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Spectroscopic analysis, density functional theory (DFT) studies and surface enhanced Raman scattering (SERS) of antimycobactetial 4-[3-(4-acetylphenyl)ureido]-2-hydroxybenzoic acid (AUHB) have been studied on different silver sols. For Raman and SERS wavenumbers, very large changes are observed. Observed variations in the modes of ring may be due to surface π-electron interactions and presence of this indicated that poly substituted ring is more inclined than para substituted phenyl ring and assumes a inclined position for concentration 10-3 M. Changes in orientation are seen in SERS spectra depending on concentration. In order to find electron-rich and poor sites of AUHB, molecular electrostatic potential was also constructed. The molecular docking results show that binding affinity and interactions with the receptor DprE1 may be supporting evidence for further studies in design further AUHB pharmaceutical applications. Based on antitubercular activity of 4-aminosalicylic acid (PAS) and urea derivatives we designed, synthesized and investigated mutual PAS-urea derivatives as potential antimycobacterial agents.
In recent years, a number of drugs targeting the prostate-specific membrane antigen (PSMA) have become important tools in the diagnosis and treatment of prostate cancer. In the present work, we report on the synthesis and preclinical evaluation of a series of 18F-labeled PSMA ligands for diagnostic application based on the theragnostic ligand PSMA-617. By applying modifications to the linker structure, insight into the structure-activity relationship could be gained, highlighting the importance of hydrophilicity and stereoselectivity on interaction with PSMA and hence the biodistribution. Selected compounds were co-crystallized with the PSMA protein and analyzed by X-rays with mixed results. Among these, PSMA-1007 (compound 5) showed the best interaction with the PSMA protein. The respective radiotracer [18F]PSMA-1007 was translated into the clinic and is, in the meantime, subject of advanced clinical trials.
- MeSH
- antigeny povrchové MeSH
- glutamátkarboxypeptidasa II antagonisté a inhibitory MeSH
- lidé MeSH
- ligandy MeSH
- nádory prostaty diagnostické zobrazování MeSH
- niacinamid analogy a deriváty chemie farmakologie MeSH
- oligopeptidy chemie farmakologie MeSH
- pozitronová emisní tomografie MeSH
- radiofarmaka farmakologie MeSH
- radioizotopy fluoru chemie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In recent years, several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of theranostic radiopharmaceuticals for the treatment of prostate cancer (PC). In the second decade of the 21(st) century, a new era in nuclear medicine was initiated by the clinical introduction of small-molecule PSMA inhibitor radioligands, 40 y after the clinical introduction of (18)F-FDG. Because of the high incidence and mortality of PC, the new PSMA radioligands have already had a remarkable impact on the clinical management of PC. For the continuing clinical development and long-term success of theranostic agents, designing modern prospective clinical trials in theranostic nuclear medicine is essential. First-in-human studies with PSMA radioligands derived from small-molecule PSMA inhibitors showed highly sensitive imaging of PSMA-positive PC by means of PET and SPECT as well as a dramatic response of metastatic castration-resistant PC after PSMA radioligand therapy. This tremendous success logically led to the initiation of prospective clinical trials with several PSMA radioligands. Meanwhile, MIP-1404, PSMA-11, 2-(3-{1-carboxy-5-[(6-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL), PSMA-617, PSMA-1007, and others have entered or will enter prospective clinical trials soon in several countries. The significance becomes apparent by, for example, the considerable increase in the number of publications about PSMA-targeted PET imaging from 2013 to 2016 (e.g., a search of the Web of Science for "PSMA" AND "PET" found only 19 publications in 2013 but 218 in 2016). Closer examination of the initial success of PC treatment with PSMA inhibitor radiotracers leads to several questions from the basic research perspective as well as from the perspective of clinical demands: What lessons have been learned regarding the design of PSMA radioligands that have already been developed? Has an acceptable compromise between optimal PSMA radioligand design and a broad range of clinical demands been reached? Can the lessons learned from multiple successes within the PSMA experience be transferred to further theranostic approaches?
- MeSH
- antigeny povrchové MeSH
- diagnóza * MeSH
- glutamátkarboxypeptidasa II antagonisté a inhibitory MeSH
- lidé MeSH
- močovina chemie farmakologie terapeutické užití MeSH
- molekulová hmotnost MeSH
- objevování léků metody MeSH
- radioaktivní indikátory MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. ; 30 cm
This proposal is designed to determine whether inhibitors of soluble epoxide hydrolase (sEH), increasing endogenous level of epoxyeicosatrienoic acids (EETs), could be a potential new approach in antihypertensive drug therapy. An effects of novel sEH inhibitor, cis-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB) on blood pressure, renal function and renal injury will be tested in Goldblatt two kidney one clip (2K1C) rat model of renovascular hypertension.
Předmětem této grantové aplikace je ověření zda inhibitory solubilní epoxide hydrolázy (sEH), zvyšující koncentraci epoxyeikosatrienových kyselin (EETs) ve tkáních, mohou představovat potenciálně nový přístup v antihypertenzní terapii. Bude proto testován účinek inhibitoru sEH, cis-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoové kyseliny (c-AUCB) na krevní tlak renální funkce a tkáňové poškození ledvin u modelu renovaskulární hypertenze.
- MeSH
- antihypertenziva terapeutické užití MeSH
- epoxid hydrolasy antagonisté a inhibitory MeSH
- kyseliny hydroxyeikosatetraenové MeSH
- ledviny patofyziologie zranění MeSH
- renovaskulární hypertenze farmakoterapie patofyziologie MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
- Klíčová slova
- termoablace,
- MeSH
- chemoembolizace MeSH
- cytostatické látky terapeutické užití MeSH
- hepatektomie MeSH
- hepatocelulární karcinom chirurgie diagnóza farmakoterapie terapie MeSH
- lidé MeSH
- nádory jater * chirurgie diagnóza farmakoterapie terapie MeSH
- sorafenib terapeutické užití MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- lidé MeSH
BACKGROUND & AIMS: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). METHODS: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). RESULTS: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. CONCLUSIONS: In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.
- MeSH
- alfa-fetoproteiny MeSH
- hepatocelulární karcinom * farmakoterapie MeSH
- humanizované monoklonální protilátky MeSH
- lidé MeSH
- nádory jater * farmakoterapie MeSH
- senioři MeSH
- sorafenib MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Klíčová slova
- lenvatinib, vandetanib,
- MeSH
- folikulární adenokarcinom terapie MeSH
- inhibitory proteinkinas aplikace a dávkování farmakologie MeSH
- lidé MeSH
- medulární karcinom farmakoterapie terapie MeSH
- nádory štítné žlázy * farmakoterapie MeSH
- papilární karcinom štítné žlázy farmakoterapie MeSH
- radioizotopy jodu terapeutické užití MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- sorafenib aplikace a dávkování farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
