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EBioMedicine Oct 2021Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality, however with no effective therapy available. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality, however with no effective therapy available.
METHODS
The effect of favipiravir (FPV) in treating SFTS was evaluated by an integrated analysis on data collected from a single-arm study (n=428), a surveillance study (n=2350) and published data from a randomized controlled trial study (n=145). A 1:1 propensity score matching was performed to include 780 patients: 390 received FPV and 390 received supportive therapy only. Case fatality rates (CFRs), clinical progress, and adverse effects were compared.
FINDINGS
FPV treatment had significantly reduced CFR from 20.0% to 9.0% (odds ratio 0.38, 95% confidence interval 0.23-0.65), however showing heterogeneity when patients were grouped by age, onset-to-admission interval, initial viral load and therapy duration. The effect of FPV was significant only among patients aged ≤70 years, with onset-to-admission interval ≤5 days, therapy duration ≥5 days or baseline viral load ≤1 × 10 copies/mL. Age-stratified analysis revealed no benefit in the aging group >70 years, regardless of their sex, onset-to-admission interval, therapy duration or baseline viral load. However, for both ≤60 and 60-70 years groups, therapy duration and baseline viral load differentially affected FPV therapy efficiency. Hyperuricemia and thrombocytopenia, as the major adverse response of FPV usage, were observed in >70 years patients.
INTERPRETATION
FPV was safe in treating SFTS patients but showed no benefit for those aged >70 years. Instant FPV therapy could highly benefit SFTS patients aged 60-70 years.
FUNDING
China Natural Science Foundation (No. 81825019, 82073617 and 81722041) and China Mega-project for Infectious Diseases (2018ZX10713002 and 2015ZX09102022).
Topics: Aged; Amides; Antiviral Agents; Female; Humans; Male; Middle Aged; Pyrazines; Severe Fever with Thrombocytopenia Syndrome; Treatment Outcome; Viral Load
PubMed: 34563924
DOI: 10.1016/j.ebiom.2021.103591 -
Molecules (Basel, Switzerland) Nov 2023Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through... (Review)
Review
Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through Web of Science, PubMed, Science Direct, and SciFinder Scholar. The structure, biological activity, and mechanism of natural product derivatives containing pyrazine fragments reported from 2000 to September 2023 were reviewed. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. The results of research work show that pyrazine-modified natural product derivatives have a wide range of biological activities, including anti-inflammatory, anticancer, antibacterial, antiparasitic, and antioxidant activities. Many of these derivatives exhibit stronger pharmacodynamic activity and less toxicity than their parent compounds. This review has a certain reference value for the development of heterocyclic compounds, especially pyrazine natural product derivatives.
Topics: Pyrazines; Chemistry, Pharmaceutical; Anti-Inflammatory Agents; Anti-Bacterial Agents; Biological Products
PubMed: 37959859
DOI: 10.3390/molecules28217440 -
Molecules (Basel, Switzerland) May 2012We report herein the microwave assisted synthesis, without solvents and catalysts, of 6-substituted quinoxalines and 7-substituted pyrido[2,3b]pyrazines. The compounds...
We report herein the microwave assisted synthesis, without solvents and catalysts, of 6-substituted quinoxalines and 7-substituted pyrido[2,3b]pyrazines. The compounds were obtained in good yields and short reaction times using the mentioned procedure and two new structures are reported. A complete ¹H- and ¹³C-NMR assignment was performed using 1D and 2D-NMR. Additionally, an in vitro screening was performed on Gram-positive and Gram-negative bacteria using amoxicillin as positive reference. Compounds bearing a pyridyl group tended to have higher antibacterial activity, but the best activity against Bacillus subtilis and Proteus mirabilis was observed with quinoxaline derivatives.
Topics: Anti-Bacterial Agents; Bacteria; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Microwaves; Pyrazines; Quinoxalines; Solvents
PubMed: 22628038
DOI: 10.3390/molecules17055164 -
Molecules (Basel, Switzerland) May 2020The incorporation of the trifluoromethoxy group into organic molecules has become very popular due to the unique properties of the named substituent that has a...
