Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.

• MeSH
• aplikace orální MeSH
• bolest farmakoterapie   MeSH
• emulze MeSH
• kanabidiol * farmakologie   chemie   MeSH
• klinické křížové studie MeSH
• krysa rodu rattus MeSH
• kvalita života MeSH
• revmatoidní artritida * farmakoterapie   MeSH
• voda MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The effective treatment of inflammatory diseases, particularly their chronic forms, is a key task of modern medicine. Herein, we report the synthesis and evaluation of biocompatible polymer conjugates based on N-2-(hydroxypropyl)methacrylamide copolymers enabling the controlled release of acetylsalicylic acid (ASA)-based anti-inflammatory drugs under specific stimuli. All polymer nanotherapeutics were proposed as water-soluble drug delivery systems with a hydrodynamic size below 10 nm ensuring suitability for the parenteral application and preventing opsonization by the reticuloendothelial system. The nanotherapeutics bearing an ester-bound ASA exhibited long-term release of the ASA/salicylic acid mixture, while the nanotherapeutics carrying salicylic acid hydrazide (SAH) ensured the selective release of SAH in the acidic inflammatory environment thanks to the pH-sensitive hydrazone bond between the polymer carrier and SAH. The ASA- and SAH-containing nanotherapeutics inhibited both cyclooxygenase isoforms and/or the production of pro-inflammatory mediators. Thanks to their favorable design, they can preferentially accumulate in the inflamed tissue, resulting in reduced side effects and lower dosage, and thus more effective and safer treatment.

• MeSH
• akrylamidy chemie   farmakologie   aplikace a dávkování   MeSH
• antiflogistika farmakologie   aplikace a dávkování   chemie   MeSH
• Aspirin * aplikace a dávkování   farmakologie   chemie   MeSH
• cyklooxygenasy metabolismus   MeSH
• inhibitory cyklooxygenasy farmakologie   aplikace a dávkování   chemie   MeSH
• léky s prodlouženým účinkem * MeSH
• mediátory zánětu metabolismus   MeSH
• myši MeSH
• nanočástice * chemie   MeSH
• nosiče léků chemie   MeSH
• polymery * chemie   aplikace a dávkování   MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.

• MeSH
• aplikace orální MeSH
• biologická dostupnost * MeSH
• dospělí MeSH
• inhibitory faktoru Xa farmakokinetika   aplikace a dávkování   MeSH
• interakce mezi potravou a léky * MeSH
• jídla MeSH
• klinické křížové studie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• omezení příjmu potravy * MeSH
• příprava léků metody   MeSH
• rivaroxaban * farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

AIMS: Abiraterone treatment requires regular drug intake under fasting conditions due to pronounced food effect, which may impact patient adherence. The aim of this prospective study was to evaluate adherence to abiraterone treatment in patients with prostate cancer. To achieve this aim, an abiraterone population pharmacokinetic model was developed and patients' adherence has been estimated by comparison of measured levels of abiraterone with population model-based simulations. METHODS: A total of 1469 abiraterone plasma levels from 83 healthy volunteers collected in a bioequivalence study were analysed using a nonlinear mixed-effects model. Monte Carlo simulation was used to describe the theoretical distribution of abiraterone pharmacokinetic profiles at a dose of 1000 mg once daily. Adherence of 36 prostate cancer patients treated with abiraterone was then evaluated by comparing the real abiraterone concentration measured in each patient during follow-up visit with the theoretical distribution of profiles based on simulations. Patients whose abiraterone levels were ˂5th or ˃95th percentile of the distribution of simulated profiles were considered to be non-adherent. RESULTS: Based on this evaluation, 13 patients (36%) have been classified as non-adherent. We observed significant association (P = .0361) between richness of the breakfast and rate of non-adherence. Adherent patients reported significantly better overall condition in self-assessments (P = .0384). A trend towards a higher occurrence of adverse effects in non-adherent patients was observed. CONCLUSIONS: We developed an abiraterone population pharmacokinetic model and proposed an advanced approach to medical adherence evaluation. Due to the need for administration under fasting conditions, abiraterone therapy is associated with a relatively high rate of non-adherence.

• MeSH
• adherence k farmakoterapii * statistika a číselné údaje   MeSH
• androsteny * farmakokinetika   aplikace a dávkování   terapeutické užití   MeSH
• antitumorózní látky farmakokinetika   aplikace a dávkování   MeSH
• biologické modely * MeSH
• dospělí MeSH
• interakce mezi potravou a léky MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• nádory prostaty * farmakoterapie   MeSH
• omezení příjmu potravy MeSH
• prospektivní studie MeSH
• senioři MeSH
• terapeutická ekvivalence MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.

• Publikační typ
• časopisecké články MeSH

Nilotinib is a selective tyrosine-kinase inhibitor approved for the treatment of chronic myeloid leukemia. It is poorly soluble in aqueous media and has a low oral bioavailability. Nilotinib encapsulation into yeast glucan particles (GPs) was investigated in this work as a means of increasing bioavailability. The amorphization of nilotinib in GPs resulted in an increased dissolution rate, which was confirmed by in vitro experiments using biorelevant dissolution media. Simultaneously, GPs containing nilotinib were effectively taken up by macrophages, which was quantified in vitro on cell cultures. The overall oral bioavailability in a rat model was approximately 39 % for nilotinib delivered in a reference formulation (Tasigna) and was almost doubled when delivered in GPs. The contribution of glucan particles to the lymphatic transport of nilotinib was quantified. When delivered by GPs, cumulative nilotinib absorption via the lymphatic system increased by a factor of 10.8 compared to the reference, but still represented arelative bioavailability of only 1.12 %. The cumulative uptake of GPs in the lymph was found to be 0.54 mg after a single dose of 50 mg. Yeast glucan particles can therefore serve as a drug delivery vehicle with a dual function: dissolution rate enhancement by amorphization, and, to asmaller extent, lymphatic delivery due to macrophage uptake.

• MeSH
• aplikace orální MeSH
• glukany * MeSH
• krysa rodu rattus MeSH
• pyrimidiny MeSH
• Saccharomyces cerevisiae * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Publikace se zaměřuje na rehabilitační léčbu vybraných onemocnění.

• MeSH
• gynekologická onemocnění rehabilitace   MeSH
• hemofilie A rehabilitace   MeSH
• hemofilie B rehabilitace   MeSH
• nádory rehabilitace   MeSH
• onemocnění dna pánevního rehabilitace   MeSH
• pahýl po amputaci MeSH
• popálení rehabilitace   MeSH
• rehabilitace MeSH

• Konspekt
• Fyzioterapie. Psychoterapie. Alternativní lékařství
• NLK Obory
• rehabilitační a fyzikální medicína
• NLK Publikační typ
• kolektivní monografie

Regulation of H2S homeostasis in humans is poorly understood. Therefore, we assessed the importance of individual enzymes in synthesis and catabolism of H2S by studying patients with respective genetic defects. We analyzed sulfur compounds (including bioavailable sulfide) in 37 untreated or insufficiently treated patients with seven ultrarare enzyme deficiencies and compared them to 63 controls. Surprisingly, we observed that patients with severe deficiency in cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) - the enzymes primarily responsible for H2S synthesis - exhibited increased and normal levels of bioavailable sulfide, respectively. However, an approximately 21-fold increase of urinary homolanthionine in CBS deficiency strongly suggests that lacking CBS activity is compensated for by an increase in CSE-dependent H2S synthesis from accumulating homocysteine, which suggests a control of H2S homeostasis in vivo. In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions. Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine, increased renal losses of sulfur compounds and concomitant strong reduction in plasma total cysteine. Our results demonstrate the value of a comprehensive assessment of sulfur compounds in severe disorders of homocysteine/cysteine metabolism and provide evidence for redundancy and compensatory mechanisms in the maintenance of H2S homeostasis.

• MeSH
• cystein MeSH
• homeostáza MeSH
• homocystein MeSH
• lidé MeSH
• síra MeSH
• sulfan * metabolismus   MeSH
• sulfidy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The present study investigates the physicochemical properties and stability of a novel lipid-based formulation-surfactant-enriched oil marbles containing abiraterone acetate. While the biopharmaceutical performance of this formulation has been reported recently, this study aims to fill the gap between a promising in vivo performance and industrial applicability. A series of techniques were employed to assess the solid-state characteristics of oil marble cores along with their physicochemical properties upon stability testing. The chemical stability of abiraterone acetate in the formulation was also investigated. The core of the formulation was found to be stable both physically and chemically over 12 months of storage. The in vitro performance of stressed samples was evaluated using a dissolution experiment. The formulation has successfully self-emulsified upon incubation in bio-relevant media, resulting in a fast and complete API release. An important issue connected with the excipient used as a covering material of oil marbles has been identified. The seemingly insignificant water sorption caused agglomeration of the oil marbles and consequently compromised the dissolution rate in some of the stressed samples. Replacing HPMC with lactose as a covering material resulted in more favorable properties upon storage. Overall, it has been shown that oil marbles are an industrially applicable concept of the solidified lipid-based formulation.

• MeSH
• abirateron MeSH
• biologické přípravky * MeSH
• chemie farmaceutická metody   MeSH
• laktosa MeSH
• lipidy chemie   MeSH
• pomocné látky * chemie   MeSH
• povrchově aktivní látky chemie   MeSH
• rozpustnost MeSH
• stabilita léku MeSH
• uhličitan vápenatý MeSH
• voda MeSH
• Publikační typ
• časopisecké články MeSH

Saccharides form one of the major constituents of biological macromolecules in living organisms. Many biological processes including protein folding, stability, immune response and receptor activation are regulated by glycosylation. In this work, we optimized a capillary electrophoresis method with capacitively coupled contactless conductivity detection for the separation of eight monosaccharides commonly found in glycoproteins, namely D-glucose, D-galactose, D-mannose, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-fucose, N-acetylneuraminic acid, and D-xylose. A highly alkaline solution of 50 mM sodium hydroxide, 22.5 mM disodium phosphate, and 0.2 mM CTAB (pH 12.4) was used as a background electrolyte in a 10 μm id capillary. To achieve baseline separation of all analytes, a counter-directional pressure of -270 kPa was applied during the separation. The limits of detection of our method were below 7 μg/ml (i.e., 1.5 pg or 1 mg/g protein) and the limits of quantification were below 22 μg/ml (i.e., 5 pg or 3 mg/g protein). As a proof of concept of our methodology, we performed an analysis of monosaccharides released from fetuin glycoprotein by acid hydrolysis. The results show that, when combined with an appropriate pre-concentration technique, the developed method can be used as a monosaccharide profiling tool in glycoproteomics and complement the routinely used LC-MS/MS analysis.

• MeSH
• acetylgalaktosamin MeSH
• acetylglukosamin MeSH
• cetrimonium MeSH
• chromatografie kapalinová MeSH
• elektroforéza kapilární metody   MeSH
• elektrolyty chemie   MeSH
• fetuiny MeSH
• fosfáty MeSH
• fukosa MeSH
• galaktosa MeSH
• glukosa MeSH
• glykoproteiny chemie   MeSH
• hydroxid sodný MeSH
• kyselina N-acetylneuraminová * MeSH
• mannosa MeSH
• monosacharidy * analýza   MeSH
• tandemová hmotnostní spektrometrie MeSH
• xylosa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH