Influence of HA on Release Process of Anionic and Cationic API Incorporated into Hydrophilic Gel.

The properties of sodium hyaluronate (HA), such as hygroscopicity, flexibility, the ability to form hydrogels, as well as biocompatibility and biodegradability, are beneficial for the applications in pharmaceutical technology, cosmetics industry, and aesthetic medicine. The aim of this study was to prepare HA-based hydrogels doped with active pharmaceutical ingredient (API): a cationic drug-lidocaine hydrochloride or anionic drug-sodium. The interaction between the carrier and the implemented active pharmaceutical substances was evaluated in prepared systems by applying viscometric measurements, performing release tests of the drug from the obtained formulations, and carrying out FTIR and DSC. The data from release studies were analyzed using the zero-, first-, and second-order kinetics and Higuchi, Korsmeyer-Peppas, and Hixon-Crowell models. The respective kinetic parameters: the release rate constants, the half-release time and, in the case of the Korsmeyer-Peppas equation, the n parameter were calculated. The variability between the obtained release profiles was studied by calculating the difference (f1) and the similarity factor (f2) as well as employing statistical methods. It was revealed that the incorporation of the drugs resulted in an increase in the viscosity of the hydrogels in comparison to the respective drug-free preparations. The dissolution study showed that not entire amount of the added drug was released from the formulation, suggesting an interaction between the carrier and the drug. The FTIR and DSC studies confirmed the bond formation between HA and both medicinal substances.

Evaluation of the Effect of Antibacterial Peptides on Model Monolayers.

The aim of the study was to assess the effect of the synthesized antibacterial peptides: P2 (WKWK)2-KWKWK-NH2, P4 (C12)2-KKKK-NH2, P5 (KWK)2-KWWW-NH2, and P6 (KK)2-KWWW-NH2 on the physicochemical properties of a model biological membrane made of azolectin or lecithin. The Langmuir Wilhelmy method was used for the experiments. Based on the compressibility factor, it was determined that the monolayers formed of azolectin and peptides in the aqueous subphase are in the condensed liquid phase. At the boundary between the condensed and expanded liquid phases, there was a monolayer made of lecithin and P4, P5 or P6 in the aqueous subphase. In turn, the film consisting of lecithin alone (37.7 mN/m) and lecithin and P2 (42.6 mN/m) in the water subphase was in the expanded liquid phase. All peptides change, to varying degrees, the organization and packing of molecules in the monolayer, both those made of azolectin and of lecithin. The test results can be used for further research to design a system with the expected properties for specific organisms.

Antimicrobial and Antioxidative Activity of Newly Synthesized Peptides Absorbed into Bacterial Cellulose Carrier against Acne vulgaris.

The ongoing search for effective treatment of Acne vulgaris is concentrated, i.a., on natural peptides with antimicrobial properties. The aim of this work was the development of new amino acid derivatives with potential activity on dermal infections against selected microorganisms, including the facultative anaerobe C. acne. The peptides P1-P6 were synthesized via Fmoc solid phase peptide synthesis using Rink amide AM resin, analyzed by RP-HPLC-MS, FTIR, DPPH radical scavenging activity, and evaluated against C. acne and S. aureus, both deposited and non-deposited in BC. Peptides P1-P6 presented a lack of cytotoxicity, antimicrobial activity, or antioxidative properties correlated with selected structural properties. P2 and P4-P6 sorption in BC resulted in variable data, i.a., confirming the prospective topical application of these peptides in a BC carrier.

Modulatory Effect of Chelidonium majus Extract and Its Alkaloids on LPS-Stimulated Cytokine Secretion in Human Neutrophils.

