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Drugs Jul 2022Mavacamten (Camzyos™) is an oral small-molecule cardiac myosin inhibitor developed by MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb, for the... (Review)
Review
Mavacamten (Camzyos™) is an oral small-molecule cardiac myosin inhibitor developed by MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb, for the treatment of hypertrophic cardiomyopathy (HCM) and diseases of diastolic dysfunction. In April 2022, mavacamten was approved for use in the USA in the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM to improve functional capacity and symptoms. This article summarizes the milestones in the development of mavacamten leading to this first approval for the treatment of adults with symptomatic NYHA class II-III obstructive HCM.
Topics: Adult; Benzylamines; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Humans; Uracil
PubMed: 35802255
DOI: 10.1007/s40265-022-01739-7 -
Hepatology Communications Apr 2021Resmetirom (MGL-3196), a selective thyroid hormone receptor-β agonist, was evaluated in a 36-week paired liver biopsy study (NCT02912260) in adults with... (Randomized Controlled Trial)
Randomized Controlled Trial
Resmetirom (MGL-3196), a selective thyroid hormone receptor-β agonist, was evaluated in a 36-week paired liver biopsy study (NCT02912260) in adults with biopsy-confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI-proton density fat fraction (MRI-PDFF), and secondary endpoints included histopathology. Subsequently, a 36-week active treatment open-label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI-PDFF reduction at OLE week 36 was -11.1% (1.5%) mean reduction (standard error [SE]; < 0.0001) and -52.3% (4.4%) mean relative reduction, < 0.0001. Low-density lipoprotein (LDL) cholesterol (-26.1% [4.5%], < 0.0001), apolipoprotein B (-23.8% [3.0%], < 0.0001), and triglycerides (-19.6% [5.4%], = 0.0012; -46.1 [14.5] mg/dL, = 0.0031) were reduced from baseline. Markers of fibrosis were reduced, including liver stiffness assessed by transient elastography (-2.1 [0.8] mean kilopascals [SE], = 0.015) and N-terminal type III collagen pro-peptide (PRO-C3) (-9.8 [2.3] ng/mL, = 0.0004 (baseline ≥ 10 ng/mL). In the main and OLE studies, PRO-C3/C3M (matrix metalloproteinase-degraded C3), a marker of net fibrosis formation, was reduced in resmetirom-treated patients (-0.76 [-1.27, -0.24], = 0.0044 and -0.68, < 0.0001, respectively). Resmetirom was well tolerated, with few, nonserious adverse events. The results of this 36-week OLE study support the efficacy and safety of resmetirom at daily doses of 80 mg and 100 mg, used in the ongoing phase 3 NASH study, MAESTRO-NASH (NCT03900429). The OLE study demonstrates a potential for noninvasive assessments to monitor the response to resmetirom from an individual patient with NASH.
Topics: Adult; Biomarkers; Biopsy; Double-Blind Method; Drug Administration Schedule; Female; Humans; Lipids; Lipoproteins; Liver; Liver Cirrhosis; Magnetic Resonance Imaging; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Pyridazines; Thyroid Hormone Receptors beta; Uracil
PubMed: 33860116
DOI: 10.1002/hep4.1657 -
International Journal of Molecular... Apr 2021The appearance of uracil in the deoxyuridine moiety of DNA is among the most frequently occurring genomic modifications. Three different routes can result in genomic... (Review)
Review
The appearance of uracil in the deoxyuridine moiety of DNA is among the most frequently occurring genomic modifications. Three different routes can result in genomic uracil, two of which do not require specific enzymes: spontaneous cytosine deamination due to the inherent chemical reactivity of living cells, and thymine-replacing incorporation upon nucleotide pool imbalances. There is also an enzymatic pathway of cytosine deamination with multiple DNA (cytosine) deaminases involved in this process. In order to describe potential roles of genomic uracil, it is of key importance to utilize efficient uracil-DNA detection methods. In this review, we provide a comprehensive and critical assessment of currently available uracil detection methods with special focus on genome-wide mapping solutions. Recent developments in PCR-based and in situ detection as well as the quantitation of genomic uracil are also discussed.
