Over the past few decades, numerous polymer drug carrier systems are designed and synthesized, and their properties are evaluated. Many of these systems are based on water-soluble polymer carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, or multidrug resistance inhibitors, all covalently bound to a carrier by a biodegradable spacer that enables controlled release of the active molecule to achieve the desired pharmacological effect. Among others, the synthetic polymer carriers based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are some of the most promising carriers for this purpose. This review focuses on advances in the development of HPMA copolymer carriers and their conjugates with anticancer drugs, with triggered drug activation in tumor tissue and especially in tumor cells. Specifically, this review highlights the improvements in polymer drug carrier design with respect to the structure of a spacer to influence controlled drug release and activation, and its impact on the drug pharmacokinetics, enhanced tumor uptake, cellular trafficking, and in vivo antitumor activity.

• Klíčová slova
• HPMA copolymers, biodegradable spacer, controlled drug release, drug delivery systems, pH-controlled release,
• MeSH
• léky s prodlouženým účinkem MeSH
• lidé MeSH
• methakryláty chemie   terapeutické užití   MeSH
• nádory farmakoterapie   MeSH
• nosiče léků chemie   terapeutické užití   MeSH
• uvolňování léčiv * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• hydroxypropyl methacrylate MeSH Prohlížeč
• léky s prodlouženým účinkem MeSH
• methakryláty MeSH
• nosiče léků MeSH

BACKGROUND AND AIMS: The CONCERTO study results showing the beneficial effects of conversion from cyclosporine to tacrolimus prolonged-release (tacrolimus PR) in stabilised patients after kidney transplantation, were first published in 2011. This communication describes our first experience of conversion from cyclosporine to tacrolimus PR in stabilised kidney transplant patients. The aim was to determine whether it could be used in routine clinical practice in the Czech and Slovak Republics. METHODS: Evaluation was carried out at five transplantation centres in the Czech Republic and Slovakia. In all participating Centres, the drug conversion was conducted according to the ICH/GCP guidelines. A total of 104 patients stabilised after kidney transplantation were converted from maintenance therapy with cyclosporine to treatment with tacrolimus PR. The data were collected 26 weeks after the switch. The primary endpoint was change in kidney graft function measured from the estimated glomerular filtration rate (GFR). The effect of conversion on blood pressure, metabolic parameters and cosmetic changes was also recorded. Special attention was paid to the safety and tolerability of treatment with tacrolimus PR. RESULTS: GFR increased after six months by 10 % (P = 0.040). In addition a significant decrease in serum creatinine and triglycerides level was found together with major reduction in the incidence and severity of gingival hyperplasia and hirsutism. 3% of patients developed new onset of diabetes mellitus. Otherwise, the switch was very well-tolerated, without serious adverse events or acute rejections. CONCLUSION: Conversion from cyclosporine to tacrolimus PR was shown to be a safe therapeutic alternative with patient benefits.

• Klíčová slova
• cyclosporine, immunosuppressive conversion, kidney transplantation, tacrolimus prolonged-release,
• MeSH
• cyklosporin aplikace a dávkování   MeSH
• diabetické nefropatie patofyziologie   MeSH
• dyslipidemie etiologie   MeSH
• hirzutismus etiologie   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• hyperplazie dásní etiologie   MeSH
• imunosupresiva aplikace a dávkování   MeSH
• léky s prodlouženým účinkem MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada léků MeSH
• nemoci ledvin chirurgie   MeSH
• renální hypertenze etiologie   MeSH
• takrolimus aplikace a dávkování   MeSH
• transplantace ledvin * MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Názvy látek
• cyklosporin MeSH
• imunosupresiva MeSH
• léky s prodlouženým účinkem MeSH
• takrolimus MeSH

This study proposes a strategy to generate new anticancer therapy using hydrogel-based drug delivery systems to improve drug bioavailability and increase the therapeutic efficacy. We have synthesized biodegradable hydrogels based on N-(2-hydroxypropyl)methacrylamide (HPMA) with prolonged drug release. Pharmacokinetic data from in vitro studies showed that the in vitro release of hydrophilic drugs (doxorubicin, vinblastine) from HPMA-hydrogels is affected mainly by drug diffusion and only partially by hydrogel degradation. The release of hydrophobic drugs (cyclosporine A, CsA) actually copies the process of degradation and therefore it is slower. Hydrogels with degradation time of 50 h released the doxorubicin over a period of at least 96 h after s.c. implantation. Drug concentration at pharmacologically active levels was maintained in the bloodstream over a period of at least 4 days, ranging between 0.1 and 1 microg/ml. The therapeutic potential of HPMA-hydrogels in vivo was studied in Bcl1 leukemia. HPMA-hydrogels containing DOX were significantly more effective in inhibition of Bcl1 leukemia in comparison with free DOX or non-targeted polymeric drug (PK1). The efficacy of therapeutic combination using unspecific, hydrogel-based therapy with specific, antibody-targeted therapy at late stages of Bcl1 leukemia was also tested. In contrast to application of DOX alone, a cocktail of DOX with CsA as a blocker of P-glycoprotein (Pgp) incorporated into HPMA-hydrogel blocked the proliferation of Pgp-overexpressing multidrug resistant cell lines in vitro by induction of apoptosis.

• MeSH
• cyklosporin farmakokinetika   farmakologie   MeSH
• doxorubicin farmakokinetika   farmakologie   MeSH
• hydrogely farmakokinetika   farmakologie   MeSH
• implantované léky farmakokinetika   farmakologie   MeSH
• inhibitory růstu farmakologie   MeSH
• lékové transportní systémy metody   MeSH
• léky s prodlouženým účinkem farmakokinetika   farmakologie   MeSH
• leukemie P388 farmakoterapie   patologie   MeSH
• methakryláty farmakokinetika   farmakologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buňky kultivované účinky léků   patologie   MeSH
• nosiče léků farmakokinetika   farmakologie   MeSH
• protinádorové látky farmakokinetika   farmakologie   MeSH
• reagencia zkříženě vázaná farmakokinetika   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• cyklosporin MeSH
• doxorubicin MeSH
• hydrogely MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• implantované léky MeSH
• inhibitory růstu MeSH
• léky s prodlouženým účinkem MeSH
• methakryláty MeSH
• nosiče léků MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH

In recent years, polymer drug carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with pH-triggered drug release have shown enhanced uptake in solid tumors and excellent antitumor activity. Here, the impact of the structure of the acid-labile spacer between the drug and the polymer carrier on the biodistribution of both the drug and the carrier was studied using in vivo noninvasive multispectral optical imaging of dual fluorescently labeled HPMA copolymers. Five different spacers containing a pH-sensitive hydrazone bond were synthesized and used to combine a fluorescent model drug with a polymer backbone, conjugated with another non-releasable fluorescent dye. Two copolymers differing in polymer chain structure (linear and star-like) and molecular weight (30 and 200kDa) were used to distinguish between carriers with molecular weights above and below the limit for renal filtration. The rate of model drug release from the conjugates was determined in vitro. The biodistributions of the six most promising conjugates were investigated in vivo in athymic nude mice inoculated with human colon carcinoma xenograft. The structure of the spacer in the vicinity of the hydrazone bond significantly influenced the release rate of the model drug. The slow release rate of a pyridyl group bearing spacer resulted in a greater amount of the model drug being transported to the tumor, which was independent of the carrier structure. The results of this study emphasize the importance of careful selection of the structure and appropriate spacer when designing polymer conjugates intended for passive tumor targeting.

• Klíčová slova
• HPMA copolymers, Multispectral optical imaging, Passive tumor targeting, Tumor accumulation, Xenograft tumor model, pH-responsive drug release,
• MeSH
• akrylamidy analýza   MeSH
• fluorescenční barviva aplikace a dávkování   farmakokinetika   MeSH
• indoly aplikace a dávkování   farmakokinetika   MeSH
• karbocyaniny aplikace a dávkování   farmakokinetika   MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem analýza   MeSH
• lidé MeSH
• molekulární modely MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku farmakoterapie   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• DY-676 MeSH Prohlížeč
• fluorescenční barviva MeSH
• indoly MeSH
• karbocyaniny MeSH
• léky s prodlouženým účinkem MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč

Long-acting injectable formulations represent a rapidly emerging category of drug delivery systems that offer several advantages compared to orally administered medicines. Rather than having to frequently swallow tablets, the medication is administered to the patient by intramuscular or subcutaneous injection of a nanoparticle suspension that forms a local depot from which the drug is steadily released over a period of several weeks or months. The benefits of this approach include improved medication compliance, reduced fluctuations of drug plasma level, or the suppression of gastrointestinal tract irritation. The mechanism of drug release from injectable depot systems is complex, and there is a lack of models that would enable quantitative parametrisation of the process. In this work, an experimental and computational study of drug release from a long-acting injectable depot system is reported. A population balance model of prodrug dissolution from asuspension with specific particle size distribution has been coupled with the kinetics of prodrug hydrolysis to its parent drug and validated using in vitro experimental data obtained from an accelerated reactive dissolution test. Using the developed model, it is possible to predict the sensitivity of drug release profiles to the initial concentration and particle size distribution of the prodrug suspension, and subsequently simulate various drug dosing scenarios. Parametric analysis of the system has identified the boundaries of reaction- and dissolution-limited drug release regimes, and the conditions for the existence of a quasi-steady state. This knowledge is crucial for the rational design of drug formulations in terms of particle size distribution, concentration and intended duration of drug release.

• Klíčová slova
• Hydrolysis, Injectable depot systems, Nanosuspension, Paliperidone palmitate, Particle size distribution, Reactive dissolution,
• MeSH
• antipsychotika * MeSH
• injekce intramuskulární MeSH
• léky s prodlouženým účinkem MeSH
• lidé MeSH
• prekurzory léčiv * MeSH
• rozpustnost MeSH
• suspenze MeSH
• uvolňování léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika * MeSH
• léky s prodlouženým účinkem MeSH
• prekurzory léčiv * MeSH
• suspenze MeSH

The development of new drug delivery platforms including the use of nanotechnology has been found of great interest in recent years. Two different loading approaches of the model antimycotic drug clotrimazole into the nanofibrous polycaprolactone and polydioxanone structures including electrospinning of a drug-polymer blend and impregnation of nanofibers with drug have been tested. The final amount of clotrimazole in the nanofibrous materials was determined by HPLC analysis and Raman spectroscopy. The electrospinning of blend approach allowed the adsorption of clotrimazole in a quantity of up to 30 % using mixtures with polymer/clotrimazole ratios from 2:1 to 8:1 (w/w). Ethanolic clotrimazole solutions with concentrations from 2.5 to 3.5 mg L-1 were used for adsorbing clotrimazole in blank nanofibers for 1-3 h with final clotrimazole content ranging from 3.0 to 5.7 %. Furthermore, a comparative liberation study including comparison with commercially available creams was carried out in low pressure flow system. The results obtained confirmed well controlled release of clotrimazole from both types of nanofibers. Compared to commercial pharmaceutical formulations containing 1 % clotrimazole where first-order release kinetics was observed, nanofibrous materials provided linear controlled release (zero-order kinetics) in the tested 3 h period.

• Klíčová slova
• Automation, Drug release, Electrospinning, Nanofibers, Polycaprolactone, Polydioxanone,
• MeSH
• klotrimazol * chemie   MeSH
• léky s prodlouženým účinkem MeSH
• nanovlákna * chemie   MeSH
• polymery chemie   MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• klotrimazol * MeSH
• léky s prodlouženým účinkem MeSH
• polymery MeSH

This study was a Phase II, open-label, multicenter, single-arm, cross-over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). In Days -30 to -1 of screening period, patients received their IR-T-based regimen; during Days 1-7, patients received study IR-T (same dose as screening). On Day 7, the first 24-hours PK profile was taken; patients were then converted to PR-T (1 mg:1 mg), with a second 24-hours PK profile taken on Day 14. The primary end-point was tacrolimus area under the blood concentration-time curve over 24 hours (AUC24 ); secondary end-points were maximum concentration Cmax and concentration at 24 hours C24 . The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%-125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR-T:IR-T LSM ratio (90% CI) was similar overall for AUC24 , max , and C24 , and for kidney and liver recipients for AUC24 (LSM ratio, kidney 91.8%; liver 104.1%) and C24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC24 and C24 , and between PR-T and IR-T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR-T to PR-T at the same total daily dose, using the same therapeutic drug monitoring method.

• Klíčová slova
• heart transplantation, kidney transplantation, liver transplantation, pediatrics, pharmacokinetics, tacrolimus,
• MeSH
• alografty MeSH
• dítě MeSH
• imunosupresiva aplikace a dávkování   farmakokinetika   MeSH
• klinické křížové studie MeSH
• léky s prodlouženým účinkem farmakokinetika   MeSH
• lidé MeSH
• mladiství MeSH
• monitorování léčiv MeSH
• plocha pod křivkou MeSH
• předškolní dítě MeSH
• příjemce transplantátu MeSH
• rejekce štěpu prevence a kontrola   MeSH
• rozvrh dávkování léků MeSH
• takrolimus aplikace a dávkování   farmakokinetika   MeSH
• transplantace jater * MeSH
• transplantace ledvin * MeSH
• transplantace srdce * MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• imunosupresiva MeSH
• léky s prodlouženým účinkem MeSH
• takrolimus MeSH

• MeSH
• biokompatibilní materiály chemická syntéza   MeSH
• chemické modely MeSH
• lékové transportní systémy * MeSH
• léky s prodlouženým účinkem * MeSH
• polymery chemická syntéza   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biokompatibilní materiály MeSH
• léky s prodlouženým účinkem * MeSH
• polymery MeSH

This study evaluated the effects of ropinirole prolonged-release (RPR) in comparison with ropinirole immediate-release (RIR) on sleep-related disorders in Parkinson disease (PD).Thirty-three PD patients (aged 62.5 [SD, 8] years; PD duration, 9 [SD, 4] years) were evaluated on a stable dose of RIR and 5 to 13 weeks after switch to the closest possible dose of RPR. The following questionnaires were administered: Epworth Sleepiness Scale, PD Sleep Scale, Pittsburgh Sleep Quality Index, REM Sleep Behavior Disorder Screening Questionnaire, and PD Questionnaire 39. We further monitored the occurrence of restless legs syndrome and sleep attacks (SAs). Motor disability was evaluated by PD diary and by Unified Parkinson Disease Rating Scale part 3 on medication (ON) and after medication withdrawal (OFF). In 8 patients with marked subjective sleep disturbance, polysomnography, and multiple sleep latency test were performed.After switching to RPR, there was an improvement in PD Sleep Scale (94.9 [SD, 23] vs 102.2 [SD, 27]; P < 0.05 corrected), Pittsburgh Sleep Quality Index (7.2 [SD, 3] vs 5.8 [SD, 3]; P < 0.05 corrected), Epworth Sleepiness Scale (14.1 [SD, 5] vs 12.0 [SD, 6]; P < 0.05 corrected) and Unified Parkinson Disease Rating Scale part 3 in the ON state (20.9 [SD, 10] 10 vs 17.6 [SD, 10]; P < 0.05 corrected). Thirteen patients reported disappearance of SAs on RPR. Polysomnography and multiple sleep latency test showed no changes in a subgroup of 8 patients after the switch to RPR.Ropinirole prolonged-release compared with RIR improved subjective quality of sleep, reduced daytime sleepiness, and led to disappearance of SAs in some patients possibly due to a more stable plasma level of ropinirole.

• MeSH
• agonisté dopaminu aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• antiparkinsonika aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• indoly aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kvalita života MeSH
• léky s prodlouženým účinkem aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• Parkinsonova nemoc komplikace   farmakoterapie   patofyziologie   MeSH
• poruchy spánku a bdění etiologie   MeSH
• psychiatrické posuzovací škály MeSH
• senioři MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté dopaminu MeSH
• antiparkinsonika MeSH
• indoly MeSH
• léky s prodlouženým účinkem MeSH
• ropinirole MeSH Prohlížeč

Despite the importance of drug release testing of parenteral depot formulations, the current in vitro methods still require ameliorations in biorelevance. We have investigated here the use of muscle tissue components to better mimic the intramuscular administration. For convenient handling, muscle tissue was used in form of a freeze-dried powder, and a reproducible process of incorporation of tested microspheres to an assembly of muscle tissue of standardized dimensions was successfully developed. Microspheres were prepared from various grades of poly(lactic-co-glycolic acid) (PLGA) or ethyl cellulose, entrapping flurbiprofen, lidocaine, or risperidone. The deposition of microspheres in the muscle tissue or addition of only isolated lipids into the medium accelerated the release rate of all model drugs from microspheres prepared from ester-terminated PLGA grades and ethyl cellulose, however, not from the acid-terminated PLGA grades. The addition of lipids into the release medium increased the solubility of all model drugs; nonetheless, also interactions of the lipids with the polymer matrix (ad- and absorption) might be responsible for the faster drug release. As the in vivo drug release from implants is also often faster than in simple buffers in vitro, these findings suggest that interactions with the tissue lipids may play an important role in these still unexplained observations.

• Klíčová slova
• PLGA, biorelevant,, depot microspheres,, in vitro release,, intramuscular,,
• MeSH
• celulosa analogy a deriváty   MeSH
• flurbiprofen aplikace a dávkování   MeSH
• kopolymer kyseliny glykolové a mléčné MeSH
• léky s prodlouženým účinkem * MeSH
• lidokain aplikace a dávkování   MeSH
• mikrosféry MeSH
• nosiče léků MeSH
• parenterální infuze * MeSH
• pomocné látky MeSH
• prasata MeSH
• příprava léků MeSH
• risperidon aplikace a dávkování   MeSH
• svaly metabolismus   MeSH
• techniky in vitro MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• celulosa MeSH
• ethyl cellulose MeSH Prohlížeč
• flurbiprofen MeSH
• kopolymer kyseliny glykolové a mléčné MeSH
• léky s prodlouženým účinkem * MeSH
• lidokain MeSH
• nosiče léků MeSH
• pomocné látky MeSH
• risperidon MeSH