OBJECTIVE: The aim of the study was the assessment of adherence to antiretroviral (ARV) treatment in a population of people living with HIV (PWH), improving the awareness of PWH, drawing attention to the risk of developing HIV drug resistance and subsequent treatment failure. METHODS: The basic cohort consisted of PWH followed up long-term at the HIV centre of the University Hospital Pilsen. Adherence to treatment was assessed by ARV levels. Nucleoside analogs were determined in urine by high pressure liquid chromatography (HPLC), in relation to clinical data, viral load (HIV RNA), and absolute CD4 and CD8 T cell counts. To assess mental and physical state of the patients, a modified SF-36 questionnaire was used to measure social relationships, education and ability to relax. RESULTS: From a group of 131 PWH, 18 (13.7%) with zero levels and 113 (86.3%) with any detectable ARV levels were followed for 6-12 months. A statistically significant lower viral load was demonstrated in patients who adhered to the treatment at the time of the test as indicated by ARV levels in the urine. CD4 T lymphocyte values in adherent patients were, as expected, statistically significantly higher. A significant difference for CD8 T lymphocyte was not demonstrated. A survey assessed subjective factors influencing the degree of adherence. PWH consider important: quality care enabling trust, low risk of developing opportunistic infections, self-sufficiency, quality of sleep, managing leisure activities, and good family relationships. Quality of life evaluation and satisfaction in the monitored areas were similar in both groups of PWH. CONCLUSIONS: Non-adherence leads to deterioration of CD4 and viral load levels and may be the cause of the development of HIV drug resistance and treatment failure on the part of the patient. PWH with zero or low urinary nucleoside levels were repeatedly instructed about the need for regular and sustained medication use. Regular checks with a laboratory examination service are needed to detect early emergence of resistance and side effects of the treatment, which are initially only detectable in the laboratory.
- MeSH
- Medication Adherence * psychology MeSH
- Adult MeSH
- HIV Infections * drug therapy psychology MeSH
- Cohort Studies MeSH
- Quality of Life * MeSH
- Anti-HIV Agents * therapeutic use urine MeSH
- Middle Aged MeSH
- Humans MeSH
- CD4 Lymphocyte Count MeSH
- Viral Load MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
D-xylofuranosyl nucleoside analogues bearing alkylthio and glucosylthio substituents at the C3'-position were prepared by photoinitiated radical-mediated hydrothiolation reactions from the corresponding 2',5'-di-O-silyl-3'-exomethylene uridine. Sequential desilylation and 5'-O-butyrylation of the 3'-thiosubstituted molecules produced a 24-membered nucleoside series with diverse substitution patterns, and the compounds were evaluated for their in vitro antiviral activity against three dangerous human RNA viruses, SARS-CoV-2, SINV and CHIKV. Eight compounds exhibited SARS-CoV-2 activity with low micromolar EC50 values in Vero E6 cells, and two of them also inhibited virus growth in human Calu cells. The best anti-SARS-CoV-2 activity was exhibited by 2',5'-di-O-silylated 3'-C-alkylthio nucleosides. Twelve compounds showed in vitro antiviral activity against CHIKV and fourteen against SINV with low micromolar EC50 values, with the 5'-butyryl-2'-silyl-3'-alkylthio substitution pattern being the most favorable against both viruses. In the case of the tested nucleosides, removal of the 2'-O-silyl group completely abolished the antiviral activity of the compounds against all three viruses. Overall, the most potent antiviral agent was the disilylated 3'-glucosylthio xylonucleoside, which showed excellent and specific antiviral activity against SINV with an EC50 value of 3 μM and no toxic effect at the highest tested concentration of 120 μM.
- MeSH
- Antiviral Agents * pharmacology chemical synthesis chemistry MeSH
- Chlorocebus aethiops MeSH
- Humans MeSH
- Nucleosides * pharmacology chemical synthesis chemistry MeSH
- RNA Viruses * drug effects MeSH
- SARS-CoV-2 drug effects MeSH
- Vero Cells MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Hydrogen sulfide (H2S) is an endogenous gasotransmitter with cardioprotective and antiviral effects. In this work, new cysteine-selective nucleoside-H2S-donor hybrid molecules were prepared by conjugating nucleoside biomolecules with a thiol-activatable dithioacetyl group. 5'-Dithioacetate derivatives were synthesized from the canonical nucleosides (uridine, adenosine, cytidine, guanosine and thymidine), and the putative 5'-thio metabolites were also produced from uridine and adenosine. According to our measurements made with an H2S-specific sensor, nucleoside dithioacetates are moderately fast H2S donors, the guanosine derivative showed the fastest kinetics and the adenosine derivative the slowest. The antioxidant activity of 5'-thionucleosides is significantly higher than that of trolox, but lower than that of ascorbic acid, while intact dithioacetates have no remarkable antioxidant effect. In human Calu cells, the guanosine derivative showed a moderate anti-SARS-CoV-2 effect which was also confirmed by virus yield reduction assay. Dithioacetyl-adenosine and its metabolite showed similar acute cardiac effects as adenosine, however, it is noteworthy that both 5'-thio modified adenosines increased left ventricular ejection fraction or stroke volume, which was not observed with native adenosine.
- MeSH
- Adenosine analogs & derivatives MeSH
- Antioxidants * pharmacology chemistry MeSH
- Antiviral Agents * pharmacology chemical synthesis chemistry MeSH
- Cell Line MeSH
- COVID-19 Drug Treatment MeSH
- Humans MeSH
- Nucleosides pharmacology chemistry metabolism MeSH
- SARS-CoV-2 drug effects metabolism MeSH
- Hydrogen Sulfide * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Obor medicinální chemie se často potýká s problémem suboptimálních vlastností aktivních látek. Za účelem zlepšení těchto vlastností byla vyvinuta řada důmyslných přístupů tvorby proléčiv. Proléčivo je inaktivovaná forma léčiva, která dočasně modifikuje jeho vlastnosti. V těle je pak proléčivo (nejčastěji enzymaticky) transformováno zpět na aktivní léčivo. Proléčiva mohou upravit řadu vlastností jako např. absorpci, rozpustnost, či cílené doručení do tkáně. Poměr proléčiv mezi schválenými léky v posledních letech stoupá, což podtrhuje význam této strategie pro medicinální chemii i klinické využití.
The field of medicinal chemistry is often struggling with suboptimal properties of active compounds. To address this issue, many sophisticated prodrug approaches have been developed. Prodrug is an inactive form of a drug which temporarily alters its properties. In the body, the prodrug is (most often enzymatically) transformed back to the parent active drug. Prodrugs can modify variety of properties such as absorption, solubility, or tissue targeted delivery. The number of prodrugs among approved drugs has been rising in the past years which underlines the importance of prodrugs for medicinal chemistry and clinical use.
Osteoporosis is a multifactorial disease influenced by genetic and environmental factors, which contributes to an increased risk of bone fracture, but early diagnosis of this disease cannot be achieved using current techniques. We describe a generic platform for the targeted electrochemical genotyping of SNPs identified by genome-wide association studies to be associated with a genetic predisposition to osteoporosis. The platform exploits isothermal solid-phase primer elongation with ferrocene-labeled nucleoside triphosphates. Thiolated reverse primers designed for each SNP were immobilized on individual gold electrodes of an array. These primers are designed to hybridize to the SNP site at their 3'OH terminal, and primer elongation occurs only where there is 100% complementarity, facilitating the identification and heterozygosity of each SNP under interrogation. The platform was applied to real blood samples, which were thermally lysed and directly used without the need for DNA extraction or purification. The results were validated using Taqman SNP genotyping assays and Sanger sequencing. The assay is complete in just 15 min with a total cost of 0.3€ per electrode. The platform is completely generic and has immense potential for deployment at the point of need in an automated device for targeted SNP genotyping with the only required end-user intervention being sample addition.
- Publication type
- Journal Article MeSH
The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) are among the most prevalent and well-characterized modified nucleosides in eukaryotic RNA. Both of these modifications are dynamically regulated by a complex set of epitranscriptomic regulators called writers, readers, and erasers. Altered levels of m6A and also several regulatory proteins were already associated with diabetic tissues. This review summarizes the current knowledge and gaps about m6A and m6Am modifications and their respective regulators in the pathophysiology of diabetes mellitus. It focuses mainly on the more prevalent type 2 diabetes mellitus (T2DM) and its treatment by metformin, the first-line antidiabetic agent. A better understanding of epitranscriptomic modifications in this highly prevalent disease deserves further investigation and might reveal clinically relevant discoveries in the future.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC50 = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by X-ray crystallography.
- MeSH
- HIV Infections * drug therapy MeSH
- HIV Reverse Transcriptase metabolism MeSH
- HIV-1 * metabolism MeSH
- Reverse Transcriptase Inhibitors MeSH
- Anti-HIV Agents * chemistry MeSH
- Humans MeSH
- Drug Design MeSH
- Rilpivirine therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Influenza virus causes severe respiratory infection in humans. Current antivirotics target three key proteins in the viral life cycle: neuraminidase, the M2 channel and the endonuclease domain of RNA-dependent-RNA polymerase. Due to the development of novel pandemic strains, additional antiviral drugs targetting different viral proteins are still needed. The protein-protein interaction between polymerase subunits PA and PB1 is one such possible target. We recently identified a modified decapeptide derived from the N-terminus of the PB1 subunit with high affinity for the C-terminal part of the PA subunit. Here, we optimized its amino acid hotspots to maintain the inhibitory potency and greatly increase peptide solubility. This allowed thermodynamic characterization of peptide binding to PA. Solving the X-ray structure of the peptide-PA complex provided structural insights into the interaction. Additionally, we optimized intracellular delivery of the peptide using a bicyclic strategy that led to improved inhibition in cell-based assays.
