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

BACKGROUND AND PURPOSE: Lymphatic transport of drugs after oral administration is an important mechanism for absorption of highly lipophilic compounds. Direct measurement in lymph duct cannulated animals is the gold standard method, but non-invasive cycloheximide chylomicron flow blocking method has gained popularity recently. However, concerns about its reliability have been raised. The aim of this work was to investigate the validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport using model compounds with high to very high lipophilicity, that is, abiraterone and cinacalcet. EXPERIMENTAL APPROACH: Series of pharmacokinetic studies were conducted with abiraterone acetate and cinacalcet hydrochloride after enteral/intravenous administration to intact, lymph duct cannulated and/or cycloheximide pre-treated rats. KEY RESULTS: Mean total absolute oral bioavailability of abiraterone and cinacalcet was 7.0% and 28.7%, respectively. There was a large and significant overestimation of the lymphatic transport extent by the cycloheximide method. Mean relative lymphatic bioavailability of abiraterone and cinacalcet in cycloheximide method was 28-fold and 3-fold higher than in cannulation method, respectively. CONCLUSION AND IMPLICATIONS: Cycloheximide chylomicron flow blocking method did not provide reliable results on lymphatic absorption and substantially overestimated lymphatic transport for both molecules, that is, abiraterone and cinacalcet. This non-invasive method should not be used for the assessment of lymphatic transport and previously obtained data should be critically revised.

• MeSH
• aplikace orální MeSH
• biologická dostupnost MeSH
• biologický transport MeSH
• chylomikrony * metabolismus   MeSH
• cykloheximid farmakologie   MeSH
• intestinální absorpce * MeSH
• krysa rodu rattus MeSH
• léčivé přípravky MeSH
• reprodukovatelnost výsledků MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Background: A novel QDOT MICRO (Biosense Webster, Inc., Irvine, CA) catheter with optimized temperature control and microelectrodes was designed to incorporate real-time temperature sensing with contact force detection and microelectrodes to streamline ablation workflow. The QDOT-MICRO feasibility study evaluated the workflow, performance, and safety of temperature-controlled catheter ablation in patients with symptomatic paroxysmal atrial fibrillation with conventional ablation setting. Methods: This was a non-randomized, single-arm, first-in-human study. The primary outcome was pulmonary vein isolation (PVI), confirmed by entrance block after adenosine and/or isoproterenol challenge. Safety outcomes included incidences of early-onset primary adverse events (AEs) and serious adverse device effects (SADEs). Device performance was evaluated via physician survey. Results: All evaluated patients (n = 42) displayed 100% PVI. Two primary AEs (4.8%) were reported: 1 pericarditis and 1 vascular pseudoaneurysm. An additional SADE of localized infection was reported in 1 patient. No stroke, patient deaths, or other unanticipated AEs were reported. Average power delivered was 32.1±4.1 W, with a mean temperature of 40.8°C±1.6°C. Mean procedure (including 20-minute wait), fluoroscopy, and radiofrequency application times were 129.8, 6.7, and 34.0 minutes, respectively. On device performance, physicians reported overall satisfactory performance with the new catheter, with highest scores for satisfaction and usefulness of the temperature indicator. Conclusions: Initial clinical experience with the novel catheter showed 100% acute PVI success and acceptable safety and device performance in temperature-controlled ablation mode. There were no deaths, stroke, or unanticipated AEs. Fluoroscopy and procedural times were short and similar or better than reported for prior generation catheters.

• Publikační typ
• časopisecké články MeSH

The study presents a novel vancomycin-releasing collagen wound dressing derived from Cyprinus carpio collagen type I cross-linked with carbodiimide which retarded the degradation rate and increased the stability of the sponge. Following lyophilization, the dressings were subjected to gamma sterilization. The structure was evaluated via scanning electron microscopy images, micro-computed tomography, and infrared spectrometry. The structural stability and vancomycin release properties were evaluated in phosphate buffered saline. Microbiological testing and a rat model of a wound infected with methicillin-resistant Staphylococcus aureus (MRSA) were then employed to test the efficacy of the treatment of the infected wound. Following an initial mass loss due to the release of vancomycin, the sponges remained stable. After 7 days of exposure in phosphate buffered saline (37°C), 60% of the material remained with a preserved collagen secondary structure together with a high degree of open porosity (over 80%). The analysis of the release of vancomycin revealed homogeneous distribution of the antibiotic both across and between the sponges. The release of vancomycin was retarded as proved by in vitro testing and further confirmed by the animal model from which measurable concentrations were observed in blood samples 24 hours after the subcutaneous implantation of the sponge, which was more than observed following intraperitoneal administration. The sponge was also highly effective in terms of reducing the number of colony-forming units in biopsies extracted from the infected wounds 4 days following the inoculation of the wounds with the MRSA solution. The presented sponges have ideal properties to serve as wound dressing for prevention of surgical site infection or treatment of already infected wounds.

• MeSH
• antibakteriální látky farmakokinetika   MeSH
• hojení ran účinky léků   MeSH
• kapři MeSH
• karbodiimidy farmakokinetika   MeSH
• kolagen farmakokinetika   MeSH
• krysa rodu rattus MeSH
• methicilin rezistentní Staphylococcus aureus účinky léků   MeSH
• obvazy MeSH
• vankomycin farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Objectives: Surgical wounds resulting from biofilm-producing microorganisms represent a major healthcare problem that requires new and innovative treatment methods. Rifampin is one of a small number of antibiotics that is able to penetrate such biofilms, and its local administration has the potential to serve as an ideal surgical site infection protection and/or treatment agent. This paper presents two types (homogeneous and sandwich structured) of rifampin-releasing carbodiimide-cross-linked fresh water fish collagen wound dressings. Methods: The dressings were prepared by means of the double-lyophilization method and sterilized via gamma irradiation so as to allow for testing in a form that is able to serve for direct clinical use. The mechanical properties were studied via the uniaxial tensile testing method. The in vivo rifampin-release properties were tested by means of a series of incubations in phosphate-buffered saline. The microbiological activity was tested against methicillin-resistant staphylococcus aureus (MRSA) employing disc diffusion tests, and the in vivo pharmacokinetics was tested using a rat model. A histological examination was conducted for the study of the biocompatibility of the dressings. Results: The sandwich-structured dressing demonstrated better mechanical properties due to its exhibiting ability to bear a higher load than the homogeneous sponges, a property that was further improved via the addition of rifampin. The sponges retarded the release of rifampin in vitro, which translated into at least 22 hours of rifampin release in the rat model. This was significantly longer than was achieved via the administration of a subcutaneous rifampin solution. Microbiological activity was proven by the results of the disc diffusion tests. Both sponges exhibited excellent biocompatibility as the cells penetrated into the scaffold, and virtually no signs of local irritation were observed. Conclusions: We present a novel rifampin-releasing sandwich-structured fresh water fish collagen wound dressing that has the potential to serve as an ideal surgical site infection protection and/or treatment agent.

• MeSH
• antibakteriální látky farmakologie   MeSH
• biofilmy účinky léků   MeSH
• hojení ran účinky léků   MeSH
• infekce chirurgické rány farmakoterapie   MeSH
• kolagen farmakologie   MeSH
• krysa rodu rattus MeSH
• methicilin rezistentní Staphylococcus aureus účinky léků   MeSH
• obvazy MeSH
• potkani Wistar MeSH
• rifampin farmakologie   MeSH
• ryby metabolismus   MeSH
• sladká voda MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Aim: To assess the systemic and local immunological response to subcutaneous implants of a vascular graft covered with collagen extracted from the European carp (freshwater fish) or with collagen of bovine origin. Methods: Pieces of a vascular graft covered by pure bovine (Bos taurus, BOV, n=14) or carp (Cyprinus carpio, CYP, n=14) collagen 5 mm in size were implanted subcutaneously in the dorsum of a Balb/cOla mice. A sham operation group of 12 animals served as the control. At 7 and 14 days after the operation, one-half of each group was terminated and blood for serum, spleen, and implant with surrounding tissue were collected. Mean cytokine (TNF-α, IL-10, IL-4, IL-1β, IL-13, and IFN-γ) levels in serum were determined using ELISA. Spleen cell cultures were used for in vitro testing of lymphocyte proliferation and cytokine secretion. Local expressions of IL-6, IL-10, TNF-α, TGF-β, CCL-2, and CCL-3 were determined using PCR. Results: We found no significant difference among control, BOV, and CYP groups in mean cytokine serum levels at seven days. At day 14, the BOV group had higher levels of TNF-α (P=.018) and both the BOV and CYP groups had lower levels of IL-4 (P=.011 and P=.047, respectively) compared with the control group. Both tested implants showed only a minimal effect on the production of selected cytokines. Cell proliferation in the CYP group stimulated by CYP gel at 14 days was significantly lower than by BOV gel in BOV group (P=.0031) or by CYP gel in the control group (P=.041). The difference between the groups in the local RNA expression of all the tested mediators both at 7 and at 14 days was not significant apart from a lower level of TNF-α in the BOV group compared to CYP at 14 days (P=.013). Conclusions: Implants covered with carp collagen induce an immunological response that is comparable to that of bovine collagen covered implants in a mouse model.

• MeSH
• buněčné mikroprostředí MeSH
• cévní protézy * MeSH
• cytokiny krev   MeSH
• kapři MeSH
• kolagen imunologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• myši inbrední BALB C MeSH
• proliferace buněk MeSH
• skot MeSH
• slezina cytologie   MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Úvod: Pedální bypass je jednou z léčebných možností záchrany končetiny u kritické končetinové ischemie. Metoda: Retrospektivní analýza dat 20 pacientů, u kterých byl proveden pedální bypass na II. chirurgické klinice VFN a 1. LF UK buď jako jednoduchý (14 pacientů), nebo větvený konduit (6 pacientů) a kteří měli alespoň jedno sledování po dimisi. U větveného bypassu bylo hlavní raménko napojeno na pedální tepnu lepší kvality a odbočka na tepnu na opačné straně nohy. Ve skupině s větveným bypassem bylo hlavní tělo zhotoveno jako reverzní bypass z v. saphena magna u všech pacientů. U jednoduchého bypassu bylo 9 pacientů s reverzním bypassem z v. saphena magna, 3 pacienti s allograftem a po 1 pacientovi s PTFE graftem a in situ bypassem z v. saphena magna. Výsledky: Rozdíl v délce trvání operace nebyl významný. V pooperačním období bylo nutno reoperovat jednoho pacienta s jednoduchým bypassem pro krvácení z rány a perioperační mortalita byla zaznamenána u jednoho pacienta z téže skupiny. Ve sledovaném období jsme neprokázali významný rozdíl v primární nebo sekundární průchodnosti, v počtu amputací či celkovém přežití. Závěr: Na našem souboru pacientů jsme neprokázali významný rozdíl ani v průchodnosti, ani v zachování končetiny či peroperačních komplikacích. Domníváme se proto, že zvýšení rizika selhání rekonstrukce vytvořením další anastomózy není dostatečně vyváženo předpokládaným zlepšením hemodynamiky přidáním odbočky na druhou pedální tepnu. Rozšíření použití větveného bypassu tak bude zřejmě muset předcházet zlepšení techniky zejména použití primárně větveného žilního štěpu.

Introduction: Pedal bypass is a therapeutic option for limb salvage in critical limb ischemia. Method: Retrospective analysis of 20 patients who underwent either simple (14 patients) or branched (6 patients) pedal bypass in a single center and had at least one postoperative follow-up. In patients with branched pedal bypass, the main trunk was connected to the pedal artery of better quality and the side branch to an artery on the opposite side of the foot. The main trunk was constructed as a reverse saphenous bypass in all patients with branched bypass. From patients with simple bypass, nine had reverse saphenous graft, three had an allograft, one patient had in situ saphenous graft, and one PTFE prosthesis. Results: The difference in the operation time was not significant. One patient with simple bypass required reoperation for wound bleeding and there was one case of perioperative mortality in the same group. The difference between the groups in the primary or secondary patency rates, limb salvage and overall survival was not significant. Conclusions: We did not find any significant difference in patency rates, limb salvage, or perioperative complications between patients with simple and branched pedal bypass in our cohort. We believe that the anticipated benefits of constructing an additional branch are masked by the disadvantageous presence of an additional anastomosis. Adoption of a branched pedal bypass may therefore require further improvements perhaps the utilization of a branched saphenous graft.

• Klíčová slova
• pedální bypass,
• MeSH
• dolní končetina diagnostické zobrazování   krevní zásobení   patofyziologie   MeSH
• ischemie diagnóza   chirurgie   MeSH
• lidé MeSH
• onemocnění periferních arterií * diagnostické zobrazování   chirurgie   MeSH
• pooperační péče MeSH
• retrospektivní studie MeSH
• transplantace cév MeSH
• výkony cévní chirurgie metody   MeSH
• záchrana končetiny * metody   MeSH
• Check Tag
• lidé MeSH

Návrh teambuildingového projektu pre zdravotníckych záchranárov záchrannej zdravotnej služby je možným prostriedkom v prevencii syndrómu vyhorenia. Tento návrh bol vypracovaný na základe výsledkov prieskumnej štúdie realizovanej v marci 2012 formou dotazníka Inventár prejavov syndrómu vyhorenia Tošnera a Tošnerovej (2002) zameraného na zistenie miery ohrozenia syndrómom vyhorenia v štyroch oblastiach: rozumovej, emocionálnej, telesnej a sociálnej rovine u zdravotníckych záchranárov záchrannej zdravotnej služby vybranej záchrannej zdravotnej služby. Z výsledkov prieskumu vyplynulo, že zdravotnícki záchranári sú najviac ohrození sociálnymi a emocionálnymi faktormi vplývajúcimi na vznik syndrómu vyhorenia, a preto bol pre nich vytvorený návrh teambuildingového programu ako žiadaná forma prevencie, ktorá má tendenciu patriť k základnému edukačnému balíku zdravotníckych záchranárov ako prostriedku prevencie eliminujúceho vplyv týchto faktorov.

Proposal for a team building project for paramedics emergency medical services is a potential agent in preventing burnout. The proposal was developed based on the results of an exploratory study carried out in March 2012 by a questionnaire inventory of symptoms of burnout and Tošner Tošnerová (2002) focused on measuring the risk of burnout syndrome in four areas: cognitive, emotional, physical and social level in paramedics emergency medical services selected emergency medical services. The survey showed that medical rescuers are most at risk of social and emotional factors affecting the formation of burnout and has been created for their team building program proposal as requested form of prevention, which tends to belong to the basic educational package paramedics as a means of eliminating the impact of prevention these factors.

• MeSH
• dospělí MeSH
• interpersonální vztahy MeSH
• kontinuální vzdělávání metody   statistika a číselné údaje   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• primární prevence * metody   MeSH
• profesionální vyhoření * prevence a kontrola   psychologie   MeSH
• průzkumy a dotazníky MeSH
• psychický stres komplikace   prevence a kontrola   psychologie   MeSH
• statistika jako téma MeSH
• tělesná výchova metody   MeSH
• urgentní lékařství * pracovní síly   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH