Bioavailability Research Articles

Stable self-assembled oral metformin-bridged nanocochleates against hepatocellular carcinoma

AbstractDespite its established anti-diabetic activity, Metformin hydrochloride (MET) has been repurposed for the management of hepatocellular carcinoma (HCC). Owing to MET high aqueous solubility and poor oral permeability, a novel nanoplatform is sought to overcome the current challenges of traditional formulations. In this study, we developed MET-bridged nanocochleates (MET-CO) using a direct bridging method followed by optimization and assessment using various in-vitro and in-vivo pharmacokinetic methods. The optimized nanocochleates MET-CODCP 19, containing dicetyl phosphate (DCP), displayed uniform snail-shaped nano-rolls measuring 136.41 ± 2.11 nm with a PDI of 0.241 ± 0.005 and a highly negative ζ-potential of -61.93 ± 2.57 mV. With an impressive MET encochleation efficiency (> 75%), MET-CODCP 19 exhibited a controlled biphasic release profile, with minimal initial burst followed by prolonged release for 24 h. Importantly, they showed significant MET permeation in both in-vitro Caco-2 and ex-vivo intestinal models compared to non-DCP containing formula or MET solution. The in-vivo oral bioavailability study demonstrated pronounced improvements in the pharmacokinetic parameters with a 5.5 relative bioavailability compared to MET solution. Notably, a significant reduction in IC50 values in HepG2 cells after 24 h of treatment was observed. Furthermore, the optimized formulation showed a significant downregulation of anti-apoptotic and cancer stemness genes, with 12- and 2-fold lower expression compared to MET solution. These promising results highlight the efficacy of the novel MET-bridged nanocochleates as a stable nanoplatform for enhancing the oral bioavailability of MET and boosting its anticancer potential against HCC. Graphical Abstract

Development and In Vitro Characterization of Azadirachta Indica Gum Grafted Polyacrylamide Based pH-Sensitive Hydrogels to Improve the Bioavailability of Lansoprazole.

The present study intended to develop a pH-responsive hydrogel based on Neem gum (Ng) to improve Lansoprazole (LSP) oral bioavailability. Azadirachta Indica seed extract was used to obtain Ng. pH-responsive hydrogel formulations (F1-F9) were prepared using different Ng ratios, Acrylamide (AAm), and methylene-bis-acrylamide (MBA). The formulated hydrogels were characterized through FTIR, thermal analysis, swelling ratio, SEM, sol-gel ratios, In-Vitro drug release, and cytotoxicity analysis. Azadirachta Indica was extracted to produce a powder containing 21.5 % Ng. Prepared hydrogels showed maximum swelling at pH 7.4, whereas the swelling at an acidic pH was insignificant. LSP-loaded hydrogel demonstrated a regulated release of LSP for up to 24 h and indicated a Super Case II transport release mechanism. During the cytotoxic evaluation, the delivery system showed minimal cytotoxicity towards normal cells, while percent cytotoxicity was carried out for a longer duration (up to 96 h). The present study revealed Azadirachta indica gum-based pH-responsive hydrogel as a promising technique for precisely delivering LSP.

Development and characterization of a self-nano emulsifying drug delivery system (SNEDDS) for Ornidazole to improve solubility and oral bioavailability of BCS class II drugs

Development and characterization of a self-nano emulsifying drug delivery system (SNEDDS) for Ornidazole to improve solubility and oral bioavailability of BCS class II drugs

Silibinin-Loaded Amphiphilic PLGA–Poloxamer Nanoparticles: Physicochemical Characterization, Release Kinetics, and Bioactivity Evaluation in Lung Cancer Cells

Despite its potential against several carcinomas, the pharmacological efficacy of silibinin (SLB) is hampered by poor solubility, absorption, and oral bioavailability. To face these issues, we developed polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) coated with hydrophilic polyethene oxide (PEO) for controlled and targeted SLB delivery. NPs were produced at two different SLB loadings and presented a spherical shape with smooth surfaces and stable size in water and cell culture medium. The encapsulation efficiencies were found to be >84%, and thermal analysis revealed that the SLB was present in an amorphous state within the NPs. In vitro SLB release experiments revealed that at the lowest SLB loading, desorption of the active molecule from the surface or nanoporosities of the NPs mainly dictates release. In contrast, at the highest SLB loading, diffusion primarily regulates release, with negligible contributions from other mechanisms. Cell experiments showed that, compared with the free drug, SLB loaded in the produced NPs significantly increased the bioactivity against H1299, H1975, and H358 cells.

