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Virologica Sinica Aug 2023Cap-dependent endonuclease (CEN) in the polymerase acidic protein (PA) of influenza A virus (IAV) represents a promising drug target due to its critical role in viral...
Cap-dependent endonuclease (CEN) in the polymerase acidic protein (PA) of influenza A virus (IAV) represents a promising drug target due to its critical role in viral gene transcription. The CEN inhibitor, baloxavir marboxil (BXM), was approved in Japan and the US in 2018 and several other countries subsequently. Along with the clinical use of BXM, the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern. Herein, we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A, an analogue of BXM. The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes, including pH1N1, H3N2, H7N9 and H9N2, in MDCK cells, and the 50% effective concentration (EC) was calculated to nanomole level and comparable to that of baloxavir acid (BXA), the active form of BXM. Furthermore, in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice, with reduced viral RNA loads and alleviated pulmonary damage. Importantly, serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage. Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA. Taken together, our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance, which provides critical clues for future drug development and drug resistance surveillance.
Topics: Animals; Mice; Humans; Oxazines; Pyridines; Endonucleases; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Thiepins; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Antiviral Agents; Influenza, Human; Drug Resistance, Viral
PubMed: 37290559
DOI: 10.1016/j.virs.2023.06.002 -
Journal of Enzyme Inhibition and... Dec 2023Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle and apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma...
Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle and apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma (HEPG2), larynx cancer (HEP2), lung cancer (H460), colon cancers (HCT116 and Caco2), and hypopharyngeal cancer (FADU), and normal Vero cell lines were used. Compounds and displayed outstanding effects on the investigated cell lines and were further tested for their antioxidant activity in MCF7, H460, FADU, HEP2, HEPG2, HCT116, Caco2, and Vero cells by measuring superoxide dismutase (SOD), malondialdehyde content (MDA), reduced glutathione (GSH), and nitric oxide (NO) content. Besides, Annexin V-FITC apoptosis detection and cell cycle DNA index using the HEPG-2 cell line were established on both compounds as well. Furthermore, compounds and were assessed for their EGFR kinase (Wild and T790M) inhibitory activities, revealing eligible potential. Additionally, molecular docking, ADME, and SAR studies were carried out for the investigated candidates.
Topics: Animals; Chlorocebus aethiops; Humans; ErbB Receptors; Protein Kinase Inhibitors; Molecular Docking Simulation; Drug Screening Assays, Antitumor; Vero Cells; Caco-2 Cells; Lung Neoplasms; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Structure-Activity Relationship; Mutation; Pyrimidines; Pyridines; Molecular Structure
PubMed: 36317648
DOI: 10.1080/14756366.2022.2135512 -
Annals of Oncology : Official Journal... Aug 2023The multicenter, randomized, phase IV, intergroup AGO-B WSG PreCycle trial (NCT03220178) evaluated the impact of CANKADO-based electronic patient-reported outcome (ePRO)... (Randomized Controlled Trial)
Randomized Controlled Trial
Significantly longer time to deterioration of quality of life due to CANKADO PRO-React eHealth support in HR+ HER2- metastatic breast cancer patients receiving palbociclib and endocrine therapy: primary outcome analysis of the multicenter randomized AGO-B WSG PreCycle trial.
BACKGROUND
The multicenter, randomized, phase IV, intergroup AGO-B WSG PreCycle trial (NCT03220178) evaluated the impact of CANKADO-based electronic patient-reported outcome (ePRO) assessment on quality of life (QoL) in hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer (MBC) patients receiving palbociclib and an aromatase inhibitor or palbociclib + fulvestrant. CANKADO PRO-React, a European Union-registered medical device, is an interactive autonomous application reacting to patient self-reported observations.
PATIENTS AND METHODS
Between 2017 and 2021, 499 patients (median age 59 years) from 71 centers were randomized (2 : 1, stratified by therapy line) between an active version of CANKADO PRO-React (CANKADO-active arm) and a version with limited functionality (CANKADO-inform arm). A total of 412 patients (271 CANKADO-active; 141 CANKADO-inform) were available for analysis of the primary endpoint, time to deterioration (TTD) of QoL [10-point drop on the Functional Assessment of Cancer Therapy-General (FACT-G) score], using an Aalen-Johansen estimator for cumulative incidence function of TTD DQoL (QoL deterioration) with 95% pointwise confidence intervals (CIs). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and DQoL.
RESULTS
In all patients [intention-to-treat (ITT)-ePRO], cumulative incidence of DQoL was significantly more favorable (lower) in the CANKADO-active arm (hazard ratio 0.698, 95% CI 0.506-0.963). Among first-line patients (n = 295), the corresponding hazard ratio was 0.716 (0.484-1.060; P = 0.09), and in second-line patients (n = 117) it was 0.661 (0.374-1.168; P = 0.2). Absolute patient numbers declined in later visits; FACT-G completion rates were 80% and higher until about visit 30. Mean FACT-G scores showed a steady decline from baseline and an offset in favor of CANKADO-active. No significant differences in clinical outcome were observed between arms: median PFS (ITT population) was 21.4 (95% CI 19.4-23.7) (CANKADO-active) and 18.7 (15.1-23.5) months (CANKADO-inform); median OS was not reached (CANKADO-active) and 42.6 months (CANKADO-inform).
