Pacienti cévní chirurgie jsou vystaveni riziku tzv. sekundárního traumatu, které vzniká na podkladě patologických změn způsobených nejdříve ischemií a následně reperfuzí. Ischemicko ‐reperfuzní syndrom v důsledku oxidativního stresu a vystupňované buněčné smrti pak podstatnou měrou přispívá k vysoké perioperační morbiditě a mortalitě těchto pacientů. Ve snaze o snížení negativního dopadu těchto procesů, byla vyvinuta řada opatření, k nimž patří i koncept vzdálené ischemické prekondice. S ohledem na analogii mezi patofyziologií ischemické prekondice a poruch dýchání ve spánku můžeme usuzovat na menší dopad ischemicko ‐reperfuzních změn u pacientů s obstrukční spánkovou apnoe.
Vascular surgery patients are exposed to the risk of secondary trauma, which arises on the basis of pathological changes caused first by ischemia and then by reperfusion. Ischemia-reperfusion syndrome due to oxidative stress and increased cell death contributes significantly to the high perioperative morbidity and mortality of these patients. In an attempt to reduce the negative impact of these processes, a number of measures have been developed, including the concept of remote ischemic preconditioning. Based on the analogy between the pathophysiology of ischemic preconditioning and sleep disordered breathing, we can hypothesize a smaller impact of ischemia-reperfusion changes in patients with obstructive sleep apnea.
- MeSH
- anestetika terapeutické užití MeSH
- farmakoterapie metody MeSH
- karotická endarterektomie škodlivé účinky MeSH
- lidé MeSH
- nemoci ledvin etiologie mortalita MeSH
- oxidační stres fyziologie MeSH
- pooperační komplikace etiologie klasifikace mortalita patofyziologie MeSH
- přivykání k ischémii dějiny metody MeSH
- reperfuzní poškození * etiologie mortalita patofyziologie terapie MeSH
- simendan farmakologie terapeutické užití MeSH
- transplantace škodlivé účinky MeSH
- výkony cévní chirurgie * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Kardiovaskulárne ochorenia sú podľa štatistiky WHO [Cardiovascular disease (CVDs)] príčinou úmrtia 17,9 miliónov pacientov ročne, čo percentuálne predstavuje približne 31 % všetkých úmrtí. Aj napriek významnému pokroku farmakologickej terapie stav pacientov často vyústi do zlyhania srdca. V priebehu dekád bolo v liečbe zlyhania srdca uplatnených mnoho rôznych skupín liečiv, ale žiadne z nich nelieči toto ochorenie kauzálne. Istú nádej priniesli experimentálne štúdie fínskych výskumníkov s tzv. vápnikovými senzitizérmi. Ich najvýznamnejším predstaviteľom je levosimendan, dodnes využívaný v terapii akútneho zlyhania srdca.
According to WHO, cardiovascular diseases (CVDs) are responsible for 17.9 million deaths annually, which represents approximately 31% of all deaths. Despite significant progress in pharmacotherapy, many patients often proceed into the heart failure. Numerous substances and various drug groups were employed in the heart failure treatment during last several decades, not a single of them however can treat the heart failure causally. Certain hope represented studies of Finish researchers with so-called calcium sensitizers. Main representative of this group is levosimendan, which is used nowadays present in the therapy of acute heart failure.
- MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- simendan farmakologie terapeutické užití MeSH
- srdeční selhání * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Dysregulation of iron homeostasis is one of the important processes in the development of many oncological diseases, such as pancreatic cancer. Targeting it with specific agents, such as an iron chelator, are promising therapeutic methods. In this study, we tested the cytotoxicity of novel azulene hydrazide-hydrazone-based chelators against pancreatic cancer cell lines (MIA PaCa-2, PANC-1, AsPC-1). All prepared chelators (compounds 4-6) showed strong cytotoxicity against pancreatic cancer cell lines and high selectivity for cancer cell lines compared to the healthy line. Their cytotoxicity is lower than thiosemicarbazone-based chelators Dp44mT and DpC, but significantly higher than hydroxamic acid-based chelator DFO. The chelator tested showed mitochondrial and lysosomal co-localization and its mechanism of action was based on the induction of hypoxia-inducible factor-1-alpha (HIF-1α), N-myc downstream-regulated gene-1 (NDRG1) and transferrin receptor 1 (TfR1). This strongly implies that the cytotoxic effect of tested chelators could be associated with mitophagy induction. Lipinski's rule of five analyses was performed to determine whether the prepared compounds had properties ensuring their bioavailability. In addition, the drug-likeness and drug-score were calculated and discussed.
- MeSH
- azuleny MeSH
- chelátory železa farmakologie MeSH
- hydraziny MeSH
- hydrazony farmakologie MeSH
- kyseliny hydroxamové MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory slinivky břišní * farmakoterapie MeSH
- receptory transferinu MeSH
- thiosemikarbazony * farmakologie MeSH
- železo MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2-6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2-6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.
Akutní oběhové selhání (AOS) je závažnou a život ohrožující komplikací u novorozenců. Během celého novorozeneckého období se mohou vyskytnout situace, které způsobují AOS. Diagnostika AOS je komplikována velikostí pacientů, omezenými invazivními metodami a intra- i extrakardiálními zkraty. Spektrum farmak, která ovlivňují oběhovou soustavu je poměrně široké. Každý lék ovlivňuje cirkulaci na jiné úrovni a jiným způsobem, proto musí být terapie individualizovaná a efekt na hemodynamiku je třeba pravidelně kontrolovat. Popsaný efekt terapie však často vychází z experimentálních studií nebo ze studií na dospělých pacientech. Tyto výsledky je proto obtížné extrapolovat na novorozence. Recentní studie prokázaly, že dokážeme dobře ovlivnit některé parametry oběhového systému u oběhově kompromitovaných novorozenců, ale bez pozitivního vlivu na dlouhodobý psychomotorický vývoj.
Acute circulatory failure (ACF) is a serious and life-threatening complication in a newborn. ACF can occur throughout the whole neonatal life. Diagnosis of ACF is complicated by the size of patients, limited invasive methods and presence of intra and extracardiac shunts. The spectrum of drugs affecting the circulatory system is relatively broad. However, explored effects are often based on experimental studies or studies in adults. Thus, it is difficult to extrapolate these conclusions to neonates. Moreover, each drug affects the circulation at a different level and in a different way. The optimal therapy must therefore be tailored and the effect on hemodynamics must be monitored accordingly. Recently published data revealed that we can sufficiently influence some parameters of the circulatory system in circulatory compromised newborns, but without a positive effect on long-term neurological outcome.
- MeSH
- adrenalin terapeutické užití MeSH
- dopamin terapeutické užití MeSH
- hormony kůry nadledvin terapeutické užití MeSH
- hypotenze * farmakoterapie MeSH
- intenzivní péče o novorozence * metody MeSH
- lidé MeSH
- novorozenec MeSH
- sildenafil citrát terapeutické užití MeSH
- simendan terapeutické užití MeSH
- srdeční selhání farmakoterapie MeSH
- vasopresiny terapeutické užití MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- přehledy MeSH
Inhibition of the human O-linked β-N-acetylglucosaminidase (hOGA, GH84) enzyme is pharmacologically relevant in several diseases such as neurodegenerative and cardiovascular disorders, type 2 diabetes, and cancer. Human lysosomal hexosaminidases (hHexA and hHexB, GH20) are mechanistically related enzymes; therefore, selective inhibition of these enzymes is crucial in terms of potential applications. In order to extend the structure-activity relationships of OGA inhibitors, a series of 2-acetamido-2-deoxy-d-glucono-1,5-lactone sulfonylhydrazones was prepared from d-glucosamine. The synthetic sequence involved condensation of N-acetyl-3,4,6-tri-O-acetyl-d-glucosamine with arenesulfonylhydrazines, followed by MnO2 oxidation to the corresponding glucono-1,5-lactone sulfonylhydrazones. Removal of the O-acetyl protecting groups by NH3/MeOH furnished the test compounds. Evaluation of these compounds by enzyme kinetic methods against hOGA and hHexB revealed potent nanomolar competitive inhibition of both enzymes, with no significant selectivity towards either. The most efficient inhibitor of hOGA was 2-acetamido-2-deoxy-d-glucono-1,5-lactone 1-naphthalenesulfonylhydrazone (5f, Ki = 27 nM). This compound had a Ki of 6.8 nM towards hHexB. To assess the binding mode of these inhibitors to hOGA, computational studies (Prime protein-ligand refinement and QM/MM optimizations) were performed, which suggested the binding preference of the glucono-1,5-lactone sulfonylhydrazones in an s-cis conformation for all test compounds.
- MeSH
- antigeny nádorové chemie metabolismus MeSH
- beta-hexosaminidasa, beta řetězec chemie metabolismus MeSH
- histonacetyltransferasy chemie metabolismus MeSH
- hyaluronoglukosaminidasa chemie metabolismus MeSH
- hydrazony chemická syntéza chemie farmakologie MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- laktony chemie MeSH
- lidé MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- oxidy chemie MeSH
- sloučeniny manganu chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Hydrazide-hydrazones have been described as a scaffold with antimicrobial and cytotoxic activities as well as iodinated compounds. A resistance rate of bacterial and fungal pathogens has increased considerably. That is why we synthesized and screened twenty-two iodinated hydrazide-hydrazones 1 and 2, ten 1,2-diacylhydrazines 3 and their three reduced analogues 4 for their antibacterial, antifungal, and cytotoxic properties. Hydrazide-hydrazones were prepared by condensation of 4-substituted benzohydrazides with 2-/4-hydroxy-3,5-diiodobenzaldehydes, diacylhydrazines from identical benzohydrazides and 3,5-diiodosalicylic acid via its chloride. These compounds were investigated in vitro against eight bacterial and eight fungal strains. The derivatives were found potent antibacterial agents against Gram-positive cocci including methicillin-resistant Staphylococcus aureus with the lowest values of minimum inhibitory concentrations (MIC) of 7.81 μM. Four compounds inhibited also human pathogenic fungi (MIC of ≥1.95 μM). The derivatives had different degrees of cytotoxicity for HepG2 and HK-2 cell lines (IC50 values from 11.72 and 26.80 μM, respectively). Importantly, normal human cells exhibited lower sensitivity. The apoptotic effect was also investigated. In general, the presence of 3,5-diiodosalicylidene scaffold (compounds 1) is translated into enhanced both antimicrobial and cytotoxic properties whereas its 4-hydroxy isomers 2 share a low biological activity. N'-Benzoyl-2-hydroxy-3,5-diiodobenzohydrazides 3 have a non-homogeneous activity profile. Focusing on 4-substituted benzohydrazide part, the presence of an electron-withdrawing group (F, Cl, CF3, NO2) was found to be beneficial.
- MeSH
- antibakteriální látky chemie farmakologie MeSH
- antifungální látky chemie farmakologie MeSH
- antitumorózní látky chemie farmakologie MeSH
- Bacteria účinky léků MeSH
- buňky Hep G2 MeSH
- houby účinky léků MeSH
- hydraziny chemie MeSH
- hydrazony chemie MeSH
- lidé MeSH
- objevování léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Based on the broad spectrum of biological activity of hydrazide-hydrazones, trifluoromethyl compounds, and clinical usage of cholinesterase inhibitors, we investigated hydrazones obtained from 4-(trifluoromethyl)benzohydrazide and various benzaldehydes or aliphatic ketones as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). They were evaluated using Ellman's spectrophotometric method. The hydrazide-hydrazones produced a dual inhibition of both cholinesterase enzymes with IC50 values of 46.8-137.7 µM and 19.1-881.1 µM for AChE and BuChE, respectively. The majority of the compounds were stronger inhibitors of AChE; four of them (2-bromobenzaldehyde, 3-(trifluoromethyl)benzaldehyde, cyclohexanone, and camphor-based 2o, 2p, 3c, and 3d, respectively) produced a balanced inhibition of the enzymes and only 2-chloro/trifluoromethyl benzylidene derivatives 2d and 2q were found to be more potent inhibitors of BuChE. 4-(Trifluoromethyl)-N'-[4-(trifluoromethyl)benzylidene]benzohydrazide 2l produced the strongest inhibition of AChE via mixed-type inhibition determined experimentally. Structure-activity relationships were identified. The compounds fit physicochemical space for targeting central nervous systems with no apparent cytotoxicity for eukaryotic cell line together. The study provides new insights into this CF3-hydrazide-hydrazone scaffold.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- centrální nervový systém účinky léků MeSH
- cholinesterasové inhibitory farmakologie MeSH
- hematoencefalická bariéra účinky léků patologie MeSH
- hydraziny chemie MeSH
- hydrazony chemie farmakologie MeSH
- kinetika MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias' treatment. OBJECTIVE: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. METHODS: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman's method. We calculated also physicochemical and structural parameters for CNS delivery. RESULTS: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. CONCLUSION: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- Electrophorus MeSH
- hydraziny chemická syntéza chemie farmakologie MeSH
- hydrazony chemická syntéza chemie farmakologie MeSH
- koně MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.
- MeSH
- bezpečnost pacientů MeSH
- kardiotonika škodlivé účinky terapeutické užití MeSH
- kontrakce myokardu účinky léků MeSH
- lidé MeSH
- simendan škodlivé účinky terapeutické užití MeSH
- srdeční selhání diagnóza farmakoterapie mortalita patofyziologie MeSH
- vazodilatace účinky léků MeSH
- vazodilatancia škodlivé účinky terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