Closing the Design-Make-Test-Analyze Loop: Interplay between Experiments and Predictions Drives PROTACs Bioavailability.

The drug development landscape is expanding to include drug modalities such as PROteolysis-TArgeting Chimeras (PROTACs) and peptides, offering possibilities for previously intractable biological targets. However, with their size and chemical nature, they diverge from established frameworks for the prediction of oral bioavailability. This evolution to larger and more complex molecules necessitates new methodologies and prediction models to continuously expand on bioavailability guidelines. We describe the high-capacity adoption of two chromatographic physicochemical assays and their application for iterative compound optimization to achieve oral bioavailability. We further describe how these data underpin the continuous refinement of internal machine learning models, which guide compound synthesis decisions in the molecular design phase. Based on data for a set of 691 PROTACs, and two project examples, we confirm a sweet spot for oral bioavailability at log D values higher than the norm for small molecules and show how experimental data and prediction models synergize to effectively drive chemistry optimization.

In silico prediction of the pharmacological potential of new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine

The development of new drug-like molecules based on 7-R-8-hydrazine derivatives of 1,3-dimethylxanthine is promising in view of the known pharmacological effect of theophylline and functional hydrazine derivatives. In silico methods make it possible to rationalize the synthesis and reduce the number of chemical compounds at the stage of virtual screening by eliminating potentially ineffective molecules. The aim of the work was to carry out а virtual design and predictive evaluation of pharmacological activity of new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine by in silico methods. Materials and methods. To perform in silico prediction of the pharmacological potential of several new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine, we used the online services. As 12 model compounds, we chose 12 derivatives of 5-(2-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)hydrazine)-5-phenylpentanoic acid with linear and branched alkyl substituents at the 7th position of the basic heterocycle: methyl-, ethyl-, n-propyl-, n-butyl, i-butyl, n-amyl, i-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl. The use of the freely available web tool SwissADME made it possible to calculate physicochemical parameters and to determine the drug-likeness properties of molecules. And other Internet platforms allowed to predict the spectrum of biological activity of the target compounds. Results. In silico analysis of the pharmacological potential of model compounds was performed. Three biological actions (peripheral vasodilator, kidney function stimulant, lipoprotein lipase inhibitor) with high Pa values are predicted for all derivatives of the series. The ADME parameters of the molecules were evaluated and their potential drug-like properties were determined. Conclusions. It was established that the extension of the alkyl substituent at the 7th position of the basic heterocycle should lead to a deterioration of the ADME parameters of the molecules, potentially reduce their oral bioavailability, but should not radically affect their biological activity profile. Compounds 1–3 and 5 are predicted to be orally bioavailable. They should be characterized by a wide spectrum of biological activity with the highest probability of vasodilator effect on peripheral vessels. In the future, it is advisable to carry out targeted synthesis of hit compounds and thorough in vitro, in vivo studies, and for compounds with violated physicochemical criteria – structural optimization of molecules in order to find a lead compound.

Evaluation of oral bioavailability and other pharmacy effects on sleep quality by using zaleplon nano emulsifying drug delivery systems carrying

Evaluation of oral bioavailability and other pharmacy effects on sleep quality by using zaleplon nano emulsifying drug delivery systems carrying

Enhanced Anti-inflammatory Effects of Diclofenac Delivered Orally via Polyvinylpyrrolidone K30/Silk Fibroin Nanoparticles in a Murine Model of Carrageenan-Induced Paw Edema.

Diclofenac has a relatively low oral bioavailability (50-60%) and is quickly metabolized with a half-life of less than 1 h. Therefore, the oral therapeutic effect of diclofenac is not optimal. This research developed polyvinylpyrrolidone K30-functionalized silk fibroin nanoparticles as an effective delivery system for diclofenac (FNPs-PVP-DC). The FNPs-DC and FNPs-PVP-DC were formulated by two methods of adsorption and solvent exchange. Depending on the formulation factors, the obtained particles exhibited different properties of nano-scale sizes (400-800 nm), narrow size distribution, negatively charged surfaces (-17 to -19 mV), high PVP K30 incorporation (23%-50%), pHpzc of ~6.6, and appropriate chemical interactions. Interestingly, particles formulated by the adsorption method showed low drug encapsulation efficiencies of < 15%, whereas the solvent exchange method yielded moderate results of ~40%. The FNPs-DC possessed aggregated patterns, while the FNPs-PVP-DC were more uniformly distributed. All formulations limited diclofenac release (< 20%) under gastric conditions and sustained its release in the intestinal environment. In in-vivo carrageenan-induced paw edema mice model, the FNPs-PVP-DC demonstrated a 20-30% higher anti-inflammatory effect and a faster onset of action (within 1 h) compared to pure diclofenac at the same dose (5 mg/kg). These findings suggest that FNPs-PVP-DC have promising potential as novel oral anti-inflammatory products.

‘Tabs versus Jabs’ time and motion study involving experiential learning student pharmacists: how long to prepare intravenous versus oral antibiotics?

Abstract Introduction Approximately one-third of inpatients in Scotland are prescribed antibiotics1. Patients prescribed IV antibiotics should be reviewed regularly and switched to oral therapy when clinically appropriate. Optimising IV to oral switch (IVOST) is often perceived as challenging2 and risks associated with IV access and patient comfort benefits to IVOST are well known. Workforce time required to administer IV medicines compared to oral equivalents is rarely considered in the risk-benefit assessment to IVOST2. To quantify this difference, a medicines administration time and motion study was undertaken. Aim To conduct a time and motion study to explore antibiotic administration in NHS Lanarkshire (NHSL) district general hospitals: University Hospitals Hairmyres, Wishaw, and Monklands. Objectives To measure time taken by nursing staff to prepare and administer IV/oral antibiotics. To explore potential nursing time saved if IVOST. To make recommendations to NHSL’s Antimicrobial Management Committee on inpatient antibiotic use. To involve final year Student Pharmacists in a multidisciplinary (MDT) project during placement. Methods Data were collected by Student Pharmacists on Antimicrobial/Surgical Experiential Learning (EL) placements as a novel approach to specialist EL. Data were collected during midday medication rounds in a surgical ward at each hospital. Nurses were observed administering antibiotics and the time taken recorded included medicine preparation; patient identification; assessment of peripheral venous catheter; and gathering IV equipment. The timer stopped when medication was administered to the patient. IV infusion duration was not included. Data were recorded in an Excel spreadsheet in HH:MM:SS. This study did not require review by an NHS Research Ethics Committee under the updated Governance Arrangements for Research Ethics Committees (GAfREC) 2020 Edition; although local permission was sought from service leads. Results Mean nursing time to prepare IV antibiotic administration was 11 minutes 55 seconds (n=20). Mean nursing time for oral administration was 1 minute 59 seconds (n=10). Nursing staff take 6 times longer to prepare IV compared to oral antibiotics for patient administration. Potential nursing time saved per individual IVOST is approximately 10 minutes. Discussion/Conclusion Results suggest IVOST would reduce nursing time involved in medicines administration, with IVOST for one patient taking antibiotics three times daily potentially saving 30 minutes of nursing time alone. Some antibiotics have excellent oral bioavailability and this project highlights the need to educate clinical teams on selecting oral route for high bioavailability antibiotics when safe and clinically appropriate. Student pharmacists observed that nurses managed multiple interruptions and spent time looking for IV equipment, commenting that IV antibiotics produced more waste (single use plastics, syringes, packaging). Student pharmacists had a better understanding of medicines administration and nursing roles following involvement in the study. Limitations Small sample size, time constraints, data did not include infusion durations or administrations outside drug rounds. Benefits of IVOST are well known and the results of this study are comparable to similar studies in the UK. NHSL’s Antimicrobial Team are disseminating key information from this study in line with local and national guidelines. Student Pharmacists effectively contributed to a novel EL placement project and this improved their understanding of nursing roles within the MDT.

OPTIMIZED SOLID LIPID NANOPARTICLES FOR ENHANCED ORAL BIOAVAILABILITY AND OSTEOGENIC EFFECT OF IPRIFLAVONE: FORMULATION, CHARACTERIZATION, AND IN VITRO EVALUATION

Objective: This study aimed to enhance the oral bioavailability of Ipriflavone (IP) and evaluate its osteogenic effect on human osteosarcoma cells (MG-63) by developing Ipriflavone-loaded Solid Lipid Nanoparticles (IP-SLN). Methods: IP-SLNs were prepared using a modified solvent evaporation method with probe sonication. Formulation optimization employed Central Composite Design (CCD) with independent variables, including lipid amount, surfactant concentration, and sonication time. Characterization was performed using Transmission Electron Microscopy (TEM). In vitro drug release and ex vivo permeation studies were conducted to assess drug release kinetics and bioavailability. Cytotoxicity, Alkaline Phosphatase (ALP) activity, and calcium deposition studies on MG-63 cells evaluated osteogenic effects. Results: TEM images showed round particles with an average diameter of 43.24±3 nm, a zeta potential of-9.53 mV, and a drug entrapment efficiency of 76.53±1.84%. In vitro drug release from IP-SLN was 79.02% compared to 14.21% from IP after 48 h, following the Korsmeyer-Peppas model and first-order kinetics. Ex vivo permeation of IP-SLN was approximately 2-fold higher than IP dispersion. Cytotoxicity studies revealed no toxicity on MG-63 cells. ALP activity and calcium deposition studies indicated that IP-SLN stimulated osteoblast differentiation, increasing alkaline phosphatase activity and mineralization. Pharmacokinetic studies demonstrated that IP-SLN increased the relative bioavailability by 515% compared to ipriflavone. Conclusion: IP-SLN formulations significantly improved the oral bioavailability and osteogenic effects of ipriflavone on MG-63 cells, suggesting potential for novel therapeutic applications in osteoporosis treatment.

OPTIMIZATION OF PROCESS PARAMETERS FOR ENHANCING THE SKIN PERMEATION EFFICIENCY OF NISOLDIPINE LOADED ULTRA DEFORMABLE VESICLES IN TRANSDERMAL PATCHES

Objective: The study aimed to address the limitations of oral delivery and enhance the bioavailability of nisoldipine (NSD) through the development of transferosomal transdermal patches containing ultra-deformable transferosomes. Methods: NSD, known for its low oral bioavailability and adverse effects, was encapsulated in transferosomes using a thin film hydration method. 17 formulations were made using Box Behnken Design, varying Dipalmitoylphosphatidylcholine (DPPC), span-80, and stirring speed, and were evaluated for vesicle size, Polydispersity Index (PDI), and Entrapment Efficiency (EE%). The optimal formulation, selected based on these parameters, was combined into Transdermal Patches (TPs). The patches underwent extensive testing for physicochemical properties, in vitro and ex-vivo permeation, and skin irritancy. Results: The results showed transferosomes with Vesicle Sizes (VS) ranging from 124±2.25 to 400±1.55 nm and EE% from 52.88±0.23 to 90.01±1.58%, with Zeta Potentials (ZP) between-48 to-20 mV. The patch thickness (0.66±0.02 mm) and weight per square inch (382.1±1.69 mg) showed consistent manufacturing, while the Water Vapor Transmission Rate (WVT) (1.54±0.01g/m²/24h), low moisture content (1.07±0.01%), and regulated moisture absorption (3.78±0.01%) maintained formulation stability. In vitro and ex-vivo permeation indicated superior drug permeation for transferosomal patches (NP) compared to plain nisoldipine patches (NP-N), with permeation directly proportional to PEG-400 concentration. Additionally, the transferosomal patches were found to be free from skin irritation. Conclusion: The optimized Niosoldipine transferosomal patch (NP-3) composition displays good folding endurance (FE) 97.67±0.47, required for transdermal systems, and successfully allows drug permeation (DP) at 86.39±2.64% in a short timescale. Hence, the study concludes that transferosomal patches of NSD offer a promising approach for effective transdermal delivery, potentially improving hypertension management by providing a controlled and prolonged drug release.

Prodigiosin Demonstrates Promising Antiviral Activity Against Dengue Virus and Zika Virus in In‐silico Study

ABSTRACTDengue (DENV) and Zika virus (ZIKV), transmitted by Aedes mosquitoes, pose significant public health challenges. Effective treatments for these viruses remain elusive, highlighting the urgent need for new efficient antiviral therapies. This study explores prodigiosin, a microbial tripyrrole pigment, as an antiviral agent against both DENV and ZIKV employing advanced analytical approaches which integrate molecular docking, CASTp 3.0 validation and molecular dynamics (MD) simulations providing insights into molecular interactions at an atomic level. Prodigiosin exhibited favourable drug‐likeness properties, meeting Lipinski's rule of five and demonstrating optimal physicochemical and pharmacokinetic characteristics according to Ghose's, Veber's, Egan's and Muegge's filters, essential for oral bioavailability. Absorption, Distribution, Metabolism, Excretion, and Toxicity profiling indicated high intestinal absorption, minimal risk for drug‐drug interactions and a low toxicity profile, with no AMES toxicity, hepatotoxicity, or skin sensitization. Molecular docking revealed prodigiosin's strong binding affinities to NS5 methyltransferases of both DENV (−7.6 kcal/mol) and ZIKV (−7.7 kcal/mol) viruses, suggesting potential disruption of viral replication. Notably, prodigiosin's binding affinities were comparable to ribavirin‐5'‐triphosphate and chloroquine, known inhibitors of DENV and ZIKV, respectively. MD simulations confirmed stable and specific interactions with prodigiosin with low root‐mean‐square deviation values. Additional analyses, including root‐mean‐square fluctuation, radius of gyration and solvent‐accessible surface area, indicated compact and stable complexes. These multi‐parametric in‐silico analytical strategies provide a novel perspective of prodigiosin as an antiviral agent, demonstrating its drug interactions at the molecular level. These promising results suggest that prodigiosin could serve as a broad‐spectrum antiviral agent against both DENV and ZIKV, warranting further experimental validation for therapeutic development against flaviviral infections.

A novel, sensitive, and fast ultra-high-performance liquid chromatography tandem mass spectrometry method for TNG908 determination in dog plasma and pharmacokinetic study.

TNG908 is a potent and selective protein arginase methyltransferase 5 (PRMT5) inhibitor that is currently going through phase I/II clinical development for the treatment of non-small cell lung cancer. To facilitate pharmacokinetic and toxicokinetic studies of TNG908, here, we reported an ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the detection of TNG908 in dogs. The dog plasma samples were precipitated by acetonitrile and analyzed using a Waters ACQUITY BEH C18 column combined with a Thermo triple quadrupole mass spectrometer. The mobile phase consisted of 0.1% formic acid solution and acetonitrile, at a flow rate of 0.3mL/min. TNG908 and internal standard were monitored by selective reaction monitoring (SRM) with m/z 410.2 > 150.1 and m/z 394.2 > 278.1, respectively. The method demonstrated excellent linearity over the concentration range of 1-1000 ng/mL, with a correlation coefficient greater than 0.995. Acetonitrile-mediated protein precipitation showed high extraction efficiency and a recovery above 80%. The validated assay was further applied to measure TNG908 in dog plasma after oral and intravenous administration and achieved success. The obtained pharmacokinetic parameters indicated low clearance of TNG908 (3.7 ± 0.8mL/min/kg) and moderate oral bioavailability (>36.4%).

Smart Mesoporous Silica Nanoparticles Loading Curcumin Inhibit Liver Cancer.

Curcumin (CUR) as one of the natural edible pigments is approved by the World Health Organization due to its nontoxic and anticancer effect. However, the utility of CUR is restricted due to its low oral bioavailability. Nanoparticle drug delivery systems like mesoporous silica nanoparticles (MSNs) have been extensively used due to their high specific surface area, high loading rate, and ease of modification. This study developed lactobionic acid (LA)-modified carboxymethyl chitosan (CMCS)-coated MSNs to deliver CUR specifically targeting hepatocellular carcinoma. Among these nanoparticles, LA targets liver cancer cells. CMCS utilizes pH-responsive release of CUR. The LA-CMCS-MSN@CUR (MSN@CUR) were evaluated using several methods, including Fourier transform infrared spectroscopy, transmission electron microscopy, and zeta potential measurements. Liver cellular uptake of MSN@CUR depends on a specific LA receptor-mediated endocytosis mechanism. Additionally, MSN@CUR performed with a better antitumor effect than Cur in H22 orthotopic transplantation of liver cancer and H22 solid tumor mouse models. Treatment with MSN@CUR significantly reduced the protein of VEGF, p-PI3K, and AKT, increased the protein of caspases 3 and 8, ultimately inhibited tumor migration, and promoted apoptosis. This study provides a new path for delivery of natural active ingredients with excellent bioavailability in the antitumor field.

Causal associations of tea consumption on risk of pancreatic adenocarcinoma and the mediating role of vascular endothelial growth factor D levels.

Tea is one of the most widely consumed beverages in the world. However, the association between tea and risk of pancreatic adenocarcinoma remains controversial. This study aimed to investigate the causal relationship between tea consumption and risk of pancreatic adenocarcinoma and to explore their mediating effects. The two-sample Mendelian randomisation (MR) analysis showed an inverse causal relationship between tea intake and pancreatic adenocarcinoma (OR: 0·111 (0·02, 0·85), P < 0·04). To examine the mediating effects, we explored the potential mechanisms by which tea intake reduces the risk of pancreatic adenocarcinoma. Based on the oral bioavailability and drug-like properties in Traditional Chinese Medicine Systems Pharmacology database, we selected the main active ingredients of tea. We screened out the fifteen representative targeted genes by Pharmmapper database, and the gene ontology enrichment analysis showed that these targeted genes were related to vascular endothelial growth factor (VEGF) pathway. The two-step MR analysis of results showed that only VEGF-D played a mediating role, with a mediation ratio of 0·230 (0·066, 0·394). In conclusion, the findings suggest that VEGF-D mediates the effect of tea intake on the risk of pancreatic adenocarcinoma.

Development of Small Molecular Hyper-activators of Human Caseinolytic Peptidase P (hClpP) with a [1,8]-Naphthyridinone Scaffold as Novel Anti-cancer Agents.

Based on a clinical staged small molecular hClpP activator ONC201, a class of novel hClpP agonists with a [1,8]naphthyridinone scaffold were designed, synthesized and evaluated in a series of biochemical and biological assays. Mechanism studies for the representative compound F20 indicated that it can potently bind to and activate hClpP, efficiently promote the degradation of hClpP substrates, robustly induce ATF4/CHOP regulated integrated stress responses, strongly inhibit cell growth and effectively induce apoptosis in a subset of cancer cell lines. F20 showed good PK profiles when dosed by intravenous injection and exhibited moderate oral bioavailability in mice.

Forced stability studies and estimation of encapsulated ellagic acid in nano-formulations using UV-spectroscopy

Abstract There is a growing interest in dietary materials to explore their therapeutic activities. Ellagic acid is considered as a dietary supplement and is naturally present in fruits and other foods. It has anticancer, antimalarial, antiviral, antioxidant, and anti-inflammatory activities. These activities can be enhanced with nanoformulations, which can increase its oral bioavailability. However, there is a need for an economical, simple, sensitive, and robust analytical method for the estimation of entrapped ellagic acid in the nanoformulations. Therefore, the present study presents the development and validation of a UV–visible spectroscopy method for the estimation of EA in nanoformulations. The phosphate buffer (pH 7.2) and the detection wavelength of 253.5 nm were used for the method development, and its validation was performed according to the ICH Q2A (R1) guidelines. The coefficient of determination value of the developed method was found to be 0.9988 in the concentration range of 1 μg mL−1 to 6 μg mL−1. The method was found to be linear, precise, sensitive, and robust. This method can be used for the estimation of EA in nanoformulations, bulk dosage forms, and other pharmaceutical formulations.

Zolmitriptan niosomal transdermal patches: combating migraine via epigenetic and endocannabinoid pathways and reversal of migraine hypercoagulability.

Conventional zolmitriptan (ZOL) has limited oral bioavailability, many adverse effects, and poor membrane penetrability that negatively influences its accessibility to its 5-HT1B/1D receptor binding pocket, located transmemberanous. This work aimed at preparing transdermal ZOL-nanoformulation (niosomes) to surpass these limitations and to explore novel antimigraine mechanisms for ZOL via modulation of the epigenetically-altered chronification genes (RAMP-1, NPTX-2) or microRNAs and affecting the endocannabinoid CB-1/MAPK pathway. The prepared ZOL niosomes (Fsp60/6-1:1) exhibited %EE of 57.28%, PS of 472.3nm, PDI of 0.366, and ZP of -26 mV were cast into patch with content uniformity of 93.12%, maintained endurance after 200-times folding, no interaction between its components (FT-IR), a biphasic release pattern and good stability after storage at 4°C for 6 months. In-vivo ZOL-patch application in rats with nitroglycerin-induced migraine showed significant management of migraine pain symptoms and photophobia assessed behaviorally, decreased brain levels of the trigeminal neuronal activation marker (c-fos), the migraine pain neurotransmitter (CGRP) and the serum levels of different migraine pain markers (substance P, nitric-oxide, and TNF-α). It also significantly decreased RAMP-1, NPTX-2, miR-382-5p, and CB-1/MAPK gene expression reflecting improved efficacy and brain receptors delivery to a much greater extent than conventional ZOL has done. Additionally, this nanoformulation significantly opposed migraine-induced platelet activation and hypercoagulable status in both central and peripheral circulations as evidenced by the significant decrease in adenosine diphosphate, thrombin, factor X, CD41, and Von-Willebrand factor levels assessed peripherally and centrally. TPFsp60/6-1:1 significantly improved ZOL efficacy and accessibility to brain-receptors to a much greater extent than conventional ZOL-solution.KeywordsEndocannabinoid receptors; Epigenetically-altered genes; Hemostatic pathways; Niosomal patch; Transdermal; Zolmitriptan.

Vesicular Carriers for Improved Oral Anticoagulation Competence of Rivaroxaban: In Vitro and In Vivo Investigation

Rivaroxaban is an anticoagulant for avoidance and therapy of thromboembolic disorders. Unfortunately, oral bioavailability of rivaroxaban is compromised with dose increments. Accordingly, the aim was to test nano-vesicular lipid systems for improved oral anticoagulation activity of rivaroxaban. Rivaroxaban loaded niosomes, bilosomes and spanlastic formulations were prepared. The prepared systems were assessed in terms of particle size, zeta potential, transition electron microscopic features (TEM), entrapment efficiency, in-vitro drug release, and in-vivo anticoagulation performance in rats. The prepared vesicular systems exposed spherical negatively charged vesicles with mean particle size values between 136.6 nm to 387.9 nm depending on the composition. Rivaroxaban was efficiently entrapped in the vesicular systems with entrapment efficiency values ranging from 92.4% to 94.0%. Rivaroxaban underwent sustained release from the fabricated vesicular systems. The in vivo performance of the tested preparation revealed significant enhancement of the anticoagulation parameters. This was manifested from the prolonged clotting time, and prothrombin time. Moreover, the cut tails of the examined rats receiving the formulated nano-systems exposed a lengthy tail bleeding time compared to those receiving the un-processed rivaroxaban aqueous dispersion. In Conclusion, niosomes, bilosomes and spanlastic nano-dispersions have a potential to overwhelm the oral anticoagulation efficiency of rivaroxaban with spanlastic ranked as best.Graphical

Identification of Oral Bioavailable Coumarin Derivatives as Potential AR Antagonists Targeting Prostate Cancer.

Androgen receptor (AR) is a crucial driver of prostate cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative 1, which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound 4a (IC50 = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC50 = 0.060 μM) and demonstrated excellent selectivity over other nuclear receptors in vitro. Especially, 4a showed superior efficacy against ARF876L/T877A and ARW741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles (F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.