The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2'-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid leukemia cell lines, MOLM-13 and SKM-1, through their prolonged cultivation in increasing concentrations of DAC. The resistant cell variants, MOLM-13/DAC and SKM-1/DAC, exhibited cross-resistance to cytarabine and gemcitabine, but remained sensitive to AZA. Existing studies have suggested that the loss of deoxycytidine kinase (DCK) may play an important role in DAC resistance. DCK is critical for DAC activation, but the precise mechanisms of its downregulation remain incompletely understood. We identified a novel point mutation (A180P) in DCK, which results in acquired DAC resistance. Although the DCK mRNA was actively transcribed, the mutant protein was not detected in DAC-resistant cells. The transfection of HEK293 cells with the mutant DCK, combined with proteasomal inhibition, revealed rapid proteasomal degradation, establishing a mechanistic link between the A180P mutation and DCK loss, not previously described. This highlights the importance of also evaluating DCK at the protein and/or enzymatic activity levels in patients. The loss of functional DCK impairs the phosphorylation of deoxynucleosides, conferring resistance to DAC, gemcitabine, and cytarabine, but AZA, phosphorylated by uridine-cytidine kinase, remains effective and may represent a therapeutic alternative for patients with acquired DAC resistance.

• MeSH
• akutní myeloidní leukemie * genetika   farmakoterapie   MeSH
• azacytidin * farmakologie   analogy a deriváty   MeSH
• chemorezistence * genetika   účinky léků   MeSH
• cytarabin farmakologie   MeSH
• decitabin * farmakologie   MeSH
• deoxycytidin analogy a deriváty   farmakologie   MeSH
• deoxycytidinkinasa * genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• protinádorové antimetabolity * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The design of MB327, a bispyridinium compound that ameliorates the nicotinic effects of acute organophosphorus nerve agent (NA) intoxication, followed an observation made by the German pharmacologist Klaus Schoene in the 1970s, who noted therapeutic activity in bispyridinium molecules missing the usual oxime group, CHNOH. Some of these compounds protected mice against soman. One structurally related to obidoxime called HY10 had this action. Its oxime moieties were capped by tert-butyl groups: CH=NOtBu. We modified HY10 by changing the bridge between the pyridinium units from a dimethylene ether to a trimethylene group (CH2OCH2 → CH2CH2CH2) and prepared a novel relative of trimedoxime, called LB1, whose synthesis and stereochemistry are described. Unlike obidoxime or trimedoxime, LB1 because of its capped oxime groups, cannot directly reactivate NA inhibited acetylcholinesterase. Its antidotal activity in mice is now reported. The therapeutic efficacy of LB1, atropine alone, atropine with LB1, atropine with an oxime (HI-6, obidoxime or trimedoxime), and atropine with an oxime and LB1, was studied by determining the LD50 values of the NAs soman, sarin, or tabun in mice treated with these compounds or mixtures. LB1 exceeded MB327 in toxicity and its activity was insufficient for a useful addition to the current standard antidotal treatment (protective ratio data are compared to those of MB327). Although this study produced largely negative biological results, the therapeutically beneficial mechanism of the effective bispyridinium non-oxime analogues is unclear, and has been demonstrated only in vivo. The present study points out directions in structural optimisation unlikely to yield the desired therapeutic outcomes and provides a literature review that could promote creative thinking for the design of widely-desirable non-oxime therapeutics for anticholinesterase inhibitors.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota * chemická syntéza   chemie   farmakologie   terapeutické užití   MeSH
• atropin terapeutické užití   farmakologie   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• myši MeSH
• nervová bojová látka * toxicita   MeSH
• organofosforové sloučeniny * toxicita   MeSH
• oximy chemie   MeSH
• pyridinové sloučeniny * chemická syntéza   chemie   terapeutické užití   farmakologie   MeSH
• soman toxicita   MeSH
• trimedoxim chemie   chemická syntéza   farmakologie   terapeutické užití   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• akomodace oka účinky léků   MeSH
• atropin * aplikace a dávkování   farmakologie   MeSH
• axiální délka oka účinky léků   MeSH
• lidé MeSH
• mladiství MeSH
• myopie * farmakoterapie   terapie   MeSH
• oční roztoky aplikace a dávkování   MeSH
• progrese nemoci MeSH
• sourozenci MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• akutní myeloidní leukemie * farmakoterapie   MeSH
• azacytidin terapeutické užití   MeSH
• cílená molekulární terapie * metody   MeSH
• isocitrátdehydrogenasa antagonisté a inhibitory   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kongresy jako téma MeSH
• lidé MeSH
• protinádorové látky terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• pyridiny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• novinové články MeSH
• zprávy MeSH

Myelodysplastic syndromes (MDS) are myeloid malignancies with heterogeneous genotypes and phenotypes, characterized by ineffective haematopoiesis and a high risk of progression towards acute myeloid leukaemia (AML). Prognosis for patients treated with hypomethylating agents (HMAs), as is azacytidine, the main drug used as frontline therapy for MDS is mostly based on cytogenetics and next generation sequencing (NGS) of the initial myeloid clone. Although the critical influence of the epigenetic landscape upon cancer cells survival and development as well on tumour environment establishment is currently recognized and approached within current clinical practice in MDS, the heterogenous response of the patients to epigenetic therapy is suggesting a more complex mechanism of action, as is the case of RNA methylation. In this sense, the newly emerging field of epitranscriptomics could provide a more comprehensive perspective upon the modulation of gene expression in malignancies, as is the proof-of-concept of MDS. We initially did RNA methylation sequencing on MDS patients (n = 6) treated with azacytidine and compared responders with non-responders. Afterwards, the genes identified were assessed in vitro and afterwards validated on a larger cohort of MDS patients treated with azacytidine (n = 58). Our data show that a more accurate prognosis could be based on analysing the methylome and thus we used methylation sequencing to differentially split high-grade MDS patients with identical demographical and cytogenetic features, between azacytidine responders and non-responders.

• MeSH
• azacytidin * farmakologie   terapeutické užití   MeSH
• epigeneze genetická účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methylace RNA MeSH
• metylace DNA * účinky léků   MeSH
• myelodysplastické syndromy * genetika   farmakoterapie   patologie   MeSH
• prognóza MeSH
• protinádorové antimetabolity terapeutické užití   farmakologie   MeSH
• sekvenční analýza RNA MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• transkriptom genetika   účinky léků   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

This study aims to describe movement disorders secondary to cocaine use. To our knowledge, while these presentations have been previously reported in the literature, a comprehensive review has not been published yet. We searched six databases from 1986 to 2022 without language restriction. Case reports, case series, and literature reviews have been analysed to find associations between cocaine use and movement disorders. The present study encompasses epidemiology, clinical manifestations, pathophysiology, and diagnostic challenges of abnormal movements associated with cocaine use. This review highlights the importance of proper initial evaluation and investigation taking into account the broad spectrum of differential diagnoses and exclusion of primary movement disorders. The role of the dopaminergic system in movement disorders is reviewed. Cocaine use is associated with movement disorders such as dystonia, parkinsonism, akathisia, and tics. The complex interaction of multiple factors, including other neurological conditions, such as Tourette syndrome, and additional substances of abuse is discussed. The presentation of these manifestations is often heterogeneous and does not follow a specific pattern. In this way, future research is needed to improve our understanding of the pathophysiological mechanisms and develop novel drug targets for these disorders. Increased awareness among the general public and policymakers could translate into reduced stigma and improved care.

• MeSH
• kokain škodlivé účinky   MeSH
• lidé MeSH
• pohybové poruchy * diagnóza   etiologie   patofyziologie   MeSH
• poruchy spojené s užíváním kokainu komplikace   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The relative inhibitory activities of diazabicyclooctanes (avibactam, relebactam, zidebactam, nacubactam, durlobactam), boronic acid derivatives (vaborbactam, taniborbactam, xeruborbactam), and penicillin-based sulfone derivative enmetazobactam were evaluated against several intrinsic and acquired class C β-lactamases. By contrast to vaborbactam and enmetazobactam, taniborbactam, xeruborbactam, and all diazabicyclooctanes demonstrated effective activities against most AmpC enzymes. Notably, durlobactam exhibited the most pronounced inhibitory effect. Interstingly, the chromosomal AmpC of Acinetobacter baumannii was the least sensitive enzyme to the newly developed β-lactamase inhibitors.

