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

Drug delivery to central nervous pathologies is compromised by the blood-brain barrier (BBB). A clinically explored strategy to promote drug delivery across the BBB is sonopermeation, which relies on the combined use of ultrasound (US) and microbubbles (MB) to induce temporally and spatially controlled opening of the BBB. We developed an advanced in vitro BBB model to study the impact of sonopermeation on the delivery of the prototypic polymeric drug carrier pHPMA as a larger molecule and the small molecule antiviral drug ribavirin. This was done under standard and under inflammatory conditions, employing both untargeted and RGD peptide-coated MB. The BBB model is based on human cerebral capillary endothelial cells and human placental pericytes, which are co-cultivated in transwell inserts and which present with proper transendothelial electrical resistance (TEER). Sonopermeation induced a significant decrease in TEER values and facilitated the trans-BBB delivery of fluorescently labeled pHPMA (Atto488-pHPMA). To study drug delivery under inflamed endothelial conditions, which are typical for e.g. tumors, neurodegenerative diseases and CNS infections, tumor necrosis factor (TNF) was employed to induce inflammation in the BBB model. RGD-coated MB bound to and permeabilized the inflamed endothelium-pericyte co-culture model, and potently improved Atto488-pHPMA and ribavirin delivery. Taken together, our work combines in vitro BBB bioengineering with MB-mediated drug delivery enhancement, thereby providing a framework for future studies on optimization of US-mediated drug delivery to the brain.

• MeSH
• antivirové látky aplikace a dávkování   chemie   farmakologie   farmakokinetika   MeSH
• endoteliální buňky * účinky léků   metabolismus   MeSH
• hematoencefalická bariéra * metabolismus   MeSH
• kokultivační techniky * MeSH
• lidé MeSH
• mikrobubliny * MeSH
• oligopeptidy * chemie   aplikace a dávkování   farmakokinetika   MeSH
• pericyty * metabolismus   účinky léků   MeSH
• polymery chemie   aplikace a dávkování   MeSH
• ribavirin aplikace a dávkování   chemie   farmakokinetika   MeSH
• systémy cílené aplikace léků metody   MeSH
• ultrazvukové vlny MeSH
• zánět farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

In our previous research, we concluded that polymeric micelles based on hyaluronic acid are able to penetrate into the deeper layers of skin tissue. The aim of this work was to characterize the mechanisms involved in the uptake by skin cells, which is important for understanding the influence of the carrier composition on the drug penetration. To reach this goal, we used micelles encapsulating curcumin made of oleyl-hyaluronan (HAC18:1) and hexyl-hyaluronan (HAC6) covalently linked with fluorescent Nile Blue. This labeling enabled us to track the micelle-forming derivative and also micelle payload into the keratinocytes and fibroblasts by fluorescent microscopy and flow cytometry. The regulation of both the passive and active cellular uptake was used to determine the mechanism of micelle internalization. Furthermore, the changes of membrane fluidity were measured for these derivatives by FRAP. Using these methods we concluded that carriers entered the cells using both active and passive transport. Passive transport was facilitated by the affinity of the carrier to the cell membrane, especially in the case of HAC18:1 carrier, which changed significantly the membrane fluidity. The active transport was dependent on cell type, but mainly driven by the clathrin-mediated endocytosis and macropinocytosis. Surprisingly, the main HA receptor, CD44, was not involved in the uptake. We can conclude that these carrier systems could be used for the local transport of active substances or hydrophobic drugs into the skin cells using the advantage of passive transport of oleyl-HA derivative.

• MeSH
• aplikace lokální MeSH
• endocytóza MeSH
• fibroblasty metabolismus   MeSH
• keratinocyty metabolismus   MeSH
• kožní absorpce * MeSH
• kultivované buňky MeSH
• kurkumin aplikace a dávkování   MeSH
• kůže metabolismus   MeSH
• kyselina hyaluronová aplikace a dávkování   MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• polymery aplikace a dávkování   MeSH
• systémy cílené aplikace léků * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Transdermální podání umožňuje systémovou aplikaci léčiv přes kůži, aniž by pacient musel přípravek pozřít (podání per os) nebo podstoupit invazivní injekční aplikaci (např. podání intra venam). Podání transdermálních lékových forem přináší řadu výhod, avšak jejich účinek může být významně snížen nesprávnou technikou aplikace, která je u jednotlivých přípravků odlišná. Tato práce přináší základní přehled kapalných, polotuhých a tuhých transdermálních léčivých přípravků dostupných v České republice a zaměřuje se na informace o jejich správné aplikaci.

Transdermal application allows to administer the drug through the skin with the systemic effect, without the need for the preparation to be swallowed (oral administration) or for the patient to undergo the invasive application of injection (e.g., intravenous administration). Transdermal delivery offers a wide range of benefits; however, their effect may be significantly affected by the improper technique of the application that differs for each preparation. This paper introduces the basic overview of liquid, semi-solid and solid transdermal delivery systems available in Czech Republic with the specific focus on their correct application.

• MeSH
• aplikace kožní * MeSH
• estrogeny aplikace a dávkování   terapeutické užití   MeSH
• lékové formy * MeSH
• lidé MeSH
• okluzivní ošetření rány MeSH
• polymery aplikace a dávkování   terapeutické užití   MeSH
• testosteron aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Geografické názvy
• Česká republika MeSH

• Klíčová slova
• veverimer,
• MeSH
• acidóza * etiologie   farmakoterapie   metabolismus   MeSH
• chronická renální insuficience * farmakoterapie   komplikace   metabolismus   MeSH
• hydrogenuhličitany metabolismus   MeSH
• lidé MeSH
• polymery aplikace a dávkování   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH

Při léčbě a prevenci očních onemocnění jsou většině pacientů podávány konvenční lékové formy, zejména oční kapky a masti. Jejich nevýhodou je nízká biodostupnost léčiva a nutnost časté aplikace. Novým trendem ve vývoji očních přípravků je použití moderních pomocných látek a lékových forem, které zajistí vyšší biologickou dostupnost léčiva. Pouze několik moderních přípravků se však dostalo do běžné klinické praxe, další jsou předmětem klinických hodnocení.

For the treatment and prevention of ocular diseases, most patients are treated with conventional drug delivery formulations such as eye drops or ointments. Their disadvantage is the low bioavailability of the drug and frequent application. The new trends in the development of ophthalmic preparations include the use of modern excipients and dosage forms to achieve higher bioavailability of the drug. However, only a few modern devices have come into common clinical practice while others are being investigated in clinical trials.

• Klíčová slova
• oční inserty, Mydrane,
• MeSH
• biologická dostupnost MeSH
• fotochemoterapie metody   MeSH
• gely aplikace a dávkování   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• injekce nitrooční klasifikace   škodlivé účinky   MeSH
• lékové formy * MeSH
• lidé MeSH
• masti aplikace a dávkování   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• oční nemoci * farmakoterapie   prevence a kontrola   terapie   MeSH
• oční protézy klasifikace   MeSH
• oční roztoky aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• polymery analýza   aplikace a dávkování   terapeutické užití   MeSH
• verteporfin aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH

The delivery of nitric oxide (NO) specifically to solid tumours was explored in this study as a strategy to augment the passive accumulation of nanomedicines in tumours induced by the Enhanced Permeability and Retention (EPR) effect. An increase in accumulation was achieved by the binding of the chemical precursor of NO, based on an organic nitrate, to a water-soluble synthetic polymer drug carrier. Four structurally different N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer NO donors were synthesized. Depending on their chemical structure, two of these donors were hydrolytically stable, while two rapidly released the parent nitrate under acidic conditions, mimicking the intracellular environment. The polymer NO donors were shown to overcome the drawbacks related to low-molecular-weight NO releasing compounds, namely systemic toxicity, lack of site specificity, and fast blood clearance. The NO donors showed intracellular NO release upon incubation with tumour cells. In vivo, they potentiated the EPR effect, resulting in an increased accumulation of polymer-bound cytotoxic drug doxorubicin (Dox) in EL4 T-cell lymphoma inoculated in mice. This led to a better therapeutic outcome in the treatment of lymphoma with the high-molecular-weight polymer conjugates carrying Dox but not in the treatment with the free Dox. The localized augmentation of the EPR effect via the tumour-specific NO delivery system can be viewed as a promising strategy to potentiate polymer-based tumour therapy without increasing systemic toxicity.

• MeSH
• antibiotika antitumorózní aplikace a dávkování   MeSH
• buněčné linie MeSH
• donory oxidu dusnatého aplikace a dávkování   MeSH
• doxorubicin aplikace a dávkování   MeSH
• lidé MeSH
• lymfom T-buněčný farmakoterapie   MeSH
• myši inbrední C57BL MeSH
• nosiče léků aplikace a dávkování   MeSH
• polymery aplikace a dávkování   MeSH
• synergismus léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A sustained effort to maximize the therapeutic effect of newly discovered active pharmaceutical ingredients (APIs) leads to the search for and development of advanced drug formulations. In this regard, a range of multicomponent and nanostructured systems that often combine the properties of solid and liquid materials have been developed. Besides the sophisticated supramolecular synthesis the development of these systems also requires in-depth view into their local architecture at atomic-resolution level. As these materials naturally exist at the borderline between the solid and liquid phases, the high-quality diffraction data are inherently unavailable. Therefore the structural description of these materials requires development of novel and highly efficient strategies. The aim of all this process is formulation of computation-experimental procedures allowing for precise characterization of the complex pharmaceutical systems including composite solids, nanocrystalline systems as well as partially ordered materials. In this regard, NMR crystallography belongs among the most successful approaches. In this contribution we report our recent achievements in characterizing atomic-resolution structure of complex pharmaceutical solids such as peptide derivatives of boronic acid, hybrid organic-inorganic liquisolid drug delivery systems, polymer-drug solid dispersions and mucoadhesive buccal films.

• Klíčová slova
• krystalové struktury,
• MeSH
• algináty chemie   MeSH
• Aspirin chemie   MeSH
• ciklopirox chemie   MeSH
• farmaceutická technologie klasifikace   MeSH
• krystalografie * metody   MeSH
• léčivé přípravky MeSH
• magnetická rezonanční spektroskopie * metody   MeSH
• nanomedicína dějiny   metody   MeSH
• polymery aplikace a dávkování   chemie   MeSH
• sloučeniny boru chemie   MeSH
• Publikační typ
• práce podpořená grantem MeSH

A BCL1 leukemia-cell-targeted polymer-drug conjugate with a narrow molecular weight distribution consisting of an N-(2-hydroxypropyl)methacrylamide copolymer carrier and the anticancer drug pirarubicin is prepared by controlled radical copolymerization followed by metal-free click chemistry. A targeting recombinant single chain antibody fragment (scFv) derived from a B1 monoclonal antibody is attached noncovalently to the polymer carrier via a coiled coil interaction between two complementary peptides. Two pairs of coiled coil forming peptides (abbreviated KEK/EKE and KSK/ESE) are used as linkers between the polymer-pirarubicin conjugate and the targeting protein. The targeted polymer conjugate with the coiled coil linker KSK/ESE exhibits 4× better cell binding activity and 2× higher cytotoxicity in vitro compared with the other conjugate. Treatment of mice with established BCL1 leukemia using the scFv-targeted polymer conjugate leads to a markedly prolonged survival time of the experimental animals compared with the treatment using the free drug and the nontargeted polymer-pirarubicin conjugate.

• MeSH
• akrylamidy chemie   MeSH
• cílená molekulární terapie MeSH
• cyklin D1 antagonisté a inhibitory   imunologie   MeSH
• imunoglobuliny - fragmenty aplikace a dávkování   imunologie   MeSH
• imunokonjugáty aplikace a dávkování   chemie   MeSH
• leukemie imunologie   patologie   terapie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• monoklonální protilátky chemie   imunologie   MeSH
• myši MeSH
• nosiče léků aplikace a dávkování   chemie   MeSH
• peptidy chemie   imunologie   MeSH
• polymery aplikace a dávkování   chemie   MeSH
• syntetická chemie okamžité shody MeSH
• systémy cílené aplikace léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: To evaluate the effects of synthetic osmotic dilators (Dilapan-S/ Dilasoft) in women who required induction of labour in a large prospective multicentre international observational study. MATERIALS AND METHODS: Primary outcomes were duration of Dilapan-S/Dilasoft insertion (hours), total induction - delivery interval (hours) and the rate of vaginal deliveries within 24 h (%). Secondary outcomes were the number of dilators inserted, Bishop score increase after extraction of Dilapan-S/Dilasoft, complications during induction (uterine contractions, uterine tachysystole and hyperstimulation, effect on the fetus) and post induction (infections and neonatal outcomes), agents / procedures used for subsequent induction of labour, immediate rate of spontaneous labours following cervical ripening period, rate of spontaneous vaginal deliveries, rate of instrumental vaginal deliveries and caesarean sections. RESULTS: Total of 543 women were recruited across 11 study sites, of which, 444 women were eligible for analysis. With Dilapan-S/Dilasoft use of <12 h (n = 188) the overall vaginal delivery rate was 76.6% with 45.7% of these births occurring within 24 h, 66% within 36 h and 75.5% within 48 h from insertion of Dilapan-S/Dilasoft. The mean insertion-delivery interval for this group was 24.3(±10.4) hours. With Dilapan-S/Dilasoft use of >12 h (n = 256), the overall vaginal delivery rate was 64.8%, with 16% of these births occurring within 24 h, 48.4% within 36 h and 54.7% within 48 h from insertion of Dilapan-S/Dilasoft. The mean insertion-delivery interval for this group was 39.1(±29.2) hours. The mean gain in the Bishops score was +3.6(±2.3). The mean number of Dilapan-S/Dilasoft dilators used was 3.8 (±1.1). The overall rate of caesarean section was 30.1%. The overall complication rate was low including infection risk. No adverse neonatal outcome was attributable to the use of Dilapan-S/Dilasoft. CONCLUSION: Dilapan-S/Dilasoft are safe and effective methods for cervical ripening. Their use is associated with low maternal and neonatal complication rates. Future research should aim at level I clinical trials comparing Dilapan-S to other mechanical or pharmacological cervical ripening agents. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02318173.

• MeSH
• dospělí MeSH
• indukovaný porod metody   MeSH
• lidé MeSH
• mladý dospělý MeSH
• polymery aplikace a dávkování   MeSH
• prospektivní studie MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH