Increase of protein synthesis by uridine supplement in lectin-stimulated peripheral blood lymphocytes and EB virus-transformed B cell line of hereditary orotic aciduria type I.

Yazaki, Makoto; Okajima, Kazuki; Suchi, Mariko; Morishita, Hideko; Wada, Yoshiro

doi:10.1620/tjem.153.189

Cited by 4 publications

(3 citation statements)

References 11 publications

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“…Administration of compound 15 to an infected mouse should have two opposing effects: (i) It should inhibit the ODCase enzyme of the parasite, and unless the enzyme can be replaced in a timely manner, this will be fatal to the parasite. (ii) It will lead to a temporary loss of ODCase activity in the host which may lead to impairment of many functions including the immune regulation of the parasite infection . The second effect is proposed as a possibility for the mice study where higher in vivo doses of 15 were needed in order to reach the effective doses for P. chabaudi chabaudi that are 20–25 times higher than that of P. falciparum .…”

Section: Resultsmentioning

confidence: 99%

“…(ii) It will lead to a temporary loss of ODCase activity in the host which may lead to impairment of many functions including the immune regulation of the parasite infection. 42 The second effect is proposed as a possibility for the mice study where higher in vivo doses of 15 were needed in order to reach the effective doses for P. chabaudi chabaudi that are 20−25 times higher than that of P. falciparum. We hypothesized that adjunct uridine therapy should improve the outcome of mice treated with compound 15.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Antimalarial Activities of 6-Iodouridine and Its Prodrugs and Potential for Combination Therapy

et al. 2013

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Resistance by Plasmodium falciparum to almost all clinically used antimalarial drugs requires the development of new classes of antimalarials. 6-Iodouridine (15), a novel and potent inhibitor of orotidine 5'-monophosphate decarboxylase (ODCase), exhibited efficacy in a mouse model infected by P. chabaudi chabaudi. Compound 15 exhibited promising antimalarial activity against P. falciparum, including drug-resistant isolates, and no rapid drug-resistant populations of the parasite were observed when challenged with 15. Uridine provided options to overcome any toxicity in the host but still suppressing the parasite load when treated with 15. In drug combination studies, compound 15 showed good efficacy in vivo with artemisinin and azithromycin. The propionyl ester of 15 exhibited superior antimalarial efficacy. Antimalarial activities of 15 and its prodrugs and potential for combination therapy are discussed in the context of novel strategies.

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Section: Resultsmentioning

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Antimalarial Activities of 6-Iodouridine and Its Prodrugs and Potential for Combination Therapy

et al. 2013

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“…From the clinical experience with leflunomide as a licensed immunosuppressive antirheumatic drug, it could then be predicted that the mt toxicity in lymphocytes impairs the proliferation of lymphocytes in response to mitotic stimuli, interferes with CD4 recovery and thus is immunosuppressive. Impaired cellmediated immune responses and reduced CD4 and CD8 lymphocyte subsets were also observed in several patients with an inherited defect in the de novo synthesis of pyrimidines; their immunodeficiency improved upon uridine therapy [52,61]. It was also shown that uridine antagonized the inhibition of lymphocytes by leflunomide [62,63].…”

Section: Perspectivementioning

confidence: 99%

Uridine in the Prevention and Treatment of Nrti-Related Mitochondrial Toxicity

Walker

Venhoff

2005

Antiviral Therapy

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Long-term side effects of antiretroviral therapy are attributed to the mitochondrial (mt) toxicity of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their ability to deplete mtDNA. Studies in hepatocytes suggest that uridine is able to prevent and treat mtDNA depletion by pyrimidine NRTIs [zalcitabine (ddC) and stavudine (d4T)] and to fully abrogate hepatocyte death, elevated lactate production and intracellular steatosis. Uridine was also found to improve the liver and haematopoietic toxicities of zidovudine (AZT), which are unrelated to mtDNA depletion, and to prevent neuronal cell death induced by ddC. Most recently, uridine was found to prevent the onset of a lipoatrophic phenotype (reduced intracellular lipids, increased apoptosis, mtDNA depletion and mt depolarization) in adipocytes incubated long-term with d4T and AZT. Various steps of mt nucleoside utilization may be involved in the protective effect, but competition of uridine metabolites with NRTIs at polymerase y or other enzymes is a plausible explanation. Pharmacokinetic studies suggest that uridine serum levels can be safely increased in humans to achieve concentrations which are protective in vitro (50–200 μM). Uridine was not found to interfere with the antiretroviral activity of NRTIs. Mitocnol, a sugar cane extract which effectively increases uridine in human serum, was beneficial in individual HIV patients with mt toxicity and is now being tested in placebo-controlled randomized trials. Until these data become available, the risk-benefit calculation of using uridine should be individualized. The current safety data justify the closely monitored use of uridine in individuals who suffer from mt toxicity but who cannot be switched to less toxic NRTIs.

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