Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates

Epilepsy is a chronic neurological disorder affecting nearly 65–70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30-40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity. The synthesized 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivatives were primarily screened in the maximal electroshock-induced seizure (MES) test in mice. Next, the most promising compounds (17, 22) were investigated in 6 Hz (32 mA) psychomotor seizure model. Protective effect of compound 22 was almost similar to that of levetiracetam. Moreover, these compounds did not induce genotoxic and hemolytic changes in human cells as well as they were characterized by low cellular toxicity. Taking into account the structural requirements for good anticonvulsant activity of 4-alkyl-5-aryl-1,2,4-triazole-3-thiones, it is visible that small electron-withdrawing substituents attached to phenyl ring have beneficial effects both on affinity towards VGSCs and protective activity in the animal models of epilepsy

Hop Flower Supercritical Carbon Dioxide Extracts Coupled with Carriers with Solubilizing Properties—Antioxidant Activity and Neuroprotective Potential

Lupuli flos shows many biological activities like antioxidant potential, extended by a targeted effect on selected enzymes, the expression of which is characteristic for neurodegenerative changes within the nervous system. Lupuli flos extracts (LFE) were prepared by supercritical carbon dioxide (scCO2) extraction with various pressure and temperature parameters. The antioxidant, chelating activity, and inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase by extracts were studied. The extracts containing ethanol were used as references. The most beneficial neuroprotective effects were shown by the extract obtained under 5000 PSI and 50 °C. The neuroprotective effect of active compounds is limited by poor solubility; therefore, carriers with solubilizing properties were used for scCO2 extracts, combined with post-scCO2 ethanol extract. Hydroxypropyl-β-cyclodextrin (HP-β-CD) in combination with magnesium aluminometasilicate (Neusilin US2) in the ratio 1:0.5 improved dissolution profiles to the greatest extent, while the apparent permeability coefficients of these compounds determined using the parallel artificial membrane permeability assay in the gastrointestinal (PAMPA GIT) model were increased the most by only HP-β-CD

Co-Dispersion Delivery Systems with Solubilizing Carriers Improving the Solubility and Permeability of Cannabinoids (Cannabidiol, Cannabidiolic Acid, and Cannabichromene) from <i>Cannabis sativa</i> (Henola Variety) Inflorescences

Cannabinoids: cannabidiol (CBD), cannabidiolic acid (CBDA), and cannabichromene (CBC) are lipophilic compounds with limited water solubility, resulting in challenges related to their bioavailability and therapeutic efficacy upon oral administration. To overcome these limitations, we developed co-dispersion cannabinoid delivery systems with the biopolymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) and magnesium aluminometasilicate (Neusilin US2) to improve solubility and permeability. Recognizing the potential therapeutic benefits arising from the entourage effect, we decided to work with an extract instead of isolated cannabinoids. Cannabis sativa inflorescences (Henola variety) with a confirming neuroprotective activity were subjected to dynamic supercritical CO2 (scCO2) extraction and next they were combined with carriers (1:1 mass ratio) to prepare the co-dispersion cannabinoid delivery systems (HiE). In vitro dissolution studies were conducted to evaluate the solubility of CBD, CBDA, and CBC in various media (pH 1.2, 6.8, fasted, and fed state simulated intestinal fluid). The HiE-Soluplus delivery systems consistently demonstrated the highest dissolution rate of cannabinoids. Additionally, HiE-Soluplus exhibited the highest permeability coefficients for cannabinoids in gastrointestinal tract conditions than it was during the permeability studies using model PAMPA GIT. All three cannabinoids exhibited promising blood-brain barrier (BBB) permeability (Papp higher than 4.0 × 10−6 cm/s), suggesting their potential to effectively cross into the central nervous system. The improved solubility and permeability of cannabinoids from the HiE-Soluplus delivery system hold promise for enhancement in their bioavailability

Natural Guardians: Natural Compounds as Radioprotectors in Cancer Therapy

Cancer remains a significant global health challenge, with millions of deaths attributed to it annually. Radiotherapy, a cornerstone in cancer treatment, aims to destroy cancer cells while minimizing harm to healthy tissues. However, the harmful effects of irradiation on normal cells present a formidable obstacle. To mitigate these effects, researchers have explored using radioprotectors and mitigators, including natural compounds derived from secondary plant metabolites. This review outlines the diverse classes of natural compounds, elucidating their roles as protectants of healthy cells. Furthermore, the review highlights the potential of these compounds as radioprotective agents capable of enhancing the body’s resilience to radiation therapy. By integrating natural radioprotectors into cancer treatment regimens, clinicians may improve therapeutic outcomes while minimizing the adverse effects on healthy tissues. Ongoing research in this area holds promise for developing complementary strategies to optimize radiotherapy efficacy and enhance patient quality of life

Antimicrobial, Probiotic, and Immunomodulatory Potential of <i>Cannabis sativa</i> Extract and Delivery Systems

The compounds present in hemp show multidirectional biological activity. It is related to the presence of secondary metabolites, mainly cannabinoids, terpenes, and flavonoids, and the synergy of their biological activity. The aim of this study was to assess the activity of the Henola Cannabis sativae extract and its combinations with selected carriers (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer, magnesium aluminometasilicate, and hydroxypropyl-β-cyclodextrin) in terms of antimicrobial, probiotic, and immunobiological effects. As a result of the conducted research, the antimicrobial activity of the extract was confirmed in relation to the following microorganisms: Clostridium difficile, Listeria monocytogenes, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus pyrogenes, Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Pseudomonas aereuginosa, and Candida albicans (microorganism count was reduced from ~102 CFU mL−1 to −1 in most cases). Additionally, for the system with hydroxypropyl-β-cyclodextrin, a significant probiotic potential against bacterial strains was established for strains Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus rhamnosus, Lactobacillus reuteri, Pediococcus pentosaceus, Lactococcus lactis, Lactobacillus fermentum, and Streptococcus thermophilus (microorganism count was increased from ~102 to 104–107). In terms of immunomodulatory properties, it was determined that the tested extract and the systems caused changes in IL-6, IL-8, and TNF-α levels

One Molecule, Many Faces: Repositioning Cardiovascular Agents for Advanced Wound Healing

Chronic wound treatments pose a challenge for healthcare worldwide, particularly for the people in developed countries. Chronic wounds significantly impair quality of life, especially among the elderly. Current research is devoted to novel approaches to wound care by repositioning cardiovascular agents for topical wound treatment. The emerging field of medicinal products’ repurposing, which involves redirecting existing pharmaceuticals to new therapeutic uses, is a promising strategy. Recent studies suggest that medicinal products such as sartans, beta-blockers, and statins have unexplored potential, exhibiting multifaceted pharmacological properties that extend beyond their primary indications. The purpose of this review is to analyze the current state of knowledge on the repositioning of cardiovascular agents’ use and their molecular mechanisms in the context of wound healing

Design of Paracetamol Delivery Systems Based on Functionalized Ordered Mesoporous Carbons

The oxidized ordered mesoporous carbons of cubic and hexagonal structure obtained by two templating methods (soft and hard) were applied for the first time as delivery systems for paracetamol&mdash;the most common antipyretic and analgesic drug in the world. The process of carbon oxidation was performed using an acidic ammonium persulfate solution at 60 &deg;C for 6 h. The functionalization was found to reduce the specific surface area and pore volume of carbon materials, but it also led to an increasing number of acidic oxygen-containing functional groups. The most important element and the novelty of the presented study was the evaluation of adsorption and release ability of carbon carriers towards paracetamol. It was revealed that the sorption capacity and the drug release rate were mainly affected by the materials&rsquo; textural parameters and the total amount of surface functional groups, notably different in pristine and oxidized samples. The adsorption of paracetamol on the surface of ordered mesoporous carbons occurred according to different mechanisms: donor&ndash;acceptor complexes and hydrogen bond formation. The adsorption kinetics was assessed using pseudo-first- and pseudo-second-order models. The regression results indicated that the adsorption kinetics was more accurately represented by the pseudo-second-order model. Paracetamol was adsorbed onto the carbon materials studied following the Langmuir type isotherm. The presence of oxygen-containing functional groups on the surface of ordered mesoporous carbons enhanced the amount of paracetamol adsorbed and its release rate. The optimal drug loading capacity and expected release pattern exhibited oxidized ordered mesoporous carbon with a hexagonal structure obtained by the hard template method

Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation

The presence of active pharmaceutical ingredients (APIs) in the forms of different polymorphic states can induce differences in their physicochemical properties. In the case of poorly soluble APIs, like the oncological drug sorafenib tosylate, small variations in solubility may result in large bioavailability differences. The control of its therapeutic dose is crucial from the effective pharmacotherapy point of view and the reduction of side effects. Therefore, this study aimed to assess the influence of sorafenib tosylate polymorphic forms on its solubility and, consequently, permeability, based on passive diffusion through membranes simulating the gastrointestinal tract (GIT) conditions. In the first part of the work, two crystalline forms of sorafenib tosylate were identified using the X-ray powder diffraction, FT-IR, and Raman spectroscopy. Subsequently, solubility studies were carried out. Both forms of sorafenib tosylate were insoluble in 0.1 N hydrochloric acid (HCl), in acetate buffer (pH 4.5), and in phosphate buffer (pH 6.8). Solubility (mg/mL) of form I and III of sorafenib tosylate in 0.1 N HCl + 1.0% SDS was 0.314 ± 0.006 and 1.103 ± 0.014, respectively, in acetate buffer pH 4.5 + 1.0% SDS it was 2.404 ± 0.012 and 2.355 ± 0.009, respectively, and in phosphate buffer pH 6.8 + 1.0% SDS it was 0.051 ± 0.005 and 1.805 ± 0.023, respectively. The permeability study was assessed using the parallel artificial membrane permeability assay (PAMPA) model. The apparent permeability coefficient (Papp—cm s−1) of form I and III in pH 1.2 was 3.01 × 10−5 ± 4.14 × 10−7 and 3.15 × 10−5 ± 1.89 × 10−6, respectively, while in pH 6.8 it was 2.72 × 10−5 ± 1.56 × 10−6 and 2.81 × 10−5 ± 9.0 × 10−7, respectively. Changes in sorafenib tosylate concentrations were determined by chromatography using the high-performance liquid chromatography (HPLC)–DAD technique. As a result of the research on the structural polymorphism of sorafenib tosylate, its full spectral characteristics and the possibility of using FT-IR and Raman spectroscopy for the study of polymorphic varieties were determined for the first time, and the HPLC method was developed, which is appropriate for the assessment of sorafenib solubility in various media. The consequences of various physicochemical properties resulting from differences in the solubility of sorafenib tosylate polymorphs are important for pre-formulation and formulation studies conducted with its participation and for the safety of oncological sorafenib therapy

THE POSSIBILITY OF USING X-RAY POWDER DIFFRACTION, INFRARED AND RAMAN SPECTROSCOPY IN THE STUDY OF THE IDENTIFICATION OF STRUCTURAL POLYMORPHS OF ACETAMINOPHEN

Paracetamol (acetaminophen), a pain-killer with antipyretic properties, shows structural polymorphism. It occurs in three polymorphic forms: monoclinic, orthorhombic, and unstable form III. In the study, the commercially available samples of paracetamol (P1 and P2) were examined using X-ray powder diffraction, infrared, and Raman spectroscopy. Results demonstrated that all of the methods defined polymorphic forms of paracetamol in the samples. However, only Raman spectroscopy and PXRD methods detected impurities in the sample P1. These methods transpired to be more sensitive than the FT-IR method, which identified samples of paracetamol as one structural form (monoclinic polymorph). Moreover, the Raman spectroscopy identified impurities in the form P1 as changes in the crystalline form