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Journal of the College of Physicians... Jun 2024To evaluate the effect of favipiravir administered to diabetic and non-diabetic COVID-19 patients on the QT/QTc interval.
OBJECTIVE
To evaluate the effect of favipiravir administered to diabetic and non-diabetic COVID-19 patients on the QT/QTc interval.
STUDY DESIGN
Analytical study. Place and Duration of the Study: Republic of Turkey, Ministry of Health, State Hospital, Corlu, Tekirdag, Turkiye, from March to September 2021.
METHODOLOGY
Electrocardiogram (ECG) analysis was performed on all participants (n=180) divided into four groups. Group 1 included only healthy volunteers. Group 2 included only cases diagnosed with T2DM. Group 3 included only severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) cases. Group 4 included cases diagnosed with both SARS and T2DM. Favipiravir was administered only to the cases in Group 3 and Group 4. In the cases that were administered favipiravir, the QT/QTc interval was calculated and recorded at different time intervals on the first and fifth days of the therapy. The difference between groups was determined by Tukeye's test after ANOVA. Pearson's correlation test was used to determine whether there was a linear relationship between two numericals. The alpha significance value was determined to be <0.05 in all statistical analyses.
RESULTS
When all groups were compared, it was seen that both QT and QTc values increased in Groups 3 and 4, which were administered favipiravir (p <0.05). Favipiravir may cause an increased risk of ventricular and atrial arrhythmias.
CONCLUSION
Favipiravir may cause QT interval prolongation, particularly in SARS-Cov-2 patients diagnosed with T2DM.
KEY WORDS
COVID-19, Drug-induced long QT syndrome, Intra-infarct haemorrhage; Favipiravir, Type 2 diabetes mellitus.
Topics: Humans; Pyrazines; Amides; Male; Female; Electrocardiography; Middle Aged; Diabetes Mellitus, Type 2; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Long QT Syndrome; SARS-CoV-2; Adult; Turkey; Aged
PubMed: 38840347
DOI: 10.29271/jcpsp.2024.06.659 -
Inorganic Chemistry Jun 2024The pyrazine-coordinated dinuclear and mononuclear ruthenium complexes were synthesized through the framework conversion reactions of the triply chlorido-bridged...
The pyrazine-coordinated dinuclear and mononuclear ruthenium complexes were synthesized through the framework conversion reactions of the triply chlorido-bridged diruthenium(II) complex [{Ru(bbpma)}(μ-Cl)] (bbpma; benzylbis(2-pyridylmethyl)amine, []) in the presence of pyrazine, which could function as the simple molecular multinucleation ligand of metal compounds. A reduction reaction of -[RuCl(bbpma)] with zinc in the presence of hydrochloric acid afforded [] in solution, and the following addition of pyrazine (1 equiv) in the solution led to the formation of a singly pyrazine (pz)-bridged diruthenium complex, [{Ru(μ-ClZnCl)(bbpma)}(μ-pz)] ([]). The stoichiometric two-electron oxidation of [] was successfully proceeded, and a Ru(III)-Ru(III) species, [{RuCl(bbpma)}(μ-pz)](PF) ([,](PF)), was isolated. The reaction of [] with excess amounts of pyrazine without hydrochloric acid afforded mononuclear Ru(III) and Ru(II) complexes containing one or two pyrazine, -[RuCl(pz)(bbpma)] ( = 2; []; = 1; []). The details of the electrochemical and spectroscopic properties of []-[] in organic and aqueous solutions were discussed.
PubMed: 38837355
DOI: 10.1021/acs.inorgchem.4c01001 -
Cellular and Molecular Biology... Jun 2024Skin photoaging is a skin degenerative disease that causes patients to develop malignant tumors. The existing clinical treatment of photoaging has limitations. This...
Skin photoaging is a skin degenerative disease that causes patients to develop malignant tumors. The existing clinical treatment of photoaging has limitations. This greatly reduces the recovery rate of photoaging patients. Studies have confirmed that Ligusticum wallichii Franch (LWF) monomer tetramethylpyrazine (TMP) alleviates various skin diseases. The combination of traditional Chinese medicine and Western medicine helps with this process. Our research aimed to explore the specific treatment mode and molecular mechanism of TMP in treating skin photoaging. CCK-8 assays were used to evaluate the activity and toxicity of HaCaT cells. β-galactosidase aging, Carbonyl compound and nitrosylated tyrosine assays were used to analyze the aging of HaCaT cells. ROS assays and ELISA were used to analyze the enrichment of ROS. The molecular docking experiment analyzed the binding of TMP and HIF-1α. qRT-PCR and Western blot were used to detect the activation of skin aging-related pathways. HE staining was used to analyze the thickness of the stratum corneum skin on the back skin of mice. 200μg/L LWF alleviates cellular photoaging and mouse skin photoaging by reducing ROS enrichment. Its monomer TMP plays an important role in this process. The combination of TMP and HIF-1α accelerates the degradation of ROS by activating the Nrf2/ARE signaling pathway. This process reduces the apoptosis of cells damaged by light. In addition, we also found that the combination of TMP and retinoic acid (RA) is more beneficial for the treatment of skin damage caused by light in mice. The combination therapy of TMP and RA alleviates skin oxidative stress response through overexpression of HIF-1α. This plan is beneficial for the treatment of skin photoaging.
Topics: Pyrazines; Skin Aging; Hypoxia-Inducible Factor 1, alpha Subunit; Animals; Humans; Reactive Oxygen Species; Mice; Signal Transduction; Vitamin A; Skin; HaCaT Cells; Molecular Docking Simulation
PubMed: 38836676
DOI: 10.14715/cmb/2024.70.6.14 -
Cellular and Molecular Biology... Jun 2024The prognosis of patients with multiple myeloma (MM) has significantly improved over the past ten years because of several innovative treatments, including the...
The prognosis of patients with multiple myeloma (MM) has significantly improved over the past ten years because of several innovative treatments, including the proteasome inhibitor Bortezomib and immunomodulatory drugs (IMiDs) like Thalidomide and Lenalidomide. The present study aimed to determine the effectiveness of Bortezomib-based regimens on survival state of MM patients. This retrospective study included 204 newly diagnosed MM patients who were registered at Nanakali Hospital for Blood Diseases and Cancer, Erbil- Iraq, between April 2008 and April 2022. The patients were split into two primary groups: those receiving treatment with Bortezomib and those not. Clinical and laboratory data, treatment type, responsiveness to induction therapy, and survival results were examined in the enrolled patients' medical records. The mean patient age was 60 years, males constituted 55.8% of the included patients. At the time of diagnosis, 98 individuals (48%) had stage 3 illness. Except for the LDH, which was noticeably higher in the non-Bortezomib group, the patients laboratory results did not substantially change between the Bortezomib and non-Bortezomib groups (p = 0.001). In patients treated with Bortezomib, the complete response (CR) rate following induction was substantially greater (35.2%) than in those treated without Bortezomib (9.1%). Compared to the non-Bortezomib group, the median survival time of the Bortezomib group was considerably greater (p < 0.001). Bortezomib has a significant role in inducing a CR before bone marrow (BM) transplantation, and it has a significant role in the survival outcome in MM.
Topics: Humans; Multiple Myeloma; Bortezomib; Male; Middle Aged; Female; Aged; Retrospective Studies; Treatment Outcome; Adult; Antineoplastic Combined Chemotherapy Protocols; Survival Analysis
PubMed: 38836665
DOI: 10.14715/cmb/2024.70.6.25 -
Journal of Chemical Theory and... Jun 2024In recent years, machine learning (ML) surrogate models have emerged as an indispensable tool to accelerate simulations of physical and chemical processes. However,...
In recent years, machine learning (ML) surrogate models have emerged as an indispensable tool to accelerate simulations of physical and chemical processes. However, there is still a lack of ML models that can accurately predict molecular vibrational spectra. Here, we present a highly efficient multitask ML surrogate model termed Vibrational Spectra Neural Network (VSpecNN), to accurately calculate infrared (IR) and Raman spectra based on dipole moments and polarizabilities obtained on-the-fly via ML-enhanced molecular dynamics simulations. The methodology is applied to pyrazine, a prototypical polyatomic chromophore. The VSpecNN-predicted energies are well within the chemical accuracy (1 kcal/mol), and the errors for VSpecNN-predicted forces are only half of those obtained from a popular high-performance ML model. Compared to the ab initio reference, the VSpecNN-predicted frequencies of IR and Raman spectra differ only by less than 5.87 cm, and the intensities of IR spectra and the depolarization ratios of Raman spectra are well reproduced. The VSpecNN model developed in this work highlights the importance of constructing highly accurate neural network potentials for predicting molecular vibrational spectra.
PubMed: 38825857
DOI: 10.1021/acs.jctc.4c00173 -
Hematological Oncology Jul 2024Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world... (Observational Study)
Observational Study
Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease.
Topics: Humans; Male; Female; Antibodies, Monoclonal; Aged; Immunoglobulin Light-chain Amyloidosis; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Prospective Studies; Lenalidomide; Bortezomib; Adult; Treatment Outcome
PubMed: 38824453
DOI: 10.1002/hon.3289 -
Bioorganic Chemistry Aug 2024Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while...
Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.
Topics: fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Antineoplastic Agents; Pyrazines; Cell Proliferation; Animals; Structure-Activity Relationship; Molecular Structure; Protein Kinase Inhibitors; Drug Screening Assays, Antitumor; Mice; Dose-Response Relationship, Drug; Drug Discovery; Thiophenes; Proteolysis; Aniline Compounds; Cell Line, Tumor; Neoplasms, Experimental
PubMed: 38820938
DOI: 10.1016/j.bioorg.2024.107477 -
Food Chemistry Oct 2024Understanding the evolution of aroma profiles in stored sesame paste (SP) is essential for maintaining its quality. This study investigated the storage quality of SP and...
Understanding the evolution of aroma profiles in stored sesame paste (SP) is essential for maintaining its quality. This study investigated the storage quality of SP and potential aroma markers indicative of sensory degradation. The descriptive sensory analysis demonstrated changes in aroma attributes during storage, transitioning from roasted sesame and nutty aromas to fermented and green aromas. Physicochemical analysis showed deepening color, intensified lipid oxidation, decreased levels of bioactive components, increased particle aggregation, and deteriorated flowability over 63 days at 40 °C. Gas chromatography-olfactometry-mass spectrometry identified 37 aroma-active compounds, with pyrazines, aldehydes, and phenols identified as the major constituents. Partial least squares regression analysis revealed 2-ethyl-3-methyl-pyrazine, 2-methoxy-4-vinylphenol, and benzaldehyde as key aroma-active compounds contributing significantly to the distinctive aromas "roasted nut and roasted sesame" found in SP. Conversely, hexanal and dimethyl disulfide emerged as potential markers of undesirable aromas in SP, including "rancid, green, and fermented". These findings provide insights into SP changes during storage, which is vital for preservation and quality enhancement strategies.
Topics: Sesamum; Odorants; Gas Chromatography-Mass Spectrometry; Food Storage; Taste; Humans; Volatile Organic Compounds; Olfactometry
PubMed: 38815324
DOI: 10.1016/j.foodchem.2024.139809 -
Journal of Agricultural and Food... Jun 2024Structure-activity relationships of diazinoyl nicotinic insecticides (diazinoyl isomers and 5- or 6-substituted pyrazin-2-oyl analogues) are considered in terms of...
Structure-activity relationships of diazinoyl nicotinic insecticides (diazinoyl isomers and 5- or 6-substituted pyrazin-2-oyl analogues) are considered in terms of affinity to the insect nicotinic acetylcholine receptor (nAChR) and insecticidal activity against the imidacloprid-resistant brown planthopper. Among the test compounds, 3-(6-chloropyridin-3-ylmethyl)-2-(pyrazinoyl)iminothiazoline shows the highest potency in nAChR affinity and insecticidal activity. acetylcholine binding protein (AChBP) mutants (Y55W + Q57R and Y55W + Q57T) are utilized to compare molecular recognition of nicotinic insecticides with diverse pharmacophores. -nitro- or -cyanoimine imidacloprid or acetamiprid, respectively, exhibits a high affinity to these AChBP mutants at a similar potency level. Intriguingly, the pyrazin-2-oyl analogue has a higher affinity to AChBP Y55W + Q57R than that to Y55W + Q57T, thereby indicating that pyrazine nitrogen atoms contact Arg57 guanidinium and Trp55 indole NH. Furthermore, nicotine prefers AChBP Y55W + Q57T over Y55W + Q57R, conceivably suggesting that the protonated nicotine is repulsed by Arg57 guanidinium, consistent with its inferior potency to insect nAChR.
Topics: Animals; Insecticides; Receptors, Nicotinic; Hemiptera; Structure-Activity Relationship; Insect Proteins; Neonicotinoids; Nitro Compounds; Aplysia; Nicotine
PubMed: 38814790
DOI: 10.1021/acs.jafc.4c01499 -
Journal of Molecular Modeling May 2024The compounds of the "565" parent ring structure have received much attention from researchers because of their excellent detonation performance. In the present study,...
CONTEXT
The compounds of the "565" parent ring structure have received much attention from researchers because of their excellent detonation performance. In the present study, 81 derivatives were designed by introducing different substituents based on 6-dinitrophenyl-5,6,7,8-tetrahydro-4-imidazo[4,5-e]furazano[3,4-b] pyrazine (DIOP), which is a compound of the parent ring structure of 565, and the performance of these derivatives, such as the electronic structure, energy gap, heat of formation, and detonation performance, were investigated. Among these energy-containing derivatives, the density ranges from 1.70 to 2.17 g/cm, the detonation velocity ranges from 8.01 to 10.26 km/s, and the detonation pressure ranges from 27.99 to 49.88 GPa. Through comprehensive analysis of several properties of DIOP derivatives, it was found that the oxygen balance of derivatives with the -ONO group was greater than zero and close to zero, while the oxygen balance of derivatives with other groups was almost all less than zero. Among them, G8 (D = 10.1 km/s, P = 47.72 GPa), H8 (D = 10.11 km/s, P = 47.92 GPa), and I8 (D = 10.26 km/s, P = 49.88 GPa) had higher detonation velocity and pressure among all derivatives, and their impact sensitivity was better than RDX. Therefore, three potential high-energy and less sensitive energy-containing derivatives, G8, H8, and I8, were screened out. The intramolecular interactions of the three derivatives were further analyzed, and it was found that there were intensive van der Waals interactions and significant spatial steric effects within the molecules, which had a positive effect on reducing the shock sensitivity of the compounds. Moreover, the three derivatives have a large degree of stacking, which leads to a high density.
METHODS
All calculations in this paper are performed using Gaussian16 based on density functional theory. Firstly, the structures of the derivatives were optimized at the level of B3LYP-D3/6-311G**, and then single-site energy calculations were carried out at the level of M06-2X-D3/def2-TZVPP, to reveal the effects of single substituents versus multiple substituents and isomerism on the properties of the DIOP-based energetic derivatives. Multiwfn was used to plot the density of states (DOS) of the derivatives and to calculate the molecular surface electrostatic potential at 0.001 e/Bohr electron density, 0.25 Bohr lattice spacing surface.
PubMed: 38814476
DOI: 10.1007/s00894-024-05993-2