The solubility of weakly basic drugs within passage though GI tract leads to pH-dependent or even incomplete release of these drugs from extended release formulations and consequently to lower drug absorption and bioavailability. The aim of the study was to prepare and evaluate hydrophilic-lipophilic (hypromellose-montanglycol wax) matrix tablets ensuring the pH-independent delivery of the weakly basic drug verapamil-hydrochloride by an incorporation of three organic acidifiers (citric, fumaric, and itaconic acids) differing in their concentrations, pK a, and solubility. The dissolution studies were performed by the method of changing pH values, which better corresponded to the real conditions in the GI tract (2 h at pH 1.2 and then 10 h at pH 6.8). Within the same conditions, pH of matrix microenvironment was measured. To determine relationships between the above mentioned properties of acidifiers and the monitored effects (the amount of released drug and surface pH of gel layer in selected time intervals-360 and 480 min), the full factorial design method and partial least squares PLS-2 regression were used. The incorporation of the tested pH modifiers significantly increased the drug release rate from matrices. PLS-components explained 75% and 73% variation in the X- and Y-data, respectively. The obtained results indicated that the main crucial points (p < 0.01) were the concentration and strength of acidifier incorporated into the matrix. Contrary, the acid solubility surprisingly did not influence the selected effects except for the surface pH of gel layer in time 480 min.

• MeSH
• algoritmy MeSH
• blokátory kalciových kanálů aplikace a dávkování   chemie   MeSH
• elektrody MeSH
• faktorová analýza statistická MeSH
• gely MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• léčivé přípravky aplikace a dávkování   chemie   MeSH
• methylcelulosa analogy a deriváty   MeSH
• racionální návrh léčiv MeSH
• rozpustnost MeSH
• tablety MeSH
• velikost částic MeSH
• verapamil aplikace a dávkování   chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The potential for application of any nanoparticles, including silver nanoparticles (AgNPs), is strongly dependent on their stability against aggregation. Therefore, improvement of this parameter is a key task, especially in the case of AgNPs, because a correlation between size and biological activity has been demonstrated. In the present work, a natural stabilizer, gelatin, was investigated for the stabilization of AgNPs in an aqueous dispersion. The particles were prepared via a modified Tollens process, and the gelatin modifier was added prior to the reducing agent. The stability against aggregation of the AgNPs prepared by this method was more than one order of magnitude higher (on the basis of the critical coagulation concentration (CCC)) than that of AgNPs prepared via a similar method but without the assistance of gelatin. Their high stability against aggregation was confirmed over wide pH range (from 2 to 13) in which the particles did not exhibit rapid aggregation; such stability has not been previously reported for AgNPs. Additionally, gelatin not only fulfills the role of a unique stabilizer but also positively influences the modified Tollens process used to prepare the AgNPs. The diameter of the gelatin-modified AgNPs was substantially smaller in comparison to those prepared without gelatin. The polydispersity of the dispersion significantly narrowed. Moreover, the gelatin-stabilized AgNPs exhibited long-term stability against aggregation and maintained high antibacterial activity when stored for several months under ambient conditions.

• MeSH
• antibakteriální látky * chemie   farmakologie   MeSH
• Bacteria růst a vývoj   MeSH
• časové faktory MeSH
• koncentrace vodíkových iontů MeSH
• kovové nanočástice chemie   MeSH
• stabilita léku MeSH
• stříbro * chemie   farmakologie   MeSH
• želatina * chemie   farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The solubility of weakly basic drugs in passage through gastrointestinal tract leads to their pH-dependent release from extended release formulations and to lower drug absorption and bioavailability. The aim of this study was to modulate the micro-environmental pH of hypromellose/montanglycol wax matrices and to observe its influence on the release of weakly basic drug verapamil hydrochloride (VH) with a pH-dependent solubility with respect to gel layer formation and its dynamics. For this study, malic and succinic acids differing in their solubility and pKa were selected as pH modifiers. The dissolution studies were performed by the method of changing pH. Within the same conditions, pH, thickness, and penetration force of the gel layer were measured as well. From the PCA sub-model, it is evident that a higher acid concentration ensured lower gel pH and conditions for higher drug solubility, thus creating larger gel layer with smaller rigidity, resulting in higher VH release during the dissolution test. Incorporation of stronger and more soluble malic acid (100 mg/tablet) created the most acidic and the thickest gel layer through which a total of 74% of VH was released. Despite having lower strength and solubility, matrices containing succinic acid (100 mg/tablet) released a comparable 71% of VH in a manner close to zero-order kinetics. The thinner and less rigid gel layers of the succinic acid matrices allowed an even slightly faster VH release at pH 6.8 than from matrices containing malic acid. Thus acid solubility is more parametrically significant than acid pKa for drug release at pH 6.8.

• MeSH
• deriváty hypromelózy * MeSH
• gely MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem chemie   MeSH
• maláty chemie   MeSH
• multivariační analýza MeSH
• rozpustnost MeSH
• sukcináty chemie   MeSH
• tablety MeSH
• uvolňování léčiv MeSH
• verapamil aplikace a dávkování   chemie   metabolismus   MeSH
• vosky * MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: The objective of this work was to gather an international consensus group to propose a global definition and diagnostic approach of laryngopharyngeal reflux (LPR) to guide primary care and specialist physicians in the management of LPR. METHODS: Forty-eight international experts (otolaryngologists, gastroenterologists, surgeons, and physiologists) were included in a modified Delphi process to revise 48 statements about definition, clinical presentation, and diagnostic approaches to LPR. Three voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 8/10. Votes were anonymous and the analyses of voting rounds were performed by an independent statistician. RESULTS: After the third round, 79.2% of statements (N = 38/48) were approved. LPR was defined as a disease of the upper aerodigestive tract resulting from the direct and/or indirect effects of gastroduodenal content reflux, inducing morphological and/or neurological changes in the upper aerodigestive tract. LPR is associated with recognized non-specific laryngeal and extra-laryngeal symptoms and signs that can be evaluated with validated patient-reported outcome questionnaires and clinical instruments. The hypopharyngeal-esophageal multichannel intraluminal impedance-pH testing can suggest the diagnosis of LPR when there is >1 acid, weakly acid or nonacid hypopharyngeal reflux event in 24 h. CONCLUSION: A global consensus definition for LPR is presented to improve detection and diagnosis of the disease for otolaryngologists, pulmonologists, gastroenterologists, surgeons, and primary care practitioners. The approved statements are offered to improve collaborative research by adopting common and validated diagnostic approaches to LPR. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:1614-1624, 2024.

• MeSH
• elektrická impedance MeSH
• laryngofaryngeální reflux * diagnóza   MeSH
• larynx * MeSH
• lidé MeSH
• monitorování jícnového pH MeSH
• otorinolaryngologové MeSH
• průzkumy a dotazníky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A new type of promising chitosan beads with advanced properties were obtained under microwave radiation according to Green Chemistry principles. Biomaterials were prepared using chitosan as raw material and glutamic acid/1,5-pentanodiol mixture as crosslinking agents. Additionally beads were modified with Tilia platyphyllos extract to enhance their antioxidant properties. Beads were investigated over their chemical structure by FT-IR analysis. Also their morphology has been investigated by SEM method. Additionally swelling capacity of the obtained hydrogels was determined. Lack of cytotoxicity has been confirmed by MTT assay. Proliferation studies were carried out on L929 mouse fibroblasts. Advanced properties of the obtained beads were investigated by studying pH sensitivity and antioxidant properties by DPPH method. Also susceptibility to degradation and biodegradation by Sturm Test method was evaluated. Results shows that proposed chitosan beads and their eco-friendly synthesis method can be applied in cell therapy and tissue engineering.

• MeSH
• antioxidancia farmakologie   MeSH
• biokompatibilní materiály farmakologie   MeSH
• buněčné kultury metody   MeSH
• chitosan chemie   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• mikrosféry * MeSH
• mikrovlny * MeSH
• myši MeSH
• proliferace buněk účinky léků   MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Phosphoinositides are phosphatidylinositol derived, well known to be second messengers in various cell signaling pathways as well as in processes such as cell differentiation, cellular stress response, gene transcription, and chromatin remodeling. The pleckstrin homology domain of phospholipase C-delta 1 is responsible for recognizing and binding to PI(4,5)P2 and for this reason has been widely used to study this phosphoinositide as a biosensor when it is conjugated to a fluorescent tag. In this work, we modified the primary structure of pleckstrin homology domain by site-specific mutagenesis to change the specificity for phosphoinositides. We obtained 3 mutants: K30A, W36F, and W36Y with different specificity to phosphoinositides. Mutant domain K30A recognized PI(4,5)P2 , PI(3,4,5)P3 , phosphatidic acid (PA), and weakly PI(3,5)P2 . Mutant domain W36F recognized all the phosphoinositides studied and the PA. Finally, mutant domain W36Y seemed to interact with PA and all the other phosphoinositides studied, except PI(3)P. The changes in recognition argue against a simple charge and nonpolar region model for these interactions and more in favor of a specific docking region with a specific recognition site. We conducted in silico modeling that explains the mechanisms behind the observed changes and showed that aromatic amino acids appear to play more important role, than previously thought, in the specificity of phospholipids' binding domains.

