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Persistent racial disparities in health outcomes have catalyzed legislative reforms and heightened scientific focus recently. However, despite the well-documented properties of skin pigments in binding drug compounds, their impact on therapeutic efficacy and adverse drug responses remains insufficiently explored. This perspective examines the intricate relationships between variation in melanin-based skin pigmentation and pharmacokinetics and -dynamics, highlighting the need for considering diversity in skin pigmentation as a variable to advance the equitability of pharmacological interventions. The article provides guidelines on the selection of New Approach Methods (NAMs) to foster inclusive study designs in preclinical drug development pipelines, leading to an improved level of translatability to the clinic.

Decade-long efforts in medicinal biotechnology have enabled large-scale in-vitro production of optimised therapeutic RNA constructs for stable in-vivo delivery and modify the expression of disease-related genes. The success of lipid nanoparticle-formulated mRNA vaccines against Severe acute respiratory syndrome Coronavirus-2 (SARS-Cov2) has opened a new era of RNA therapeutics and non-viral drug delivery systems. The major limiting factor in the clinical translation of RNA-based drugs is the availability of suitable delivery vehicles that can protect RNA payloads from degradation, offer controlled release, and pose minimal inherent toxicity. Unwanted immune response, payload size constraints, genome integration, and non-specific tissue targeting limit the application of conventional viral drug-delivery vehicles. This review summarises current research on nano-sized drug carriers, including lipid nanoparticles, polymer-based formulations, cationic nanoemulsion, and cell-penetrating peptides, for targeted therapeutic RNA delivery. Further, this paper highlights the biomimetic approaches (i.e. mimicking naturally occurring bio-compositions, molecular designs, and systems), including virus-like particles (VLPs), exosomes, and selective endogenous eNcapsidation (SEND) technology being explored as safer and more efficient alternatives. [ABSTRACT FROM AUTHOR]

Background: Optimal management of anaemia following surgery for colorectal cancer remains unclear. Peri-operative anaemia is common in patients undergoing resectional surgery for colorectal cancer. A significant amount of research has been conducted into the management of pre-operative anaemia; however, little work has investigated post-operative anaemia. We intended to investigate the facilitators of and barriers against the standardised correction of post-operative anaemia. These can aid in identifying optimum treatment for patients following surgery for colorectal cancer. Methods: Four focus groups were held with 29 participants from a multidisciplinary panel of healthcare professionals from two different NHS hospital sites in the UK. The discussions were audio recorded and underwent professional transcription. Transcripts were checked against recordings before undergoing thematic analysis using a realist approach. Results: Four themes were identified. The key barriers to standardised post-operative anaemia correction were a lack of protocoled guidelines or a defined pathway, insufficient education and training, and systemic barriers, such as financial drivers and drug availability. The key facilitator identified was collaboration and communication. Discussion: This study has identified several key barriers and thresholds which can be used in future studies to improve the standardised management of post-operative anaemia. [ABSTRACT FROM AUTHOR]

Background: Cannabidiol (CBD) shows interesting therapeutic properties but has yet to demonstrate its full potential in clinical trials partly due to its low solubility in physiologic media. Two different formulations of CBD (amorphous and lipid-based) have been optimized and enable an increase in bioavailability in piglets. In vivo studies are time-consuming, costly and life-threatening. Therefore, we need to develop in vitro tests that can predict what will happen in vivo. Methods: Comparisons in terms of dissolution were made especially by using different media (FaSSGF, FaSSIF, FeSSIF, HCl 0.1N with or without SLS, phosphate buffer pH 6.8 with or without SLS) and different conditions (sink or non-sink conditions). These in vitro results were confronted with in vivo results to select the most appropriate dissolution test conditions. Results: The importance of the presence of surfactants to enable solubilization of CBD was demonstrated. Neutral media enabled a relatively good prediction of the extent of absorption observed in vivo, whereas the rate of absorption was more complicated to predict. Conclusions: FeSSIF media, and FaSSIF sink media to a lesser extent, were the only compositions enabling predictions of both extent and rate, indicating that emulsification is possibly a major contributor to the in vivo availability of the drug. [ABSTRACT FROM AUTHOR]

Advances in adaptive immunity have greatly contributed to the development of cancer immunotherapy. However, its over‐low efficacy and insufficient invasion of immune cells in the tumor tissue, and safety problems caused by cytokine storm, have seriously impeded further clinical application for solid tumor immunotherapy. Notably, the immune microenvironment of the lungs is naturally enriched with alveolar macrophages (AMs). Herein, we introduce a novel nebulized magnetothermal immunotherapy strategy to treat orthotopic lung cancer by using magnetothermal nanomaterial (Zn−CoFe2O4@Zn−MnFe2O4−PEG, named ZCMP), which can release iron ions via an acid/thermal‐catalytic reaction to maximize the use of lung's immune environment through the cascade activations of AMs and natural killer (NK) cells. Nebulized administration greatly enhance drug bioavailability by localized drug accumulation at the lesion site. Upon mild magnetic hyperthermia, the released iron ions catalyze endogenous H2O2 decomposition to produce reactive oxygen species (ROS), which triggers the M1 polarization of AMs, and the resultant inflammatory cytokine IFN‐β, IL‐1β and IL‐15 releases to activate c‐Jun, STAT5 and GZMB related signaling pathways, promoting NK cells proliferation and activation. This innovative strategy optimally utilizes the lung's immune environment and shows excellent immunotherapeutic outcomes against orthotopic lung cancer. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative disorder with limited symptomatic treatment options. Targeting phosphodiesterase 4 (PDE4) has shown a promising result in several preclinical studies. In our study, we aim to repurpose US FDA-approved PDE4 inhibitor for PD. Through in-silico study, we identified roflumilast (ROF) as the potential candidate targeting PDE4B2. In Drosophila PD expressing the A30P mutant α-synuclein model, ROF exhibited anti-PD effects as indicated by negative geotaxis and antioxidant activities. Given the low brain distribution of ROF (<50%) at clinical doses, incorporation into nanostructured lipid carriers (NLCs) was carried out to enhanced blood-brain barrier permeability. In vitro release studies indicated sustained ROF release from NLCs (≈75%) over 24 h. Single-dose oral toxicity studies reported no mortality or toxicity signs. ROF-loaded NLCs significantly alleviated behavioural deficits, increased antioxidant parameters (p < 0.05), and reduced TNF-α and IL-6 levels (p < 0.5) in the striatum compared to pure ROF. ROF-loaded NLCs demonstrated potential anti-PD effects with high efficacy than pure ROF. Our study suggests that nanostructured lipid carriers (NLCs) can be a promising drug delivery system to overcome limitations associated with poor brain bioavailability of lipophilic drugs like ROF for PD treatment. Further investigation related to brain occupancy and underlying mechanisms of our formulation is warranted to confirm and strengthen our current findings. [ABSTRACT FROM AUTHOR]

The development of nanodelivery systems for delivery of hydrophobic and hydrophilic drugs particularly lipid nanoparticles (LNP), has seen significant advancements in recent years. Fine-tuning LNP formulations is crucial due to the impact of various parameters on their efficacy quality. The study investigated the influence of formulation variables on amoxicillin-loaded LNPs designed for anti-Helicobacter pylori activity. Size, polydispersity index (PDI), Zeta potential and entrapment efficiency (EE) were evaluated across diverse formulations. The impact of particle size on drug release and encapsulation was explored. Artificial intelligence (AI)-based design of experiments generated formulations to minimize the particle size, PDI and Zeta potential while maximizing the EE, accounting for factor interactions. Additionally, the user friendliness of QbD (Quality by Design), Machine Learning (ML), and design of experiment (DoE) were compared. To optimize amoxicillin (amox)-loaded LNP, a Box-Behnken design with 27 formulations were chosen. Each formulation was measured for particle size distribution, zeta potential, PDI, and entrapment efficiency. LNP ranged in size from 200 to 600 nm, zeta potential from − 5 to -40 mV, PDI from 0.1 to 1, and EE from 5 to 100%. Characterization included DLS, FESEM, FTIR, and SEM. The obtained results were statistically analyzed. This study demonstrates the potential of AI-driven DoE for optimizing LNP formulations. We explained the effect of different parameters, lipid concentration, surfactant concentration, sonication time and sonication speed on nanoparticles and derived a formula for further prediction. The identified formulations exhibited desired antibiotic efficiency with minimum chemical usage, suggesting the effectiveness of this approach. Further research explored it as a drug with more bioavailability, stability, and cheap alternatives to traditional medicines, with more side effects and less bioavailability. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersions (ASDs) have been extensively utilized to improve the bioavailability of drugs that have low aqueous solubility. The influence of different excipients on the conversion of amorphous drugs into their crystalline forms in ASDs has been extensively researched. However, there is limited knowledge examining the impact of film coating materials on the physical stability of oral tablet formulations containing ASDs. In this study, we demonstrate that plasticizers present in film coats can have a detrimental impact on the physical stability of ASDs. We systematically compared two frequently used plasticizers in film coats: triacetin and polyethylene glycol 3350 (PEG 3350). To gain mechanistic insights into the detrimental effects of plasticizers on the physical stability of ASDs, plasticizer leaching studies and physical stability studies of solvent-evaporated and spray-dried intermediates (SDI) using two BCS class II drugs were conducted. Triacetin was found to leach into the tablet core within one week when stressed at 40 °C/75 % RH, whereas no leaching was observed for PEG 3350, as discerned from spectroscopic studies. We also found that triacetin-containing ASDs exhibited greater amorphous to crystalline form conversion of the drug compared to PEG 3350-containing ASDs after stability testing. Moreover, the incorporation of triacetin into polymers was found to cause a significant depression of glass transition temperature and upon equilibration with moisture, a drop below room temperature. Overall, these observations underscore the importance of carefully selecting plasticizers to be present in film coatings when developing ASD pharmaceutical products. [Display omitted] [ABSTRACT FROM AUTHOR]

Triamcinolone acetonide (TA) is a corticosteroid, and widely used in the treatment of eye diseases such as macular edema, proliferative vitreoretinopathy, and chronic uveitis. It's also used in diseases such as osteoarthritis and rheumatoid arthritis. Despite the width of its usage, it has toxicity in the eye. Nanogels are advantageous in applying toxic and low bioavailability drugs thanks to their swelling ability and stability. In the presented study, to minimize the disadvantages of TA, and to reach the drug into the back segment of the eye, TA-loaded chitosan (CS) nanogel (CS-TA Nanogel) has been prepared, and in vitro characterized. CS-TA nanogels were prepared by ionic gelation and characterized by SEM, FTIR, and TGA. Drug release profile, and in vitro cytotoxicity was determined to evaluate the efficacy of nanogels for intravitreal eye applications. DNA damage, and oxidative stress caused by nanogels in eye endothelial cells were investigated. CS and CS-TA nanogels were synthesized in the sizes range 200-300 nm with an overall positive charge surface. The loading efficiency of TA on nanogels was determined as 50%. Cells exposed to 250 µg/ml free TA showed 74% viability, while this rate was 90% in cells exposed to CS-TA nanogels. 8-OHdG levels were determined as 54.93 ± 1.118 ng/mL in control cells and 92.47 ± 0.852 ng/mL in cells exposed to 250 µg/ml TA. TA both induces oxidative stress and causes DNA damage in HRMEC cells. However, administration of TA with carrier increased cell viability, total antioxidant capacity, and reduced oxidative DNA damage. [ABSTRACT FROM AUTHOR]

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) "phenoconversion" factors, like drug–drug interactions and comorbidities. To address these limitations, a more phenotypic approach would be desirable, for which pharmacometabolomics (PMx) could be useful by studying and elucidating drug metabolism in patient samples, such as blood and urine. Methods: This study explored the potential of PMx to analyze real-world drug metabolite profiles of the extensively studied drug cyclosporine (CsA) using 24-h urine samples from 732 kidney and 350 liver transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT identifier NCT03272841). Detected metabolites were matched with existing information on CsA metabolism gathered through a comprehensive literature review, aiming to confirm previously reported metabolites and identify potentially unreported ones. Results: Our analyses confirmed the urinary presence of CsA and six known metabolites. Additionally, we detected three known metabolites not previously reported in urine and identified one unreported metabolite, potentially suggesting the involvement of glutathione conjugation. Lastly, the observed metabolic patterns showed no notable differences between kidney and liver transplant recipients. Conclusions: Our findings demonstrate the potential of PMx to enhance the understanding of drug metabolism, even for well-studied compounds such as CsA. Moreover, this study highlights the value of PMx in real-world drug metabolism research and its potential to complement PGx in advancing personalized medicine. [ABSTRACT FROM AUTHOR]

The current study's objective was to formulate and evaluate a liposomal cream containing tolnaftate in order to improve the drug's bioavailability. Tolnaftate is a drug having low permeability which results in decreased drug absorption and so is the bioavailability. To overcome these problems tolnaftate is incorporated in liposomes. Liposome vesicular drug delivery system was preferred due to its greater solubility, permeability and bioavailability. It carries a substantial amount of drug which increased the drug's penetration. The liposomes were prepared using a variety of phospholipids, specifically soy lecithin and egg phosphatidylcholine in varying ratios. Liposomes were prepared by ethanol injection method and evaluated for morphology, percentage practical yield, percentage entrapment efficiency, drug content and invitro drug release study. The formulation with the best result according to the evaluation parameters was F2 with greater percentage drug entrapment, drug content and in-vitro drug release was considered to be optimized formulation and this F2 formulation was further evaluated by SEM, DSC and XRD. Liposomal cream was formulated using the optimized formulation. Spreadability, Viscocity, pH measurement and in-vitro drug release were evaluated for liposomal cream. Formulation F2 and optimized liposomal cream formulation showed in-vitro drug release of 92.44% and 77.48% respectively at the end of 8th hour. [ABSTRACT FROM AUTHOR]

Purpose: Supersaturated formulations have been widely explored for improving the oral bioavailability of drugs by using mesoporous silica (MS) to generate supersaturation via molecular adsorption; however, this is followed by precipitation. Several precipitation inhibitors (PI) have been explored to prevent precipitation and maintain the drug in solution for a longer period. However, the combined approach of MS and PIs, the impact of MS and Silica, and the loading of high-molecular-weight neutral molecules such as Cyclosporine A (CsA) have not yet been explored. The present study aimed to explore the impact of MS and a hydroxypropyl methylcellulose (HPMC) matrix on the supersaturation and bioavailability of the neutral drug CsA. Methods: A CsA-loaded mesoporous silica/HPMC ternary matrix and CsA-HPMC and CsA-MS controls were prepared, and physicochemical characterization was carried out. The ternary matrix and controls were investigated for the Non-sink Mini FaSSIF dissolution and biorelevant transfer studies. Furthermore, drug release modeling was performed using DDSolver, and pharmacokinetic studies were performed to assess the impact on oral bioavailability compared with the marketed formulation. Results: The study suggested that the co-loaded CsA, HPMC, and MS demonstrated higher supersaturation than CsA-loaded silica and CsA-HPMC controls. A significant improvement in FaSSIF single medium (2-fold) and biorelevant transfer (3.37-fold) increase in the dissolution profile was observed for the co-loaded CsA-MS-HPMC samples. The in vitro dissolution profile was corroborated by pharmacokinetic studies, which showed a 1.19-fold higher oral bioavailability of CsA-MS-HPMC compared to that of CsA-MS and CsA-HPMC. Conclusion: The pharmacokinetics indicated that CsA-MS-HPMC co-loaded samples demonstrated supersaturation and improved bioavailability compared with the physical mixture. [ABSTRACT FROM AUTHOR]

AbstractImplementing therapeutic deep eutectic systems (THDESs) in various drug delivery systems (DDSs) has expanded enormously. THDESs offer eco-friendly alternatives to conventional organic solvents, featuring adaptable and simple preparation methods with high-yield products. Previously, the solubility of risperidone (RISP) was immensely enhanced by forming a hydrophobic THDES of RISP with capric acid (CA). To build upon the previous findings and utilize the hydrophobic properties of THDES, a self-emulsifying drug delivery system (SEDDS) was developed. A stable SEDDS formulation was successfully developed using the THDES as the nonpolar phase, a nonionic surfactant, Tween 20, and a co-surfactant, PEG 400. By employing a pseudo-ternary phase diagram, the ideal ratio of Tween 20 to PEG 400 was determined to be 3:1. The developed SEDDS demonstrated robust stability in thermal stability tests, dispersity evaluations, and dilution tests, exhibiting no instances of phase separation or precipitation. Gratifyingly, the in vitro dissolution of RISP through the developed SEDDS showed a higher release by 3-fold after 5 min and achieved 90% release within 2 hours. More interestingly, the plasma profile of RISP and the SEDDS were compared in rats, which revealed an improved drug bioavailability, as indicated by the attained higher AUC0–∞ (3907.06 versus 3426.28 h µg/ml) and a significantly higher Cmax (68.97 versus 50.35 µg/ml) with the SEDDS formulation when compared to RISP. [ABSTRACT FROM AUTHOR]