Due to certain differences in terms of molecular structure, isoquinoline alkaloids from Chelidonium majus engage in various biological activities. Apart from their well-documented antimicrobial potential, some phenanthridine and protoberberine derivatives as well as C. majus extract present with anti-inflammatory and cytotoxic effects. In this study, the LC-MS/MS method was used to determine alkaloids, phenolic acids, carboxylic acids, and hydroxybenzoic acids. We investigated five individually tested alkaloids (coptisine, berberine, chelidonine, chelerythrine, and sanguinarine) as well as C. majus root extract for their effect on the secretion of IL-1ß, IL-8, and TNF-α in human polymorphonuclear leukocytes (neutrophils). Berberine, chelidonine, and chelerythrine significantly decreased the secretion of TNF-α in a concentration-dependent manner. Sanguinarine was found to be the most potent inhibitor of IL-1ß secretion. However, the overproduction of IL-8 and TNF-α and a high cytotoxicity for these compounds were observed. Coptisine was highly cytotoxic and slightly decreased the secretion of the studied cytokines. The extract (1.25-12.5 µg/mL) increased cytokine secretion in a concentration-dependent manner, but an increase in cytotoxicity was also noted. The alkaloids were active at very low concentrations (0.625-2.5 µM), but their potential cytotoxic effects, except for chelidonine and chelerythrine, should not be ignored.

Quality of Life in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Palliative Chemotherapy.

The goal of this study was to explore quality of life in patients with advanced non-small-cell lung cancer (NSCLC) in an attempt to single out features that could help predict the possibility of non-completion of chemotherapy. The survey tool was the Quality of Life Questionnaire Core-30 (QLQ-C30) with the module Lung Cancer 13 (LC-13) developed by the European Organization for Research and Treatment of Cancer. The assessment of quality of life (QoL) was performed in 58 patients with advanced NSCLC before palliative chemotherapy and it was repeated in 43 patients who completed at least three cycles of chemotherapy. We found that the patients who failed to complete the chemotherapy course distinctly showed, in contradistinction to those who completed it, poor physical functioning in (67.6 ± 16.3 vs. 78.3 ± 21.3 points, respectively, p < 0.05) and the lack of appetite (27.1 ± 38.0 vs. 48.9 ± 37.5 points, respectively p < 0.05). At the end of palliative chemotherapy alopecia, sore throat, and constipation significantly worsened QoL, but global health status remained unchanged. In conclusion, poor physical functioning and loss of appetite seem to harbinger a risk of non-completion of chemotherapy in advanced NSCLC.

Comparison of Polyphenol Profile and Antimutagenic and Antioxidant Activities in Two Species Used as Source of Solidaginis herba - Goldenrod.

European Pharmacopoeia accepts two equivalent species Solidago canadensis L. and S. gigantea Aiton as goldenrod (Solidaginis herba). We compared phytochemical profile of both species from invasive populations in Poland. Further, we compared in vitro antimutagenic and antioxidant activities of solvent extracts from aerial (AP) and underground parts (UP). In S. gigantea, flavonoid profile was dominated by quercetin glycosides, with quercitrin as the major compound. In S. canadensis, quercetin and kaempferol rutinosides were two major constituents. Caffeoylquinic acids (CQAs) were less diverse with 5-CQA as a main compound. In UP, over 20 putative diterpenoids were detected, mostly unidentified. Several CQAs were present in higher amounts than in AP. Antioxidant and antimutagenic activities were different between species and organs, with the strongest inhibition of lipid peroxidation by Et2 O and AcOEt fractions from AP of both species (IC50 13.33 - 16.89 µg/mL) and BuOH fraction from S. gigantea UP (IC50  = 13.32 µg/mL). Chemical mutagenesis was completely inhibited by non-polar fractions, but oxidative mutagenesis was inhibited up to 35% only by S. canadensis. No clear relationship was found between chemical profiles and antimutagenic activity. In conclusion, both species have diverse activity and their phytochemical profiles should be considered in quality evaluation. UP of these weeds can also provide potential chemopreventive substances for further studies.

ANTIRADICAL AND ANTIMICROBIAL ACTIVITY OF PHENOLIC FRACTIONS OBTAINED FROM HONEYS.

Honey is a natural product consisting of multiple components which determine its dietary and medicinal properties. In this work there were studied methanol fractions obtained from seven honeys from Lower Silesia (Poland) collected in different seasons of three successive years. Melissopalynologic studies revealed that two of them were polyfloral, and five were classified as monofloral (two buckwheat and three rapes). The amount of phenolic compounds in honeys varied from 0.09 to 0.38 mg per g of honey. Honeys harvested in 2010 were the richest in phenolic compounds and especially rich was buckwheat honey, comparing to 2011- 2012. Determination of antioxidant potential with the DPPH radical revealed that the strongest antiradical activity was exhibited by extracts obtained from polyfloral (1.22 TAU(515/mg)) and buckwheat (1.06 TAU(515lmg)) honeys, while the highest number of antiradical units was observed for rape honey (3.64 TAU(515/g)). Polyphenolic fractions exhibited various bactericidal activities against Klebsiella pneumoniae and Staphylococcus aureus and weak or no activity was observed against Pseudomonas aeruginosa.

Polyphenol Profile of Cistus × incanus L. and Its Relevance to Antioxidant Effect and α-Glucosidase Inhibition.

The European Food Safety Authority recommends C. incanus as a natural source of antioxidants. Its activity is essentially determined by polyphenols, although specific compounds are not finally indicated. The available plant material comes from different subspecies and locations, which can lead to differences in chemical composition and potency. For this reason, we conducted a detailed analysis of the polyphenol content and antioxidant activity of 52 different C. incanus teas from Turkey, Albania, Greece, and unspecified regions. We focused special attention on ellagitannins, which have not been properly determined so far. Besides oxidative stress, hyperglycemia is an essential component of cardiometabolic diseases. Therefore, in subsequent experiments, we evaluated the ability of C. incanus extracts and individual polyphenols to inhibit α-glucosidase. Using statistical methods, we analyzed how differences in chemical composition affect activity. The results showed that C. incanus is a rich source of ellagitannins (2.5-19%), which dominate among polyphenols (5.5-23%). Turkish-origin products had higher ellagitannin content and a greater antioxidant effect (FRAP, ABTS) than Albanian and Greek products. In contrast, the flavonoid and phenolic acid contents and DPPH values were at similar levels in all products. An in-depth analysis of their composition indicated that all groups of polyphenols are involved in the antioxidant effect, but a significant contribution can be attributed to ellagitannins and flavonoids. C. incanus extracts showed a high capacity to inhibit α-glucosidase activity (IC50 125-145 µg/mL). Ellagitannins were the most effective inhibitors (IC50 0.7-1.1 µM), with a potency exceeding acarbose (3.3 mM). In conclusion, C. incanus, due to the presence of ellagitannins and flavonoids, exhibits powerful antioxidant and α-glucosidase inhibitory effects.

In Search of High-Yielding and Single-Compound-Yielding Plants: New Sources of Pharmaceutically Important Saponins from the Primulaceae Family.

So far, only a few primrose species have been analyzed regarding their saponin composition and content. Moreover, the roots of only two of them are defined by the European Union (EU) Pharmacopoeia monograph and commercially utilized by the pharmaceutical industry. Thus, this study intended to find some new sources of main triterpene saponins from Primulae radix, namely primulasaponins I and II together with the closely related sakurasosaponin. Using isolated standards, UHPLC-ESI-HRMS served to assess over 155 Primulaceae members qualitatively and quantitatively. Nine examples of plants accumulating over 5% of primulasaponin I in their roots were found. Among them, in one case, it was found as the almost sole secondary metabolite with the concentration of 15-20% (Primula grandis L.). A reasonable content of primulasaponin II was found to be typical for Primula vulgaris Huds. and P. megaseifolia Boiss. & Bal. The sakurasosaponin level was found in seven species to exceed 5%. The finding of new, single and rich sources of the abovementioned biomolecules among species that were never analyzed phytochemically is important for future research and economic benefit. The chemotaxonomic significance of the occurrence of these three saponins in Primulaceae is discussed.

The use of kinetic N-order model in description of active substance release from various drug forms. Part 1. Premises and mathematical analysis of the N-order model.