• MeSH
• Acinetobacter baumannii * účinky léků   enzymologie   MeSH
• antibakteriální látky * farmakologie   chemie   MeSH
• azabicyklické sloučeniny * farmakologie   chemie   MeSH
• bakteriální proteiny * antagonisté a inhibitory   metabolismus   MeSH
• beta-laktamasy * metabolismus   MeSH
• bicyklické sloučeniny heterocyklické farmakologie   chemie   MeSH
• cyklooktany MeSH
• inhibitory beta-laktamasy * farmakologie   chemie   MeSH
• kyseliny boronové * farmakologie   chemie   MeSH
• laktamy MeSH
• mikrobiální testy citlivosti * MeSH
• peniciliny farmakologie   chemie   MeSH
• piperidiny MeSH
• sulfony farmakologie   chemie   MeSH
• Publikační typ
• časopisecké články MeSH

This study compared decitabine exposure when administered IV (DEC-IV) at a dose of 20 mg/m2 for 5-days with orally administered decitabine with cedazuridine (DEC-C), as well as the clinical efficacy and safety of DEC-C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC-IV or oral DEC-C (days 1-5 in a 28-day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC-C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5-day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC-C were consistent with those previously observed with DEC-IV. Next-generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC-C in patients with AML.

• MeSH
• akutní myeloidní leukemie * farmakoterapie   mortalita   MeSH
• aplikace orální MeSH
• decitabin * aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• intravenózní podání MeSH
• klinické křížové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   farmakokinetika   škodlivé účinky   aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• uridin * analogy a deriváty   aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   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
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

There are currently no pharmacological treatments for cocaine use disorder. Recently there has been a great deal of interest in the potential of psychedelic drugs such as psilocybin to treat psychiatric disorders. Human studies have indicated that a single administration of psilocybin can have long-lasting effects. Few preclinical studies have examined a role for psilocybin in addiction models. The goal of the current study was to determine whether psilocybin would enhance extinction following cocaine self-administration in male and female mice and rats and thus result in an attenuation of cue-induced drug-seeking. In experiments in mice, 16 female and 19 male mice underwent 8d of cocaine self-administration (0.5 mg/kg/infusion) and extinction training. Immediately following extinction trials, mice were injected with vehicle or 1.0 mg/kg psilocybin. Following the conclusion of extinction training, mice were tested for cue-induced reinstatement. In experiments in rats, 24 female and 23 male rats underwent 15d of cocaine self-administration (0.8 mg/kg/infusion) and extinction training. Immediately following extinction trials, rats were injected with vehicle, 1.0 mg/kg psilocybin, or 2.5 mg/kg psilocybin. Following the conclusion of extinction training, rats were tested for cue-induced reinstatement. Psilocybin administered following extinction trials had no effect, as both female and male mice and rats demonstrated significant cue-induced reinstatement. These data suggest that psilocybin is ineffective at altering cocaine-seeking behavior in the paradigm and doses used in the current study. It remains to be seen whether treatment with psilocybin under different conditions may be useful in the long-standing goal of finding pharmacotherapies to treat CUD.

• MeSH
• autoaplikace * MeSH
• chování při shánění drogy * účinky léků   MeSH
• extinkce (psychologie) * účinky léků   MeSH
• halucinogeny * farmakologie   aplikace a dávkování   MeSH
• inhibitory vychytávání dopaminu farmakologie   aplikace a dávkování   MeSH
• kokain * farmakologie   aplikace a dávkování   MeSH
• krysa rodu rattus MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• operantní podmiňování účinky léků   MeSH
• podněty * MeSH
• pohlavní dimorfismus MeSH
• poruchy spojené s užíváním kokainu farmakoterapie   psychologie   MeSH
• potkani Sprague-Dawley MeSH
• psilocybin * farmakologie   aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Our observational study analysed fungal infection frequency within cohorts with versus without antifungal prophylaxis (AFP) among newly diagnosed first-line venetoclax and azacitidine (VEN + AZA)-treated acute myeloid leukaemias in Czech, Austrian and Slovak haematology centres. Among 186 patients, 85 (46%) received antifungal prophylaxis, while 101 (54%) received no prophylaxis. Fungal infections occurred in 1/85 patients with prophylaxis (1%) and 5/101 patients without prophylaxis (5%) (p = 0.222). No significant difference was recorded between cohorts with and without AFP in terms of death rate (p = 0.296) and overall survival (p = 0.844). In conclusion, most infections were not severe, developing during the first treatment-cycle and did not affect patients' overall outcome.

• MeSH
• akutní myeloidní leukemie * farmakoterapie   komplikace   MeSH
• antifungální látky * terapeutické užití   aplikace a dávkování   MeSH
• azacytidin * aplikace a dávkování   terapeutické užití   MeSH
• bicyklické sloučeniny heterocyklické * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mykózy * prevence a kontrola   etiologie   MeSH
• protokoly protinádorové kombinované chemoterapie * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sulfonamidy * aplikace a dávkování   terapeutické užití   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
• multicentrická studie MeSH
• pozorovací studie MeSH