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Expert Opinion on Pharmacotherapy 2023
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pyrazoles; Pyrimidines; Piperidines; Protein Kinase Inhibitors
PubMed: 37350553
DOI: 10.1080/14656566.2023.2229734 -
Veterinary Research Dec 2023Porcine reproductive and respiratory syndrome virus (PRRSV) infection has caused huge economic losses in global swine industry over the last 37 years. PRRSV commercial...
Porcine reproductive and respiratory syndrome virus (PRRSV) infection has caused huge economic losses in global swine industry over the last 37 years. PRRSV commercial vaccines are not effective against all epidemic PRRSV strains. In this study we performed a high-throughput screening (HTS) of an FDA-approved drug library, which contained 2339 compounds, and found vidofludimus (Vi) could significantly inhibits PRRSV replication in Marc-145 cells and primary porcine alveolar macrophages (PAMs). Compounds target prediction, molecular docking analysis, and target protein interference assay showed that Vi interacts with dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in the de novo pyrimidine synthesis pathway. Furthermore, PRRSV infection was restored in the presence of excess uridine and cytidine which promote pyrimidine salvage, or excess orotate which is the product of DHODH in the de novo pyrimidine biosynthesis pathway, thus confirming that the antiviral effect of Vi against PRRSV relies on the inhibition of DHODH. In addition, Vi also has antiviral activity against Seneca virus A (SVA), encephalomyocarditis virus (EMCV), porcine epidemic diarrhea virus (PEDV), and pseudorabies virus (PRV) in vitro. These findings should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV and other swine viral infections.
Topics: Animals; Swine; Porcine respiratory and reproductive syndrome virus; Dihydroorotate Dehydrogenase; Porcine Reproductive and Respiratory Syndrome; Molecular Docking Simulation; Cell Line; Virus Replication; Antiviral Agents; Pyrimidines; Swine Diseases
PubMed: 38124181
DOI: 10.1186/s13567-023-01251-0 -
Current Gastroenterology Reports May 2024Treatment of Inflammatory Bowel Diseases (IBD) is challenging; thus, the need for newer therapeutic options with an oral route of administration has led to the... (Review)
Review
PURPOSE OF REVIEW
Treatment of Inflammatory Bowel Diseases (IBD) is challenging; thus, the need for newer therapeutic options with an oral route of administration has led to the development of novel small molecules drugs (SMDs). We aim to highlight the most common Adverse events (AEs) associated with SMDs and recommendations on monitoring for AEs before and during treatment.
RECENT FINDINGS
SMDs, such as Tofacitinib, a JAK inhibitor, have been associated with laboratory abnormalities, infections, and risk of thromboembolic events. Therefore, oral agents with greater selectivity in JAK inhibition, such as tofacitinib and upadacitinib, were later developed. Ozanimod and etrasimod, S1PR agonists, require closer safety profile monitoring by clinicians. Multiple therapies have been recently developed with variable efficacy. However, they have been associated with AEs, and some require close monitoring prior to and during therapy. Clinicians should highlight these adverse events to patients while reassuring the safety profile of these novel SMDs for IBD is favorable.
Topics: Humans; Inflammatory Bowel Diseases; Administration, Oral; Janus Kinase Inhibitors; Gastrointestinal Agents; Drug Monitoring; Pyrimidines; Heterocyclic Compounds, 3-Ring; Piperidines
PubMed: 38353899
DOI: 10.1007/s11894-024-00923-x -
Global Heart 2023This systematic review and meta-analysis aimed to determine the efficacy of macitentan in patients with pulmonary hypertension (PH). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This systematic review and meta-analysis aimed to determine the efficacy of macitentan in patients with pulmonary hypertension (PH).
METHODS
A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of PH with macitentan, compared with placebo or blank, were reviewed. Studies were pooled to weighted mean differences (WMDs) and risk ratios (RRs), with 95% confidence intervals (CIs).
RESULTS
Six RCTs (enrolling 1,003 participants) met the inclusion criteria. Macitentan showed significant effects on 6-min walk distance (6MWD) (WMD 12.06 m, 95% CI 2.12 to 21.99 m), pulmonary vascular resistance (PVR) (WMD -186.51 dyn·s/cm, 95% CI -232.72 to -140.29 dyn·s/cm), mean pulmonary artery pressure (mPAP) (WMD -3.20 mmHg, 95% CI -5.93 to -0.47 mmHg), N-terminal pro-brain natriuretic peptide (NT-proBNP) (WMD -232.47 ng/L, 95% wCI -318.22 to -146.72 ng/L), and cardiac index (WMD 0.39 L/min/m, 95% CI 0.20 to 0.58 L/min/m).
CONCLUSION
Macitentan significantly improved 6MWD, PVR, mPAP, NT-proBNP, and cardiac index in patients with PH. Macitentan should be further validated in patients with PH.
Topics: Humans; Hypertension, Pulmonary; Treatment Outcome; Randomized Controlled Trials as Topic; Pyrimidines
PubMed: 37901601
DOI: 10.5334/gh.1274 -
Pediatric Cardiology Dec 2023The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of... (Randomized Controlled Trial)
Randomized Controlled Trial
The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO, work rate at the ventilatory anaerobic threshold (VAT), VO at VAT, and ventilatory efficiency (VE/VCO) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.
Topics: Humans; Child; Oxygen Consumption; Sulfonamides; Exercise; Pyrimidines; Exercise Test; Exercise Tolerance
PubMed: 37382636
DOI: 10.1007/s00246-023-03204-y -
Expert Opinion on Therapeutic Patents 2023Pyrimidine nucleotides are essential for the parasite's growth and replication. Parasites have only a pathway for the biosynthesis of pyrimidine nucleotides.... (Review)
Review
INTRODUCTION
Pyrimidine nucleotides are essential for the parasite's growth and replication. Parasites have only a pathway for the biosynthesis of pyrimidine nucleotides. Dihydroorotate dehydrogenase (DHODH) enzyme is involved in the rate-limiting step of the pyrimidine biosynthesis pathway. DHODH is a biochemical target for the discovery of new antimalarial agents.
AREA COVERED
This review discussed the development of patented DHODH inhibitors published between 2007 and 2023 along with their chemical structures and activities.
EXPERT OPINION
DHODH enzyme is involved in the rate-limiting fourth step of the pyrimidine biosynthesis pathway. Thus, inhibition of DHODH using species-selective inhibitors has drawn much attention for treating malaria because they inhibit parasite growth without affecting normal human functions. Looking at the current scenario of antimalarial drug resistance with most of the available antimalarial drugs, there is a huge need for targeted newer agents. Newer agents with unique mechanisms of action may be devoid of drug toxicity, adverse effects, and the ability of parasites to quickly gain resistance, and DHODH inhibitors can be those newer agents. Many DHODH inhibitors were patented in the past, and the dependency of on pyrimidine provided a new approach for the development of novel antimalarial agents.
Topics: Humans; Dihydroorotate Dehydrogenase; Antimalarials; Plasmodium falciparum; Oxidoreductases Acting on CH-CH Group Donors; Patents as Topic; Pyrimidines; Enzyme Inhibitors; Pyrimidine Nucleotides
PubMed: 37942637
DOI: 10.1080/13543776.2023.2280596 -
Journal of Medicinal Chemistry Dec 2023MA (-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an...
MA (-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers. However, the discovery of potent and selective ALKBH5 inhibitors remains a challenge. We identified as a novel and selective inhibitor of ALKBH5 by structure-based virtual screening and optimization. was not a 2-oxoglutarate analogue and could selectively inhibit the demethylase activity of ALKBH5 over FTO. increased the abundance of mA modifications in AML cells, reduced the mRNA stability of , and inhibited cell cycle progression. Furthermore, significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. Collectively, our results highlight the development of a selective probe for ALKBH5 that will pave the way for the further study of ALKBH5 targeting therapies.
Topics: Humans; Mice; Animals; Ketoglutaric Acids; Dioxygenases; Pyrimidines; Leukemia, Myeloid, Acute; AlkB Homolog 5, RNA Demethylase; Microtubule-Associated Proteins; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 37983486
DOI: 10.1021/acs.jmedchem.3c01374 -
Cancer Discovery Jun 2024Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an...
UNLABELLED
Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months (95% CI, 5.7-7.4) and median overall survival was 15.9 months (95% CI, 11.8-18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3-4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance.
SIGNIFICANCE
Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897.
Topics: Humans; Colorectal Neoplasms; Cetuximab; Proto-Oncogene Proteins p21(ras); Female; Male; Middle Aged; Aged; Mutation; Adult; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Pyrimidines; Neoplasm Metastasis; Treatment Outcome; Acetonitriles; Piperazines
PubMed: 38587856
DOI: 10.1158/2159-8290.CD-24-0217 -
European Journal of Paediatric... Jan 2024Purines and pyrimidines are essential components as they are the building blocks of vital molecules, such as nucleic acids, coenzymes, signalling molecules, as well as... (Review)
Review
Purines and pyrimidines are essential components as they are the building blocks of vital molecules, such as nucleic acids, coenzymes, signalling molecules, as well as energy transfer molecules. Purine and pyrimidine metabolism defects are characterised by abnormal concentrations of purines, pyrimidines and/or their metabolites in cells or body fluids. This phenomenon is due to a decreased or an increased activity of enzymes involved in this metabolism and has been reported in humans for over 60 years. This review provides an overview of neurological presentations of inborn errors of purine and pyrimidine metabolism. These conditions can lead to psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscular symptoms. Clinical signs are often nonspecific and thus overlooked, but some diseases are treatable and early diagnosis may improve the child's future. Although these metabolic hereditary diseases are rare, they are most probably under-diagnosed. When confronted with suggestive clinical or laboratory signs, clinicians should prescribe genetic testing in association with a biochemical screening including thorough purine and pyrimidine metabolites analysis and/or specific enzyme evaluation. This is most likely going to increase the number of confirmed patients.
Topics: Child; Humans; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Genetic Testing; Pyrimidines
PubMed: 38056117
DOI: 10.1016/j.ejpn.2023.11.013 -
JAMA Feb 2024
Topics: Humans; Benzenesulfonamides; Chronic Cough; Pyrimidines; Sulfonamides
PubMed: 38349375
DOI: 10.1001/jama.2023.26029