The paper presents the premises and equations which are the basis of the mathematical n-order model, which contrarily to standard models based on the laws of chemical kinetics, i.e. 0-order and 1-order kinetics, enables categorization of the investigated process taking into account two parameters: the rate at which it occurs, and actual order, which it is distinguished by. Standard models, which assume in advance the kinetic order of the described processes, may be used with satisfactory accuracy to analyze only a low percentage of performed experiments. However, as shown in practice, the order of many physico-chemical processes, including those which are most interesting for us, active substance release from the drug form, may assume intermediate values, what is manifested as various types of "smooth non-linearities" in the obtained release profiles, which cannot be explained on the basis of assumed standard theories. N-order model may be numbered among the group of physical mathematical models based on the premises of chemical kinetics, possessing the analytical structure of internally non-linear function. It is characterized by two parameters: release rate constant K and order coefficient N.

The use of kinetic N-order model in description of active substance release from various drug forms. Part 2. Analysis of paracetamol and sodium diclofenac release from methylcellulose.

The first part of the monograph presented the premises and equations which are the basis for the proposed mathematical n-order model. This non-linear physical model obeying the laws of chemical kinetics was used to describe the processes of active substance release from drug form. The possibilities of its application in the mathematical description and detailed analysis of the kinetics of paracetamol and sodium diclofenac release from various viscosity gels based on methylcellulose were investigated. Moreover, the effect of temperature on the release profiles of the above-mentioned active substances from investigated formulations was analyzed. On the basis of a series of performed experiments and detailed comparative statistical analysis of the estimators of two parameters characterizing n-order model: release rate constant K and order coefficient of the release process N, it was demonstrated that the active substance release rate from formulations with uncontrolled release is correlated with actual order of the process. Also, the proposed n-order model was compared with models obeying the laws of chemical kinetics: 0-order model, 1-order model and with diffusion Higuchi "square root of time" model, and the comparison demonstrated superiority of the n-order model over standard models. A non-linear statistical analysis was performed by means of computer software Statistica Pl. v. 7.1 manufactured by StatSoft Polska and Mathematica v. 5.0 manufactured by Wolfram Research.

Influence of CYP2C19 Genotypes on the Occurrence of Adverse Drug Reactions of Voriconazole among Hematological Patients after Allo-HSCT.

The aim of this study was to determine the influence of different CYP2C19 genotypes on selected liver function parameters, and ADR occurrence during VCZ prophylaxis in adult patients after allo-HSCT (allogeneic hematopoietic stem cell transplantation). CYP2C19 mutations were determined in a cohort of 30 adults using PCR-RFLP methods established by Sim et al. and Goldstein and Blaisdell. The patients' protocol included biometrical and biochemical data, information on the underlying disease, chemotherapy, molds infections occurring during VCZ treatment, adverse drug reactions typical for the use of voriconazole, and probable drug - drug interactions. The observation and reporting of ADR took place from the -1 until the +20th day of VCZ therapy. For statistical analysis the χ2 test was used (p < 0.05). Among the examined patients 23 suffered from at least one side effect during VCZ therapy. Most frequent ADR were gastrointestinal disturbances (n = 15), nervous system (n = 11) and skin (n = 7) disorders. Patients with at least one loss of function allele (*2) were more likely to experience adverse drug reactions than those, with different genotypes. Due to the limited number of patients the result could not be proven with a statistical significance. Previous determination of CYP2C19 genotype may be a useful tool for prevention of adverse drug reactions during VCZ prophylaxis among patients after allo-HSCT.

Application of an anionic polymer in the formulation of floating tablets containing an alkaline model drug.

BACKGROUND: Gastric residence time is the key factor affecting the bioavailability of active pharmaceutical ingredients absorbed mainly through the gastric mucous membrane and influencing the local activity of some drugs. OBJECTIVES: The aim of this study was the development of a new composition of non-effervescent floating tablets and the evaluation of the effect of an anionic polymer and compressive force on the floating properties and release characteristics of tablets containing a model alkaline drug, chlorhexidine (CHX). MATERIAL AND METHODS: Direct compression was applied to a polyacrylic acid derivative and sorbitol to fabricate the tablets. Drug release was analyzed using several kinetic models. The formulations floated on the surface of the fluid for 24 h. The values of the rate constants, statistical parameters, and half-release time (t0.5) were calculated. RESULTS: The diffusion coefficient n falls between 0.54 ±0.02 and 0.81 ±0.03 for most formulations. The floating time (FT) and floating lag time (FLT) were found to depend on the amount of polymer incorporated in the formulations. A high compressive force sustained the release of the drug but reduced the FT and FLT. Based on the FT and t0.5, it was determined that the C1 composition is the optimal formulation with FT >24 h and t0.5 between 113 ±2 and 144 ±13 min, depending on the drug release model. CONCLUSIONS: The application of an anionic polymer results in a prolonged release of the drug from the tablets and allows them to float on fluid surfaces.

[Is low pre-pregnancy body mass index a risk factor for preterm birth and low neonatal birth weight?]. / Niski BMI przed zajsciem w ciaze: czy jest czynnikiem ryzyka porodów przedwczesnych i niskiej masy urodzeniowej noworodków?

OBJECTIVES: A pregnant woman's weight is an extremely important factor in the course of pregnancy and delivery. Not only obesity but also being underweight may lead to complications in pregnancy such as: preterm delivery and low neonatal birth weight. DESIGN: The aim of this study was to analyze the relationship between a low BMI and outcome of pregnancy, birth weight and general well being of the neonates. MATERIAL AND METHODS: 415 patients who were hospitalized in the Department of Obstetrics and Reproduction Wroclaw Medical University between 1996-2005 was done. The patients were divided into 3 groups I--Underweight (BMI <19,8), II--Appropriate weight (BMI 19,8-26,0) and III--Overweight (BMI>26,0). RESULTS: The frequency of preterm deliveries as well as low neonatal birth weight <2500g, in underweight mothers was higher than in other groups. CONCLUSIONS: Low pre-pregnancy BMI is an important factor risk factor in preterm deliveries. There was no correlation between BMI and the general well being of the neonates.

Antiradical and antioxidant activity of flavones from Scutellariae baicalensis radix.

We evaluated the antioxidant properties of four main flavones from Scutellaria baicalensis: baicalein, wogonin and their glucuronides - baicalin and wogonoside. We used three in vitro assays: free radical scavenging with 2,2'-diphenylpicrylhydrazyl radical, transition metal ions reducing power by phosphomolybdenum assay and inhibition of the hydroxyl radical-induced peroxidation of linoleic acid assay. All flavones have antioxidant capacity, which differs depending on the structure and mechanisms of activity. In all tests, only baicalein - the aglycone with three adjacent hydroxyl groups - exhibited consistent antioxidant effect. Wogonin protected linoleic acid against oxidation. Baicalin displayed less potent antioxidant properties whereas wogonoside did not have significant antioxidant activity.

Antiradical activity of hydrolyzed and non-hydrolyzed extracts from Helichrysi inflorescentia and its phenolic contents.

A methanol extract was obtained from defatted (petroleum ether) inflorescence of Helichrysum arenarium (L.) Moench (perennial herb native to Middle and Southeast Europe). The extract was evaporated under reduced pressure and the dry residue was dissolved in hot water. The aqueous solution was stored for 6 d at 4 degrees C and the precipitate discarded. The remaining solution was divided into three aliquots a, b and c. Part a was extracted with ethyl acetate to obtain extract (A), part b was extracted with diethyl ether to obtain extract (B) and part c was subjected to alkaline hydrolysis and then extracted with diethyl ether to obtain extract (C). Extracts (A), (B) and (C) were evaporated under reduced pressure to obtain the dry residues A, B and C which were further investigated for phenolic compound content by TLC and HPLC and for antiradical activity with 2,2-diphenyl-1-picrylhydrazyl radical (DPPH*) as a substrate. Residue C exhibited stronger antiradical properties than non-hydrolysed residues A and B. HPLC analysis showed a great increase of caffeic acid in residue C. We concluded that the hydrolysis process led to a significant increase of free caffeic acid (strong antioxidant) concentration resulting in increased antiradical activity of residue C.