinal toxicity characterized by mitochondrial dysfunction, oxidative stress, lipid peroxidation, and oxidative DNA injury. By targeting mitochondrial bioenergetic dysfunction and redox disequilibrium, adenosine triphosphate (ATP) emerges as a biologically plausible candidate for retinal cytoprotection. This study aimed to evaluate the protective effect of ATP against tamoxifen-induced retinal toxicity in a rat model. Materials and Methods: Twenty-four male albino Wistar rats were randomly assigned to four groups: healthy control (HG), ATP-alone (ATPG, 4 mg/kg, intraperitoneally), tamoxifen-alone (TAMG, 5 mg/kg, orally), and tamoxifen plus ATP-treated (ATAG; ATP, 4 mg/kg, intraperitoneally; tamoxifen, 5 mg/kg, orally). Treatments were administered once daily for 30 days. Oxidative stress markers (malondialdehyde, total glutathione), antioxidant enzyme activities (superoxide dismutase, catalase), and oxidative DNA damage (8-hydroxy-2′-deoxyguanosine) were assessed in ocular tissues. Retinal histopathological evaluation included hematoxylin–eosin staining with semiquantitative assessment of edema, vascular congestion, polymorphonuclear leukocyte infiltration, and cytoplasmic vacuolization, together with quantitative measurements of retinal layer thicknesses and ganglion cell layer (GCL) cell counts. Results: Tamoxifen administration induced marked oxidative stress, antioxidant depletion, and increased oxidative DNA damage in ocular tissues, accompanied by significant thickening of retinal layers, reduced GCL cell counts, and pronounced disruption of retinal architecture. By comparison, ATP co-administration significantly suppressed lipid peroxidation and restored antioxidant defenses, thereby reducing oxidative DNA damage and preserving retinal structural integrity, as reflected by partial normalization of retinal layer thicknesses, preservation of GCL cell counts, and the presence of only mild residual edema. Conclusions: These findings indicate that ATP attenuates tamoxifen-induced retinal toxicity by supporting mitochondrial energy balance and redox homeostasis. Accordingly, ATP administration may represent a promising protective approach for reducing retinal injury associated with long-term tamoxifen therapy. Full article

Background/Objectives: Dravet Syndrome (DS) is a severe form of epilepsy that typically manifests in the first year of life and often requires polytherapy with two or more antiseizure medications (ASMs) to achieve adequate seizure control. Whereas the combination of stiripentol (STP) and cannabidiol (CBD) has demonstrated clinical efficacy, it presents significant formulation challenges due to the low aqueous solubility and poor oral bioavailability of both compounds. Furthermore, the high daily dosages of STP (approximately 50 mg/kg/day or higher) and the oily nature of conventional CBD formulations often hinder patient compliance, as pediatric patients frequently reject these treatments due to unfavorable organoleptic properties. Methods: Nanostructured lipid carriers (NLCs) containing STP and CBD suspended in an aqueous medium were developed. The formulation was optimized using Response Surface Methodology (RSM) and subjected to comprehensive in vitro and in vivo characterization. Results: The optimized formulation exhibited a mean particle size of 175.3 nm, a polydispersity index (PDI) of 0.232, a zeta potential of −8.35 mV, and an encapsulation efficiency greater than 99% for both drugs. Physicochemical characterization via atomic force microscopy, differential scanning calorimetry, thermogravimetric analysis, X-ray diffraction, and Fourier transform infrared spectroscopy revealed spherical nanoparticles without aggregation, with the drugs molecularly dispersed within the lipid matrix. Both STP and CBD showed sustained release profiles and demonstrated oral pharmacokinetic profiles that were comparable or superior to current commercial products. Conclusions: This novel formulation represents a promising therapeutic alternative for DS, enabling the co-administration of STP and CBD while potentially enhancing CBD bioavailability and treatment adherence in pediatric populations. Full article