Topics: Animals; DNA; DNA Repair; DNA Replication; Genetic Testing; Genome; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; In Situ Hybridization; Nucleotides; Polymerase Chain Reaction; Signal Transduction; Uracil; Uracil-DNA Glycosidase
PubMed: 33918885
DOI: 10.3390/ijms22083902 -
Viruses May 2021Deoxyuridine in DNA has recently been in the focus of research due to its intriguing roles in several physiological and pathophysiological situations. Although not an... (Review)
Review
Deoxyuridine in DNA has recently been in the focus of research due to its intriguing roles in several physiological and pathophysiological situations. Although not an orthodox DNA base, uracil may appear in DNA via either cytosine deamination or thymine-replacing incorporations. Since these alterations may induce mutation or may perturb DNA-protein interactions, free living organisms from bacteria to human contain several pathways to counteract uracilation. These efficient and highly specific repair routes uracil-directed excision repair initiated by representative of uracil-DNA glycosylase families. Interestingly, some bacteriophages exist with thymine-lacking uracil-DNA genome. A detailed understanding of the strategy by which such phages can replicate in bacteria where an efficient repair pathway functions for uracil-excision from DNA is expected to reveal novel inhibitors that can also be used for biotechnological applications. Here, we also review the several potential biotechnological applications already implemented based on inhibitors of uracil-excision repair, such as Crispr-base-editing and detection of nascent uracil distribution pattern in complex genomes.
Topics: Bacteriophages; Biotechnology; DNA, Viral; Drug Development; Humans; Models, Molecular; Nucleic Acids; Protein Conformation; Structure-Activity Relationship; Uracil; Uracil-DNA Glycosidase; Viruses
PubMed: 34068736
DOI: 10.3390/v13050875 -
Expert Review of Clinical Pharmacology 2016TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil... (Review)
Review
TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI). TAS-102 has been shown to significantly improve overall survival and progression-free survival in patients with refractory metastatic colorectal cancer (mCRC) in placebo-controlled randomized phase II and III trials. The current review summarizes mechanisms of action, pharmacokinetics/dynamics and preclinical and clinical data of TAS-102 in colorectal cancer. TAS-102 is a new salvage-line treatment option for patients with mCRC. TAS-102 is well tolerated and has great potential in future clinical drug combination therapies.
Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Neoplasm Metastasis; Pyrrolidines; Randomized Controlled Trials as Topic; Survival Rate; Thymine; Trifluridine; Uracil
PubMed: 26677869
DOI: 10.1586/17512433.2016.1133285 -
Molecular Immunology Jan 2021Mucosal-associated invariant T cells (MAIT cells) represent a potential therapeutic target as they can tune or enhance immune responses. They recognise and become... (Review)
Review
Mucosal-associated invariant T cells (MAIT cells) represent a potential therapeutic target as they can tune or enhance immune responses. They recognise and become activated by antigens, presented by the monomorphic MHC-I related molecule, MR1. To assess the significance of MAIT cells in human diseases, a better understanding of the MAIT cell-MR1-antigen interaction is imperative. Easy access to MR1 ligands and MAIT cells activators can help achieve this. In this review, we summarise current literature that has identified the natural ligands and drug-like molecules that activate MAIT cells and provide insight into their key molecular interactions with MR1 and MAIT T cell receptors (TCRs). We focus on the progress made in synthesizing and isolating 5-amino-6-d-ribitylaminouracil (5-A-RU), a key precursor in the synthesis of the known natural ligands, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil(5-OP-RU) and 5-(2-oxoethylideneamino)-6-d-ribitylaminouracil (5-OE-RU), and also on the stabilisation and optimisation of the latter compounds.
Topics: Animals; Histocompatibility Antigens Class I; Humans; Ligands; Mucosal-Associated Invariant T Cells; Receptors, Antigen, T-Cell; Ribitol; Uracil
PubMed: 33293098
DOI: 10.1016/j.molimm.2020.11.017 -
Journal of Pharmaceutical and... Nov 2022Establishing dihydropyrimidine dehydrogenase (DPD) activity is highly important in determining the correct starting dose of fluoropyrimidines such as 5-fluorouracil and...
Quantification of uracil, dihydrouracil, thymine and dihydrothymine for reliable dihydropyrimidine dehydrogenase (DPD) phenotyping critically depend on blood and plasma storage conditions.
Establishing dihydropyrimidine dehydrogenase (DPD) activity is highly important in determining the correct starting dose of fluoropyrimidines such as 5-fluorouracil and capecitabine. The concentration ratio of endogenous uracil with its metabolite dihydrouracil (DHU) is a well-known parameter that is linked to DPD activity. Concentration ratios such as thymine over its DPD-converted metabolite dihydrothymine (DHT) is less described and may serve as an alternative diagnostic biomarker for DPD activity. In this study, we describe the development and validation of an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for the quantification of uracil, DHU, thymine, and DHT in human plasma. In addition, stability experiments were performed. Uracil and thymine were quantified up to 80.0 ng/mL and DHU and DHT up to 800 ng/mL. Intra- and inter-assay precision were maximum 8.0 % and 7.6 %. respectively. Also, recovery was adequate and significant matrix-effects and carry-over were excluded. Stability experiments showed that uracil concentrations increased with 27-52 % when stored for 1 or 2 h at ambient temperatures compared to cold storage. Thymine, DHU, and DHT concentrations remained stable, thymine after 1 h in plasma excluded, showing the DHT:T ratio might be a more robust marker for DPD activity than DHU:U. In conclusion, we present here a novel assay capable of quantifying uracil, thymine, DHU and DHT in a single analytical run. We provide additional data showing increased stability for DHU, thymine and DHT compared to uracil. This assay may be used as a diagnostic test in future studies, establishing the association of these endogenous biomarker concentrations with DPD activity and safety to treatment with fluoropyrimidines. In addition, future research should also be focused on reducing pre-analytical instability. Standardization in this field is essential to set proper reference values and to allow inter-study comparison on clinical outcomes.
Topics: Biomarkers; Capecitabine; Chromatography, Liquid; Dihydrouracil Dehydrogenase (NADP); Fluorouracil; Humans; Tandem Mass Spectrometry; Thymine; Uracil
PubMed: 36099723
DOI: 10.1016/j.jpba.2022.115027 -
Molecules (Basel, Switzerland) Aug 2020We report on the density functional theory (DFT) modelling of structural, energetic and NMR parameters of uracil and its derivatives (5-halogenouracil (5XU), X = F, Cl,...
We report on the density functional theory (DFT) modelling of structural, energetic and NMR parameters of uracil and its derivatives (5-halogenouracil (5XU), X = F, Cl, Br and I) in vacuum and in water using the polarizable continuum model (PCM) and the solvent model density (SMD) approach. On the basis of the obtained results, we conclude that the intramolecular electrostatic interactions are the main factors governing the stability of the six tautomeric forms of uracil and 5XU. Two indices of aromaticity, the harmonic oscillator model of aromaticity (HOMA), satisfying the geometric criterion, and the nuclear independent chemical shift (NICS), were applied to evaluate the aromaticity of uracil and its derivatives in the gas phase and water. The values of these parameters showed that the most stable tautomer is the least aromatic. A good performance of newly designed xOPBE density functional in combination with both large aug-cc-pVQZ and small STO(1M)-3G basis sets for predicting chemical shifts of uracil and 5-fluorouracil in vacuum and water was observed. As a practical alternative for calculating the chemical shifts of challenging heterocyclic compounds, we also propose B3LYP calculations with small STO(1M)-3G basis set. The indirect spin-spin coupling constants predicted by B3LYP/aug-cc-pVQZ(mixed) method reproduce the experimental data for uracil and 5-fluorouracil well.
Topics: Density Functional Theory; Halogens; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Structure; Solvents; Uracil
PubMed: 32872098
DOI: 10.3390/molecules25173931 -
American Journal of Cardiovascular... Sep 2022Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states.
Topics: Benzylamines; Cardiomyopathy, Hypertrophic; Humans; Sarcomeres; Uracil
PubMed: 35435607
DOI: 10.1007/s40256-022-00532-x -
International Journal of Molecular... Oct 2021Among non-covalent interactions, halogen bonding is emerging as a new powerful tool for supramolecular self-assembly. Here, along with a green and effective method, we...
Among non-covalent interactions, halogen bonding is emerging as a new powerful tool for supramolecular self-assembly. Here, along with a green and effective method, we report three new halogen-bonded cocrystals containing uracil derivatives and 1,2,4,5-tetrafluoro-3,6-diiodobenzene as X-bond donor coformer. These multicomponent solids were prepared both by solvent-drop grinding and solution methods and further characterized by powder and single-crystal X-ray diffraction, Fourier-transformed infrared spectroscopy, and thermal methods (TGA-DSC). In order to study the relative importance of hydrogen versus halogen bonds in the crystal packing, computational methods were applied.
Topics: Crystallization; Crystallography, X-Ray; Halogens; Models, Molecular; Molecular Conformation; Molecular Structure; Spectrum Analysis; Uracil
PubMed: 34639004
DOI: 10.3390/ijms221910663