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The Journal of International Medical... Mar 2023This study aimed to investigate the safety and efficacy of vericiguat in patients with heart failure (HF). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aimed to investigate the safety and efficacy of vericiguat in patients with heart failure (HF).
METHODS
We conducted a comprehensive literature review of the PubMed, Embase, and Cochrane Library databases up to 14 December 2022 for studies comparing vericiguat with placebo in patients with HF. Clinical data were extracted and cardiovascular deaths, adverse effects, and HF-related hospitalization were analyzed using Review Manager software (version 5.3), after quality assessment of the enrolled studies.
RESULTS
Four studies (6705 patients) were included in this meta-analysis. There were no significant differences in the basic characteristics of the included studies. There was no significant difference in adverse effects between the vericiguat group and placebo group, and no significant differences between the groups in terms of cardiovascular death and HF hospitalization.
CONCLUSION
This meta-analysis indicated that vericiguat was not an effective drug for HF; however, more clinical trials are required to verify its efficacy.
Topics: Humans; Heart Failure; Hospitalization; Treatment Outcome; Heterocyclic Compounds, 2-Ring; Pyrimidines; Treatment Failure
PubMed: 36896460
DOI: 10.1177/03000605231159333 -
Cell Nov 2021The cyclic pyrimidines 3',5'-cyclic cytidine monophosphate (cCMP) and 3',5'-cyclic uridine monophosphate (cUMP) have been reported in multiple organisms and cell types....
The cyclic pyrimidines 3',5'-cyclic cytidine monophosphate (cCMP) and 3',5'-cyclic uridine monophosphate (cUMP) have been reported in multiple organisms and cell types. As opposed to the cyclic nucleotides 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP), which are second messenger molecules with well-established regulatory roles across all domains of life, the biological role of cyclic pyrimidines has remained unclear. Here we report that cCMP and cUMP are second messengers functioning in bacterial immunity against viruses. We discovered a family of bacterial pyrimidine cyclase enzymes that specifically synthesize cCMP and cUMP following phage infection and demonstrate that these molecules activate immune effectors that execute an antiviral response. A crystal structure of a uridylate cyclase enzyme from this family explains the molecular mechanism of selectivity for pyrimidines as cyclization substrates. Defense systems encoding pyrimidine cyclases, denoted here Pycsar (pyrimidine cyclase system for antiphage resistance), are widespread in prokaryotes. Our results assign clear biological function to cCMP and cUMP as immunity signaling molecules in bacteria.
Topics: Amino Acid Sequence; Bacteria; Bacteriophages; Burkholderia; Cyclic CMP; Cyclization; Escherichia coli; Models, Molecular; Mutation; Nucleotides, Cyclic; Phosphorus-Oxygen Lyases; Pyrimidines; Uridine Monophosphate
PubMed: 34644530
DOI: 10.1016/j.cell.2021.09.031 -
Nature May 2022The cyclic oligonucleotide-based antiphage signalling system (CBASS) and the pyrimidine cyclase system for antiphage resistance (Pycsar) are antiphage defence systems in...
The cyclic oligonucleotide-based antiphage signalling system (CBASS) and the pyrimidine cyclase system for antiphage resistance (Pycsar) are antiphage defence systems in diverse bacteria that use cyclic nucleotide signals to induce cell death and prevent viral propagation. Phages use several strategies to defeat host CRISPR and restriction-modification systems, but no mechanisms are known to evade CBASS and Pycsar immunity. Here we show that phages encode anti-CBASS (Acb) and anti-Pycsar (Apyc) proteins that counteract defence by specifically degrading cyclic nucleotide signals that activate host immunity. Using a biochemical screen of 57 phages in Escherichia coli and Bacillus subtilis, we discover Acb1 from phage T4 and Apyc1 from phage SBSphiJ as founding members of distinct families of immune evasion proteins. Crystal structures of Acb1 in complex with 3'3'-cyclic GMP-AMP define a mechanism of metal-independent hydrolysis 3' of adenosine bases, enabling broad recognition and degradation of cyclic dinucleotide and trinucleotide CBASS signals. Structures of Apyc1 reveal a metal-dependent cyclic NMP phosphodiesterase that uses relaxed specificity to target Pycsar cyclic pyrimidine mononucleotide signals. We show that Acb1 and Apyc1 block downstream effector activation and protect from CBASS and Pycsar defence in vivo. Active Acb1 and Apyc1 enzymes are conserved in phylogenetically diverse phages, demonstrating that cleavage of host cyclic nucleotide signals is a key strategy of immune evasion in phage biology.
Topics: Bacteria; Bacterial Proteins; Bacteriophage T4; Bacteriophages; CRISPR-Cas Systems; Endonucleases; Escherichia coli; Nucleotides, Cyclic; Oligonucleotides; Pyrimidines
PubMed: 35395152
DOI: 10.1038/s41586-022-04716-y -
Clinical and Translational Science Feb 2022Milvexian (BMS-986177/JNJ-70033093) is a small molecule, active-site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety,... (Randomized Controlled Trial)
Randomized Controlled Trial
Milvexian (BMS-986177/JNJ-70033093) is a small molecule, active-site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two-part, double-blind, placebo-controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200- and 500-mg panels investigated the pharmacokinetic impact of a high-fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once- or twice-daily) or placebo for 14 days. All milvexian dosing regimens were safe and well-tolerated, with only mild treatment-emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half-life (T ) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose-proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose-dependent fashion. In MAD panels, steady-state milvexian plasma concentration was reached within 3 and 6 dosing days with once- and twice-daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.
Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Factor XIa; Female; Food-Drug Interactions; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pyrimidines; Triazoles
PubMed: 34558200
DOI: 10.1111/cts.13148 -
Cancer Cell Sep 2022Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against...
Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
Topics: Animals; Brain Neoplasms; Enzyme Inhibitors; Glioma; Isocitrate Dehydrogenase; Leukemia; Mice; Mutation; Pyrimidines; Salicylanilides; Triazoles
PubMed: 35985343
DOI: 10.1016/j.ccell.2022.07.011 -
Cancer Cell Sep 2022Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable...
Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5'-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks-an "on-target" effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.
Topics: Animals; Glioma; Humans; Mice; Pyrimidines; Uridine
PubMed: 35985342
DOI: 10.1016/j.ccell.2022.07.012 -
Drugs Dec 2021Abrocitinib (Cibinqo) is an oral small-molecule inhibitor of Janus kinase 1 (JAK1) being developed by Pfizer for the treatment of moderate-to-severe atopic dermatitis... (Review)
Review
Abrocitinib (Cibinqo) is an oral small-molecule inhibitor of Janus kinase 1 (JAK1) being developed by Pfizer for the treatment of moderate-to-severe atopic dermatitis (AD). In September 2021, abrocitinib was approved in the UK and Japan for the treatment of moderate-to-severe AD in adults and adolescents 12 years and older who are candidates for systemic therapy. Abrocitinib has also received a positive CHMP opinion in the EU for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. Regulatory applications for the drug have also been submitted for review to several other countries, including the USA and Australia. This article summarizes the milestones in the development of abrocitinib leading to this first approval for the treatment of moderate-to-severe AD.
Topics: Clinical Trials as Topic; Dermatitis, Atopic; Drug Approval; Drug Interactions; Humans; Janus Kinase Inhibitors; Pyrimidines; Sulfonamides
PubMed: 34807428
DOI: 10.1007/s40265-021-01638-3 -
Proceedings of the National Academy of... Jan 2023Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid...
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the rs72613567-A variant in humans and by the knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the -induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.
Topics: Animals; Humans; Mice; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Pyrimidines
PubMed: 36669104
DOI: 10.1073/pnas.2217543120 -
Drugs Jul 2021Infigratinib (TRUSELTIQ), a fibroblast growth factor receptor (FGFR)-specific tyrosine kinase inhibitor, is being co-developed by QED Therapeutics and Helsinn for the... (Review)
Review
Infigratinib (TRUSELTIQ), a fibroblast growth factor receptor (FGFR)-specific tyrosine kinase inhibitor, is being co-developed by QED Therapeutics and Helsinn for the treatment of cholangiocarcinoma, urothelial carcinoma and other FGFR-driven conditions. Infigratinib was recently approved in the USA for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by a test approved by the US Food and Drug Administration. This article summarizes the milestones in the development of infigratinib leading to this first approval for advanced cholangiocarcinoma.
Topics: Antineoplastic Agents; Cholangiocarcinoma; Humans; Neoplasm Metastasis; Phenylurea Compounds; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Fibroblast Growth Factor; United States; United States Food and Drug Administration
PubMed: 34279850
DOI: 10.1007/s40265-021-01567-1 -
Expert Opinion on Pharmacotherapy Oct 2021The significant morbidity and mortality in patients with heart failure (HF), notably in the most advanced forms of the disease, justify the need for novel therapeutic...
INTRODUCTION
The significant morbidity and mortality in patients with heart failure (HF), notably in the most advanced forms of the disease, justify the need for novel therapeutic options. In the last year, the soluble guanylate cyclase (sGC) stimulator, vericiguat, has drawn the attention of the medical community following the report of reduced clinical outcomes in patients with worsening chronic HF (WCHF).
AREAS COVERED
The authors review the available data on the mechanism of action of vericiguat (cyclic guanosine monophosphate (cGMP) pathway), its clinical development program, its role in HF management, and its future positioning in the therapeutic recommendations.
EXPERT OPINION
cGMP deficiency has deleterious effects on the heart and contributes to the progression of HF. Different molecules, including nitric oxide (NO) donors, phosphodiesterase inhibitors, and natriuretic peptides analogues, target the NO-sCG-cGMP pathway but have yielded conflicting results in HF patients. Vericiguat acts as a sGC stimulator thus targeting the NO-sGC-cGMP pathway by a different mechanism that complements the current pharmacotherapy for HF. Vericiguat has shown an additional statistical add-on therapy efficacy by reducing morbi-mortality in patients with WCHF. A better evaluation of HF severity might be an important determinant to guide the use of vericiguat among the available therapies.
Topics: Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Pyrimidines; Soluble Guanylyl Cyclase; Stroke Volume
PubMed: 34074190
DOI: 10.1080/14656566.2021.1937121