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In Vitro Alternative Methods for the Assessment of Dermal Irritation and Inflammation
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
David W. Hobson, James A. Blank
Incorporation of uridine into RNA — This assay is based upon the incorporation of 3H-uridine into RNA of the cultured cells. It has been reported to be a rapid means of measuring sublethal cytotoxicity and to provide a good correlation with in vivo damage as judged by the Draize test.50,51
Sleep-Promoting Substance (SPS) and Nucleosides
Published in Shojiro Inoué, Biology of Sleep Substances, 2020
Uridine is a natural pyrimidine nucleoside widely distributed in the organism as a constituent of RNA. It is characterized by having a barbiturate ring in its structure (see Figure 3). Uridine is distributed not only in bodily tissues but also in body fluids. In our isolation studies of SPS, the amount of uridine in the brainstem was calculated by the values detected in SPS fractions of the brainstems of sleep-deprived rats. It was found that the content of uridine varied from 4 to 10 nmol/brainstem.1
Orotic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Orotic aciduria represents pyrimidine nucleotide starvation in man. It appears to be the first human nutritional auxotrophic disease to be recognized. The therapeutic effect of uridine is supportive of this hypothesis.
The role of biomarkers in stage III non-small cell lung cancer
Published in Expert Review of Respiratory Medicine, 2023
Rafael Rosell, María González-Cao, Masaoki Ito, Mariacarmela Santarpia, Andrés Aguilar, Jordi Codony-Servat
To date, three systems against ferroptosis have been identified with different subcellular localizations. GPX4 lies in the cytosol and mitochondria, while FSP1 is on the plasma membrane, and DHODH is in the mitochondria. In addition to brequinar, several small molecules, DHODH inhibitors, are available, such as leflunomide (Arava), approved for treatment of rheumatoid arthritis, also teriflunomide (Aubagio) (Figures 2, 3). Other DHODH inhibitors can be seen in a review on the dysregulation of de novo nucleotide biosynthesis pathway enzymes in cancer [52]. DHODH inhibitors selectively inhibit the tumor growth of KRAS-mutant cell lines [53], therefore providing hints that DHODH could synergize with other drugs targeting KRAS-mutant NSCLCs (Figure 3). One potential limitation to the anticancer clinical activity of DHODH inhibitors could be the amount of uridine in plasma [54]. Uridine acts downstream of the enzymatic activity of DHODH, which transforms dihydroorotate to orotate [55]. The levels of free uridine in human volunteer plasma are as high as 8.19 μM [56]. It could be foreseen that in studies employing DHODH inhibitors the measurement of uridine plasma levels could be of ancillary assistance.
Advances in prodrug design for Alzheimer’s disease: the state of the art
Published in Expert Opinion on Drug Discovery, 2022
Valentin Travers--Lesage, Serge M. Mignani, Patrick Dallemagne, Christophe Rochais
The preparation of a glycosylated prodrug 14 of the anti-neuroinflammatory acetyl-p-phenylenediamine, both increased BBB permeation and water solubility (Table 2). The prodrug demonstrated promising properties in vivo alleviating both amyloid deposition and neuroinflammation associated with procognitive effect in transgenic models [32]. A glycosylation strategy was also followed to increase the solubility of Silybin, a natural compound that demonstrated neuroprotective properties in vivo. A trehalose moiety was conjugated to Silybin with a phosphate linker 15 and improved both its stability and by 3-fold its solubility. The resulted prodrug demonstrated its ability to reduce amyloid growth and toxicity [33]. Already developed in oncology field, glycosylation of bases has been also applied to neurodegenerative diseases and more specifically AD. In this context, the uridine prodrug PN401 16 has demonstrated some neuroprotective effects in animal models [34]. In addition, another glycosylated catecholamine prodrug 17 [35] or other types have been patented in the recent years [36–38].
Investigational drugs in phase II clinical trials for acute coronary syndromes
Published in Expert Opinion on Investigational Drugs, 2020
Amit Rout, Ajaypaul Sukhi, Rahul Chaudhary, Kevin P Bliden, Udaya S Tantry, Paul A Gurbel
AZD5718 (AstraZeneca, Cambridge, United Kingdom) is a selective 5-lipoxygenase activating protein (FLAP) inhibitor that inhibits LTB4 production [11]. In the phase I (NCT02632526), study, pharmacodynamics (PD), pharmacokinetics (PK) and safety in healthy male subjects after single and multiple ascending doses were evaluated. Overall, AZD5718 was well tolerated with 63 adverse events, mainly headache, in a total of 96 subjects. Only 1% of the drug was cleared renally. Its metabolism mainly involves cytochrome P450 (3A4 and 3A5 isoforms) and uridine 5′-diphosphate glucuronosyltransferase conjugation. The half-life of the drug was around 10–12 hours, and steady state was achieved after 3 days of repeated dosing. Decreased levels of LTB4 in blood and LTE4 in urine were noted after both single and multiple doses [11]. The study suggested that once-daily dosing is optimal to achieve complete inhibition of both LTB4 and LTE4. Currently, AZD5718 is undergoing phase II trial (NCT03317002) in Europe. This is a randomized, single-blind, placebo-controlled, and multicenter trial in patients with CAD and is expected to be completed by 2020. The study aims to evaluate efficacy, safety, and tolerability after 4 or 12 weeks of treatment in patients with ACS [12].