SciencePharma (Poland)

Here, we present the results of a limited, blind, placebo-controlled study examining the effect of the multi-component preparation Glucaferon consisting primarily of beta-glucans obtained from the edible Oyster mushroom, and biologically active substances with verified antioxidant and anti-inflammatory activity on the effectiveness of routine therapy for moderate-to-severe acute SARS-CoV-2-caused infection. There were enrolled 60 subjects (males and females) aged 18 to 75 years, who received a 10-day-long therapy in accordance with the “Prevention, Diagnostics and Treatment of new coronavirus infection (COVID-19). Temporary Guidelines. Version 11”. Inclusion criteria were as follows: males and females aged 18 to 75 years, with positive PCR SARS-CoV-2 result, body temperature ≥ 38.5°C for 3 days; presence of typical CT scan confirmed coronavirus pneumonia; patients’ consent to hospitalization and participation in the study. Patients included in the study were randomized into 2 groups per 30 subjects. In control group, subjects received routine treatment and placebo; in comparison group — routine treatment combined with the preparation Glucaferon. By the end of treatment, all patients in both groups showed positive dynamics. An X-ray examination revealed significantly decreased intensity and size of pre-identified “ground glass” areas of compaction in lung tissue. Residual effects manifested as reticular changes, low-intensity areas of compaction without clear contours. Blood oxygen saturation was also restored to normal levels. Anosmia in both groups was noted by no more than 6% of patients. Patients’ assessment of the intensity of the two most severe symptoms, cough and shortness of breath, using visual analogue scales, also revealed positive dynamics. Despite that the majority of study patients had prerequisites for a complicated COVID-19 course as well as critical levels of laboratory parameters detected in some patients upon admission, the use of Glucaferon caused no negative or adverse reactions, nor stimulated an immune response, while the preparation Glucaferon demonstrated a clinically significant anti-inflammatory effect.

Aim:Copper-61 has attracted wide attention from both physicists and radiochemists in recent years due to its favorable physical decay properties (3.33 h half-life, 61.5% + , Emax 1.22 MeV) and ease of production for PET imaging, as well as potential for radionuclide therapy with its therapeutic counterpart radionuclide copper-67 [1].Herein, we performed a comparison of the stability, in vitro uptake, in vivo pharmacokinetic and imaging characteristics of the [ 61 Cu]Cu-labeled DOTA-TATE and NOTA-TATE compared with the clinical standard [ 68 Ga] Ga-DOTA-TATE in a preclinical model of a neuroendocrine tumor (NET).Materials and methods: Copper-61 was produced via natural zinc liquid target irradiation using an IBA Cyclone 18/9 cyclotron, followed by post-processing [2,3].The DOTA-TATE and NOTA-TATE conjugated peptides were labeled with copper-61, and the radiopharmaceuticals stability was assessed up to 6 h after EOS in both final formulation (15% EtOH/NaCl) and mice serum.In vitro evaluation of the cell uptake of the radiolabeled peptides was performed in pancreatic tumoral cell line AR42J to prove the specificity of the peptides towards the SST receptors (SSTr).Control and primary tumor-bearing mice were i.v.injected with the radiolabeled peptides and imaged in a micro-PET/ MRI. Results:The radiolabeling process of [ 61 Cu]Cu-DOTA-TATE and [ 61 Cu] Cu-NOTA-TATE resulted in high molar activity (18.5-37GBq/mol) and high radiochemical purity over 95%.Both gallium-68 and copper-61 labeled peptides exhibited increasing cellular uptake with time in AR42J cells that overexpress SSTr.Both [ 61 Cu]Cu-NOTA-TATE and [ 61 Cu] Cu-DOTA-TATE accumulated in AR42J tumors but to different extents.[ 61 Cu]Cu-DOTA-TATE show high uptake in non-targeted organs, such as the liver and gastrointestinal tract.Whereas [ 61 Cu]Cu-NOTA-TATE showed fast, primarily renal, clearance and low uptake in non-targeted organs at 1 h p.i. Tumor detectability was visually improved at 4 h p.i. for [ 61 Cu]Cu-NOTA-TATE, at this time point all the activity has cleared with only significant uptake in the tumor.Ex vivo biodistribution data confirmed the PET/MRI images, [ 61 Cu]Cu-NOTA-TATE have recorded the highest tumor uptake seen at 4 h p.i. (12.81 0.99%ID/g, n = 3).Conclusion: [ 61 Cu]Cu-NOTA-TATE had significant better biodistribution profile and imaging properties than [ 61 Cu]Cu-DOTA-TATE and showed similar biodistribution and pharmacokinetics to [ 68 Ga]Ga-DOTA-TATE at 1 h p.i., while showing enhanced imaging characteristics for late time point imaging.[ 61 Cu]Cu-NOTA-TATE showed to have promising characteristic to be translated to human clinical trials.

The purpose of this study was to evaluate the properties and pharmacokinetics of liposomal vitamin C in powder form obtained by a method devoid of organic solvents. The powder and liposome morphology were analyzed using scanning electron microscopy (SEM) and cryogenic transmission electron microscopy (cryo-TEM), respectively. Additionally, the carrier particle size, size distribution (STEP-Technology®; L.U.M. GmbH, Berlin, Germany), and zeta potential value were determined. The pharmacokinetic parameters of liposomal and non-liposomal vitamin C (AUC, Cmax, C10h, and C24h) were compared in a randomized, single-dose, double-blind, cross-over trial (ClinicalTrials.gov ID: NCT05843617) involving healthy adult volunteers (n = 10, 1000 mg dose). The process of spray drying used to transform liquid suspensions of the liposomes into powder form did not adversely affect the quality of the carrier particles obtained. Compared to non-encapsulated vitamin C, oral administration of the liposomal formulation resulted in significantly better absorption of ascorbic acid into the bloodstream, which equated to a higher bioavailability of the liposomal product (30% increase in AUC, p < 0.05). The duration of elevated vitamin C blood levels was also longer (C24h increase of 30%, p < 0.05). Although the results obtained are promising and suggest higher bioavailability for the liposomal form of vitamin C, the limited sample size necessitates further research with a larger cohort to confirm these findings.

The fusion of penetrating peptides (PPs), e.g., cell penetration peptides (CPPs), or antimicrobial peptides (AMPs) together with antimicrobial agents is an expanding research field. Specific AMPs, such as lactoferricin B (LfcinB), have demonstrated strong antibacterial, antifungal, and antiparasitic activity, as well as valuable anticancer activity, proving beneficial in the development of anticancer conjugates. The resulting conjugates offer potential dual functionality, acting as both an anticancer and an antimicrobial agent. This is especially necessary in cancer treatment where microbial infections pose a critical risk. Leukemic cells frequently exhibit altered outer lipid membranes compared to healthy cells, making them more sensitive to compounds that interfere with their membrane. In this communication, we revisited and reanalyzed our earlier research on LfcinB and its conjugates. Furthermore, we carried out new experiments with a specific focus on cell proliferation, changes in membrane asymmetric phosphatidylserine location, intracellular reactive oxygen species (ROS) generation, mitochondrial functions, and in vitro bacterial topoisomerase inhibition.

Hematopoietic cell transplantation (HCT) is often considered a last resort leukemia treatment, fraught with limited success due to microbial infections, a leading cause of mortality in leukemia patients. To address this critical issue, we explored a novel approach by synthesizing antileukemic agents containing antibacterial substances. This innovative strategy involves conjugating fluoroquinolone antibiotics, such as ciprofloxacin (CIP) or levofloxacin (LVX), with the cell-penetrating peptide transportan 10 (TP10). Here, we demonstrate that the resultant compounds display promising biologic activities in preclinical studies. These novel conjugates not only exhibit potent antimicrobial effects but are also selective against leukemia cells. The cytotoxic mechanism involves rapid disruption of cell membrane asymmetry leading to membrane damage. Importantly, these conjugates penetrated mammalian cells, accumulating within the nuclear membrane without significant effect on cellular architecture or mitochondrial function. Molecular simulations elucidated the aggregation tendencies of TP10 conjugates within lipid bilayers, resulting in membrane disruption and permeabilization. Moreover, mass spectrometry analysis confirmed efficient reduction of disulfide bonds within TP10 conjugates, facilitating release and activation of the fluoroquinolone derivatives. Intriguingly, these compounds inhibited human topoisomerases, setting them apart from traditional fluoroquinolones. Remarkably, TP10 conjugates generated lower intracellular levels of reactive oxygen species compared with CIP and LVX. The combination of antibacterial and antileukemic properties, coupled with selective cytostatic effects and minimal toxicity toward healthy cells, positions TP10 derivatives as promising candidates for innovative therapeutic approaches in the context of antileukemic HCT. This study highlights their potential in search of more effective leukemia treatments. SIGNIFICANCE STATEMENT: Fluoroquinolones are commonly used antibiotics, while transportan 10 (TP10) is a cell-penetrating peptide (CPP) with anticancer properties. In HCT, microbial infections are the primary cause of illness and death. Combining TP10 with fluoroquinolones enhanced their effects on different cell types. The dual pharmacological action of these conjugates offers a promising proof-of-concept solution for leukemic patients undergoing HCT. Strategically designed therapeutics, incorporating CPPs with antibacterial properties, have the potential to reduce microbial infections in the treatment of malignancies.

Vilanterol (VT) and fluticasone furoate (FF) are components recently used in dry powder inhaler (DPI) to be administrated for patients with respiratory diseases, such as asthma or chronic obstructive pulmonary disease (COPD). In the present study, an approach to an analytical procedure development and validation is presented. Next generation impactor (NGI) and high performance liquid chromatography (HPLC) with UV detector were applied to determine two compounds and fine particle dose (FPD) of each active ingredients in DPI. The most satisfying chromatographic separation was obtained on Poroshell SB C18 (100 mm × 4.6 mm, 2.7 µm) column applying gradient elution by phosphonate buffer and acetonitrile. VT and FF were detected on a UV detector at wavelength of 210 nm and 245 nm, respectively. Among various coating agents, 4% polyethylene glycol PEG 200 in acetone (w/v) was selected as the most effective. Although various physicochemical properties of VT and FF, the analytical procedure allows simultaneously determine two compounds at different wavelengths. Limit of quantitative (LOQ) of vilanterol and fluticasone furoate were determined as 0.049 µg/ml and 0.032 µg/ml, respectively, what is desirable to determine of FPD of active ingredients in microdoses in DPI. The analytical procedure was determined as linear and accurate in the range of LOQ – 2.5 µg/ml and LOQ – 10.0 µg/ml of VT and FF, respectively. The coefficient of determination (R2) was found to be 0.9999 and 1.000 for VT and FF, respectively.

A numberof metathesis reactions were successfully conducted in4-methyltetrahydropyran, including both standard model dienes, aswell as more complex substrates, such as analogues of biologicallyactive compounds and active pharmaceutical ingredients. To place thissolvent in a context of pharmaceutical R + D, larger-scale synthesesof SUAM 1221, a prolyl endopeptidase inhibitor with potential applicationin Alzheimer disease treatment, and a derivative of sildenafil, ananalogue of the popular Viagra drug, were executed. In the lattercase, despite all the setup being made in air, the metathesis reactionat a 33 g scale proceeded very well with relatively low catalyst loadingand without need of aqueous workup or column chromatography.

Pharmacological and physicochemical classification of bases' selected analogues of nucleic acids is proposed in the study. Structural parameters received by the PCM (Polarizable Continuum Model) with several types of calculation methods for the structures in vacuo and in the aquatic environment together with the huge set of extra molecular descriptors obtained by the professional software and literature values of biological activity were used to search the relationships. Principal Component Analysis (PCA) together with Factor Analysis (FA) and Multiple Linear Regressions (MLR) as the types of the chemometric approach based on semi-empirical ab initio molecular modeling studies were performed. The equations with statistically significant descriptors were proposed to demonstrate both the common and differentiating characteristics of the bases' analogues of nucleic acids based on the quantum chemical calculations and biological activity data. The obtained QSAR models can be used for predicting and explaining the activity of studied molecules.