Background: Cystic echinococcosis (CE) is a common neglected parasitic disease. Nanoparticles containing drugs have been widely utilized in various formulations for several purposes, including improving the bioavailability of drugs by increasing the solubility and dissolution rate of the nanoparticles. The purpose of this study was to evaluate the effects of solid lipid nanoparticles containing albendazole and conjugated to albumin (B-SLN + ABZ) as a novel treatment approach for hydatid cysts in vivo. Methods: Albendazole-loaded solid lipid nanoparticles were prepared by emulsification and solvent evaporation method. The experimental mice were assessed for prophylactic and therapeutic effects of the drugs. Ultrastructural changes were observed by transmission electron microscopy. Results: The variance analysis of the fitted model indicated that the Glyceryl monostearate (GMS)/soy lecithin concentration ratio and the amount of albendazole had a significant effect on nanoparticle size. The GMS/soy lecithin concentration ratio and the amount of albendazole had a notable effect on nanoparticle polydispersity index (PdI) and entrapment efficiency (EE%), respectively. During chemoprophylaxis, the B-SLN + ABZ group showed a lower number and weight of cysts (0.90 ± 0.73 and 15.01 ± 10.46, respectively) compared with the ABZ + SLN group (1.4 ± 0.51 and 26.73 ± 9.92, respectively). In addition, therapeutic efficacy analysis showed a significant reduction in wet weights of metacestodes in mice treated with both B-SLN + ABZ (29.37 ± 13.82 mg) and SLN + ABZ (35.88 ± 7.49 mg) compared with the control group (59.78 ± 3.80 mg). Conclusions: The results showed that B-SLN + ABZ nanoparticles were more effective against E. granulosus cysts compared with free ABZ. The cysts in the animals receiving B-SLN + ABZ every 24 h showed more ultrastructural changes. [ABSTRACT FROM AUTHOR]

Access to health care is a fundamental human right. However, nearly one-third of the global population have no access to it. This magnitude is even much worse in low- and middle-income countries. A cross-sectional study was conducted from April 12 to June 5, 2024 to determine availability, price and affordability of essential medicines for managing cardiovascular diseases using WHO/HAI methodology in Addis Ababa, Ethiopia. Data on the availability and price of the lowest priced generic medicines were collected from five public, ten private and eight other sectors in Addis Ababa, Ethiopia. The availability was assessed as the percentage of health facilities that stocked the listed medicines. The prices of these medicines were evaluated across all sectors. Price variations were calculated to identify differences among these settings. Additionally, medicine prices were compared against the management sciences for health (MSH) International Reference Prices to calculate the Median Price Ratio (MPR), providing a standardized measure of price affordability and accessibility. The data was analyzed using WHO/HAI work book Excel sheet V 15. The overall availability of generic drugs in all sectors was found to be 34.52%. The availability was 33.73, 40.58, 29.8 and 33.99% in Public, Private, Kenema and Red Cross pharmacies, respectively. The median price ratios for the medications used to treat cardiovascular disease were 3.49, 7.24, 2.84 and 5.2 at Public, Private, Kenema, and Red Cross Pharmacies, respectively. Majority of the medicines were found to be unaffordable, costing up to 352.44 days' wage of the lowest paid government employee to cover a one-month standard treatment. In conclusion, the study underscores significant challenges in the availability, pricing, and affordability of LPG medications to treat CVDs in Ethiopia. [ABSTRACT FROM AUTHOR]

The absorption and bioavailability of most tyrosine kinase inhibitors are affected by gastrointestinal pH as they are weak basic lipophilic drugs. Hence, concomitant use of acid reducing agents (ARAs) is frequently restricted. Particularly comedication of crystalline dasatinib (Sprycel) and proton‐pump inhibitors (PPIs) should be avoided. Drug–drug interaction (DDI) studies with PPIs report approximately 40%‐80% bioavailability reduction of dasatinib. Limitations in the design of these studies do not allow for assessing the near maximum DDI as timing of PPI dosing was either not reported or 22 h prior to dasatinib intake. We conducted a DDI study of crystalline dasatinib and omeprazole in healthy, fasted participants, investigating the impact of PPI comedication on dasatinib plasma exposure at a time point when the near maximum DDI effect is expected. Participants were administered omeprazole (day 2‐5) to reach steady state. On day 6, a single dose of crystalline dasatinib was given. Crystalline dasatinib dosing alone on day 1 served as control (single dose). The dosing interval between omeprazole administration and crystalline dasatinib was 10 h (median [range: 9‐10 h]). Dasatinib Cmax and AUC0‐24 were reduced by 96% and 89% by omeprazole comedication. Cmax was 224.6 ± 104.7 ng/mL (mean ± SD) and 8.0 ± 4.5 ng/mL (P < .0001) and AUC0‐24 was 797.6 ± 274.5 and 90.6 ± 38.1 h·ng/mL (P < .0001) without and with omeprazole. T1/2 was 5.7 ± 1.5 h (mean ± SD) with crystalline dasatinib dosing alone and could not be reliably calculated with comedication. To ensure optimal patient outcome, it is vital to investigate bioavailability of pH‐sensitive drugs at the maximal DDI effect of ARAs to understand the worst‐case influence for efficient clinical management. [ABSTRACT FROM AUTHOR]

There is increasing evidence that the intestinal microbiota plays an integral role in disease pathogenesis and treatment. Specifically, the intestinal microbiota significantly influences the pharmacokinetics and pharmacodynamics of orally administered drugs through direct involvement in drug metabolism and, consequently, drug bioavailability. However, the gut microbiota also exerts immunoregulatory effects on the liver—the organ primarily responsible for drug metabolism—thereby indirectly impacting the body's capacity to metabolise and process drugs. Individual differences in this pathway substantially contribute to the variability in clinical drug treatment outcomes observed between patients. This review examines the impact of liver immune responses, as triggered by the intestinal microbiota, on the activity of drug-metabolising enzymes and discusses the implications for precision medicine. [ABSTRACT FROM AUTHOR]

The article in the journal "Leukemia & Lymphoma" discusses a case of chronic lymphocytic leukemia (CLL) with MDM2 amplification as an alternative pathway to TP53 dysfunction. The patient, a 55-year-old male, had a complex karyotype CLL with no detectable TP53 mutation or deletion but harbored a high-level MDM2 amplification. This MDM2 amplification led to TP53 dysregulation, resulting in an inferior response to chemoimmunotherapy. The study highlights the importance of understanding alternative mechanisms of TP53 dysregulation in CLL to optimize patient outcomes and treatment strategies. [Extracted from the article]

Aging affects the structure and functions of all organs and systems in the organism. In the elderly, significant changes in hormonal levels are observed. These translate to a predisposition for chronic diseases, including cardiovascular, neurodegenerative, and metabolic disorders. Therefore, tremendous scientific effort is focused on investigating molecular mechanisms and drugs with the potential to reduce hormonal changes in old age and their impact. Sirtuin 1 (SIRT1), a member of the sirtuin family of deacetylases, has been extensively studied as a regulator of multiple pathways related to antioxidant properties, optimal immune response, and metabolism. SIRT1 plays a key role in regulating various hormonal pathways and maintaining homeostasis. In the present study, we review the interplay between SIRT1 and hormonal regulations, including the endocrine role of the hypothalamic–pituitary–thyroid, –adrenal, –gonadal, and –liver axes, of other endocrine glands, and of non-endocrine tissues in the aging organism. The application of natural SIRT1 activators, such as resveratrol, curcumin, paeonol, and Buyang Huanwu Decoction, for the treatment of aging and senescence is discussed. SIRT1 activators improve mitochondrial function, reduce oxidative stress, and promote longevity, but their clinical application is limited by low bioavailability and poor permeability across biological barriers. For this reason, advanced delivery strategies are being considered, including nose-to-brain drug delivery and nanotechnology-based formulations. [ABSTRACT FROM AUTHOR]

α-Glucosidase inhibitors seem to be most effective in the treatment of diabetes. β-Lactams have been reported to have some antidiabetic properties with α-glucosidase inhibitory activity. The current study aims to evaluate the potential of newly synthesized β-lactams B8–B14 as α-glucosidase inhibitors that can help to control high blood glucose levels in type 2 diabetes mellitus. The synthesized 3-nitrophenyl imine derivatives (1 eq.) reacted with ethenone (1 eq.) in benzene by a Staudinger cycloaddition reaction to afford β-lactams B8–B14, which was confirmed by advanced spectroscopic techniques and elemental analysis. The antihyperglycemic studies revealed that compounds B8, B9 and B12–B14 at a dosage of 5 mg kg−1 and after 24 h of administration showed a higher percentage decrease in blood sugar (12.61–21.07%) than the reference drug glibenclamide (11.74%). In line with in vitro studies, β-lactams B8 and B9 proved to be potent inhibitors of α-glucosidase enzyme with IC50 values 3.33 μM and 2.21 μM, respectively, higher than the standard drug acarbose (IC50 = 5.47 μM). Further, in vivo experiments confirmed that the most potent antidiabetic agents B8 and B9 significantly decrease the ALT level (71.1–74.3%) to prevent liver injury induced by diabetes. The higher antioxidant potential confirmed the role of B9 as a lead antidiabetic agent to manage the ROS generated by diabetes. AutoDock Vina was used to identify the catalytic sites of α-glucosidase and to remove water molecules and add hydrogen and Kollman charges to the protein structure. In molecular docking studies, B9 fits tightly within the catalytic pocket of the α-glucosidase enzyme with a binding affinity of −9.1 kcal mol−1, supporting its potential as a strong α-glucosidase inhibitor. The most potent compound, B9, was found to have optimal lipophilicity (2.63), the highest drug-likeness (86.9%) and excellent gastrointestinal absorption that are suitable for bioavailability and drug design. Moreover, these physiochemical properties also showed excellent correlation with the α-glucosidase inhibitory and antidiabetic activity. Overall, these excellent results suggest that the most potent compound, B9, has the potential to develop as a therapeutic drug in the future to treat diabetes with α-glucosidase inhibitory activity. [ABSTRACT FROM AUTHOR]

Salinomycin, a naturally occurring polyether ionophore antibiotic isolated from Streptomyces albus, has been demonstrated potent cytotoxic activity against a variety of cancer cell lines. In particular, it exhibits selective targeting of cancer stem cells. However, systemic toxicity, drug resistance and low bioavailability of the drug significantly limit its potential applications. In this study, the C20‐epi‐isothiocyanate of salinomycin was designed and synthesized, and then reacted with amines as a versatile synthon to assemble a series of salinomycin thiourea derivatives, which improved the druggability of salinomycin. The antiproliferative activities of the compounds were evaluated in vitro against A549, HepG2, HeLa, 4T1, and MCF‐7 cancer cell lines using the CCK‐8 assay. The pharmacological results showed that some salinomycin thiourea derivatives exhibited excellent inhibitory activity against at least one of the tested tumor cells and high selectivity. Further mechanistic studies showed that compound 9 f, containing a 3,5‐difluorobenzyl moiety, could directly induce apoptosis, probably by increasing caspase‐9 protein expression and cell cycle arrest in G1 phase in a concentration dependent manner. [ABSTRACT FROM AUTHOR]

Active Pharmaceutical Ingredients-Ionic liquids (API-ILs) can increase drug solubility and bioavailability of solid drugs without changing the structure of drug molecules. In the present work, nonivamide (pelargonic acid vanillylamide, PAVA) was used as the active drug and choline (Ch) and citric acid (CA) were selected as the ions to prepare PAVA–based ionic liquid ([Ch][PAVA] and [PAVA]3 [CA]), respectively. The characterization and physical properties of [Ch][PAVA] and [PAVA]3 [CA], such as FT–IR spectra, 1H NMR spectra, thermal stability and hydrophilicity, were investigated. And the irritant effects of the PAVA–based ionic liquids were measured by the animal irritation experiment. [Ch][PAVA] has higher decomposition temperatures, better hydrophilicity and comparable irritant effects. The results show that the PAVA–based ILs synthesized in this study may potentially serve as a promising novel riot control agent. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) induces an acute reactive state of microglia, which contribute to secondary injury processes through phagocytic activity and release of cytokines. Several receptor tyrosine kinases (RTK) are activated in microglia upon TBI, and their blockade may reduce the acute inflammation and decrease the secondary loss of neurons; thus, RTKs are potential therapeutic targets. We have previously demonstrated that several members of the Fibroblast Growth Factor Receptor (FGFR) family are transiently phosporylated upon TBI; the availability for drug repurposing of FGFR inhibitors makes worthwhile the elucidation of the role of FGFR in the acute phases of the response to TBI and the effect of FGFR inhibition. Methods: A closed, blunt, weight-drop mild TBI protocol was employed. The pan-FGFR inhibitor Rogaratinib was administered to mice 30min after the TBI and daily up to 7 days post injury. Phosphor-RTK Arrays and proteomic antibody arrays were used to determine target engagement and large-scale impact of the FGFR inhibitor. pFGFR1 and pFGFR3 immunostaining were employed for validation. As outcome parameters of the TBI injury immunostainings for NeuN, VGLUT1, VGAT at 7dpi were considered. Results: Inhibition of FGFR during TBI restricted phosphorylation of FGFR1, FGFR3, FGFR4 and ErbB4. Phosphorylation of FGFR1 and FGFR3 during TBI was traced back to Iba1+ microglia. Rogaratinib substantially dowregulated the proteomic signature of the neuroimmunological response to trauma, including the expression of CD40L, CXCR3, CCL4, CCR4, ILR6, MMP3 and OPG. Prolonged Rogaratinib treatment reduced neuronal loss upon TBI and prevented the loss of excitatory (vGLUT+) synapses. Conclusion: The FGFR family is involved in the early induction of reactive microglia in TBI. FGFR inhibition selectively prevented FGFR phosphorylation in the microglia, dampened the overall neuroimmunological response and enhanced the preservation of neuronal and synaptic integrity. Thus, FGFR inhibitors may be relevant targets for drug repurposing aimed at modulating microglial reactivity in TBI. [ABSTRACT FROM AUTHOR]

A major shortcoming in the treatment of mesangial cell-associated diseases such as IgA nephropathy, diabetic nephropathy, or lupus nephritis, which frequently progress to end-stage renal disease, is poor drug availability in the glomerular mesangium. Drug delivery via active targeting of nanoparticles, using ligands attached to the particle surface for target cell recognition to increase the biodistribution to the mesangium, is a promising strategy to overcome this hurdle. However, although several glomerular tissue targeting approaches have been described, so far no study has demonstrated the particles' ability to deliver sufficient drug amounts combined with an appropriate nanoparticle target retention time to trigger relevant biological effects in the mesangium. In our study, we encapsulated erastin, a ferroptosis-inducing model compound, into adenovirus-mimetic, mesangial cell-targeting nanoparticles, enabling the direct visualisation of biological effects through ferroptosis-dependent histological changes. By intravital microscopy and analysis of histological sections, we were not only able to localise the injected particles over 10 days within the target cells but also to demonstrate biological activity in the renal glomeruli. In conclusion, we have characterised adenovirus-mimetic nanoparticles as a highly suitable drug delivery platform for the treatment of mesangial cell-associated diseases and additionally provided the basis for a potential renal disease model. [ABSTRACT FROM AUTHOR]

Background: Drug policies and interventions require an ongoing understanding of the local demand for illegal drugs. How illegal drugs are distributed to consumers is critical in the demand process. To overcome barriers to purchasing illegal drugs, people utilize their peers to purchase substances for them. These brokered drug sales allow buyers to leverage their peer networks to make purchases. For brokers, this form of exchange allows them to obtain drugs for free. This drug acquisition strategy is underappreciated in understanding how local drug market's function. Methods: This paper presents findings from a brief survey on brokering collected from a random sample (N = 241) of active illegal drug injectors recruited from two syringe services programs in Ohio, USA. Results: Findings indicate that 30-day and lifetime brokering behavior is common (71% and 90% respectively). Respondents who brokered in the last 30 days (n = 181) purchased drugs for an average of 7 people and from an average of 4 different sellers. Among this group, over 84% indicated that they used drugs with the person they brokered for, 49% reported often or always inflating the price to the buyer, and 27% indicated they removed some drug before returning to the buyer. Conclusion: Measuring brokering offers new insight on the dynamics of drug markets, how they operate, and ways to measure their activity. The demand for illegal drugs incorporates the increased use of a drug, changes in the use of different drugs, and/or a novel drug being used. Accessing drugs via brokering accommodates these dynamics. By including brokering in drug market activity, the concept and scope of illegal drug markets transform into networks and not places. [ABSTRACT FROM AUTHOR]

Haloperidol, a conventional antipsychotic, was mixed with piperine in a ketamine-induced schizophrenia rat model to evaluate the interaction potential of this mixture through in-vitro and in-vivo analyses. Piperine, known for its CYP450 enzyme inhibitory effects, enhances the bioavailability of various drugs. Initial in-vitro assays using a high-throughput fluorometric method showed that the haloperidol–piperine mixture inhibited CYP3A4 and CYP2D6 enzymes, comparable to positive controls. In-vivo pharmacokinetic results revealed that piperine significantly increased haloperidol's plasma concentration and area under the curve while reducing clearance, indicating enhanced bioavailability. Pharmacodynamic assessments showed reductions in locomotor activity, immobility time, dopamine levels, and nitric oxide, with increased superoxide dismutase levels in the haloperidol–piperine group compared to haloperidol alone, reflecting enhanced therapeutic efficacy. These findings indicate that piperine can increase haloperidol exposure, potentially allowing for dose reduction and minimizing dose-related side effects. Limitations of this study include reliance on a rat model, which may not fully replicate human metabolism, and lack of long-term safety assessment. Future studies should explore the clinical applicability of this mixture in human trials, particularly focusing on safety, dosage optimization, and long-term effects. Additionally, understanding piperine's role in different metabolic pathways could guide the development of targeted bioavailability enhancers, improving efficacy for a range of CYP450-metabolized medications. [ABSTRACT FROM AUTHOR]

Background/Objectives: This study evaluates the efficacy of twin screw melt granulation (TSMG), and hot-melt extrusion (HME) techniques in enhancing the solubility and dissolution of simvastatin (SIM), a poorly water-soluble drug with low bioavailability. Additionally, the study explores the impact of binary polymer blends on the drug's miscibility, solubility, and in vitro release profile. Methods: SIM was processed with various polymeric combinations at a 30% w/w drug load, and a 1:1 ratio of binary polymer blends, including Soluplus® (SOP), Kollidon® K12 (K12), Kollidon® VA64 (KVA), and Kollicoat® IR (KIR). The solid dispersions were characterized using modulated differential scanning calorimetry (M-DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FTIR). Dissolution studies compared the developed formulations against a marketed product. Results: The SIM-SOP/KIR blend showed the highest solubility (34 µg/mL), achieving an approximately 5.5-fold enhancement over the pure drug. Dissolution studies showed that SIM-SOP/KIR formulations had significantly higher release profiles than the physical mixture (PM) and pure drug (p < 0.01). Additionally, their release was similar to a marketed formulation, with 100% drug release within 30 min. In contrast, the SIM-K12/KIR formulation exhibited strong miscibility, but limited solubility and slower release rates, suggesting that high miscibility does not necessarily correlate with improved solubility. Conclusions: This study demonstrates the effectiveness of TSMG, and HME as effective continuous manufacturing technologies for improving the therapeutic efficacy of poorly water-soluble drugs. It also emphasizes the complexity of polymer–drug interactions and the necessity of carefully selecting compatible polymers to optimize the quality and performance of pharmaceutical formulations. [ABSTRACT FROM AUTHOR]

The application of ketoconazole (KET) in ocular drug delivery is restricted by its poor aqueous solubility though its broad-spectrum antifungal activity. The aim of this study is to develop an ion-sensitive in situ gel (ISG) of KET to promote its ocular bioavailability in topical application. The solubility of KET in water was increased by complexation with hydroxypropyl-β-cyclodextrin (HPβCD), then KET-HPβCD inclusion complex (KET-IC) was fabricated into an ion-sensitive ISG triggered by sodium alginate (SA). The in vitro drug release and antifungal activities investigations demonstrated that the KET-IC-ISG formulation increased drug release and anti-fungal activities compared to pure KET. The ex vivo rabbit corneal permeation studied demonstrated higher permeability of KET-IC-ISG formulation (Papp of (6.34 ± 0.21) × 10−4 cm/h) than pure KET (Papp of (3.09 ± 0.09) × 10−4 cm/h). The cytotoxicity assay and the ocular irritation study in rabbits confirmed the KET-IC-ISG safety and well tolerance. The ocular pharmacokinetics of KET in rabbits was investigated and the results showed that the KET-IC-ISG increased its bioavailability in cornea by 47-fold. In conclusion, the KET-IC-ISG system promoted the precorneal retention, the ocular drug bioavailability and the developed formulation is a potential strategy to treat mycotic keratitis. [ABSTRACT FROM AUTHOR]

Active components of natural products, which include paclitaxel, curcumin, gambogic acid, resveratrol, triptolide and celastrol, have promising anti-inflammatory, antitumor, anti-oxidant, and other pharmacological activities. However, their clinical application is limited due to low solubility, instability, low bioavailability, rapid metabolism, short half-life, and strong off-target toxicity. To overcome these drawbacks, cell membrane-based biomimetic nanosystems have emerged that avoid clearance by the immune system, enhance targeting, and prolong drug circulation, while also improving drug solubility and bioavailability, enhancing drug efficacy, and reducing side effects. This review summarizes recent advances in the preparation and coating of cell membrane-coated biomimetic nanosystems and in their applications to disease for targeted natural products delivery. Current challenges, limitations, and prospects in this field are also discussed, providing a research basis for the development of multifunctional biomimetic nanosystems for natural products. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we aimed to comparatively analyse the indicators of availability to orphan drugs in South Korea, the United States of America, Europe Union, and Japan. Methods: For 169 drugs designated as orphan drugs in South Korea between 2012 and 2021, information on the drugs designated as orphan drugs from each jurisdiction was extracted by country. Then, the availability indicators (approval time, drug lag time, and designation gap) were analysed for the drugs approved in each jurisdiction. Results: The approval rate of drugs designated as orphan drugs were 11.22% and 6.31% in the USA and EU, respectively, which was lower than that of orphan drugs in South Korea and Japan. The highest number of approved drugs was in the USA (87 drugs), EU 27 drugs, Japan 22 drugs and Korea 21 drugs. Furthermore, the approval time significantly differed between South Korea and the other countries. South Korea had a significantly different drug lag time and designation gap compared with the USA and EU. Conclusion: Our findings show that to fundamentally improve the access to treatments for rare disease, a policy of regulatory science that can comprehensively support the early stages of research and development and commercialisation is needed. [ABSTRACT FROM AUTHOR]

Naproxen (NAP) is a non-steroidal anti-inflammatory drug (NSAID) that belongs to the arylpropionic acid class. Classified as a Biopharmaceutical Classification System (BCS) class II drug, NAP exhibits low water solubility, thus resulting in restricted oral bioavailability. This study aimed to evaluate the effectiveness of pharmaceutical salts in enhancing the solubility and oral bioavailability of NAP. Two novel NAP salts, specifically naproxen-ethylenediamine (NAP-EDA) and naproxen-trometamol (NAP-TRIS), were synthesized using a 2:1 and 1:1 stoichiometric ratio, respectively. The NAP-EDA and NAP-TRIS powders were thoroughly characterized using single-crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC), providing a comprehensive understanding of their structural and thermal properties. Additionally, the solubilities and dissolution rates of NAP-EDA and NAP-TRIS salts were assessed in water and a pH 6.86 phosphate buffer. Notably, the solubility of NAP-TRIS salt increased markedly, by 397.5-fold in water and 6.2-fold at pH 6.86. Furthermore, in vivo pharmacokinetic studies in rats revealed that NAP-TRIS salt displayed faster absorption and higher peak blood concentrations compared to NAP. These results indicate that the NAP-TRIS salt effectively enhanced the solubility and oral bioavailability of naproxen. In conclusion, this study underscores the potential of pharmaceutical salts, particularly NAP-TRIS, in improving the solubility and oral bioavailability of drugs with low aqueous solubility, presenting a promising avenue for advancing drug delivery and therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Microneedling, a minimally invasive technique traditionally used in dermatology, has emerged as a promising approach to cancer therapy. The procedure involves creating microchannels in the skin using fine needles, enhancing the delivery of therapeutic agents directly into tumor tissues. This method overcomes the limitations of conventional cancer treatments, such as systemic toxicity and poor drug penetration, by facilitating localized and controlled drug delivery. Microneedling can also stimulate immune responses and induce tissue regeneration, potentially enhancing the effectiveness of immunotherapy and promoting tumor suppression. Recent studies have shown that microneedling can be combined with nanoparticles, chemotherapeutics, or gene therapies, allowing for a more precise and targeted treatment of cancer cells while minimizing damage to healthy tissues. Additionally, microneedling-based drug delivery systems can improve the bioavailability of drugs, reducing required dosages and associated side effects. The technique has been instrumental in treating skin cancers, such as melanoma, but its potential application in other solid tumors is currently being explored. While promising, further clinical studies are needed to optimize microneedling parameters and evaluate its long-term safety and efficacy in cancer therapy. As the field progresses, microneedling may revolutionize the delivery of cancer therapeutics, offering a cost-effective, patient-friendly option that complements existing treatments. [ABSTRACT FROM AUTHOR]

Abstract Persistent racial disparities in health outcomes have catalyzed legislative reforms and heightened scientific focus recently. However, despite the well-documented properties of skin pigments in binding drug compounds, their impact on therapeutic efficacy and adverse drug responses remains insufficiently explored. This perspective examines the intricate relationships between variation in melanin-based skin pigmentation and pharmacokinetics and -dynamics, highlighting the need for considering diversity in skin pigmentation as a variable to advance the equitability of pharmacological interventions. The article provides guidelines on the selection of New Approach Methods (NAMs) to foster inclusive study designs in preclinical drug development pipelines, leading to an improved level of translatability to the clinic.

The letter to the editor discusses the impact of adding rituximab to the treatment of adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. The study conducted in Mexico found that adding rituximab was associated with higher odds of achieving a 3-month complete molecular response and a potential benefit in mortality. The study also highlighted the importance of early deep responses in improving prognosis for patients with this type of leukemia. The findings suggest that adding rituximab to standard chemotherapy regimens may be beneficial in certain cases without increasing toxicity. [Extracted from the article]

Wound infection poses a significant global health threat, as it is a leading cause of morbidity and mortality among surgical patients and individuals with burn injuries, resulting in substantial healthcare burdens and devastating outcomes worldwide. Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli have frequently been implicated as major pathogens causing wound infections. This has eventually and consistently given rise to antimicrobial resistance divulging a need to mitigate infectious outbreaks. Herein, we employed a computational density functional theory (DFT) method at ωB97XD/6-311++g(d, p) level of theory to evaluate the performance of the thiophene derivative 5-(4-bromo-5-(methylthio)thiophen-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol 4, which is experimentally synthesized into five compounds (4a, 4b, 4c, 4d, and 4e). The chemical reactivity, kinetic stability, nature of interactions and functional characteristics of the thiophene derivatives were ascertained. The resistance gene PDB ID: 1K25, 2D45, 4UOT, and 7K2X were employed and docked with thiophene derivatives. Interestingly, molecular docking analysis demonstrated that ligands 4a, 4b, 4c, 4d, and 4e are more effective against proteins 1K25, 4U0T and 7K2X than amoxicillin and methicillin. Upon docking with the 2D45 protein, compounds 4c and 4e (− 5.9 kcal/mol) exhibited potential similar to that of methicillin (− 5.9 kcal/mol), while 4a and 4b showed slightly better affinities (− 6.1 kcal/mol and 6.0 kcal/mol). Using Lipinski's Rule of Five (Ghose filter, Veber rules, Muegge filter, and Egan's rule), 4d and 4e were determined to be the most promising candidates for drug development due to their compliance with all evaluated criteria, indicating favourable properties for oral bioavailability and drug likeness. This research suggested that thiophene derivatives can serve as promising antibacterial agents against wound-infected bacteria. [ABSTRACT FROM AUTHOR]

Therapeutic deep eutectic solvents (THEDES) are a type of deep eutectics that can be used as active pharmaceutical ingredients (APIs) by enhancing the drug bioavailability, by increasing the solubility of APIs in aqueous solutions or by increasing their permeability through biological barriers. In this study, we demonstrate the utility of designer THEDES, based on Quillaja Saponin (SAP), a triterpene natural product to unravel the antimicrobial potential of such THEDES. THEDES were prepared by gently mixing and heating five different α- hydroxy acids- malic, citric, tartaric, glycolic, lactic acids and SAP with water as a third component in the THEDES. The antimicrobial assays were performed with the as-prepared SAP-THEDES and among the panel of bacterial strains, saponin-malic acid THEDES [SMA-THEDES] displayed potent activity in disassembling PA biofilms, demonstrating that the SMA-THEDES can serve as therapeutic antibacterial biomaterials. To further optimize, a Box-Behnken- response surface methodology (RSM) experimental design was done and at the optimum conditions of SAP (1.014 m.mol), Malic acid (1.003 m.mol), Water (0.117 m.mol), SMA-THEDES exhibited maximum MIC of P. aeruginosa with the minimum absorbance at 590 nm of 0.105. The effectiveness of SMA-THEDES as antibiofilm agents on P. aeruginosa with the mechanism studies have been explored. The colony count from the in vivo infection zebrafish model in the treatment group showed a decline of > 2 fold for SMA-THEDES. Toxicity studies did not reveal any abnormality in liver and brain enzyme levels. Liver morphology images show no severe cytological alterations when treated with SMA-THEDES and were almost similar to the normal liver. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) is a multifactorial social problem affecting men worldwide. While phosphodiesterase type 5 inhibitors (PDE5) like sildenafil are commonly used, they often present side effects, underscoring the need for alternative therapies. Therefore, this study investigated the potential of phytochemicals from Detarium senegalense in the management of ED. A library of phytochemicals from Detarium senegalense was generated, prepared, and interacted with six key enzymes implicated in ED, including PDE5, using the Schrödinger Maestro suite. The results identified catechin, epicatechin, and gallic acid as the leading compounds with significant binding affinities for the targeted enzymes. Catechin and epicatechin (−9.877 and −11.408 kcal/mol, respectively) exhibited comparable binding affinities to sildenafil (−11.926 kcal/mol) on PDE5. The MD simulation results also revealed superior stability and ability to maintain interaction with key amino acids at the active site of PDE5 over the entire simulation period for these compounds. These compounds also demonstrated favorable ADMET profiles over sildenafil, including high gastrointestinal absorption and no violation of Lipinski's rule, indicating good bioavailability and drug likeness. These findings suggest that flavonoids from Detarium senegalense, especially catechin and epicatechin, have potential in the management of ED by interacting with multiple targets involved in its pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Malaria, a tropical neglected disease, imposes a significant burden on global health, leading to the loss of thousands of lives annually. Its gold standard treatment is a combination therapy of lumefantrine (LUM) and artemether (ART). Nanotechnology holds significant potential for improving drug bioavailability and potency while reducing adverse effects. Objectives: This study aimed to develop lipid-core nanocapsules containing ART and LUM and evaluate their effects in an experimental cerebral malaria model (ECM). Methods: The polymeric interfacial deposition method was used to develop lipid-core nanocapsules (LNCs) containing ART and LUM (LNCARTLUM) and were characterized using micrometric and nanometric scales. Male C57BL/6 mice were infected with Plasmodium (P.)berghei ANKA (PbA, 1 × 105 PbA-parasitized red blood cells, intraperitoneally). On day 5 post-infection, PbA-infected mice were orally administered with ART + LUM, LNCARTLUM, blank nanocapsules (LNCBL), or ethanol as a control. Parasitemia, clinical scores, and survival rates were monitored throughout the experiment. Organ-to-body weight ratios, cytokine quantification, and intravital microscopy analyses were conducted on day 7 post-infection. Results: LNCs were successfully developed and characterized. The treatment with LNCARTLUM in ECM resulted in complete clearance of parasitemia at 10 dpi, decreased clinical scores, and maintained 100% survival rates. Thereated mice exhibited splenomegaly and reduced TNF-α, IL-1β, and MCP1 levels in the brain. Furthermore, the LNCARTLUM treatment protected the brain microvasculature, reducing the number of cells in the rolling process and adherent to the microvasculature endothelium. Conclusion: Nanoformulations can potentially improve the efficacy of antimalarial drugs and be considered a promising approach to treat malaria. [ABSTRACT FROM AUTHOR]

The self‐organization of microbes into biofilms provides multiple benefits including tolerance to mechanical stress and resistance to immune defences and antibiotics. Coupled to a compromised mucociliary function, these traits have dire consequences in cystic fibrosis patients – persistent infections are the main reason for morbidity and mortality. Thereby, disease progression is associated with universal colonization by Pseudomonas aeruginosa, which selects for a slimy phenotype to adapt to the lung microenvironment. Recognizing this, drug‐delivery vehicles that break down the mucoid extracellular matrix made of alginate are designed to enable better penetration and biofilm dispersion. In parallel, a protective layer responds to the proteolytic activity of the pathogen and thus controls drug availability. To realize this architecture, silica nanoparticles are loaded with imipenem, and then coated with elastin and alginate lyase in a layer‐by‐layer fashion using ultrasound. The nanoscale formulations eradicate up to 80% of the total biomass and reduce the bacterial viability in biofilms by 3 logs, considerably outperforming the bulk antibiotic in vitro, whereby the effects are correlated to changes in the viscoelasticity. Furthermore, the stimuli‐responsive nanocarriers are safe and effective in animal models of P. aeruginosa infection, presenting a considerable therapeutic promise in the challenging context of lung diseases. [ABSTRACT FROM AUTHOR]

Background: Migraine is a widespread, recurrent primary headache disorder primarily characterized by severe pulsatile headache, typically on one or both sides. It is often accompanied by nausea, vomiting, and hypersensitivity to sound and light. Despite the availability of multiple drugs for migraine management, the condition often becomes chronic due to untimely or irrational drug use, significantly distressing patients and increasing the burden on families and society. Over the past two decades, numerous clinical studies on migraine have been published. This study aimed to provide a comprehensive summary of the current status and trends of migraine clinical trials through bibliometric analysis. Methods: We used visual network tools such as CiteSpace and VOSviewer to perform a knowledge graph analysis of publications related to migraine clinical trials extracted from the WoSCC. Results: This study analyzed 1,129 articles published in 389 journals from 61 countries. The number of publications on migraine clinical trials has steadily increased from 2004 to 2023. The United States and Albert Einstein College of Medicine are the leading countries and institutions in this field, respectively. Richard B. Lipton is the most prolific author, making significant contributions to the research. The journal Headache has the highest number of publications and citations in this area. Keywords such as "efficacy," "RCT," "CGRP," "prophylaxis," "disability," "depression," "questionnaire," and "real-world effectiveness" received significant attention. Conclusion: This study identified reliable research hotspots and provided directions for clinicians. The treatment of migraine continues to be challenging. Future trends may include continued growth in migraine classification, risk factor analysis, and comorbidity studies. Research on CGRP and epigenetics will advance the progress of precision medicine in the migraine field. [ABSTRACT FROM AUTHOR]

Background: In this study, we aimed to evaluate the differing global access to acute and preventive medications for migraine and tension-type headache. Methods: A custom-built questionnaire created by members of the International Headache Society Juniors Group was sent to International Headache Society members worldwide, including a list of acute and preventive treatments for migraine and tension-type headache. This list was based on evidence-based medicine guidelines. For each treatment, participants were asked about availability, type of reimbursement and variability of access within their country. Results: Eighty-four members completed the questionnaire providing data for 84 countries. The majority were neurologists (88%) and worked at an academic/university hospital (62%). Of participants, 36% were located in high-income economy countries and 13% were located in low-income economies. Common preventive treatments such as propranolol and topiramate were available in most countries (respectively in 99% and 92% of responding countries). Sumatriptan was available in most countries (95%), whereas other triptan availability was lower. Novel migraine treatments such as rimegepant and erenumab were only available in 14% and 46% of the assessed countries, respectively. Conclusions: Availability of headache medications, ranging from simple analgesics to novel therapies migraine-specific drugs, varied greatly across the world. Actions are needed to improve effective drug availability in many countries to ensure an adequate management of people living with headache. [ABSTRACT FROM AUTHOR]

Drug administration is commonly used to treat chronic wounds but faces challenges such as poor bioavailability, instability, and uncontrollable release. Existing drug delivery platforms are limited by chemical instability, poor functionality, complex synthesis, and toxic by-products. Presently, research efforts are focused on developing novel drug carriers to enhance drug efficacy. Guanidinium Covalent Organic Nanosheets (gCONs) offer promising alternatives due to their high porosity, surface area, loading capacity, and ability to provide controlled, sustained, and target-specific drug delivery. Herein, we successfully synthesized self-exfoliated gCONs using a Schiff base condensation reaction and embedded curcumin (CUR), a polyphenolic pleiotropic drug with antioxidant and anti-inflammatory properties, via the wet impregnation method. The BET porosimeter exhibited the filling of gCON pores with CUR. Morphological investigations revealed the formation of sheet-like structures in gCON. Culturing human dermal fibroblasts (hDFs) on gCON demonstrated cytocompatibility even at a concentration as high as 1000 µg/mL. Drug release studies demonstrated a controlled and sustained release of CUR over an extended period of 5 days, facilitated by the high loading capacity of gCON. Furthermore, the inherent antioxidant and anti-inflammatory properties of CUR were preserved after loading into the gCON, underscoring the potential of CUR-loaded gCON formulation for effective therapeutic applications. Conclusively, this study provides fundamental information relevant to the performance of gCONs as a drug delivery system and the synergistic effect of CUR and CONs addressing issues like drug bioavailability and instability. [ABSTRACT FROM AUTHOR]

Background: Breeds of animals differ with respect to anatomical, physiological and behavioural traits hence the study of interbreed variation in pharmacokinetics becomes necessary. The aim of the current investigation was to determine the pharmacokinetics of enrofloxacin following intravenous bolus administration to assess the influence of breed on drug pharmacokinetics and availability. Methods: In the present study the pharmacokinetics of a common antimicrobial drug, enrofloxacin and its metabolite, ciprofloxacin was studied in adult, non-pregnant and dry Badri cows, wherein a commercial preparation of enrofloxacin (10% v/v) was administered at a dose rate of 7.5 mg/kg intravenously as a single dose. The plasma samples were collected at regular intervals and subjected to analysis by HPLC after appropriate processing. The results obtained were analysed using a software tool, "PK Solver" to obtain the pharmacokinetic parameters. Result: From the study, it was revealed that the Badri cattle showed a distribution half-life of 0.11 h, a volume of distribution of 7.63 L.kg-1, an elimination half-life of 4.27 h and an MRT of 5.93 h for enrofloxacin. Whereas, a maximum plasma concentration level of 0.12 µg.ml-1 was observed for ciprofloxacin in the current study. According to the results obtained in the pharmacokinetic study, an individualized dosage regimen containing a priming dose of 5 mg/kg and a maintenance dose of 4.5 mg/kg with an interval of 24 hours was suggested for the enrofloxacin in Badri cattle. The results of our current study when compared with the previously available literature on other cattle breeds suggested that the Badri cattle differed with respect to pharmacokinetic properties and further studies will be required to determine the conclusive reason for the differences. [ABSTRACT FROM AUTHOR]

Objective: This proposed scoping review aims to examine studies assessing the impact of drug shortages on population-level drug utilization trends. The objectives of this review are to a) assess which drugs have been studied and describe associated drug characteristics, b) determine jurisdictions and healthcare settings that have conducted these studies, and c) describe how changes in drug use and the extent of shortage impacts are reported in literature. Introduction: Drug shortages continue to impair drug access and delivery of quality care across the world. However, the impact of drug supply disruptions on availability and drug use are understudied in current literature. This proposed scoping review will identify this gap and inform future research initiatives aimed at determining the real-world impacts of drug shortages. Inclusion criteria: Published and unpublished observational studies reporting on the effects of drug supply chain disruptions (shortages, discontinuations, and safety-based withdrawals) on consequent utilization trends faced by pharmaceutical products (i.e. prescription drugs, over-the-counter drugs, vaccines, therapy products, pharmaceutical solutions). Literature reviews, meta-analyses, randomized control trials, case series, case reports, and opinion pieces will be excluded. Methods: The search strategy will combine two key search concepts: drug shortages and drug utilization. The search will be conducted in MEDLINE and EMBASE. This will be followed by an extensive grey literature search in grey literature databases, targeted websites and Google. Furthermore, reference lists of included articles will be searched. Articles will be independently screened, selected and extracted by two reviewers. Data will be descriptively analyzed and presented in tables. Trial registration: Review registration number: Open Science Framework, https://osf.io/2p6e5. [ABSTRACT FROM AUTHOR]

Inulin, a naturally occurring polysaccharide derived from plants such as chicory root, has emerged as a significant ingredient in pharmaceutical sciences due to its diverse therapeutic and functional properties. This review explores the multifaceted applications of inulin, focusing on its chemical structure, sources, and mechanisms of action. Inulin's role as a prebiotic is highlighted, with particular emphasis on its ability to modulate gut microbiota, enhance gut health, and improve metabolic processes. The review also delves into the therapeutic applications of inulin, including its potential in managing metabolic health issues such as diabetes and lipid metabolism, as well as its immune-modulating properties and benefits in gastrointestinal health. Furthermore, the article examines the incorporation of inulin in drug formulation and delivery systems, discussing its use as a stabilizing agent and its impact on enhancing drug bioavailability. Innovative inulin-based delivery systems, such as nanoparticles and hydrogels, are explored for their potential in controlled release formulations. The efficacy of inulin is supported by a review of clinical studies, underscoring its benefits in managing conditions like diabetes, cardiovascular health, and gastrointestinal disorders. Safety profiles, regulatory aspects, and potential side effects are also addressed. This comprehensive review concludes with insights into future research directions and the challenges associated with the application of inulin in pharmaceutical sciences. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of melt-sonocrystallization technique (MS) on the physicochemical characteristics and dissolution of a poorly soluble drug (ketoprofen). Methods: Ketoprofen was heated in paraffin oil bath at 97 °C and then poured into a beaker containing 25 mL deionized water at 25 °C and immediately treated using a probe ultrasonicator at different ultrasonic times, and varying amplitudes at frequency of 20 KHz. Prepared suspensions were evaluated for the effect of temperature and energy of production. Powders were characterized using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infra-red spectrophotometry (FTIR). The Heckle plot, Carr's compressibility index, and Hausner's ratio were used to determine compressibility properties. Furthermore, the angle of slide was used to evaluate flow characteristics. Results: There was a significant reduction in particle size characteristics following melt-sonocrystallization (p < 0.05). The SEM micrographs revealed needle-shaped particles with smooth surfaces. There was no significant difference in DSC thermograms with peaks ranging from 97.3 to 98.1 °C (p < 0.05). The FT-IR spectra showed two specific sharp and symmetrical peaks at (1654.5 cm-1) and (1697.3 cm-1). Also, distinctive peaks of ketoprofen remained detectable in XRD patterns, indicating that the substance had not undergone structural modification. The solubility increased by 15 %. There was no improvement in flowability or compressibility. Dissolution was greatly improved from 67 to 85 %. Conclusion: Melt-sonocrystallization reduces particle size, solubility, and dissolution with no structural modification to ketoprofen. In vivo investigation of drug bioavailability from the generated powders would be required. [ABSTRACT FROM AUTHOR]

Multiple iterations required to design ocular implants, which will last for the desired operational period of months or even years, necessitate the use of in-silico models for ocular drug delivery. In this study, we developed an in-silico model to simulate the flow of Aqueous Humor (AH) and drug delivery from an implant to the Trabecular Meshwork (TM). The implant, attached to the side of the intraocular lens (IOL), and the TM are treated as porous media, with their effects on AH flow accounted for using the Darcy equation. This model accurately predicts the physiological values of Intraocular Pressure (IOP) for both healthy individuals and glaucoma patients, as reported in the literature. Results reveal that the effective diffusivity of the drug within the implant is the critical parameter that can alter the bioavailability time period (BTP) from a few days to months. Intuitively, BTP should increase as effective diffusivity decreases. However, we discovered that with lower levels of initial drug loading, BTP declines when effective diffusivity falls below a specific threshold. Our findings further reveal that, while AH flow has a minimal effect on the drug release profile at the implant site, it significantly impacts drug availability at the TM. [Display omitted] • Developed an in-silico model that can simulate drug delivery from ocular implants. • Validated the predicted intra-ocular pressure values with the values reported in the literature. • For lower levels of loaded drug in the implant, bioavailability time period starts reducing as effective diffusivity is reduced below a certain threshold level. • Neglecting Aqueous Humor (AH) flow effects can result in substantially wrong predictions of drug availability at the Trabecular Meshwork. [ABSTRACT FROM AUTHOR]

Hydroxycamptothecin (HCPT) is commonly used in the treatment of liver cancer; however, its low water solubility and poor stability significantly limit its clinical application. In recent years, research on exosomes has deepened considerably. Exosomes possess a unique phospholipid bilayer structure, enabling them to traverse tissue barriers, which provides natural advantages as drug carriers. Nevertheless, delivering exosomes safely and efficiently to target cells remains a major challenge. In this study, we utilized the affinity of the SP94 peptide for human liver cancer cell receptors. HCPT was coated with exosomes in our experimental design, and the exosome membrane was modified with SP94 peptide to facilitate drug delivery to liver cancer cells. Exosomes were purified from bone marrow mesenchymal stem cells, and targeted peptides were attached to their surfaces via post-insertion techniques. Subsequently, HCPT was incorporated into the exosomes through electroporation. Using the HepG2 hepatoma cell line, we evaluated a series of in vitro pharmacodynamics and studied pharmacokinetics and tissue distribution in animal models. The results indicated that ligand-targeted, modified drug-carrying exosomes significantly enhance drug bioavailability, prolong retention time in vivo, and facilitate liver targeting. Moreover, this approach reduces drug nephrotoxicity, enhances anti-tumor efficacy, and lays the groundwork for the development of novel liver cancer-targeting agents. [ABSTRACT FROM AUTHOR]

Objective: Colon adenocarcinoma is characterized by the downregulation of the retinoic acid receptor, making natural retinoids such as all-trans retinoic acid, 9-cis retinoic acid and 13-cis retinoic acid effective in treatment and chemoprevention due to their ability to increase RARβ expression. However, major limitations to their use include tolerability and acquired resistance. In this study, we evaluated fenretinide, a semisynthetic derivative of all-trans retinoic acid, in an HT-29 cell line. Fenretinide was evaluated both as a free drug and encapsulated in self-assembling phosphatidylcholine nanosystems with the aim of increasing the aqueous solubility and cell availability of the drug. Methods: Fenretinide was encapsulated in lipid nanosystems obtained in water by the dispersion of an amphiphilic mixture of phospholipids, glyceryl tributyrate and polysorbate 80. The physico-chemical characterization of the nanosystems was carried out by dynamic light scattering and spectrophotometry. The biological activity was evaluated by quantitative phase imaging microscopy, MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Results: Fenretinide in phosphatidylcholine nanosystems was more active than free fenretinide in inhibiting HT-29 cells' proliferation, as indicated by quantitative phase imaging data. Indeed, encapsulated fenretinide increased duplication time, decreased dry mass and decreased the rate of cell growth more efficiently than fenretinide. Moreover, encapsulated fenretinide effectively decreased the motility of the cells that survived the treatment. Conclusions: The results indicate that the proposed nanosystems can be considered a valuable alternative to natural retinoids in the chemoprevention and treatment of colorectal cancer. This is due to the favorable pharmacologic characteristics of fenretinide in colorectal cancer and the improved drug activity provided by nanoencapsulation. [ABSTRACT FROM AUTHOR]