multimodal phase Dotaz Zobrazit nápovědu
Eight different stationary phases based on two aminopropyl silicas of different brands suitable for multimodal chromatography applications have been prepared by a four-component Ugi reaction. The intention was to synthesize stationary phases significantly differing in their properties hereby demonstrating flexibility of the Ugi synthetic protocol. Diverse functional groups including a nonpolar long aliphatic chain, phenyl moiety, cholic acid scaffold, phenylboronic and monosaccharide units, charged betaine, and arginine moieties were immobilized on a silica surface. The novel sorbents were extensively characterized by elemental analysis, Raman spectroscopy, and chromatography. Considering the anchored chemical structures covalently bonded to the silica surface, reversed-phase, hydrophilic, and ion-exchange separation modes were expected. The chromatographic evaluation was performed directed to map the potential of the individual columns specifically in the mentioned chromatographic modes. The Ugi synthetic protocol has proven to be a simple, feasible, and versatile tool for the synthesis of sorbents of variable properties. The newly prepared stationary phases differed considerably in hydrophobicity and ion-exchange ability. A significant influence of the supporting aminopropyl silica on the final chromatographic behavior was observed. Finally, one practical example confirming applicability of the newly prepared sorbents was demonstrated in separation of cytarabine.
- Klíčová slova
- Ugi reaction, hydrophilic interaction, hydrophobic interaction, ion-exchange interaction, multimodal phase,
- Publikační typ
- časopisecké články MeSH
Avian (ortho)reovirus (ARV), which belongs to Reoviridae family, is a major domestic fowl pathogen and is the causative agent of viral tenosynovitis and chronic respiratory disease in chicken. ARV replicates within cytoplasmic inclusions, so-called viral factories, that form by phase separation and thus belong to a wider class of biological condensates. Here, we evaluate different optical imaging methods that have been developed or adapted to follow formation, fluidity and composition of viral factories and compare them with the complementary structural information obtained by well-established transmission electron microscopy and electron tomography. The molecular and cellular biology aspects for setting up and following virus infection in cells by imaging are described first. We then demonstrate that a wide-field version of fluorescence recovery after photobleaching is an effective tool to measure fluidity of mobile viral factories. A new technique, holotomographic phase microscopy, is then used for imaging of viral factory formation in live cells in three dimensions. Confocal Raman microscopy of infected cells provides "chemical" contrast for label-free segmentation of images and addresses important questions about biomolecular concentrations within viral factories and other biological condensates. Optical imaging is complemented by electron microscopy and tomography which supply higher resolution structural detail, including visualization of individual virions within the three-dimensional cellular context.
- Klíčová slova
- Assembly, Holography, Infection, Phase Separation, RNA Packaging, Raman Microscopy, Tomography, Viral Inclusion Bodies, Viroplasm,
- MeSH
- buněčné inkluze virové MeSH
- buněčné linie MeSH
- elektronová mikroskopie MeSH
- multimodální zobrazování MeSH
- Reoviridae * MeSH
- replikace viru MeSH
- virové replikační kompartmenty * MeSH
- Publikační typ
- časopisecké články MeSH
High-performance liquid chromatography (HPLC) is an ideal tool for enantiomeric separations of different drugs. In this study, the direct enantioseparation of bupropion, an atypical antidepressant structurally related to cathinone, was explored by using five chiral columns, including three based on derivatized cyclofructans, macrocyclic glycopeptide teicoplanin, and an immobilized amylose derivative under multimodal elution conditions. Baseline enantioseparation was obtained on the LarihcShell CF6-RN column, with derivatized cyclofructan 6, in the polar organic mode. The effects of the mobile-phase composition, type and content of major components, the nature and the amount of mobile-phase additives, and the column temperature on the retention, selectivity, and resolution were investigated to optimize enantioseparation. The calibration curve was linear in the range of 10-125 μg/ml for each enantiomer. The limits of detection and quantification were 0.1 and 0.3 μg/ml for both enantiomers of bupropion. The chiral recognition was controlled especially by H bonds, π-π, dipole-dipole interactions, and steric effects. Finally, the developed method was applied to the determination of bupropion in the commercially available drug.
- Klíčová slova
- bupropion, derivatized cyclofructan-based chiral stationary phase, enantioseparation, pharmaceutical analysis,
- MeSH
- bupropion * MeSH
- chromatografie kapalinová MeSH
- glykopeptidy * chemie MeSH
- stereoizomerie MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- bupropion * MeSH
- glykopeptidy * MeSH
Rectal carcinoma cannot be controlled only by surgical technique despite radical resection (TME, systematic lymphadenectomy). Therefore, progressive rectal carcinoma of stage 2 + 3 that are detectable pre-operatively by CT and 3-D endosonography, should be treated by a multimodal concept. Based on recent Scandinavian and Dutch studies, we introduced a modified post-operative short-term radiation in which the acute toxicity on tumor tissue corresponds to that of the Swedish and Dutch studies (5 x 5 Gy), its late toxicity, however, is reduced by 20%. Thus, we expect to reduce long-term damages to the pelvic organs, i.e. incontinence. A phase 2 study revealed good therapeutic management due to interdisciplinary tumor conference and a high acceptance by patients. The post-operative rate of wound healing is a bit higher, but does not influence the time of hospitalization.
- MeSH
- karcinom patologie radioterapie MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- nádory rekta patologie radioterapie MeSH
- radiační poranění MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
The metabolism of ethimizol in the human body has been investigated. Focus was on the detection and demonstration of the regioselective pathway of metabolic demethylation of ethimizol by determining the presence of the corresponding metabolites in blood, saliva and urine. Isolation, purification and identification of the metabolites present in the biological samples was achieved by applying a combination of the following methods: solid phase extraction, high performance liquid chromatography, high performance thin layer chromatography, nuclear magnetic resonance and mass spectrometry. The suggested chemical structures were definitely established by comparing the physicochemical characteristics of the ethimizol metabolites obtained from the individual biological fluids with the characteristics of synthetized authentic derivatives.
- MeSH
- chromatografie na tenké vrstvě MeSH
- etimizol krev metabolismus moč MeSH
- hmotnostní spektrometrie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- referenční hodnoty MeSH
- sliny chemie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- etimizol MeSH
Ixazomib is the first oral proteasome inhibitor to enter the clinic. Given the efficacy of bortezomib in combination with cyclophosphamide and dexamethasone, we studied the combination of ixazomib, cyclophosphamide and dexamethasone (ICd) in newly diagnosed multiple myeloma (NDMM) and patients with measurable disease, irrespective of transplant eligibility, were enrolled. The phase 1 was to determine the maximum tolerated dose (MTD) of cyclophosphamide in the combination. Patients received ixazomib 4 mg (days 1, 8, 15), dexamethasone 40 mg (days 1, 8, 15, 22), and cyclophosphamide 300 or 400 mg/m2 days 1, 8, 15, 22; cycles were 28 days. We enrolled 51 patients, 10 in phase 1 and 41 patients in phase 2. The median age was 64.5 years (range: 41-88); 29% had high or intermediate risk FISH. The MTD was 400 mg/m2 of cyclophosphamide weekly. The best confirmed response in all 48 patients included ≥ partial response in 77%, including ≥ VGPR in 35%; 3 patients had a sCR. The response rate for all 48 evaluable patients at 4-cycles was 71%; the median time to response was 1.9 months. Common adverse events included cytopenias, fatigue and GI intolerance. ICd is a convenient, all oral combination that is well tolerated and effective in NDMM.
- MeSH
- cyklofosfamid aplikace a dávkování MeSH
- dexamethason aplikace a dávkování MeSH
- dospělí MeSH
- glycin aplikace a dávkování analogy a deriváty MeSH
- kombinovaná terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom diagnóza farmakoterapie mortalita MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sloučeniny boru aplikace a dávkování MeSH
- staging nádorů MeSH
- transplantace hematopoetických kmenových buněk MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- cyklofosfamid MeSH
- dexamethason MeSH
- glycin MeSH
- ixazomib MeSH Prohlížeč
- sloučeniny boru MeSH
Hydrophilic interaction liquid chromatography (HILIC) represents a modern MS-friendly approach to the analysis of polar compounds. To date especially silica-based HILIC stationary phases are utilized. Recently the papers concerning retention of polar analytes on unmodified titania and zirconia as well as a polybutadiene modified zirconia stationary phase under HILIC conditions have been published. In this work the investigation of a highly hydrophobic carbon-coated zirconia column under HILIC conditions was reported. The influence of buffer concentration, buffer type, pH and temperature on the elution and chromatographic efficiency were studied. The processes participating on the retention of polar compounds showed a multimodal character. The retention was governed rather by surface adsorption than phase partition in high ACN mobile phases. The ligand exchange remained an important retention force although the access of the analytes to the active surface was significantly hindered by the carbon coating. Besides ligand exchange and hydrophilic interactions also the hydrophobic carbon layer was involved in the retention of carboxylic acids and especially xanthines in the organic rich mobile phase.
- MeSH
- acetonitrily chemie MeSH
- adsorpce MeSH
- chromatografie kapalinová přístrojové vybavení metody MeSH
- hydrofobní a hydrofilní interakce MeSH
- koncentrace vodíkových iontů MeSH
- kyseliny karboxylové chemie MeSH
- regresní analýza MeSH
- uhlík chemie MeSH
- xanthiny chemie MeSH
- zirkonium chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetonitrile MeSH Prohlížeč
- acetonitrily MeSH
- kyseliny karboxylové MeSH
- uhlík MeSH
- xanthiny MeSH
- zirconium oxide MeSH Prohlížeč
- zirkonium MeSH
A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m2, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.
- MeSH
- antitumorózní látky aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- biologické markery MeSH
- chronická myeloidní leukemie farmakoterapie mortalita patologie MeSH
- dítě MeSH
- imatinib mesylát aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- inhibitory proteinkinas aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- kojenec MeSH
- kombinovaná terapie MeSH
- kostní dřeň patologie MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- prognóza MeSH
- progrese nemoci MeSH
- staging nádorů MeSH
- stupeň nádoru MeSH
- terapie neúspěšná MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- biologické markery MeSH
- imatinib mesylát MeSH
- inhibitory proteinkinas MeSH
Celebrex and radiotherapy in advanced head and neck cancer. This phase I dose-escalation study seeks to determine the phase II recommended dose of cyclooxygenase type 2 (COX-2) inhibitor in patients with locally advanced squamous cell head and neck (H&N) cancer, treated with accelerated radiotherapy. Anti-vasculogenic effect of this treatment on serum vascular endothelial growth factor (VEGF) is examined. Patients were irradiated with curative intent (72Gy in 6weeks). Celecoxib was administered throughout the radiotherapy course. Serum VEGF level were tested during radiotherapy and in follow-up. Tumor specimens were stained to quantify the COX-2 expression. Thirty-two patients completed the treatment. The dose of celecoxib was escalated (200, 400 and 800mg bid, then de-escalated to 600mg bid). The acute toxicity related to the treatment in the first and second cohort did not reach grade III; in the third cohort three patients had grade III radiation toxicity and one had celecoxib-related toxicity. In the last fourth cohort the toxicity was acceptable. Significant VEGF level drop (p=0.011) was found between radiation day 1 and post-treatment visit. Significant decrease (p=0.022) of the VEGF level was shown in patients with high COX-2 expression in the tumor. Phase II recommended dose of celecoxib combined with accelerated radiotherapy in advanced H&N cancer was 600mg bid. A significant decrease of the post-treatment serum VEGF level compared to the initial level was noticed only in patients with high COX-2 expression in tumors.
- MeSH
- celekoxib MeSH
- cyklooxygenasa 2 metabolismus MeSH
- dospělí MeSH
- inhibitory cyklooxygenasy 2 aplikace a dávkování škodlivé účinky MeSH
- klinické zkoušky, fáze II jako téma MeSH
- kombinovaná terapie škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory hlavy a krku farmakoterapie metabolismus radioterapie MeSH
- pyrazoly aplikace a dávkování škodlivé účinky MeSH
- senioři MeSH
- spinocelulární karcinom farmakoterapie metabolismus radioterapie MeSH
- sulfonamidy aplikace a dávkování škodlivé účinky MeSH
- vaskulární endoteliální růstový faktor A krev účinky léků MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- práce podpořená grantem MeSH
- Názvy látek
- celekoxib MeSH
- cyklooxygenasa 2 MeSH
- inhibitory cyklooxygenasy 2 MeSH
- pyrazoly MeSH
- sulfonamidy MeSH
- vaskulární endoteliální růstový faktor A MeSH
BACKGROUND: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. METHODS: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. FINDINGS: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53). INTERPRETATION: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. FUNDING: Cerevast Therapeutics.
- MeSH
- cévní mozková příhoda terapie MeSH
- dvojitá slepá metoda MeSH
- fibrinolytika terapeutické užití MeSH
- ischemie mozku terapie MeSH
- kombinovaná terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- tkáňový aktivátor plazminogenu terapeutické užití MeSH
- trombolytická terapie škodlivé účinky metody MeSH
- ultrazvuková terapie škodlivé účinky metody MeSH
- výsledek terapie MeSH
- zbytečná diagnóza a terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- fibrinolytika MeSH
- tkáňový aktivátor plazminogenu MeSH