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- Conspectus
- Veřejné zdraví a hygiena
- NML Fields
- veřejné zdravotnictví
- preventivní medicína
- pediatrie
- NML Publication type
- publikace WHO
Cíl: Cílem práce bylo z dostupné literatury provést srovnávací analýzu infekce virem SARS-CoV-2 u dětských pacientů se zhoubným nádorem a porovnat ji s vážností infekce v běžné dětské populaci a také provést analýzu aplikované antivirové léčby u dětských onkologických pacientů. Nemocní se zhoubnými nádory jsou dle Evropského centra pro prevenci a kontrolu nemocí (ECDC) rizikovou skupinou. Pro léčbu COVID-19 je obecně doporučován remdesivir. Remdesivir se metabolizuje systémem cytochromů (CYP2C8, CYP2D6 a CYP3A4) a esterázami na aktivní formu, kterou je nukleosid trifosfát. Jako analog adenosinu ovlivňuje virovou replikaci. Metodika: Analýza byla provedena na základě vyhodnocení článků týkajících se dětských onkologických pacientů s onemocněním COVID-19. Články byly vyhledány ve vědeckých databázích (PubMed, Web of Science) a byla v nich zkoumána zejména onkologická diagnóza pacientů, smrtnost infekce virem SARS-CoV-2, potřeba JIP péče a použitá antivirová terapie. Výsledky: Podle aktuálních dat WHO se smrtnost onemocnění COVID-19 v celé dětské populaci pohybuje na úrovni 0,04 % a potřeba JIP péče je okolo 1 %. Z 25 analyzovaných článků o onemocnění COVID-19 u dětských onkologických pacientů vyplynulo, že smrtnost je v této specifické skupině několikanásobně vyšší než v celé dětské populaci (3,53 %) a totéž platí i o JIP péči (9,39 %). Nejčastěji se virem SARS-CoV-2 infikují děti s hematologickými malignitami. Až 56,2 % dětským onkologickým pacientům musela být kvůli COVID-19 upravena onkologická terapie. Jako antivirovou léčbu je i v této kohortě pacientů možné nouzově použít remdesivir za souběžné monitorace jaterních a renálních funkcí. Závěr: Remdesivir lze nouzově použít i u dětských onkologických pacientů, pokud budou monitorovány jejich jaterní a renální funkce a jejich medikace a klinický stav tomu neodporuje. Dostupné studie naznačují, že remdesivir je v pediatrické populaci obecně dobře tolerován.
Aim: The aim of this work was to perform an analysis of SARS-CoV-2 infection in paediatric patients with malignancies and the treatment used, and compare it with the severity of SARS-CoV-2 infection in overall paediatric population. According to European Centre for Disease Prevention and Control (ECDC), patients with neoplasms are a high risk group. Generally, remdesivir is recommended as a treatment. It is metabolised via system of cytochromes (CYP2C8, CYP2D6, CYP3A4) and esterases into its active form – nucleoside triphosphate. As an adenosine analogue, it affects viral replication. Methods: The research was conducted by an analysis of papers concerning paediatric cancer patients with COVID-19. The articles were sourced from scientific databases (PubMed, Web of Science) and mainly the information about cancer diagnosis, COVID-19 mortality, necessity of ICU care and antivirals used were investigated. Results: According to the data published by WHO, COVID-19 related mortality in overall paediatric population oscillates around 0.04% and ICU admission rate around 1%. From 25 analysed articles regarding COVID-19 in paediatric oncology patients, it has resulted that the mortality in this specific group is significantly higher (3.53%), the same is applicable to ICU care necessity (9.39%). Children with haematological malignancies are most often infected with SARS-CoV-2 virus. Notably, 56.2% of paediatric oncology patients had to have their oncological therapy modified because of COVID-19. Remdesivir (under emergency use authorization) can be used in this cohort of patients as an antiviral treatment with concomitant surveillance of hepatic and renal functions. Conclusion: Remdesivir (under emergency authorization) can be used in paediatric oncology patients if hepatic and renal functions are monitored and their medication and clinical status does not refute it. Available studies suggest that remdesivir is well tolerated in paediatric population.
- Keywords
- Remdesivir,
- MeSH
- Adenosine Monophosphate analogs & derivatives pharmacology therapeutic use MeSH
- Antiviral Agents administration & dosage therapeutic use MeSH
- COVID-19 * MeSH
- Child MeSH
- COVID-19 Drug Treatment MeSH
- Risk Assessment MeSH
- Humans MeSH
- Neoplasms * complications MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