Background/Objectives: While doxorubicin (DOX) and trastuzumab (TRZ) improve overall survival in women with breast cancer, these two anti-cancer drugs increase the risk of developing heart failure. As a novel and largely unexplored approach, our aim was to evaluate whether the prophylactic use of the sodium-glucose co-transporter 2 inhibitor empagliflozin (EMPA), with and without the angiotensin converting enzyme inhibitor perindopril (PER), is cardioprotective in preventing DOX + TRZ-mediated cardiotoxicity. Methods: In a chronic in vivo murine model, female mice received prophylactic treatment with PER (3 mg/kg), EMPA (10 mg/kg), or EMPA + PER via oral gavage for a total of 3 weeks as a run-in period prior to weekly administration of DOX + TRZ (8 mg/kg and 3 mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Results: In mice treated with DOX + TRZ, the left ventricular ejection fraction (LVEF) decreased from 75 ± 2% at baseline to 40 ± 4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 58 ± 3%, 66 ± 3%, and 67 ± 4% at week 6, respectively (p < 0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX + TRZ-treated mice. Prophylactic administration with PER, EMPA, or EMPA + PER, however, improved myofibril integrity at week 6 in mice receiving DOX + TRZ. Finally, although the Bax/Bcl-xL ratio was significantly elevated by 1.5-fold in mice treated with DOX + TRZ, this marker of apoptosis was attenuated by prophylactic treatment with either PER, EMPA, or EMPA + PER. Conclusions: Prophylactic administration of EMPA mitigated adverse cardiovascular remodeling in a chronic in vivo model of DOX + TRZ-mediated cardiotoxicity. Full article

Background: Erectile dysfunction (ED) and premature ejaculation (PE) are prevalent conditions affecting men’s sexual health, for which tadalafil and dapoxetine have shown promise in their treatment, respectively. Conventional oral dosage forms face limitations, including variable absorption and delayed onset of action. In this study, we developed electrospun nanofibers using polyvinylpyrrolidone for buccal drug delivery as an alternative dosage form to oral tablets. This route offers advantages such as easy administration, suitability for those with difficulty swallowing, particularly the elderly, and a rapid onset of action via the blood capillaries, which might improve bioavailability. Methods: PVP nanofibers loaded with tadalafil and dapoxetine were fabricated using a modified electrospinning procedure with the Spraybase system, where an 8% (w/v) PVP ethanol solution containing 1.5% dapoxetine and 0.5% tadalafil was electrospun under controlled conditions (800 µL/h flow rate, 15 cm distance, 0.55 mm needle, and 8–10 kV) to produce uniform fibers. Results: The morphology of the nanofibers was characterized using SEM, revealing smooth, uniform fibers with an average diameter of 218 ± 50 nm for drug-loaded nanofibers. This nanofibrous system also demonstrated ultra-rapid disintegration occurring within 4 ± 1 s and consistent drug loading and encapsulation efficiency for both drugs. The release profile showed a burst drug release after 15 min, which accounted for >45% for tadalafil and >50% for dapoxetine, followed by a sustained increment in the drug release that reached > 60% for tadalafil and >78% for dapoxetine after 30 min until a complete drug release (100%) for both drugs after 180 min. In vitro cytotoxicity studies on human dermal fibroblasts confirmed the safety of both medications, with cell viability exceeding 50%, at concentrations of 1.56 to 25 µg/mL for tadalafil and 4.69 to 9.38 µg/mL for dapoxetine after 24 and 48 h of incubation. Conclusions: These findings highlight the potential of PVP-based nanofibers as a novel buccal delivery system for the combined treatment of ED and PE. Full article

Background: Antimicrobial resistance (AMR) is a global health threat arising from inappropriate antibiotic use. Data on the prescription of antibiotics in emergency departments (EDs), critical care points for infection management, are limited. Objective: This study aimed to assess systemic antibiotic use in an Indonesian ED. Methods: This retrospective observational study was conducted in the Cilacap Teaching Hospital ED in 2022. Data, including patient demographics and systemic antibiotic prescription details (World Health Organization Anatomical Therapeutic Chemical (WHO ATC): J01) were extracted from electronic medical records. Antibiotic use was analyzed according to age groups (children [0–14 years], adults [15–64 years], and the elderly [≥65 years]), administration route, and the World Health Organization Access, Watch, and Reserve classification. Results: Among all ED visits during the study period, 52.1% (14,396/27,640) received systemic antibiotics, and adults comprised 68.5% (9861/14,396) of antibiotic-exposed cases. Cephalosporins were the most frequently prescribed antibiotics in all age groups (42.4–50.9%). Penicillins were more frequently prescribed in children (29.9%) than in adults (10.0%) and the elderly (6.6%), whereas fluoroquinolones were more commonly prescribed in the elderly (21.1%) than in adults (16.2%) and children (3.8%). Watch-class antibiotics, comprising 63.9% of all prescriptions, were commonly prescribed in the elderly (71.9%). Oral route was the predominant form (65.8%), particularly in children (76.5%). The most frequently prescribed antibiotics differed across age groups, with amoxicillin followed by cefixime in children, and cefixime followed by ceftriaxone in both adults and the elderly. Conclusions: This study showed high antibiotic exposure and identified age-related differences in antibiotic prescribing, and patterns that warrant further evaluation within antimicrobial stewardship frameworks, to optimize antibiotic use and mitigate AMR. Full article