CONCLUSIONS
PreCycle is the first multicenter randomized eHealth trial demonstrating a significant benefit for MBC patients receiving oral tumor therapy when using an interactive autonomous patient empowerment application.
Topics: Humans; Middle Aged; Female; Breast Neoplasms; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Pyridines; Receptor, ErbB-2
PubMed: 37201751
DOI: 10.1016/j.annonc.2023.05.003 -
Biomedicine & Pharmacotherapy =... Jun 2024Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However,...
Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However, few studies have focused on their role in ameliorating hepatic metabolic disturbances. In the present study, the effects of NMN and NR on the liver of mice with nonalcoholic fatty liver disease (NAFLD) were investigated via transcriptome and metabolome analyses. NMN and NR reduced body weight gain, improved glucose homeostasis, regulated plasma lipid levels, and ameliorated liver injury, oxidative stress, and lipid accumulation in mice with HFD-induced NAFLD. Integrated transcriptome and metabolome analyses indicated that NMN and NR altered the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and linoleic acid metabolism pathways, increased saturated fatty acid (palmitic acid, stearate, and arachidic acid) content, and increased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content. Quantitative reverse transcription PCR (qRT-PCR) showed that NMN and NR primarily promoted arachidonic acid and linoleic acid catabolism via cytochrome P450 (CYP450) enzymes. This study established a theoretical foundation for the potential use of NMN and NR in future clinical settings.
Topics: Animals; Niacinamide; Pyridinium Compounds; Non-alcoholic Fatty Liver Disease; Nicotinamide Mononucleotide; Male; Mice, Inbred C57BL; Transcriptome; Metabolome; Mice; Liver; Oxidative Stress; Lipid Metabolism; Diet, High-Fat
PubMed: 38729053
DOI: 10.1016/j.biopha.2024.116701 -
Multiple Sclerosis (Houndmills,... Sep 2023Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial.
OBJECTIVE
To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS.
METHODS
A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP).
RESULTS
Ibudilast's treatment effect was observed compared to placebo for thalamic MTR ( = 0.03) but not for TV ( = 0.68) while TV correlated with T2 lesion volume ( < 0.001). CDP associated with thalamic MTR ( = 0.04) but not with TV ( = 0.7).
CONCLUSION
Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity.
CLINICALTRIALS.GOV
NCT01982942.
Topics: Humans; Multiple Sclerosis; Magnetic Resonance Imaging; Multiple Sclerosis, Chronic Progressive; Brain; Pyridines; Atrophy
PubMed: 37537928
DOI: 10.1177/13524585231187289 -
Anesthesiology Dec 2023
Topics: Animals; Rabbits; Dabigatran; Cardiopulmonary Bypass; Antithrombins; Heparin
PubMed: 37721861
DOI: 10.1097/ALN.0000000000004700 -
Anesthesiology Dec 2023
Topics: Animals; Rabbits; Dabigatran; Cardiopulmonary Bypass; Antithrombins; Heparin
PubMed: 37721862
DOI: 10.1097/ALN.0000000000004701 -
A Gastroenterologist's guide to drug interactions of small molecules for inflammatory bowel disease.United European Gastroenterology Journal Jun 2024Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few... (Review)
Review
Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.
Topics: Humans; Drug Interactions; Inflammatory Bowel Diseases; Piperidines; Pyrimidines; Gastrointestinal Agents; Gastroenterologists; United States Food and Drug Administration; Pyridines; Heterocyclic Compounds, 3-Ring; Indans; Oxadiazoles; Triazoles
PubMed: 38532266
DOI: 10.1002/ueg2.12559 -
Cephalalgia : An International Journal... Apr 2024The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor... (Clinical Trial)
Clinical Trial
BACKGROUND
The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine.
METHODS
This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed ( [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN).
RESULTS
Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified.
CONCLUSIONS
Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified. Clinicaltrials.gov: NCT03266588.
Topics: Humans; Migraine Disorders; Male; Female; Adult; Middle Aged; Pyridines; Piperidines; Calcitonin Gene-Related Peptide Receptor Antagonists; Young Adult; Aged; Adolescent; Treatment Outcome
PubMed: 38659334
DOI: 10.1177/03331024241232944 -
Clinical Neurophysiology : Official... Oct 2023To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA).
METHODS
We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively.
RESULTS
In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes.
CONCLUSIONS
sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance.
SIGNIFICANCE
Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA.
Topics: Humans; Pyridostigmine Bromide; Muscular Atrophy, Spinal; Electromyography; Muscles; Muscle Fatigue; Muscle, Skeletal
PubMed: 37595479
DOI: 10.1016/j.clinph.2023.06.024