The incorporation of the trifluoromethoxy group into organic molecules has become very popular due to the unique properties of the named substituent that has a "pseudohalogen" character, while the chemical properties of the synthesized compound, especially heterocycles with such a group, are less studied. As trifluoromethoxy-substituted pyrazines are still unknown, we have developed efficient and scalable methods for 2-chloro-5-trifluoromethoxypyrazine synthesis, showing the synthetic utility of this molecule for Buchwald-Hartwig amination and the Kumada-Corriu and Suzuki and Sonogashira coupling reactions. Some comparisons of chlorine atom and trifluoromethoxy group stability in these transformations have been carried out.
Topics: Amination; Halogenation; Molecular Structure; Proton Magnetic Resonance Spectroscopy; Pyrazines
PubMed: 32397388
DOI: 10.3390/molecules25092226 -
Discovery Medicine Dec 2011The ubiquitin-proteasome pathway regulates many basic cellular processes and has been proven to be a promising target for cancer therapy. Bortezomib is the first U.S.... (Review)
Review
The ubiquitin-proteasome pathway regulates many basic cellular processes and has been proven to be a promising target for cancer therapy. Bortezomib is the first U.S. Food and Drug Administration (FDA) approved proteasome inhibitor used in the treatment of newly diagnosed multiple myeloma, relapsed/refractory multiple myeloma, and mantle cell lymphoma. The anti-cancer mechanisms of bortezomib elucidated by preclinical studies include: upregulation of proapoptotic proteins (e.g., Noxa, IκB), inhibition of NFκB and its anti-apoptotic target genes, suppression of several anti-apoptotic proteins (e.g., Bcl-XL, Bcl-2, and STAT-3), down-regulation of expression of several proteins involved in DNA repair pathways, and induction of endoplasmic reticulum (ER) stress and pro-apoptotic Unfolded Protein Response (UPR). Bortezomib has potent chemo-/radio-sensitizing effects and can overcome traditional drug resistance in tumors when used in combination with potential chemotherapies. Although bortezomib has been successful in improving clinical outcomes when used in hematological malignancies, relapse may occur in those patients who responded initially. Furthermore, some cytotoxicities (such as peripheral neuropathy) were found to be associated with bortezomib treatment. These observations have encouraged researchers to search for the next generation proteasome inhibitors (including carfilzomib and marizomib) that could overcome bortezomib resistance and have improved properties, reduced toxicities, and broader anticancer activities, based on the lessons learned from the mechanisms and use of bortezomib. This review summarizes the current status of bortezomib as well as several other proteasome inhibitors that are currently under clinical and preclinical investigation.
Topics: Animals; Boronic Acids; Bortezomib; Clinical Trials as Topic; Drug Resistance; Humans; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Signal Transduction; Ubiquitin
PubMed: 22204764
DOI: No ID Found -
Scientific Reports Feb 2018Ants use pheromones to coordinate their communal activity. Volatile pyrazines, for instance, mediate food resource gathering and alarm behaviors in different ant...
Ants use pheromones to coordinate their communal activity. Volatile pyrazines, for instance, mediate food resource gathering and alarm behaviors in different ant species. Here we report that leaf-cutter ant-associated bacteria produce a family of pyrazines that includes members previously identified as ant trail and alarm pheromones. We found that L-threonine induces the bacterial production of the trail pheromone pyrazines, which are common for the host leaf-cutter ants. Isotope feeding experiments revealed that L-threonine along with sodium acetate were the biosynthetic precursors of these natural products and a biosynthetic pathway was proposed.
Topics: Animals; Ants; Ecosystem; Gas Chromatography-Mass Spectrometry; Pheromones; Pyrazines; Serratia marcescens; Sodium Acetate; Threonine
PubMed: 29416082
DOI: 10.1038/s41598-018-20953-6 -
Molecules (Basel, Switzerland) Apr 2022Class I histone deacetylases, HDAC1, HDAC2, and HDAC3, represent potential targets for cancer treatment. However, the development of isoform-selective drugs for these...
Class I histone deacetylases, HDAC1, HDAC2, and HDAC3, represent potential targets for cancer treatment. However, the development of isoform-selective drugs for these enzymes remains challenging due to their high sequence and structural similarity. In the current study, we applied a computational approach to predict the selectivity profile of developed inhibitors. Molecular docking followed by MD simulation and calculation of binding free energy was performed for a dataset of 2-aminobenzamides comprising 30 previously developed inhibitors. For each HDAC isoform, a significant correlation was found between the binding free energy values and in vitro inhibitory activities. The predictive accuracy and reliability of the best preforming models were assessed on an external test set of newly designed and synthesized inhibitors. The developed binding free-energy models are cost-effective methods and help to reduce the time required to prioritize compounds for further studies.
Topics: Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Molecular Docking Simulation; Protein Isoforms; Pyrazines; Reproducibility of Results
PubMed: 35458724
DOI: 10.3390/molecules27082526 -
Proceedings of the National Academy of... Sep 2019Marine polychaetes , commonly known as fireworms, emit bright blue-green bioluminescence. Until the recent identification of the luciferase enzyme, little progress had...
Marine polychaetes , commonly known as fireworms, emit bright blue-green bioluminescence. Until the recent identification of the luciferase enzyme, little progress had been made toward characterizing the key components of this bioluminescence system. Here we present the biomolecular mechanisms of enzymatic (leading to light emission) and nonenzymatic (dark) oxidation pathways of newly described luciferin. Spectral studies, including 1D and 2D NMR spectroscopy, mass spectrometry, and X-ray diffraction, of isolated substances allowed us to characterize the luciferin as an unusual tricyclic sulfur-containing heterocycle. luciferin does not share structural similarity with any other known luciferins. The structures of the bioluminescent system's low molecular weight components have enabled us to propose chemical transformation pathways for the enzymatic and nonspecific oxidation of luciferin.
Topics: Animals; Biosynthetic Pathways; Color; Indoles; Luminescent Agents; Luminescent Measurements; Luminescent Proteins; Molecular Structure; Oxidation-Reduction; Polychaeta; Pyrazines
PubMed: 31462497
DOI: 10.1073/pnas.1902095116 -
Antiviral Research Nov 2013Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. It is... (Review)
Review
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. It is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5'-triphosphate (RTP). Its antiviral effect is attenuated by the addition of purine nucleic acids, indicating the viral RNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide. Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options. A Phase III clinical evaluation of favipiravir for influenza therapy has been completed in Japan and two Phase II studies have been completed in the United States. In addition to its anti-influenza activity, favipiravir blocks the replication of many other RNA viruses, including arenaviruses (Junin, Machupo and Pichinde); phleboviruses (Rift Valley fever, sandfly fever and Punta Toro); hantaviruses (Maporal, Dobrava, and Prospect Hill); flaviviruses (yellow fever and West Nile); enteroviruses (polio- and rhinoviruses); an alphavirus, Western equine encephalitis virus; a paramyxovirus, respiratory syncytial virus; and noroviruses. With its unique mechanism of action and broad range of antiviral activity, favipiravir is a promising drug candidate for influenza and many other RNA viral diseases for which there are no approved therapies.
Topics: Amides; Antiviral Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; DNA-Directed RNA Polymerases; Enzyme Inhibitors; Humans; Influenza, Human; Japan; Pyrazines; RNA Viruses; United States
PubMed: 24084488
DOI: 10.1016/j.antiviral.2013.09.015 -
Talanta Jul 2023Gas chromatography coupled with ion mobility spectrometry (IMS) is an analytical tool which is rapidly becoming widespread in the analysis of food volatiles. Despite...
Gas chromatography coupled with ion mobility spectrometry (IMS) is an analytical tool which is rapidly becoming widespread in the analysis of food volatiles. Despite this increasing popularity, an assessment of the IMS response for several flavor compound classes is not yet available. This study focuses on alkyl pyrazines and their determination in roasted hazelnut pastes. These Maillard reaction products are crucial to determine the aromatic profile of roasted foods and are suitable markers for industrial roasting monitoring. The instrumental response of 8 alkyl pyrazines was studied using a model matrix and a matrix matching approach. The results showed a relevant effect of the pyrazine ring substitution pattern on the concentration-response curve trends, highlighting that an external standardization of the IMS response is required to make possible relative abundance comparisons between analytes. A response standardization was therefore developed and applied to determine alkyl pyrazines in samples with different roasting intensity and geographical and botanical origin.
Topics: Gas Chromatography-Mass Spectrometry; Corylus; Pyrazines; Ion Mobility Spectrometry; Volatile Organic Compounds
PubMed: 37088040
DOI: 10.1016/j.talanta.2023.124568