• MeSH
• aminokyseliny aromatické chemie   MeSH
• fosfatidylinositolfosfáty metabolismus   MeSH
• fosfolipasa C delta chemie   MeSH
• krysa rodu rattus MeSH
• molekulární modely MeSH
• mutageneze cílená MeSH
• mutantní proteiny chemie   metabolismus   MeSH
• PH-doména * MeSH
• sekvence aminokyselin MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mesoporous material SBA-15 was functionalized with different polar and nonpolar groups: 3-aminopropyl, (SBA-15-NH2), 3-isocyanatopropyl (SBA-15-NCO), 3-mercaptopropyl (SBA-15-SH), methyl (SBA-15-CH3) and phenyl (SBA-15-Ph). The resulting surface grafted materials were investigated as matrices for controlled drug delivery. Anticancer agent, pemetrexed (disodium pemetrexed heptahydrate) was selected as a model drug and loaded in the unmodified and functionalized SBA-15 materials. Materials were characterized by elemental analysis, infrared spectroscopy, transmission electron microscopy, nitrogen adsorption/desorption analysis, small angle X-ray scattering, powder X-ray diffraction, solid state NMR spectroscopy and thermogravimetry. It was shown that surface modification has an impact on both encapsulated drug amount and release properties. Release experiments were performed into two media with different pH: simulated body fluid (pH = 7.4) and simulated gastric fluid (pH = 2). In general, the effect of pH was reflected by the lower release of pemetrexed under acidic conditions (pH = 2) compared to slightly alkaline saline environment (pH = 7.4). The release rate of pemetrexed from propylamine-, propylisocyanate- and phenyl-modified SBA-15 was found to be effectively controlled by intermolecular interactions as compared to that from pure SBA-15, SBA-15-SH, and SBA-15-CH3, that evidenced a steady and similar release. The highest release was observed for methyl-functionalized material whose hydrophobic surface accelerates the pemetrexed release. The data obtained from release studies were fitted using various kinetic models to determine the pemetrexed release mechanism and its release rate. The best correlations were found for Korsmeyer-Peppas and Higuchi models. Moreover, the theoretical three-parameter model for drug release kinetic was applied to calculate the strength of drug-support interactions. The in vitro cell study was performed on SKBR3 cancer cells and obtained results demonstrated that the modification of the mesoporous silica material by grafted polar/nonpolar groups may significantly affect the compatibility of this material with cells, drug release from this material and subsequent biological activity of PEM.

• MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem chemie   farmakokinetika   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• oxid křemičitý * chemie   farmakokinetika   farmakologie   MeSH
• pemetrexed * chemie   farmakokinetika   farmakologie   MeSH
• povrchové vlastnosti MeSH
• protinádorové látky * chemie   farmakokinetika   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIMS: High Al resistance of Rumex obtusifolius together with its ability to accumulate Al has never been studied in weakly acidic conditions (pH > 5.8) and is not sufficiently described in real soil conditions. The potential elucidation of the role of organic acids in plant can explain the Al tolerance mechanism. METHODS: We established a pot experiment with R. obtusifolius planted in slightly acidic and alkaline soils. For the manipulation of Al availability, both soils were untreated and treated by lime and superphosphate. We determined mobile Al concentrations in soils and concentrations of Al and organic acids in organs. RESULTS: Al availability correlated positively to the extraction of organic acids (citric acid < oxalic acid) in soils. Monovalent Al cations were the most abundant mobile Al forms with positive charge in soils. Liming and superphosphate application were ambiguous measures for changing Al mobility in soils. Elevated transport of total Al from belowground organs into leaves was recorded in both lime-treated soils and in superphosphate-treated alkaline soil as a result of sufficient amount of Ca available from soil solution as well as from superphosphate that can probably modify distribution of total Al in R. obtusifolius as a representative of "oxalate plants." The highest concentrations of Al and organic acids were recorded in the leaves, followed by the stem and belowground organ infusions. CONCLUSIONS: In alkaline soil, R. obtusifolius is an Al-hyperaccumulator with the highest concentrations of oxalate in leaves, of malate in stems, and of citrate in belowground organs. These organic acids form strong complexes with Al that can play a key role in internal Al tolerance but the used methods did not allow us to distinguish the proportion of total Al-organic complexes to the free organic acids.

• MeSH
• analýza hlavních komponent MeSH
• biologický transport MeSH
• hliník farmakokinetika   MeSH
• koncentrace vodíkových iontů MeSH
• kyselina citronová metabolismus   MeSH
• kyselina octová metabolismus   MeSH
• kyselina oxalová metabolismus   MeSH
• látky znečišťující půdu farmakokinetika   MeSH
• molekulová hmotnost MeSH
• půda chemie   MeSH
• Rumex účinky léků   metabolismus   MeSH
• tkáňová distribuce MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Úvod: Interferón alfa (IFN-α) sa používa viac ako 30 rokov na liečbu myeloproliferatívnej neoplázie. Rekombinantný IFN-α (rIFN-α) a pegylovaný IFN-α (Peg-IFN-α) vo viacerých klinických štúdiách, dokazuje efektivitu v liečbe esenciálnej trombocytémie (ET) a polycytémie vera (PV) ako aj včasného štádia primárnej myelofibrózy (PMF). Cieľom práce bolo retrospektívne hodnotenie efektivity a tolerability IFN-α v bežnej klinickej praxi. Súbor a metody: Táto práca obsahuje retrospektívnu štúdiu 60 pacientov s myeloproliferatívnou neopláziou, ktorí sa liečili rIFN-α a Peg-IFN-α mimo klinických štúdií. Výsledky: Skupina 60 pacientov s diagnózou PV 34 (57 %), ET 5 (8 %), PMF 21 (35 %) s vekovým mediánom 43 rokov (16–70). Medián trvania liečby 107,5 mesiacov, v skupine 11 pacientov liečených Peg-IFN-α medián trvania liečby 24 mesiacov. Medián sledovania 164 mesiacov. 24 pacientov (40 %) dosiahlo kompletnú hematologickú odpoveď (KHR), 29 pacientov (48 %) parciálnu hematologickú odpoveď a 7 pacientov (12 %) nesplnilo kritéria pre parciálnu hematologickú odpoveď. 42 pacientov (70 %) malo počas liečby nežiaduce účinky: chronický: „flu-like“ syndróm, psychické, dermatologické, očné, neurologické. 13 pacientov (22 %) ukončilo liečbu z dôvodu toxicity. Záver: IFN-α je efektívny pri kontrole ochorenia u významnej časti pacientov s Ph negatívnou MPN. Napriek tomu jeho klinické použitie, limitujú nežiaduce účinky. Retrospektívne klinické závery si vyžadujú ďalšie štúdium efektu IFN-α u našich pacientov.

Introduction: Interferon alfa (IFN-α) has been used for over 30 years to treat myeloproliferative neoplasms. Recombinant IFN-α (rIFN-α) and pegylated IFN-α (Peg-IFN-α) have been shown to provide effective therapy for essential thrombocythemia (ET) and polycythaemia vera (PV), as well as early stage primary myelofibrosis (PMF) in several clinical studies. Patients and methods: This report presents a retrospective analysis of 60 patients with MPN who were treated with rIFN-α or Peg-IFN-α outside clinical trials. Results: Retrospective stratification at diagnosis included 34 (57%) patients with PV, 5 (8%) with ET and 21 (35%) with PMF. Median age was 43 years (16-70). Median treatment duration was 107.5 months, with 11 patients treated with Peg IFN-α for a median duration of 24 months. Median follow up was 164 months. 24 patients (40%) achieved complete remission, 29 patients (48%) achieved partial remission and 7 patients (12%) failed to achieve partial remission. Toxicities were recorded in 42 patients (70%): chronic „flu-like syndrome“, psychiatric toxicity, hepatotoxicity, dermatotoxicity, ocular and neurotoxicity. Thirteen (22%) patients stopped the treatment because of toxicity. Conclusion: IFN-α effectively controls disease in a significant proportion of Ph-negative MPN patients. However, its use in clinical practice has unfortunately been limited by side effects. These results support the need for further efficacy studies of IFN-α in this group of patients.

• MeSH
• imunologické faktory MeSH
• interferon alfa * škodlivé účinky   terapeutické užití   toxicita   MeSH
• interpretace statistických dat MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• myeloproliferativní poruchy * farmakoterapie   MeSH
• retrospektivní studie MeSH
• trombóza etiologie   MeSH
• Check Tag
• lidé MeSH

BACKGROUND: Resistance of cancer cells to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The drug resistance of tumor cells can be significantly modified by specific features of tumor microenvironment, such as oxygen depletion (hypoxia), glucose/energy deprivation and acidosis. METHODS: The effects of acidic tumor-like microenvironment on cytotoxicity of antabuse (disulfiram, DSF)/Cu(2+) complexes to MCF-7 breast carcinoma and HT-29 colon carcinoma cells were studied. RESULTS: We show that acidic pH significantly potentiates toxicity of DSF/Cu(2+) complex to breast and colon cancer cells. This phenomenon is associated with changes in cell metabolism, altered Akt kinase and NFκB activity and increased reactive oxygen species production. CONCLUSION: Specific pH of tumor microenvironment enhances cytotoxicity of DSF/Cu(2+) to breast and colon cancer cells.

• MeSH
• buňky HT-29 MeSH
• disulfiram chemie   MeSH
• fosforylace MeSH
• komplexní sloučeniny chemická syntéza   chemie   toxicita   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• měď chemie   MeSH
• MFC-7 buňky MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory prsu metabolismus   patologie   MeSH
• nádory tračníku metabolismus   patologie   MeSH
• NF-kappa B metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   toxicita   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH